bluuebunny/crossref_metadata_2025_split huggingface dataset:
Both GEF domains of the autism and epilepsy-associated Trio protein are required for proper tangential migration of GABAergic interneurons
Authors: Eid Lara , Lokmane Ludmilla , Raju Praveen K. , Tadoum Samuel Boris Tene , Jiang Xiao , Toulouse Karolanne , Lupien-Meilleur Alexis , Charron-Ligez François , Toumi Asmaa , Backer Stéphanie , Lachance Mathieu , Lavertu-Jolin Marisol , Montseny Marie , Lacaille Jean-Claude , Bloch-Gallego Evelyne , Rossignol Elsa 
Published: January 2023

AbstractRecessive mutations in theTRIOgene are associated with intellectual deficiency (ID), autism spectrum disorder (ASD) and developmental epileptic encephalopathies (DEE). TRIO is a dual guanine nucleotide exchange factor (GEF) that activates Rac1, Cdc42 and RhoA. Trio has been extensively studied in excitatory neurons, and has recently been found to regulate the switch from tangential to radial migration in GABAergic interneurons (INs), through GEFD1-Rac1-dependent SDF1α/CXCR4 signalling. Given the central role of Rho-GTPases during neuronal migration and the implication of IN pathologies in ASD and DEE, we investigated the relative roles of both Trio’s GEF domains in regulating the dynamics of INs tangential migration. InTrio-/-mice, we observed reduced numbers of tangentially migrating INs, with intact progenitor proliferation. Further, we noted increased growth cone collapse in developing INs, suggesting altered cytoskeleton dynamics. To bypass the embryonic mortality ofTrio-/-mice, we generatedDlx5/6Cre;Trioc/cconditional mutant mice, which develop spontaneous seizures and behavioral deficits reminiscent of ASD and ID. These phenotypes are associated with reduced cortical IN density and functional cortical inhibition. Mechanistically, this reduction of cortical IN numbers reflects a premature switch to radial migration, with an aberrant early entry in the cortical plate, as well as major deficits in cytoskeletal dynamics, including enhanced leading neurite branching and slower nucleokinesis reflecting reduced actin filament condensation and turnover. Further, we show that both Trio GEFD1 and GEFD2 domains are required for proper IN migration, with a dominant role of the RhoA-activating GEFD2 domain. Altogether, our data show a critical role of the DEE/ASD-associatedTriogene in the establishment of cortical inhibition and the requirement of both GEF domains in regulating IN migration dynamics.
Prophylaxis and Treatment of SARS-CoV-2 infection by an ACE2 Receptor Decoy
Authors: Tada Takuya , Dcosta Belinda M. , Zhou Hao , Landau Nathaniel R. 
Published: January 2023

SummaryThe emergence of SARS-CoV-2 variants with highly mutated spike proteins has presented an obstacle to the use of monoclonal antibodies for the prevention and treatment of SARS-CoV-2 infection. We show that a high affinity receptor decoy protein in which a modified ACE2 ectodomain is fused to a single domain of an immunoglobulin heavy chain Fc region dramatically suppressed virus loads in mice upon challenge with a high dose of parental SARS-CoV-2 or Omicron variants. The decoy also potently suppressed virus replication when administered shortly post-infection. The decoy approach offers protection against the current viral variants and, potentially, against SARS-CoV-2 variants that may emerge with the continued evolution of the spike protein or novel viruses that use ACE2 for virus entry.
RNAP promoter search and transcription kinetics in liveE. colicells
Authors: Bettridge Kelsey , Harris Frances E. , Yehya Nicolás , Xiao Jie 
Published: January 2023

AbstractBacterial transcription has been studied extensivelyin vitro, which has provided indepth insight regarding transcription mechanisms. However, the live cell environment may impose different rules on transcription than the homogenous and simplifiedin vitroenvironment. How an RNA polymerase (RNAP) molecule searches rapidly through the vast nonspecific chromosomal DNA in the three-dimensional nucleoid space and binds a specific promoter sequence remains elusive. The kinetics of transcriptionin vivocould also be impacted by specific cellular environments including nucleoid organization and nutrient availability. In this work, we investigated the promoter search dynamics and transcription kinetics of RNAP in liveE. colicells. Using single-molecule tracking (SMT) and fluorescence recovery after photobleaching (FRAP) and combining with different genetic, drug inhibition, and growth conditions, we observed that RNAP’s promoter search is facilitated by nonspecific DNA interactions and largely independent of nucleoid organization, growth condition, transcription activity, or promoter classes. RNAP’s transcription kinetics, however, is sensitive to these conditions and mainly modulated at the levels of actively engaged RNAP and the promoter escape rate. Our work establishes a foundation for further mechanistic studies of bacterial transcription in live cells.
The illusion of personal health decisions for infectious disease management: disease spread in social contact networks
Authors: Michalska-Smith Matthew , Enns Eva A , White Lauren A , Gilbertson Marie L J , Craft Meggan E 
Published: January 2023

