bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Effects of Education on Cognition in Older Age: Evidence from Genotyped Siblings1
Authors: Fletcher Jason , Topping Michael , Zheng Fengyi , Lu Qiongshi 
Published: May 2021

AbstractA growing literature has sought to tie educational attainment with later-life cognition and Alzheimer’s disease outcomes. This paper leverages sibling comparisons in educational attainment as well as genetic predictors (polygenic scores) for cognition, educational attainment, and Alzheimer’s disease to estimate effects of educational attainment on cognition in older age in the United Kingdom. We find that the effects of education on cognition are confounded by family background factors (∼40%) and by genetics (<10%). After adjustments, we continue to find large effects of education. College graduates have cognition scores that are approximately 0.75 SD higher than those who report no credentials. We also find evidence that educational effects on cognition are smaller for those with high polygenic scores for Alzheimer’s disease.
Cancer patient survival can be accurately parameterized, revealing time-dependent therapeutic effects and doubling the precision of small trials
Authors: Plana Deborah , Fell Geoffrey , Alexander Brian M. , Palmer Adam C. , Sorger Peter K. 
Published: May 2021

SUMMARYIndividual participant data (IPD) from completed oncology clinical trials are a valuable but rarely available source of information. A lack of minable survival distributions has made it difficult to identify factors determining the success and failure of clinical trials and improve trial design. We imputed survival IPD from ∼500 arms of phase III oncology trials (representing ∼220,000 events) and found that they are well fit by a two-parameter Weibull distribution. This makes it possible to use parametric statistics to substantially increase trial precision with small patient cohorts typical of phase I or II trials. For example, a 50-person trial parameterized using Weibull distributions is as precise as a 90-person trial evaluated using traditional statistics. Mining IPD also showed that frequent violations of the proportional hazards assumption, particularly in trials of immune checkpoint inhibitors (ICIs), arise from time-dependent therapeutic effects and hazard ratios. Thus, the duration of ICI trials has an underappreciated impact on the likelihood of their success.
Missing-value imputation and in-silico region detection for spatially resolved transcriptomics
Authors: Wang Linhua , Liu Zhandong 
Published: May 2021

AbstractWe are pleased to introduce a first-of-its-kind algorithm that combines in-silico region detection and spatial gene-expression imputation. Spatial transcriptomics by 10X Visium (ST) is a new technology used to dissect gene and cell spatial organization. Analyzing this new type of data has two main challenges: automatically annotating the major tissue regions and excessive zero values of gene-expression due to high dropout rates. We developed a computational tool—MIST—that addresses both challenges by automatically identifying tissue regions and estimating missing gene-expression values for individual tissue regions. We validated MIST detected regions across multiple datasets using manual annotation on the histological staining images as references. We also demonstrated that MIST can accurately recover ST’s missing values through hold-out experiments. Furthermore, we showed that MIST could identify subtle intra-tissue heterogeneity and recover spatial gene-gene interaction signals. We therefore strongly encourage using MIST prior to downstream ST analysis because it provides unbiased region annotations and enables accurately de-noised spatial gene-expression profiles.
Campylobacter jejuni trigger signaling through host cell focal adhesions to inhibit cell motility and impede wound repair
Authors: Klappenbach Courtney M , Negretti Nicholas M. , Aaron Jesse , Chew Teng-Leong , Konkel Michael E. 
Published: May 2021

