bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multi-attribute decision-making in macaques relies on direct attribute comparisons
Authors: Perkins Aster Q. , Gillis Zachary S. , Rich Erin L. 
Published: October 2023

AbstractIn value-based decisions, there are frequently multiple attributes, such as cost, quality, or quantity, that contribute to the overall goodness of an option. Since one option may not be better in all attributes at once, the decision process should include a means of weighing relevant attributes. Most decision-making models solve this problem by computing an integrated value, or utility, for each option from a weighted combination of attributes. However, behavioral anomalies in decision-making, such as context effects, indicate that other attribute-specific computations might be taking place. Here, we tested whether rhesus macaques show evidence of attribute-specific processing in a value-based decision-making task. Monkeys made a series of decisions involving choice options comprising a sweetness and probability attribute. Each attribute was represented by a separate bar with one of two mappings between bar size and the magnitude of the attribute (i.e., bigger=better or bigger=worse). We found that translating across different mappings produced selective impairments in decision-making. When like attributes differed, monkeys were prevented from easily making direct attribute comparisons, and choices were less accurate and preferences were more variable. This was not the case when mappings of unalike attributes within the same option were different. Likewise, gaze patterns favored transitions between like attributes over transitions between unalike attributes of the same option, so that like attributes were sampled sequentially to support within-attribute comparisons. Together, these data demonstrate that value-based decisions rely, at least in part, on directly comparing like attributes of multi-attribute options.Significance StatementValue-based decision-making is a cognitive function impacted by a number of clinical conditions, including substance use disorder and mood disorders. Understanding the neural mechanisms, including online processing steps involved in decision formation, will provide critical insights into decision-making deficits characteristic of human psychiatric disorders. Using rhesus monkeys as a model species capable of complex decision-making, this study shows that decisions involve a process of comparing like features, or attributes, of multi-attribute options. This is contrary to popular models of decision-making in which attributes are first combined into an overall value, or utility, to make a choice. Therefore, these results serve as an important foundation for establishing a more complete understanding of the neural mechanisms involved in forming complex decisions.
Concurrent behavioral modelling and multimodal neuroimaging reveals how feedback affects the performance of decision making in internet gaming disorder
Authors: Zeng Xinglin , Sun Ying Hao , Gao Fei , Hua Lin , Tan Weijie , Yuan Zhen 
Published: October 2023

AbstractInternet gaming disorder (IGD) raises questions on how feedback from the previous gaming round affects the risk-taking behavior in the subsequent round. Forty-two participants underwent a sequential risk-taking task, which was measured be behavioral modeling. Concurrent electroencephalogram and functional near-infrared spectroscopy (EEG-fNIRS) recordings were performed to demonstrate when, where and how the previous-round feedback affects the decision making to the next round. We discovered that the IGD illustrated heightened risk-taking propensity as compared to the HCs, indicating by the computational modeling (p= 0.028). EEG results also showed significant time window differences in univariate and multivariate pattern analysis between the IGD and HCs after the loss of the game. Further, reduced brain activation in the prefrontal cortex during the task was detected in IGD as compared to that of the control group. Risky decision-making in IGD might be due to the complex interplay between emotional response and other cognitive factors.
Design of intrinsically disordered protein variants with diverse structural properties
Authors: Pesce Francesco , Bremer Anne , Tesei Giulio , Hopkins Jesse B. , Grace Christy R. , Mittag Tanja , Lindorff-Larsen Kresten 
Published: October 2023

