bluuebunny/crossref_metadata_2025_split huggingface dataset:
Influence of age on functional memory T cell diversity
Authors: Fang Fengqin , Cao Wenqiang , Zhu Weikang , Lam Nora , Li Lingjie , Gaddam Sadhana , Wang Yong , Kim Chulwoo , Lambert Simon , Zhang Huimin , Hu Bin , Farber Donna L. , Weyand Cornelia M. , Goronzy Jörg J. 
Published: May 2021

AbstractMemory T cells exhibit considerable diversity that determines their ability to be protective and their durability. Here, we examined whether changes in T cell heterogeneity contribute to the age-associated failure of immune memory. By screening for age-dependent T cell surface markers, we have identified CD4 and CD8 memory T cell subsets that are unrelated to previously defined subsets of central and effector memory cells. Memory T cells expressing the ecto-5’-nucleotidase CD73 constitute a functionally distinct subset of memory T cells that declines with age. They exhibit many features favorable for immune protection, including longevity and polyfunctionality. They have a low turnover, but are poised to display effector functions and to develop into cells resembling tissue-resident memory T cells (TRM). Upstream regulators of differential chromatin accessibility and transcriptomes include transcription factors that are characteristic for conferring these superior memory features as well as facilitating CD73 expression. CD73 is not just a surrogate marker of these regulatory networks but is directly involved in T cell survival and TRMdifferentiation Interventions preventing the decline of this T cell subset or increasing CD73 expression have the potential to improve immune memory in older adults.
A connectivity-constrained computational account of topographic organization in primate high-level visual cortex
Authors: Blauch Nicholas M. , Behrmann Marlene , Plaut David C. 
Published: May 2021

Inferotemporal cortex (IT) in humans and other primates is topo-graphically organized, containing multiple hierarchically-organized areas selective for particular domains, such as faces and scenes. This organization is commonly viewed in terms of evolved domain-specific visual mechanisms. Here, we develop an alternative, domain-general and developmental account of IT cortical organization. The account is instantiated as an Interactive Topographic Network (ITN), a form of computational model in which a hierarchy of model IT areas, subject to connectivity-based constraints, learns high-level visual representations optimized for multiple domains. We find that minimizing a wiring cost on spatially organized feedforward and lateral connections within IT, combined with constraining the feedforward processing to be strictly excitatory, results in a hierarchical, topographic organization. This organization replicates a number of key properties of primate IT cortex, including the presence of domain-selective spatial clusters preferentially involved in the representation of faces, objects, and scenes, columnar responses across separate excitatory and inhibitory units, and generic spatial organization whereby the response correlation of pairs of units falls off with their distance. We thus argue that domain-selectivity is an emergent property of a visual system optimized to maximize behavioral performance while minimizing wiring costs.Significance StatementWe introduce the Interactive Topographic Network, a framework for modeling high-level vision, to demonstrate in computational simulations that the spatial clustering of domains in late stages of the primate visual system may arise from the demands of visual recognition under the constraints of minimal wiring costs and excitatory between-area neuronal communication. The learned organization of the model is highly specialized but not fully modular, capturing many of the properties of organization in primates. Our work is significant for cognitive neuroscience, by providing a domain-general developmental account of topo-graphic functional specialization, and for computational neuroscience, by demonstrating how well-known biological details can be successfully incorporated into neural network models in order to account for critical empirical findings.
Antibody Display of cell surface receptor Tetraspanin12 and SARS-CoV-2 spike protein
Authors: Hsieh Fu-Lien , Chang Tao-Hsin 
Published: May 2021

AbstractIn previous work, Hsieh and Higgins presented a novel structure of antibodies identified from malaria-exposed individuals, in which the extracellular immunoglobulin (Ig)-like domain of leukocyte-associated immunoglobulin-like receptor 1 (LAIR1) is presented on the third complementarity determining regions (CDR3) of the Ig heavy chain. Here we develop an Antibody Display technology based on this LAIR1-containing antibody, by grafting proteins of interest (POI) onto the heavy chain CDR3 while retaining the biological properties of the POI. As a proof of principle, we displayed the second extracellular domain of Tetraspanin12 (Tspan12EC2) and the receptor-binding domain (RBD) of SARS-CoV-2 spike protein on the heavy chain CDR3. Our data revealed that Antibody Display Tspan12EC2bound to Norrie Disease Protein (Norrin) and Antibody Display SARS-CoV-2 RBD bound to angiotensin-converting enzyme 2 (ACE2) and neutralizing nanobodies. Collectively, Antibody Display technology offers the general strategy of designing novel antibodies by grafting POI onto the CDR3.
ppx: Programmatic access to proteomics data repositories
Authors: Fondrie William E , Bittremieux Wout , Noble William S 
Published: May 2021

