bluuebunny/crossref_metadata_2025_split huggingface dataset:
The genetic architecture of Alzheimer disease risk in the Ohio and Indiana Amish
Authors: Osterman Michael D. , Song Yeunjoo E. , Adams Larry D. , Laux Renee A. , Caywood Laura J. , Prough Michael B. , Clouse Jason E. , Herington Sharlene D. , Slifer Susan H. , Lynn Audrey , Fuzzell M. Denise , Fuzzell Sarada L. , Hochstetler Sherri D. , Miskimen Kristy , Main Leighanne R. , Dorfsman Daniel A. , Ogrocki Paula , Lerner Alan J. , Ramos Jairo , Vance Jeffery M. , Cuccaro Michael L. , Scott William K. , Pericak-Vance Margaret A. , Haines Jonathan L. 
Published: July 2021

ABSTRACTAlzheimer disease (AD) is the most common type of dementia and is currently estimated to affect 6.2 million Americans. It ranks as the sixth leading cause of death in the United States and the proportion of deaths due to AD has been increasing since the year 2000 while the proportion of many other leading causes of deaths have decreased or remained constant. The risk for AD is multifactorial, including genetic and environmental risk factors. ThoughAPOEremains the largest genetic risk factor for AD, more than 26 other loci have been associated with AD risk. Here, we recruited from a population of Amish adults from Ohio and Indiana to investigate AD risk and protective genetic effects. With slightly lower incidence and later age of onset, it is thought that the Amish may hold protective genetic variants for AD. As a founder population that typically practices endogamy, variants that are rare in the general population may be at higher frequency in the Amish population. We characterized the genetic architecture of AD risk in the Amish and compared this to a non-Amish population, elucidating the lower relative importance ofAPOEand differing genetic architecture of the Amish compared to a general European ancestry population.
Serine ADP-ribosylation marks nucleosomes for ALC1-dependent chromatin remodeling
Authors: Mohapatra Jugal , Tashiro Kyuto , Beckner Ryan L. , Sierra Jorge , Kilgore Jessica A. , Williams Noelle S. , Liszczak Glen 
Published: July 2021

AbstractSerine ADP-ribosylation (ADPr) is a DNA damage-induced post-translational modification catalyzed by the PARP1/2:HPF1 complex. As the list of PARP1/2:HPF1 substrates continues to expand, there is a need for technologies to prepare mono- and poly-ADP-ribosylated proteins for biochemical interrogation. Here we investigate the unique peptide ADPr activities catalyzed by PARP1 in the absence and presence of HPF1. We then exploit these activities to develop a method that facilitates installation of ADP-ribose polymers onto full-length proteins with precise control over chain length and modification site. A series of semi-synthetic ADP-ribosylated histone proteins are prepared which demonstrate that ADPr at H2BS6 or H3S10 converts nucleosomes into robust substrates for the chromatin remodeler ALC1. Importantly, we found ALC1 selectively remodels ‘activated’ substrates within heterogeneous nucleosome populations and that nucleosome serine ADPr is sufficient to stimulate ALC1 activity in nuclear extracts. Our study identifies a biochemical function for nucleosome serine ADPr and describes a method that is broadly applicable to explore the impact that site-specific serine mono- and poly-ADPr have on protein function.
Neural activity tracking identity and confidence in social information
Authors: Trudel Nadescha , Rushworth Matthew FS , Wittmann Marco K 
Published: July 2021

AbstractHumans learn about the environment either directly by interacting with it or indirectly by seeking information about it from social sources such as conspecifics. The degree of confidence in the information obtained through either route should determine the impact that it has on adapting and changing behaviour. We examined whether and how behavioural and neural computations differ during non-social learning as opposed to learning from social sources. Trial-wise confidence judgments about non-social and social information sources offered a window into this learning process. Despite matching exactly the statistical features of social and non-social conditions, confidence judgments were more accurate and less changeable when they were made about social as opposed to non-social information sources. In addition to subjective reports of confidence, differences were also apparent in the Bayesian estimates of participants’ subjective beliefs. Univariate activity in dorsomedial prefrontal cortex (dmPFC) and posterior temporo-parietal junction (pTPJ) more closely tracked confidence about social as opposed to non-social information sources. In addition, the multivariate patterns of activity in the same areas encoded identities of social information sources compared to non-social information sources.
A cell type-specific multiomics uncovers a guard cell-specific RAF15-SnRK2.6/OST1 kinase cascade
Authors: Wang Hongliang , Wang Yubei , Li Rongxia , Ren Weiwei , Sang Tian , Zhao Bing , Wang Xiao , Zhang Xuebin , Dai Shaojun , Hsu Chuan-Chih , Song Chun-Peng , Wang Pengcheng 
Published: July 2021