AbstractIntrinsically disordered proteins (IDPs) perform a wide range of functions in biology, suggesting that the ability to design IDPs could help expand the repertoire of proteins with novel functions. Designing IDPs with specific structural or functional properties has, however, been diffcult, in part because determining accurate conformational ensembles of IDPs generally requires a combination of computational modelling and experiments. Motivated by recent advancements in effcient physics-based models for simulations of IDPs, we have developed a general algorithm for designing IDPs with specific structural properties. We demonstrate the power of the algorithm by generating variants of naturally occurring IDPs with different levels of compaction and that vary more than 100 fold in their propensity to undergo phase separation, even while keeping a fixed amino acid composition. We experimentally tested designs of variants of the low-complexity domain of hnRNPA1 and find high accuracy in our computational predictions, both in terms of single-chain compaction and propensity to undergo phase separation. We analyze the sequence features that determine changes in compaction and propensity to phase separate and find an overall good agreement with previous findings for naturally occurring sequences. Our general, physics-based method enables the design of disordered sequences with specified conformational properties. Our algorithm thus expands the toolbox for protein design to include also the most flexible proteins and will enable the design of proteins whose functions exploit the many properties afforded by protein disorder.
The evolution of gestation length in eutherian mammals
Authors: Danis Thodoris , Rokas Antonis 
Published: October 2023

SummaryGestation length, or the duration of pregnancy, is a critical component of mammalian reproductive biology1. Eutherian mammals exhibit striking variation in their gestation lengths2–5, which has traditionally been linked to and allometrically scales with variation in other life history traits, including body mass and lifespan5–8. How the phenotypic landscape of gestation length variation, including its associations with body mass and lifespan variation, changed over mammalian evolution remains unknown. Phylogeny-informed analyses of 845 representative extant eutherian mammals showed that gestation length variation substantially differed in both whether and how strongly it was associated with body mass and lifespan across mammalian clades. For example, gestation length variation in Chiroptera and Cetacea was not associated with lifespan or body mass but was strongly associated only with body mass in Carnivora. We also identified 52 adaptive shifts in gestation length variation across the mammal phylogeny and 14 adaptive shifts when considering all three life history traits; the placements of six adaptive shifts are common in the two analyses. Notably, two of these shifts occurred at the roots of Cetacea and Pinnipedia, respectively, coinciding with the transition of these clades to the marine environment. The varying dynamics of the phenotypic landscape of gestation length, coupled with the varying patterns of associations between gestation length and two other major life history traits, raise the hypothesis that evolutionary constraints on gestation length have varied substantially across mammalian phylogeny. This variation in constraints implies that the genetic architecture of gestation length differs between mammal clades.
Exploring the Roles of RNAs in Chromatin Architecture Using Deep Learning
Authors: Kuang Shuzhen , Pollard Katherine S. 
Published: October 2023

AbstractRecent studies have highlighted the impact of both transcription and transcripts on 3D genome organization, particularly its dynamics. Here, we propose a deep learning framework, called AkitaR, that leverages both genome sequences and genome-wide RNA-DNA interactions to investigate the roles of chromatin-associated RNAs (caRNAs) on genome folding in HFFc6 cells. In order to disentangle thecis- andtrans-regulatory roles of caRNAs, we compared models with nascent transcripts,trans-located caRNAs, open chromatin data, or DNA sequence alone. Both nascent transcripts andtrans-located caRNAs improved the models’ predictions, especially at cell-type-specific genomic regions. Analyses of feature importance scores revealed the contribution of caRNAs at TAD boundaries, chromatin loops and nuclear sub-structures such as nuclear speckles and nucleoli to the models’ predictions. Furthermore, we identified non-coding RNAs (ncRNAs) known to regulate chromatin structures, such as MALAT1 and NEAT1, as well as several novel RNAs, RNY5, RPPH1, POLG-DT and THBS1-IT, that might modulate chromatin architecture throughtrans-interactions in HFFc6. Our modeling also suggests that transcripts from Alus and other repetitive elements may facilitate chromatin interactions throughtransR-loop formation. Our findings provide new insights and generate testable hypotheses about the roles of caRNAs in shaping chromatin organization.
Fertility is compromised after oocyte-specific deletion of Katanin A-subunit,Katna1, but notKatnal1
Authors: Yuen Wai Shan , Zhang Qing-Hua , Dunstan Monique , Aidhikari Deepak , O’Connor Anne E , Dunleavy Jessica EM , O’Bryan Moira K , Carroll John 
Published: October 2023