AbstractThe volume of proteomics and mass spectrometry data available in public repositories continues to grow at a rapid pace as more researchers embrace open science practices. Open access to the data behind scientific discoveries has become critical to validate published findings and develop new computational tools. Here, we present ppx, a Python package that provides easy, programmatic access to the data stored in ProteomeXchange repositories, such as PRIDE and MassIVE. The ppx package can either be used as a command line tool or a Python package to retrieve the files and metadata associated with a project when provided its identifier. To demonstrate how ppx enhances reproducible research, we used ppx within a Snakemake workflow to reanalyze a published dataset with the open modification search tool ANN-SoLo and compared our reanalysis to the original results. We show that ppx readily integrates into workflows and our reanalysis produced results consistent with the original analysis. We envision that ppx will be a valuable tool for creating reproducible analyses, providing tool developers easy access to data for development, testing, and benchmarking, and enabling the use of mass spectrometry data in data-intensive analyses. The ppx package is freely available and open source under the MIT license at: https://github.com/wfondrie/ppx
Loss of Rnf43 accelerates Kras-mediated neoplasia and remodels the tumor immune microenvironment in pancreatic adenocarcinoma
Authors: Hosein Abdel Nasser , Dangol Gita , Okumura Takashi , Roszik Jason , Rajapakshe Kimal , Siemann Megan , Ghosh Bidyut , Monberg Maria , Guerrero Paola A. , Zaid Mohamed , Singhi Aatur , Haymaker Cara L , Clevers Hans , Woermann Sonja M. , Abou-Elkacem Lotfi , Maitra Anirban 
Published: May 2021

AbstractRNF43 is an E3 ubiquitin ligase that is recurrently mutated in pancreatic ductal adenocarcinoma (PDAC) and precursor cystic neoplasms of the pancreas. The impact of RNF43 mutations on PDAC is poorly understood and autochthonous models have not been sufficiently characterized. In this study we describe a genetically engineered mouse model (GEMM) of PDAC with conditional expression of oncogenic Kras and deletion of the catalytic domain of Rnf43 (KRC) in exocrine cells. We demonstrate that Rnf43 loss results in an increased incidence of high-grade cystic lesions of the pancreas and PDAC. Importantly, KRC mice have a significantly decreased survival compared to mice containing only an oncogenic Kras mutation. By use of single cell RNA sequencing we demonstrated that KRC tumor progression is accompanied by a decrease in macrophages, as well as an increase in T and B lymphocytes with evidence of increased immune checkpoint molecule expression and affinity maturation, respectively. This was in stark contrast to the tumor immune microenvironment observed in the Kras/Tp53 driven PDAC GEMM. Furthermore, expression of the chemokine, CXCL5, was found to be specifically decreased in KRC cancer cells by means of epigenetic regulation and emerged as a putative candidate for mediating the unique KRC immune landscape. This GEMM establishes RNF43 as a bona fide tumor suppressor gene in PDAC and puts forth a rationale for an immunotherapy approach in this subset of PDAC cases.
Lateral Preoptic Area Neurons Signal Cocaine Self-Administration Behaviors
Authors: Coffey Kevin R. , Venkat Vaishnavi , West Mark O. , Barker David J. 
Published: May 2021

AbstractThe lateral preoptic area is implicated in numerous aspects of substance use disorder. In particular, the lateral preoptic area is highly sensitive to the pharmacological properties of psychomotor stimulants, and its activity promotes drug-seeking in the face of punishment and reinstatement during abstinence. Despite the lateral preoptic areas complicity in substance use disorder, how precisely lateral preoptic area neurons encode the individual components of drug self-administration has not been ascertained. To bridge this gap, we examined how the firing of single lateral preoptic area neurons correlates with three discrete elements of cocaine self-administration: 1) drug-seeking (pre-response), 2) drug-taking (response), and 3) receipt of the cocaine infusion. A significant subset of lateral preoptic area neurons responded to each component with a mix of increases and decreases in firing-rate. A majority of these neurons encoded the operant response with increases in spiking, though responses during the drug-seeking, taking, and reciept windows were highly correlated.
Experimental demonstration of tethered gene drive systems for confined population modification or suppression
Authors: Metzloff Matthew , Yang Emily , Dhole Sumit , Clark Andrew G. , Messer Philipp W. , Champer Jackson 
Published: May 2021

ABSTRACTHoming gene drives hold great promise for the genetic control of natural populations. However, current homing systems are capable of spreading uncontrollably between populations connected by even marginal levels of migration. This could represent a substantial sociopolitical barrier to the testing or deployment of such drives and may generally be undesirable when the objective is only local population control, such as suppression of an invasive species outside of its native range. Tethered drive systems, in which a locally confined gene drive provides the CRISPR nuclease needed for a homing drive, could provide a solution to this problem, offering the power of a homing drive and confinement of the supporting drive. Here, we demonstrate the engineering of a tethered drive system inDrosophila, using a regionally confined CRISPR Toxin-Antidote Recessive Embryo (TARE) drive to support modification and suppression homing drives. Each drive was able to bias inheritance in its favor, and the TARE drive was shown to spread only when released above a threshold frequency in experimental cage populations. After the TARE drive had established in the population, it facilitated the spread of a subsequently released split homing modification drive (to all individuals in the cage) and of a homing suppression drive (to its equilibrium frequency). Our results show that the tethered drive strategy is a viable and easily engineered option for providing confinement of homing drives to target populations.
SARS-CoV-2-specific memory B cells can persist in the elderly despite loss of neutralising antibodies
Authors: Jeffery-Smith Anna , Burton Alice R , Lens Sabela , Rees-Spear Chloe , Patel Monika , Gopal Robin , Muir Luke , Aiano Felicity , Doores Katie J , Chow J. Yimmy , Ladhani Shamez N , Zambon Maria , McCoy Laura E , Maini Mala K 
Published: May 2021

AbstractMemory B cells (MBC) can provide a recall response able to supplement waning antibodies with an affinity-matured response better able to neutralise variant viruses. We studied a cohort of vulnerable elderly care home residents and younger staff, a high proportion of whom had lost neutralising antibodies (nAb), to investigate their reserve immunity from SARS-CoV-2-specific MBC. Class-switched spike and RBD-tetramer-binding MBC with a classical phenotype persisted five months post-mild/asymptomatic SARS-CoV-2 infection, irrespective of age. Spike/RBD-specific MBC remained detectable in the majority who had lost nAb, although at lower frequencies and with a reduced IgG/IgA isotype ratio. Functional spike/S1/RBD-specific recall was also detectable by ELISpot in some who had lost nAb, but was significantly impaired in the elderly, particularly to RBD. Our findings demonstrate persistence of SARS-CoV-2-specific MBC beyond loss of nAb, but highlight the need for careful monitoring of functional defects in RBD-specific B cell immunity in the elderly.One sentence summaryCirculating class-switched spike and RBD-specific memory B cells can outlast detectable neutralising antibodies but are functionally constrained in the elderly.
A role for ecologically-tuned chunking in the evolution of advanced cognition demonstrated by modelling the cleaner fish market problem
Authors: Prat Yosef , Bshary Redouan , Lotem Arnon 
Published: May 2021

AbstractWhat makes cognition ‘advanced’ is an open and not precisely defined question. One perspective involves increasing the complexity of associative learning, from conditioning to learning sequences of events (‘chaining’) to representing various cue combinations as ‘chunks’. Here we develop a weighted-graph model to study the conditions for the evolution of chunking ability, based on the ecology of the cleaner fishLabroides dimidiatus. Cleaners must learn to serve visitor clients before resident clients, because a visitor leaves if not attended while a resident waits for service. This challenge has been captured in various versions of the ephemeral-reward task, which has been proven difficult for a range of cognitively capable species. We show that chaining is the minimal requirement for solving the laboratory task, that involves repeated simultaneous exposure to an ephemeral and permanent food source. Adding ephemeral-ephemeral and permanent-permanent combinations, as cleaners face in the wild, requires individuals to have chunking abilities to solve the task. Importantly, chunking parameters need to be calibrated to ecological conditions in order to produce adaptive decisions. Thus, it is the fine tuning of this ability which may be the major target of selection during the evolution of advanced associative learning.
Chronic PPARγ Stimulation Shifts Amyloidosis to Higher Fibrillarity but Improves Cognition
Authors: Blume Tanja , Deussing Maximilian , Biechele Gloria , Peters Finn , Zott Benedikt , Schmidt Claudio , Franzmeier Nicolai , Wind Karin , Eckenweber Florian , Sacher Christian , Shi Yuan , Ochs Katharina , Kleinberger Gernot , Xiang Xianyuan , Focke Carola , Lindner Simon , Gildehaus Franz-Josef , Beyer Leonie , von Ungern-Sternberg Barbara , Bartenstein Peter , Baumann Karlheinz , Adelsberger Helmuth , Rominger Axel , Cumming Paul , Willem Michael , Dorostkar Mario M. , Herms Jochen , Brendel Matthias 
Published: May 2021

AbstractBackgroundWe undertook longitudinal β-amyloid positron emission tomography (Aβ-PET) imaging as a translational tool for monitoring of chronic treatment with the peroxisome proliferator-activated receptor gamma (PPARγ) agonist pioglitazone in Aβ model mice. We thus tested the hypothesis this treatment would rescue from increases of the Aβ-PET signal while promoting spatial learning and preservation of synaptic density.MethodsPS2APP mice (N=23; baseline age: 8 months) and AppNL-G-F mice (N=37; baseline age: 5 months) were investigated longitudinally for five months using Aβ-PET. Groups of mice were treated with pioglitazone or vehicle during the follow-up interval. We tested spatial memory performance and confirmed terminal PET findings by immunohistochemical and biochemistry analyses.ResultsSurprisingly, Aβ-PET and immunohistochemistry revealed a shift towards higher fibrillary composition of Aβ-plaques during upon chronic pioglitazone treatment. Nonetheless, synaptic density and spatial learning were improved in transgenic mice with pioglitazone treatment, in association with the increased plaque fibrillarity.ConclusionThese translational data suggest that a shift towards higher plaque fibrillarity protects cognitive function and brain integrity. Increases in the Aβ-PET signal upon immunomodulatory treatments targeting Aβ aggregation can thus be protective.
The genetic and epigenetic landscape of the Arabidopsis centromeres
Authors: Naish Matthew , Alonge Michael , Wlodzimierz Piotr , Tock Andrew J. , Abramson Bradley W. , Lambing Christophe , Kuo Pallas , Yelina Natasha , Hartwick Nolan , Colt Kelly , Kakutani Tetsuji , Martienssen Robert A. , Bousios Alexandros , Michael Todd P. , Schatz Michael C. , Henderson Ian R. 
Published: May 2021

AbstractCentromeres attach chromosomes to spindle microtubules during cell division and, despite this conserved role, show paradoxically rapid evolution and are typified by complex repeats. We used ultra-long-read sequencing to generate the Col-CEN Arabidopsis thaliana genome assembly that resolves all five centromeres. The centromeres consist of megabase-scale tandemly repeated satellite arrays, which support high CENH3 occupancy and are densely DNA methylated, with satellite variants private to each chromosome. CENH3 preferentially occupies satellites with least divergence and greatest higher-order repetition. The centromeres are invaded by ATHILA retrotransposons, which disrupt genetic and epigenetic organization of the centromeres. Crossover recombination is suppressed within the centromeres, yet low levels of meiotic DSBs occur that are regulated by DNA methylation. We propose that Arabidopsis centromeres are evolving via cycles of satellite homogenization and retrotransposon-driven diversification.One-sentence summaryLong read sequencing and assembly of the Arabidopsis centromeres reveals their genetic and epigenetic topography.
Complete protection by a single dose skin patch delivered SARS-CoV-2 spike vaccine
Authors: McMillan Christopher L.D. , Choo Jovin J.Y. , Idris Adi , Supramaniam Aroon , Modhiran Naphak , Amarilla Alberto A. , Isaacs Ariel , Cheung Stacey T.M. , Liang Benjamin , Bielefeldt-Ohmann Helle , Azuar Armira , Acharya Dhruba , Kelly Gabrielle , Fernando Germain J.P. , Landsberg Michael J. , Khromykh Alexander A. , Watterson Daniel , Young Paul R. , McMillan Nigel A.J. , Muller David A. 
Published: May 2021

AbstractSARS-CoV-2 has infected over 160 million people and resulted in more than 3.3 million deaths, and we still face many challenges in the rollout of vaccines. Here, we use the high-density microarray patch to deliver a SARS-CoV-2 spike subunit vaccine directly to the skin. We show the vaccine, dry-coated on the patch is thermostable, and delivery of spike via HD-MAP induced greater cellular and antibody immune responses, with serum able to potently neutralize clinically relevant isolates including those from the B.1.1.7 and B.1.351 lineages. Finally, a single dose of HD-MAP-delivered spike provided complete protection from a lethal virus challenge, demonstrating that HD-MAP delivery of a SARS-CoV-2 vaccine is superior to traditional needle-and-syringe vaccination and has the potential to greatly impact the ongoing COVID-19 pandemic.
Cryo-EM Structure of the Photosynthetic LH1-RC Complex from Rhodospirillum rubrum
Authors: Tani K. , Kanno R. , Ji X.-C. , Hall M. , Yu L.-J. , Kimura Y. , Madigan M. T. , Mizoguchi A. , Humbel B. M. , Wang-Otomo Z.-Y. 
Published: May 2021

AbstractWe present a cryo-EM structure of the light-harvesting-reaction center (LH1-RC) core complex from purple phototrophic bacterium Rhodospirillum (Rsp.) rubrum at 2.76 Å resolution. The LH1 complex forms a closed, slightly elliptical ring structure with 16 αβ-polypeptides surrounding the RC. Our biochemical analysis detected rhodoquinone (RQ) molecules in the purified LH1-RC, and the cryo-EM density map specifically positions RQ at the QA site in the RC. The geranylgeraniol sidechains of bacteriochlorophyll (BChl) aG coordinated by LH1 β-polypeptides exhibit a highly homologous tail-up conformation that allows for interactions with the bacteriochlorin rings of nearby LH1 α-associated BChls aG. The structure also revealed key protein–protein interactions in both N- and C-terminal regions of the LH1 αβ-polypeptides, mainly within a face-to-face structural subunit. Our findings enable to evaluate past experimental and computational results obtained with this widely used organism and provide crucial information for more detailed exploration of light-energy conversion, quinone transport, and structure–function relationships in pigment-protein complexes.
Multi-omics consensus ensemble refines the classification of muscle-invasive bladder cancer with stratified prognosis, tumour microenvironment and distinct sensitivity to frontline therapies
Authors: Lu Xiaofan , Meng Jialin , Su Liwen , Jiang Liyun , Wang Haitao , Zhu Junkai , Huang Mengjia , Cheng Wenxuan , Xu Li , Ruan Xinjia , Zhou Yujie , Yeh Shuyuan , Liang Chaozhao , Yan Fangrong 
Published: May 2021

ABSTRACTThe molecular classification of muscle-invasive bladder cancer (MIBC) based on transcriptomic signatures has been extensively studied. The complementary nature of information provided by different molecular profiles motivated us to refine MIBC classification by aggregating multi-omics data. We generated a consensus ensemble through ten multi-omics integrative clustering approaches on 396 MIBCs from TCGA. A total of 701 MIBCs from different sequencing technologies were used for external validation. Associations between subtypes and prognosis, molecular profiles, the tumour microenvironment, and potential response to frontline therapies were further analyzed. Nearest template prediction and random forest classification were used to develop a predictive signature/classifier for MIBC refinement. We identified four integrative consensus subtypes of MIBC, which were further designated basal-inflamed, basal-noninflamed, luminal-excluded and luminal-desert by immune profiling. Of note, the refinement of basal-like MIBC classification adds to the literature by identifying a basal-noninflamed MIBC subtype presenting with a significantly poor outcome and a global immune-cold phenotype, which might be triggered by Chr4 deletion and high activation of the oncogenic NRF2 pathway. In contrast, basal-inflamed MIBC showed high immunocyte infiltration and high expression of potential targets for immunotherapy. Using an external metastatic MIBC cohort in which patients received anti-PD-L1 treatment, we suggested that basal-inflamed MIBC had a higher likelihood of responding to immunotherapy than other MIBCs. The R package “refineMIBC” was offered as a research tool to refine MIBC from a single-sample perspective (https://github.com/xlucpu/refineMIBC). This consensus ensemble refines the intrinsic MIBC subtypes, which provides a blueprint for the clinical development of rational targeted and immunotherapeutic strategies.