Understanding and embracing diversity is at the core of Prudential Advisors' approach to its relationship with clients This is also why the business is a member of the Luminaries Class of 2024 in two categories The first is the Broker-Dealer Firm – Corporate Social Responsibility category was nominated for an Individual Award – in the Luminaries with Heart category To better understand the business’ efforts vice president of strategic initiatives at Prudential Advisors vice president of business and market expansion in Prudential’s Individual Life business sat down with Think Advisor Contributor Bobbie Turner to discuss the company’s efforts ●     Prudential’s Blueprints to Black Wealth strategy and how that program has developed over the last several years; ●      How advisors can embrace client diversity to grow their business ●      The importance of authentic community partnerships registered investment advisors and wealth managers with comprehensive coverage of the products services and information they need to guide their clients in making critical wealth Metrics details Expanded TA repeats form non-B DNA secondary structures that stall replication forks the expanded TA-dinucleotide repeats are susceptible to cleavage by the MUS81 nuclease These findings identify a distinct biomarker that underlies the synthetic lethal dependence on WRN and support the development of therapeutic agents that target WRN for MSI-associated cancers Prices may be subject to local taxes which are calculated during checkout END-seq, ChIP–seq, whole-genome sequencing and Pacbio CLR data have been deposited in the Gene Expression Omnibus (GEO) database under the accession number GSE149709. Source data are provided with this paper Prioritization of cancer therapeutic targets using CRISPR–Cas9 screens WRN helicase is a synthetic lethal target in microsatellite unstable cancers Werner syndrome helicase is required for the survival of cancer cells with microsatellite instability Werner syndrome helicase is a selective vulnerability of microsatellite instability-high tumor cells Comprehensive analysis of indels in whole-genome microsatellite regions and microsatellite instability across 21 cancer types Microsatellite instability as a biomarker for PD-1 blockade RecQ helicases: multifunctional genome caretakers ATR prohibits replication catastrophe by preventing global exhaustion of RPA DNA breaks and end resection measured genome-wide by end sequencing ATM and PRDM9 regulate SPO11-bound recombination intermediates during meiosis Sensitive mapping of recombination hotspots using sequencing-based detection of ssDNA Dual roles of Poly(dA:dT) tracts in replication initiation and fork collapse Large-scale stable opening of supercoiled DNA in response to temperature and supercoiling in (A + T)-rich regions that promote low-salt cruciform extrusion Formation of (dA-dT)n cruciforms in Escherichia coli cells under different environmental conditions Superhelical torsion in cellular DNA responds directly to environmental and genetic factors Molecular basis for expression of common and rare fragile sites Sequence and nuclease requirements for breakage and healing of a structure-forming (AT)n sequence within fragile site FRA16D CtIP maintains stability at common fragile sites and inverted repeats by end resection-independent endonuclease activity Genome-wide identification of structure-forming repeats as principal sites of fork collapse upon ATR inhibition Chromosomal instability mediated by non-B DNA: cruciform conformation and not DNA sequence is responsible for recurrent translocation in humans Structure-specific endonucleases: guardians of fragile site stability ATR and ATM differently regulate WRN to prevent DSBs at stalled replication forks and promote replication fork recovery A molecular portrait of microsatellite instability across multiple cancers Detection of long repeat expansions from PCR-free whole-genome sequence data Detecting expansions of tandem repeats in cohorts sequenced with short-read sequencing data Long-read sequencing for rare human genetic diseases On the wrong DNA track: molecular mechanisms of repeat-mediated genome instability Fragile sites in cancer: more than meets the eye Comprehensive molecular characterization of human colon and rectal cancer The ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium Identification of a chromosome 18q gene that is altered in colorectal cancers Predicting tumor response to PD-1 blockade Genetic diversity of tumors with mismatch repair deficiency influences anti-PD-1 immunotherapy response ATR inhibition potentiates ionizing radiation-induced interferon response via cytosolic nucleic acid-sensing pathways Mitotic progression following DNA damage enables pattern recognition within micronuclei 53BP1 enforces distinct pre- and post-resection blocks on homologous recombination CDK1 phosphorylates WRN at collapsed replication forks Crystal structure of the Mus81-Eme1 complex BEDTools: a flexible suite of utilities for comparing genomic features MEME SUITE: tools for motif discovery and searching The Sequence Alignment/Map format and SAMtools ExpansionHunter: a sequence-graph-based tool to analyze variation in short tandem repeat regions Minimap2: pairwise alignment for nucleotide sequences Mosdepth: quick coverage calculation for genomes and exomes Tandem repeats finder: a program to analyze DNA sequences Next-generation characterization of the Cancer Cell Line Encyclopedia Download references Awasthi for assistance with Southern blotting; D Tran and the CCR Genomics core for sequencing support; M Lawrence for computational assistance; and F laboratory is supported by the Francis Crick Institute (FC10212) and the European Research Council (ERC-ADG-666400) The Francis Crick Institute receives core funding from Cancer Research UK Fugger is the recipient of fellowships from the Benzon Foundation and the Lundbeck Foundation laboratory is funded by the MRC MR/R009368/1; A.C.-M is the recipient of a fellowship from AstraZeneca; E.M.C is supported by the Damon Runyon Cancer Research Foundation are supported by a pilot grant from the Dana-Farber Department of Medical Oncology laboratory is supported by the Intramural Research Program of the NIH an Ellison Medical Foundation Senior Scholar in Aging Award (AG-SS- 2633-11) the Department of Defense Idea Expansion (W81XWH-15-2-006) and Breakthrough (W81XWH-16-1-599) Awards the Alex’s Lemonade Stand Foundation Award These authors contributed equally: Niek van Wietmarschen MRC Weatherall Institute of Molecular Medicine performed END-seq and flow cytometry experiments upon WRN and performed preliminary analysis of END-seq data; W.J.N performed MUS81–EME1 in situ END-seq and PCR; A.T Southern blotting and designed ATR-mutant WRN cDNA; E.M.C generated the inducible WRN shRNA in KM12 and HCT116 cells performed and analysed the HSEC western blot and viability experiments and analysed the CCLE and WRN dependency data; E.C Foster performed the HSEC and long-read sequencing experiments; N.W performed western blotting and helped to generate WRN(3A) and WRN(6A) cells; J.N analysed the CCLE and WRN dependency data; S.S analysed nucleotide composition of broken versus non-broken repeats and replication timing; E.D performed ExpansionHunter and exSTRa bioinformatic analysis; M.A.E analysed the data and designed bioinformatic pipelines; R.L.W Fugger provided recombinant MUS81–EME1; J.A.S provided advice about PCR across repeats; K.U provided advice about repeat expansion biology; C.H.F provided advice about secondary structure biology; R.M.B provided advice about structure specific nucleases and recombination intermediates; P.J.M helped design in situ experiments with recombinant proteins; P.S.M provided advice on WGS experiments and analyses; A.J.B wrote the manuscript with comments from the other authors Peer review information Nature thanks Sergei Mirkin and the other anonymous reviewer(s) for their contribution to the peer review of this work Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations Source data Venn diagram showing overlap between peaks identified from END-seq and RPA-bound ssDNA ChIP–seq for KM12-shWRN cells treated with doxycycline for 72 h n = 1,000 random datasets were generated to test significance of overlap using one-sided Fisher’s exact test (P < 2.2 × 10−16) Composite plot of END-seq (black: positive-strand reads grey: negative-strand reads) and RPA-bound ssDNA ChIP–seq (blue: positive-strand reads red: negative-strand reads) signal around DSB sites in KM12-shWRN cells treated with doxycycline for 72 h Heat map displaying intensity of END-seq signal in KM12-shWRN cells treated with doxycycline for 72 h relative to the centre of the gap between positive- and negative-strand peaks Calculated size distribution from the reference genome of (TA)n repeats either located in gaps between positive and negative END-seq peaks (black broken sites) or located elsewhere in the genome (grey determined from KM12-shWRN cells treated with doxycycline for 72 h Source data Genome browser screenshot displaying END-seq profiles of common fragile sites FRA16D FRA10B and FRA7I as normalized read density (RPM) for KM12-shWRN cells treated with DMSO (NT) or doxycycline (shWRN) for 72 h The number of uninterrupted (TA)n repeat units in the hg19 reference genome at DSB sites is indicated Genome browser screenshot displaying END-seq profiles of PATRRs on chromosomes 11 and 22 as normalized read density (RPM) for KM12-shWRN cells treated with DMSO (NT) or doxycycline (shWRN) for 72 h Quantitative PCR with reverse transcription (qRT–PCR) analysis quantification (n = 1) of MUS81 and SLX4 mRNA levels in KM12-shWRN cells transfected with non-targeting siRNAs (siCTRL) Representative images of metaphase spreads from KM12-shWRN cells treated with doxycycline (shWRN) and non-targeting siRNAs (siCTRL) Data are representative of three independent experiments Flow cytometric profiles for KAP1 phosphorylation in exponentially growing KM12-shWRN cells treated with doxycycline (shWRN) Genome browser screenshot displaying END-seq profiles as normalized read density (RPM) for KM12-shWRN cells treated with