bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comprehensive Assessment of Sleep Duration, Insomnia and Brain Structure within the UK Biobank Cohort
Authors: Stolicyn Aleks , Lyall Laura M. , Lyall Donald M. , Høier Nikolaj , Adams Mark J. , Shen Xueyi , Cole James H. , McIntosh Andrew M. , Whalley Heather C. , Smith Daniel J. 
Published: June 2023

AbstractStudy ObjectivesTo assess for associations between sleeping more than or less than recommended by the National Sleep Foundation (NSF), and self-reported insomnia, with brain structure.MethodsData from the UK Biobank cohort were analysed (Nbetween 9K and 32K, dependent on availability, aged 44 to 82 years). Sleep measures included self-reported adherence to NSF guidelines on sleep duration (sleeping between 7 and 9 hours per night), and self-reported difficulty falling or staying asleep (insomnia). Brain structural measures included global and regional cortical or subcortical morphometry (thickness, surface area, volume), global and tract-related white matter microstructure, brain age gap (difference between chronological age and age estimated from brain scan), and total volume of white matter lesions.ResultsLonger-than-recommended sleep duration was associated with lower overall grey and white matter volumes, lower global and regional cortical thickness and volume measures, higher brain age gap, higher volume of white matter lesions, higher mean diffusivity globally and in thalamic and association fibers, and lower volume of the hippocampus. Shorter-than-recommended sleep duration was related to higher global and cerebellar white matter volumes, lower global and regional cortical surface areas, and lower fractional anisotropy in projection fibers. Self-reported insomnia was associated with higher global grey and white matter volumes, and with higher volumes of the amygdala, hippocampus and putamen.ConclusionsSleeping longer than recommended by the NSF is associated with a wide range of differences in brain structure, potentially indicative of poorer brain health. Sleeping less than recommended is distinctly associated with lower cortical surface areas. Future studies should assess the potential mechanisms of these differences and investigate long sleep duration as a putative marker of brain health.
Brain flexibility increases during the peri-ovulatory phase of the menstrual cycle
Authors: Liparoti Marianna , Cipriano Lorenzo , Lopez Emahnuel Troisi , Polverino Arianna , Minino Roberta , Sarno Laura , Sorrentino Giuseppe , Lucidi Fabio , Sorrentino Pierpaolo 
Published: June 2023

AbstractThe brain operates in a flexible dynamic regime, generating complex patterns of activity (i.e neuronal avalanches). This study aimed to describe how brain dynamics change according to menstrual cycle (MC) phases.Brain activation patterns were estimated from resting state magnetoencephalography (MEG) scans, acquired women at early follicular (T1), peri-ovulatory (T2) and mid-luteal (T3) phases of MC. We investigated the functional repertoire (number of ways in which large bursts of activity spread through the brain) and the region-specific influence on large-scale dynamics across MC. Finally, we assessed the relationship between sex hormones and changes in brain dynamics.A significantly larger number of visited configuration patterns, in T2 than in T1, in the beta frequency band was observed. No relationship between changes in brain dynamics and sex hormones was showed. Finally, we showed that, in the beta band, the left posterior cingulate gyrus and the right insula were more present in the functional repertoire in T2 than in T1, while the right pallidum was more present in T1 than in T2.In summary, we showed a hormone independent increase of brain dynamics during the ovulatory phase. Moreover, we demonstrated that several specific brain regions play a key role in determining this change.
Epidemiological impact and cost-effectiveness of expanding formal PrEP provision to PrEP-eligible MSM expressing PrEP-intention in the Netherlands
Authors: Wang Haoyi , Popping Stephanie , van de Vijver David , Jonas Kai. J. 
Published: June 2023

