Metrics details Colorectal cancer has the second highest mortality among cancer sites worldwide and even poorer postoperative quality of life preventive strategies for colorectal cancer should be established This study aimed to cross-sectionally explore dietary patterns affecting the intestinal metabolism of bile acids (BAs) We collected fecal samples for intestinal microbiota and BA analysis We used the Bristol scale to determine 1-week defecation status the brief-type self-administered diet history questionnaire was used for habitual dietary intake status Reduced-rank regression analysis revealed dietary patterns related to fecal BA levels The relationship between dietary patterns and fecal BA levels was adjusted for defecation status and intestinal microbiota variables using analysis of covariance Reduced-rank regression analysis generated two dietary pattern scores related to fecal BA levels the score was associated with a greater intake of leafy and root vegetables and higher values were associated with greater fecal cholic and chenodeoxycholic acid levels and lower deoxycholic and lithocholic acid levels the score was associated with greater rice intake and lower Western sweets and higher values were associated with lower deoxycholic and lithocholic acid levels These relationships remained after adjusting for intestinal microbiota and defecation status variables BA metabolism regulation in the intestinal tract may prevent the development and recurrence of colorectal cancer the effect of diet on intestinal BA metabolism should be evaluated on a food basis rather than on a nutrient basis only a few studies in populations with similar dietary habits (same region and sex) have evaluated the relationship between diet and intestinal BA metabolism Whether relatively small dietary changes can alter BA metabolism in the intestinal tract remains unclear This study aimed to explore dietary patterns affecting intestinal BA metabolism using RRR in young female Japanese participants Participants were recruited from the Yamagata Prefectural Yonezawa University of Nutrition Sciences and Sakura no Seibo Junior College The inclusion criteria were as follows: (1) aged 18–29 years (2) not previously diagnosed with hypertension (3) not currently receiving treatment for gastrointestinal disease and (4) not habitually taking medications for diarrhea or constipation Five male participants who volunteered for this study were excluded from the analysis to control for the effects of confounding factors To assess the natural defecation status and collect fecal samples we excluded two participants who received diarrheal or constipation medication 1 week before fecal sampling Written informed consent was obtained from all participants The Ethics Committee of the Yamagata Prefectural Yonezawa University of Nutrition Sciences approved our study protocol (Approval No which followed the principles of the Declaration of Helsinki the participants were instructed to live normally without any restrictions on physical activity and dietary intake The study was conducted without considering the menstrual period of the participants as a factor The participants were fully instructed regarding the BSFS and they were asked to self-assess and record the fecal form immediately after defecation The participants also recorded all medications administered over this period and they maintained these records until the feces were collected The participants collected their feces at a convenient time after recording their defecation status for 1 week The feces were collected at once in a special fecal collection cup which was then placed in a cool bag with a coolant and submitted to the researcher as soon as possible (i.e. samples collected in the early morning on weekdays were submitted in the morning; samples collected on campus were submitted promptly; if the samples were collected on a holiday or at night the researcher picked up the sample at the participant’s home) The participants also evaluated their collected feces using the BSFS The submitted fecal samples were stored at − 80 °C until use 100 mg of fecal sample was suspended in 0.9 mL of sodium acetate buffer (100 mM pH 5.6) mixed with ethanol in a 2-mL tube with zirconia beads and then heat-treated at 85 °C for 30 min After centrifugation at 18,400 × g for 10 min the supernatant was diluted four-fold with water and subjected to solid-phase extraction using a Bond Elut C18 cartridge (Agilent Technologies The solvent of the obtained extract was evaporated and the residue was dissolved in 50% ethanol with an internal standard This solution was filtered through a hydrophilic polytetrafluoroethylene filter and used as a sample for LC-QTOF-MS analysis We used an LC-QTOF-MS instrument consisting of Waters ACQUITY UPLC and an electrospray ionization probe (Waters Separation was performed via gradient elution using 0.1% formic acid aqueous solution (solvent A) and acetonitrile containing 0.1% formic acid (solvent B) at a flow rate of 0.5 mL/min The gradient elution program for solvent B was as follows: 0 − 0.5 min The QTOF mass spectrometer was operated in negative ion mode The desolvation and collision gases were nitrogen and argon We used the following parameters: capillary voltage Leucine enkephalin was used as the lock mass nutrient and food item intakes were energy-adjusted using the energy density model and expressed as density (per 1000 kcal of energy intake) After energy adjustment using the density method (g/1000 kcal) the 53 food and beverage intakes estimated based on the BDHQ were used as explanatory variables Random sample cross-validation and subsequent van der Voet’s test were used to define the optimal number of dietary patterns RRR was performed using the statistical software package SAS® OnDemand for Academics (SAS Institute Inc. The distributions of fecal BA levels were right-skewed; hence natural log transformation was applied to make the distribution more symmetric The Shapiro–Wilk test was used to assess the normality of our dataset Relationships between normally distributed variables were evaluated using Pearson’s correlation whereas variables that were not normally distributed were analyzed using Spearman’s correlation We assessed differences among the three groups based on dietary pattern scores using one-way analysis of variance If Levene’s test showed homogeneity of variance we used Tukey’s test for post hoc pairwise multiple comparisons Games–Howell test was used for samples with nonhomogeneous variances Data were presented as means ± standard deviation Analysis of covariance (ANCOVA plus Sidak post hoc test) was used to evaluate the relationship between dietary patterns and fecal BA levels excluding the effects of defecation status and intestinal microbiota were performed using the Statistical Package for the Social Sciences software ver p-values of < 0.05 were considered to indicate statistical significance Table 1 shows the participant characteristics The mean body mass index (BMI) was 21.3 kg/m2 and the majority (79%) of the participants had normal body weight (18.5 ≤ BMI < 25 kg/m2) The mean total BA concentration in the feces was 4.21 µmol/g The mean frequency of defecation was 8.6 times/week and 74.4% of the participants had normal feces Spearman correlation coefficients between fecal BA levels and habitual nutrient intake in young female participants Fecal CA levels were strongly correlated with CDCA levels (r = 0.896; p < 0.001 Fecal DCA levels were strongly correlated with LCA levels (r = 0.721; p < 0.001 primary BA (CA + CDCA) levels were negatively correlated with secondary BA (DCA + LCA) levels (r = − 0.441; p < 0.001 the RRR was used to explore dietary patterns related to primary and secondary BA levels To explore dietary patterns related to primary BAs which was significantly correlated with primary BAs To explore dietary patterns related to secondary BAs we used the following intermediate response variables: insoluble fiber Table 2 shows the contribution ratio of dietary pattern scores to the response and explanatory variables and the correlation coefficient between dietary pattern scores and habitual nutrient intake One dietary pattern score for primary BAs was generated (dietary pattern [DP]−1) with a 100% contribution to the response variable Four dietary pattern scores for secondary BAs were generated (DP-2 The contribution ratio of DP-2 to the response variable was 48% We excluded DP-2 because it was very similar to DP-1 (Pearson’s correlation DP-3 had a 26.1% contribution to the response variable with a strong positive correlation with carbohydrates and a strong negative correlation with saturated fatty acids We excluded DP-4 and 5 due to their low contribution to the response variable DP-1 and DP-3 were used for further analysis Factor loadings of major food items on the dietary pattern scores generated by reduced-rank regression We divided the study participants into tertiles based on the DP-1 and DP-3 scores and assessed the differences between tertiles in defecation status, intestinal microbiota, and habitual diet (Table 3) The frequency of normal stools in tertile 3 (high) for DP-1 was significantly greater than that in tertile 1 (low) The intestinal microbiota was not significantly different in the DP-1 tertile The defecation status and intestinal microbiota were not significantly different between the DP-3 tertiles Figure 3 shows the differences in fecal BA levels between DP-1 and DP-3 tertiles. Fecal CA and CDCA levels were significantly greater as the DP-1 score increased. Conversely, the DCA and LCA were significantly lower. Furthermore, the fecal DCA levels in tertile 3 (high) for DP-3 were significantly lower than those in tertiles 1 (low) and 2. Fecal BA levels of young female participants disaggregated by dietary pattern 1 (A) and 3 (B) scores *BA levels were measured per fresh fecal mass a Tukey’s post hoc test or Games − Howell test b Tukey’s post hoc test or Games − Howell test c Tukey’s post hoc test or Games − Howell test Differences in fecal BA levels between the dietary pattern score tertiles were adjusted for variables of defecation status and intestinal microbiota using ANCOVA (Table 4.) Fecal primary BA levels were significantly greater in tertile 3 (high) for DP-1 than in tertile 1 (low) even after adjusting for defecation status and intestinal microbiota Fecal secondary BA levels for DP-1 and DP-3 were significantly lower in tertile 3 (high) than in tertile 1 (low) Supplemental Tables 4 and 5 show the relationships between total fecal BA the DP-1 score was not correlated with total BA levels but was positively correlated with CA and CDCA levels and negatively correlated with DCA and LCA levels indicating that high vegetable intake may inhibit the bacterial conversion of primary to secondary BAs by intestinal bacteria the foods with the highest load on the DP-1 score in our study were dark green leafy vegetables high rice intake may lead to low-fat intake which decreases secondary BA levels in the colonic lumen The menstrual cycle may affect fecal BA levels by mediating changes in colonic transit time the number of defecations per week was included as covariates in the ANCOVA it is necessary to investigate whether the menstrual cycle affects intestinal BA metabolism independently of alterations in defecation status causal relationships could not be determined because of the cross-sectional study design two dietary patterns associated with fecal BA levels were detected in young Japanese women Dietary patterns with high leafy green and root vegetable intake were associated with lower DCA and LCA levels in the feces and higher CA as a source of energy intake was associated with lower fecal DCA and LCA levels Our study results indicate that relatively small dietary changes can regulate intestinal BA metabolism Clinical Trial Registry: University Hospital Medical Information Network (UMIN) Center system (UMIN000045639); date of registration: 15/11/2019 Deidentified data are available from the corresponding author upon reasonable request Morgan, E. et al. 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Gastroenterology 119, 806–815. https://doi.org/10.1053/gast.2000.16495 (2000) Download references This work was supported by a Grant-in-Aid for Young Scientists (grant number: 19K20148) from the Japan Society for the Promotion of Science (YS grantee). The funding source was not involved in study execution or manuscript preparation. The authors would like to thank Enago (www.enago.jp) for the English language review Japan Society for the Promotion of Science,19K20148 Yamagata Prefectural Yonezawa University of Nutrition Sciences The authors declare no competing interests Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations Download citation DOI: https://doi.org/10.1038/s41598-025-86273-8 Anyone you share the following link with will be able to read this content: a shareable link is not currently available for this article Sign up for the Nature Briefing newsletter — what matters in science Subscribe now to get new articles and updates in your inbox » I GOT TO PAGE 67 IN THE PLANT DELIGHTS CATALOG last night the first of eight pages of Hosta entries from Tony Avent Chief Hosta Officer of contemporary horticulture I was going to allow myself one new hosta this year There are now almost 6,000 cultivars in commerce probably 500 actually are distinct and garden-worthy.” Which one can’t you live without or wish you lived with (perhaps fluctuans ‘Variegated,’ aka ‘Sagae,’  above) the “finest and most dramatic variegated hosta ever introduced.” Another personal must-have would be ‘June’ (above) the month of my birth and also one beautiful hosta I have to describe it as not just blue but nearly turquoise in spring the creamy yellow centers heating up to chartreuse against a vivid blue I’ve found ‘June’ to be a strong grower and have made numerous divisions from my original plants the ‘June’ foliage darkens to deep blue with medium green here but it’s good-looking in that combination And then of course I need an all-gold hosta as a filler in such mosaics…and the old-but-good, vase-shaped big blue hosta ‘Krossa Regal’ for my big pots (yes, Hosta pot, why not?) Δdocument.getElementById( "ak_js_1" ).setAttribute( "value" This site uses Akismet to reduce spam. Learn how your comment data is processed. Are your hostas planted in a protected area?I am assuming that you don’t have a deer problem I just finished a Master Gardner program and the lecturer for herbaceous plants recommends hosta sieboldiana elegans because it is one that slugs don’t find so delicious Glad to hear Margaret that it grows fast and divides well It will be nice to get one that I can share with them I am wanting a empress wu but i would like to have one with 10 or 15 eyes instead of just 1 or 2 eyes could you email me back to see how much it would cost I’m the type who likes to have a large clump so it will be bigger I have about 300 hostas and 76 japanese maples I like to buy with a lot of eyes I’m the type who can’t wait 5 or 10 years to wait instead of a small 1 to 3 eyes I would like a large clump Apparently ‘Empress Wu’ gets to 4-6 feet across in 5 years from a nursery plant so maybe you won’t have to wait that long…or you could buy 3 to start plant them as if one big clump and get there faster We’re in USDA Hardiness Zone 8B -coast of southernmost SC I’ve been told that hostas don’t “do well” here but would really like to add some to some shady areas of our garden – under the liveoaks Any suggestions for varieties that might perform better here I enjoy all the information you share with us Welcome, Pixie, from Zone 8B. Do I have a resource for you: Hosta Czar Tony Avent of Plant Delights (in NC) writes about them a lot, including this article on the most heat-tolerant kinds look in the lefthand sidebar on that same page under the H’s… Hope that helps Aren’t hostas also know as “deer candy” but everyone in my neck of the woods says i’ll be heart broken because the deer eat them June is my favorite – looks good all season Blue Mouse Ears is a nice small blue gray for close-up viewing Striptease is always so clean looking and distinctive from so many variegated ones and munched on by slugs later….now they look a bit “lacey” The roots are probably busy digging in despite the havoc up top and all will be just fine I have had them gnawed to the ground by deer (in the early years pre-fence here) and they just came back anyhow I forecast a happy hosta year next year for you @BRenda: I have no idea. I say say-gay, but I don’t think that’s correct. The only site I know for pronounciation of Japanese hosta names is this one where they say it’s sah – gah – eh small is better when one has a large appetite :) ‘Blue Mouse Ears’ is a sweet thing; glad you mentioned it This is a subject near and dear to my heart since I ran a hosta tissue culture lab for 20 years and introduced a number myself My last introduction was ‘First Frost’ which is actually named Hosta of the Year for 2010 I’m so pleased to say It is a beauty from the hosta ‘Halycon’ – the reverse of ‘June’ – yellow edge and blue-green center – a real stunner if I do say so myself ‘June’ is definitely my favorite…or maybe… :) Congratulations on getting the big honor with your introduction…no small feat with so many hostas in commerce and new ones coming all the time Must be a great plant…I am going looking There is going to be a new and improved (sigh!) version of ‘First Frost’ out very soon called ‘Blue Ivory’ that has a wider edge Walter’s Gardens is actually introducing this one and I have a small plant of it I love the whole “mouse” series but I’m excited about a brand new one called ‘Blueberry Waffle’ that should be out very soon because I do love the big I only found it recently and have already tracked down several plants that I wasn’t aware of that you’ve recommended and look forward to your e-mails with great anticipation so our plant choices vary some from yours but many do just fine down here in the south I’m also a huge hellebore fan and never fail to add hellebores each spring from Tony and the Tyler’s at Pine Knot Nursery It’s a beautiful day to be outside gardening in the spring sunshine but I’m inside with a bad cold – what’s a gardener to do Surf the ‘net’ for gardening topics of course While Googling for ‘Blueberry Waffles’ I came across this page and the question intrigued me I’ve read all the postings and have all the hostas mentioned plus hundreds more My question is – could I keep my ‘Empress Wu’ the ‘Blueberry Waffles’ that I already have on order for first thing next spring from the TC lab and the hosta I hybridized myself and named for my grandmother and go on from there – or – would I have to give them all back and only have one hosta in my garden if I could only have one plant I would keep my ‘Anna Blanton Goff’ – the plant I named for the lady who gave me my first piece of hosta 59 years ago when I was 5 years old I could only have one hosta what would I do to occupy my time I think at this stage we have to give you a special exemption from the “choose 1 only” thing — you are already too far around the bend for that :) I like that even your cold cannot keep you away from plants Bob Solberg comes to Knoxville to our Hosta Society sale Interesting man…American Hosta Society is in Nashville next month……June 13th-16th…. Sounds like you have some good programs there I just planted my first little garden of 8 hostas in zone 3 but my favorite one so far is the Sum and Substance Has anyone ever heard of the “Humpback Whale” but looking it up now I see it’s blue and giant and sold widely…so I bet you could adopt one A WAY TO GARDEN is the latest horticultural incarnation of me birthed in March 2008 with my own words as its primary DNA mingled with ideas shared in weekly expert interviews I have been the garden columnist for “The New York