doxycycline (shWRN) Schematic representation of DNA cruciform cleavage by MUS81–EME1 structure-specific endonuclease Venn diagram displaying overlap of END-seq TA breaks between two biological replicates of DMSO-treated KM12-shWRN cells processed with purified recombinant MUS81–EME1 enzyme in situ (MUS81–EME1) Venn diagram showing overlap in TA breaks between KM12-shWRN cells treated with doxycycline (shWRN) for 72 h and DMSO-treated cells processed with MUS81–EME1 enzyme in situ (MUS81–EME1) Venn diagram displaying overlap between TA breaks from KM12-shWRN and HCT116-shWRN genomic DNA processed in situ with MUS81–EME1 in situ (n = 1 for HCT116) Genome-wide aggregate analysis of END-seq signal around TA breaks from KM12-shWRN cells treated with doxycycline for 72 h (shWRN) (black denotes positive-strand reads or DMSO-treated KM12-shWRN cells processed with purified recombinant MUS81–EME1 enzyme in situ (blue denotes positive-strand reads Genome browser screenshot displaying END-seq profiles for DMSO-treated KM12-shWRN cells (WRN proficient) processed in situ with either purified recombinant WRN proteinase K digestion was performed between the two enzymatic treatments Source data Genome browser screenshot displaying END-seq profiles within FRA3B on chromosome 3 as normalized read density (RPM) for KM12-shWRN and eHAP-shWRN cells treated with doxycycline (shWRN) for 72 h or APH plus ATRi for 8 h Venn diagrams displaying overlap of DSBs detected after WRN depletion or APH plus ATRi treatment in KM12 and HCT116 cells n = 1,000 random datasets were generated to test significance of overlap using one-sided Fisher’s exact test for both the Venn diagrams (P < 2.2 × 10−16) Source data Box plots displaying coverage at different classes of mono- and di-nucleotide repeats in PCR-free whole-genome sequencing libraries made from HCT116 cells (TA)n repeats are split into those that overlap END-seq peaks after shWRN induction Dotted red lines indicate the average coverage over the genome Source data Box plots displaying coverage at different classes of repeats in long-read sequencing libraries made from MSI (red) and MSS (blue) cells (n = 1) Motif analysis for sequence enrichment at broken (TA)n in the KM12 cell line from long-read sequencing data Source data Source data Genome browser screenshot of a broken (TA)n (defined from KM12) MSI deletion (derived from a patient sample) and END-seq profile (in WRN-depleted KM12 cells) The sequences around the breakpoints are shown in the inset Junctions associated with six different MSI deletions from patients Seq1 represents the sequence from −50 bp to left breakpoint and Seq2 represents the sequence from right breakpoint to +50 bp and long interspersed nuclear element (LINE) short interspersed nuclear element (SINE) and long terminal repeat (LTR) elements at patient deletion breakpoints relative to their overlap with random deletion breakpoints of the same size (enrichment value = 1) B(TA)n–B(TA)n represents cases in which both breakpoints overlap with broken (TA)n repeats; B(TA)n− represents cases in which only one breakpoint overlaps with a broken (TA)n repeat Genome browser screenshots within DCC gene displaying END-seq profiles as normalized read density (RPM) for KM12-shWRN cells treated DMSO (NT) Zoom-in view of region including exons 6 and 7 of DCC gene containing two (TA)n repeats displaying END-seq peaks The highlighted sequences below were extracted from long read sequencing reads in KM12 cells The (TA)n repeat in intron 7 is where Vogelstein and colleagues previously detected an insertion This file contains Supplementary Figure 1: Source Data Gels and Supplementary Table 1: Genomic locations of PCR products Download citation DOI: https://doi.org/10.1038/s41586-020-2769-8 Anyone you share the following link with will be able to read this content: a shareable link is not currently available for this article Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research Metrics details Antibiotic-associated diarrhea (AAD) occurs in 2–25% of nursing home residents Research shows that probiotics can be effective and safe in reducing AAD probiotics are not routinely used in Dutch nursing homes The objectives of this evaluation were to develop a procedure for the implementation of probiotics to prevent AAD in nursing homes and to evaluate the implementation process of probiotics in daily care A pragmatic participatory evaluation (PPE) design was chosen as it seemed a suitable approach for implementation of probiotics as well as for evaluation of its effectiveness in daily nursing home practice Probiotics administration was implemented in three nursing homes of the Rivas Zorggroep for residents with somatic and/or psychogeriatric conditions Ninety-three residents provided data on 167 episodes of antibiotics use of which 84 episodes that included supplementation with probiotics and 83 episodes with no probiotics supplementation A multispecies probiotics was administered twice daily upon start of antibiotic treatment up to 1 week after completing the antibiotics course The occurrence of AAD was monitored and a process evaluation was conducted to assess facilitators and barriers of probiotics implementation The number of episodes with AAD when using probiotics was significantly lower than when no probiotics was used (20% vs 36%; p = 0,022 No significant differences in the occurrence of AAD were found between the residents taking amoxicillin/clavulanic acid or ciprofloxacin Reported facilitators for implementation were perceived benefits of probiotics and prescription by medical staff Reported challenges were probiotics intake by residents and individual decision-making as to which resident would benefit from it Successful implementation of probiotics demonstrated the prevention of AAD in nursing home residents ISRCTN 94786163 retrospectively registered on 3 February 2020 there is a high need for effective interventions that can reduce AAD The aim of this evaluation was twofold: 1) evaluation of changes in the occurrence of AAD by administrating multispecies probiotics to nursing home residents, and 2) evaluation of the implementation process of probiotics in daily nursing home practice. Timeline of the pragmatic participatory evaluation consisting of three phases and two time periods from which data is collected Rivas Zorggroep is an organisation that provides various types of care facilities for over 1000 residents in a total of 18 locations throughout the Netherlands Probiotics administration was implemented in three nursing homes of the Rivas Zorggroep for residents with somatic and/or psychogeriatric conditions: Alblashof in Alblasserdam (60 rooms) Participants in this PPE were residents with somatic and/or psychogeriatric conditions of three nursing homes from the Rivas Zorggroep All residents requiring amoxicillin/clavulanic acid or ciprofloxacin were allowed to participate after giving consent The dietician was designated as the main contact person for questions regarding the protocol and administration of probiotics and monitored the actual administration of probiotics together with the nursing staff data from multiple episodes of antibiotics use per resident were available Changes in residents’ stools were routinely recorded in the medical records of the residents by nursing staff Antibiotics associated diarrhoea was defined as stools described as looser than normal stools during a period of a few weeks before antibiotics use The elderly care physician extracted data from episodes of antibiotic use with and without probiotics from the medical records and judged whether the diarrhoea occurred as a result of each of the episodes of antibiotics use The elderly care physician was not blinded for who received probiotics and who not The start and end dates of the administration of probiotics and antibiotics and occurrence of adverse events were recorded The occurrence of AAD was calculated by comparing episodes of antibiotic use with or without probiotics supplementation Relationship between data collection of number of residents and episodes of antibiotics use From 27 residents data were collected from both episodes of antibiotic use with and without probiotics supplementation In 27 residents with multiple antibiotic episodes AAD occurred in 15% (n = 4) of the residents when on probiotics compared to 52% (n = 14) of the residents when antibiotics were given without probiotics One of the 13 residents not developing AAD during antibiotics treatment without probiotics actually developed AAD when using probiotics during a later episode of antibiotics use 3 (15%) of the 14 residents which did develop AAD during antibiotics treatment without probiotics did also develop AAD when taking antibiotics in combination with probiotics treatment The process evaluation was based on observations during two project team meetings and three focus group sessions two elderly care physicians and one dietician joined in at least one of the focus group sessions Results from the process evaluation were thematically categorized in facilitators challenges and protocol adaptations for implementation of probiotics in Dutch nursing homes Several facilitators for the implementation process were identified The use of probiotics fits within the current societal trend of healthy lifestyle and prevention Nursing home residents were in general curious open for improvements and had supporting families Nursing staff perceived the benefits of probiotics: They were of the opinion that it was important to contribute to less AAD to improve residents’ quality of life and to save time washing residents and changing diapers The presence of the dietician as the designated contact person for nursing staff to answer practical questions about logistics was also found to be a facilitator as it motivated the nursing staff A team of eight elderly care physicians prescribed the probiotics and supported the implementation with strong leadership from one elderly care physician that mobilized support from colleagues and prioritized and invested time in the implementation process Rivas Zorggroep management facilitated implementation by allowing the probiotics to be