bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integrating T-cell receptor and transcriptome for large-scale single-cell immune profiling analysis
Authors: Drost Felix , An Yang , Dratva Lisa M , Lindeboom Rik GH , Haniffa Muzlifah , Teichmann Sarah A , Theis Fabian , Lotfollahi Mohammad , Schubert Benjamin 
Published: June 2021

AbstractRecent advancements in single-cell immune profiling that enable the measurement of the transcriptome and T-cell receptor (TCR) sequences simultaneously have emerged as a promising approach to study immune responses at cellular resolution. Yet, combining these different types of information from multiple datasets into a joint representation is complicated by the unique characteristics of each modality and the technical effects between datasets. Here, we presentmvTCR, a multimodal generative model to learn a unified representation across modalities and datasets for joint analysis of single-cell immune profiling data. We show thatmvTCRallows the construction of large-scale and multimodal T-cell atlases by distilling modality-specific properties into a shared view, enabling unique and improved data analysis. Specifically, we demonstratedmvTCR’spotential by revealing and separating SARS-CoV-2-specific T-cell clusters from bystanders that would have been missed in individual unimodal data analysis. Finally,mvTCRcan enable automated analysis of new datasets when combined with transfer-learning approaches.Overall,mvTCRprovides a principled solution for standard analysis tasks such as multimodal integration, clustering, specificity analysis, and batch correction for single-cell immune profiling data.
AFEchidna is an R package for genetic evaluation of plant and animal breeding datasets
Authors: Zhang Weihua , Wei Ruiyan , Liu Yan , Lin Yuanzhen 
Published: June 2021

AbstractProgeny tests play important roles in plant and animal breeding programs, and mixed linear models are usually performed to estimate variance components of random effects, estimate the fixed effects (Best Linear Unbiased Estimates, BLUEs) and predict the random effects (Best Linear Unbiased Predictions, BLUPs) via restricted maximum likehood (REML) methods in progeny test datasets. The current pioneer software for genetic assessment is ASReml, but it is commercial and expensive. Although there is free software such as Echidna or the R package sommer, the Echidna syntax is complex and the R package functionality is limited. Therefore, this study aims to develop an R package named AFEchidna based on Echidna software. The mixed linear models are conveniently implemented for users through the AFEchidna package to solve variance components, genetic parameters and the BLUP values of random effects, and the batch analysis of multiple traits, multiple variance structures and multiple genetic parameters can be also performed, as well as comparison between different models and genomic BLUP analysis. The AFEchidna package is free, please email us (yzhlinscau@163.com) to get a copy if reader is interested for it. The AFEchidna package is developed to expand free genetic assessment software with the expectation that its efficiency could be close to the commercial software.
Chilean blind spots in soil biodiversity and ecosystem function research
Authors: Marín César , Rubio Javiera , Godoy Roberto 
Published: June 2021

AbstractSoil harbor up to a quarter of the world’s biodiversity, contributing to many ecosystem functions. It is of great importance to identify distribution patterns of soil organisms and their ecosystem functions to support their conservation and policy building. This has been recently analyzed at macroecological scales, but analyses at national/local scales are scarce. Here we identify and analyze the blind spots in soil taxa and ecosystem functioning data in continental Chile, through a Web of Science articles (1945-2020) search, and focusing on ten soil taxonomic groups and four ecosystem functions (nutrient cycling, decomposition, water infiltration, soil respiration). A total of 741 sampling sites were obtained from 239 articles. In 49.25% of the sites soil biodiversity was studied, while this percentage was 32.65% for ecosystem functions; in 18.10% of the sites both soil biodiversity and ecosystem functions were investigated at the same time, a surprisingly high percentage compared to global studies. By far, Bacteria/Fungi and nutrient cycling were the most investigated taxa and function, respectively. There is a significant number of soil taxa (Acari, Collembola, Nematoda, Formicoidea, Protista, Rotifera) represented by just a few sites concentrated in specific Chilean regions. Places like the central regions, the Atacama desert, and the Valdivian temperate forests present a proliferation of studies on soil Fungi, Bacteria, and nutrient cycling, reflecting historical interests of established research groups. Based on this research, we are identifying the causes of the data blind spots and invite the Chilean soil ecology community to propose ideas on how to fill them.
Mutant strains of Escherichia coli lacking global regulators, arcA and fis, demonstrate better growth fitness by pathway reprogramming under acetate metabolism
Authors: Jindal Shikha , Iyer Mahesh S. , Jyoti Poonam , Masakapalli Shyam Kumar , Venkatesh K.V. 
Published: June 2021