AbstractObjectiveReimbursed pre-exposure prophylaxis (PrEP) access in the Netherlands has reached its maximum capacity with a waiting-list of 3,000 men-who-have-sex-with-men (MSM) and 19,500 PrEP-eligible/intending MSM. This study models the epidemiological impact and cost-effectiveness of expanding PrEP provision to waiting-list and PrEP-eligible/intending MSM in the Netherlands, given the imminent national evaluation of the current PrEP programme in July 2023.MethodsWe calibrated a deterministic transmission model of HIV among MSM. Expanded PrEP provision was seeded in 01/2022, to achieve the coverage (varied at 25%,50%,75%, and 100%) for the waiting-list (n=3,000), and PrEP-eligible/intending group (n=19,500) by 01/2024. The epidemiological impact was modelled until 2030, while cost-effectiveness and the budget impact were calculated from a payer’s perspective over 40-years, and five-years, starting from 2022, respectively.ResultsExpanding PrEP provision leads to further reductions in HIV infections among MSM. Covering waiting-list and PrEP-eligible/intending MSM can avert a total of 11 (2.5%) up to 192 (45.1%) new infections by 2030. Expanding PrEP provision to over-75% of PrEP-eligible/intending MSM offers the possibility of ending the HIV epidemic by 2030. However, achieving this milestone comes with significant costs, with an incremental-cost-effectiveness-ratio of €164,100 per quality-adjusted-life-year and short-term costs of €1,074 million over five-years.ConclusionsThis study provides timely evidence for the upcoming national evaluation of the PrEP program in the Netherlands, supporting its continuation and further expansion. While expanding PrEP provision holds promise for HIV elimination, given the associated significant costs, careful consideration is crucial to balance efforts to end the HIV epidemic and the available resources.
The relationship between genotype- and phenotype-based estimates of genetic liability to psychiatric disorders, in practice and in theory
Authors: Dybdahl Krebs Morten , Appadurai Vivek , Georgii Hellberg Kajsa-Lotta , Ohlsson Henrik , Steinbach Jette , Pedersen Emil ,   iPSYCH Study Consortium, Werge Thomas , Sundquist Jan , Sundquist Kristina , Cai Na , Zaitlen Noah , Dahl Andy , Vilhjalmsson Bjarni , Flint Jonathan , Bacanu Silviu-Alin , Schork Andrew J. , Kendler Kenneth S. 
Published: June 2023

AbstractGenetics as a science has roots in studying phenotypes of relatives, but molecular approaches facilitate direct measurements of genomic variation within individuals. Agricultural and human biomedical research are both emphasizing genotype-based instruments, like polygenic scores, as the future of breeding programs or precision medicine and genetic epidemiology. However, unlike in agriculture, there is an emerging consensus that family variables act nearly independent of genotypes in models of human disease. To advance our understanding of this phenomenon, we use 2,066,057 family records of 99,645 genotyped probands from the iPSYCH2015 case-cohort study to show that state-of-the-field genotype- and phenotype-based genetic instruments explain largely independent components of liability to psychiatric disorders. We support these empirical results with novel theoretical analysis and simulations to describe, in a human biomedical context, parameters affecting current and future performance of the two approaches, their expected interrelationships, and consistency of observed results with expectations under simple additive, polygenic liability models of disease. We conclude, at least for psychiatric disorders, that phenotype- and genotype-based genetic instruments are likely noisy measures of the same underlying additive genetic liability, should be seen for the near future as complementary, and integrated to a greater extent.
Metabolism-dependent secondary effect of anti-MAPK cancer therapy on DNA repair
Authors: Aubé Fabien , Fontrodona Nicolas , Guiguettaz Laura , Vallin Elodie , Lapendry Audrey , Ricci Emiliano P. , Auboeuf Didier 
Published: June 2023

AbstractAmino acid bioavailability impacts mRNA translation in a codon depending manner. Here, we report that the anti-cancer MAPK inhibitors (MAPKi) decrease the intracellular concentration of aspartate and glutamate in melanoma cells. This results in the accumulation of ribosomes on codons corresponding to these amino acids and triggers the translation-dependent degradation of mRNAs encoding aspartate- and glutamate-rich proteins mostly involved in DNA metabolism. Consequently, cells that survive to MAPKi degrade aspartate and glutamate to generate energy, which simultaneously decreases their needs in amino acids owing to the downregulation of aspartate- and glutamate-rich proteins involved in cell proliferation. Concomitantly, the downregulation of aspartate- and glutamate-rich proteins involved in DNA repair increases DNA damage loads. Thus, DNA repair defects, and therefore mutations, are, at least in part, a secondary effect of the metabolic adaptation of cells exposed to MAPKi.
Bimodular architecture of bacterial effector SAP05 drives ubiquitin-independent targeted protein degradation
Authors: Liu Qun , Maqbool Abbas , Mirkin Federico G. , Singh Yeshveer , Stevenson Clare E. M. , Lawson David M. , Kamoun Sophien , Huang Weijie , Hogenhout Saskia A. 
Published: June 2023