administered through the medication registration system and an in-house pharmacist that took responsibility for ordering distribution and storage of the probiotics at the various locations One of the challenges for the nursing staff was that residents had to consume the probiotics Many residents did not want to drink in the afternoon out of fear for nycturia Probiotics were mostly mixed with water by nursing staff while it was also allowed to mix these with dairy products not all residents liked the taste of the probiotics in water It was a challenge for the dietician to break the habit of nurses to mix the probiotics with water and convince them to choose more tasty options administration of probiotics required extra time from nursing staff especially because it was not allowed to administer it at the same time as the antibiotics Another challenge was to take the individual situation of each resident into account as to decide for each whether the use of probiotics was a beneficial option or not This PPE design had several limitations that need further discussion and reflection The protocol for implementation of probiotics for prevention of AAD in older people was specifically developed for the nursing home practice of the Rivas Zorggroep in the Netherlands The protocol was only evaluated in three nursing homes the outcome of the present process evaluation may not be representative for other nursing homes in the Netherlands It is recommended that other long-term care facilities that want to implement probiotics adapt the protocol according to their own internal organisation and context and take into account the facilitators and barriers as experienced in this PPE Another limitation is that a convenience sample of nursing home residents was used to evaluate the changes in AAD comparing a group with probiotics to a group with no probiotics Data for comparison were collected retrospectively (no probiotics) and prospectively (probiotics) and for 27 out of 93 residents comparison data derived from the same person The total number of eligible residents that were on amoxicillin/clavulanic acid during the period of the study and the number of those eligible residents receiving probiotics was not registered A certain degree of selection bias may thus have occurred and the observed significant differences in occurrence of AAD incidence with or without probiotics should therefore be interpreted with caution residents were not randomly allocated to the two groups The observed significant differences in occurrence of AAD might therefore also be due to other unknown factors rather than to probiotics supplementation Another limitation of the present PPE was that delayed-onset AAD and possible effects of probiotics on the frequency of delayed-onset of AAD were not monitored a standardized method such as the Bristol stool form chart for classification of the form of stool and blinding of the elderly care physician for probiotic use might have resulted in more objective assessment of the stool consistency Cost-related outcome measures were not evaluated in the present PPE but its outcome warrants further studies into the cost-effectiveness of probiotics Another interesting subject for further research is whether this multispecies probiotics can prevent recurrent urinary tract and other infections that occur in older people since that objective was not included in the present study successful implementation of probiotics demonstrated a reduction in the occurrence of AAD in nursing home residents Further studies are recommended to investigate whether probiotic use for prevention of AAD is cost-effective and whether it can prevent recurrent infections in older people The raw data used to produce the results presented in this manuscript is available as a supplementary file (S2 Data) Statistical Package for the Social Sciences Dutch Medical Research in Human Subjects Act (Wet Medisch-wetenschappelijk Onderzoek) Probiotics for Antibiotic-Associated Diarrhoea (PAAD): A prospective observational study of antibiotic-associated diarrhoea (including Clostridium difficile-associated diarrhoea) in care homes Antibiotic use in nursing homes nursing homes Clostridium difficile infection: How to deal with the problem Available from: https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/340851/Clostridium_difficile_infection_how_to_deal_with_the_problem.pdf%5Cnhttp://www.dh.gov.uk/prod_consum_dh/groups/dh_digitalassets/documents/digitalasset/dh_093218.pdf Expert consensus document: the international scientific association for probiotics and prebiotics consensus statement on the scope and appropriate use of the term probiotic Probiotics for the prevention and treatment of antibiotics-associated diarrhea Probiotics for the prevention of antibiotic-associated diarrhea in outpatients—a systematic review and meta-analysis Probiotics for the prevention of Clostridium difficile- associated diarrhea in adults and children (Review) Probiotics in prevention of antibiotic associated diarrhoea Participatory research: what is the history Thorpe KE, Zwarenstein M, Oxman AD, Treweek S, Furberg CD, Altman DG, et al. A pragmatic-explanatory continuum indicator summary (PRECIS): a tool to help trial designers. J Clin Epidemiol. 2009;62(5):464–75. https://doi.org/10.1016/j.jclinepi.2008.12.011 The effect of a multispecies probiotic on the intestinal microbiota and bowel movements in healthy volunteers taking the antibiotic amoxycillin Agamennone V, Krul CAM, Rijkers G, Kort R. A practical guide for probiotics applied to the case of antibiotic-associated diarrhea in The Netherlands. BMC Gastroenterol. 2018;18(1):103. https://doi.org/10.1186/s12876-018-0831-x Guidance on the characterisation of microorganisms used as feed additives or as production organisms Participatory research methods: a methodological approach in motion Effect of a fermented milk combining Lactobacillus acidophilus CL1285 and Lactobacillus casei in the prevention of antibiotic-associated diarrhea: a randomized Savings from the use of a probiotic formula in the prophylaxis of antibiotic-associated diarrhea Strain-specificity and disease-specificity of probiotic efficacy: a systematic review and meta-analysis No evidence of harms of probiotic Lactobacillus rhamnosus GG ATCC 53103 in healthy elderly - a phase i open label study to assess safety Safety assessment of probiotics for human use Choosing an appropriate probiotic product for your patient: an evidence-based practical guide Download references The authors thank Winclove BV for providing probiotics Heidi Schaffels-Stuijt and Anne-Marie Doppen for their support with the implementation of probiotics The authors also thank the nursing staff of Rivas for their support throughout the evaluation The PPE was funded by Winclove Probiotics BV The funding was used for personnel costs of HAW Probiotics in the PPE were provided by Winclove Probiotics BV. Winclove Probiotics BV also provided information on the use of the Multispecies probiotics for the implementation protocol The funder Winclove Probiotics BV had no influence on the drafting finalization and submission of the manuscript commented on and approved on the final manuscript The institutional review board and the client council of the Rivas Zorggroep approved the implementation and evaluation of probiotics All participants gave written informed consent for using their data. No data of individual participants is reported in the manuscript. The data file S2 Data contains data that cannot be traced back to individuals to conduct the participatory pragmatic evaluation Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations unless otherwise stated in a credit line to the data Download citation DOI: https://doi.org/10.1186/s12876-020-01297-w Avoiding complacency is the first order of business for St Xavier’s first-year cross country head coach Andy Wietmarschen The Bombers have won the past two Division I state championships Wietmarschen knows what it will take to keep the title streak alive “I think this team has a great shot at continuing the success that the St Xavier cross country program has enjoyed over the last 30-plus years,” said Wietmarschen we’ve stressed at the beginning of the season that nothing is given to us because we represent St The Bombers will be a trio of seniors who helped lead the team to a state title and sixth-place finish at the Nike Cross Nationals in 2013 and Cole Grabowski bring championship training and experience to the team and sophomore Chris Reischel will boost the varsity squad this season after contributing on the junior varsity last season Despite graduating several key members of last year’s team this year’s group is poised to reload and three-peat “We lost some great runners and teammates with the graduating senior class I’m more concerned than the runners about the guys that left,” said Wietmarschen are more focused on leaving their mark on this team We knew that we were going to have new guys stepping into new roles The guys are excited by the challenges these new roles are presenting.” The returning seniors helped set the standard last year they are setting the standard of excellence in practice and showing their new varsity teammates what it takes to reach the highest level of success “The guys that have won state championships and participated in the Nike Cross Nationals the last two years worked incredibly hard in earning those distinctions,” said Wietmarschen With what the team has been able to accomplish over the last two seasons Wietmarschen feels the pressure of inheriting a program that has dominated over three decades under the leadership of his predecessors Larry Merkel and Mike Dehring Having been an assistant coach for the past nine years as well as an alumni of the program the assistant coaching staff remained intact after Dehring stepped down following the 2013 season “I’ve had the opportunity to learn from Mike and Larry over the last nine years so I don’t think that the guys see too much of a difference from last year to this year,” said Wietmarschen “I don’t know of many places that have had three consecutive coaches that are as close to one another as we are and