ABSTRACTCampylobacter jejuni is a major foodborne pathogen that exploits the focal adhesions of intestinal cells to promote invasion and cause severe gastritis. Focal adhesions are multiprotein complexes involved in bidirectional signaling between the actin cytoskeleton and the extracellular matrix. We investigated the dynamics of focal adhesion structure and function in C. jejuni infected cells using a comprehensive set of approaches, including confocal microscopy of live and fixed cells, immunoblots, and super-resolution iPALM. We found that C. jejuni infection of epithelial cells results in an increased focal adhesion size and altered topology. These changes resulted in a persistent modulatory effect on the host cell focal adhesion, as evidenced by an increase in cell adhesion strength, a decrease in individual cell motility, and a reduction of collective cell migration. We discovered that C. jejuni infection causes an increase in phosphorylation of paxillin and an alteration of paxillin turnover at the focal adhesion, which together represent a potential mechanistic basis for altered cell motility. Finally, we observed that infection of epithelial cells with the C. jejuni wild-type strain in the presence of protein synthesis inhibitor, a C. jejuni CadF and FlpA fibronectin-binding protein mutant, or a C. jejuni flagellar export mutant blunts paxillin phosphorylation and partially re-establishes individual host cell motility and collective cell migration. These findings provide a potential mechanism for the restricted intestinal repair observed in C. jejuni-infected animals and raise the possibility that bacteria targeting extracellular matrix components can alter cell behavior after binding and internalization by manipulating focal adhesions.
Predictive evolution of metabolic phenotypes using model-designed selection niches
Authors: Jouhten Paula , Konstantinidis Dimitrios , Pereira Filipa , Andrejev Sergej , Grkovska Kristina , Ghiachi Payam , Beltran Gemma , Almaas Eivind , Mas Albert , Warringer Jonas , Gonzalez Ramon , Morales Pilar , Patil Kiran R. 
Published: May 2021

AbstractTraits lacking fitness benefit cannot be directly selected for under Darwinian evolution. Thus, features such as metabolite secretion are currently inaccessible to adaptive laboratory evolution. Here, we utilize environment-dependency of trait correlations to enable Darwinian selection of fitness-neutral or costly traits. We use metabolic models to design selection niches and to identify surrogate traits that are genetically correlated with cell fitness in the selection niche but coupled to the desired trait in the target niche. Adaptive evolution in the selection niche and subsequent return to the target niche is thereby predicted to enhance the desired trait. We experimentally validate the theory by evolvingSaccharomyces cerevisiaefor increased secretion of aroma compounds in wine fermentation. Genomic, transcriptomic, and proteomic changes in the evolved strains confirmed the predicted flux re-routing to aroma biosynthesis. The use of model-designed selection niches facilitates the predictive evolution of fitness-costly traits for ecological and biotechnological applications.
Experimental recommendations for estimating lower extremity loading based on joint and activity
Authors: Hullfish Todd J. , Drazan John F. , Baxter Josh R. 
Published: May 2021

ABSTRACTResearchers often estimate joint loading using musculoskeletal models to solve the inverse dynamics problem. This approach is powerful because it can be done non-invasively, however, it relies on assumptions and physical measurements that are prone to measurement error. The purpose of this study was to determine the impact of these errors – specifically, segment mass and shear ground reaction force - have on analyzing joint loads during activities of daily living. We preformed traditional marker-based motion capture analysis on 8 healthy adults while they completed a battery of exercises on 6 degree of freedom force plates. We then scaled the mass of each segment as well as the shear component of the ground reaction force in 5% increments between 0 and 200% and iteratively performed inverse dynamics calculations, resulting in 1,681 mass-shear combinations per activity. We compared the peak joint moments of the ankle, knee, and hip at each mass-shear combination to the 100% mass and 100% shear combination to determine the percent error. We found that the ankle was most resistant to changes in both mass and shear and the knee was resistant to changes in mass while the hip was sensitive to changes in both mass and shear. These results can help guide researchers who are pursuing lower-cost or more convenient data collection setups.
LSD and psilocybin flatten the brain’s energy landscape: insights from receptor-informed network control theory
Authors: Singleton S. Parker , Luppi Andrea I. , Carhart-Harris Robin L. , Cruzat Josephine , Roseman Leor , Nutt David J. , Deco Gustavo , Kringelbach Morten L. , Stamatakis Emmanuel A. , Kuceyeski Amy 
Published: May 2021