SUMMARYMulticellular organisms such as plants contain different cell types with specialized functions. Analyzing the characteristics of each cell type reveals specific cell functions and enhances understanding of organization and function at the organismal level. Here we report a highly-sensitive and efficient cell type-specific multiomics pipeline, combining simplified flow cytometry-based cell sorting for fluorescent protoplasts and optimized nanoscale proteomics and metabolomics methods, which allow in-depth analysis of the proteomes and metabolomes of a particular cell type. Using this method, we quantitatively compared the proteomes and metabolomes of guard cells and mesophyll cells and revealed that the enrichment of signal transduction-related proteins enables guard cells to respond rapidly to various environmental stimuli. We uncovered a guard cell-specific kinase cascade whereby RAF15 and OST1 mediate ABA-induced stomatal closure. This pipeline can be applied to various cell types in plant or non-plant systems to learn how cells function in highly organized multicellular organisms.
Unconstrained generation of synthetic antibody-antigen structures to guide machine learning methodology for real-world antibody specificity prediction
Authors: Robert Philippe A. , Akbar Rahmad , Frank Robert , Pavlović Milena , Widrich Michael , Snapkov Igor , Slabodkin Andrei , Chernigovskaya Maria , Scheffer Lonneke , Smorodina Eva , Rawat Puneet , Mehta Brij Bhushan , Vu Mai Ha , Mathisen Ingvild Frøberg , Prósz Aurél , Abram Krzysztof , Olar Alex , Miho Enkelejda , Haug Dag Trygve Tryslew , Lund-Johansen Fridtjof , Hochreiter Sepp , Haff Ingrid Hobæk , Klambauer Günter , Sandve Geir Kjetil , Greiff Victor 
Published: July 2021

AbstractMachine learning (ML) is a key technology for accurate prediction of antibody-antigen binding. Two orthogonal problems hinder the application of ML to antibody-specificity prediction and the benchmarking thereof: The lack of a unified ML formalization of immunological antibody specificity prediction problems and the unavailability of large-scale synthetic benchmarking datasets of real-world relevance. Here, we developed the Absolut! software suite that enables parameter-based unconstrained generation of synthetic lattice-based 3D-antibody-antigen binding structures with ground-truth access to conformational paratope, epitope, and affinity. We formalized common immunological antibody specificity prediction problems as ML tasks and confirmed that for both sequence and structure-based tasks, accuracy-based rankings of ML methods trained on experimental data hold for ML methods trained on Absolut!-generated data. The Absolut! framework thus enables real-world relevant development and benchmarking of ML strategies for biotherapeutics design.Graphical abstractThe software framework Absolut! enables (A,B) the generation of virtually arbitrarily large numbers of synthetic 3D-antibody-antigen structures, (C,D) the formalization of antibody specificity as machine learning (ML) tasks as well as the exploration of ML strategies for real-world antibody-antigen binding or paratope-epitope prediction.HighlightsSoftware framework Absolut! to generate an arbitrarily large number of synthetic 3D-antibody-antigen structures that contain biological layers of antibody-antigen binding complexity that render ML predictions challengingImmunological antibody specificity prediction problems formalized as machine learning tasks for which the in silico complexes are immediately usable as benchmark datasetsExploration of machine learning prediction accuracy as a function of architecture, dataset size, choice of negatives, and sequence-structure encodingRelative ML performance learnt on Absolut! datasets transfers to experimental datasets
Bcl-3 suppresses Th9 differentiation by regulating glutamine utilization
Authors: Tang Wanhu , Wang Hongshan , Murphy Philip M. , Siebenlist Ulrich 
Published: July 2021