I would hope that they think of me in the same regard.” all of the assistant coaches from last year decided to stay with the team so there is a certain continuity that their presence brings to the team as well They are a great group of guys who can relate to all 130 of runners on some level.” The new head coach and new varsity runners can relate to one another Larry Merkel and Mike Dehring have done a phenomenal job for the last 30-plus years so to follow in their footsteps is quite intimidating,” said Wietmarschen “I told the guys at our opening meeting that we are all in the same boat The runners need to step up and fulfill new roles coaching this team is a great honor and privilege and I am very excited to guide this team throughout the season.” Things you buy through our links may earn Vox Media a commission the one a friend drags you to on a night you’d planned to stay in and re-watch The Sopranos for the fourth time A quick introduction or two when you first get there you’ll be left alone and forced to decide whether you’ll go out on a limb and start conversation with a stranger who could hate you or stay safe and fade into uninvited guest oblivion and one that I bet the pioneers behind Long Haired Businessmen (LHB) would have no trouble making If their ability to forge inroads into unfamiliar comedic territory is any indication of their fearlessness and Ben Wietmarschen might take off their shirts and say something like “I know our nipples are bigger than normal but are they side show big…and would you mind licking them?” Created by and starring Kareman and brought to life by the inimitable stylings of Hana El Assad Long Haired Businessmen is a lesson in middle fingering norms and jumping in with both feet Tell me about your comedy background and those of your co-creators before the show but directors would see it and random casting directors would see it and That’s was then I realized that making your own shit is definitely where it’s at That show ran at the UCB Theatre and right around then is when I got on Harold night and Maude night so that all happened within the last year was on a Harold team called Deckard with me and we thought each other was hilarious so once Deckard got broken up we knew we had to collaborate together and I started pitching ideas and the title came up during the pitch session It was one of those things where you say the title and you go “Oh that’s funny” but you don’t have anything to back it up but then we decided it was funny enough to commit to so we built out the concept and made it work We had a couple of trigger lines that we had scripted and made sure got in there to move each sketch along but the method was: script the scenario and improvise the dialogue one of the first episodes where the copy machine doesn’t work came from our thinking “That’s a basic scenario for an office setting and let’s just have these guys with long hair have it get in the way as they fix the copy machine.” And we would beat it out a little bit once we knew what the situation was but once we were filming it was follow the improv What other web series are you excited about right now His stuff’s more short film than web series but he drops new ones like every month or so and they’re always great Do you have any wisdom to impart to new online content creators Well I would start off by saying Long Haired has done well for what it is and for not having any promotional things behind it but it’s not like it’s blowing up or anything but I would say you gotta really be true to your idea I think a lot of times people make the mistake of trying to make something that will blow up as opposed to making something that they like Audiences have an innate ability to pick up on that Long Haired Businessmen might not be for everyone but I think most people can recognize that we’re having fun doing it and they respond to that The second step is keeping them short and easy to produce “I’m gonna make this web series and it’s all about New York City and we’re going to all these different places in New York” and it’s like but you need five grand and two weeks to do that.” I think that gets in people’s way Go in with a simple idea that has one location or something that you can just do in a weekend or a day Try to reach out to places like Splitsider or CollegeHumor if you can Not being bashful is another thing — just pimp it out I didn’t just think you’d call and put me on Splitsider You have to put yourself out there for those things Do you think there’s something about the artist’s personality that’s not as enterprising as somebody in a different There are definitely people hustling though I think it’s less of a screw missing and more of people just being scared That insecurity that comes with making shit and putting stuff out there It’s not like you or I feel any less fearful when we’re like hey look at our thing It’s just part of the process — you made this thing You’re not gonna spend all this time making something and then not try and get people to see it A lot of it is just sacking up and taking the criticism when it comes you realize that it’s not as complicated and daunting as you thought it would be Here are your three reasons to watch (and skip all haircuts for the next 18 months): The combination of long hair and suits is shocking enough LHB creators were shrewd in downplaying the humor surrounding this tireless sight gag Anything more animated would’ve taken away from the underlying brilliance of a simple Every beat feels authentic because of the actors’ improv adeptness the realism comes as much from intangibles as it does from eerily accurate corporate dialogue Less experimental creators might’ve worried about the staying power of a series oriented around one jarring visual Thank God they realized the expansive realm of longhaired possibilities Password must be at least 8 characters and contain: you’ll receive occasional updates and offers from New York DNA is shaped like a ladder with four letters A links with T on the other side to form a rung long stretches of back-to-back As and Ts form unusual DNA structures A study led by NCI researchers reinforces a recent idea that targeting an enzyme called WRN may be a new way to treat certain cancers No existing drugs are known to specifically target the enzyme but the NCI team—as well as several drug companies—are searching for one The new study addresses the big question of why MSI-high cancer cells depend so heavily on WRN WRN unwinds unusual DNA structures that occur more frequently in MSI-high cancer cells than in other cancer cells, the NCI researchers found. In MSI-high cancer cells that lacked WRN, these unusual structures eventually cause the DNA to shatter, killing the cells.  The findings, published September 30 in Nature, may change how cancer researchers think about microsatellite instability, said the study’s senior researcher, André Nussenzweig, Ph.D., of NCI’s Center for Cancer Research Teams from several other institutions also collaborated on the study.  was awed by over and over again when he looked through the microscope at MSI-high colorectal cancer cells that were engineered to lack WRN “In 40% of the cells, the chromosomes look like dust,” Dr He and his colleagues also noticed something else: The breaks occurred in the same areas in the genome, even in different kinds of lab-grown colorectal cancer cells. Nearly all of the breaks were near a long series of the same two DNA letters, or bases as if there was a stutter in the DNA.  Repeats of back-to-back Ts and As are found in healthy cells and cancer cells without MSI many TA repeats were much longer than normal Some were expanded several hundred times.  “I’d never seen anything like that before,” Dr scientists can finally read these elusive sections of DNA “It’s becoming clear that [we] are missing too many important [DNA] elements” with the standard way of sequencing As researchers eventually shift to using the newer technologies more features of DNA are likely to be discovered the new technologies are only available at a handful of large research institutions the team explored why long TA repeats are more likely to break the researchers suspected it had something to do with the shape DNA is usually shaped like a twisted ladder Ts and As on the opposite sides of the ladder link up But if there are a bunch of Ts and As next to one another on the same side of the ladder they can mistakenly connect with each other forming an X-shaped structure called a DNA cruciform he discovered that TA repeats readily form these structures long TA repeats did indeed form DNA cruciforms The enzyme’s job is to untangle these structures so that the DNA can get copied.  back-to-back repeats of certain DNA bases (TA repeats) are longer than normal (expanded TA repeat) These DNA sections often form an usual X-shaped structure called a DNA cruciform DNA can’t get copied and the cell will eventually die,” Dr WRN unwound DNA cruciforms in MSI-high cancer cells other enzymes cut the oddly-shaped DNA in a last-ditch effort to get rid of the structures.  Cells can typically recover from one or two DNA cuts But in the MSI-high cancer cells lacking WRN so many DNA cuts are made that chromosomes shatter and the cells die “Developing drugs that block WRN to treat MSI-high cancer is an exciting prospect,” Dr That’s because while blocking WRN is unlikely to have much of an effect on healthy cells “it’s super toxic in microsatellite unstable cells,” he said That kind of relationship—where an existing defect makes the cancer cells especially susceptible to a specific treatment—is called synthetic lethality It is especially sought out in cancer treatment approaches because it may cause fewer side effects by sparing healthy cells But Dr. Mirkin raised some concerns about blocking WRN. People with Werner syndrome age much faster and have a higher risk of cancer than people without the disorder And DNA cruciforms can occur in healthy cells But cancer treatment is always a balance of benefits and harms “Our findings may also provide a way to identify patients who might benefit from treatment with WRN-blocking drugs—even if the prospect of such a treatment is a long way down the road,” Dr Because the elongated TA repeats occur in the same spots the researchers say they could be a sort of marker to tell if a person’s cancer is dependent on WRN—and may therefore benefit from treatment with a WRN-blocking drug.  