AbstractKatanins are microtubule severing enzymes that play roles in shaping diverse microtubule-based structures during all cell cycle stages. To address the role of katanin A-subunits in mammalian oocytes, we have used theZp3-CreLoxapproach to specifically delete katanin A1 (Katna1) and katanin A-like 1 (Katnal1) from the start of oocyte growth in mice. Here, we show thatKatnal1is not required for normal female fertility, but that deletion ofKatna1causes a 50% decrease in fertility. Further investigation inKatna1-/-oocytes revealed no effect on MI spindle morphology but a significant effect on the morphology of MII spindles. This was accompanied by a decreased rate of fertilisation. ResultantKatna1+/-heterozygous embryos that reached the 2-cell stage developed at normal rates to the blastocyst stage. Diploid homozygous parthenotes derived fromKatna1-/-oocytes revealed a reduced rate of blastocyst formation, decreased cell number and increased nuclear size. The ability of the paternal allele to rescue preimplantation development suggests the origin of the decrease in the fertility of conditionalKatna1-/-mice lies in abnormalities arising in the egg to embryo transition prior to embryonic genome activation.
Genetic analysis of selection bias in a natural experiment: Investigating in-utero famine effects on elevated body mass index in the Dutch Hunger Winter Families Study
Authors: Zhou Jiayi , Indik Claire E. , Kuipers Thomas B. , Li Chihua , Nivard Michel G. , Ryan Calen P. , Tucker-Drob Elliot M. , Taeubert M. Jazmin , Wang Shuang , Wang Tian , Conley Dalton , Heijmans Bastiaan T. , Lumey LH , Belsky Daniel W. 
Published: October 2023

ABSTRACTNatural-experiment designs that compare survivors of in-utero famine exposure to unaffected controls suggest that in-utero undernutrition predisposes to development of obesity. However, birth rates drop dramatically during famines. Selection bias could arise if factors that contribute to obesity also protect fertility and/or fetal survival under famine conditions. We investigated this hypothesis using genetic analysis of a famine-exposed birth cohort. We genotyped participants in the Dutch Hunger Winter Families Study (DHWFS, N=950; 45% male), of whom 51% were exposed to the 1944-1945 Dutch Famine during gestation and 49% were their unexposed same-sex siblings or “time controls” born before or after the famine in the same hospitals. We computed body-mass index (BMI) polygenic indices (PGIs) in DHWFS participants and compared BMI PGIs between famine-exposed and control groups. Participants with higher polygenic risk had higher BMIs (Pearson r=0.42, p<0.001). However, differences between BMI PGIs of famine-exposed participants and controls were small and not statistically different from zero across specifications (Cohen’s d=0.10, p>0.092). Our findings did not indicate selection bias, supporting the validity of the natural-experiment design within DHWFS. In summary, our study outlines a novel approach to explore the presence of selection bias in famine and other natural experiment studies.
A multi-hospital, clinician-initiated bacterial genomics program to investigate treatment failure in severeStaphylococcus aureusinfections
Authors: Giulieri Stefano G. , Leroi Marcel , Daniel Diane , Chean Roy , Bond Katherine , Walker Harry , Holmes Natasha E. , Mothobi Nomvuyo , Alexander Adrian , Jenney Adam , Beckett Carolyn , Mahony Andrew , Stevens Kerrie , Sherry Norelle L. , Howden Benjamin P. 
Published: October 2023

AbstractBacterial genomics is increasingly used for infectious diseases surveillance, outbreak control and prediction of antibiotic resistance. With expanding availability of rapid whole-genome sequencing, bacterial genomics data could become a valuable tool for clinicians managing bacterial infections, driving precision medicine strategies. Here, we present a novel clinician-driven bacterial genomics framework that applies within-patient evolutionary analysis to identify in real-time microbial genetic changes that have an impact on the outcome of severeStaphylococcus aureusinfections, a strategy that is increasingly used in cancer genomics. Our approach uses a combination of bacterial genomics and novel microbiological testing to identify and track bacterial adaptive mutations that underlie antibiotic treatment failure. We show real-life examples of the impact of our approach and propose a roadmap for the use of bacterial genomics to advance the management of severe bacterial infections.
The impact of spatial connectivity on NPIs effectiveness
Authors: Sabbatini Chiara E. , Pullano Giulia , Di Domenico Laura , Rubrichi Stefania , Bansal Shweta , Colizza Vittoria 
Published: October 2023