AbstractClose contacts between individuals provide opportunities for the transmission of diseases, including COVID-19. Individuals take part in many different types of interactions, including those with classmates, co-workers, and household members; the conglomeration of all of these interactions produces a complex social contact network interconnecting individuals across the population. Thus, while an individual might decide their own risk tolerance in response to a threat of infection, the consequences of such decisions are rarely so confined, propagating far beyond any one person. We asses the effect of different population-level risk-tolerance regimes, population structure in the form of age and household-size distributions, and different types of interactions on epidemic spread in plausible human contact networks to gain insight into how contact network structure affects pathogen spread through a population. In particular, we find that changes in behaviour of vulnerable individuals in isolation is insufficient to reduce those individuals’ infection risk, that population structure can have varied and counter-acting effects on epidemic outcomes, and that, in general, interactions among co-workers have a greater contribution to disease spread than do interactions among children at school. Taken together, these results promote a nuanced understanding of disease spread on contact networks, with implications for public health strategies.
A surprising lack of presaccadic benefits during visual change detection
Authors: Gupta Priyanka , Sridharan Devarajan 
Published: January 2023

AbstractEven before the eyes move, visual sensitivity improves at the target of the planned eye movement. Yet, it is unknown if such “presaccadic” benefits are merely sensory, or also influence decisional processes. We teased apart these contributions with signal detection theory, and discovered a surprising absence of presaccadic benefits in visual change detection tasks. Participants planned and executed saccades while concurrently detecting and localizing either orientation or contrast changes. Spatial choice bias reliably improved presaccadically but, surprisingly, without a concomitant increase in perceptual sensitivity. Additional investigation with an orientation estimation task, and a Bayesian “variable precision” model, revealed that sensory precision increased at the saccade target, but only for the most recent of two successive stimuli. Moreover, the recent stimulus perceptually biased feature estimates of the prior stimulus, rendering accurate change detection even more challenging. Our results uncover novel perceptual and decisional mechanisms that mediate presaccadic change detection.Lay SummaryPlanning a rapid eye movement (saccade) changes how we perceive our visual world. Even before we move the eyes visual sensitivity improves at the impending target of eye movements, a phenomenon termed “presaccadic attention”. We report a surprising lack of such presaccadic attention benefits in a common, everyday setting: change detection. In fact, presaccadic attention renders change detection more challenging by biasing percepts toward the most recent of successive stimuli at the saccade target location. With a Bayesian model, we show how such perceptual and choice biases induced by eye movement planning affect change detection behavior. Our findings may have critical implications for real-world scenarios, like driving, that involve rapid gaze shifts in dynamically changing environments.
Single-cell transcriptional analysis of lamina propria lymphocytes in the jejunum reveals ILC-like cells in pigs
Authors: Wang Junhong , Gao Ming , Cheng Mingyang , Sun Yu , Lu Yiyuan , Li Xiaoxu , Shi Chunwei , Wang Jianzhong , Wang Nan , Yang Wentao , Jiang Yanlong , Huang Haibin , Yang Guilian , Zeng Yan , Wang Chunfeng , Cao Xin 
Published: January 2023

AbstractPigs are the most suitable model to study various therapeutic strategies and drugs for human beings, while knowledge about tissue- and cell-type-specific transcriptomes and heterogeneity is poorly available. Here, we focused on the intestinal immunity of pigs. Through single-cell sequencing (scRNA-seq) and flow cytometry analysis of the types of immune cells in the jejunum of pigs, we found that innate lymphoid cells (ILCs) existed in the lamina propria lymphocytes (LPLs) of the jejunum. Then, through flow sorting of Live/Dead (L/D)-Lineage(LIN)-CD45+cells and scRNA-seq, we found that ILCs in the porcine jejunum were mainly ILC3s, with a small number of ILC1s, ILC2s, and NK cells. Through a gene expression map, we found that ILCs coexpressed IL-7Rα, ID2, and other genes and differentially expressed RORC, GATA3, and other genes but did not express the CD3 gene. According to their gene expression profiles, ILC3s can be divided into four subgroups, and genes such as CXCL8, CXCL2, IL-22, IL-17, and NCR2 are differentially expressed. To further detect and identify ILC3s, we prepared RORC monoclonal antibodies and verified the classification of ILCs in the porcine jejunum subgroup and the expression of related hallmark genes at the protein level by flow cytometry. For systematically characterizing of ILCs in the porcine intestines, we combined our pig ILCs dataset with publicly available human and mice ILCs data and identified that the humans and pigs ILCs shared more common features than those mice ILCs in gene signatures and cell states. For the first time, our results showed in detail the gene expression of porcine jejunal ILCs, the subtype classification of ILCs, and the markers of various ILCs, which provides a basis for an in-depth exploration of porcine intestinal mucosal immunity.Abstract FigureGraphical abstract
Interaction of mitochondrial polygenic score and environmental factors in LRRK2 p.Gly2019Ser parkinsonism
Authors: Lüth Theresa , Gabbert Carolin , König Inke R. , Caliebe Amke , Koch Sebastian , Laabs Björn-Hergen , Hentati Faycel , Sassi Samia Ben , Amouri Rim , Spielmann Malte , Klein Christine , Grünewald Anne , Farrer Matthew J. , Trinh Joanne 
Published: January 2023