The scientists are now working on developing a simple test for finding elongated TA repeats in patients’ tumors Scientists currently define microsatellite instability as an abundance of small DNA changes like the addition or deletion of one or two DNA letters But the study findings suggest that definition may need to be refined The large DNA expansions—a result of the long TA repeats—that they observed are very different from the small DNA changes that are considered the hallmark of microsatellite instability There may even be two different kinds of microsatellite instability one marked by small DNA changes and the other by large DNA expansions Melanoma Cells Are More Likely to Spread after a Stopover in Lymph Nodes A More Treatable Kind of Metastatic Cancer If you would like to reproduce some or all of this content, see Reuse of NCI Information for guidance about copyright and permissions In the case of permitted digital reproduction please credit the National Cancer Institute as the source and link to the original NCI product using the original product's title; e.g. “Study Reinforces Treatment Idea for Cancer with Microsatellite Instability was originally published by the National Cancer Institute.” The dates displayed for an article provide information on when various publication milestones were reached at the journal that has published the article activities on preceding journals at which the article was previously under consideration are not shown (for instance submission All content on this site: Copyright © 2025 Elsevier B.V. The Centre of Political Philosophy is pleased to announce a lecture by Han van Wietmarschen associate professor at ULC -London's Global University interaction and conflict in a globalizing world ZANESVILLE - An application to forgive Muskingum Recreation Center more than $300,000 in delinquent property tax remains unanswered a lawsuit filed last year against the facility is still pending in court and little is expected to change under new management MRC board president submitted an application to the Ohio Department of Taxation requesting exemption and remission from real property taxes due by MRC for the 2016 and 2017 tax years Muskingum County Auditor Debra Nye attached an addendum to the application recommending the state grant the exemption which would forgive a total of $327,193 in property tax due to the county communications director for the Ohio Department of Taxation stated in an email that the application is still pending and currently being reviewed by staff He further stated that he could not say for certain when a final determination would be made According to the most recent information on the county treasurer's website MRC is currently indebted to the county $441,613 as property tax is now delinquent for the 2018 tax year seems to know who will assume responsibility for that or any of the other debts attached to the defunct program just four years after MRC began operations on the Ohio University Zanesville campus the four partners who oversee operations — OUZ Genesis Healthcare System and Muskingum Family YMCA — decided in the wake of financial distress that OUZ would take on the financial leadership role While operations were to remain under the ownership of MRC the board would be reconstructed and OUZ would become the soul governing member claiming the facility as one of its affiliated entities.  denied requests for information regarding the finances of the MRC under the non-profit corporation exclusion under public records laws Wietmarschen further indicated he could not speak in reference to a breach of contract lawsuit filed against MRC by Caprice Dittmar Dittmar was a paid member of the MRC when her membership was cancelled after she spoke out about the cleanliness of the pool complained about poor water quality that resulted in rashes on herself other patrons and employees of the facility which has been continued numerous times over the past year, is scheduled for jury trial in January The Muskingum Recreation Center was made possible by private donors as well as New Market Tax Credits (NMTC) financed through PNC The idea was to create a facility to work in cooperation with the Muskingum YMCA by providing a facility that would accommodate an indoor community pool and recreation center for the Muskingum County community.  area residents have long complained that the facility did not operate as a community recreation center, considering membership fees were higher the MRC board decided to partner with the Licking County Family YMCA to oversee the daily operations of the facility "In looking at the integration of the YMCAs the Licking County Family YMCA has the most capacity to oversee daily operations of MRC," said Ed Bohren "While the Muskingum Family YMCA is a founding partner of the MRC it does not currently operate a recreation center and lacks the depth of resources to assume operational oversight of the MRC.  The Licking County YMCA mission is to put Christian principles into practice through programs that build healthy spirit "Our mission is in alignment with the MRC to provide a safe clean and well-maintained facility that promotes health "The missing link in Muskingum County is youth and family That is something we will focus on with MRC." the Licking County YMCA provided $246,000 in financial assistance to families in the Licking County area who couldn't afford memberships.  executive director of the Muskingum Family YMCA the MRC will be an extension of the Muskingum Family YMCA "That was the idea from the beginning," Radde said.  there will be a new look at the former Muskingum Rec Center that will align more with the feel and mission of the YMCA.  scholarships will be available so that everyone has an opportunity to enjoy the facility amenities.  Please select what you would like included for printing: Copy the text below and then paste that into your favorite email application This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply Service map data © OpenStreetMap contributors Metrics details Bloom syndrome is a cancer predisposition disorder caused by mutations in the BLM helicase gene Cells from persons with Bloom syndrome exhibit striking genomic instability characterized by excessive sister chromatid exchange events (SCEs) We applied single-cell DNA template strand sequencing (Strand-seq) to map the genomic locations of SCEs Our results show that in the absence of BLM SCEs in human and murine cells do not occur randomly throughout the genome but are strikingly enriched at coding regions specifically at sites of guanine quadruplex (G4) motifs in transcribed genes We propose that BLM protects against genome instability by suppressing recombination at sites of G4 structures particularly in transcribed regions of the genome Here we show that SCEs in BLM-deficient cells occur frequently at sites of G4 motifs especially those present in transcribed genes we show that although LOH events appear to be more frequent in BLM-deficient cells these events were exceedingly rare in our study recombination at G4 motifs in transcribed genes is a major contributor to genome instability and cancer predisposition in BS High-resolution mapping of SCEs and common fragile site hotspots b Representative Strand-seq libraries generated from a a WT fibroblast and b a BS fibroblast Mapped DNA template strand reads are plotted on directional chromosome ideograms; reads mapping to the Crick (positive) strand of the reference genome are shown in green those mapping to the Watson (negative) strand are shown in orange SCEs are identified as a switch in template strand state d Number of SCEs detected during a single cell cycle in c primary fibroblasts and d EBV-transformed B-lymphocytes obtained from healthy donor and BS patients Each grey point represents number of SCEs detected in a single-cell Strand-seq library e SCE mapping resolutions across all eight cell lines Lines represent percentage of the total number of SCEs mapped at resolutions below indicated values g Correlations between average numbers of SCEs/chromosome/library and chromosome size for f WT and g BS cells R2-values are color-matched to the cell lines h Example of SCE hotspot detected within FRA3B (FHIT) Mapped SCE regions for each cell line were uploaded onto the UCSC Genome Browser Black bars represent genomic locations of SCE regions; size indicates mapping resolution using the BAIT program Red box indicates the location of the SCE hotspot as detected by Strand-seq This suggests that BLM has a minor role in the processing of stalled or collapsed replication forks at CFSs We next investigated the distribution of SCEs relative to specific genomic features of interest (FOIs) We developed a custom algorithm that compares SCE distributions with simulated random distributions in relation to a given FOI (see Methods section) we performed a permutation analysis to calculate the frequency of actual SCE regions overlapping with an FOI and compared it against the expected background frequency This analysis yields relative SCE enrichments for a given FOI and allows for statistical assessment of the strength of the association Bloom syndrome SCEs are enriched at G4 motifs in active genes Relative SCE enrichments (red points) over random distributions (violin plots) for SCEs that overlap with one or multiple a genes; b G4 motifs (G3+N1–7G3+N1-7G3+N1-7G3+); c active genes containing one or more G4 motifs; d active genes without G4 motifs; e silent genes containing one or more G4 motifs; and f silent genes without G4 motifs All values were normalized to the median permuted value for overlap of SCEs with FOIs (out of 1,000 permutations) and relative SCE enrichments over these values were plotted on the y-axis p-values indicate the fraction of permuted overlaps (out of 1,000 permutations) equal to or higher than overlap with observed SCE regions Significant p-values are indicated as follows: *p < 0.05 