AbstractBackgroundFrance implemented a combination of non-pharmaceutical interventions (NPIs) to manage the COVID-19 pandemic between September 2020 and June 2021. These included a lockdown in the fall 2020 – the second since the start of the pandemic – to counteract the second wave, followed by a long period of nighttime curfew, and by a third lockdown in the spring 2021 against the Alpha wave. Interventions have so far been evaluated in isolation, neglecting the spatial connectivity between regions through mobility that may impact NPI effectiveness.MethodsFocusing on September 2020 – June 2021, we developed a regionally-based epidemic metapopulation model informed by observed mobility fluxes from daily mobile phone data and fitted the model to regional hospital admissions. The model integrated data on vaccination and variants spread. Scenarios were designed to assess the impact of the Alpha variant, characterized by increased transmissibility and risk of hospitalization, of the vaccination campaign and alternative policy decisions.ResultsThe spatial model better captured the heterogeneity observed in the regional dynamics, compared to models neglecting inter-regional mobility. The third lockdown was similarly effective to the second lockdown after discounting for immunity, Alpha, and seasonality (51% vs 52% median regional reduction in the reproductive number R0, respectively). The 6pm nighttime curfew with bars and restaurants closed, implemented in January 2021, substantially reduced COVID-19 transmission. It initially led to 49% median regional reduction of R0, decreasing to 43% reduction by March 2021. In absence of vaccination, implemented interventions would have been insufficient against the Alpha wave. Counterfactual scenarios proposing a sequence of lockdowns in a stop-and-go fashion would have reduced hospitalizations and restriction days for low enough thresholds triggering and lifting restrictions.ConclusionsSpatial connectivity induced by mobility impacted the effectiveness of interventions especially in regions with higher mobility rates. Early evening curfew with gastronomy sector closed allowed authorities to delay the third wave. Stop-and-go lockdowns could have substantially lowered both healthcare and societal burdens if implemented early enough, compared to the observed application of lockdown-curfew-lockdown, but likely at the expense of several labor sectors. These findings contribute to characterize the effectiveness of implemented strategies and improve pandemic preparedness.
The origin and maintenance of supergenes contributing to ecological adaptation in Atlantic herring
Authors: Jamsandekar Minal , Ferreira Mafalda S. , Pettersson Mats E. , Farell Edward , Davis Brian W. , Andersson Leif 
Published: October 2023

AbstractChromosomal inversions are associated with local adaptation in many species. However, questions regarding how they are formed, maintained and impact various other evolutionary processes remain elusive. Here, using a large genomic dataset of long-read and short-read sequencing, we ask these questions in one of the most abundant vertebrates on Earth, the Atlantic herring. This species has four megabase-sized inversions associated with ecological adaptation that correlate with water temperature. TheSandNinversion alleles at these four loci dominate in the southern and northern parts, respectively, of the species distribution in the North Atlantic Ocean. By determining breakpoint coordinates of the four inversions and the structural variations surrounding them, we hypothesize that these inversions are formed by ectopic recombination between duplicated sequences immediately outside of the inversions. We show that these are old inversions (>1 MY), albeit formed after the split between Atlantic herring and its sister species, the Pacific herring. They are yet to reach mutation-flux equilibrium, but the largeNeof herring combined with the common occurrence of opposite homozygotes across the species distribution has allowed effective purifying selection to prevent accumulation of genetic load and repeats within the inversions.
Feasibility of intranasal delivery of thin-film freeze-dried monoclonal antibodies
Authors: Yu Yu-Sheng , Xu Haiyue , AboulFotouh Khaled , Williams Gerallt , Suman Julie , Sahakijpijarn Sawittree , Cano Chris , Warnken Zachary N. , Wu Kevin C.-W. , Williams Robert O. , Cui Zhengrong 
Published: October 2023

AbstractMonoclonal antibodies (mAbs) administered intranasally as dry powders can be potentially applied for the treatment or pre-exposure prevention of viral infections in the upper respiratory tract. However, a method to transform the mAbs from liquid to dry powders suitable for intranasal administration and a device that can spray the dry powders to the desired region of the nasal cavity are needed to fully realize the potentials of the mAbs. Herein, we report that thin-film freeze-drying can be applied to prepare aerosolizable mAb dry powders and that the dry powders can be sprayed into the posterior nasal cavity using Aptar Pharma’s Unidose (UDS) Powder Nasal Spray System. AUG-3387, a human-derived mAb that neutralizes the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was used in the present study. First, we prepared AUG-3387 thin-film freeze-dried powders (i.e., TFF AUG-3387 powders) from liquid formulations containing different levels of mAbs. The TFF AUG-3387 powder with the highest solid content (i.e., TFF AUG-3387C powder) was then chosen for further characterization, including the evaluation of the plume geometry, spray pattern, and particle size distribution after the powder was sprayed using the UDS Powder device. Finally, the deposition patterns of the TFF AUG-3387C powder sprayed using the UDS Powder device were studied using 3D-printed nasal replica casts based on an adult model and a child model. It is concluded that it is feasible to intranasally deliver mAbs as dry powders by transforming the mAbs into dry powders using thin-film freeze-drying and then spray the powder using the UDS Powder device.
Optimization of a deep mutational scanning workflow to improve quantification of mutation effects on protein-protein interactions
Authors: Bendel Alexandra M. , Skendo Kristjana , Klein Dominique , Schimada Kenji , Kauneckaite-Griguole Kotryna , Diss Guillaume 
Published: October 2023

AbstractDeep Mutational Scanning (DMS) assays are powerful tools to study sequence-function relationships by measuring the effects of thousands of sequence variants on protein function. During a DMS experiment, several technical artefacts might distort non-linearly the functional score obtained, potentially biasing the interpretation of the results. We therefore tested several technical parameters in the deepPCA workflow, a DMS assay for protein-protein interactions, in order to identify technical sources of non-linearities. We found that parameters common to many DMS assays such as amount of transformed DNA, timepoint of harvest and library composition can cause non-linearities in the data. Designing experiments in a way to minimize these non-linear effects will improve the quantification and interpretation of mutation effects.
A novel class of ultra-stable endospore appendages decorated with collagen-like tip fibrillae
Authors: Sleutel Mike , Zegeye Ephrem Debebe , Llarena Ann Katrin , Pradhan Brajabandhu , Fislage Marcus , O’Sullivan Kristin , Aspholm Marina , Remaut Han 
Published: October 2023

AbstractBacterial endospores are remarkable examples of biological resilience, representing a dormant and heavily fortified differentiation form capable of withstanding physical and chemical stressors detrimental to vegetative cells. In pathogenic firmicutes, spores also form an infectious particle and can take up a central role in the environmental persistence and dissemination of disease. A poorly understood aspect of spore-mediated infection is the fibrous structures or ‘endospore appendages’ (ENAs) that have been seen to decorate the spores of pathogenic Bacilli and Clostridia. New methodological approaches are opening an unprecedented window on these long enigmatic structures. Using cryoID, Alphafold modelling and genetic approaches we identify a novel class of ultra-robust ENAs formed byBacillus paranthracis. We demonstrate that L-ENA are encoded by a three-gene cluster (ena3) that contains all components for the self-assembly of ladder-like protein nanofibers of stacked heptameric rings, their anchoring to the exosporium, and their termination in a trimeric ‘ruffle’ made of a collagen-like BclA paralogue. Phylogenomic analyses shows theena3gene cluster as a mobile element with a polyphyletic distribution across pathogenic Bacilli.