Times,” where I began my journalism career decades ago I host a public-radio podcast; I also teach online plus hold tours at my 2.3-acre Hudson Valley (NY) Zone 6A garden and always say no to chemicals and yes to great plants Design by Purr. Volume 12 - 2021 | https://doi.org/10.3389/fpsyg.2021.674402 This article is part of the Research TopicEmergentist Approaches to LanguageView all 20 articles Recent work on the application of neural networks to language modeling has shown that models based on certain neural architectures can capture syntactic information from utterances and sentences even when not given an explicitly syntactic objective We examine whether a fully data-driven model of language development that uses a recurrent neural network encoder for utterances can track how child language utterances change over the course of language development in a way that is comparable to what is achieved using established language assessment metrics that use language-specific information carefully designed by experts Given only transcripts of child language utterances from the CHILDES Database and no pre-specified information about language our model captures not just the structural characteristics of child language utterances but how these structures reflect language development over time We establish an evaluation methodology with which we can examine how well our model tracks language development compared to three known approaches: Mean Length of Utterance We discuss the applicability of our model to data-driven assessment of child language development including how a fully data-driven approach supports the possibility of increased research in multilingual and cross-lingual issues Although less detailed than many available alternatives MLU is simple and fast to compute consistently while metrics based on identification of specific language structures have traditionally required expert manual analysis MLU use in many languages other than English is considerably more straightforward than adaptation of metrics that rely on identification of specific lexical or grammatical items and MLU is less susceptible to issues relating to differences among varieties of the same language While there may seem to be inherent trade-offs associated with the use of approaches to tracking language development based on detailed language-specific structural analysis and based on superficial utterance characteristics we investigate whether accurate measurements of language development can be made quickly reliably and without reliance on analyses requiring linguistic expertise through the use of data and neural network approaches to natural language processing we aim to track language development in a way that is as fine-grained as can be obtained with carefully crafted language-specific metrics reliable and widely applicable as with MLU Our present goal is not to create a new metric but to examine whether computational models built only from transcribed utterances can capture how child language utterances change through the course of language development at a fine enough resolution to serve as a foundation for new ways to measure syntactic development Scoring schemes originally intended for manual computation, such as IPSyn, are designed partly to account for the strengths and limitations of human annotators, without regard for how to leverage syntactic analysis technology. Recognizing the different strengths in manual and automatic syntactic analysis, Lubetich and Sagae (2014) examined the extent to which IPSyn-like scoring can be performed automatically without a pre-defined list of targeted syntactic structures leaving it up to a data-driven model to select the relevant structures in the output of an automatic syntactic parser Their approach is to teach a machine to reproduce IPSyn scores just by looking at automatically generated parse trees with no information about how IPSyn scores are computed or what they mean Starting from the assumption that these parse trees contain sufficient syntactic information to assess language development figuring out what structures to focus on is left to the machine we show that our neural language model successfully discovers how to score child language samples according to language development more accurately than existing implementations of MLU and automated IPSyn scoring This result suggests that neural network language models are capable of encoding how syntactic development in progresses in English-speaking children and creates promising directions for accurate data-driven measurement of language development Our experiments involve a specific kind of language model based on a type of recurrent neural network, more specifically the Long Short-Term Memory network, or LSTM (Hochreiter and Schmidhuber, 1997) The model is trained using longitudinal child language data from the CHILDES Database We first describe the neural network model We then describe how the model was trained and how our experiments were conducted The general language model formulation commonly assumed in natural language processing and computational linguistics is based on word predictions the model is designed to estimate the probability of strings in the language as the product of the conditional probabilities of each word in the string given the preceding words the model predicts words in a string (a sentence or an utterance) from previous words: the probability of the string P(S) is the probability of the word sequence (or token sequence) t1t2…tN of length N−1 to which special tokens representing the beginning of sentence (BOS) and end of sentence (EOS) have been prepended and appended The probability of this sequence is the product of the probability of each word ti given the preceding words t0…ti−1 Notice that the product above does not include the probability of t0; since every string starts with the special token BOS its probability is 1 and does not affect the product is the probability of ending the string (i.e. ending the utterance or sentence) given all the previous words when learning to predict what word follows chairs the network learns that chairs is the plural of chair A simple feedforward neural network with an input layer This network can implement a bigram language model with units in the input and output layers representing different words in a vocabulary the unit with highest activation in the output layer is the model's prediction for the next word The hidden layer receives activation from the embedding layer and from the hidden layer in the previous time step A simple recurrent neural network unrolled for L time steps Our model of child language development is based on the simple assumptions that language is acquired over time and development is monotonic It is intended to pick up on what changes in utterances through language development Monotonicity here does not mean that the child's language is always increasingly more similar to some ultimate form and it does not mean that development progresses linearly but simply that typical development does not regress the assumption is that given two appropriately sized language samples (lists of utterances) from the same child collected at different times during language development it should be possible for a model to distinguish between the earlier and later samples The key idea is that if a model can sort these language samples chronologically it must do so by figuring out what changes in the language over time Since recurrent neural language models encode some information about syntax they are a promising way to encode the language samples to be compared and sorted the goal is to have one model that makes accurate predictions across different children Even though some children may learn certain things at different rates and at different ages the model must be able to sort the language samples for a new individual child it has never encountered before Although the idea of ordering language samples is the key for how we intend to capture changes in language over time the model is ultimately intended to score individual language samples in the same way one would score a language sample using an instrument such as IPSyn We design our model to score individual language samples or learn the neural network parameters from data by repeatedly choosing a pair of language samples and adjusting the model's parameters to make it more likely that the sample originally produced at a later time receives a higher score Our neural model of child language development can be thought of as being composed of two modules, which together can assign a score to a language sample containing a certain number of utterances from a child. The first module consists primarily of an LSTM language model, or more precisely a Bidirectional LSTM (BiLSTM) encoder (Graves, 2012) which is used to encode utterances into a vector representation Given a language sample composed of a certain number of utterances the LSTM language model encodes each utterance simply by processing the utterance one word at a time Recall that every utterance ends with a special EOS token It is the activation of the topmost hidden layer of our model at the last time step which corresponds to having the EOS token as input that we use as (half of) the representation of the sentence This specific representation is chosen because it is the result of the model having processed all of the words in the utterance and the recurrent nature of the model makes it possible for information about the entire utterance to be captured at this last time step A common practice when encoding strings with an LSTM network is to repeat the process on the reversed string with separate parameters The string is then encoded forwards and backwards the hidden representation for the EOS token is used as half of the representation for the sentence the hidden representation for the BOS token gives us the other half of the representation for the sentence Once representations for individual utterances are computed a single representation for the entire language sample composed of these individual utterances is simply the average of the representations of the individual utterances and the representation for the entire language sample is taken to be the average vector of all utterance vectors in the sample with input consisting of several utterances which are each encoded to create a representation for the entire set of utterances (labeled as Language Sample Vector) Our model for encoding and scoring language samples composed of utterances Each utterance is encoded by a Bidirectional LSTM network Utterance representations consisting of the concatenations of the first and last tokens are averaged into a vector that represents the entire language sample a score is computed for the entire language sample With the two modules that together encode a list of utterances and produce a language development score the remaining questions are how to make the encoder module focus on how the grammar of utterances change over the course of language development and how to make the score produced by the second module track language development based on what the first module encodes These two questions are addressed jointly through end-to-end training of the model An important distinction between our utterance encoder and a typical neural language model trained as described above using a word prediction objective is that our encoder is trained using the language sample sorting task directly When a typical language model is trained without a specific task as an objective it learns from its training strings what it needs for its word prediction task The same network architecture can also be trained on tasks that are not word prediction tasks the error signal that is used to adjust the weights of the network comes directly from the model predicting a different word from what was observed in a specific position in a training string an error signal is obtained when the language model has been used to encode the utterances in two distinct language samples the scorer module assigns scores for these two language samples and the sorted order of the scores does not correspond to the chronological order of the samples the error is propagated through the entire network so that weights can be updated in a way that is specific to the task Training the model requires longitudinal language data from multiple children 100-utterance language samples are organized chronologically Parameters (network weights) for both modules are initialized randomly the model is presented with data from each child 20 times and each time a maximum of 100 samples are chosen randomly from the samples from that child Every language sample is encoded with the first module and scored with the second module Within the set of 100 randomly chosen samples every sample is paired with every other sample to create 100 × 99 training pairs The scores for the two samples are then compared The model's training objective is to make sure chronologically later samples have higher scores than earlier samples The number of times data for each child is presented (20) and the number of samples chosen randomly for each child (100) are meta-parameters of the model The model's meta-parameters and meta-parameter tuning process are described in the next section with a pair of language samples being provided to the model and parameters across the entire model being adjusted in response to errors This means that the two modules are trained together and influence each other With weight updates (parameter learning) in neural networks being error-driven each time an incorrect prediction is made (i.e. the model fails to predict the chronological order the samples) the error is propagated from the ultimate prediction down to the representation of the average of the utterances in each sample down to the representations of each individual utterance produced by the language model encoder and all of the parameters in the entire model are updated to make the correct prediction more likely Over the process of training the entire model the language model learns to prefer encodings of the utterances that will make the chronological ordering task more accurate the encoder learns to model language development by focusing on the differences in the representations of the two language samples from different times Because the training material consists of data from multiple children the model prefers patterns that apply generally one can imagine a very patient intelligent entity with limited memory and no knowledge of grammar looking at two sets of utterances produced by the same child several months apart This entity knows what set of utterances was produced later and starts to look for patterns that could be used to determine the chronological order of the samples the presence of individual words or sequences of words might seem promising but when presented with a long list of pairs of languages samples this entity notices that certain structural patterns are more predictive of chronological order If it is really structural patterns that are most predictive of order of the samples over many passes over many pairs of samples the entity will learn a list of what patterns to look for and how to weigh these patterns against other patterns This list might end up being similar in many ways to the list of structures used in metrics like IPSyn This is approximately what motivates our model Finally, to prevent the model from picking up on differences in the topics discussed at different ages or the differences in vocabulary, we use the morphosyntactic tags (MacWhinney, 2000) from US English CHILDES transcripts instead of the surface word forms as the tokens in our model These tags differentiate between parts-of-speech such as nouns Experiments using the observable surface forms (the words themselves) produced very similar results The encoder in our model is a BiLSTM with a 50-unit embedding layer and seven hidden layers each with 200 units for each direction (forward and backward) the BiLSTM encoder produces encodings for each utterance as a vector of 400 dimensions resulting from the concatenation of the topmost hidden layer for each direction at the last time step (i.e. the 200-dimensional vector obtained after processing the EOS token in the forward direction and the 200-dimensional vector obtained after processing the BOS token in the backward direction) We chose the size of the language samples to be 100 utterances motivated partly by the size of the language samples used to computer IPSyn scores The scoring module is a feedforward network with one hidden layers of 200 units It takes the representation of a language sample as a vector of 400 dimensions and produces a real-valued score The ranking task used to train the network involves encoding and scoring two language samples and comparing the resulting scores for each language sample and y is +1 if A comes before B chronologically and −1 if B comes before A chronologically When the model's predictions for the scores of the two samples order the samples correctly and the value is used in parameter updates to reduce loss Training our model requires longitudinal data from multiple children and we included in our dataset utterances from corpora that contained transcripts collected from the same child at least 6 months apart we included only corpora from which we could extract at least 75 language samples containing 100 complete utterances not including repetitions and for which we could determine the age of the child in months Having a certain number of language samples per child ensures that the data will be useful to the model during training and that we reduce the amount of noise in our evaluation While it is possible that corpora with fewer than 75 samples would also be useful we found there were a sufficient number of corpora that fit our criteria Data from other children that did not fit our criteria was used as development data and in the process of meta-parameter tuning The corpora and 16 children included in the final dataset are: The transcripts for each child were split into samples of 100 utterances each, and the child age corresponding to each sample was recorded to determine the reference ordering during training and evaluation. From each transcript in CHAT format (MacWhinney, 2000) containing part-of-speech and morphological analysis for each utterance To conduct experiments excluding word forms to avoid having our model capture the effect of topic in ordering samples we simply used the most basic form of each lexical item's tag (e.g excluding the base form of words and morphological information These baselines are meant to represent what can be obtained with a straightforward approach that does not require structural analysis of language samples (MLU) and more precise assessment instruments that were designed based on fine-grained language-specific knowledge that require linguistic analysis (DSS and IPSyn) and IPSyn were obtained simply by running the available tools on each of the language samples to obtain scores for our model we used our dataset in a leave-one-child-out cross-validation scheme This means that with a dataset including data for 16 children Transcripts for each of the 16 children were then scored using a model that was trained with no data for that specific child To score transcripts from children outside of our dataset we would simply train a single model using data for all 16 children in our dataset Our leave-one-child-out cross-validation allows us to estimate how the model performs on unseen children by each time training with data from 15 children and scoring transcripts from a child excluded from the model Unlike in previous work to automate measurement of syntactic development (Sagae et al., 2005; Hassanali et al., 2014; MacWhinney et al., 2020) or to obtain a data-driven approximation to an existing metric (Lubetich and Sagae, 2014) the target for the scores in our model is not simply another value that can be derived for each transcript Since the goal of our model is to track development over time and assign scores that reflect the chronological order of language samples for a child we evaluate our model and compare it to baselines based on this task directly we compute the Spearman rank correlation coefficient between the scores for each language sample and the child's age in whole months corresponding to each language sample ranges from −1 to +1 and reflects the strength of the correlation between two rankings Our reference ranking is the age in months A perfect Spearman rank correlation of +1 would indicate that the scores assigned by our model perfectly sort the language samples chronologically A Spearman rank correlation of zero would indicate that there is no correlation between the order derived from the scores of our model and chronological order the better suited for tracking language development we consider a metric to be We compute Spearman coefficients for each child between age and MLU, age and DSS scores, age and IPSyn scores, and age and the scores assigned to transcripts by our model. Since we compare these coefficients to each other directly, we obtain a bootstrapped error estimate for each coefficient by resampling the set of transcripts used to compute the Spearman coefficient 10,000 times. Table 1 shows the results obtained for each of the 16 children using MLU For the convenience of having a single value that represents how well each of these metrics correlate with language development over time we also provide the average values of all children per metric we caution that the meaning of such an average value may not be straightforward to interpret in isolation Since the set of transcripts for each child contains transcripts from a different range of ages it is expected that the rank coefficient from some children will be higher than for others it is easier for any of these metrics to rank two samples 2 years apart than it is to rank two samples 2 months apart these scores are meant to be interpreted in relation to each other we would not claim that IPSyn scores have an average rank correlation of 0.77 with age and rather that the average rank correlation is 0.77 for this specific dataset Spearman rank correlation coefficients between age in months and four language development scores for the 16 children in our dataset The results in Table 1 show that while MLU is an effective approach to approximate the level of language development over time across a variety of children The average Spearman coefficient between age and MLU is 0.662 the lowest correlation between age and a tested metric The coefficients for DSS and IPSyn are very close The average Spearman coefficient between age and our model is 0.807 The scores obtained with our model correlate with age to a higher degree than DSS or IPSyn scores do in this dataset but this is likely due at least in part to the fact that the model was tuned with these transcripts in mind Although meta-parameter tuning was performed based on results obtained using transcripts from children not used in our evaluation various factors such as the number of units and layers in the network and the learning rate were influenced by observing the training process itself even if separate validation transcripts were used which uses no pre-specified language-specific knowledge and learns its parameters entirely from transcripts performs on par with metrics designed by experts to capture language-specific phenomena This is a significant result in that the model derives all of its knowledge of the language and of the task from the training dataset consisting of utterance sets from various children only our model outperforms MLU across all four children in this set although the age correlation of our model for one of the children (Emily 0.432) is substantially below the age correlation values for DSS (0.643) and IPSyn (0.629) The very small number of languages for which a detailed metric such as IPSyn is available further stresses the scale of the larger task of making resources available for language development research in various languages allowing for both greater depth of language-specific findings and cross-lingual research We present a different way to approach this situation through data While our current goal is not to provide a new metric for English or any specific language we show that current neural network language modeling is capable of capturing some aspects of the language development process to the extent necessary to track language development in individual children at a level of precision substantially greater than with MLU and comparable to that obtained with a detailed language-specific metric such as IPSyn Our results can serve as the foundation for data-driven metrics in different languages requiring only longitudinal data in the form of transcripts it can be used to score a language sample from a new child by first encoding the utterances using the BiLSTM language model and scoring the resulting using the feed-forward network which requires several passes through a sizable collection of transcripts scoring new language samples can be done seemingly instantly with a current consumer-grade general-purpose computer The amount of computation required for scoring a language sample is greater than what would take to obtain the MLU score for the same language sample but it is comparable to the amount of computation required for automatic IPSyn scoring The use of language samples from multiple children during training results in a model that produces scores that are not specific to any one child and are comparable across children Since training consists of repeated attempts to predict the order of language sample pairs from different children using a single scoring model these scores can be used to compare the level of development of a child to that of another child in a similar way to how MLU or IPSyn scores are used which operate on known scales defined explicitly the scores from our data driven model are dependent on the dataset used for training there is not even a pre-defined range for the scores produced by the model scores from models trained with different datasets may not be directly comparable numerically To keep the scores of a practical language development metric that uses our approach and a specific dataset within a pre-defined range a sigmoid function can be applied to the value produced by the scoring module The results in Table 1 provide a strong indication that neural network language models trained with longitudinal data can capture structures relevant to the measurement of language development In addition to adding to the growing body of knowledge related to whether and how neural networks can derive syntactic structure from text alone our work also points to an area of application of this apparent ability of recurrent networks to model language structure our experiment involved data for only 16 children and much work still needs to be done toward a usable metric or a set of metrics for various languages Further validation of our approach through extrinsic methods such as verifying that previous research results obtained with IPSyn or DSS scores can be replicated with scores obtained from our fully data-driven model would be needed to examine the potential practical utility of the approach and not yet at a stage that can provide clear information about what specific kinds of information a model such as ours learns from language data suggest these models learn a fair amount of syntax since fluent generation would be unlikely without it the question remains if our model learns to score language development based on syntax or other more superficial features of the utterance strings While it is a safe assumption that our model does learn to leverage utterance length in scoring since it contains information relevant to the task it is unlikely that the performance of the model can be attributed to superficial string characteristics alone The levels of rank correlation with age obtained with scores produced by our model with DSS and with IPSyn further suggest that our model captures syntactic development Given the similarity of the correlation coefficients obtained with our model and with IPSyn and the extent to which IPSyn scores are based on syntactic structures it is reasonable to expect that our model's success is due to its modeling of syntax Initial experiments with the original word forms in the utterances produced very similar results as the ones presented but it was not clear if the model learned what changes in the grammar as language development progresses or what children tend to talk about at different ages To isolate the effect of syntactic structure we used only plain part-of-speech tags to represent the words in the utterance strings completely removing any information about topic This makes it likely that the model does in fact rely on syntactic structure especially since our neural language model encoder is trained not with the word prediction objective but the language sample ordering objective The correlation coefficient for age and our length model is 0.711 putting it closer to MLU than to our full model Although this ablated model scores language samples based on length the advantage it has over MLU is that it can consider the distribution of lengths of the utterances in the sample the coefficients for MLU and for the length model were similar with the exception of Naomi from the Sachs corpus (0.732 with MLU vs 0.910 with the length model) and Nathaniel from the Snow corpus (0.190 with MLU vs For each of these syntactic dependency types we construct a dataset containing an equal number of utterances where the corresponding grammatical relation appears and utterances where the corresponding grammatical relation does not appear We then encode each of these utterances using our BiLSTM utterance encoder to obtain a vector representation for the utterance as described in section A Neural Network Model of Child Language Development This vector is the concatenation of the encodings of the beginning of sentence token (BOS) and the end of sentence token (EOS) We then train a classifier to detect whether each of these fixed length vectors correspond to an utterance where the grammatical relation in question appears or does not appear we take an equal number of utterances containing a CMOD dependency relation (approximately a relative clause) and not containing a CMOD relation and train a binary classifier (in this case a feed-forward network with 50 hidden units) to predict if the original utterance contains a CMOD relation These vector encodings do not contain the tokens in the original utterance so this prediction must be made based on what information from the utterance the model encodes once it is trained these vector encodings are expected to capture the information necessary for ordering utterances chronologically such as a relative clause represented by the syntactic dependency type CMOD is useful to the model in the ordering task we expect to be able to detect whether or not the utterance contains a relative clause from the vector alone We use an equal number of utterances containing and not containing each dependency type so that identification of dependency types cannot be made based on frequency information we test each classifier on an unseen set of utterances also consisting of an equal number of utterances containing and not containing the dependency type in question The accuracy of these classifiers, shown in Table 2 confirm that our model does capture a substantial amount of syntactic information Since each syntactic dependency type is tested with an equal number of utterances containing and not containing the dependency type an accuracy of 50% would correspond to no ability to detect the dependency type from the vector encoding of the utterance while an accuracy of 100% would correspond to perfect ability to detect the dependency type which would require the presence of the syntactic dependency to be encoded in the vector Since the syntactic annotation used to train our classifiers experiment is produced automatically it would be unrealistic to expect accuracy of 100% Each dependency type was identified by its corresponding classifier with accuracy of at least 60% and SUBJ (82.3%) were the dependency types identified with highest accuracy and XMOD (69.2%) were the dependency types identified with lowest accuracy These results support our expectation that our model encodes syntactic structure Accuracy in detection of the 20 most common syntactic dependency types in our dataset from utterance encodings produced by our model While MLU values can be interpreted in the context of different populations this advantage is due to how coarse-grained the metric is More precise metrics based on inventories of specific structures would need to be adapted based on expertise of the relevant language structures for each population fine-grained scoring relative to a population represented in a specific dataset without the need for the assumption of a mainstream or standard variant at the expense of other equally valid variants Although MLU is the most convenient approach for assessment of language development since it does not require a language-specific scoring scheme like IPSyn does and it does not require a longitudinal dataset like our data-driven approach does it is not as precise as the alternatives considered When considering the application of an approach like IPSyn or our data-driven approach to a new population whose language may not be identical to that of populations used to validate these metrics If no data is available and data collection is impractical one might be well-served by turning to language expertise to adapt a metric like IPSyn When considering the amount of variety in English and will continue to be difficult to scale is likely to continue to become easier to deal with based on the trend observed for the past couple of decades While this brings non-trivial questions about best practices for construction of datasets that represent a language or a specific variant of a language it is preferable to address these questions imperfectly but explicitly than to leave them unacknowledged hiding the potential for inequity in research results Although our goal is not to create a new metric for language development in English and several issues remain unaddressed before our work can be leveraged into metrics that can be used in practice our work is significant in that it shows that recurrent neural networks without any pre-specified knowledge about language beyond the inductive bias inherent in their architecture can learn the child language acquisition process to the extent necessary to track language development in sets of transcripts as accurately as established metrics We support our claim that our model learns syntactic structure by showing that it outperforms a baseline based on Mean Length of Utterance and by removing all semantic information from transcripts to prevent the model from leveraging topic information and other cues In addition to demonstrating how neural language models can capture the language development process successfully we hope that our work will serve as the basis for future work on modeling and measuring language development that will focus on a wider variety of languages and language varieties creating the possibility for new language-specific and cross-lingual research on child language and development of syntax Publicly available datasets were analyzed in this study. This data can be found here: http://childes.talkbank.org The author confirms being the sole contributor of this work and has approved it for publication The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest I am grateful to the reviewers for their insightful comments and suggestions Google Scholar CrossRef Full Text | Google Scholar “Do RNNs learn human-like abstract word order preferences?” in Proceedings of the Society for Computation in Linguistics (New York Google Scholar Neural Network Methods for Natural Language Processing Google Scholar Supervised Sequence Labelling with Recurrent Neural Networks Google Scholar Gurunath Shivakumar Transfer learning from adult to children for speech recognition: evaluation Automatic generation of the index of productive syntax for child language transcripts CrossRef Full Text | Google Scholar “Adam: a method for stochastic optimization,” in 3rd International Conference on Learning Representations Google Scholar Simple and accurate dependency parsing using bidirectional lstm feature representations CrossRef Full Text | Google Scholar Developmental sentence scoring: a clinical procedure for estimating syntactic development in children's spontaneous speech doi: 10.1146/annurev-linguistics-032020-051035 CrossRef Full Text | Google Scholar Assessing the ability of lstms to learn syntax-sensitive dependencies CrossRef Full Text | Google Scholar “Data-driven measurement of child language development with simple syntactic templates,” in Proceedings of the 25th International Conference on Computational Linguistics: Technical Papers (Dublin) Google Scholar The CHILDES Project: Tools for Analyzing Talk Google Scholar CrossRef Full Text | Google Scholar Sources of hierarchical inductive bias in sequence-to-sequence networks CrossRef Full Text | Google Scholar “Efficient estimation of word representations in vector space,” in Workshop Track Proceedings of the First International Conference on Learning Representations (Scottsdale Google Scholar Index of productive syntax for children who speak african american english Machine-scored syntax: comparison of the clan automatic scoring program to manual scoring A primer in bertology: what we know about how bert works CrossRef Full Text | Google Scholar Morphosyntactic annotation of CHILDES transcripts CrossRef Full Text | Google Scholar “Automatic measurement of syntactic development in child language,” in Proceedings of the 43rd Annual Meeting on Association for Computational Linguistics-ACL'05 (Ann Arbor Google Scholar “Adding syntactic annotations to transcripts of parent-child dialogs,” in Proceedings of the Fourth International Conference on Language Resources and Evaluation (Lisbon) Google Scholar CrossRef Full Text | Google Scholar From feedforward to recurrent lstm neural networks for language modeling CrossRef Full Text | Google Scholar “Sequence to sequence learning with neural networks,” in Proceedings of the 27th International Conference on Neural Information Processing Systems (Montreal Google Scholar “Word representations: a simple and general method for semi-supervised learning,” in Proceedings of the 48th Annual Meeting of the Association for Computational Linguistics (Uppsala) Google Scholar Autobiographical memory and past time reference CrossRef Full Text | Google Scholar “CoNLL 2018 shared task: multilingual parsing from raw text to universal dependencies,” in Proceedings of the CoNLL 2018 Shared Task: Multilingual Parsing from Raw Text to Universal Dependencies (Brussels) Citation: Sagae K (2021) Tracking Child Language Development With Neural Network Language Models Received: 01 March 2021; Accepted: 11 June 2021; Published: 08 July 2021 Copyright © 2021 Sagae. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) distribution or reproduction in other forums is permitted provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited in accordance with accepted academic practice distribution or reproduction is permitted which does not comply with these terms *Correspondence: Kenji Sagae, c2FnYWVAdWNkYXZpcy5lZHU= Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher 94% of researchers rate our articles as excellent or goodLearn more about the work of our research integrity team to safeguard the quality of each article we publish Fernandes was intentional about reaching out to woman-owned businesses to seek participants “Churn Homemade Ice Cream and Coffee was the first company I contacted and theirs was the first response I got,” says Fernandes “Their prompt was the most interesting and the CEO was super receptive to having the collaboration for the social impact competition.” Alcohol-infused ice cream was the focus of the winning Churn case competition proposal and Fernandes and her student colleagues (Raka Mazumder “We focused on whether Churn should enter the market and what they needed to do There were a lot of technical and interesting factors,” she says There were so many things to consider!” “I’ve worked on client projects before but this was the most client-involved project we’ve had and it wasn’t just us presenting to Kelley: She was implementing our ideas as we presented them to her.” The semester-long project encompassed several deliverables and the partnership is now an ongoing 180 Degrees project.  “Churn is currently working on the ice cream but Kelley needs some social media help too we’re pivoting and working on a social media strategy and doing some consulting for the company too.”  The team presented their project at the WIB spring conference on February 25 WIB advisor Carla Bevins Assistant Teaching Professor of Business Communication and is helping the team devise posting schedules and assessments of Churn’s organizational structure all aimed at streamlining posting and marketing responsibilities The collaboration includes biweekly meetings with Costa to present updates and hear feedback as plans roll-out Fernandes has been involved with WIB in various capacities over the past couple of years but hosting a case competition was a major responsibility.  and I was intimidated,” she admits.  “But the WIB and 180 initiative provides an opportunity for undergrad women to be introduced into consulting and case competitions I ran the competition for WIB and was involved with both clubs and able to encourage students to participate It was the perfect collaboration and intersection.”  With her career goals pointed to consulting work Fernandes learned a lot by being the lead for this competition including hosting the case competition in November The ultimate goal was to have a campus wide case competition and to partner with a company There were 13 teams and the top five teams made presentations to Costa.  “Our 180 Degrees consulting team ended up winning the case competition You really learn so much when you teach other people and I enjoyed working with the other students One of the most valuable aspects of the work with Churn was creating a supportive space for students including giving and getting feedback.  “We had regular office hours and helped all the students — even those who didn’t win got feedback It was learning how to create slides and how to think about different problems.”  Fernandes worked on a technical-based project during an internship with Deloitte and she says that experience informed her work with Churn.  “Learning how to speak with a client is so important [Before the Deloitte internship] I didn’t realize how important building a relationship in the beginning is to making meetings go well,” she says She used that awareness in her work with Costa “I have to speak and create conversation to build the relationship.” and Fernandes credits her Tepper School coursework on decision science and behavioral decision making as extremely helpful Though much of the feedback she gave to the winning Churn team was heavy on data analysis “Data is only important if you can drive insights from it Data has to be connected back to the company and the human component You need to ask why things are important and present that to your client My classes helped me understand the ‘why’ and to build a good example from that you need to ask ‘What does this data actually mean Fernandes says one important core of the WIB organization is creating opportunities for women to find mentors “I was intimidated by everyone at CMU,” says Fernandes She taught me how to put myself first and that I was valid I could be friends with the women at WIB even if we weren’t all on the board together,” she says.  Tepper School alumna Lynn Fernandez (BS 2022) has also been a mentor to her.  “She’s like an older sister,” says Fernandes Fernandez graduated last year and is now working at Bank of America.  “Women empower other women to speak up,” Fernandes adds “I have been the only female in many environments and found that people spoke over me or that I spoke less but it’s different in a woman-led environment Female mentorship [helps improve the situation] but there are still microaggressions that make women feel their voices shouldn’t be heard in their workspace.”  Fernandes will be working at the Strategy& department in PriceWaterhouseCooper (PwC) in New York City and she credits the experiences she’s had at the Tepper School with her successful placement.  “Both 180 Degrees and WIB connected me with the folks at PwC I’m interested in consulting and excited to be involved in these clubs Women’s Consulting Experience is how I got into PwC and I got to apply as a sophomore for a junior year internship.”  “Social impact work for a consulting company would be my ultimate goal,” she adds “My dream career would be focused on how businesses can make more of an impact in social good.”  A previous 180 Degrees project Fernandes worked on with George Mark Hospital targeted pediatric palliative care.  “That was an experience I never thought I would have and I was very lucky to have that opportunity to make an impact,” she says.  George Mark provides a home place for terminally ill children to live and the goal with that 180 Degrees consulting project was to pass legislation in California to have Medicaid reimbursements for the hospice units Fernandes says it was important work that gave her much to reflect upon.  My main work stream was to interview legislators and researchers to figure out how to make a bill pass in California,” she says.  “180 Degrees gives you an opportunity to create an impact and contribute to society we are given hypothetical problems but in real life [The George Mark experience] helped me learn how to do research and I did the same thing with Churn.”  With volunteering as one of her major interests Fernandes loves to help out various organizations in the Pittsburgh community an organization dedicated to connecting participants to culinary employment opportunities through training and mentorship.  “I love to volunteer because I get to be an observer and hopefully a participant of the strong Pittsburgh community: Pittsburgh people are really nice and supportive,” she says.  Food insecurity is an issue she cares about and she has worked to get more people invested in helping.  “My favorite volunteer event is Rise Against Hunger at CMU This year more than 300 people participated and we packaged 77,000 meals for the organization It was great to see the CMU community come together With compassion as her motivator and technical knowledge from her internships and Tepper School courses providing the know-how there’s no doubt that Fernandes will continue to make a difference and be a changemaker among the business world post graduation The Intelligent Future of Business is bright with students like her leading the charge The first time most people could communicate with a computer that responded like a real person was in 2022 when OpenAI publicly launched ChatGPT. Just two months later, the app set the record for the fastest-growing user base with 100 million monthly active users The service was prone to mistakes and hallucinations, but the conversations felt more or less real. Since then, advancements in artificial intelligence (AI) as a technology have been stunning. AIs have passed the Turing test, a standard that determines whether a machine thinks by whether a human believes they are communicating with another human being AIs score better now than humans on the SAT “I would say that AI is part of the human system,” said Martin Hilbert a professor of communication in the College of Letters and Science at UC Davis Hilbert is among the many social scientists across Letters and Science who study AI to answer questions about people and society and to develop technologies that may drive our future This work touches nearly every part of daily life from health to education to the way we communicate with each other Their work shows that at this point in history AI and human society are inextricably intertwined “It’s the end of our species if you take seriously what it’s about,” said Hilbert but it means there is an artificial element that also possesses the defining aspect of our species We’re no longer the only being in our universe that has this knowledge business down.” The 2013 film Her tells the story of a man who falls in love with the chatbot embedded in his computer’s operating system the voice who speaks to him during nearly every waking moment — like the chatbots that seem imminent — feels like it comes from flesh and blood AI is a type of computer program that works like a very long series of probabilistic if-then statements that rely on data to find the right response whether it’s on ChatGPT or a chatbot that helps us book a flight online its responses are based on a database of similar interactions that help it predict what to say This technology that could help to solve some of society’s problems is actually reorganizing society itself. In a 2023 paper on SSRN Hilbert named this kind of technology-driven reorganization “algorithmification.” “Algorithmification does to knowledge what digitalization does to information,” said Hilbert Digitization created widespread access and use of information that was once contained exclusively in books Hilbert argues that algorithmification expands the reach access and potential of knowledge and information processing that was only done by human minds Hilbert explained that this shift is only the most recent iteration of our social evolution whic has been the primary way humans have evolved for the past 10,000 years and it has affected every living person in human societies “You could get rid of your cellphone and you could never touch money and you could go out into the desert and maybe you could survive for a few weeks or a month,” said Hilbert “You would still be a human but you would be like a human thousands of years ago You would not be evolving with the rest of us in society.” Greg Watry explores how this type of AI is enabling discoveries from the smallest to the largest scales.  there’s a lot of fear about AI costing people jobs and even making some jobs obsolete is to understand how to use AI technologies for your benefit While entire job categories are unlikely to be replaced Hilbert also said that workers who don’t use AI will likely be replaced by workers who do AI will also make it possible to significantly accelerate contributions to education medicine and so many other areas by its ability to produce language and software code “While we have put much effort into writing code for marketing and security we haven’t really started yet writing code for education and healthcare or for arts and entertainment to the same degree,” said Hilbert “We still need thousands of teachers around the world If there are certain tasks that can be alleviated with algorithms The promise of AI has captured the imagination of venture capital firms investing in the future UC Davis alumnus Vince Lane is a venture capitalist investor with a focus on AI and other “frontier technologies” like software-as-a-service (SAAS) and cybersecurity An entrepreneur with over 25 years of startup and corporate experience Lane is also a member of the Letters and Science Dean’s Advisory Council “If you don't utilize artificial intelligence then you aren't even being looked upon as a viable company,” said Lane Lane saw this kind of disruption in the 1990s with the earliest widespread access to the world wide web but said he was too young and early in his career to be a major part of it helping to steer its course through strategic investments and advice Lane said that AI is going to break through the limits of what we can accomplish on our own This includes speeding up technological and bio-medical advancements It also includes streamlining functionality for logistics and software development He said that these kinds of innovations are going to make everyone more efficient and happier in their day-to-day lives I will say that even though I'm so ingrained the whole community is moving very I think it's one of the biggest disruptors of our century,” said Lane Our lives are increasingly going to involve interactions with AI These interactions in particular are a focus of research about how we can be sure those interactions help us as individuals and as a society “We are going to increasingly interact with AI models in the future,” said Jingwen Zhang “We have to really think about the ideal scenario of how humans interact with them and how AI models are designed to benefit humans.” Zhang studies how AI can help improve public health, and she has been experimenting with a chatbot that can motivate us to act. She and her research team designed an AI chatbot that crafts personalized persuasive messages that help us make sure to get in our steps every day The chatbot can be downloaded via app on any device In Zhang’s first field experiment with the technology the AI chatbot delivered a single 10-minute conversation to the study’s participants That single conversation increased people’s intention to exercise by 37% increasing the duration and dynamic nature of the interactions could have a much stronger effect professor and chair in the Department of Linguistics and his focus is on how large language models (LLMs) impact society from a language perspective A language isn’t only a vocabulary of words and structures of grammar to make meaning out of them Sagae is studying the cultural values contained in LLMs in terms of moral values he and his research team have been asking participants to fill out questionnaires that help to define their values Sagae is measuring variations in cultural morals with the Moral Foundations Questionnaire that can score an individual’s values in terms of harm/care One of his findings is that LLMs are most likely to contain the moral values if the LLM is trained on web pages from the U.S. the embedded values in how it communicates with people from any part of the world will represent values from the U.S The way we communicate with AIs might also affect how we communicate with each other because we are in a moment where more and more of our everyday interactions are with computers and not individual human beings This could have its biggest impact on children who are still learning how to communicate through language “People are not looking seriously yet at what it means for kids to communicate with machines,” said Sagae Children might grow up learning how to use language outside of a community context which has always been the way we learn languages they could learn more and more  how to use language from an entity that has no emotional connection to the world “There is certainly potential for us to benefit greatly from the technology,” said Sagae “but there is still a lot of work needed to get us to the understanding that will unlock that potential without unintended harm.” Adapted from an original artlcle part of a series published by the College of Letters & Science magazine Alex Russell is a writer with the College of Letters & Science University of California, Davis Copyright © The Regents of the University of California Utah — Do you have a collection of trial size toiletries building somewhere in your home Maybe free toothbrushes and paste from the dentist Or maybe you’ve been hoarding extra soups and shampoos from hotels David and Jared Sagae want to hear from you The brothers saw a need for smaller hygiene items at local shelters They started the charity Trial Size Donations They’ve collected thousands of small soaps Then they ship them throughout Utah and several other states David and Jared must pay out of pocket to ship them That’s why we made Trial Size Donations this week’s Pay It Forward recipient Do you work at a company with employees who travel a lot They would love to put a collection bin in your office for those unused hotel toiletries You can contact David and Jared at their website: www.TrialSizeDonations.org A Seattle startup gets on the artificial-intelligence train with work in natural language understanding and by helping developers create voice controls used on devices a Seattle software company specializing in natural language understanding as related to artificial intelligence all have doctorates in computer-engineering related fields Yao and Chen studied at Johns Hopkins and Sagae at Carnegie Mellon The idea: Yao came up with the idea for the company while at Johns Hopkins He flew to Seattle to interview at the Allen Institute for Artificial Intelligence (AI2) and told Allen CEO Oren Etzioni he wanted to start his own company Voice-operated tech: Kitt.ai is creating an open platform for developers to create voice and text commands that can then be incorporated into applications The company specializes in natural language understanding and makes it easy for developers to create voice controls so the developers don’t have to build it from scratch System agnostic: Kitt.ai’s platform will work with any system such as Amazon’s Alexa or custom-built programs “We want to build an open-developer community that can support all kinds of dialogue systems for all kinds of platforms out there,” Yao said AI: Kitt.ai launched its first product last week which lets developers create “hotwords” to command systems by voice Hotwords such as “Hey Siri” or “OK Google” wake up artificial-intelligence machines How it works: Individual developers cannot access the big companies’ back-end technology so Kitt.ai built a system that quickly codes hot words for anyone A developer could create a command that says “Hey Rosie Kitt.ai’s system would produce code that developers can then plug into their device Commercial money: Kitt.ai plans to make money mostly from large corporations The company will charge small companies a small fee and will license the service to larger commercial firms Big backers: Kitt.ai has received funding from AI2 named for Amazon’s voice-powered digital assistant is currently incubated within Madrona’s offices It did not disclose its total funding numbers Stay secure and make sure you have the best reading experience possible by upgrading your browser After back-to-back weekends of historic events ONE Championship returns to the iconic Lumpinee Boxing Stadium with another captivating installment of its weekly Asia primetime event series The world’s largest martial arts organization will continue to keep its global fan base roaring with ONE Friday Fights 55 The event is jam-packed with a dozen Muay Thai A pair of ferocious strikers look to secure a six-figure contract in the main event Battle-hardened Thai veteran Avatar PK Saenchai will try to collect the 100th victory of his career but Russia’s Kiamran Nabati intends to keep his undefeated record intact and deny his rival of a landmark moment The card also features the highly anticipated returns of #3-ranked flyweight kickboxing contender Taiki Naito surging Russian knockout artist Natalia Diachkova and three-division Lumpinee Boxing Stadium Muay Thai World Champion Panthep VK Khaoyai And opening the show is the first-ever submission grappling match in ONE Friday Fights history as Japanese bantamweight studs Shoya Ishiguro and Toshiyasu Sagae look to set the pace for a thrilling night of action View this post on Instagram A post shared by ONE Championship (@onechampionship) View this post on Instagram A post shared by ONE Championship (@onechampionship) View this post on Instagram A post shared by ONE Championship (@onechampionship) View this post on Instagram A post shared by ONE Championship (@onechampionship) View this post on Instagram A post shared by ONE Championship (@onechampionship) View this post on Instagram A post shared by ONE Championship (@onechampionship) View this post on Instagram A post shared by ONE Championship (@onechampionship) View this post on Instagram A post shared by ONE Championship (@onechampionship) View this post on Instagram A post shared by ONE Championship (@onechampionship) Metrics details reduction of the intersite electronic transfer integral t by an alternating electric field is a promising strategy for controlling strongly correlated systems with a competing energy balance between t and the Coulomb repulsion energy Here we describe a charge localization induced by the 9.3 MV cm−1 instantaneous electric field of a 1.5 cycle (7 fs) infrared pulse in an organic conductor α-(bis[ethylenedithio]-tetrathiafulvalene)2I3 A large reflectivity change of >25% and a coherent charge oscillation along the time axis reflect the opening of the charge ordering gap in the metallic phase which is the reverse of the photoinduced melting of electronic orders is attributed to the ~10% reduction of t driven by the strong (a) CO insulator-to-metal transition (red arrow melting) and metal-to-CO insulator transition (blue arrow freezing) for both thermal (equilibrium) and optical (non-equilibrium) transitions in α-(ET)2I3 (b) CO gap is opened by the decrease of transfer integral t because of the competing energy balance between Coulomb interaction V and t induced by the strong AC electric field E(ω) the optical response of the metallic phase at T>TCO remains unclear In this study, we perform pump-probe transient reflectivity measurements for the metallic phase of α-(ET)2I3 using 7 fs 1.5 cycle infrared pulses. Our results demonstrate the optical freezing of charges or, equivalently, photoinduced charge localization in the metallic phase (blue arrow in Fig. 1a) We discuss the mechanism on the basis of theories that have been proposed for non-equilibrium states generated by high-frequency CW and pulsed AC fields (a) Optical conductivity (σ) spectra of α-(ET)2I3 at 40 K (CO: dashed blue curve) and at 140 K (metal: solid red curve) The spectrum of the 7 fs pulse is indicated by the orange curve (b) Reflectivity (R) spectra at 40 K (CO) and at 140 K (metal) (c) The spectra for three temperature differentials: [R(40 K)−R(140 K)]/R(140 K) (solid curve with blue shading) [R(190 K)−R(140 K)]/R(140 K) (dashed curve ( × 3) with red shading) and [R(170 K)−R(140 K)]/R(140 K) (dashed–dotted curve ( × 3)) (d) Reflectivities measured at 0.09 and 0.64 eV (indicated by the blue arrows on the spectrum in b) (a) Transient reflectivity (ΔR/R) spectra for Iex=0.8 and 0.12 mJ cm−2 at td=30 fs (closed blue circles for Iex=0.8 mJ cm−2 open blue circles for Iex=0.12 mJ cm−2) and 300 fs (closed black circles for Iex=0.8 mJ cm−2) after excitation by a 7-fs pulse ΔR/R at td=300 fs after a 100-fs pulse excitation for Iex=0.8 mJ cm−2 is shown as the crosses plotted as a two-dimensional (probe energy–delay time) map Positive and negative ΔR/R are shown by the blue and red shadings (a) Time evolution of transient reflectivity (ΔR/R) observed at 0.64 eV for Iex=0.8 mJ cm−2 (solid curve) and 0.12 mJ cm−2 (dashed–dotted curve) The cross-correlation between the pump and the probe pulses is also indicated by the orange shading The dashed blue curve shows the positive component of ΔR/R reflecting the photoinduced charge localization which was estimated assuming that the negative component grows exponentially (dashed red curve) (b) Oscillating component of the time profile The time-resolved spectra of the oscillating component obtained by wavelet (WL) analysis (blue curve for 0–40 fs red curve for 80–120 fs) are shown in the inset Optical conductivity spectra at 10 K (CO) and 140 K (metal) are shown by the black curves in the inset although the amplitude was much smaller (<1% of the ΔR/R signal) than the present case Because of the ultrafast decay within 50 fs (corresponding to the energy scale of ħ/50 fs=0.08 eV) of the photoinduced state we cannot verify the insulating gap below 0.1 eV clearly indicates that the charge motion on the corresponding energy scale is frozen as if the charge distribution on the ET molecules were analogous to that in the CO insulator Such a short lifetime indicates that the transient CO state is not adequately stabilized by vibrational and lattice motions demonstrating that the mechanism of the photoinduced charge localization is completely different from that of the insulator-to-metal transition (a) Transient reflectivity (ΔR/R) at 0.64 eV as a function of electric field for various temperatures Inset: temperature dependence of ΔR/R at E0=11.7 MV cm−1 (b) Positive component of ΔR/R derived by subtracting the negative component (see text) as a function of E0 together with 1/t' in units of t0 (E0<13 MV cm−1) calculated from equation 1 (solid red curve) (c) Zeroth-order Bessel function J0∝t' as a function of E0 the effective t (= t′) can be represented as we can estimate that the change in J0∝t′ is approximately 10% for a typical instantaneous field of 9.3 MV cm−1 (Iex=0.8 mJ cm−2) (b) Change in TCO (=ΔTCO/TCO) as a function of decreasing transfer integral t (−Δt/t) shown by the black closed circles The dashed line serves as a guide to the eye The dashed red arrows indicate that a 10% reduction in t causes a 12% increase in TCO it is reasonable to assume that ΔR/R is proportional to the efficiency of the transient charge localization this is estimated to be φ=1.66 × 10−4[rad] at most and is too small to cause a detectable momentum shift Such shift would be detected if the width of the asymmetric pulse were shorter than ~3 fs at this wavelength Another problem lies in the mechanism driving the reduced t which should be applicable to events before the excitation ends The reason why the photoinduced CO persists for ~50 fs after the 7 fs pulse is unclear at the moment Further experiments and theoretical considerations will be needed to clarify this issue this report demonstrates a large reflectivity increase (>25%) and a coherent CO gap oscillation along the time axis indicating the opening of a CO gap by the 9.3 MV cm−1 electric field of a 1.5 cycle 7 fs near-infrared pulse in an organic conductor α-(ET)2I3 The plausible mechanism for such a dramatic change in the electronic state is the reduction of t (~10%) driven by this strong high-frequency field A broadband infrared spectrum for the 7-fs pulse covering 1.2–2.3 μm, shown by the orange curve in Fig. 2a was obtained by focusing a carrier-envelope phase stabilized idler pulse (1.7 μm) from an optical parametric amplifier (Quantronix HE-TOPAS pumped by Spectra-Physics Spitfire-Ace) onto a hollow fibre set within a Kr-filled chamber (Femtolasers) Pulse compression was performed using both active mirror (OKO Technologies 19-ch linear MMDM) and chirped mirror (Femtolasers The pulse width derived from the autocorrelation of the generated second harmonic was 7 fs The instantaneous electric field on the sample surface (excitation diameter 200 μm) for a typical excitation intensity can be evaluated as where Ipeak=1.14 × 1011 W cm−2 represents the peak power for an excitation intensity Iex of 0.8 mJ cm−2 We performed transient reflectivity experiments using both 7 and 100 fs pulses The excitation photon energies for 7 and 100 fs pulses were 0.6–0.95 eV (7 fs) and 0.89 eV (100 fs) In the transient reflectivity measurement using a 7-fs pulse the probe pulse reflected from the sample was detected by InGaAs detector (New-Focus model 2034) after passing through a spectrometer (Bunkoukeiki The pump-on and pump-off were alternately switched by the feed-back-controlled optical chopper (New Focus Each probe shot was sampled using boxcar integrators (Stanford Research the observed intensity of respective shots was recorded in the PC Optical freezing of charge motion in an organic conductor (eds.)Special Topics: Photo-induced phase transitions and their dynamics Electrodynamics of correlated electron materials Theory of photoinduced phase transitions in itinerant electron systems Femtosecond structural dynamics in VO2 during an ultrafast solid-solid phase transition Ultrafast optical switching to a metallic state by photoinduced Mott transition in a halogen-bridged nickel-chain compound Time evolution of the electronic structure of 1T-TaS2 through the insulator-metal transition Photoinduced metallic state mediated by spin-charge separation in a one-dimensional organic Mott insulator Optical modulation of effective on-site Coulomb energy for the Mott transition in an organic dimer insulator Optical properties of a vibrationally modulated solid state Mott insulator Terahertz-field-induced insulator-to-metal transition in vanadium dioxide metamaterial Photoinduced insulator-to-metal transition in a Perovskite manganite Gigantic photoresponse in ¼-filled-band organic salt (EDO-TTF)2PF6 Coherent orbital waves in the photo-induced insulator-metal dynamics of a magnetoresistive manganite Photoinduced melting of a stripe-type charge-order and metallic domain formation in a layered BEDT-TTF-based organic salt Femtosecond snapshots of gap-forming charge-density-wave correlations in quasi-two-dimensional dichalcogenides 1T-TaS2 and 2H-TaSe2 Time-domain classification of charge-density-wave insulators Transient electronic structure and melting of a charge density wave in TbTe3 Ultrafast switching to a stable hidden quantum state in an electronic crystal Ultrafast transient generation of spin-density-wave order in the normal state of BaFe2As2 driven by coherent lattice vibrations Ultrafast modulation of the chemical potential in BaFe2As2 by coherent phonons Dynamical band flipping in fermionic lattice systems: An ac-field-driven change of the interaction from repulsive to attractive Repulsion-to-attraction transition in correlated electron systems triggered by a monocycle pulse Dynamic localization of a charged particle moving under the influence of an electric field Intra- and interdimer transfer integrals effectively modified by pulsed and continuous-wave lasers for controlling charge transfers in molecular crystals structure and physical properties of a two-dimensional organic metal di[bis(ethylenedithiolo)tetrathiofulvalene] triiodide Field and frequency dependent transport in the two-dimensional organic conductor α-(BEDT-TTF)2I3 Nonuniform site-charge distribution and fluctuations of charge order in the metallic state of α-(BEDT-TTF) 2I3 Strong optical nonlinearity and its ultrafast response associated with electron ferroelectricity in an organic conductor Collective excitations in the charge-ordered phase of α-(BEDT-TTF) 2I3 Early-stage dynamics of light-matter interaction leading to the insulator-to-metal transition in a charge ordered organic crystal Structural genealogy of BEDT-TTF-based organic conductors II Charge ordering in α-(BEDT-TTF)2I3 by synchrotron X-ray diffraction Charge order with structural distortion in organic conductors: Comparison between θ-(ET)2RbZn(SCN)4 and α-(ET)2I3 Download references Kayanuma (Tokyo Institute of Technology) for their insightful discussions This work was supported by Grant-in-Aid for Scientific Research (A) No Toyota Physical and Chemical Research Institute developed the 7-fs light source and carried out the transient reflectivity measurements using them performed the 100-fs transient reflectivity experiments performed the synthesis and the characterization of the single crystal Yonemitsu made theoretical considerations and calculations Yonemitsu wrote the paper after discussing with all the co-authors The authors declare 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Volume 9 - 2018 | https://doi.org/10.3389/fphar.2018.00029 Liver disease is one of the most risk factors threatening human health It is of great significance to find drugs that can treat liver diseases especially for acute and chronic hepatitis The search for drugs with good efficacy from traditional natural medicines has attracted more and more attention one of the China's traditional medical systems has been widely used by the Tibetan people for the prevention and treatment of liver diseases for hundreds of years The present paper summarized the natural Tibetan medicines that have been used in Tibetan traditional system of medicine to treat liver diseases by bibliographic investigation of 22 Tibetan medicine monographs and drug standards One hundred and ninety three species including 181 plants and 5 minerals were found to treat liver diseases in traditional Tibetan medicine system The most frequently used species are Carthamus tinctorius and pharmacological activities were described in detail These natural medicines might be a valuable gift from the old Tibetan medicine to the world and would be potential drug candidates for the treatment of liver diseases Further studies are needed to prove their medicinal values in liver diseases treatment elucidate the underlying mechanism of action and clarify their side effects or toxicity with the help of modern phytochemical 3,105 natural medicines including 2,644 plants and 140 minerals have been used in Tibetan medicine system TTM has long-term clinical practices and accumulated rich experience in the treatment of various diseases It has proved particularly beneficial in the treatment of chronic diseases It is worth noting that TTM has been widely used for the treatment of liver diseases in clinical practice Many TTM monographs and official drug standards recorded a lot of natural medicines and prescriptions that were traditionally used to treat a variety of liver diseases and lack of systematic summary and induction a bibliographic investigation of TTM monographs and drug standards and data mining were performed to sample information on natural Tibetan medicines used to treat liver diseases and reported biological activities are shown in detail These data can provide a good reference for their development and utilization we reviewed the most frequently used TTM in terms of their original species In order to know the most frequently used Tibetan medicines for the treatment of liver diseases, data mining was performed to obtain the usage frequency of each medicine in traditional Tibetan prescriptions by using Traditional Chinese Medicine Inheritance Support System (TCMISS) (Version 2.5) (Yan et al., 2016) All collected prescriptions were manually entered into the TCMISS software and the usage frequency of each medicine was ranked from large to small by clicking on the “Frequency Statistics” module we searched the online Chinese databases (e.g. and CNKI) and international databases (e.g. and Google Scholar) to obtain the active ingredients and biological/pharmacological effects of the selected species using their vernacular This paper recorded the uses of 193 species of natural Tibetan medicines for the treatment of various liver diseases in the traditional Tibetan medical system. The scientific name, family, medicinal part, treated disease, and reported biological activities of these natural medicines are given in Table 1 and Table S2 (see Supplementary Material) These medicines were distributed among 54 families The most common families are: Gentianaceae (14%) herb (71%) is the primary source of these medicinal plant species the whole plant was the most frequently used (39%) rhizome and inflorescence (2% each) (Figure S3) The most frequently used Tibetan medicines for the treatment of liver diseases in traditional Tibetan medical system these species are quite different from the ones reported in our article It may be due to the specific mountain flora and Herpetospermum pedunculosum) reported in the present study are mainly distributed in Tibetan Plateau the liver heat belongs to the category of “mKhris-pa” disease Symptoms of liver heat disease mainly include loss of appetite There were 23 species (9.02%) recorded in the treatment of extensive liver diseases and 6 species were described to be able to treat viral hepatitis It is noteworthy that 5 Chrysosplenium plants (Chrysosplenium carnosum and Chrysosplenium nepalense) and Sphaerophysa salsula were used to cure liver cirrhosis 3 Rhododendron plants (Rhododendron anthopogon and Rhododendron primuliflorum) were clearly indicated for the treatment of liver cancer These information are of great value for the development of potential candidate drugs The number and percentage of traditional Tibetan medicines used in the treatment of various liver diseases Out of 193 species traditionally used for liver diseases treatment, 51 species (26.42%) have been experimentally demonstrated to have various biological and pharmacological activities associated with liver diseases (Table 1 and Table S2) These findings have proved the validity of these species traditionally used in the treatment of liver diseases there are still 142 species (73.58%) that lack modern experimental evidences more in-depth studies are necessary in order to make better use of these traditional Tibetan medicines In order to know the most frequently used Tibetan medicines for the treatment of liver diseases, data mining based on TCMISS software was performed to obtain the usage frequency of these medicines in traditional Tibetan prescriptions. As a result, 303 prescriptions for the treatment of liver diseases were collected from Tibetan monographs and drug standards. Species with used frequencies above 20 are shown in Table 1 and Figure 2 The top five Tibetan medicines are Ku-gong (Carthamus tinctorius) with the used frequency of 125 and Ju-ru-re (Phyllanthus emblica) with 71 and biological/pharmacological activities of these five Tibetan medicines have been summarized in detail The most frequently used natural Tibetan medicines for the treatment of liver diseases in traditional Tibetan medical system hydroxysafflor yellow A is the major bioactive compound and so is usually used as the marker for controlling the quality of safflower in pharmaceutical industry and drug standards These results suggest that Ku-gong (safflower) may serve as a drug candidate for various liver diseases treatment and inhibited proliferation by modulating the expression levels of miRNA-21 and miRNA-22 in hepatic cancer cells (Huh-7) Di-da (Tibetan: ) is a widely used traditional Tibetan medicine in China. It originates from multiple plant species. S. chirayita, S. mussotii, S. franchetiana, and H. elliptica are the most commonly used species of Di-da in China. In traditional theory, Di-da is bitter in flavor and cold in property (Health Bureau of Tibet et al., 1979) and so has been commonly used for the treatment of liver and gallbladder diseases which exhibited significant anti-hepatitis B virus activity Franchetiana could exert a protective effect against liver injury caused by CCl4 and increase SOD level in rats with experimental steatohepatitis induced by high-fat diet known as “Se-ji-mei-duo” () in Tibetan or “Bolengguazi” in Chinese is one of the most representative Tibetan medicines It is bitter in flavor and cold in property and frequently used in the traditional Tibetan system of medicine for the treatment of icterohepatitis belongs to the Cucurbitaceae family and is widely distributed in Tibet and Yunnan of China India and Nepal at elevations of about 2300–3500 m and this effect could be promoted through pharmaceutical application of liposome These findings mentioned above support the traditional applications of H pedunculosun seeds by Tibetan medicine practitioners in liver diseases treatment In traditional Tibetan system of medicine, Ju-ru-re is described as sweet, sour, astringent in flavor and cool in property. It is frequently used for the treatment of liver diseases, blood heat, sore throat, dry mouth, indigestion, abdominal pain, and cough for thousands of years (Health Bureau of Tibet et al., 1979; Chinese Pharmacopoeia Commission, 2015) emblica is a deciduous tree and widely grown and sometimes cultivated in subtropical and tropical areas including China and Yunnan at elevations of 200–2300 m emblica at 50–100 μg/mL significantly inhibited cell growth of six human cancer cell lines including hepatocellular carcinoma cell (HepG2) these modern pharmacological studies indicated that Ju-ru-re may have a good potential to develop into a candidate drug for the treatment of liver diseases despite the good benefits of Tibetan medicines in the treatment of liver diseases were indicated in our article their potential toxicity should also be given enough attention It is especially important to take precautions against drug-induced liver injury when selecting Tibetan medicines and their doses More experiments should be encouraged to identify their side effects or toxicity so that they can be used safely and effectively Nature medicines including medicinal plants animals and minerals are nature's gift to human beings which play an important role in the fight against various diseases Many commonly used drugs of modern medicine have originated directly or indirectly from them Tibetan medicine is an important part of the world's traditional medical system The Tibetan people living in the Qinghai-Tibet Plateau have accumulated rich experience in medication in their struggle against natural conditions and diseases It is recognized that traditional Tibetan medicine has a good curative effect in the treatment of liver diseases cardiovascular and cerebrovascular diseases tinctorius was frequently used to treat liver diseases in TTM system tinctorius in treating liver diseases deserves further exploration and utilization it is also need to pay special attention to several active compounds isolated from the most frequently used Tibetan herbs and ellagic acid may be good and promising drug candidates for treating liver diseases because of their exact hepatoprotective effect as well as high concentration levels in the corresponding species In order to assess the potential of these compounds for druggability multidisciplinary approaches should be integrated to perform more pharmacological studies and also to assess their potential toxicity Rigorous in vivo experiments and even clinical studies involving different mechanisms are still needed to confirm their effectiveness in the treatment of liver diseases this study provides the first compilation of data for the ethnomedicinal knowledge of TTM in the treatment of liver diseases The medicinal species with high frequency of use may signpost the probable existence of valuable active compounds In order to better develop and utilize these traditional Tibetan medicines more efforts should be made to evaluate their biological activities in vivo and clarify their side effects or toxicity by using pharmacological and analyzed the data; C-LH: wrote the Tibetan names of natural medicines; GF: conceived and designed the study; and YZ: amended the paper The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest The authors gratefully acknowledge the financial support from Key Project of Sichuan Provincial Department of Education (no Science Development Fund of Chengdu University of Traditional Chinese Medicine (no Cultivation Program of Outstanding Young Academic and Technological Leaders of Sichuan Province (no and Major Project of National Social Science Foundation of China (no The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fphar.2018.00029/full#supplementary-material Prevalence and risk factors of alcoholic liver disease among Tibetan native adults in Lhasa CrossRef Full Text Hepatoprotective effects of the extract of Terminalia billerica (Gaertn.) 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in rats CrossRef Full Text Hydroxysafflor yellow A protects against chronic carbon tetrachloride-induced liver fibrosis and pharmacological aspects of Halenia elliptica: a comprehensive review In vitro anticancer screening of Tibetan medicines CrossRef Full Text In vitro and in vivo hepatoprotective and antioxidant activity of ethanolic extract from Meconopsis integrifolia (Maxim.) Franch Influence of bear bile on rat hepatocarcinoma induced by diethylnitrosamine Anti-hepatitis B virus active constituents from Swertia chirayita Towards a better understanding of medicinal uses of Carthamus tinctorius L in traditional Chinese medicine: a phytochemical and pharmacological review Comparison of protective effects of two kinds of lagotises against mice liver injury induced by carbon tetrachloride CrossRef Full Text Diagnosis and treatment of hepatic echinococcosis in Tibet CrossRef Full Text Fan G and Zhang Y (2018) Natural Medicines Used in the Traditional Tibetan Medical System for the Treatment of Liver Diseases Received: 08 August 2017; Accepted: 10 January 2018; Published: 30 January 2018 Copyright © 2018 Li, Li, Xu, Du, Huan Gang, Fan and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited *Correspondence: Gang Fan, ZmFuZ2FuZzExMTFAMTYzLmNvbQ== Metrics details Heme serves as a prosthetic group in hemoproteins including subunits of the mammalian mitochondrial electron transfer chain The first enzyme in vertebrate heme biosynthesis is ubiquitously expressed and essential for producing 5-aminolevulinic acid (ALA) We previously showed that Alas1 heterozygous mice at 20–35 weeks (aged-A1+/−s) manifested impaired glucose metabolism mitochondrial malformation in skeletal muscle potentially linked to autophagy dysfunction we investigated autophagy in A1+/−s and a sarcopenic phenotype in A1+/−s at 75–95 weeks (senile-A1+/−s) Senile-A1+/−s exhibited significantly reduced body and gastrocnemius muscle weight indicating an accelerated sarcopenic phenotype Decreases in total LC3 and LC3-II protein and Map1lc3a mRNA levels were observed in aged-A1+/−s under fasting conditions and in Alas1 knockdown myocyte-differentiated C2C12 cells (A1KD-C2C12s) cultured in high- or low-glucose medium ALA treatment largely reversed these declines Reduced AMP-activated protein kinase (AMPK) signaling was associated with decreased autophagy in aged-A1+/−s and A1KD-C2C12s AMPK modulation using AICAR (activator) and dorsomorphin (inhibitor) affected LC3 protein levels in an AMPK-dependent manner Our findings suggest that heme deficiency contributes to accelerated sarcopenia-like defects and reduced autophagy in skeletal muscle indicating that age-dependent mitochondrial dysfunction could be attributed partially to age-dependent heme deficiency in SM These facts prompted us to investigate autophagy in SM of aged-A1+/−s suffering from insulin resistance We also analyzed autophagic activity in SM of aged-A1+/−s The reduced autophagic activity might be attributed to the AMP-activated kinase (AMPK) signaling reduction in SM of aged-A1+/−s Senile Alas1+/− mice exhibit a decline in body weight (a) Body weight of wild-type (WTs) and Alas1+/− mice (A1+/−s) at 45–60 weeks (WTs: n = 16 A1+/−s: n = 21) and at 75–90 weeks of age (n = 9 per group) (b–e) Gastrocnemius muscle weight (b) and gastrocnemius muscle weight standardized by tibia length (c) and triceps brachii muscle weight (d) and triceps brachii muscle weight standardized by humeral length (e) in senile mice (75–90 weeks; n = 4 per group) (f) Holding impulse (HI) (body weight [g] x hanging time [sec]) from the hanging wire test assessing muscle strength) at 15 and 26–34 weeks (n = 6 per group) and at 75–90 weeks (WT: n = 9; A1+/−s: n = 8) of age (g) Grip strength (grams) at 15 weeks (WT: n = 20; A1+/−s: n = 16) at 30–35 weeks (WT: n = 15; A1+/−s: n = 13) and A1+/−s represents Alas1 heterozygous mice Results are means ± standard error of the mean * p < 0.05 indicates a significant difference between groups Since autophagic activities under normally fed conditions are generally lower, we examined them under fed and fasting conditions. Alas1 mRNA levels in SM of aged-A1+/−s were confirmed to be significantly lower than aged-WTs under fasting conditions like under fed conditions, while were not significantly augmented by fasting, unlike in aged-WTs (Fig. 2a). and LC3 protein levels in skeletal muscle of aged Alas1+/− mice under the fed and fasting conditions (a,b) Levels of Alas1 mRNA (a) and map1lc3a mRNA (b) in skeletal muscle of aged mice (20–35 weeks old; n = 6 per group) (c,d) Total LC3 protein and LC3-II protein levels under fed (c) and fasting (d) conditions ALA-administered A1+/−s (ALA-adm-A1+/−s): n = 3) (e) Total LC3 protein and LC3-II protein in skeletal muscle of young mice (10 weeks old; WTs n = 6; A1+/−s n = 5) under the fasting conditions ALA-adm-A1+/−s represents A1+/−s orally administered with ALA The data presented are representative of results obtained from multiple independent experiments each performed with biological replicates and technical replicates. Results are means ± standard error of the mean.* p < 0.05 ** p < 0.01 indicate significant differences between groups No significant differences were observed in the ratios of LC3-I to LC3-II among aged-WTs as well as in the C2C12 cell experiments below (data not shown) Decreased autophagic activity in Alas1-knockdown and heme-deficient C2C12 myocytes (a,b) Total LC-3 protein and LC3-II protein levels in C2C12 myocytes cultured in high-glucose medium without (a) or with (b) chloroquine (CQ) (control C2C12 myocytes: CT n = 4; Alas1-knockdown C2C12 myocytes: A1KD (c,d) Levels in myocytes cultured in low-glucose medium without (c) or with CQ (d) (n = 4 for each condition) (e) Levels in CQ-treated myocytes cultured in low-glucose medium with or without succinylacetone (SA) a heme biosynthesis inhibitor (n = 6 for each condition) and A1KD represents Alas1-knockdown C2C12 myocytes A1KD + ALA represents Alas1-knockdown C2C12 myocytes treated with ALA The presented data are representative of results obtained from multiple independent experiments each performed with biological replicates and technical replicates These data suggest that a deficiency of heme rather than ALA can decrease autophagic activity in SM and myocytes Proteins Expression in autophagy regulatory pathways in skeletal muscle of aged Alas1+/− mice under fasting conditions (a) Levels of Thr172-phosphorylated AMPKα (p-AMPKα) and total p70S6K in skeletal muscle of aged mice (20–35 weeks; WT: n = 5 (b) Levels of Ser51-phosphorylatd eIF2α (p-eIF2α) ALA-adm-A1+/−s: n = 4) with quantifications below (d) p62 and Nrf2 protein levels (WT: n = 5 (e) p-AMPKα and total AMPKα levels in young mice (10–15 weeks; WT: n = 5 indicating that heme deficiency-related autophagy decrease in SM is not associated with Nrf2 modulation Expression of AMPKα and eIF2α in C2C12 myocytes cultured in low glucose medium Levels of Thr172-phosphorylated AMPKα (p-AMPKα) and ALA-treated Alas1 knockdown C2C12 (A1KD + ALA) myocytes (CT indicating that ALA treatment effectively enhances the phosphorylation of these proteins In young-A1+/−s, there were reductions in the mean protein levels of p-AMPKα and the mean p-AMPKα/AMPKα ratio in SM, although these reductions were not significant (Fig. 4e) These results suggest that decreased autophagic activities in heme-deficient SM and myocytes under fasting/low-glucose conditions are associated with decreases in AMPK activation and/or eIF2α phosphorylation we compared these pathways in SM of A1+/−s between under fed and fasting conditions AMPK and eIF2α signaling under fed and fasting conditions in aged Alas1+/− mice Protein levels of Thr172-phosphorylated AMPKα (p-AMPKα) and total eIF2α in skeletal muscle of aged-WTs and A1+/−s (n = 3 for each condition) To evaluate the impact of AMPK and eIF2α signaling on autophagy in A1KD-C2C12s we analyzed the protein levels of LC3 in CQ-treated A1KD-C2C12s following treatment with AICAR sarubrinal (a phosphatase inhibitor that increases phosphorylated eIF2α) Impact of AMPK or eIF2α signaling modulation on autophagy in Alas1-knockdown C2C12 myocytes cultured in low-glucose medium (a,b) LC3-I/II protein levels in chloroquine (CQ)-treated control (CT) and Alas1-knockdown C2C12 (A1KD) myocytes under low-glucose conditions treated with ALA or salubrinal (an eIF2α dephosphorylation inhibitor) (a) suggesting that the senile wildtype controls sponteneously manifest sarcopnia-like defects These data indicate that ALA deficiency might accelerate defects similar to ‘sarcopenia’ characterized by an age-dependent decrease in muscle mass and strength suggesting that ALA administration at a pharmacological dose increases skeletal muscle mass We consider that the effect of ALA administration in A1+/−s is substantially similar to that in wild-type controls our focus was on the muscle weight of A1 ± mice as the effect of heme deficiency on skeletal muscle weight had not been previously investigated These results indicate that heme deficiency is primarily responsible for the suppression of autophagic processes in SM and myocytes it is plausible that age-related heme deficiency may significantly contribute to the development of sarcopenia-like defects the administration of ALA could represent a viable pharmacological strategy to mitigate the progression of sarcopenia-like defects this mechanism is unlikely to play a significant role in the reduced autophagy observed in SM under heme-depleted conditions given the scant expression of GATA-1 in SM These results suggest that heme deficiency is not necessary for decreased autophagic activity they indicate that heme depletion may reduce AMPK signaling could be a candidate for mediating these eIF2α signaling perturbations and one of the mechanisms through which ALA may exert its therapeutic effect could be by enhancing autophagy via increased heme levels in SM our analysis of Alas1 knockout heterozygous mice and Alas1 knockdown C2C12 myocytes revealed that heme deficiency accelerates sarcopenia-like defects and reduces autophagy within skeletal muscle We identified a decrease in AMPK signaling as the primary cause of this autophagic dysfunction our findings suggest that 5-aminolevulinic acid (ALA) may enhance autophagy by improving AMPK signaling ALA administration could potentially be a viable treatment approach for mitigating age-related changes such as sarcopenia was placed on the exposed section of the cage lid and elevated vertically by grasping the tail The negative force generated by the animal as it resisted removal from the grip platform (the cage lid) was measured three consecutive measurements were recorded per mouse For autophagy induction under low-glucose conditions C2C12 cells were initially cultured in high-glucose DMEM with 2% horse serum for three days followed by culturing in low-glucose (500 mg/L) DMEM with 2% horse serum for an additional day Chloroquine diphosphate (Tokyo Chemical Industry) and salubrinal (Cayman Chemical) were treated for one day on the final day of myocyte differentiation induction The final concentration of each drug was 50 μM for CQ When equal variances were assumed in the F-test Welch’s t-test was employed for analysis except data on hanging wire tests and grip strength tests For data on hanging wire tests and grip strength tests one-way ANOVA with Bonferroni post hoc test was used to evaluate differences in age between subjects from different clusters EZR was used for the statistical analysis of this study All data supporting the findings of this study are available within the paper and assembly of heme centers in mitochondrial respiratory complexes Wearing red for signaling: the heme-bach axis in heme metabolism oxidative stress response and iron immunology Heme as a differentiation-regulatory transcriptional cofactor Higashikawa, F., Noda, M., Awaya, T., Tanaka, T. & Sugiyama, M. 5-Aminolevulinic acid, a precursor of heme, reduces both fasting and postprandial glucose levels in mildly hyperglycemic subjects. Nutritionhttps://doi.org/10.1016/j.nut.2013.02.008 (2013) Structure and expression of the gene encoding rat nonspecific form δ-aminolevulinate synthase expression and regulation of the nonspecific form of the 5-aminolevulinate synthase gene in mouse Heme deficiency in erythroid lineage causes differentiation arrest and cytoplasmic iron overload Transgenic rescue of erythroid 5-aminolevulinate synthase-deficient mice results in the formation of ring sideroblasts and siderocytes Animal models for X-linked sideroblastic anemia 5-aminolevulinic acid (ALA) deficiency causes impaired glucose tolerance and insulin resistance coincident with an attenuation of mitochondrial function in aged mice Heterozygous disruption of ALAS1 in mice causes an accelerated age-dependent reduction in free heme Autophagy: Renovation of cells and tissues Autophagy is required to maintain muscle mass Sayer, A. A. & Cruz-Jentoft, A. Sarcopenia definition, diagnosis and treatment: consensus is growing. Age Ageinghttps://doi.org/10.1093/ageing/afac220 (2022) Autophagy as a Potential Target for Sarcopenia Lifelong Ulk1-mediated autophagy deficiency in muscle induces mitochondrial dysfunction and contractile weakness AMPK: A key regulator of energy stress and calcium-induced autophagy AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1 Transcriptional up-regulation of ULK1 by ATF4 contributes to cancer cell survival Phosphorylation of p62 activates the Keap1-Nrf2 pathway during selective autophagy Role of autophagy in diabetes and mitochondria Mfn2 deficiency links age-related sarcopenia and impaired autophagy to activation of an adaptive mitophagy pathway The 5,7-dimethoxyflavone suppresses sarcopenia by regulating protein turnover and mitochondria biogenesis-related pathways Mouse models of sarcopenia: Classification and evaluation The decline in skeletal muscle mass with aging is mainly attributed to a reduction in type II muscle fiber size Histochemical characteristics of soleus muscle in angiotensin-converting enzyme gene knockout mice is localized in autophagosome membranes after processing Treatment of sarcopenia and glucose intolerance through mitochondrial activation by 5-aminolevulinic acid Heme-dependent induction of mitophagy program during differentiation of murine erythroid cells PGC-1α promotes exercise-induced autophagy in mouse skeletal muscle GCN2 upregulates autophagy in response to short-term deprivation of a single essential amino acid Skeletal muscle autophagy and its role in sarcopenia and organismal aging Tamura, Y. et al. Efficacy and safety of 5-aminolevulinic acid combined with iron on skeletal muscle mass index and physical performance of patients with sarcopenia: A multicenter, double-blinded, randomized-controlled Trial (ALADDIN Study). Nutrientshttps://doi.org/10.3390/nu15132866 (2023) size and proportion of different fiber types studied in whole vastus lateralis muscle from 15- to 83-year-old men Striking differences between the kinetics of regulation of respiration by ADP in slow-twitch and fast-twitch muscles in vivo Alpha1-syntrophin-deficient skeletal muscle exhibits hypertrophy and aberrant formation of neuromuscular junctions during regeneration Myostatin inhibition in combination with antisense oligonucleotide therapy improves outcomes in spinal muscular atrophy A hacked kitchen scale-based system for quantification of grip strength in rodents Download references This study was supported by JSPS KAKENHI (Grant-in-Aid for Scientific Research(C)) Grant Number 18K06949 to O.N and was a cooperative research effort with SBI Pharmaceuticals and KIYAN PHARM who provided financial support for the work Major of Innovative Medical Science Research Yamagata University School of Medicine/Research Center for Molecular Genetics Institute for Promotion of Medical Science Research Study concept and design: O.N.; Investigation: T.A Download citation DOI: https://doi.org/10.1038/s41598-024-73049-9 Your browser does not support JavaScript, or it is disabled．Please check the site policy for more information a new film called “Familia” is casting a spotlight on the tough circumstances Japanese-Brazilians find themselves in while living in Japan While the title means “family” in Portuguese “Familia” is a story that asks whether people from different countries with different mother tongues can comprise a family Cast with the Japanese actors are Japanese-Brazilians with no prior acting experience whose experiences inform and elevate the storytelling The story follows the interactions of the protagonist a young Japanese-Brazilian man who loses his father to suicide after his family comes to Japan the harsh conditions faced by Brazilians begin to surface on screen when we can be neither Japanese nor Brazilian?” said he can identify with what his character feels Sagae was born in Japan but has Brazilian nationality Even though he has never been to the South American country he was bullied at school for being different He cried and asked his parents why he had to suffer like this Other cast members shared similar experiences came to Japan from Brazil when she was 9 and lives in Tokyo who lives in Shizuoka Prefecture and portrays Marcos’ childhood friend recalls how he had always been discriminated against Producer Tomoo Ito said it was director Izuru Narushima's intention to cast amateur actors who are Japanese-Brazilian to bring the film closer to reality The number of Japanese-Brazilians coming to Japan and settling in the country increased following changes to the Immigration Control and Refugee Recognition Law in 1990 which allowed foreigners of Japanese descent to work in the country But schools were not prepared to receive the children failing to provide Japanese language education programs Many children ended up skipping school or turning to delinquency And after Lehman Brothers went bankrupt in 2008 and a worldwide economic downturn ensued many Japanese-Brazilians lost their jobs and were forced into poverty according to the Immigration Services Agency The production team held auditions at nine locations where many Japanese-Brazilians live Toyohashi in Aichi Prefecture and Oizumi in Gunma Prefecture Filming was done at the Homi public housing estate in Toyota Production members interviewed them about their experiences and many appeared as extras “Because they know the actual conditions of Brazilians living in Japan I think their feelings seep through the screen,” the director said Although “Familia” shows its subjects struggling with poverty the cast members said they are happy that the film sheds light on what their lives are actually like “I felt like I joined the production on behalf of Brazilians,” said Sagae “The movie shows how we really live and suffer,” Waked added Given the falling birthrate and aging population there is an increasing need for foreign workers in Japan meaning more support is needed to ensure mistakes from the past do not repeat themselves “(What is shown in the movie) could happen anywhere in Japan in the future,” said Kiyoe Ito a nonprofit organization that has been supporting Brazilians at the Homi housing estate from about 30 years ago It would be a big step forward (toward an inclusive society) if people who are not interested see the film.” “Familia” is currently showing nationwide and there are plans to show the film in Brazil as well EDITORIAL: Blockbuster anime’s message of hope to public tired of pandemic Japan as an alien land through lens of filmmaker with mixed roots Shiga area tries to keep school for Brazilians afloat during pandemic Film shows different side of 30-year war holdout Onoda Information on the latest cherry blossom conditions Please right click to use your browser’s translation function.) A series based on diplomatic documents declassified by Japan’s Foreign Ministry Here is a collection of first-hand accounts by “hibakusha” atomic bomb survivors chefs and others involved in the field of food introduce their special recipes intertwined with their paths in life A series about Japanese-Americans and their memories of World War II In-house News and Messages No reproduction or republication without written permission By subscribing, you agree to our Terms of Use and Privacy Policy nanamica has released an inaugural collaboration with Batoner featuring a lineup of cold-weather essentials Combining functional and artisanal elements Batoner lent its premium knitwear approach to a line-up of core pieces in nanamica’s pared-back style Each of Batoner’s pieces is crafted in a Sagae City factory in the Yamagata prefecture a region famous for its knitwear manufacturing it has deeper roots with inspiration from Okuyama Meriyasu who established the original brand in 1951 Metrics details Capturing the dynamic processes of biomolecular systems in atomistic detail remains difficult despite recent experimental advances Although molecular dynamics (MD) techniques enable atomic-level observations simulations of “slow” biomolecular processes (with timescales longer than submilliseconds) are challenging because of current computer speed limitations we developed a method to accelerate MD simulations by high-frequency ultrasound perturbation The binding events between the protein CDK2 and its small-molecule inhibitors were nearly undetectable in 100-ns conventional MD but the method successfully accelerated their slow binding rates by up to 10–20 times Hypersound-accelerated MD simulations revealed a variety of microscopic kinetic features of the inhibitors on the protein surface such as the existence of different binding pathways to the active site the simulations allowed the estimation of the corresponding kinetic parameters and exploring other druggable pockets This method can thus provide deeper insight into the microscopic interactions controlling biomolecular processes which makes MSM approaches less than straightforward to use as a representative system in which the binding event would be nearly undetectable in standard MD The simulations showed a significant acceleration of the binding process under hypersound irradiation compared to standard MD simulations The hypersound-accelerated simulations revealed the existence of various conformationally and energetically diverse binding pathways suggesting that the assumption of a single pathway/transition state made in conventional kinetic models may be inaccurate The present method allowed not only the estimation of kinetic parameters of slow-binding inhibitors but also the full exploration of druggable sites This approach would thus be helpful for efficiently understanding the microscopic mechanism of slow biomolecular processes A (Top) Generation of hypersound shock waves in six directions (+X (Bottom) Each shock wave consisted of 5 cycles and involved 80 (=16 × 5 cycles) velocity pulses (indicated by vertical bars) applied every N MD time steps (see “Methods” for details) F Time dependence of E mass density and F the pressure measured at different X positions; the corresponding positions are shown in (B) and (C) Shock waves were generated in the X = 0–1 nm region [X0 surface in (A)] of the simulation box This analysis proved the effectiveness of the hypersound-perturbed simulations in enhancing the sampling of infrequent binding events; this approach can thus be applied to extract further atomic-level information on these processes B Representative binding pathways of A CS3 and B CS242 ligands to the ATP-binding pocket of CDK2 (Top) Projections of binding conformations observed in the whole set of MD trajectories (colored dots) and of a representative binding pathway (black line) onto the first and second principal components (PC1 and PC2) calculated from principal component analysis (PCA) Ten (CS3) and 7 (CS242) representative binding poses (magenta sticks) on CDK2 (gray surfaces) are shown alongside the crystallographic pose (green sticks) the closest conformation to which was assigned as Pose 1 (Bottom) Potential energy (black) and free energy (red) trajectories corresponding to the pathway shown in the PCA map The highest-energy transition state is indicated by a black (potential energy) or red (free energy) arrow The upper panel shows an enlarged view of these trajectories close to the highest-energy transition state Note that transition states occur A immediately before/after the ligand enters the CDK2 pocket and B during conformational rearrangements taking place after pocket entry C Schematic illustration of microscopic and macroscopic kinetic models The conventional kinetic model assumes a single binding pathway with a single transition state the ligand binds to the protein through multiple pathways with different highest-energy transition state conformations the native interactions in the CDK2 structure were stably maintained during a series of hypersound-perturbed simulations with different frequencies and amplitudes of shock waves confirming that the local high-energy regions do not induce thermal denaturation of CDK2 These results suggest that hypersound perturbation accelerates the protein-ligand association process by enhancing the cooperative local motions of the solvent molecules without affecting the native structure of the biomolecules highlighting the general applicability of this approach for the acceleration of molecular processes in solution which currently hampers the experimental assessment of its impact Further applications of the present technique to model other biomolecular (e.g. protein conformational changes and protein–protein interactions) and non-biomolecular (e.g. phase transitions of materials) processes are required to assess its general effectiveness in modeling slow dynamic events 50 ligands were randomly placed around the protein and away from the binding site (>17 Å) by translating the ligand in the bound crystal structure a total of 20,068 water molecules were included in an 8.5 × 8.5 × 8.5 nm3 cubic box hypersound-induced velocities are defined as each system was equilibrated as described in the following subsections A time step of 2 fs was used in all MD runs and kinetic energy of the system were analyzed using MD trajectories obtained with a Nose–Hoover thermostat with a time constant of 0.3 ps and calculated using the coordinates and velocities saved every 2 fs and kinetic energy in the hypersound-perturbed MD simulations of liquid water were estimated by focusing on wave propagation along the X direction The instantaneous temperature in this region was estimated to be 400–500 K based on the kx value of bulk water at 300 K (~0.3 kcal/mol The pressure of water in the +X direction of the cubic simulation box was estimated from the X components of the velocities of the water molecules that crossed the YZ plane at a given X during the observation time Δt according to the modified van der Waals equation for liquid systems \(\frac{2m}{S\varDelta t}{\sum }_{i}{v}_{{\rm{x}}}^{{\rm{i}}}\) was calculated to be 1.298 × 108 Pa based on the water molecules that crossed the YZ plane at X = 2 nm (corresponding to the mid-point between the origin and the center of the simulation box) during a Δt interval of 50 ps Using the saturated vapor pressure of water at 298 K (P = 0.032 × 105 Pa) the a parameter was estimated to be 0.423 (atm L2 mol−2) The pressure under hypersound irradiation was then determined from the hypersound-perturbed MD trajectory using the estimated value and the sum of the vx values of the water molecules that crossed the YZ plane at each selected X point during a Δt interval of 0.4 ps we analyzed the MD trajectories of the system containing the CDK2 protein and 50 ligand molecules Ligand binding within individual CDK2 sites (ATP pocket and allosteric site 2) was considered to occur if at least two distances between an atom belonging to the protein pocket (see below) and any ligand heavy atom were below 5 Å The following atoms of the protein pocket were used in the distance calculation: Val18 (beta carbon Advanced analysis of CS3 and CS242 binding to the ATP pocket is described in the following subsection we identified 67 (CS3) and 14 (CS242) MD trajectories that captured binding events In approximately half of these MD trajectories and the ligand separated from the ATP pocket within 1–40 ns the ligand remained stably bound to the protein until the end of the simulation; these trajectories were thus extended to 200 ns to further examine the behavior of the bound ligands indicating that some of these binding conformations are commonly observed in the 27 (CS3) and 14 (CS242) trajectories The association rate constant under hypersound irradiation (kon) and effective temperature under hypersound irradiation (T) were estimated as follows using the experimental kon values measured without any perturbation and the trajectories obtained from conventional and hypersound-perturbed MD simulations The kinetics of the binding between protein (P) and ligand (L) were analyzed according to the following reaction scheme: The second-order reaction rate is defined as where [P], [L], and [PL] are the concentrations of the protein, ligand, and protein–ligand complex, respectively. The initial binding rate is proportional to the initial concentrations of P and L ([P]0 and [L]0, respectively). If [P] ≈ [P]0 and [L] ≈ [L]0, the following relation can be derived by solving equation [2] the kon values were estimated to be 3.68 × 106 (CS3) and 1.92 × 106 M−1 s−1 (CS242) The kon constant can also be described using the Arrhenius equation To assess how enhancing the thermal motions of the solvent or ligand molecules affects the probability of observing the ligand-binding event we performed a conventional MD protocol in which the water or ligand diffusion coefficients were adjusted to the values observed in the hypersound-perturbed MD simulation because of the excessively increased diffusion coefficient of water molecules (11.6 ± 0.1 × 10−5 cm2/s at 375 K or 9.5 ± 0.1 × 10−5 cm2/s at 355 K) when the ligands and solvent were coupled separately to temperature baths at 375 K/355 K and 309 K the diffusion coefficients of the ligands remained 0.21 ± 0.09 × 10−5 cm2/s (CS3) and 0.22 ± 0.05 × 10−5 cm2/s (CS242) This is presumably because stably formed hydrogen bond networks in water near room temperature would hamper free diffusion of ligand molecules even if their kinetic energy is enhanced drastically increasing the thermal motions of solvent molecules (i.e. 375/355 K) appears to be required for significant enhancement of ligand diffusion demonstrating distinct effects from hypersound irradiation which induces a significant acceleration in ligand diffusion by moderately enhancing cooperative local motions of solvent molecules The specific binding sites of each of the ATP-competitive inhibitors (CS3 and CS242) and allosteric inhibitors (2AN and 9YZ) on the CDK2 surface were determined as follows the root-mean-square fluctuation of the ligand was calculated every 10 ns of the individual 100-ns hypersound-perturbed MD trajectories obtained with N = 50 steps a stable CDK2–ligand complex was considered to be formed during the 10-ns period and residues that interact with the ligand (<5 Å) were extracted from the mean coordinates of the protein and ligand the frequency of ligand interactions at each CDK2 residue (fint) was calculated across all stable complex structures and normalized by the number of MD trajectories after excluding residues that frequently interacted with all ligands (fint of more than 0.1) as nonspecific binding sites residues with higher fint values were identified as specific binding sites Further information on research design is available in the Nature Research Reporting Summary linked to this article The hypersound-perturbed MD code is available free of charge at https://github.com/clinfo/gromacs (https://doi.org/10.5281/zenodo.4646306) A secondary RET mutation in the activation loop conferring resistance to vandetanib How does a drug molecule find its target binding site Cloud computing approaches for prediction of ligand binding poses and pathways Protein-peptide association kinetics beyond the seconds timescale from atomistic simulations Complete protein-protein association kinetics in atomic detail revealed by molecular dynamics simulations and Markov modelling a special-purpose machine for molecular dynamics simulation An Introduction to Markov State Models and Their Application to Long Timescale Molecular Simulation Accurate estimation of protein folding and unfolding times: beyond Markov state models Structural change in lipid bilayers and water penetration induced by shock waves: molecular dynamics simulations Denaturation of hen egg white lysozyme in electromagnetic fields: a molecular dynamics study Sonic degradation of high polymers in solution Sonochemistry and sonocatalysis of iron carbonyls Nucleus factory on cavitation bubble for amyloid beta fibril CSAR benchmark exercise of 2010: selection of the protein-ligand complexes Modification of food systems by ultrasound Sonochemical nanosynthesis at the engineered interface of a cavitation microbubble Hydrodynamic radii of native and denatured proteins measured by pulse field gradient NMR techniques Accurate prediction of complex structure and affinity for a flexible protein receptor and its inhibitor Equilibrium fluctuations of a single folded protein reveal a multitude of potential cryptic allosteric sites Discovery of a potential allosteric ligand binding site in CDK2 High-throughput kinetic analysis for target-directed covalent ligand discovery Kinetics of protein-ligand unbinding: predicting pathways Protein-protein binding pathways and calculations of rate constants using fully-continuous ColDock: concentrated ligand docking with all-atom molecular dynamics simulation General atomic and molecular electronic structure system A well-behaved electrostatic potential based method using charge restraints for deriving atomic charges: the RESP model Development and testing of a general amber force field Improved side-chain torsion potentials for the Amber ff99SB protein force field Comparison of simple potential functions for simulating liquid water GROMACS 4: algorithms for highly efficient Particle mesh Ewald: an N⋅log(N) method for Ewald sums in large systems LINCS: A linear constraint solver for molecular simulations A molecular dynamics method for simulations in the canonical ensemble Canonical dynamics: equilibrium phase-space distributions Canonical sampling through velocity rescaling Molecular dynamics with coupling to an external bath Polymorphic transitions in single crystals: a new molecular dynamics method Extended K-means with an efficient estimation of the number of clusters Intelligent Data Engineering and Automated Learning—IDEAL 2000 Role of desolvation in thermodynamics and kinetics of ligand binding to a kinase Download references Fukuda for the critical reading of the paper This study was supported by the Ministry of Education Japan) projects “Priority Issue on Post-K Computer (Building Innovative Drug Discovery Infrastructure through Functional Control of Biomolecular Systems)” and “Program for Promoting Researches on the Supercomputer Fugaku (Application of Molecular Dynamics Simulation to Precision Medicine Using Big Data Integration System for Drug Discovery)” (to Y.O.) Foundation for Computational Science (FOCUS) Establishing Supercomputing Center of Excellence (to Y.O.) the K supercomputer-based drug discovery project by Biogrid pharma consortium (to Y.O.) and a Japan Society for the Promotion of Science (JSPS) KAKENHI Grant (Nos The simulations were carried out on the K computer and HPCI systems provided by the RIKEN and Tokyo Institute of Technology (TSUBAME) through the HPCI System Research Project (project IDs: hp140042 Mitsugu Araki, Yukari Sagae & Yasushi Okuno Shigeyuki Matsumoto & Yasushi Okuno Research and Development Group for In Silico Drug Discovery Center for Cluster Development and Coordination (CCD) Foundation for Biomedical Research and Innovation at Kobe (FBRI) Peer review information Nature Communications thanks the anonymous reviewer(s) for their contribution to the peer review of this work Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations Download citation DOI: https://doi.org/10.1038/s41467-021-23157-1 Journal of Computer-Aided Molecular Design (2022) Keywords:　Ecosystems / Biodiversity　Environmental Technology　Local government　 which runs east to west through Sagae before flowing into the Mogami River of being named the second dirtiest river in the prefecture making it an urgent issue to improve its water quality each measuring 1.8-meters long by 1.5-meters wide and planted with watercress and swamp morning-glory (Ipomoea aquatic) An aeration device was placed in the center of the river to directly aerate the water by pumping air through a one-meter tube to increase the level of dissolved oxygen Water quality will be regularly checked both upstream and downstream of the garden rafts to assess the effects of purification efforts The prefectural government hopes that the participation of citizens will increase public awareness of the water quality and environment of the river and it intends to hold hands-on activities and seminars on environmental conservation so that citizens and companies in Sagae can join in other green activities to protect the Numa River This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License National Report Upper House election campaigns came to a halt around Japan on July 8 as politicians from all sides prayed for the recovery of former Prime Minister Shinzo Abe Politicians denounced the shooting as an attack against democracy and many returned to Tokyo from the campaign trail to work out a response to the violence or lend a hand to Abe’s office on July 8 to help a rookie candidate of the ruling Liberal Democratic Party in the Yamagata prefectural district Kishida appeared in front of supporters and gave a 10-minute speech as planned Kishida was scheduled to travel to JR Koriyama Station in Fukushima Prefecture to deliver a stump speech from 2:30 p.m a prefectural assembly member of the LDP informed supporters about the last-minute cancellation “Former Prime Minister Abe was reportedly shot in Nara Prefecture and Prime Minister Kishida must return to his office,” the member said Kishida had flown by helicopter from Sagae to the prime minister’s office in Tokyo He said he would immediately summon all Cabinet members to discuss how the government should handle the situation including the Upper House election schedule canceled a scheduled trip to Okinawa Prefecture where he was expected to deliver a speech on behalf of local LDP candidates scrapped plans to give an endorsement speech for an LDP candidate on July 8 in Kurume Takaichi had received strong support from Abe when she ran for LDP president last year who held senior positions in the Abe administration rushed to Abe’s office in Tokyo’s Nagatacho district after the shooting and held a 10-minute meeting with Abe’s staff members “I told them that all Cabinet members have returned from the campaign trail so we can provide help to them if they need it,” Hagiuda told reporters a former LDP Upper House member who took a senior post in the Abe administration “Violence is an abominable act,” Arai told reporters He said he was with Abe in Osaka on the previous day “I didn’t expect this at all,” Arai said in a faltering voice Abe was scheduled to travel from Nara to Kyoto to deliver a stump speech at the busy Shijo-Kawaramachi crossing later on July 8 showed up at the location around 12:35 p.m in a campaign vehicle decorated with a banner featuring Abe’s name “I am praying for a miracle,” Nishida told the crowd “I sincerely hope (Abe) survives and recovers.” Senior members of the main opposition Constitutional Democratic Party of Japan also canceled their campaign activities on July 8 “We need to work across party lines and respond to the incident to prevent this kind of thing from happening again,” Kenta Izumi “To secure the safety of political activities I want to share such awareness with other parties and think about issuing a joint statement.” Even staunch critics of Abe strongly condemned the violence and prayed for the recovery of the former prime minister said in a video posted on her Twitter account that Abe was a victim of “an act of barbarism.” “The party and I are strictly against any and all violence,” she said Nippon Ishin (Japan Innovation Party) decided to suspend all campaign activities on July 8 Party leader Ichiro Matsui said he had talked with Abe over the phone before the campaign started but we have agreed on the idea of making Japan better,” Matsui said “Abe is someone that Japan needs for the future,” he said Matsui said Nippon Ishin will resume campaign activities on July 9 to show that “violence cannot stop democracy head of the Democratic Party for the People expressed anger over the shooting and sent wishes for Abe’s recovery Tamaki said the DPP will suspend outdoor speeches on July 8 for security reasons prayed for Abe’s recovery at a news conference “I am shocked by the news,” she said in tears I simply cannot tolerate this act of barbarism.” Business leaders were also shocked and saddened by the news chairman of Keizai Doyukai (Japan Association of Corporate Executives) said he learned about the shooting during a meeting in Karuizawa “An impermissible thing occurred while we were discussing the challenges facing Japan and its excellence,” Sakurada told reporters condemned the attack and praised Abe for bolstering the Japanese economy “I just hope he can continue to make Japan healthy and better,” Niinami said Kishida’s hopes for top LDP post hurt by gamble in Hiroshima Opposition rallies to upset LDP in Shizuoka by-election Vox Populi Vox Dei is a daily column that runs on Page 1 of The Asahi Shimbun and supermarket shelves are stacked with bags of freshly harvested rice from various regions marketed under brand names such as Shinnosuke Rice farmers in Hokkaido and the Tohoku region are said to be having a banner year where the yield per unit of area was reportedly the highest in the nation But the operator of a large-scale farm in the town of Takahata in southern Yamagata was unexpectedly glum our company is having the worst crisis since it was founded," said Toshihiro Yamaguchi The cause of his distress is that the novel coronavirus pandemic has brought down the price of rice by 10 to 20 percent The decline in rice consumption due to restaurant closures has left rice dealers with piles of surplus stock in their warehouses "The rice price has fallen for two years in a row and we just can't see the future," he went on "I'm afraid more rice farmers will be giving up." depopulation has progressed at an alarming rate in the last 10 years triggering mass retirements among older farmers Determined to protect his community from dilapidation Yamaguchi has taken over abandoned farmland and hired younger locals to groom into successors He also plans to remodel vacant homes in the days ahead and bring in out-of-towners to build a workforce The history of rice farming overlaps the history of Japan The grain also served as a currency and a financial index There were times when skyrocketing rice prices triggered popular uprisings in various parts of the nation domestic consumption of rice shrank to about half the peak level bread overtook rice for the first time in household spending The recent "carb control" dietary fad isn't helping I predict that consumers will continue to stick to this trend of eating less rice I tasted Yamaguchi's lovingly grown rice sold under the brand name Tsuyahime Savoring the exquisite sweetness unique to new rice I tried to imagine 100 years ahead and wondered what will have become of Japan traditionally a rice growing and eating nation sometimes referred to as "Mizuho no Kuni" (literally Vox Dei is a popular daily column that takes up a wide range of topics the column provides useful perspectives on and insights into contemporary Japan and its culture VOX POPULI: Pandemic worse than fallout from quake VOX POPULI: Message of hope in Fukushima rice named after school song VOX POPULI: Column has had the scoop on how Japan’s women feel for 70 years VOX POPULI: Taisho Era’s folksy poem still resonates with Nobel laureate VOX POPULI: Provincial areas felt left behind in Suga’s vaccine rollout program VOX POPULI: Autumn revives Japan’s ‘love affair’ with ‘hagi’ bush clover The 59th Japan Science Fiction Convention (Nihon SF Taikai) revealed the list of nominees for the 51st Seiun Awards on Thursday The nominees in the Japanese Novel category are: The story in the nominated Hello World novel is the original concept behind the Hello World anime film, and Nozaki wrote both the novel and the film's screenplay. (The film has a separate, later novelization by Shuka Matsuda.) Ogawa also received a nomination in the Japanese short story category for “Twin Star Cyclone Runaway." the venerable SF Magazine which has been running since 1959 and Monthly Model Graphix magazine's July 2019 cover feature "Studio Nue no SF Design-Ron" (Studio Nue's Science-Fiction Designs: An Analysis Locus magazine posted the nominees in the Best Translated Novel The awards this year are again separated into nine categories: Japanese Novel, Japanese Short Story, Translated Novel, Translated Short Story, Media, Comic The nominees were chosen among works that were released between January 1 and December 31 The attendees of "F-CON" in Fukushima, the 59th Japan Science Fiction Convention, will vote on the winners. The staff will announce the winners at the convention, which takes place from March 13-14, 2021. The event was originally scheduled to take place on August 22-23, but the organizers delayed the event until next year due to the new coronavirus disease (COVID-19) "Seiun Shō" literally translates to "nebula awards," but the Japan SF Con's Seiun Awards are more akin to the Hugo Awards in that the attendees of each respective convention vote on the winners the Science Fiction and Fantasy Writers of Japan's Nihon SF Taishō honors that are the rough Japanese equivalent of the Science Fiction and Fantasy Writers of America's Nebula Awards the Seiun Awards honor all forms of speculative fiction — including but not limited to science fiction — and related materials Last year, the SSSS.GRIDMAN anime won the Media category, and Tsukumizu's Girls' Last Tour manga won the Comic category Sources: Japan Science Fiction Convention, Animation Business Journal (Tadashi Sudo) a student at the main campus of the Murayama School for Special Needs Education a member of 〈Watashi no Kaisha〉 run by the social welfare corporation Honobonokai in Toriigaoka ‘Kizashi and Manazashi’ is an open call exhibition that has been held in Yamagata since 2019 It focuses on the “expressions” (kizashi) of people with disabilities and the “gaze” (manazashi) that follows them TAKEDA Kazue is one of the people working behind the scenes on the exhibition She visits welfare facilities and individuals all over Japan to ask about expressive activities that are currently taking place there was a person who would take equipment outside and line it up in the parking lot on a near-daily basis from the perspective of those who wanted to use the equipment continued to take photographs and document it from their own honest point of view: “Why are they doing this?” They saw in this person’s collection of “mischievous” activities an expression of the person’s will “Actions seen as problematic behavior could This is why the ‘Kizashi and Manazashi’ exhibition introduces the ‘expressions’ (kizashi) that emerge from such relationships,” says Takeda a facility operated by the social welfare corporation Honobonokai It is located in the residential area of Toriigaoka Attached to the building was a café and bakery operated by the facility When we peeked into the bakery from the outside the workers were getting ready for their day “They choose good ingredients and make really tasty bread users who engage in creative activities such as handweaving and drawing were also getting ready to begin work We found ENDO Aya slowly stacking papers and notebooks on the table we saw that each sheet of paper was covered in rows of colorful letters Staff member KADOONO Rina explains: “Aya has been writing things like the lyrics to her favorite songs and the names of anime characters for years she always takes them all home.” Next to the sheets of paper she had stacked CD lyric booklets in the same manner Her family bought them for her as a reward for her hard work “All of these things are packed with Aya’s ‘love.’ I think they serve as good luck charms for her,” says Kadoono Tidying her space in this manner has become Aya’s pre-work routine Aya doesn’t write letters like these at work Aya holds a piece of cloth close to her face and quietly moves a needle up and down “The bright colors and detailed touch of Aya’s embroidery remind me of the letters she writes.” When she first started embroidery she created single lines of thread that lay flat creating pieces with a flavor that is uniquely hers Sometimes Kadoono will suggest a new material and ask “Want to try it?” Although Aya furrows her brow and seems reluctant initially she soon develops her own style of expression in the new medium I would freeze and think of reasons not to try it such as ‘Why did you choose this motif?’ But Aya’s love and desire to try new things spring up as creative energy and I always look forward to seeing what she will create,” Kadoono says with a straight gaze Follow us on social media for notifications about The Nippon Foundation DIVERSITY IN THE ARTS events The December issue of Shogakukan's Monthly Flowers magazine published the final chapter of Yumi Tamura's 7SEEDS spinoff manga on Saturday The spinoff manga will be compiled into book form and published in early 2018 The magazine also revealed that Tamura will launch a new manga titled Mystery to Iu Nakare (pictured at right) in the next issue on November 28 and the 100-page first chapter will feature a color spread Tamura published a one shot manga last year with the same title Shogakukan's Zōkan Flowers will republish the 78-page one shot in its winter issue on November 14 to commemorate the new Mystery to Iu Nakare series The original one shot revolved around two detectives who come across the mystery of a university student named Totonō Kunō The student is suspected of murdering his classmate Sagae after Sagae's body was discovered in a neighborhood park Tamura ended the original 7SEEDS manga in the magazine's July issue and launched the spinoff manga in the October issue on August 26 who suddenly wakes up one day to find herself in the middle of the ocean and none of them remember how they got into their current situation where a "guide" explains to them that they are part of a government project to cryogenically preserve groups of people to ensure humanity's survival after scientists predicted the destruction of the world Natsu's group finds that they are in Japan after a catastrophe and must learn how to survive in their new post-apocalyptic reality The original manga's 35th and final volume shipped on August 10 A limited edition of the 35th volume included a drama CD Tamura launched the series in 2001 in Bessatsu Shōjo Comic magazine, before eventually moving it to Monthly Flowers. The manga won the Shōjo Category of the 52nd Annual Shogakukan Manga Awards in 2007 <The manga has about 4.9 million copies in print.>Shogakukan published a fanbook for the manga Tamura's 27-volume Basara manga ran in Bessatsu Shōjo Comic from 1990-1998. Viz Media published the manga in English in 2003-2008. The manga inspired the 13-episode Legend of Basara television anime series in 1998 Viz Media also published Tamura's two-volume Chicago manga in 2002-2003, and her one-volume Wild Com manga in 2004 Tamura's Tomoe ga Yuku! manga inspired an OVA series in 1991-1992 which was originally published in Japanese language on 4 Mar a member of 〈Sakuranbo Kyouseien〉 in Sagae City appeared in the distance as we drove along the national highway We passed golden rice paddies dancing with dragonflies and orchards growing apples we arrived at the main campus of the Murayama School for Special Needs Education The school building was surrounded by trees and was illuminated by soothing natural daylight Students’ cheerful voices echoed through the hallways and classrooms NAGAHAMA Tetsuya (who goes by “Tecchin”) is a senior in high school here He spends every lunch break drawing in the classroom “He draws things up so fast—dozens of pictures every day without fail,” says his mother who works as a teacher at a nursery school She showed us some of the works he had created so far The tote bags and paper bags filled with bundles of drawings that she handed to us were incredibly heavy “I think Tecchin’s drawings make use of techniques he developed himself.” I recalled Takeda’s words before the interview: Tetsuya is autistic and is not very good at speaking he was unable to express his emotions and often threw tantrums or cried in panic he learned to communicate what was on his mind by showing people pictures and words on a magnetic drawing board such as “I want to eat chocolate ice cream.” Then after participating in an open call exhibition when he entered junior high school he began to express his feelings and desires “I was worried that he might not be interested in other people since he had been playing by himself for so long I realized how rich and expansive Tecchin’s world is,” says Naoko there is a drawing he made of many people and animals smiling and waving their hands I could tell that he was happy to see all the daycare members and staff waving goodbye to him as he rode home from the after-school daycare program He doesn’t show what he’s feeling outwardly Drawing has now become Tetsuya’s means of everyday communication Shiho has long been an observer of Tetsuya’s quest for self-expression and ingenuity in the way he lives his life I became acutely aware of how we can compensate for our weaknesses in order to create a more livable society,” Shiho says How can we empathize with the minds of other people which she developed naturally while growing up with Tetsuya is also useful in her own work with children Please view the main text area of the page by skipping the main menu. The page may not be displayed properly if the JavaScript is deactivated on your browser Japanese version an inclusive sport climbing facility which includes people with disabilities among its staff please disable the ad blocking feature and reload the page This website uses cookies to collect information about your visit for purposes such as showing you personalized ads and content By clicking “Accept all,” you will allow the use of these cookies Users accessing this site from EEA countries and UK are unable to view this site without your consent it is one of the largest indoor climbing facilities in the country The facility includes a variety of areas for people of all skill levels to enjoy The facility was opened after the head of the operating company and others were deeply moved while watching a sport climbing competition by blind athletes As a type A facility providing continuous support for employment services for people with disabilities Nobaria employs people with mental disorders intellectual disabilities and other conditions The Los Angeles 2028 Paralympic Games will include sport climbing among its events to come here and feel the joy of sport climbing.” Our weekly ePaper presents the most noteworthy recent topics in an exciting © 2025 The Japan News - by The Yomiuri Shimbun