AbstractGlobal regulatory transcription factors play a significant role in controlling microbial metabolism under genetic and environmental perturbations. A systems-level effect of carbon sources such as acetate on microbial metabolism under disrupted global regulators has not been well established. Acetate is one of the substrates available in a range of nutrient niches such as the mammalian gut and high-fat diet. Therefore, investigating the study on acetate metabolism is highly significant. It is well known that the global regulators arcA and fis regulate acetate uptake genes in E. coli under glucose condition. In this study, we deciphered the growth and flux distribution of E.coli transcription regulatory knockout mutants ΔarcA, Δfis and double deletion mutant, ΔarcAfis under acetate using 13C-Metabolic Flux Analysis which has not been investigated before. We observed that the mutants exhibited an expeditious growth rate (~1.2-1.6 fold) with a proportionate increase in acetate uptake rates compared to the wild-type. 13C-MFA displayed the distinct metabolic reprogramming of intracellular fluxes, which conferred an advantage of faster growth with better carbon usage in all the mutants. Under acetate metabolism, the mutants exhibited higher fluxes in the TCA cycle (~18-90%) and lower gluconeogenesis flux (~15-35%) with the proportional increase in growth rate. This study reveals a novel insight by stating the sub-optimality of the wild-type strain grown under acetate substrate aerobically. These mutant strains efficiently oxidize acetate to acetyl-CoA and therefore are potential candidates that can serve as a precursor for the biosynthesis of isoprenoids, biofuels, vitamins and various pharmaceutical products.ImportanceUnravelling the role of global regulatory genes on microbial metabolism of substrates available in various growth niche is important. Studies have shown that the global transcriptional regulators arcA and fis, under glucose availability, suppress the acetate uptake genes indicating a link between nutrient source and gene regulatory control. This work is focused on deciphering the influence of these regulators on acetate metabolism in E.coli. Growth studies using knockout strains (ΔarcA, Δfis and ΔarcAfis) and 13C Metabolic flux analysis defined precise metabolic phenotypes under acetate metabolism. Interestingly, the mutants showed metabolic readjustment to facilitate optimal biomass requirements and a better balance between energy and precursor synthesis, resulting in better growth, which lacked in the wild-type strain. The outcomes of this study will be leveraged in understanding the regulatory control under various nutrient shifts.
High affinity FcγR activating function depends on IRAP+endosomal-signaling platforms
Authors: Benadda Samira , Nugues Mathilde , Bens Marcelle , De Luca Mariacristina , Pellé Olivier , Monteiro Renato C. , Evnouchidou Irini , Saveanu Loredana 
Published: June 2021

AbstractAlthough endocytosis of cell surface receptors is generally thought to terminate the signaling, for some receptors, endocytosis sustains signaling. We wondered if endosomal signaling participates to the function of the receptors for Fc immunoglobulin fragments (FcRs) that are highly internalized after their activation. We demonstrate here that four different FcRs follow distinct endocytic pathways after activation. While FcαRI is internalized into lysosomes, FcγRIIA is internalized and partially retained in early endosomes, whereas the inhibitory receptor FcγRIIB is internalized in endosomes decorated by the autophagy marker LC3. Interestingly, the high affinity FcγRI is internalized in specialized endosomal compartments described by the Insulin Responsive AminoPeptidase (IRAP), where it remains associated with the active form of the signaling kinase Syk. Our results show that FcγRI has the ability to build endosomal-signaling platforms, which depend on the presence of IRAP and Rab14. Destabilization of the endosomal signaling platforms compromised the ability of peritoneal macrophages to kill tumor cells by antibody-dependent cell mediated cytotoxicity, indicating that FcγRI endosomal signaling is required for the therapeutic action of anti-tumor monoclonal antibodies.One sentence summaryBinding of immune complexes to FcγRI receptor leads to receptor internalization and sustained signaling from endosomes described by the Insulin Responsive AminoPeptidase and the small GTPase Rab14.
Directed Evolution of AAV Targeting Primate Retina by Intravitreal Injection Identifies R100, a Variant Demonstrating Robust Gene Delivery and Therapeutic Efficacy in Non-Human Primates
Authors: Kotterman Melissa , Beliakoff Ghezal , Croze Roxanne , Vazin Tandis , Schmitt Christopher , Szymanski Paul , Leong Meredith , Quezada Melissa , Holt Jenny , Barglow Katherine , Hassanipour Mohammad , Schaffer David , Francis Peter , Kirn David 
Published: June 2021