SummaryBcl-3 is an atypical member of the IκB protein family that plays important and diverse roles in both innate and adaptive immunity, including Th17-dependent autoimmunity models in mice. When naïve mouse splenic CD4+ T cells were cultured under Th17 conditions in vitro, we unexpectedly found that the most highly differentially expressed gene between wild type and Bcl-3-deficient (KO) Th17 cells encoded the cytokine IL-9. We therefore investigated the role of Bcl-3 in Th9 cell differentiation. When naïve CD4+ T cells were cultured under Th9-polarizing conditions in vitro, the extent of Th9 differentiation observed in wild type cells was increased in Bcl-3 KO cells and conversely was decreased in cells overexpressing Bcl-3. The suppressive effect of Bcl-3 on Th9 differentiation was cell-autonomous, and NF-κB inhibitors abolished increased Th9 differentiation in Bcl-3 KO cells. Consistent with this, in the Th9 transfer model of OVA-induced allergic airway inflammation, mice receiving Bcl-3 KO cells had greater immune cell infiltration in the lung than mice receiving wild type cells.Mechanistically, unsupervised transcriptomic analysis revealed differentially expressed genes in KO cells, including the glutamine transporter Slc1a5, which was downregulated. The functional significance of this was suggested by the ability of increasing concentrations of glutamine in the media to reduce the difference in Th9 differentiation between WT and KO cells. Our results suggest a novel role for Bcl-3 as a negative regulator of Th9 differentiation, in part by limiting glutamine accessibility through downregulation of Slc1a5.
Multi-modal locomotor costs explain sexual size but not shape dimorphism in a leaf-mimicking insect
Authors: Boisseau Romain P. , Büscher Thies H. , Klawitter Lexi J. , Gorb Stanislav N. , Emlen Douglas J. , Tobalske Bret W. 
Published: July 2021

AbstractIn most arthropods, adult females are larger than males, and male competition is a race to quickly locate and mate with scattered females (scramble competition polygyny). In this context, smaller males may be favored due to more efficient locomotion leading to higher mobility during mate searching while larger males may benefit from increased speed and higher survivorship. Understanding how body size affects different aspects of the locomotor performance of males is therefore essential to shed light on the evolution of this widespread mating system. Using a combination of empirical measures of flight performance and substrate adhesion, and modelling of body aerodynamics, we show that large body size impairs both flight and landing (attachment) performance in male leaf insects (Phyllium philippinicum), a species where relatively small and skinny males fly through the canopy in search of large sedentary females. Smaller males were more agile in the air, ascended more rapidly during flight, and had a lower risk of detaching from the substrates on which they walk and land. Our models revealed variation in body shape affected body lift and drag, but tradeoffs with weight meant that effects were negligible, suggesting that flight costs do not explain the evolution of strong sexual dimorphism in body shape in this species.Graphical abstract
Autoimmunity increases susceptibility to and mortality from sepsis
Authors: Jensen Isaac J. , Jensen Samantha N. , McGonagill Patrick W. , Griffith Thomas S. , Mangalam Ashutosh K. , Badovinac Vladimir P. 
Published: July 2021

SummaryOur prior publication detailing how sepsis influences subsequent development of EAE presented a conceptual advance in understanding the post-sepsis chronic immunoparalysis state (Jensen et al., 2020). However, the reverse scenario (autoimmunity prior to sepsis) defines a high-risk patient population whose susceptibility to sepsis remains poorly defined. Herein, we present a retrospective analysis of University of Iowa Hospital and Clinics patients demonstrating increased sepsis incidence among MS, relative to non-MS, patients. To interrogate how autoimmune disease influences host susceptibility to sepsis well-established murine models of MS and sepsis, EAE and CLP, respectively, were utilized. EAE, relative to non-EAE, mice were highly susceptible to sepsis-induced mortality with elevated cytokine storms. These results were further recapitulated in LPS andS. pneumoniaesepsis models. This work highlights both the relevance of identifying highly susceptible patient populations and expands the growing body of literature that host immune status at the time of septic insult is a potent mortality determinant.
Synthetic genomic reconstitution reveals principles of mammalianHoxcluster regulation
Authors: Pinglay Sudarshan , Bulajić Milica , Rahe Dylan P. , Huang Emily , Brosh Ran , German Sergei , Cadley John A. , Rieber Lila , Easo Nicole , Mahony Shaun , Maurano Matthew T. , Holt Liam J. , Mazzoni Esteban O. , Boeke Jef D. 
Published: July 2021

AbstractPreciseHoxgene expression is crucial for embryonic patterning. Intra-Hoxtranscription factor binding and distal enhancer elements have emerged as the major regulatory modes controllingHoxgene expression. However, quantifying their relative contributions has remained elusive. Here, we introduce ‘synthetic regulatory reconstitution’, a novel conceptual framework for studying gene regulation and apply it to theHoxAcluster. We synthesized and delivered variant ratHoxAclusters (130-170 kilobases each) to an ectopic location in the mouse genome. We find that aHoxAcluster lacking distal enhancers recapitulates correct patterns of chromatin remodeling and transcription in response to patterning signals, while distal enhancers are required for full transcriptional output. Synthetic regulatory reconstitution is a generalizable strategy to decipher the regulatory logic of gene expression in complex genomes.One-Sentence SummaryReconstitution of gene regulation using large DNA constructs unravels the regulatory logic of a developmental gene locus.
Shallow neural networks trained to detect collisions recover features of visual loom-selective neurons
Authors: Zhou Baohua , Li Zifan , Kim Sunnie S. Y. , Lafferty John , Clark Damon A. 
Published: July 2021