AbstractIn eukaryotes, targeted protein degradation (TPD) typically depends on a series of interactions among ubiquitin ligases that transfer ubiquitin molecules to substrates leading to degradation by the 26S proteasome. We previously discovered that the bacterial effector protein SAP05 mediates ubiquitin-independent TPD. SAP05 forms a ternary complex via interactions with the von Willebrand Factor Type A (vWA) domain of the proteasomal ubiquitin receptor Rpn10 and the Zinc-finger (ZnF) domains of the SQUAMOSA-PROMOTER BINDING PROTEIN-LIKE (SPL) and GATA BINDING FACTOR (GATA) transcription factors (TFs). This leads to direct TPD of the TFs by the 26S proteasome. Here, we report the crystal structures of the SAP05-vWA complex at 2.17 Å resolution and of the SAP05-ZnF(SPL5) complex at 2.20 Å resolution. Structural analyses revealed that SAP05 displays a unique bimodular architecture with two distinct non-overlapping surfaces, a ‘loop surface’ with three protruding loops that form electrostatic interactions with ZnF, and a ‘sheet surface’ featuring two β-sheets, loops and ⍺-helices that establish polar interactions with vWA. SAP05 binding to ZnF TFs involves single amino acids responsible for multiple contacts, while SAP05 binding to vWA is more stable due to the necessity of multiple mutations to break the interaction. In addition, positioning of the SAP05 complex on the 26S proteasome points to a mechanism of protein degradation. Collectively, our findings demonstrate how a small bacterial bimodular protein can bypass the canonical UPS cellular proteolysis pathway, enabling ubiquitin-independent TPD in eukaryotic cells. This knowledge holds significant potential for the creation of novel TPD technologies.
KaScape: A sequencing-based method for global characterization of protein-DNA binding affinity
Authors: Chen Hong , Xu Yongping , Jin Jianshi , Su Xiao-dong 
Published: June 2023

AbstractIt is difficult to exhaustively screen all possible DNA binding sequences for a given transcription factor (TF). Here, we develop a method named “KaScape”, by which, TFs bind to all possible DNA sequences in the same DNA pool where the DNA sequences are prepared by randomized oligo synthesis and the random length can be adjusted to, e.g., 4, 5, 6, or 7, etc. After separating the bound from unbound double-strand DNA, their sequences are determined by next-generation sequencing. To demonstrate the relative binding affinities of all possible DNA sequences determined by KaScape, we develop a three-dimensional KaScape viewing software based on a K-mer graph. We apply KaScape to 12 plant TF familyAtWRKY proteins and find that allAtWRKY proteins bind to the core sequence GAC with similar profiles. KaScape not only can detect binding sequences that are consistent with the consensus W-box “TTGAC(C/T)”, but also other sequences with weak affinity. KaScape provides a high-throughput, easy-to-operate, sensitive, and exhaustive method to quantitatively characterize the relative binding strength of a TF to all possible binding sequences, allowing us to comprehensively characterize the specificity and affinity landscape of transcription factors, particularly for moderate and low affinity binding sites.HighlightsA general method, KaScape, using NGS (next-generation sequencing) with a series of random dsDNA for exhaustive characterization of protein-DNA binding.A K-mer-based analysis and display software tool KGViewer developed to analyze the relative affinity landscape of KaScape results.
NeuronalNdst1depletion accelerates prion protein clearance and slows neurodegeneration in prion infection
Authors: Aguilar-Calvo Patricia , Malik Adela , Sandoval Daniel R. , Barback Christopher , Orrù Christina D. , Standke Heidi G. , Thomas Olivia , Dwyer Chrissa A. , Pizzo Donald P. , Bapat Jaidev , Soldau Katrin , Ogawa Ryotaro , Riley Mckenzie B. , Nilsson K. Peter R. , Kraus Allison , Caughey Byron , Iliff Jeffrey J. , Vera David , Esko Jeffrey D. , Sigurdson Christina J. 
Published: June 2023