we decided to further investigate the link between G4 motifs This result suggests that even at our stringent 10Kbp cutoff for SCE region size there is noise present in the permutation analysis we conclude that actual SCE enrichments at G4 structures are almost certainly much higher than reported in this study As including larger SCE regions only affects SCE enrichments for BS cell lines we also conclude that the enrichments we detect are indeed specific for BS cells these results support that G4 structures are a major cause of SCE formation in BS cells This points to a synergistic effect of transcriptional activity and the presence of G4 motifs in genes on the enrichment of SCEs in BS cells Bloom syndrome SCE enrichments occur at transcribed G4 motifs a Intragenic G4 motifs can occur on either the transcribed strand (RNA shown in red) or on the non-transcribed strand; b–h relative SCE enrichments (red points) over random distributions (violin plots) for SCEs overlapping with h for intergenic G4 motifs and G4 motifs occurring on c intragenic transcribed strands; d non-transcribed strands; e transcribed strands of active genes; f non-transcribed strands for active genes; g transcribed strands for silent genes; and h non-transcribed strands for silent genes Confirmation of SCE enrichments at G4 motifs in Blm−/− mouse ES cells p-values were calculated using t-test and ANOVA b–g Relative SCE enrichments (red points) over random distributions (violin plots) for SCEs overlapping one or more (b) genes; c G4 motifs; and G4 motifs occurring on d transcribed strands of active genes; e non-transcribed strands for active genes; f transcribed strands for silent genes; and g non-transcribed strands for silent genes h Frequency of observed SCE regions occurred on the same homolog as allele-specific G4 motifs Indicated is the homolog containing G4 motif concordant indicates SCE occurred on same homolog discordant indicates SCE occurred on opposite homolog Number of allelic G4 motifs included in analysis is shown above each bar p-values were calculated using binomial distributions based on a 50% chance of SCE and G4 motif occurring on the same homolog No significant deviation from the expected 50/50 ratio was detected in the WT or the Blm+/− cell lines these results confirm that SCEs mainly form at G4 structures in absence of Blm and especially at those G4s present in the transcribed strands of active genes these results were obtained using systems that rely on selection of cells that underwent LOH at a specific locus we could detect and track LOH events throughout the entire genome based on single-nucleotide polymorphisms between the parental mouse strains we kept the WT and Blm mutant ES cells in continuous culture for 30 passages (~ 75 cell divisions) which would result in 3.8 × 1022 offspring cells for each parental cell compared to an estimated 1.2 × 1010 cells in an adult mouse body We performed single-cell whole-genome sequencing (scWGS) at different timepoints (passages 0 and identified chromosomal regions that underwent LOH (see Methods) We also identified chromosomal and local copy number variations (CNVs) to confirm that LOH regions are not caused by deletions and to determine if the Blm−/− cells display aberrant levels of CNVs Low levels of loss of heterozygosity in Blm−/− mouse ES cells Frequency of a unique LOH regions; b aneuploidy; and c local copy number variations detected at in single-cell whole genome sequencing libraries at different passages in WT The number of single-cell sequencing libraries included in the analysis is shown above each bar p-values for LOH events were calculated using binomial distributions but the exact mechanism behind this phenotype is not fully understood A major obstacle to unravelling the cause of BS SCEs was that SCEs cannot be accurately mapped using standard cytogenetic detection methods as this technique does allow for high-resolution mapping Even though the technique is limited by loss of DNA during preparation of single-cell sequencing libraries leading to low coverage within individual libraries (~ 1–2% genome coverage) we show here that SCEs in both normal and BS cells could be mapped at kilobase resolutions allowing for robust analysis on SCE locations and thus their causes We show that SCEs frequently occur at sites of G4 structures in both BLM deficient human and murine cells While there does not appear to be a direct effect of transcriptional activity on SCE enrichment patterns strong SCE enrichments in BS cells were observed in transcribed genes containing one or more G4 motifs especially when the G4 motif was present on the transcribed DNA strand The observation that SCEs were enriched on homolog-specific G4 motifs in the Blm mutant ES cells provides further evidence that G4 structures can directly trigger SCE formation The use of Strand-seq bypasses these issues because SCE regions are identified as the region between sequencing reads any SCE overlap with G4 motifs requires that the G4 motif lies within the identified SCE region and therefore does not have to be covered by sequencing reads itself BLM helicase suppresses recombination at G4 structures Model for the role of BLM in suppressing recombination at sites of G4 structures G4 structures are more likely to form or persist in the absence of unwinding by BLM They can form at G4 motifs throughout the genome but formation is promoted by transcription especially if the G4 motif is present on the transcribed strand BLM unwinds the G4 structure before the genomic region is replicated Stalled forks require homologous recombination (HR)-mediated repair leading to formation of a double Holliday junction (dHJ) dHJs cannot be dissolved by the BLM-TOPO3α-RMI1-RMI2 (BTRR) complex and must be resolved by MUS81-EME1 or GEN1 leading to frequent formation of sister chromatid exchanges event the proposed chromosome fragility is likely to play a role in the strong cancer predisposition associated with the syndrome The following cell lines were obtained from the Corriell Cell Repository: GM07492 and GM07545 (primary fibroblasts GM12891 and GM12892 (EBV-transformed B-lymphocytes and GM16375 and GM17361 (EBV-transformed B-lymphocytes The WT hybrid mouse ES cell line F121.6 (129Sv-Cast/EiJ) was a kind gift from Joost Gribnau (Erasmus University Fibroblasts were cultured in Dulbecco's modified Eagle's medium (DMEM) (Life Technologies) supplemented with 10% v/v fetal bovine serum (FBS) (Sigma Aldrich) and 1% v/v penicillin–streptomycin (Life Technologies) B-lymphocytes in RPMI1640 (Life Technologies) supplemented with 15% v/v FBS and 1% v/v penicillin–streptomycin ES cells were cultured on mitotically arrested mouse embryonic fibroblast cells in DMEM (Life Technologies) supplemented with 15% v/v FBS (Bodinco BV) 1% v/v non-essential amino acids (Life Technologies) 50 µM 2-mercaptoethanol (ThermoFisher Scientific) and 1,000 U ml−1 leukemia inhibitor factor (Merck) All cells were cultured at 37 °C in 5% CO2 BrdU (Invitrogen) was added to exponentially growing cell cultures at 40 µM final concentration Timing of BrdU pulse was 12 h for ES cells Blm mutants were generated using CRISPR/Cas9 genome editing. sgRNAs were designed to cleave the Blm gene at sites flanking exon 19 and cloned into PX459 plasmid52 Combinations of two plasmids (30 μg each) were transfected into F121.6 cells by means of electroporation (Biorad Genepulser XL) Cells were incubated for 24 h before puromycin (1 µg/ml) was added to cell culture medium Screening for Blm mutant clones was performed by allele-specific PCR of genomic region containing putative deletion Exponentially growing cells were collected and RNA was isolated using the Nucleospin RNA kit (Macherey Nagel) Reverse transcription was performed using Superscript II Reverse Transcriptase (Invitrogen) with random hexamers (Invitrogen) Quantitative PCR was performed using SYBR Green I Master (Roche) on the LightCycler480 (Roche) 96 libraries were pooled and 250–450 bp-sized fragments were isolated and purified DNA quality and concentrations were assessed using the High Sensitivity dsDNA kit (Agilent) on the Agilent 2100 Bio-Analyzer and on the Qubit 2.0 Fluorometer (Life Technologies) Exponentially growing cells were harvested and RNA was isolated using the Nucleospin RNA kit (Macherey Nagel) RNA-sequencing libraries were prepared using the NEBNext Ultra RNA Library Prep kit for Illumina (NEB) combined with the NEBNext rRNA Depletion kit (NEB) Complementary DNA quality and concentrations were assessed using the High Sensitivity dsDNA kit (Agilent) on the Agilent 2100 Bio-Analyzer and on the Qubit 2.0 Fluorometer (Life Technologies) Clusters were generated on the cBot (HiSeq2500) and single-end 50 bp reads (Strand-seq and RNA-seq) or paired-end 150 bp reads (scWGS) were generated were generated using the HiSeq2500 sequencing platform (Illumina) SCE were identified and mapped with the BAIT software package56 As BAIT also detects stable chromosomal rearrangements events that occurred at the exact same locations in > 5% of cells from one cell line were excluded from the analysis SCEs were assigned to homologs by splitting.bam files into separate files for each genetic background based on reads covering informative polymorphisms and using BAIT to identify on which homologs SCEs occurred BAIT-generated.bed files containing the locations of all mapped SCEs were uploaded to the USCS genome browser and hotspots were identified as regions containing multiple overlapping SCEs p-values were assigned to putative SCE hotspots using a custom R-script based on capture–recapture statistics the genome was divided into bins of the same size as the putative hotspot and the chance of findings the observed number of SCEs in one bin was calculated based on the total number of SCEs detected in the cell line Mapped reads were aligned and quantified using STAR aligner55 FPKM values were calculated for all genes and based on these genes were assigned active (FPKM > 1) or silent (FPKM < 1) status Reads were aligned to either 129 Sv or Cast/EiJ genetic background based on covered single-nucleotide polymorphisms (SNPs) Reads lacking informative SNPs were discarded Reads (129 Sv) were assigned a positive (Crick) orientation Cast/EiJ reads a negative (Watson) orientation The resulting.bam files were analyzed using BAIT and LOH events were detected as switches from mixed background to pure 129 Sv or Cast/EiJ background in the absence of deletions (as detected using AneuFinder) The Strand-seq, scWGS, and RNA-seq data reported in this paper have been submitted to the Arrayexpress database under accession E-MTAB-5976. SCE enrichment analysis software is available through GitHub (https://github.com/Vityay/GenomePermute) Bloom syndrome: a mendelian prototype of somatic mutational disease A manyfold increase in sister chromatid exchanges in Bloom’s syndrome lymphocytes Bromodeoxyuridine does not contribute to sister chromatid exchange events in normal or Bloom syndrome cells A replication model for sister-chromatid exchange Role of the BLM helicase in replication fork management Relationship between sister chromatid exchange and mutagenicity The Bloom’s syndrome gene product promotes branch migration of holliday junctions The Bloom’s syndrome helicase suppresses crossing over during homologous recombination Role for BLM in replication-fork restart and suppression of origin firing after replicative stress The Werner and Bloom syndrome proteins catalyze regression of a model replication fork and colocalization with gamma-H2AX after topoisomerase I-induced replication damage Interhomolog recombination and loss of heterozygosity in wild-type and Bloom syndrome helicase (BLM)-deficient mammalian cells Mutator phenotype and DNA double-strand break repair in BLM helicase-deficient human cells Cancer predisposition caused by elevated mitotic recombination in Bloom mice The Bloom’s syndrome helicase unwinds G4 DNA BLM unfolds G-quadruplexes in different structural environments through different mechanisms A conserved G4 DNA binding domain in RecQ family helicases DNA secondary structures: stability and function of G-quadruplex structures G-quadruplexes and their regulatory roles in biology G-quadruplex-induced instability during leading-strand replication Genome instability: a mechanistic view of its causes and consequences DNA template strand sequencing of single-cells maps genomic rearrangements at high resolution Single-cell template strand sequencing by Strand-seq enables the characterization of individual homologs Induction of sister chromatid exchanges at common fragile sites Breaking bad: R-loops and genome integrity Aguilera, A. & Gaillard, H. Transcription and recombination: when RNA meetsDNA. Cold Spring Harb. Perspect. Biol. 6, https://doi.org/10.1101/cshperspect.a016543 (2014) Collaborating functions of BLM and DNA topoisomerase I in regulating human rDNA transcription Chang, E. Y. et al. RECQ-like helicases Sgs1 and BLM regulate R-loop-associated genome instability. J. Cell Biol., https://doi.org/10.1083/jcb.201703168 (2017) G-quadruplexes in promoters throughout the human genome Conserved elements with potential to form polymorphic G-quadruplex structures in the first intron of human genes Highly prevalent putative quadruplex sequence motifs in human DNA G-quadruplex structures mark human regulatory chromatin High-throughput sequencing of DNA G-quadruplex structures in the human genome Structure and function of the regulatory HRDC domain from human Bloom syndrome protein Mechanistic insight into the interaction of BLM helicase with intra-strand G-quadruplex structures Somatic intragenic recombination within the mutated locus BLM can correct the high sister-chromatid exchange phenotype of Bloom syndrome cells Loss of heterozygosity induced by a chromosomal double-strand break BLM is required for faithful chromosome segregation and its localization defines a class of ultrafine anaphase bridges Nuclear structure in normal and Bloom syndrome cells Intramolecular G-quartet motifs confer nuclease resistance to a potent anti-HIV oligonucleotide BLM helicase facilitates telomere replication during leading strand synthesis of telomeres Relationships between putative G-quadruplex-forming sequences Regulation of gene expression by the BLM helicase correlates with the presence of G-quadruplex DNA motifs Disruption of dog-1 in Caenorhabditis elegans triggers deletions upstream of guanine-rich DNA DNA replication through G-quadruplex motifs is promoted by the Saccharomyces cerevisiae Pif1 DNA helicase FANCJ promotes DNA synthesis through G-quadruplex structures Interaction between the helicases genetically linked to Fanconi anemia group J and Bloom’s syndrome FANCJ coordinates two pathways that maintain epigenetic stability at G-quadruplex DNA Genome engineering using the CRISPR-Cas9 system Single-cell whole genome sequencing reveals no evidence for common aneuploidy in normal and Alzheimer’s disease neurons BAIT: Organizing genomes and mapping rearrangements in single cells Single-cell sequencing reveals karyotype heterogeneity in murine and human malignancies Download references and Peter Stirling for critical reading of this manuscript Inge Kazemier and Karina Hoekstra-Wakker for technical assistance and all members of the Lansdorp laboratories in Vancouver and Groningen for discussions and feedback Financial support was provided by an Advanced Grant from the European Research Council to P.M.L European Research Institute for the Biology of Ageing created and characterized Blm mutant cell lines supervised next-generation sequencing efforts wrote the manuscript with assistance from S.M. The authors declare no competing financial interests Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations Download citation DOI: https://doi.org/10.1038/s41467-017-02760-1 Sign up for the Nature Briefing newsletter — what matters in science International Review of NeurobiologyCitation Excerpt :Liuwei Dihuang decoction (LWDH) is a classic CHM formula consisting of Radix rehmanniae [Di huang (地黄)] LWDH has been prescribed as a primary or adjuvant treatment for many conditions clinical studies were conducted to evaluate potential neuroprotective mechanisms of LWDH in Parkinson's model (Tseng Pharmacology and TherapeuticsCitation Excerpt :The long-term therapeutic efficacy of LW has been well established LW has remained one of the most popular TCM formulae prescribed for primary or adjuvant treatment of many types of diseases (Chen et al. the results of our studies have shown that LW exerts a broad spectrum of pharmacological effects such as ameliorating the decline in learning and memory (Zhou et al. 2013) and the decline in function related to aging processes and geriatric diseases (Sangha et al. as well as enhancing the estrogenic activity during menopause (Limopasmanee et al. Journal of Chromatography B: Analytical Technologies in the Biomedical and Life SciencesCitation Excerpt :Rehmannia glutinosa Libosch which belongs to the family of Scrophulariaceae is also one of the earliest known and most important edible crude herbs used for various medicinal purposes in East Asia officinalis Sieb are key ingredient herbs in Liuwei Dihuang decoction (LWDHD) which has been clinically used for the treatment of “Kidney-Yin” deficiency syndrome in China for a long time [9–11] officinalis exhibits a variety of biological activities such as immune regulation [12,13] anti-arrhythmia [16] and anti-microbial effects [17] The show must go on ‒ the Sausage Queen show Reigning Sausage Queen Betty Wietmarschen is part of the group that organized the event No wieners crowned: Bockfest canceling 2023 Sausage Queen pageant 🌭 Prost! Here's when the 31st annual Bockfest returns to Cincinnati 🍻 "I was absolutely bummed when I heard it wasn't happening this year," she told The Enquirer "It's a tradition that needs to continue." Preliminary rounds of the gender-neutral pageant which have traditionally played a role in the lead-up to Bockfest The German restaurant and beer garden in Corryville will kick off Sausage Queen festivities with a keg-tapping stein-hoisting contest and live music by the Polka Warriors Bockfest in general is a good time," Harten said Downtown:Flying Pig full marathon already sold out. Here's how to get on the waitlist Steve Hampton, executive director of the Brewery District Community Urban Redevelopment Corp., which puts on a number of Bockfest events told The Enquirer the pageant was canceled because organizers were pressed for time The group also lost a few key members who had organized Sausage Queen in the past "The idea is not to take away from Bockfest ‒ this festival that everyone in Cincinnati loves ‒ but to just make sure this great event still happens," Wietmarschen said "We're all really proud to be Sausage royalty and we don't want to see this event die." Xavier and Summit Country Day boys cross country teams.  the wait was agonizing 17-minute period following the Division I boys race at the 91st annual boys cross country championships at National Trail Raceway in Hebron.  The Bombers paced the National Trail Runway under a light rain anxiously awaiting the results of a review that would determine if they were the Division I state team championship.  Officials deemed the Bombers state champions as they edged out Mason for the top spot “We’ve waited since last November waiting another 15-20 minutes is not a big deal," St Xavier head coach Andrew Wietmarschen said but this is something that they’ve wanted since we left here last year I’m proud of all those guys that showed up today – it’s truly a team."  Xavier finished fourth at last year's state championship The Bombers won the Troy Regional over the Comets by 40 points then held on Saturday for the program's sixth career state title and first since 2013.  “I think coming back nobody pegged us as the team to beat," Wietmarschen said "I think other folks thought there were some teams better than us but these guys believed all throughout the winter all throughout track season and into the summer They wanted to win a state championship and they did everything they possible could to win one today The wait was especially agonizing for Nathan Mountain then logged an impressive fifth-place finish Saturday but accepted his medal without knowing whether or not his club was tops in Ohio then welcomed him to the party with a dog-pile jubilee behind the podium once he stepped down.  