AbstractAnimals have evolved sophisticated visual circuits to solve a vital inference problem: detecting whether or not a visual signal corresponds to an object on a collision course. Such events are detected by specific circuits sensitive to visual looming, or objects increasing in size. Various computational models have been developed for these circuits, but how the collision-detection inference problem itself shapes the computational structures of these circuits remains unknown. Here, inspired by the distinctive structures of LPLC2 neurons in the visual system of Drosophila, we build an anatomically-constrained shallow neural network model and train it to identify visual signals that correspond to impending collisions. Surprisingly, the optimization arrives at two distinct, opposing solutions, only one of which matches the actual dendritic weighting of LPLC2 neurons. The LPLC2-like solutions are favored when a population of units is trained on the task, but not when units are trained in isolation. The trained model reproduces experimentally observed LPLC2 neuron responses for many stimuli, and reproduces canonical tuning of loom sensitive neurons, even though the models are never trained on neural data. These results show that LPLC2 neuron properties and tuning are predicted by optimizing an anatomically-constrained neural network to detect impending collisions.
Dual inhibition of anti-apoptotic proteins BCL-XL and MCL-1 enhances cytotoxicity of Nasopharyngeal carcinoma cells
Authors: Rahman Siti Fairus Abdul , Azlan Azali , Lo Kwok-Wai , Azzam Ghows , Mohana-Kumaran Nethia 
Published: July 2021

AbstractOne of the many strategies that cancer cells use to evade cell death is through upregulation of the BCL-2 anti-apoptotic proteins. Hence, these proteins have become attractive therapeutic targets. Given that different cell population rely on different anti-apoptotic proteins for survival, it is crucial to determine which proteins are important for NPC survival. Here we determined the survival requirements for the NPC cells using combination of CRISPR/Cas9 technique and pharmacological approaches. A human apoptosis RT2 Profiler PCR Array was first employed to profile the anti-apoptotic gene expressions in NPC cell lines HK-1 and C666-1. The HK-1 cells expressed all the anti-apoptotic genes (MCL-1, BFL-1, BCL-2, BCL-XL, and BCL-w). Similarly, the C666-1 cells expressed all the anti-apoptotic proteins except BFL-1 (undetectable level). Notably, both cell lines highly expressed MCL-1. Deletion of MCL-1 sensitized cells to A-1331852 suggesting that MCL-1 and BCL-XL may be important for NPC cell survival. Co-inhibition of MCL-1 and BCL-2 with MCL-1 selective inhibitor S63845 and BCL-2 selective inhibitor ABT-199 inhibited NPC cell proliferation but the effect on cell viability was more profound with co-inhibition of MCL-1 and BCL-XL with S63845 and A-1331852, implying that MCL-1 and BCL-XL are crucial for NPC cell survival. Furthermore, co-inhibition of MCL-1 and BCL-XL inhibited the growth and invasion of NPC spheroids. Deletion of BFL-1 sensitized cells to A-1331852 suggesting that BFL-1 may play a role in NPC cell survival. Taken together co-inhibition of BCL-XL and MCL-1/BFL-1 could be potential treatment strategies for NPC.
Nonstoichiometric balanced complexes: Implications on the effective deficiency of the underlying metabolic network
Authors: Langary Damoun , Küken Anika , Nikoloski Zoran 
Published: July 2021