AbstractSelect prion diseases are characterized by widespread cerebral plaque-like deposits of amyloid fibrils enriched in heparan sulfate (HS), a major extracellular matrix component. HS facilitates fibril formationin vitro, yet how HS impacts fibrillar plaque growth within the brain is unclear. Here we found that prion-bound HS chains are highly sulfated, and that the sulfation is essential for HS accelerating prion conversionin vitro. Using conditional knockout mice to deplete the HS sulfation enzyme, Ndst1 (N-deacetylase, N-sulfotransferase), from neurons or astrocytes, we investigated how reducing HS sulfation impacts survival and prion aggregate distribution during a prion infection. Neuronal Ndst1-depleted mice survived longer and showed fewer and smaller parenchymal plaques, shorter fibrils, and increased vascular amyloid, consistent with enhanced aggregate transit toward perivascular drainage channels. The prolonged survival was strain-dependent, affecting mice infected with extracellular, plaque-forming, but not membrane bound, prion strains. Live PET imaging revealed rapid clearance of prion protein monomers into the CSF in mice expressing unsulfated HS, further suggesting that HS sulfate groups hinder transit of extracellular prion monomers. Our results directly show how a host cofactor slows the spread of prion protein through the extracellular space and identify an enzyme target to facilitate aggregate clearance.Author summaryPrions cause a rapidly progressive neurologic disease and death with no curative treatment available. Prion aggregates accumulate exponentially in the brain in affected individuals triggering neuronal loss and neuroinflammation. Yet the additional molecules that facilitate aggregation are largely unknown, and their identification may lead to new therapeutic targets. We have found that prions in the brain preferentially bind to a highly sulfated endogenous polysaccharide, known as heparan sulfate (HS). Here we use genetically modified mice that express poorly sulfated neuron-derived HS, and infect mice with different prions strains. We find that the mice infected with a plaque-forming prion strain show a prolonged survival and fewer plaques compared to the controls. We also found that the prion protein was efficiently transported in the interstitial fluid in mice having poorly sulfated HS, suggesting that the prion protein is more readily cleared from the brain. Our study provides insight into how HS retains prion aggregates in the brain to accelerate disease and indicates the specific HS biosynthetic enzymes to target for enhancing protein clearance.
WITHDRAWN: Knockout of HD domain 5’-nucleotidase inT. bruceitriggers cell death linked to DNA damage and downregulation of glutamine uptake
Authors: Deng Yue Wen , Pontikos Michael A. , Baniasadi Hamid , Williams Noelle S. , Phillips Margaret A. 
Published: June 2023

Withdrawal StatementThe authors have withdrawn their manuscript because we have uncovered problems with the reliability of some data in the manuscript. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Meta-metabolomic Responses of River Biofilms to Cobalt Exposure and Use of Dose-response Model Trends as an Indicator of Effects
Authors: Colas Simon , Marie Benjamin , Milhe-Poutingon Mathieu , Lot Marie-Claire , Boullemant Amiel , Fortin Claude , Le Faucheur Séverine 
Published: June 2023

ABSTRACTMetabolites are low molecular-weight molecules produced during cellular metabolism. The global expression of the meta-metabolome (metabolomics at the community level) could thus potentially be used to characterize the exposure of an organism or a community to a specific stressor. Here, the meta-metabolomic fingerprints of mature biofilms were examined after 1, 3 and 7 days of exposure to five concentrations of cobalt (0, 1 x 10-7, 1 x 10-6, 5 x 10-6and 1 x 10-5M) in aquatic microcosms. The global changes in meta-metabolomic fingerprints were in good agreement with those of the other biological parameters studied (cobalt bioaccumulation, biomass, chlorophyll content). To better understand the dose-responses of the biofilm meta-metabolome, the untargeted LC-HRMS metabolomic data were further processed using the DRomics tool to build dose-response model curves and to calculate benchmark doses (BMD). These BMDs were aggregated into an empirical cumulative density function. A trend analysis of the metabolite dose-response curves suggests the presence of a concentration range inducing defense mechanisms (CRIDeM) between 4.7 x 10-7and 2.7 x 10-6M, and of a concentration range inducing damage mechanisms (CRIDaM) from 2.7 x 10-6M to the highest Co concentration. The present study demonstrates that the molecular defense and damage mechanisms can be related to contaminant concentrations and represent a promising approach for environmental risk assessment of metals.SYNOPSISThis study focuses on the interpretation of the metabolite dose-response trends in river biofilms exposed to cobalt to identify concentration range inducing cellular mechanisms and improve the environmental risk assessment of metals.
SARS-CoV-2 variants of concern exhibit differential gastro-intestinal tropism and pathogenesis in the Syrian golden hamster model
Authors: Nagaraj Santhosh K. , Joy Christy M. , Narayan Rohan , Shiraz Rishad , Kaur Sumandeep , Khatun Oyahida , Dubey Sagar , Tripathi Shashank 
Published: June 2023

AbstractThe Coronavirus Disease 2019 (COVID-19) pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has taken its toll on worldwide public health infrastructure. SARS-CoV-2 is reported to exhibit wide tissue tropism, contributing to its severe pathogenicity that often culminates in multiple-organ failure. The onslaught of this disease has intensified due to the emergence of variants of concern (VOC), such as Delta and Omicron. These variants have been linked to gastrointestinal (GI) symptoms, suggesting a potential fecal-oral route of viral transmission. Here we compared the broad tissue tropism of ancestral Hong-Kong SARS-CoV-2 (SARS-CoV-2 HK) against Delta and Omicron VOCs in aa hamster model by analyzing tissue samples collected from the upper and lower respiratory system and the GI tract. We observed an overall increase in vRNA load and pro- inflammatory cytokines, especially in GI tracts of animals infected with Delta virus, indicating selective virus tropism and pathology in these tissues. However, no apparent spike in Delta viral load was observed in the large intestine and fecal matter. Overall, our research investigates the wide range of tissues that various SARS-CoV-2 strains can infect in hamsters and presents evidence supporting the increased preference of Delta VOCs for infecting the GI tract.
CRISPR-dependent base editing screens identify separation of function mutants of RADX with altered RAD51 regulatory activity
Authors: Adolph Madison B. , Garje Atharv S. , Balakrishnan Swati , Morati Florian , Modesti Mauro , Chazin Walter J. , Cortez David 
Published: June 2023

AbstractRAD51 forms nucleoprotein filaments to promote homologous recombination, replication fork reversal, and fork protection. Numerous factors regulate the stability of these filaments and improper regulation leads to genomic instability and ultimately disease including cancer. RADX is a single stranded DNA binding protein that modulates RAD51 filament stability. Here, we utilize a CRISPR-dependent base editing screen to tile mutations acrossRADXto delineate motifs required for RADX function. We identified separation of function mutants of RADX that bind DNA and RAD51 but have a reduced ability to stimulate its ATP hydrolysis activity. Cells expressing these RADX mutants accumulate RAD51 on chromatin, exhibit replication defects, have reduced growth, accumulate DNA damage, and are hypersensitive to DNA damage and replication stress. These results indicate that RADX must bind RAD51 and promote RAD51 ATP turnover to regulate RAD51 and genome stability during DNA replication.
Pyranthiones/Pyrones: “Click and Release” Donors for Subcellular Hydrogen Sulfide Delivery and Labeling
Authors: Huang Wei , Escorihuela Jorge , Laughlin Scott T. 
Published: June 2023

AbstractHydrogen sulfide (H2S), one of the most important gasotransmitters, plays a critical role in endogenous signaling pathways of many diseases. However, developing H2S donors with both tunable release kinetics and high release efficiency for subcellular delivery has been challenging. Here, we describe a click and release reaction between pyrone/pyranthiones and bicyclononyne (BCN). This reaction features a release of CO2/COS with second-order rate constants comparable to Strain-Promoted Azide-Alkyne Cycloaddition reactions (SPAACs). Interestingly, pyranthiones showed enhanced reaction rates compared to their pyrone counterparts. We investigated pyrone biorthogonality and demonstrated their utility in protein labeling applications. Moreover, we synthesized substituted pyranthiones with H2S release kinetics that can address the range of physiologically relevant H2S dynamics in cells and achieved quantitative H2S release efficiencyin vitro. Finally, we explored the potential of pyranthiones as H2S/COS donors for mitochondrial-targeted H2S delivery in living cells.