AbstractPsychedelics like lysergic acid diethylamide (LSD) and psilocybin offer a powerful window into the function of the human brain and mind, by temporarily altering subjective experience through their neurochemical effects. A recent model postulates that serotonin 2a (5-HT2a) receptor agonism allows the brain to explore its dynamic landscape more readily, as reflected by more diverse (entropic) brain activity. We postulate that this increase in entropy may arise in part from a flattening of the brain’s control energy landscape, which can be observed using network control theory to quantify the energy required to transition between recurrent brain states measured using functional magnetic resonance imaging (fMRI) in individuals under LSD, psilocybin, and placebo conditions. We show that LSD and psilocybin reduce the amount of control energy required for brain state transitions, and, furthermore, that, across individuals, LSD’s reduction in control energy correlates with more frequent state transitions and increased entropy of brain state dynamics. Through network control analysis that incorporates the spatial distribution of 5-HT2a receptors from publicly available (non-drug) positron emission tomography (PET) maps, we demonstrate the specific role of this receptor in reducing control energy. Our findings provide evidence that 5-HT2a receptor agonist compounds allow for more facile state transitions and more temporally diverse brain activity. More broadly, by combining receptor-informed network control theory with pharmacological modulation, our work highlights the potential of this approach in studying the impacts of targeted neuropharmacological manipulation on brain activity dynamics.Significance StatementWe present a multi-modal framework for quantifying the effects of two psychedelic drugs (LSD and psilocybin) on brain dynamics by combining functional magnetic resonance imaging (fMRI), diffusion MRI (dMRI), positron emission tomography (PET) and network control theory. Our findings provide evidence that psychedelics flatten the brain’s control energy landscape, allowing for more facile state transitions and more temporally diverse brain activity. We also demonstrate that the spatial distribution of serotonin 2a receptors - the main target of LSD and psilocybin - is optimized for generating these effects. This approach could be used to understand how drugs act on different receptors in the brain to influence brain activity dynamics.
Distinct features of brain perivascular fibroblasts and mural cells revealed by in vivo two-photon imaging
Authors: Bonney Stephanie K. , Sullivan Liam T. , Cherry Timothy J. , Daneman Richard , Shih Andy Y. 
Published: May 2021

SUMMARYPerivascular fibroblasts (PVFs) are recognized for their pro-fibrotic role in many central nervous system disorders. Like mural cells, PVFs surround blood vessels and express Pdgfrβ. However, these shared attributes hinder the ability to distinguish PVFs from mural cells. We used in vivo two-photon imaging and transgenic mice with PVF-targeting promoters (Col1a1 or Col1a2) to compare the structure and distribution of PVFs and mural cells in cerebral cortex of healthy, adult mice. We show that PVFs localize to all cortical penetrating arterioles and their pre-capillary offshoots, as well as the main trunk of only larger ascending venules. However, the capillary zone is devoid of PVF coverage. PVFs display short-range mobility along the vessel wall and exhibit distinct structural features (flattened somata and thin ruffled processes) not seen with smooth muscle cells or pericytes. These findings clarify that PVFs and mural cells are distinct cell types coexisting in a similar perivascular niche.
Signal Inhibitory Receptor on Leukocytes-1 recognizes S100 proteins
Authors: Rumpret Matevž , von Richthofen Helen J. , van der Linden Maarten , Westerlaken Geertje H. A. , Ormeño Cami Talavera , Low Teck Y. , Ovaa Huib , Meyaard Linde 
Published: May 2021

AbstractSignal inhibitory receptor on leukocytes-1 (SIRL-1) is an inhibitory receptor with a hitherto unknown ligand, and is expressed on human monocytes and neutrophils. SIRL-1 inhibits myeloid effector functions such as reactive oxygen species (ROS) production. We here identify S100 proteins as SIRL-1 ligands. S100 proteins are composed of two calcium-binding domains. Various S100 proteins are damage-associated molecular patterns (DAMPs) released from damaged cells, after which they initiate inflammation by ligating activating receptors on immune cells. We now show that the inhibitory SIRL-1 recognizes individual calcium-binding domains of all tested S100 proteins. Blocking SIRL-1 on human neutrophils enhanced S100 protein S100A6-induced ROS production, showing that S100A6 suppresses neutrophil ROS production via SIRL-1. We conclude that SIRL-1 is an inhibitory receptor recognizing the S100 protein family of DAMPs.
An epigenomic shift in amygdala marks the transition to maternal behaviors in alloparenting virgin female mice
Authors: Seward Christopher H. , Saul Michael C. , Troy Joseph M. , Dibaeinia Payam , Zhang Huimin , Sinha Saurabh , Stubbs Lisa J. 
Published: May 2021

ABSTRACTIn many species, adults care for young offspring that are not their own, a phenomenon called alloparenting. However, most nonparental adults must be sensitized by repeated or extended exposures to newborns before they will robustly display parental-like behaviors. To capture neurogenomic events underlying the transition to active parental caring behaviors, we analyzed brain gene expression and chromatin profiles of virgin female mice co-housed with mothers during pregnancy and after birth. After an initial display of antagonistic behaviors and a surge of defense-related gene expression, we observed a dramatic shift in the chromatin landscape specifically in amygdala of the pup-exposed virgin females, accompanied by a dampening of anxiety-related gene expression. This epigenetic shift coincided with hypothalamic expression of the oxytocin gene and the emergence of behaviors and gene expression patterns classically associated with maternal care. The results outline a neurogenomic program associated with dramatic behavioral changes and suggest molecular networks relevant to human postpartum mental health.
Interplay between cell proliferation and recruitment controls the duration of growth and final size of the Drosophila wing
Authors: Diaz-Torres Elizabeth , Muñoz-Nava Luis Manuel , Nahmad Marcos 
Published: May 2021

AbstractHow organs robustly attain a final size despite perturbations in cell growth and proliferation rates is a fundamental question in developmental biology. Since organ growth is an exponential process driven mainly by cell proliferation, even small variations in cell proliferation rates, when integrated over a relatively long time, will lead to large differences in size, unless intrinsic control mechanisms compensate for these variations. Here we use a mathematical model to consider the hypothesis that in the developing wing of Drosophila, cell recruitment, a process in which undifferentiated neighboring cells are incorporated into the wing primordium, determines the time in which growth is arrested in this system. Under this assumption, our model shows that perturbations in proliferation rates of wing-committed cells are compensated by an inversely proportional duration of growth. This mechanism ensures that the final size of the wing is robust in a range of cell proliferation rates. Furthermore, we predict that growth control is lost when fluctuations in cell proliferation affects both wing-committed and recruitable cells. Our model suggests that cell recruitment may act as a temporal controller of growth to buffer fluctuations in cell proliferation rates, offering a solution to a long-standing problem in the field.Graphical abstract
Mammary lineage dictates homologous recombination repair and PARP inhibitor vulnerability
Authors: Kim Hyeyeon , Casey Alison E. , Palomero Luis , Aliar Kazeera , Mahendralingam Mathepan , Parsons Michael , Narala Swami , Mateo Francesca , Hofer Stefan , Waterhouse Paul D. , Kislinger Thomas , Pujana Miquel A. , Berman Hal K. , Khokha Rama 
Published: May 2021

AbstractIt has long been assumed that all normal cells have the same capacity to engage homologous recombination (HR) and non-homologous end joining (NHEJ) to repair DNA double-strand breaks (DSBs), a concept exploited for DNA-damaging chemotherapeutics. We show that mammary epithelial lineage dictates the DSB repair pathway choice. Primary mammary proteomes and DSB repair enumeration by γ-H2AX, Rad51 and DNA-PKc foci reveal that NHEJ operates in all epithelial cells, but high-fidelity HR is restricted to the luminal lineage. This translates to divergent poly (ADP-ribose) polymerase inhibitor (PARPi) vulnerability of mammary epithelial progenitor activity in both mouse and human, irrespective of the BRCA1/2 status. Proteome-defined lineage-specific signatures correlate to breast cancer subtypes and predict PARPi response of triple-negative human breast cancer xenografts. These intrinsically divergent HR characteristics of mammary cell types underpin a new strategy for identifying PARPi responders.
EPIKOL, a chromatin-focused CRISPR/Cas9-based screening platform, to identify cancer-specific epigenetic vulnerabilities
Authors: Yedier-Bayram Ozlem , Gokbayrak Bengul , Aksu Ali Cenk , Cavga Ayse Derya , Kayabolen Alisan , Kala Ezgi Yagmur , Karabiyik Goktug , Günsay Rauf , Morova Tunc , Uyulur Fırat , Lack Nathan A. , Önder Tamer T. , Bagci-Onder Tugba 
Published: May 2021

ABSTRACTDysregulation of the epigenome due to alterations in chromatin modifier proteins commonly contribute to malignant transformation. To discover new drug targets for more targeted and personalized therapies, functional interrogation of epigenetic modifiers is essential. We therefore generated an epigenome-wide CRISPR-Cas9 knock-out library (EPIKOL) that targets a wide-range of epigenetic modifiers and their cofactors. We conducted eight screens in two different cancer types and showed that EPIKOL performs with high efficiency in terms of sgRNA distribution, depletion of essential genes and steady behaviors of non-targeting sgRNAs. From this, we discovered novel epigenetic modifiers besides previously known ones that regulate triple-negative breast cancer and prostate cancer cell fitness. With further validation assays, we confirmed the growth-regulatory function of individual candidates, including SS18L2 and members of the NSL complex (KANSL2, KANSL3, KAT8) in triple negative breast cancer cells. Overall, we show that EPIKOL, a focused sgRNA library targeting approximately 800 genes, can reveal epigenetic modifiers that are essential for cancer cell fitness and serve as a tool to offer novel anti-cancer targets. With its thoroughly generated epigenome-wide gene list, and the relatively high number of sgRNAs per gene, EPIKOL offers a great advantage to study functional roles of epigenetic modifiers in a wide variety of research applications, such as screens on primary cells, patient-derived xenografts as well asin vivomodels.
Evidence of wiring development processes from the connectome of adult Drosophila
Authors: Scheffer Louis K. 
Published: May 2021

AbstractHow is the brain wired during development? Here we look at some of the characteristics of the adult Drosophila brain, a result of this development process. From this we can speculate on at least some aspects of how the wiring was done. A common hypothesis is that surface proteins direct synapse formation among touching neurons. Assuming that surface proteins are specific to cell types, we find support for this hypothesis. The brain in general supports a wide variety of connections of different degrees of reciprocity, with ratios up to a thousand to one in the two directions of synapses between types. However, contacts between cells of the same type are always bi-directional and nearly equal strength. Furthermore, among similar cell types, at least in the mushroom body, the closer the cell type by morphology, the closer the inter-type contacts are to symmetrical. These findings are all consistent with the hypothesis that surface proteins specific to cell types determine the directivity of connections. Next we look at synapses per area, and find this varies widely and is roughly log-normally distributed. In most cases, the number of synapses saturates at higher areas, though other forms are seen - linear, flat, or decreasing with increasing area. Evidence suggests that at least some of this distinction is post-synaptic.
Vascular KATP channel structural dynamics reveal regulatory mechanism by Mg-nucleotides
Authors: Sung Min Woo , Yang Zhongying , Patton Bruce L. , Mostofian Barmak , Russo John , Zuckerman Daniel M. , Shyng Show-Ling 
Published: May 2021

ABSTRACTVascular tone is dependent on smooth muscle KATP channels comprising pore-forming Kir6.1 and regulatory SUR2B subunits, in which mutations cause Cantú syndrome. Unique among KATP isoforms, they lack spontaneous activity and require Mg-nucleotides for activation. Structural mechanisms underlying these properties are unknown. Here, we determined the first cryoEM structures of vascular KATP channels bound to inhibitory ATP and glibenclamide, which differ informatively from similarly determined pancreatic KATP channel isoform (Kir6.2/SUR1). Unlike SUR1, SUR2B subunits adopt distinct rotational “propeller” and “quatrefoil” geometries surrounding their Kir6.1 core. The previously unseen ED-rich linker connecting the two halves of the SUR-ABC core is observed in a quatrefoil-like conformation. MD simulations reveal MgADP-dependent dynamic tripartite interactions between this linker, SUR2B and Kir6.1. The structures captured implicate a progression of intermediate states between MgADP-free inactivated and MgADP-bound activated conformations wherein the ED-rich linker participates as mobile autoinhibitory domain, suggesting a conformational pathway toward KATP channel activation.