AbstractThe deficiency of a (bio)chemical reaction network can be conceptually interpreted as a measure of its ability to support exotic dynamical behavior and/or multistationarity. The classical definition of deficiency relates to the capacity of a network to permit variations of the complex formation rate vector at steady state, irrespective of the network kinetics. However, the deficiency is by definition completely insensitive to the fine details of the directionality of reactions as well as bounds on reaction fluxes. While the classical definition of deficiency can be readily applied in the analysis of unconstrained, weakly reversible networks, it only provides an upper bound in the cases where relevant constraints on reaction fluxes are imposed. Here we propose the concept of effective deficiency, which provides a more accurate assessment of the network’s capacity to permit steady state variations at the complex level for constrained networks of any reversibility patterns. The effective deficiency relies on the concept of nonstoichiometric balanced complexes, which we have already shown to be present in real-world biochemical networks operating under flux constraints. Our results demonstrate that the effective deficiency of real-world biochemical networks is smaller than the classical deficiency, indicating the effects of reaction directionality and flux bounds on the variation of the complex formation rate vector at steady state.
A single full-length VAR2CSA ectodomain variant purifies broadly neutralizing antibodies against placental malaria isolates
Authors: Doritchamou Justin Y. A. , Renn Jonathan P. , Jenkins Bethany , Fried Michal , Duffy Patrick E. 
Published: July 2021

AbstractPlacental malaria (PM) is a deadly syndrome most frequent and severe in first pregnancies. PM results from accumulation of Plasmodium falciparum (Pf)-infected erythrocytes (IE) that express the surface antigen VAR2CSA and bind to chondroitin sulfate A (CSA) in the placenta. Women become PM-resistant over successive pregnancies as they develop anti-adhesion and anti-VAR2CSA antibodies, supporting VAR2CSA as the leading PM-vaccine candidate. However, the first VAR2CSA subunit vaccines failed to induce broadly neutralizing antibody and it is still unclear whether naturally acquired protective antibodies target variant or conserved epitopes. This is crucial to determine whether effective vaccines will require incorporation of many or only a single VAR2CSA allele.Here, IgG from multigravidae was sequentially purified on five full-length VAR2CSA ectodomain variants, thereby depleting IgG reactivity to each. The five VAR2CSA variants purified ∼0.7% of total IgG and yielded both strain-transcending and strain-specific reactivity to VAR2CSA and IE-surface antigen. IgG purified on the first VAR2CSA antigen displayed broad cross-reactivity to both recombinant and native VAR2CSA variants, and inhibited binding of all isolates to CSA. IgG remaining after depletion on all variants showed significantly reduced binding-inhibition activity compared to initial total IgG.These findings demonstrate that a single VAR2CSA ectodomain variant displays neutralizing epitopes shared by multiple parasites, including maternal isolates, and suggest that a broadly effective PM-vaccine can be achieved with a limited number of VAR2CSA variants.
Structural snapshots of human PepT1 and PepT2 reveal mechanistic insights into substrate and drug transport across epithelial membranes
Authors: Killer Maxime , Wald Jiri , Pieprzyk Joanna , Marlovits Thomas C. , Löw Christian 
Published: July 2021

AbstractThe uptake of peptides in mammals plays a crucial role in nutrition and inflammatory diseases. This process is mediated by promiscuous transporters of the Solute Carrier Family 15, which form part of the Major Facilitator superfamily. Besides the uptake of short peptides, Peptide transporter 1 (PepT1) is a highly abundant drug transporter in the intestine and represents a major route for oral drug delivery. Peptide transporter 2 (PepT2) allows in addition renal drug reabsorption from ultrafiltration and brain-to-blood efflux of neurotoxic compounds. Here we present cryo-EM structures of human PepT1 in an outward open state and of human PepT2 in an inward facing partially occluded state with a bound substrate. The structures reveal the architecture of human peptide transporters and provide mechanistic insights into substrate recognition and conformational transitions during transport. Importantly, this may support future drug design efforts to increase the bioavailability of different drugs in the human body.
Structural basis of target DNA recognition by CRISPR-Cas12k for RNA-guided DNA transposition
Authors: Xiao Renjian , Wang Shukun , Han Ruijie , Li Zhuang , Gabel Clinton , Mukherjee Indranil Arun , Chang Leifu 
Published: July 2021

ABSTRACTThe type V-K CRISPR-Cas system, featured by Cas12k effector with a naturally inactivated RuvC domain and associated with Tn7-like transposon for RNA-guided DNA transposition, is a promising tool for precise DNA insertion. To reveal the mechanism underlying target DNA recognition, we determined a cryo-EM structure of Cas12k from cyanobacteria Scytonema hofmanni in complex with a single guide RNA (sgRNA) and a double-stranded target DNA. Coupled with mutagenesis and in vitro DNA transposition assay, our results revealed mechanisms for the recognition of the GGTT PAM sequence and the structural elements of Cas12k critical for RNA-guided DNA transposition. These structural and mechanistic insights should aid in the development of type V-K CRISPR-transposon systems as tools for genome editing.