AbstractTargeted AAV vectors are needed for safe and efficient delivery to and transduction of specific tissue target(s) in patients. Effective intravitreal delivery for retina gene therapy is not feasible with wildtype AAV. We employed directed evolution in nonhuman primates (NHP) to discover an AAV variant (R100) for intravitreal treatment of multiple target cells in the primate retina. R100 demonstrated superior transduction of human retinal cells compared to wildtype AAV. Furthermore, three R100-based gene therapeutics demonstrated safety, delivery, and durable pan-retinal expression of intracellular or secreted transgenes throughout the NHP retina following intravitreal administration. Finally, efficacy of R100-mediated delivery of therapeutic transgenes was demonstrated in patient-derived retinal cells (monogenic diseases) and in an NHP model of pathogenic retinal angiogenesis.
Temporal-spectral signaling of sensory information and expectations in the cerebral processing of pain
Authors: Nickel Moritz M. , Tiemann Laura , Hohn Vanessa D. , May Elisabeth S. , Ávila Cristina Gil , Eippert Falk , Ploner Markus 
Published: June 2021

AbstractThe perception of pain is shaped by somatosensory information about threat. However, pain is also influenced by an individual’s expectations. Such expectations can result in clinically relevant modulations and abnormalities of pain. In the brain, sensory information, expectations (predictions), and discrepancies thereof (prediction errors) are signaled by an extended network of brain areas. These brain areas generate evoked potentials and oscillatory responses at different latencies and frequencies. Recent evidence has provided first insights into how oscillatory responses at different frequencies signal predictions and prediction errors. However, a comprehensive picture of how evoked and oscillatory brain responses signal sensory information, predictions, and prediction errors in the processing of pain is lacking so far. We therefore built upon a neuroimaging study which investigated the spatial signalling of sensory information, predictions and predictions errors in the processing of pain (Geuter et al., 2017). To complement and extend this study, we applied brief painful stimuli to 48 healthy human participants and independently modulated sensory information (stimulus intensity) and expectations of pain intensity while measuring brain activity using electroencephalography (EEG). Pain ratings confirmed that pain intensity was shaped by both sensory information and expectations. In contrast, Bayesian analyses revealed that stimulus-induced EEG responses at different latencies (the N1, N2, and P2 components) and frequencies (alpha, beta, and gamma oscillations) were shaped by sensory information but not by expectations. Expectations, however, shaped alpha and beta oscillations before the painful stimuli. These findings indicate that commonly analyzed EEG responses to painful stimuli are more involved in signaling sensory information than in signaling expectations or mismatches of sensory information and expectations. Moreover, they indicate that the effects of expectations on pain are served by brain mechanisms which differ from those conveying effects of sensory information on pain.
Asymmetric peptidoglycan editing generates the curvature of predatory bacteria, optimizing invasion and replication within a spherical prey niche
Authors: Banks Emma J. , Valdivia-Delgado Mauricio , Biboy Jacob , Wilson Amber , Cadby Ian T. , Vollmer Waldemar , Lambert Carey , Lovering Andrew L. , Sockett R. Elizabeth 
Published: June 2021

AbstractThe vibrioid predatory bacterium Bdellovibrio bacteriovorus secretes prey wall-modifying enzymes to invade and replicate within the periplasm of Gram-negative prey bacteria. Studying self-modification of predator wall peptidoglycan during predation, we discover that Bd1075 generates self-wall curvature by exerting LD-carboxypeptidase activity in the vibrioid B. bacteriovorus strain HD100 as it grows inside spherical prey. Bd1075 localizes to the outer curved face of B. bacteriovorus, in contrast to most known shape-determinants. Asymmetric protein localization is determined by the novel function of a nuclear transport factor 2-like (NTF2) domain at the protein C-terminus. The solved structure of Bd1075 is monomeric, with key differences to other LD-carboxypeptidases. Rod-shaped Δbd1075 mutants invade prey more slowly than curved wild-type predators, and stretch and deform the invaded prey cell from within. Vibrioid morphology increases the evolutionary fitness of wild predatory bacteria, facilitating efficient prey invasion and intracellular growth of curved predators inside a spherical prey niche.
New Drosophila models to uncover the intrinsic and extrinsic factors mediating the toxicity of the human prion protein
Authors: Myers Ryan R. , Sanchez-Garcia Jonatan , Leving Daniel C. , Fernandez-Funez Pedro 
Published: June 2021

AbstractMisfolded conformations of the prion protein (PrP) are responsible for devastating neurological disorders in humans and mammals. An unresolved problem is unraveling the mechanisms governing PrP conformational dynamics, misfolding, and the cellular mechanism leading to neurodegeneration. The variable susceptibility of mammals to prion diseases can be exploited to understand the conformational dynamics of PrP. Here we present a new fly model expressing human PrP with robust phenotypes in brain neurons and the eye. Using comparable attP2 insertions, we demonstrate the heightened toxicity of human PrP compared to that of mouse and hamster PrP along with a specific interaction with the amyloid-beta peptide. Using this new highly toxic new model, we started to uncover the intrinsic (sequence / structure) and extrinsic (interactions) factors regulating PrP toxicity. As extrinsic factors, we describe the importance of the PERK - ATF4 branch of the unfolded protein response as a key cellular mechanism mediating the toxicity of human PrP. For intrinsic factors, we introduced point mutations in human PrP (N159D, D167S, N174S) that were partially protective, revealing its high propensity to misfold into toxic conformations.
Unprecedented incidence ofTrypanosoma cruziinfections in a cohort of dogs directly detected through longitudinal tracking at multi-dog kennels, Texas, USA
Authors: Busselman Rachel E. , Meyers Alyssa C. , Zecca Italo B. , Auckland Lisa D. , Castro Andres H. , Dowd Rebecca E. , Curtis-Robles Rachel , Hodo Carolyn L. , Saunders Ashley B. , Hamer Sarah A. 
Published: June 2021

AbstractCanine Chagas disease, caused by the protozoan parasiteTrypanosoma cruzi, is increasingly recognized as a health concern for dogs in the USA, and infected dogs may signal geographic regions of risk for human disease. Dogs living in multi-dog kennel environments where triatomine vectors are endemic may be at high risk for infection. We monitored a cohort of 64T. cruzi-infected and uninfected dogs from across 10 kennels in Texas, USA, to characterize changes in infection status over time. We used robust diagnostic criteria in which reactivity on multiple independent platforms was required to be considered positive. Among the 30 dogs enrolled as serologically- and/or PCR-positive, all but one dog showed sustained positiveT. cruzidiagnostic results over time. Among the 34 dogs enrolled as serologically- and PCR-negative, 10 newT. cruziinfections were recorded over a 12-month period. The resulting incidence rate was 30.7T. cruziinfections per 100 dogs per year. This study highlights the risk ofT.cruziinfection to dogs in kennel environments, despite multiple vector control methods employed by kennel owners. To protect both dog and human health, there is an urgent need to develop more integrated vector control methods as well as prophylactic and curative antiparasitic treatment options forT. cruziinfection in dogs.
Characterization of novel competitive inhibitors of P. falciparum cGMP-dependent protein kinase
Authors: Eck Tyler , de Souza Mariana Laureano , Yadav Bheemanaboina Rammohan R. , Chakrasali Ramappa , Kreiss Tamara , Siekierka John J. , Rotella David P. , Bhanot Purnima , Goodey Nina M. 
Published: June 2021

AbstractP. falciparum cGMP-dependent protein kinase (PfPKG) is an enticing anti-malarial drug target. Structurally novel isoxazole-based compounds were shown to be ATP competitive inhibitors of PfPKG. Isoxazoles 3 and 5 had Ki values of 0.7 ± 0.2 and 2.3 ± 0.9 nM, respectively, that are comparable to a known standard, 4-[2-(4-fluorophenyl)-5-(1-methylpiperidine-4-yl)-1H pyrrol-3-yl] pyridine (1.4 ± 0.5 nM). They also exhibited excellent selectivity for PfPKG over the human ortholog and the gatekeeper mutant T618Q PfPKG, which mimics the less accessible binding site of the human ortholog. The human ortholog’s larger binding site volume was predicted to explain the selectivity of the inhibitors for the P. falciparum enzyme. Analogs 4 and 6 were at least 20-fold less potent compared to 3 and 5, suggesting that removing the carbonyl group in 3 or altering the diethylamino moiety in 5 reduced affinity.
Non-Newtonian Blood Rheology Impacts Left Atrial Stasis in Patient-Specific Simulations
Authors: Gonzalo A. , García-Villalba M. , Rossini L. , Durán E. , Vigneault D. , Martínez-Legazpi P. , Flores O. , Bermejo J. , McVeigh E. , Kahn A. M. , del Alamo J. C. 
Published: June 2021

AbstractThe lack of mechanically effective contraction of the left atrium (LA) during atrial fibrillation (AF) disturbs blood flow, increasing the risk of thrombosis and ischemic stroke. Thrombosis is most likely in the left atrial appendage (LAA), a small narrow sac where blood is prone to stagnate. Slow flow promotes the formation of erythrocyte aggregates in the LAA, also known as rouleaux, causing viscosity gradients that are usually disregarded in patient-specific simulations. To evaluate these non-Newtonian effects, we built atrial models derived from 4D computed tomography scans of patients and carried out computational fluid dynamics simulations using the Carreau-Yasuda constitutive relation. We examined six patients, three of whom had AF and LAA thrombosis or a history of transient ischemic attacks (TIAs). We modeled the effects of hematocrit and rouleaux formation kinetics by varying the parameterization of the Carreau-Yasuda relation and modulating non-Newtonian viscosity changes based on residence time. Comparing non-Newtonian and Newtonian simulations indicates that slow flow in the LAA increases blood viscosity, altering secondary swirling flows and intensifying blood stasis. While some of these effects can be subtle when examined using instantaneous metrics like shear rate or kinetic energy, they are manifested in the blood residence time, which accumulates over multiple heartbeats. Our data also reveal that LAA blood stasis worsens when hematocrit increases, offering a potential new mechanism for the clinically reported correlation between hematocrit and stroke incidence. In summary, we submit that hematocrit-dependent non-Newtonian blood rheology should be considered in calculating patient-specific blood stasis indices by computational fluid dynamics.
Protection of the prodomain α1-helix correlates with latency in the transforming growth factor-β family
Authors: Le Viet Q. , Zhao Bo , Iacob Roxana E. , Tian Yuan , Toohey Cameron , Engen John R. , Springer Timothy A. 
Published: June 2021

AbstractThe 33 members of the transforming growth factor beta (TGF-β) family are fundamentally important for organismal development and homeostasis. Family members are synthesized and secreted as pro-complexes of prodomains that are non-covalently bound to the growth factor (GF). The pro-complexes of some members are latent and require activation steps to release the GF for signaling. Why some members are latent while others are non-latent is incompletely understood, but crystal structures and hydrogen-deuterium exchange (HDX) of four family members have begun to unravel how latency is regulated. Here, we extend this understanding by comparing pro-complex conformation in negative stain EM (nsEM) and HDX of ActA, BMP7, BMP9, BMP10, GDF8, TGF-β1, and TGF-β2. nsEM revealed that family members varied in either adopting cross-armed, open-armed, or V-armed configurations. Latency was achieved in both cross-armed and V-armed but not open-armed conformations. HDX revealed remarkably varying patterns of exchange between family members, consistent with large prodomain sequence divergence. We observed a strong correlation between latency and protection of the prodomain α1-helix from exchange, which in latent members coincided with greater buried surface area of the α1-helix and more hydrogen and cation-pi bonds from the prodomain fastener and GF to the α1-helix. Strong sequence conservation of the α1-helix and fastener only in latent members suggests that similar interactions are conserved and sufficient to confer latency. Moreover, most members exhibited rapid exchange in the unstructured “association region” at the prodomain N-terminus, highlighting their availability for interacting with factors that may regulate latency and extracellular storage.