I was just thinking about it the whole time," said Mountain who finished 67th at last year's state event. "I’m here for the boys so the team title meant the most It was the best feeling ever to jump into their arms once I heard we won it all."  There was no post-race drama for Summit Country Day The final result was not in question as the Silver Knights took home the program's first-ever state championship by 14 points.  The whole team took turns celebrating with a horde of blue and silver supporters along the chain-link fence adjacent to the finish line.  It felt like an overdue title as Saturday marked Summit's eight trip to state in the last decade Finishing as an 18-point runner-up to Fort Loramie last November provided extra incentive.  There was a ton," Summit head coach Kurtis Smith said "I know Northeast Ohio always comes here and dominates the state meet so these guys had a chip on their shoulder and they ran with it today They wanted to come back here and prove they belong." It was quality over quantity that paved Summit's path to being the top Division III team in the state The Silver Knights had only runner make the podium — junior Evan Lakhia who finished 19th — but high-caliber finishes from Andrew Wagner (24th) Brian DeWine (35th) and Devin Nelson (54th) lifted them over runner-up Mount Gilead.  we've been through a lot and this means a lot "Last night we had a team meeting and he said I just love running with you guys.' That really set the tone The whole race we moved up as a group and we won it as a team."  DeWine shared that sentiment with an heartfelt praising of his teammates following the race.  "I had an injury early on this season and to come back for regionals and state — it's just so special. I’ve never had a group of people I love as much as these guys Every single second I spent with them was amazing and today it really came together." Asked if he could hold back tears once his team received the trophy Lakhia was the only Greater Cincinnati runner to find the podium in Division II and III Badin junior Owen Mathews was the top local finisher in D-II at 32nd.  Mason sophomore Aiden Amshoff made the podium after finishing 14th joined him in 19th to anchor the club's runner-up finish.  Kings junior Alex Justus (12th) and Lebanon senior Sam Duncan (13th) turned in medal-winning performances as Greater Cincinnati occupied 25 percent of the final podium on the afternoon.  trustee changesMuseum also focuses on engagement plan in the community for yearContributed to the TRZANESVILLE - The Zanesville Museum of Art recently announced several changes to its Board of Directors A longtime life trustee will be retiring with a new trustee coming on the board has gained three new community members.  Milman “Bud” Linn III has a legacy unlike any other at the ZMA As well as serving through three institutional name changes four directors and a move from the museum’s previous location on Adair Avenue to its current one on Military Road Linn and the Linn family have several spaces in the museum named after them The former president and CEO of Zanesville Stoneware has given nearly four decades of service to the ZMA and has been granted emeritus status as a board member Donald Wietmarschen will be replacing Linn as a lifetime trustee He is the co-managing partner of Gottlieb Beam & Dal Ponte P.L.L. and has served the ZMA as a board member treasurer and advocate for more than a decade The other lifetime trustees are Frederic Grant III The executive committee of the board of directors have also reorganized for the year Officers are President Chad Brown of Zane State College retired executive director of Powerhouse of Southeastern Ohio Treasurer Melanie Klotzbach of North Terrace Church of Christ and  Secretary Susan Nash, co-owner of The Art Loft The executive committee is responsible for guiding the rapid growth of the museum and ensuring that it continues to fulfill its mission Three new members also joined the board in Szemetylo The museum has also adopted a new creative plan that focuses on engagement in all areas One of the main objectives for the board in the coming year will be to assist in raising funds specifically from corporate supporters.  Engaging corporations is important to the ZMA because it allows the organization to continue doing what it does and improve its already robust and diverse offerings to the community More than 10,000 guests already enjoy the ZMA’s programs galleries and collections annually and more funding from corporate supporters would allow even more of the community to enjoy what the museum brings to Zanesville and the surrounding area.  Engaging new and current audiences is another facet of the ZMA’s newly acquired plan With 8,500 works in the collection and 25 percent of those on view currently guests are engaged from the moment they walk through the doors the museum is striving for more with more than 200 programs annually ranging from preschool classes to adult workshops Group guided tours are also being increased at the museum with 43 tours and more than 600 tour guests in the previous year engagement and ultimately museum membership in the coming year The board of directors and museum staff are working hard to improve the museum every day Information and photos submitted by Daniel Pitcock marketing coordinator and finance administrator.  The construction of the DolWin4 and BorWin4 offshore grid connection projects in northern Germany has commenced Work on the DolWin4 and BorWin4 offshore grid connections which will transport power from offshore wind farms in the North Sea to the mainland where construction camps are currently being set up The lines end in Lingen and run parallel to the A-Nord direct current connection between Emden and Wietmarschen A-Nord and the two offshore lines separate and the civil engineering work from there to the converter station in Lingen is planned to begin in mid-August commissioned by the transmission system operator (TSO) Amprion will first build a cable protection pipe system into which the power cables will later be pulled the pipe strings for the cable protection pipe system will be pre-welded with installation expected to commence in mid-August This process includes sections built using the closed construction method primarily the horizontal directional drilling method as well as sections using the open construction method The same suppliers have been selected for the BorWin4 grid connection The platforms for both offshore grid connection projects will be installed by Allseas with the installation work planned to commence in 2027 The DolWin4 and BorWin4 offshore grid connection systems are among the most important energy transition projects in Germany the cables will initially run 60 kilometres and 125 kilometres at sea They cross below the island of Norderney and reach the coast in the Hilgenriedersiel they run for around 155 kilometres as underground cables toward the Hanekenfähr substation in Lingen where Amprion will connect them to its transmission network the Emsland nuclear power plant went offline in April 2023 The resulting loss of generation capacity will be replaced by 1.8 GW of offshore wind energy via BorWin4 and DolWin4 Both offshore grid connection projects are scheduled to go into operation in 2028 Get in front of your target audience in one move OffshoreWIND.biz is read by thousands of offshore wind professionals daily Daily news and in-depth stories in your inbox renewable energy is key to the future of our planet we have over 60 years’ experience and an in-depth understanding of the power and temperature control needs of wind farms We have a dedicated Wind Energy Team whose innovative strategies […] 2022 /PRNewswire/ -- Pivoton becomes part of the zvoove Group – Accelerated expansion of zvoove's market leadership in the European market for temporary staffing software – Excellent prospects for Pivoton's customers and employees.  The zvoove Group is joining forces with Pivoton Software B one of the largest providers in the market for temporary staffing software in the Netherlands zvoove is expanding into another European country with its software for temporary staffing providers "The Netherlands is one of the most important markets for temporary staffing companies worldwide The merger has a high strategic value for us and further expands our European market leadership," explains zvoove CEO Oliver Muhr our customers in Germany and Switzerland will benefit from the transaction as we now have even more temporary staffing market experts within Europe which are driven to deliver further competitive advantages via innovative software to our customers." Pivoton has a long history of success in the Netherlands and is one of the leading SaaS providers in the Dutch market for temporary staffing software Pivoton's SaaS software packages allow customers to establish fast highly efficient and legally compliant processes from recruiting to billing and payment of employees complemented by other services from Pivoton and its ecosystem of partner companies bring significant competitive advantages to customers Pivoton benefits from the strength of the zvoove Group "The merger opens up excellent prospects and new opportunities for Pivoton's employees and customers This strengthens our position in the market enormously and we are excited by this growth opportunity," affirms Pivoton CEO Paul van den Bosch Pivoton CTO Bart Hemmer adds: "By joining forces with zvoove we can now invest even more and offer our customers further competitive advantages through additional innovation and software offerings." About zvooveThe zvoove Group develops and sells innovative software solutions for temporary staffing facility management and the event industries With more than 3,000 customers and 330 employees zvoove was formed as the result of the merger of LANDWEHR Contact zvoovezvoove Group GmbHvon-Humboldt-Str. 249835 Wietmarschen-Lohnepress@zvoove.com +49 (0) 5908 938-0 Logo: https://mma.prnewswire.com/media/1653643/zvoove_Group_GmbH_Logo.jpg Do not sell or share my personal information: