Metrics details Extensive studies indicate that mitochondria dysfunction is pivotal for Alzheimer’s disease (AD) pathogenesis; while cumulative evidence suggests that increased mitochondrial stress response (MSR) may mitigate neurodegeneration in AD explorations to develop a MSR-targeted therapeutic strategy against AD are scarce and pharmacological approaches to unravel a novel molecular pathway by which NAD+-boosting agent nicotinamide mononucleotide (NMN) regulates MSR in AD models we report dyshomeostasis plasma UPRmt-mitophagy-mediated MSR profiles in AD patient samples NMN restores NAD+ metabolic profiles and improves MSR through the ATF4-dependent UPRmt pathway in AD-related cross-species models NAD+ repletion with NMN supplementation ameliorates mitochondrial proteotoxicity omics features of the hippocampus with NMN show that NMN leads to transcriptional changes of genes and proteins involved in MSR characteristics principally within the astrocyte unit rather than microglia and oligodendrocytes our work provides evidence that MSR has an active role in the pathogenesis of AD as reducing mitochondrial homeostasis via atf4 depletion in AD mice aggravates the hallmarks of the disease; conversely bolstering mitochondrial proteostasis by NMN decreases protein aggregation ultimately translating to increased healthspan it is still unclear whether mitochondrial impairments are prime culprit disease drivers and whether boosting mitochondrial biogenesis provides neuroprotection in AD little is known about NAD+ metabolism and the levels of MSR in AD patients’ blood we propose that defective MSR induces the accumulation of damaged mitochondria and improving mitochondrial homeostasis from the nucleus to the mitochondria through UPRmt-mitophagy pathways by pharmacologically NAD+-booster is an effective therapeutic strategy Given the persistent failures in anti-AD drug discovery approaches focusing on the broader aspects of the AD pathology profile a Schematic of plasma MSR indicators examination for every individual enrolled in the study The recruitment eligibility assessment led to the inclusion of 43 AD and 46 HC subjects b The distribution of MSR blood biomarker levels across AD and HC individuals is illustrated by the mountain map d Receiver operating characteristic (ROC) analysis was performed to assess the ability of plasma UPRmt and mitophagy proteins to distinguish between AD and HC and the area under the curve (AUC) value is presented e A multivariate correlation scatter matrix graph was used to examine the relationships among the MSR blood biomarkers in both Alzheimer’s disease (AD) and healthy control (HC) participants f–k Schematic illustration presents the estimated proportion of the association between plasma UPRmt levels and AD risk that is mediated by mitophagy blood biomarkers NMN restores Aβ expression in N2a APPswe cells and inhibits tau hyperphosphorylation in HEK293 cells Tau P301L after supplementing with either VEH or 500 μm NMN for 24 h a Cell viability results of N2a mouse neuroblastoma cells and overexpressing Swedish K595N and M596L mutations cells depicting a dose-dependent NMN effect Data were analyzed by one-way ANOVA followed by Sidak’s multiple comparisons test b Representative confocal images showing the APP level of the NMN-treated N2s cells Data were analyzed by a two-sided unpaired t-test and corresponding quantification of APP and its indicated protein expressions indicating NMN effects Data were analyzed by two-sided one-way ANOVA followed by Tukey’s multiple comparisons test m Representative 3D reconstruction images and corresponding quantification of colocalization of Tau5 n–r Effects of NMN on the expression levels of different p-Tau sites (Thr181 s The total Tau level change between NMN-treated and non-treated group At least three experiments were repeated independently with similar results Full scans of all the blots are in the Supplementary Data All experiments were performed independently with at least three biological replicates a–j Levels of UPRmt-related chaperone and protease proteins in N2a APPswe cells (n = 6 per group) k Confocal images of HEK293 Tau P301L cells double immunostained with ATF4 (green) and mitochondria outer membrane protein TOM20 (red) antibody l–n 3D reconstruction images of HEK293 Tau P301L cells double immunostained with CHOP (green) and CYC (red) antibodies o Relative levels of proteins implicated in the mitophagy pathway p Quantification of the colocalization of the mitochondrial protein CYC and the autophagy protein LC3 in HEK293 Tau P301L cells after treatment with NMN Immunoblot data were analyzed by two-sided one-way ANOVA followed by Tukey’s multiple comparisons test while the PCC were analyzed by two-sided unpaired t-test q UPRmt transcript levels in N2a neuroblastoma cell line All these data manifested boosting NAD+ levels with NMN appeared to improve MSR through the upregulation and/or activation of UPRmt and mitophagy pathways in AD cell models representing an epistatic link between NAD+-UPRmt signaling and mitochondrial homeostasis in vitro a A workflow diagram of NMN (500 mg/kg intraperitoneal injection) treatment began at 3.5-month-old mice for 2 months b–g The behavioral test results of 6-month-old mice b The representative swimming tracks of mice from a probe trial day (n = 16 mice in WT (VEH) time in the target quadrant in the probe trial; center platform frequency of mice passed through the platform in the probe trial at day 7; right latency to escape to a hidden platform in the MWM during a 6-day training period Data were analyzed by two-way ANOVA followed by Tukey’s multiple comparisons test and contextual and cued fear conditioning (g) tests were performed i The behavioral tests analysis as in (b–g) in 12-month-old mice (n = 13 mice in WT (VEH) New object recognition (i) and open Field test (h) tests were performed j–l The results of MWM in each group in 12-month-old mice Data were analyzed by one-way ANOVA followed by Tukey’s multiple comparisons test for (h–k) m Effects of NMN on the expression levels of APP and its indicated metabolites and Aβ were detected with 6E10 antibody (n = 6 mice per group; one-way ANOVA) n Confocal images of 4G8+ GFAP+ double-positive cells from hippocampi of 6-month-old WT Insets were enlarged from hippocampal areas The experiments were repeated from three independent experiments with the results shown as mean ± s.e.m o Soluble and insoluble Aβ1–40 and Aβ1–42 levels in hippocampal tissues (n = 9 mice; two-sided unpaired t-test) were also decreased in the NMN-treated AD mice compared with vehicle-treated These findings in transgenic mouse models of AD suggest a robust neuroprotective role of NMN against AD pathologies and cognitive deficits c Effects of NMN on the expression level of proteins involved in UPRmt and mitophagy in the 5xFAD mice hippocampi of individuals with and without NMN (n = 3 biologically independent samples; two-sided unpaired t-test) d Corresponding quantification of western blot data of (a f Representative immunostained images (e) and quantification (f) of ATF4 in the hippocampi of AD (VEH) and AD (NMN) tissues (n = 3 mice; two-sided unpaired t-test) g The mRNA expression measurement of MSR signature after supplementing with NMN in 5xFAD mice (n = 3; two-way ANOVA) h Synaptic proteins from the 6-month hippocampi were analyzed by Western blotting (n = 3 mice in each group) i–k we obtained T2-weighted anatomical images to analyze the structure difference in the ventricle system using a 9.4 Tesla magnetic resonance imaging (MRI) scanner Data were pooled from at least 3 biological replicates l Mito-nuclear protein imbalance evaluated by the ratio of mitochondrial DNA (mtDNA)-encoded protein (MTCO1) and nuclear DNA (nDNA)-encoded protein (ATP5a) in three groups (n = 3 mice; one-way ANOVA) n Representative immunostaining and quantification of the MitoSOX in the cultured primary astrocytes (n = 6 mice; two-sided unpaired t-test) p Representative electron microscopic images showing the effects of NMN on mitochondrial morphology in mouse hippocampal brain tissues The quantification was obtained in two independent experiments performed in duplicates in at least 20 ROIs q ATP Assay was performed in 6-month-old AD mice brain (n = 5 mice All experiments were performed independently with at least three biological replicates with similar results indicating NMN inhibits the collapse of the mitochondria and maintains mitochondrial fitness a Schematic of NMN injection and behavioral analysis in AAV-atf4 Knowdown mice b–d The behavioral tests analysis of 6-month-old AAV-atf4 Knowdown mice Data were analyzed by one-way ANOVA followed by Tukey’s multiple comparisons test for (b while two-way ANOVA was utilized to assess memory in the MWM test (d e Representative immunostained images and quantification of the diameter and number of both 4G8+ (red) and thioflavin S+ (ThS+ green) in the hippocampi of AAV-free AD (NMN) and AAV-atf4 AD (NMN) mice 10 μm (n = 7 mice; two-sided unpaired t-test) f Representative images showing microglial cells (red) and astrocytes (green) engulfing ThS-immunostained amyloid plaques Quantification was performed in two independent experiments in at least 10 ROIs h Corresponding quantification of microglial cells and astrocytes intensity in (f) (n = 5 mice; two-sided unpaired t-test) i Effects of NMN on the expression levels of APP and its indicated metabolites MSR analyses of hippocampal brain tissues samples of 5xFAD mice injected either AAV-free or AAV-atf4 following NMN treatment (n = 3–6 animals per group) j–l Corresponding quantification of western blot data in (i) m Soluble and insoluble Aβ1–40 and Aβ levels in 5xFAD (NMN) mice injected with AAV-free or AAV-atf4 hippocampal tissues Brain hippocampal tissues from 6-month-old WT and 5xFAD treated with NMN (n = 2 per genotype) were subjected to this scRNA-seq b Two-dimensional uniform manifold approximation and projection (UMAP) plot showing 17 distinguished clusters of single-cell events captured in scRNA-seq and heat map (d) between different cell types in 5xFAD versus 5xFAD treated with NMN e Number of up and downregulated different expression genes (DEGs) in different cell types g Volcano plots illustrating upregulated or downregulated genes in the WT compared to 5xFAD (f) and 5xFAD versus 5xFAD treated with NMN (g) in microglia cells h UMI feature plot and heat map of average gene expression of top DEGs in the microglia cluster from 5xFAD and 5xFAD+NMN mice i Functional annotation of certain microglia clusters using GO pathways enriched for their signature genes (mitochondrial-related genes) j Violin plots showing average UPRmt-related gene-expression across microglia cells k Confocal images of double immunostained with ATF4 (green) and IBA1 (red) The insert is a higher magnification of the boxed area showing the decreased level of ATF4 and upregulated level of IBA1 Arrowheads point to a colocalization of ATF4 and microglia l Transcript levels of marker genes for microglia cluster identification in the hippocampal groups of 5xFAD and 5xFAD+NMN mice (n = 6 mice; two-way ANOVA) NMN administration in the 5xFAD had nearly no impact on the MSR induction in the microglia domain b Volcano plots illustrating significant DEGs in the WT (VEH) compared to 5xFAD (VEH) and 5xFAD (VEH) versus 5xFAD (NMN) in astrocytes c Heat map revealing the expression of DEGs in astrocytes from 5xFAD (VEH) compared to 5xFAD (NMN) d GVSA enrichment analyses for mitochondrial-related pathways in the astrocyte populations of 5xFAD and 5xFAD treated with NMN mice e Violin plots indicating the mean and variance difference between 5xFAD and 5xFAD with NMN in the astrocytes clustering for UPRmt and mitophagy-associated genes f–i Representative images of 5xFAD cultured primary astrocytes showing ATF4 staining with GFAP+ astrocytes j Immunofluorescence labeling of 5xFAD and NMN-treated mouse brain with ATF4 and GFAP antibody The arrow indicates GFAP+ astrocytes were high co-labeling with ATF4 in the NMN-treated AD mouse brain The experiment was repeated twice independently with similar results k Representative images of 5xFAD cultured primary astrocytes were subjected to co-immunostaining for GFAP and ATF5 a Two-dimensional UMAP plots of re-clustered oligodendrocytes showing eight subclusters Dots are colored based on the scRNA-seq clustering b Heat map showing average gene expression of top DEGs in eight subclusters of oligodendrocytes c Violin plots indicating average gene-expression across oligodendrocytes of mitophagy (pink1 eif2a) associated genes between 5xFAD versus NMN-treated 5xFAD mice d Multiple volcano plots illustrating significant DEGs in oligodendrocyte subclusters in 5xFAD versus NMN-treated 5xFAD samples e Violin plots showing expression of UPRmt genes in oligodendrocyte subclusters f Representative immunofluorescence images and quantification of Olig2+ oligodendrocytes labeling with ATF4 The enlarged picture indicates Olig2+ oligodendrocyte was high colocalization with ATF4 in NMN-treated mice The experiment was repeated twice independently 25 μm (n = 3 mice; two-sided unpaired t-test) but it was unclear how NMN relates to MSR-dependent pathological hallmarks of AD brain dysfunction Here we provide evidence for a direct interaction between NMN and MSR signature in vitro and in vivo demonstrating that NMN supplementation ameliorates mitochondrial proteotoxicity and decreases neuronal loss as well as brain atrophy omics features of the hippocampus with NMN in 5xFAD mice showed that NMN leads to transcriptional changes of genes as well as proteins involved in MSR characteristics principally within the astrocytes rather than the microglia and oligodendrocyte units we speculate a highly favorable communication between NMN and MSR against amyloid-β aggregation and tau pathology These findings imply that enhancing mitochondrial function and proteostasis may lessen the detrimental proteotoxic stress in the context of AD little is known about NMN and MSR interconnection in the process of AD pathogenesis we found here that NMN has a dramatic effect on MSR we found that NAD+ supplementation with NMN improved ATF4-dependent UPRmt -MSR signatures in vivo and in vitro in AD models These data support the potential and promising value of astrocytes to reduce AD-related pathology and provide a plausible node for therapeutic intervention in AD one limitation of the current study is the use of N2s cells could be considered not the appropriate or state-of-the-art in vitro model the use of 5xFAD mice as a single in vivo AD genetic model can be questionable we also used 5xFAD-derived primary astrocytes and doxycycline-induced tau cell lines which we hope will increase the diversity of cell models Our work provides evidence that mitochondria have an active role in the pathogenesis of AD as reducing mitochondrial homeostasis via atf4 depletion in 5xFAD mice aggravates the hallmarks of the disease; conversely boosting mitochondrial proteostasis by NMN decreases protein aggregation The detailed information of these kits is as follows: No: JL39738 (ATF4) Continuous variables were analyzed for normality using the Kolmogorov–Smirnov test (K–S test) Variables were expressed as the mean (SD) and assessed by analysis of covariance (ANCOVA) or Kruskal–Wallis test (K–W test) followed by Bonferroni corrected post hoc comparisons The associations between plasma MSR signature biomarkers and cognition evaluation scales were tested using Pearson correlations the area under the curve (AUC) of receiver operating characteristic (ROC) was applied to evaluate the predictive utility of MSR signature biomarkers alone or combined models and the difference in the AUC was determined by utilizing DeLong statistics Statistical analyses were performed using R version 4.3.0 Statistical significance was set at a two-tailed p < 0.05 HEK 293 cells were cultured in DMEM containing 10% FBS (Gibco) and 1% Penicillin-Streptomycin (1% PS N2s (N2a cells expressing human Swedish mutant APP695) and HEK 293 cells expressing pTRE3G-cherry-BI promoter-EGFP Tau P301L were gifts from Jia-Hong Lu of Macau University and maintained with DMEM and 200 ug/ml G418 (Geneticin elective Antibiotic and grown for at least three generations before subsequent experiments A high concentration (1000 μg/ml) of G418 was used for selection and a low concentration (200 μg/ml) was used for maintenance The expression of EGFP Tau P301L is controlled by adding doxycycline (DOX 0.2 µmol/ml) to the culture medium before indicated treatments After designated treatments (MMN 500 µm/ml) cells were subjected to imaging or gathered for Western blot analysis All cell lines were maintained in the incubator at 37 °C with 5% CO2 tested for mycoplasma using mycoprobe following the manufacturer’s instructions All animal care and experiments were approved by the Committee on the Ethics of Animal Experiments of the Wenzhou Medical University (WYYY-AEC-YS-2023-0004) were used to investigate changes in learning and memory including the background white noise and decoration for at least 60 min before initiating the assay The MWM test was performed as described previously [65] The device is a circular white pool (120 cm diameter × 50 cm depth) filled with tap water with nontoxic white paint to opaque and the temperature is controlled at 22 °C A 10 cm diameter platform was located 1 cm below the water surface and only distal visual cues were available above each quadrant of the pool to help in the spatial navigation and location of the platform with 5 trials of experiments conducted each day mice explored clear water to find a platform with a red flag The platform’s location changed every trial Mice with successful consecutive findings within 60 s have good vision and the platform stayed in a constant position Mice are put in water from four directions and penalized with a 10-second standing if they can’t find the platform in time but are guided to it The following indicators were recorded: (1) the total number of entries: the number of times the animal entered the maze arm; (2) alternation: consecutively entering all three arms of the Y maze once (ABC spontaneous alternation performance (SAP) = [alternation/(the total number of entries-2)] × 100% Fear conditioning was conducted as described previously [67] the mice were given 120 s to freely explore the chamber They were then exposed to a 2 s stimulus tone (5 Hz followed by a 0.7 mA foot shock as the unconditional stimulus the mice underwent a contextual and cued test session The contextual test session involved allowing the mice to freely explore the chamber for 5 min with no stimuli and a white plastic insert was placed in the chamber The freezing time was recorded to evaluate contextual and cued memory The experiment consists of two stages: a training and a testing period conducted in a room with four identical squares (25 × 25 × 25 cm3) two identical objects are placed in the chamber at the same distance from the surroundings The mice are allowed to explore for 10 min freely one of the objects was replaced with a significantly different shape The time and frequency of exploration of the new and old objects were recorded The Recognition Index (RI) = (the number of explorations of the new object/total number of explorations) × 100% Mice were placed into the behavioral room 3 h in advance; 75% alcohol was used to remove the smell; the test was started after the mice were put in the middle of the arena for 1 min and the mice were allowed to explore freely for 10 min All the data of the mice in the arena were recorded the time spent in the corners and the center the number of times they entered the central area Mice were given a lethal anesthetic dose by i.p injection of 1% pentobarbital (50 mg/kg in saline) For tissues used in Western blot and ELISA and preserve the remaining parts at −80 °C We perfuse tissues for immunohistochemistry and immunofluorescence with physiological saline and fix the brain using 4% paraformaldehyde (PFA) at 4 °C The extracted brain is stored at −4 °C for subsequent freezing and paraffin embedding the brains immersed in 4% PFA at 4 °C overnight are placed into a pre-labeled embedding cassette After rinsing with running water for 6 h to remove the 4% PFA the tissue was placed in 75% ethanol at room temperature overnight the tissue is sequentially soaked in 85% ethanol for 2 h the tissue is immersed in soft paraffin for 2 h and hard paraffin for 1 h and the paraffin block is allowed to solidify at 4 °C for long-term storage the whole brain was soaked in 20% sucrose and then 30% sucrose for dehydration (Sakura) was placed at the bottom of the embedding cassette and the prepared brain tissue was put into the cassette and the cassette was immediately placed in a −80 °C freezer for storage Cells were seeded in a 12-well plate until reaching 80% confluence cells were incubated with 5% BSA and 0.3% Triton X-100 blocking buffer at 37 °C for 30 min and incubated overnight with 1% BSA-diluted primary antibody at 4 °C and incubated with a corresponding fluorescent secondary antibody (Abcam) for 1 h at 37 °C (protected from light) cells were washed with PBS 3 times (5 min) and mounted with an anti-fluorescent quenching reagent containing DAPI Tissue paraffin section: 5 µm thick sections were baked in a 65 °C oven for 30 min and immediately placed in xylene for dewaxing the sections were immersed in 100% ethanol followed by washing with PBS 3 times (5 min) Frozen tissue section: 30 µm thick sections were kept at room temperature for 1 h to thaw The prepared sections were subjected to antigen retrieval using a boiling sodium citrate solution After the solution reached room temperature the sections were washed with PBS for 3 times The following steps were the same as the cell culture section Images were taken with a Nikon C2si and A1R-SIM-STORM confocal microscope Z-stack images of the stained sections were acquired using a confocal microscope and converted into maximum z-stack projection images Specific primary antibodies used include: Anti-Tau (phospho S396) antibody (catalog no.ab109390; Abcam) Anti-Tau5 antibody (catalog no.ab80579; Abcam) 17–24) antibody (catalog no.800712; Biolegend) anti-human sAPPa (clone 6E10) antibody (catalog no.803014; Biolegend) anti-BACE-1 (clone D10E5) antibody (catalog no.5606; Cell Signaling) ATF4 antibody (catalog no.DF6008; Affinity) HSP70 antibody (catalog no.AF5466; Affinity) ATF5 antibody (catalog no.DF3480; Affinity) caspase-3 antibody (catalog no.19677-1-AP; protein tech) cytochrome c (A-8) antibody (catalog no.sc-13156; Santa Cruz) LAMP-1(H4A3) antibody (catalog no.sc-20011; Santa Cruz) Tom20(F-10)antibody (catalog no.sc-17764; Santa Cruz) Cathepsin D (D-7) antibody (catalog no.sc-377299; Santa Cruz) NeuN antibody (catalog no.ab177487; Abcam) a-tubulin antibody (catalog no.ab289875; Abcam) GFAP antibody(catalog no.sc-33673; Santa Cruz) S100 beta antibody (catalog no.ab52642; Abcam) ibal1 antibody (catalog no.ab283319; Abcam) Olig2 antibody (catalog no.ab109186; Abcam) For the intention of Aβ plaques evaluation tissues were stained with 6E10 antibody (Biolegend) and 4G8 antibody (Biolegend) to recognize Aβ blocked paraffin-embedded 5-μm sections were incubated with 0.1% thioflavin S (Sigma immersed twice in 80% ethanol and once in 95% ethanol for 3 min each it was followed by three washes in ddH20 water and then stained with the other subsequent experimental steps The protein concentration of each sample from different cell lines and mouse brain tissues was tested using the Bradford protein assay using 1× RIPA buffer (catalog no P0013B; Beyotime) containing protease (catalog no ST506-2; Beyotime) and phosphatase inhibitors (catalog no Brain homogenates were diluted and denatured in loading buffer and loaded (approximately 50 μg of protein) on a Bis-Tris 7.5–12.5% or Tris-Tricine 10–20% gradient gel with a current of 80 V for 120 min gels were transferred to an immobilized PVDF membrane in a Western Blot Transfer Buffer (250 mA Blocking was performed with 5% milk for 2 h at room temperatures membranes were incubated overnight at 4 °C with the primary antibody in TBST Primary antibodies used were Tau (D1M9X) antibody (catalog no.46687S; Cell Signaling) Phospho-Tau (Thr217/Thr534) antibody (catalog no Phospho-Tau (Thr231) [Thr548] antibody (catalog no Phospho-Tau (Ser202) [Ser519] antibody (catalog no Phospho-Tau (Thr181) [Thr498] antibody (catalog no anti-APP-CTF (1:1,000,) antibody (catalog no LONP1 antibody (catalog no.DFDF12119; Affinity) CLPP antibody (catalog no.DF8448; Affinity) YME1L1 antibody (catalog no.DF12024; Affinity) Beclin-1 (D40C5) antibody (catalog no.3495; Cell Signaling) BNIP3L/Nix antibody (catalog no.12396; Affinity) OPTN antibody (catalog no.A1845; ABclonal) Bcl-2 (D17C4) antibody (catalog no.3498; Cell Signaling),RIPK1 antibody (catalog no.ab32503; Affinity) RIPK3 antibody (catalog no.DF10141; Affinity) MLKL antibody (catalog no.DF7412; Affinity) ATP5a1 antibody (catalog no.DF3806; Affinity) MTCO1 antibody (catalog no.DF8920; Affinity) they were then probed with the respective secondary horseradish peroxidase (HRP)-labeled antibodies including goat anti-mouse IgG (H + L) HRP (IgG; catalog no GAM007) and goat anti-rabbit IgG (H + L) HRP (catalog no Densitometric values of single protein bands (amyloid-β et al.) or fragments or aggregates were analyzed with the software package Image Lab Software (Bio-Rad v 6.1) and normalized to GAPDH or β-actin Gamma adjustment was applied to reduce the dark background when necessary All data is analyzed using Excel and Prism (version 9.3.1) The hippocampal and cortical preparations of mice were collected and used to measure soluble Aβ The resulting insoluble pellet was homogenized with 70% formic acid Samples were centrifuged at 100,000 × g for 20 min at 4 °C Samples were neutralized in 1 M Tris buffer (pH 11 1:20 ratio dilution) and diluted in blocking buffer before loading on ELISA Aβ in the RIPA fraction was regarded as the detergent-soluble fraction while Aβ in the neutralized formic acid fraction was considered the detergent-insoluble fraction We used the human Amyloid β ELISA kit from the R&D system to identify soluble and insoluble Aβ1-40 and Aβ1-42 levels in mice (Aβ1-40: catalog no.DAB140B after killing the mice with the standard procedures and a quick collection of the designated brain tissues Veh- and NMN-treated mouse hippocampal tissues (1 mm in width) were fixed with an appropriate aldehyde fixative (2% paraformaldehyde-2.5% glutaraldehyde electron microscope fixative) After washing with 0.1 M phosphate buffer (pH 7.2) three times the tissues were post-fixed in 1% osmic acid at 4 °C for 2 h The samples were gradient dehydrated in a series of 70–100% ethanol baths the samples were placed in a 50:50 mixture of acetone and embedding media (Embed 812 Electron Microscopy Sciences) for a minimum of overnight specimens are placed in a fresh change of pure resin for 4 h then embedded in another fresh change of 100% resin and put in a 60 °C oven for 12–18 h for polymerization After the semi-thin (1–2 microns) section was used for positioning with glass knives the ultra-thin (70–90 nm) section using a diamond knife was made and collected for microstructure analysis followed by counter-staining with 3% uranyl acetate and 2.7% lead citrate The samples were then observed with an HT7800 transmission electron microscope We used Fiji software to analyze mitochondrial ultrastructure and measure mitochondrial diameter After being washed with pre-warmed PBS three times it was stained with DRAQ5 (Thermo Scientific catalog no.62254) and immediately observed under a microscope After all acquired images were graphically aligned with Slicer (v5.2.2) ROIs were circled using Fiji to calculate the corresponding ventricular volumes Mice within 24 h of birth were sterilized with 75% ethanol and whole brains were removed using autoclave instruments and transferred to dissecting dishes containing pre-cooled HBSS (Gibco) The olfactory bulb and cerebellum were removed under a microscope the meninges in the cortex were carefully peeled off and the separated hemispheres were transferred to a new HBSS The brain hemispheres were immediately cut up and transferred to a new centrifuge tube 0.25% trypsin was added and placed in a 37 °C cell incubator to digest the tissue for 30 min with the tube being flicked every 10 min to aid better digestion and the obtained cells were collected and inoculated in culture flasks using DMEM (Gibco) and incubated in a cell incubator (37 °C The culture medium was changed on the 2nd day and every 3 days after that until the astrocytes were confluent on the 7th–8th day the microglial cells were removed by a thermostatic shaker at 37 °C for 180 r/min for 30 min the oligodendrocyte precursor cells were removed at a condition of 37 °C for 240 r/min for 6 h and the rest of the cells were collected and passaged to obtain pure astrocytes The initial dataset contained 9160~9723 cells The whole dataset was projected onto the two-dimensional space using UMAP on the top 7 main targets as an initial reference the following quality measures were quantified: (1) the number of genes for which at least one read was mapped; (2) the total number of counts; (3) the percentage of counts mapping to the top 50 genes; and (4) the percentage of reads mapped to mitochondrial genes (which may be used to approximate the relative amount of endogenous RNA and is commonly used as a measure of cell quality) According to these observations and subsequent scatter-plot analyses cells with fewer than 200 detected genes and cells with an abnormally high ratio of counts mapping to mitochondrial genes were removed the final number of cells obtained ranged from 7669 to 8068 The average number of UMI per cell ranged from 9991 to 10860 and the average number of genes per cell ranged from 3040 to 3288 The average mitochondrial UMI percentage per cell ranged from 0.0320 to 0.0450 Principal component analysis (PCA) and uniform manifold approximation (UMAP) were performed The dimensionality reduction results based on PCA are visualized through UMAP for single-cell clustering The clustering algorithm utilized is the Shared Nearest Neighbor (SNN) algorithm which ultimately obtains the optimal cell grouping Three differentially expressed gene groups are identified and 595 differentially expressed genes detected After dimensionality reduction and clustering The presto method analyzed differential expression between a specified cell cluster and all others snRNA-seq-based DEGs were assessed using two tests a cell-level analysis was performed using the Wilcoxon-rank-sum test and FDR multiple-testing correction a Poisson mixed model accounting for the individual of origin for nuclei and unwanted sources of variability was performed using the R packages lme4 and RUV-seq The consistency of DEGs detected using the cell-level analysis model was assessed by comparing the directionality and rank of DEGs Consistency in directionality for all cell types was quantized by counting the fraction of the top 1000 DEGs (ranked by FDR scores) detected in cell-level analysis that showed consistent direction in the mixed model We further tested whether the differential P value and z-score ranks corresponded to genes detected as upregulated or downregulated in the cell-level analysis when computed using the mixed model only genes that were significantly approved by both models using the criteria FDR-corrected p < 0.01 in a two-sided Wilcoxon-rank-sum test and FDR-corrected p < 0.05 in a Poisson mixed model were considered The differential analysis was performed by fitting a linear model using the R package limma enrichment analyses were performed using the R package ClusterProfiler and the p-value-ranked gene lists as input All quantified data show an average of samples and no statistical methods were used to predetermine sample sizes Two-tailed unpaired t-tests were used for comparisons between the two groups Group differences were analyzed with a one-way analysis of variance (ANOVA) followed by Šidák’s multiple comparisons test or a two-way ANOVA followed by Tukey’s multiple comparisons test for various groups Prism 8.0 (GraphPad Software) was used for the statistical analysis P-values < 0.05 were considered statistically significant The main data supporting the findings of this study are available within the article and its Supplementary Information The custom code for scRNA-seq is available from the corresponding author on reasonable request Mitophagy in Alzheimer’s disease: molecular defects and therapeutic approaches Mitochondria at the neuronal presynapse in health and disease Mitochondria and calcium in Alzheimer’s disease: from cell 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Download references We would like to thank Professor Jia-Hong Lu from the University of Macau for giving us the HEK 293 cells expressing pTRE3G-cherry-BI promoter-EGFP Tau P301L and advice for this manuscript Supported by the Projects of the National Science Foundation of China (No and 82271469) and the Projects of the Natural Science Foundation of Zhejiang Province (LQ23H090007 Supported by Taizhou Science and Technology Program (No the study was also funded by the Leading Innovative and Entrepreneur Team Introduction Program of Zhejiang (2023R01002) and the Projects of the Wenzhou City Committee of Science and Technology (No The First Affiliated Hospital of Wenzhou Medical University The Center of Traditional Chinese Medicine The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University Key Laboratory Of Alzheimer’s Disease Of Zhejiang Province and CLX designed and coordinated the project and YZ helped with data analysis on neurodegeneration HJH and JNH carried out the Golgi staining The authors declare no competing interests The study was approved by the institutional Ethics Board Committee of the Wenzhou Medical University First Affiliated Hospital (KY2021-153) All participants provided written informed consent before participating in this study Relevant guidelines and regulations were followed for all methods 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/s41419-024-07062-1 Anyone you share the following link with will be able to read this content: a shareable link is not currently available for this article Using the best mouse can have a transformative effect on your overall PC experience a decent mouse controls the ebb and flow of your workflow management enabling you to work fluidly with better accuracy having a suitable mouse that offers a high-quality point-and-click experience is essential Logitech dominates the current mouse market thanks to superb offerings such as the Logitech MX Master 3S which offers a premium customizable experience in a quality wireless mouse It has an 8000 DPI sensor that tracks effortlessly across multiple surfaces and there’s a seven-button custom input that provides plenty of versatility Elsewhere, there are bargains to be had for those on the lookout for an efficient travel mouse. The Microsoft Modern Mobile Mouse is a slimline travel mouse that clicks all the right buttons for remote working A neat ambidextrous design makes it useable for lefties and righties and Microsoft’s BlueTrack technology means smooth tracking across almost any surface At TechRadar, we’ve tested dozens of top mice, including the best gaming mice to bring you our carefully curated selections below So no matter whether it’s for work or play (or a little bit of both) we’ve got the perfect solution to let you glide across the screen with ease and enjoy flawless control Below you'll find write ups for each of our picks for the best mouse of the year so you can trust our advice to help you find the best mouse for your needs and budget Logitech has once again updated its MX Master series with the MX Master 3S succeeding the popular MX Master 3 the 3S doesn't take that lofty standing for granted boasting the same versatility as its predecessors including those seven customizable buttons and three connectivity options which is a boon to pros who loathe charging we found it to be much quieter – 90% quieter It also now comes with an 8000 DPI track anywhere sensor that lets it perform beautifully even on glass surfaces We found this sensor to be more responsive and more accurate as well Read the full Logitech MX Master 3S review Microsoft updated its Mobile Mouse and gave it a nice modern refresh – thus the name with a rounded rectangular look with a lower It also features Microsoft’s BlueTrack technology so you can skip those pesky mouse pads as well as Bluetooth connectivity with up to 33 feet in range Although we haven't fully tested this mouse verified users have praised it for boasting effortless glide as well as an accurate clicky buttons that might be a little too loud for some but those buttons are also extremely satisfying to press To match the aesthetic of your existing rig It’s only less than much less like it looks Read our full Microsoft Modern Mobile Mouse review Why go for the mediocre when you can have a productivity mouse that’s both stunning, feature-rich and extremely functional? The Razer Pro Click is one of our favorites out of all the mice we've tested If macros are your life – whether you use video editors a lot or heavily rely on graphics design – this is the mouse of your dreams with 8 fully programmable buttons at your disposal Razer also gives it a whopping 16,000 DPI for the smoothest and fastest experience and slaps on the multi-host connectivity because it knows that you’re a multi-tasking machine who uses several devices at once This is one of the most responsive office mice we've ever tested being the modern professional or creator that you are This mouse has that covered as well with its gorgeous and sleek white on gray design Read the full Razer Pro Click review Whether you're working at cafes or have a small desk this follow up to Logitech’s MX Anywhere mouse is an excellent pointing-and-clicking companion That's especially if you’re a digital creator who values seamlessness This wireless mouse isn’t just designed to be super portable It's also been created to make your workflow go a lot smoother with fantastic features like three-device connectivity so you can switch from your laptop to your tablet to your phone with click of a tiny button app-specific profiles and button customizations and up to a whopping 70-day use on a full charge Some might feel that over $50 is pricey of a tiny mouse and others would probably want to also invest in a proper mouse pad we feel like it’s worth the added cost It even comes with three different shades so it can match your aesthetic Read the full Logitech MX Anywhere 3 review The Logitech Lift Ergonomic Vertical Mouse might just alleviate any wrist or arm discomfort you suffer from Whereas other mice are not exactly the best at keeping your mouse arm in its most optimal position this vertical mouse from Logitech keeps it in its natural handshake position which in turn help prevent RSI or repetitive strain injury It's also never too late to start using one Even if you're not suffering from chronic pain from mouse usage especially if you do spend a lot of time on the computer some of them saying that not only has it reduced their pre-existing wrist pain That makes it ideal for folks who spend long hours working as well Read our full Logitech Lift Ergonomic Vertical Mouse review Check out our Logitech promo codes to get the best deal on your next purchase you can always rely on Razer to come and represent Offerings such as the Razer Basilisk V3 Pro remain at the top of the tree in terms of their functionality The Razer Cobra Pro borrows all the tech from the Basilisk V3 Pro and repackages it in a smaller and more lightweight frame the Razer Cobra Pro feels like a stiff breeze could carry it away Its 30K optical sensor ensures flawlessly smooth tracking and it’s refreshing to be offered the choice of Bluetooth With up to an 8K polling rate and you’re unlikely to experience any issues with latency or reliability It also provides the facility to store up to five custom profiles and runs for an impressive 100 hours on a full charge it accommodates Razer’s signature RGB lighting until you achieve the underglow of your dreams The Razer Cobra Pro has some seriously impressive chops and is undeniably an absolute beast when it comes to both productivity and gaming which we call ‘premium’ when we’re being polite and ‘expensive’ when we’re not Whether you’re prepared to pay approximately £130 for a mouse is your business there’s very little to argue with in terms of performance Take a look at our Razer discount codes for the best Razer offers and savings and Brooklyn College alum currently living in Brooklyn Named by the CTA as a CES 2020 Media Trailblazer for his science and technology reporting John specializes in all areas of computer science as well as general science writing and the social impact of the tech industry You can find him online on Bluesky @johnloeffler.bsky.social « Back Please enable JS and disable any ad blocker Volume 9 - 2022 | https://doi.org/10.3389/fnut.2022.848392 This article is part of the Research TopicImpact of Proteins, Peptides, Amino Acids and Food Additives on Gut MicrobiotaView all 18 articles Sucralose is a non-nutritive artificial sweetener (NNS) used in foods or beverages to control blood glucose levels and body weight gain The consumption of NNS has increased in recent years over the world and many researches have indicated long-term sucralose administration altered the gut microbiome composition of mice These studies all focus on the US Food and Drug Administration (FDA) defined acceptable daily intake (ADI) Control group mice were given normal water 0.3 mg/mL of sucralose was equal to the ADI (5 mg/kg BW/day) the liver of each mouse was isolated and weighed ileum and colon were collected for H&E-stained cecum and colon were collected for 16S rRNA gene sequencing The results showed sucralose administration affects the intestinal barrier function evidenced by distinct lymphocyte aggregation in ileum and colon while not change the mice body weight The 16S rRNA gene sequencing of the mice gut microbiome suggested sucralose administration significantly changed the composition of gut microbiota a reduction of probiotics abundance (Lachnoclostridium and Lachnospiraceae) was found in cecum of T4 group mice compared with Control group which was reported positively correlated with diabetes Staphylococcus were also increased in jejunum ileum and colon by sucralose administration in T1 and T4 group These new findings indicate that low dose of sucralose (T1) alter gut microbiome in mice and these adverse health effects are equal to ADI level (T4) our study provides guidance and suggestions for the use of sucralose in foods and beverages sucralose administration significantly altered mice gut microbiome and reduced the abundance of beneficial bacteria Although many studies have deeply explored the impact of sucralose on gut microbiome, most studies were close to the concentration of ADI (5 mg/kg BW/day) (16, 17) we found low concentration sucralose also significantly altered gut microbiome by setting four concentration gradients and it might involve in the development of diabetes It provides a research basis for the adverse effect mechanism of sucralose on human health and provides guidance and theoretical support for the practical application of artificial sweeteners 0.3 mg/ml is equal to a mouse with an average body weight of 0.02 kg At the end of 16-week study, all mice were weighed individually and euthanized. The liver of each mouse was isolated and weighed. Segments of jejunum, ileum and colon were collected and fixed in 4% paraformaldehyde for H&E-stained. The contents of jejunum, ileum, cecum and colon were collected and stored at −20°C until DNA isolation and 16S rRNA gene sequencing. More detailed bioinformatics methods can be found in a previous study (19) The jejunum, ileum, and colon tissue segments (1 cm) were collected for histological staining from 3 mice per group, the tissues were rinsed with PBS, immediately fixed in 4% paraformaldehyde, and then cut into sections (4–5 mm), the H&E staining were used to stain the tissue sections according the methods described by previous study (20) Histopathological scores were calculated according to the methods described by Ma (21): Epithelial surface loss and immune cell infiltration (0: no change Microbial genomic DNA was extrtacted from each intestinal content according to the manufacturer's instructions (QIAamp DNA Stool Mini Kit QIAGEN The V4-V5 region of the bacteria 16S ribosomal RNA gene was amplified by PCR (95°C for 2 min followed by 25 cycles at 95°C for 30 s and 72°C for 30 s and a final extension at 72°C for 5 min) using primers 515 F 5′-barcode- GTGCCAGCMGCCGCGG)-3′ and 907 R 5′-CCGTCAATTCMTTTRAGTTT-3′ where the barcode is an eight-base sequence unique to each sample The PCR reactions were performed in triplicate using 20 μL mixture which contained 4 μL of 5 × FastPfu Buffer 0.8 μL of forward primer (5 μM) 0.8 μL of reverse primer (5 μM) 0.2 μL of BSA and 10 ng of template DNA Amplicons were extracted from 2% agarose gels and purified using the AxyPrep DNA Gel Extraction Kit (Axygen Biosciences U.S.) according to the manufacturer's instructions and quantified using QuantiFluor™-ST (Promega Purified PCR products were quantified by Qubit®3.0 (Life Invitrogen) and every 24 amplicons whose barcodes were different were mixed equally The pooled DNA product was used to construct Illumina Pair-End library following Illumina's genomic DNA library preparation procedure Then the amplicon library was paired-end sequenced (2 × 250) on an Illumina Novaseq platform [Mingke Biotechnology (Hangzhou) Co. The original image data files obtained by high-throughput sequencing were converted into Sequenced Reads by Base Calling analysis the results were stored in FASTQ (referred to as fq) format file which contains sequence information of reads and their corresponding sequencing quality information All statistical analyses were performed by SPSS 23.0 (IBM, New York, NY, United States) using One way ANOVA (22) Data are presented as the mean ± SEM Results were considered significant when P < 0.05 Bar chart showing the mice body weight (A) and liver weight (B) Representative H&E-stained sections from jejunum the arrowhead points in the direction where lymphocyte aggregation Histopathological scores of the H&E staining (D) Data was expressed as mean ± SEM (n = 8) and analyzed by one-way ANOVA analysis The different superscript letters on the histogram represent a significant difference (D) (P < 0.01) T3 and T4 groups were closer to control group T4 group was as far away from the control group as T1 group Alpha diversity including Shannon index (A,C,E,G) and the number of features (B,D,F,H) in control group Trichlorogalactosucrose (TGS) 1–4 (T1 and expressed as mean ± SEM (n = 8) and analyzed by one-way ANOVA analysis The different superscript letters on the boxplot represent a significant difference (P < 0.01) PCA of the mice gut microbial community composition of the Control and T1-4 group based on the Bray-Curtis distances showed distinct clusters P-value and R-value were calculated by ANOSIM and colon (D) microbial community structure between the Control group and T1–4 groups were differentiated by colors (red Phylogenetic tree analysis showing top 129 bacterial taxa based on 16S rRNA gene V4-V5 hypervariable regions after removing 21 features which were uncultured or no rank in genus level The innermost clades and labels were colored by genus The top 30 features in Control group and T1–4 groups of jejunum Each color indicates the relative abundance of a bacterial taxon on the bar chart after removing these features which were uncultured or no rank in genus level we found the Firmicutes-Allobaculum (F20) in T1 group and Firmicutes-Allobaculum (F66 F49) in T4 group increased significantly than other groups (Control Heat map indicated 68 bacterial taxa were identified by LEfSe (LDA > 3) in mice jejunum (n = 20) (A) The top 1,000 features were used for LEfSe analysis Heat map shows the average relative abundances on a Z-score and confirms that sucralose as a zero-calorie sweetener does not provide energy to the body sucralose administration induced lymphocyte aggregation which may lead to the increase of inflammatory factors These revealed that sucralose administration might disrupt intestinal barrier function the sucralose concentration and the effect on intestinal barrier of these studies all consistent with T4 group in our study we also found the intestinal barrier was significantly damaged in group T1 These results were consistent with T4 group in our study the new finding in our research was T1 (0.0003 mg/mL) group whether sucralose administration will induce diabetes by altering gut microbiota our study demonstrated sucralose administration did not change mice body weight but low dose of sucralose (0.0003 mg/mL) significantly altered mice gut microbiome Staphylococcus and Allobaculum in genus level in mice jejunum The decrease of Lachnoclostridium and Lachnospiraceae in cecum of T4 group mice Although the sucralose of ADI (0.3 mg/mL) level also altered the gut microbiome in mice the human daily intake of sucralose is usually lower than this concentration We should focus on the low dose of sucralose administration in human our research is limited to the effect of low-dose sucralose on the gut microbiome of mice and the relevance to human metabolic diseases warrant further investigation The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found below: https://www.ncbi.nlm.nih.gov/ The animal study was reviewed and approved by the Institutional Animal Care and Use Committee of Zhejiang Academy of Agricultural Sciences All authors reviewed the manuscript and contributed to the article and approved the submitted version This work was financially supported by the State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agroproducts the Open Project of Hubei Key Laboratory of Animal Nutrition and Feed Science (No and the National Natural Science Foundation of China (31972999) 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 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 Sweeteners as food additives in the XXI century: a review of what is known PubMed Abstract | CrossRef Full Text | Google Scholar Low-/no-calorie sweeteners: a review of global intakes Maternal sucralose intake alters gut microbiota of offspring and exacerbates hepatic steatosis in adulthood Maternal exposure to non-nutritive sweeteners impacts progeny's metabolism and microbiome Sucralose metabolism and pharmacokinetics in man Low-calorie sweetener consumption is increasing in the United States Effects of low-dose non-caloric sweetener consumption on gut microbiota in mice Microbial ecology of the gastrointestinal tract PubMed Abstract | CrossRef Full Text | Google Scholar Human gut microbiota/microbiome in health and diseases: a review PubMed Abstract | CrossRef Full Text | Google Scholar Gut microbiome stability and resilience: elucidating the response to perturbations in order 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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: Ying Ren, cmFuZWUxOTc0QDE2My5jb20=; Jinjun Li, bGlqaW5qdW5AemFhcy5hYy5jbg== †These authors share first authorship 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 Please upgrade your browser to improve your experience Researchers at Johns Hopkins Bloomberg School of Public Health have identified the sequence of molecular events by which tiny tick-like creatures called house dust mites trigger asthma and allergic rhinitis The researchers, whose study was published online in Nature Immunology found that allergy-triggering molecules from dust mites can interact with an immune protein called SAA1 which is better known as a sentinel against bacteria and other infectious agents The researchers showed step-by-step how this interaction between mite-molecules and SAA1 triggers an allergic-type immune response in mice The findings reveal what may be a significant new pathway by which allergic and inflammatory disorders arise They also suggest that blocking the pathway could potentially work as a preventive or treatment strategy against asthma and other allergic reactions "We think that the signaling interactions that occur immediately downstream of the mite-proteins' activation of SAA1 may be good targets for future drugs," says study senior author Marsha Wills-Karp, professor and chair of the Department of Environmental Health and Engineering at the Bloomberg School Asthma affects between 8 to 15% of people in the U.S. Researchers suspect that this inappropriate immune triggering happens when the immune system mistakes allergens—which are otherwise harmless—for pieces of bacteria or other infectious agents the molecular mechanisms underlying this misidentification haven't been well understood Wills-Karp and her colleagues zeroed in on SAA1 in the fluid that lines the airways and other mucosal surfaces A member of the evolutionarily ancient "innate immune system" of mammals SAA1 is thought to have evolved as a sentinel or early-responder molecule that recognizes and helps clear away certain types of bacteria and other infectious agents The researchers found that exposure to dust-mite proteins causes an asthma-like sensitization of the airways of the control group mice exposure to dust-mite proteins hardly had any effect in mice in which SAA1 was neutralized by antibodies or in mice whose genes for SAA1 were knocked out directly binds certain dust-mite allergens called fatty-acid binding proteins which have structural similarities with proteins found in some bacteria and parasites This allergen-SAA1 interaction releases SAA1 into its active form wherein it activates a receptor called FPR2 on airway-lining cells The airway cells then produce and secrete large quantities of interleukin-33 a protein known for its ability to stimulate allergic-type immune responses the researchers found evidence of increased production of SAA1 and FPR2 in nasal airway-lining cells from patients with chronic sinusitis—which is often linked to dust-mite allergens—compared to healthy controls "We think that different allergens take different routes to the activation of interleukin-33 and related allergic responses and this SAA1-FPR2 route seems to be one that is taken by some dust-mite allergens," Wills-Karp says She and her colleagues now plan to investigate why some people develop allergic disorders in which this pathway is hyperactive They also plan to explore the possibility of blocking this pathway as a way of treating asthma and other allergic disorders The researchers suspect that the newly described SAA1-FPR2 allergic pathway may be relevant not only in asthma and hay fever-type disorders but also in eczema and food allergies—possibly even in chronic inflammatory disorders such as rheumatoid arthritis and atherosclerosis Tagged research In an effort to better understand hearing loss scientists have created mice with supercharged listening abilities University of Michigan neurobiologist Lingchao Ji and colleagues achieved this by dialing up the test animals' expression of a nerve growth gene called neurotrophin-3 (Ntf3) The Michigan research lab previously showed increasing Ntf3 expression can improve hearing in middle-aged mice. It can also help recover some hearing in mice with damaged inner ears It does so by increasing the number of connections – called synapses – between hair cells in the ear's cochlea and the brain The hair cells react to sound vibrations and turn them into signals which the synapses then convey to the brain's neurons for interpretation "We knew that providing Ntf3 to the inner ear in young mice increased the number of synapses between inner hair cells and auditory neurons, but we did not know what having more synapses would do to hearing," says University of Michigan neurobiologist Gabriel Corfas "We were surprised to find that when we increased the number of synapses the brain was able to process the extra auditory information And those subjects performed better than the control mice in the behavioral test." The density of synapses does not alter the startle reflex so the initial detection of sound itself remains typical in spite of the reduced number of connections Instead, the synapse density seems to alter the ability to distinguish between sounds, changing what is known as the gap detection threshold – the shortest duration of silence between two sounds that is still wide enough for them to be heard as two sounds rather than one The gap detection threshold is longer when there are fewer synapses in an area as Ji and team demonstrated in their experiment with mice that had reduced Ntf3 expression This indicates that loss of inner hair cell connections causes delays in brain processing of different sound signals, as experienced by some humans with hearing challenges These delays make it difficult to comprehend speech particularly when other sounds at a similar volume are present Boosting Ntf3 expression in the mice caused an increase in the density of their synapses in turn improving their ability to process and therefore distinguish between sounds of different qualities "Animals with extra inner ear synapses have normal thresholds – what an audiologist would define as normal hearing – but they can process the auditory information in supranormal ways," explains Corfas So increasing Ntf3 expression has the potential to improve hearing in humans too "Some neurodegenerative disorders also start with loss of synapses in the brain. Therefore, the lessons from the studies in the inner ear could help in finding new therapies for some of these devastating diseases," Corfas concludes This research was published in PLOS Biology Research suggests traumatic childhood experiences embed themselves in our brains and put us at risk of mental illness but epigenetic editing may offer us hope of removing them The way depression manifested itself in mice in the laboratory of the psychiatrist and neuroscientist Eric Nestler was hauntingly relatable When put in an enclosure with an unknown mouse they sat in the corner and showed little interest When presented with the treat of a sugary drink These mice had been exposed to “social defeat stress” bigger mice had repeatedly asserted their dominance over them It is a protocol designed to induce depression in mice it affected some more than others: those with a history of early trauma “What one sees clearly in these mouse and rat models is some that are exposed to early life stress do show greater susceptibility to stress later in life,” says Nestler who is based at the Icahn School of Medicine at Mount Sinai in New York Tinkering with the epigenome could essentially give us a way to physically edit out the scars of the pastThis appears to be true for humans, too. The reasons are still unclear, but there is growing evidence that part of the answer lies in epigenetics – processes that modify the function of our genes without changing the genetic code Many researchers now think that childhood trauma biologically embeds itself in our bodies alters how our genes work and puts our mental health at risk If that thinking holds up, it opens the door to radical new treatments. Just as gene editing is promising new therapies for everything there are those who believe tinkering with the epigenome could help us reverse the damage done by trauma – essentially giving us a way to physically edit out the scars of the past It found that almost all kinds of childhood trauma – from a parent dying to substance abuse in the family – were significantly associated with mental illness in adulthood the analysis suggested that if we somehow got rid of all childhood adversity we would see a reduction in mental health diagnoses by almost a third View image in fullscreenIn experiments some mice that are exposed to early life stress showed greater susceptibility to stress later in life – a phenomenon that appears to be true for humans Photograph: AlamyBut to understand the biological components of such a link It is in these that researchers have seen how early life adversity leads to epigenetic modifications Such modifications are most easily thought of as “tags” directly on or surrounding our DNA. In different ways, they regulate how easily specific genes are read and whether or not the proteins that the genes code for are produced, a process called gene expression “The metaphor that sometimes people use is [a piece of] music,” says social and psychiatric epidemiologist Erin Dunn of Harvard University “A composer… might add certain annotations in order to bring out certain things.” In experiments, researchers can play composers and change gene expression by exposing animals to stress early in life. In one study Nestler and his colleagues separated mouse pups from their mothers for hours every day and found that several hundred genes had altered expression in a brain area associated with depression It was mice such as these that went on to develop depression at higher rates when put through the social defeat stress protocol The problem is that there is no way to replicate this in humans. It would be immoral to expose children to trauma and researchers need to remove brain tissue to analyse what epigenetic changes have taken place there. But, says neuroscientist Elisabeth Binder of the Max Planck Institute of Psychiatry in Munich: “There is evidence from postmortem brain data that we may see similar things [in humans].” She is referring to a study examining the brains of people who killed themselves The authors found epigenetic differences on stress-related genes between those who had experienced childhood abuse and individuals who had not but in order to find out people’s abuse history the authors had to ask the bereaved relatives Instead, researchers want to test living people. That means looking for epigenetic marks outside the brain, such as in saliva or blood. While it is still unclear how well they reflect changes in the brain it is the best scientists have and it does tell a compelling story – not just of epigenetic scars but of extreme evolutionary survival strategies An increasingly popular way to study epigenetic changes in people is through epigenetic clocks we pick up certain tags that correlate strongly with age and so scientists can quantify our ‘biological age’ by looking at how many we have they can determine whether we are biologically ageing quicker or slower Recently, Binder used the first ever epigenetic clock for children on three- to five-year-olds who had a known history of maltreatment She found a clear pattern: maltreated children who showed signs of depression and anxiety were biologically nearly three months older than their peers – a lot for their age View image in fullscreenEpigenetics could play a role as a biomarker to flag children at particular risk of developing depression or anxiety later in life Photograph: AlamyOn the back of such research it is tempting to think that accelerated ageing is exclusively damaging But the reality is probably more complicated says psychologist Jennifer Sumner of the University of California She differentiates two kinds of trauma: threat and deprivation. “Experiences of threat – so that’s potential for violence, for physical harm – those experiences seem to be especially linked to these indicators of accelerated biological ageing,” she says. According to her work teens reach puberty later and their biological age is unaffected Viewed through a rather grim evolutionary lens growing up faster means that you can reproduce more quickly in case your life is short But in deprived environments with limited resources Sumner says: “It may not be as beneficial to try to develop and reproduce at that time.” So some of the trauma-induced changes may be part of an evolutionary strategy that puts reproductive timing before wellbeing “The accelerated ageing can actually increase that reproductive fitness more adverse consequences for physical and mental health,” she says This seems a rough deal for people looking to live and not just propagate and raises the question: if epigenetic changes can just appear The short answer is, well, possibly. Scientists can edit the epigenome by using a version of Crispr-Cas9, the innovative gene-editing tool, where the Cas9 enzyme is deactivated so it cannot snip the DNA “It’s not like cutting the gene and inserting something,” says Subhash Pandey a neuroscientist at the University of Illinois Chicago it simply finds the right point in the genome and can then remove or add a tag In a study last year, Pandey used this epigenetic version called Crispr-dCas9 to undo an epigenetic change induced by teenage binge drinking in rats. His previous work connected that particular modification in the amygdala to increased anxiety and alcohol use in adults View image in fullscreenNeuroscientist Elisabeth Binder has found that trauma can result in accelerated ageing in children Photograph: Max Planck InstituteRats that had been injected with alcohol in adolescence were significantly more anxious than teetotal fellow rodents But when Pandey reversed the alcohol-induced change It also worked the other way around; when Pandey introduced the change to rats that did not drink in adolescence There is a long way to go before epigenetic editing could be used in humans but Pandey believes “epigenomic editing has high potential for future therapy” Kinks such as long-term efficacy and safety have to be worked out for any new therapy when it comes to depression and anxiety disorders which are shaped by a host of different genes “What’s causing depression in one person is probably very different from what’s causing depression in another person,” he says That could make it tricky to find the right tags to reverse Although concerns about side effects remain Nestler says: “We’re very interested in their potential in depression as well.” Others think drugs and editing should not overshadow what is most remarkable about epigenetics: its responsiveness to the environment “These are marks that are dynamic in response to our life experiences,” says Dunn “There are things that can [shift] people’s risk for having health outcomes.” we should try to mend children’s trauma before they get diagnosed as adults – not with mental health Crispr epigenetics could play a role as a biomarker to flag children at particular risk we do not need epigenetics to tell us that kids with a history of trauma need help Yet Dunn says: “You and I could have the exact same experience in terms of adversity but biologically it impacts us differently.” With limited public budgets there could be value in separating the truly traumatised from the resilient She is right that not everyone who goes through trauma is equally affected; that shows up even in Nestler’s mice The most depression-prone experienced trauma late in childhood whereas those who were traumatised early – and perhaps had more time to recover – showed more resilience But if we embrace epigenetic drugs and editing, there may be shortcuts to that, too. Nestler recently found a resilience-regulating gene network that can be boosted epigenetically and could offer new drug targets in adults “Most efforts in the field over decades have been to undo the bad effects of stress,” he says “One could also try to institute mechanisms of natural resilience.” there will be no shortage of tags to fiddle with The question remains whether we are willing to lend our brains to it This is the archive of The Observer up until 21/04/2025 The Observer is now owned and operated by Tortoise Media Pfizer's latest COVID booster vaccine was authorised for use based only on preliminary data from eight mice Human data from a similar booster and the original mRNA vaccine was also considered as part of the authorisation process An Instagram post claims US authorities approved Pfizer's updated COVID booster vaccine for the BA.4 and BA.5 Omicron subvariants based only on data from trials on mice The pharmaceutical company created the updated vaccine to better target the now dominant Omicron variant The claim relates to approval in the US, with the Food and Drug Administration (FDA) giving the vaccine "emergency use authorization" in August In Australia, the Therapeutic Goods Administration (TGA) has given provisional determination Pfizer is now required to submit a market authorisation application before the vaccine is given the all-clear for use in Australia.  The claim was made in a September 5 post (archived here), which included a screenshot of a Science.org article about the updated boosters "So Pfizer submitted a request for emergency use authorization for booster #5 and the only data they presented was from trials in mice," the post's caption reads On August 31, the FDA announced it had granted emergency use authorisation for both Moderna and Pfizer's updated booster vaccines Pfizer told AAP FactCheck its submission included "clinical, pre-clinical and manufacturing data" with the mice trials being the pre-clinical data "To advance the Omicron BA.4/BA.5 bivalent vaccine as rapidly as possible, regulators have advised that our submissions be based on safety and immunogenicity data generated in adults with an Omicron BA.1-adapted bivalent vaccine and supported by BA.4/BA.5 bivalent pre-clinical data and BA.4/BA.5 bivalent chemistry manufacturing and controls data," a Pfizer spokeswoman said via email "Pre-clinical data showed a booster dose of Pfizer and BioNTech's Omicron BA.4/BA.5-adapted bivalent COVID-19 vaccine generated a strong neutralising antibody response against Omicron BA.1 In a presentation to the FDA in June Pfizer outlined data relating to both BA.1 and BA.4/5 booster vaccines This included a clinical study in which 640 participants were given a booster dose of the BA.1 bivalent vaccine (page 11) along with preliminary data from eight mice given two doses of the BA.4/5 bivalent vaccine (page CC-25) Scott Roberts, an assistant professor and associate medical director of infection prevention at Yale School of Medicine told AAP FactCheck the preliminary mice data helped support the FDA decision "But this was done in conjunction with more human clinical trial data using a BA.1 bivalent booster which showed no new concerning safety signals so the assumption is this would also hold true for the BA.5 bivalent booster," Dr Roberts said in an email "Unless the vaccine manufacturer changes how the vaccine is produced they don't need to perform new and updated clinical trials since the changes were relatively minor (the mRNA was modified to BA.5)." Andrew Pekosz, a professor in molecular microbiology and immunology at John Hopkins University also confirmed the BA.4/5 booster was approved based on a number of different parameters including human data from the BA.1 bivalent vaccine "This bivalent booster showed better recognition of various Omicron sublinages and was therefore put forward to the FDA/CDC as an updated booster with better activity," Prof Pekosz told AAP FactCheck in an email "The FDA took this data and - given the millions of doses of mRNA vaccines that showed safety - recommended that the bivalent booster contain what they thought would be the dominant Omicron in the fall "That prediction turned out to be largely correct so now we have a bivalent booster that actually matches the circulating Omicron strain and boosts immune response from the original vaccine strain Dr Roberts said the process of authorisation is similar to what happens with influenza vaccines each year "There is not time to perform clinical trials with the new influenza vaccine virus every year (since the results/approval would not occur until many months into the flu season well past the time point when many would have been exposed to influenza) so a mouse model is used to determine immune response and the new strains are used to update the vaccines," he said "The vaccine is manufactured in the same method so no new clinical trials are needed." The claim Pfizer only provided data from mice trials in its application to US authorities for its BA.4/5 COVID-19 booster vaccine is misleading The authorisation was also based on pre-clinical and clinical data for the original mRNA vaccines and a bivalent BA.1 booster vaccine Experts told AAP FactCheck the emergency use authorisation process for the BA.4/5 boosters is similar to what happens with influenza vaccines each year Misleading – The claim is accurate in parts but information has also been presented incorrectly AAP FactCheck is an accredited member of the International Fact-Checking Network. To keep up with our latest fact checks, follow us on Facebook, Twitter and Instagram Every AAP FactCheck article is the result of a meticulous process involving numerous experienced journalists and producers carefully crafted and rigorously scrutinised to ensure the highest standard of accuracy and objectivity in every piece AAP FactCheck is an accredited member of the International Fact-Checking Network Metrics details Microplastics (MPs) are a significant environmental health issue and increasingly greater source of concern MPs exposure on marine organisms and humans has been documented but information about the toxicity of MPs in mammal is limited Here we used fluorescent and pristine polystyrene microplastics (PS-MPs) particles with two diameters (5 μm and 20 μm) to investigate the tissue distribution and tissue-specific health risk of MPs in mice Results indicated that MPs accumulated in liver with a tissue-accumulation kinetics and distribution pattern that was strongly depended on the MPs particle size analyses of multiple biochemical biomarkers and metabolomic profiles suggested that MPs exposure induced disturbance of energy and lipid metabolism as well as oxidative stress blood biomarkers of neurotoxicity were also altered Our results uncovered the distribution and accumulation of MPs across mice tissues and revealed significant alteration in several biomarkers that indicate potential toxicity from MPs exposure our data provided new evidence for the adverse consequences of MPs widespread use and persistence of MPs is expected to lead to its accumulation in the environment and greater exposure risk for wild organisms and human populations over time data on tissue accumulation of MPs in mammalian models would be indispensable for risk assessment of MPs in human health The purpose of this study is to quantify the distribution and accumulation of MPs in mice (Mus musculus) tissues based on fluorescence spectroscopy and address toxicological responses to MPs exposure using enzymatic biomarkers and metabolomic profiles The results of this study provide new insights about the potential health risk of MPs exposure ICR) were purchased from Qinglongshan Animal Breeding Center (Nanjing The mice were housed in stainless-steel cages and acclimated for two weeks at 25 ± 4 °C All experimental processes were in accordance with NIH Guide for the Care and Use of Laboratory animals The protocol was approved by the Committee on the Ethics of Animal Experiments of the Nanjing Military General Hospital A total of 75 mice were randomly assigned to 15 cages (n = 5 for each cage) mice were used as negative controls and treated with microplastics-free water Seven cages of mice were treated with 5 μm fluorescent PS-MPs and 7 others were treated with 20 μm fluorescent PS-MPs l mg MPs were dispersed in 5 mL Milipore Mili-Q water and treated by ultrasonic vibration then 0.5 mL of the mixed solution was given once daily (0.1 mg/day) by oral gavage (1.46 × 106 items for 5 μm PS-MPs and 2.27 × 104 items for 20 μm PS-MPs) One cage of 5 mice from each of 5 μm and 20 μm MPs treatment groups were sacrificed at 1 kidney and gut) were removed and frozen at −80 °C In order to assess the retention of MPs in mice another 10 mice were randomly assigned to 2 cages (n = 5 for each cage) and also exposed to the two sizes of fluorescent PS-MPs (0.1 mg/day by oral gavage) for 28 days Then the exposure was terminated and one week later the mice were sacrificed and tissues samples were collected and stored at −80 °C The background fluorescence of the tissues of control mice were detected and subtracted from that of MPs-treated samples To confirm the accuracy of the standard curves The tissues were also fixed in 10% formalin and stained with hematoxylin and eosin (H&E) for final observation In order to observe the presence of fluorescent-labeled polystyrene microplastic particles in tissues one bright-field image was acquired by microscopy first and then a dark-field image of the same slide was acquired by epifluorescence microscopy the two sets of images were stacked together by using AxioVision Rel The high dose was 5 times as much as the middle dose All mice were sacrificed and examined after four weeks of exposure Liver and serum samples were collected and stored at −80 °C The livers of mice from the group treated with 0.5 mg/day PS-MPs and the control group were fixed in 10% formalin and stained with H&E for microscopic observation alterations of biomarkers in mice livers due to MPs exposure were determined These markers included: energy metabolism in terms of ATP level and lactate dehydrogenase (LDH) activity; lipid metabolism as the level of total cholesterol (T-CHO) and triglycerides (TG); oxidative stress-related biomarkers glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD); neurotoxic responses in terms of acetylcholinesterase (AChE) activity All these markers were detected by using commercial kit (Nanjing Jiancheng Bioeng and the measurements were conducted according to the manufacture’s protocols biomarker responses and relative contents of serum metabolites in exposed mice were compared with control ones by one-way ANOVA and post-hoc comparison (Bonferroni) was used to discriminate between mean values Level of significance was set at P < 0.05 These analyses were performed by SPSS 15 software (SPSS Inc. multivariate principal component analysis (PCA) was used to explore the relationships among different treatments and cluster the samples into groups of homogeneous observations The specific calculations were conducted using MetaboAnalyst 3.0 The z-scores of metabolites were calculated based on the following formula: Accumulation of different sizes of MPs in mice tissues after exposure for 28 days. Concentration of MPs in 3 tissues of mice at different exposure times All animals were alive after the 4 weeks of exposure. Full details about the body weight, organ weight, relative organ weight and food-intake are provided in Table S1 No significant changes for daily food consumption were found between control and MP treated groups No significant differences were observed for the final body weight and liver weight between control and treatment groups significantly decreased in the high dose (0.5 mg/day) treatment groups significantly increased food-intake was also observed in the mid and high dose treatment group of 20 μm MPs After the tissue accumulation experiments, 5 μm and 20 μm pristine PS-MPs were used for toxicological experiments. Representative histological sections of livers from mice exposed to 0.5 mg/day were examined (Fig. 3). Compared with control mice, inflammation and lipid droplets were observed in the livers of PS-MPs-treated mice. Black arrows indicate liver inflammation and white arrows indicate lipid droplets (A) ATP levels; (B) LDH activities; (C) T-CHO levels; (D) TG levels; (E) CAT activities; (F) GSH-Px levels; (G) SOD activities and (H) AChE activities *Means significant difference between MPs-treated groups and control group (P < 0.05) #Means significant difference between different MPs-treated groups (P < 0.05) mid (B) and high (C) doses of MPs-treated groups and control group (D) Number of differential metabolites among MPs-treated groups These represent additional dietary routes for human populations to be exposed to MPs there is not published data on human tissues exposed to MPs from any source and it remains unclear if MPs would accumulate in mammalian tissues fluorescence spectroscopy and histological analyses we traced the accumulation and distribution of MPs of two sizes in the livers We observed MPs of both sizes in all three tissues the data support the hypothesis that MPs not only accumulate in digestive system but that they are also transported to other tissues through the circulatory system Most research on the toxicity of MPs has focused on their impacts on aquatic organisms in contaminated environments few studies have evaluated the adverse effects of MPs on mammals a battery of biomarkers and metabolomic profiles were used to characterize the potential toxic effects of MPs in mice The documented effects highlight impacts on energy metabolism Ingested MPs could affect the normal absorption of food and inhibit food digestion These results indicated that MPs exposure could induce imbalance in the antioxidant defense system in mice Corresponding to a potentially neurotoxic response MPs exposure also caused increases of threonine All these metabolites act as neurotransmitter substances These alterations raise the possibility that MPs exposure could induce adverse effects on neurotransmission in mice Tissue accumulation of microplastics in mice and biomarker responses suggest widespread health risks of exposure Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations Policy: Classify plastic waste as hazardous News Feature: Microplastics present pollution puzzle Tiny particles of plastic are awash in the oceans-but how are they affecting marine life The Impact of Polystyrene Microplastics on Feeding Function and Fecundity in the Marine Copepod Calanus helgolandicus Microplastic and macroplastic ingestion by a deep diving oceanic cetacean: The True’s beaked whale Mesoplodon mirus Contamination of beach sediments of a subalpine lake with microplastic particles Microplastic Pollution in Table Salts from China The discharge of certain amounts of industrial microplastic from a production plant into the River Danube is permitted by the Austrian legislation Microplastic in Terrestrial Ecosystems and the Soil Ingested microscopic plastic translocates to the circulatory system of the mussel Assimilation of polybrominated diphenyl ethers from microplastics by the marine amphipod Early warning signs of endocrine disruption in adult fish from the ingestion of polyethylene with and without sorbed chemical pollutants from the marine environment Uptake and retention of microplastics by the shore crab Carcinus maenas Occurrence of microplastics in the gastrointestinal tract of pelagic and demersal fish from the English Channel Uptake and effects of microplastics on cells and tissue of the blue mussel Mytilus edulis L Trophic level transfer of microplastic: Mytilus edulis (L.) to Carcinus maenas (L.) Food Chain Transport of Nanoparticles Affects Behaviour and Fat Metabolism in Fish Ingestion and transfer of microplastics in the planktonic food web Uptake and accumulation of polystyrene microplastics in zebrafish (Danio rerio) and toxic effects in liver As main meal for sperm whales: Plastics debris Fate of Microplastics in the Marine lsopod Idotea emarginata Pollutants bioavailability and toxicological risk from microplastics to marine mussels Microplastic moves pollutants and additives to worms reducing functions linked to health and biodiversity Does the presence of microplastics influence the acute toxicity of chromium(VI) to early juveniles of the common goby (Pomatoschistus microps) A study with juveniles from two wild estuarine populations and Metabolism in Fish Exposed to Polystyrene Nanoparticles Accumulation and embryotoxicity of polystyrene nanoparticles at early stage of development of sea urchin embryos Paracentrotus lividus Microplastics in freshwater systems: A review of the emerging threats identification of knowledge gaps and prioritisation of research needs Mice in vivo toxicity studies for monohaloacetamides emerging disinfection byproducts based on metabolomic methods Environmental contaminant mixtures at ambient concentrations invoke a metabolic stress response in goldfish not predicted from exposure to individual compounds alone Widespread distribution of microplastics in subsurface seawater in the NE Pacific Ocean Microplastics in bivalves cultured for human consumption Potential Health Impact of Environmentally Released Micro- and Nanoplastics in the Human Food Production Chain: Experiences from Nanotoxicology In vivo Biodistribution and Urinary Excretion of Mesoporous Silica Nanoparticles: Effects of Particle Size and PEGylation Physiological versus viscosity-induced effects of an acute reduction in water temperature on microsphere ingestion by trochophore larvae of the serpulid polychaete Galeolaria caespitosa Size and shape effects in the biodistribution of intravascularly injected particles Gastrointestinal persorption and tissue distribution of differently sized colloidal gold nanoparticles Repeated-dose toxicity and inflammatory responses in mice by oral administration of silver nanoparticles Photomodulation of oxidative metabolism and electron chain enzymes in rat liver mitochondria Toxicological effects of cinnabar in rats by NMR-based metabolic profiling of urine and serum Microplastic ingestion decreases energy reserves in marine worms Prostaglandins Leukot Essent Fatty Acids 82 Single and combined effects of microplastics and pyrene on juveniles (0 + group) of the common goby Pomatoschistus microps (Teleostei Methionine residues as endogenous antioxidants in proteins Chronically and acutely exercised rats: biomarkers of oxidative stress and endogenous antioxidants Natural factors to consider when using acetylcholinesterase activity as neurotoxicity biomarker in Young-Of-Year striped bass (Morone saxatilis) L-Tyrosine administration increases acetylcholinesterase activity in rats Download references This research work was financially supported by the National Natural Science Foundation of China (No 21304045) and National Key Technology Support Program (2014BAC08B07) State Key Laboratory of Pollution Control and Resource Reuse Program in Molecular and Integrative Physiological Sciences all authors performed parts of the data analysis and wrote the paper The authors declare no competing financial interests Download citation Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology Science has moved one step closer to allowing two men to reproduce without the need of a surrogate Japanese researchers created seven mice with two male biological parents using skin cells from a male mouse to form a viable egg and then fertilize it They hope this research pushes forward treatments for infertility. But, it also paves the way for men in same-sex relationships to have a child without needing a surrogate  - which has happened in increasing numbers recently 'This is the first case of making robust mammal oocytes from male cells,' Katsuhiko Hayashi of Kyushu University He went on to say it could be functional in humans within the next decade who presented their findings at the Third International Summit on Human Genome Editing in London wanted to develop a treatment for Turner's syndrome It occurs when they suffer an X chromosome that is either partially or fully missing in their genetic makeup These chromosomes are first developed in the womb and determine whether a fetus will undergo male or female development Women born with just one X chromosome are often infertile are smaller and suffer an increased risk of heart or learning disabilities Japanese researchers hope to develop a stem cell treatment to fix infertility associated with the condition They created stem cells using eight-week-old mice picking ones that had dropped a Y chromosome for some reason Same-sex couples help fuel the booming demand in the industry.  Scientists then manipulated the cells in a way to copy the remaining X chromosome and create a cell with two X genes - what would usually be considered a female cell 'The biggest trick of this is the duplication of the X chromosome,' Dr Hayashi said They turned those cells into eggs and used sperm from male mice to fertilize them in the laboratory The process led to the birth of more than a half-dozen healthy mice pups Dr Hayashi told the New Scientist he believes the door is now open to children being born from two fathers his team hopes to replicate this same process with human cells 'Purely in terms of technology, it will be possible [in humans] even in 10 years,' he told The Guardian. 'I don't know whether they'll be available for reproduction. 'That is not a question just for the scientific program, but also for [society].'  Other experts have described the research as ground-breaking, but say there are still long ways to go before two human males can have a child without the need of a woman.  More than 70,000 women in America suffer from Turner's syndrome, or around one in every 2,000. Demand for surrogates in America has boomed in recent years, partly because of an influx of same-sex couples seeking children. Scientists create mice with TWO biological fathersCommenting on this article has endedNewest{{#isModerationStatus}}{{moderationStatus}} Notifications can be managed in browser preferences. Small-scale study on humans aged 60 to 70 planned for later this year I would like to be emailed about offers, events and updates from The Independent. Read our Privacy notice The chemical in cannabis that makes people feel ‘high’ appears to improve learning and memory in older mice, a new study has found – with similar tests on humans planned for later this year. Researchers gave a low dose of tetrahydrocannabinol (THC) to mice of different ages as part of a new study investigating the brain systems involved in the ageing process. They tested the rodents’ memory and found that after the old mice received THC, their powers of recollection matched those of young mice who had not been given anything. Andras Bilkei-Gorzo, who led the study published in the journal Nature Medicine, said he is now organising a small-scale study of around 100 volunteers aged 60 to 70 to find out if similar effects are seen in humans. “THC restored the cognitive ability of the old mice to the level of the young ones,” he told The Independent. With age, the brain’s endocannabinoid system, which affects mood, memory and sensations such as pain and is also receptive to marijuana compounds, “actively declines,” he said. “Giving THC artificially activates the system in the old [mice]. It can restore signalling to a normal level.” However, when the young mice were given THC, they performed the memory task less well than those who did not receive the compound. “If you do the very same treatment, with the same dosage, to young mice, you overdrive the whole system,” said Dr Bilkei-Gorzo. “It’s at a much higher level than it should be.” Physciatrist Michael Bloomfield, from University College London, said the”well-conducted” study was “exciting” as it “opens up a whole new chemical system, called the endocannabinoid system, as a potential target for new avenues of research which could include illnesses like dementia.” “However, we are still in very early days and further research is needed. This is because THC produces very complicated and sometimes seemingly opposite effects depending on, for example, its dose, age of the person or animal, how often the drug is administered and species differences in all of the above," he said. "This means that the possibility of doctors potentially prescribing, cannabis THC or similar compounds for memory problems in older people is still a long way off.” Dr Bilkei-Gorzo and his team at the University of Bonn in Germany tested the effects of THC in mice aged two months, 12 months and 18 months. In one of the three cognitive tests used in the study, they gave the mice the choice of interacting with an object or another mouse, which they usually find “much more interesting,” choosing to spend 70 per cent of their time in the cage with the other animal. Then, 24 hours later, the scientists put the mice back in the same place, and give them the choice of interacting with the mouse they met before, or a completely new mous. “Does the animal remember it saw the animal before, and spend more time with the new one? If it can’t remember, it spends half of its time with the new one and half of its time with the older one,” said Dr Bilkei-Gorzo. “That’s what we saw in the old animals – a day after they first met the other mouse, they couldn’t distinguish between the old and new one. The young ones have no difficulty; they do distinguish and they spend more time with the new one.” However, when the old mice were given THC, they improved at recognising the mouse they had already met, to the same level as the young mice. While it would be “fantastic” if clinical studies on humans were to see similar positive results, Dr Bilkei-Gorzo said he did not recommend taking up smoking cannabis. “If everyone over 60 starts to smoke marijuana, it probably wouldn’t have a good outcome,” he said, with a slight giggle. “It’s a real danger, because we know that everything depends on the dosage and the age that you start.” Dr Doug Brown, Director of Research at Alzheimer’s Society, said: “This study shows that a component of cannabis, called THC, could have a beneficial effect on memory and learning in older mice. “Though an interesting finding, the study does not shed light on the effect of THC on people with dementia, as it only looked at age-related memory decline in mice. “The study also does not reveal anything about the effect of cannabis on dementia, or memory problems in old age, as THC is only one of many chemicals that make up cannabis, and we don’t know what effects the other chemicals might have.“ Join thought-provoking conversations, follow other Independent readers and see their replies This page has been archived and is no longer updated anaesthesia and after cardiac arrest (i.e. after death) from right and left frontal (RF/LF) parietal (RP/LP) and occipital (RO/LO) cortex ‘brain waves') for each area is shown in the Figure below the recording ranges from about 1hr before death to 30mins afterwards At this coarse time scale you can basically see a sudden decrease in brain activity after cardiac arrest - everything seems to flatline at the moment of death if we now zoom in on the moment just after death (Panels B and C below) we can see that the death process actually involves a sequence of structured stages including a surge of high-frequency brain activity that is normally associated with wakefulness and conscious awareness the neuroscientists distinguish four distinct stages of brain death Cardiac arrest stage 1 (CAS1) reflects the time (~4 seconds) between the last regular heartbeat and the loss of a oxygenated blood pulse (i.e The next stage (CAS2) lasts about 6 seconds and ends with a burst in low-frequency brain waves (so-called 'delta blip') lasts approximately 20 seconds at which point there is no more evidence of meaningful brain activity at the final stage These stages seem to reflect an organized series of distinct brain states rather than a gradual fade out of brain activity we see a sudden transition from the anaesthetised state with an increase in fast brain waves It is as if the brain is suddenly shaken from the effects of anaesthesia at the moment of death brain activity settles into a period of slower brain waves during CAS2 recordings are then dominated in CAS3 by brain waves more commonly associated with normal wakefulness during life (so-called gamma activity) the researchers also show that this ‘afterlife' brain activity is also highly coordinated across brain areas and different wavelengths These are the neural hallmarks of high-level cognitive activity these data suggests that long after clinical death the brain enters a brief state of heightened activity that is normally associated with wakeful consciousness the authors even suggest that the level of activity observed during the final active death stage (CAS3) not only resembles the waking state but might even reflect a heightened state of conscious awareness similar to the "highly lucid and realer-than-real mental experiences reported by near-death survivors" This is a pretty bold claim that critically depends on their quantification of 'consciousness' They argue that in the final stage of brain death there is actually more evidence for consciousness-related activity than during normal wakeful consciousness But how can we quantity ‘consciousness-related activity' To date, there is no handy index of consciousness that we can use to infer the true state of awareness. And even if we could derive such a consciousness metric in humans (see here) how could we relate it to the rodent experience Research in animals can only ever hint at human experience this research demonstrates a surge in brain activity after death that is consistent with active cognitive processing This suggests that a neural explanation for these experiences is at least plausible They have identified the right kind of brain activity for a neural explanation of near-death experiences yet it remains to be verified whether these signatures do actually relate directly to the subjective experience Future directions: The obvious next step is to test weather similar patterns of brain activity are observed in humans after clinical death Then it will be important to show that such activity is strongly coupled to near-death experience does the presence or absence of such activity predict whether or not the person would report a near death experience This second step is obviously fraught with technical and ethical challenges (think: The Flatliners) but would provide good evidence to link the neural phenomena to the phenomenal experience [this post is adapted from Death Wave at The Brain Box] near Mechelen (Antwerp Province) has a new resident a lioness that had been kept as a pet in a flat in Ukraine will be cared for at Planckendael Vanda had been kept in a room with no natural light When she was taken from the flat she was malnourished the lioness will be given time to recover from her ordeal before moving to a new permanent how a lion sanctuary in Kent in southeast England at the end of the year It was the family that owned Vanda that asked for her to be taken away Zoo Planckendael’s Amanda Wielemans told VRT News that "She was living in a block of flats with no natural light and was being given the wrong food and as a result was malnourished because it is of course dangerous to keep a wild animal like that” The lioness will remain at Planckendael until the end of the year and will then be taken to a lion sanctuary in the English county of Kent Vanda will be kept out of view of visitors to Planckendael "Vanda won’t be put with the other lions as they are all Asian lions We will take care of her behind the scenes” The lion keepers at Planckendael are happy that Vanda is coming "It’s a pleasure for us to be able to take care of Vanda We have the correct facilities and expertise Vanda was recused together with her 2 sisters Amani and Lira They had been bred illegally to pose for photographs Amani and Lira are currently at the Pairi Daiza animal park in Hainaut Province is being cared for at the Nature Assistance Centre in Oudsbergen (Limburg Province) A wild tusker 'Rowdy Ranga' was killed in a road accident near Mathigodu Elephant Camp on Monday after being knocked down by a speeding bus on the Thithimathi-Gonikoppa highway "He had finished grazing and was crossing the road to get back to the camp when a speeding private bus hit him," said Range Forest Officer (RFO) Surendra Ranga was aged between 45 and 48-years-old and was brought to Mathigodu camp in July 2017 from Bannerghatta forest area to be trained to use his services for capturing other "rogue" elephants that entered human landscape frequently A case has been registered against the driver Ismail Nalkath Bin Khader under the Wildlife Protection Act. The villagers were into tears as the tusker breathed his last the Ponnampet police had to intervene to control the villagers who rushed to the spot to see the elephant as he struggled for his life The forest officials who visited the spot included Mysuru wildlife division deputy conservator of forest Hanumanthappa assistant conservator of forest Prasanna and Surendra among others "It is not possible to stop traffic on this road as there is no alternative route available mitigation measures such as putting speed breakers awareness boards and holding awareness programmes should be carried out," said conservationist Col Muthanna an Indian Gaur was killed on this same place after it collided with a lorry There has to be strict enforcement of laws in this regard and proper cases should be filed against defaulters