AbstractThe objective of our study was to investigate the impact of the mitochondrial polygenic score (MGS) and lifestyle/environmental data on age at onset in LRRK2 p.Gly2019Ser parkinsonism (LRRK2-PD) and idiopathic Parkinson’s disease (iPD).In this study, we included N=486 patients withLRRK2-PD and N=9259 patients with iPD from AMP-PD, Fox Insight, and a Tunisian Arab-Berber founder population. Genotyping data was utilized to perform the MGS analysis, using 14 Single Nucleotide Polymorphisms (SNPs) from genes causally associated with mitochondrial function and PD risk. Additionally, lifestyle and environmental data were obtained from the PD risk factor questionnaire (PD-RFQ). Correlation analyses and linear regression models were used to assess the relationship between MGS, lifestyle/environment, and AAO.We observed that higher MGS was associated with earlier AAO in patients withLRRK2-PD (p=4.0×10−4, β=-0.18) but not in patients with iPD. A correlation between MGS and AAO was visibly stronger in European ancestryLRRK2-PD patients (p=0.01, r=-0.16) than in Tunisian Arab-Berber patients (p=0.44, r=-0.05). We found that the MGS interacted with coffee (p=0.03, β=-0.38) and caffeinated soda consumption (p=0.03, β=-0.37) inLRRK2-PD and with caffeine soda consumption (p=0.047, β=-0.22) and pesticide exposure (p=0.02, β=-0.37) in iPD. Thus, patients with a high MGS had an earlier AAO only if they consumed caffeine or were exposed to pesticides.The MGS related to mitochondrial function was associated with AAO inLRRK2-PD but not iPD with an ethnic-specific effect. Caffeine consumption or pesticide exposure interacted with MGS to predict PD AAO. Our study suggests gene-environment interactions as modifiers of AAO inLRRK2-PD.
A quantitative theory for genomic offset statistics
Authors: Gain Clément , Rhoné Bénédicte , Cubry Philippe , Salazar Israfel , Forbes Florence , Vigouroux Yves , Jay Flora , François Olivier 
Published: January 2023

AbstractGenomic offset statistics predict the maladaptation of populations to rapid habitat alteration based on association of genotypes with environmental variation. Despite substantial evidence for empirical validity, genomic offset statistics have well-identified limitations, and lack a theory that would facilitate interpretations of predicted values. Here, we clarified the theoretical relationships between genomic offset statistics and unobserved fitness traits controlled by environmentally selected loci, and proposed a geometric measure to predict fitness after rapid change in local environment. he predictions of our theory were verified in computer simulations and in empirical data on African pearl millet (Cenchrus americanus) obtained from a common garden experiment. Our results proposed a unified perspective on genomic offset statistics, and provided a theoretical foundation necessary when considering their potential application in conservation management in the face of environmental change.
Modulation of Giant Depolarizing Potentials (GDPs) in Human Large Basket Cells by Norepinephrine and Acetylcholine
Authors: Yang Danqing , Qi Guanxiao , Ort Jonas , Witzig Victoria , Bak Aniella , Delev Daniel , Koch Henner , Feldmeyer Dirk 
Published: January 2023

AbstractRhythmic brain activity has been implicated in many brain functions and it is sensible to neuromodulation, but so far very few studies have investigated this activity on the cellular levelin vitroin human tissue samples. In this study we revealed and characterized a novel rhythmic network activity in human neocortex. Intracellular patch-clamp recordings showed that giant depolarizing potentials (GDPs) were frequently found in human cortical neurons. GDPs appeared in a low frequency band (∼ 0.3 Hz) similar to that described for slow oscillationsin vivoand displayed large amplitudes and long decay times. Under the same experimental conditions, no rhythmic activity was found in L2/3 of the rat neocortex. GDPs were predominantly observed in a subset of L2/3 interneurons considered to be large basket cells based on previously described morphological features. In addition, GDPs are highly sensitive to norepinephrine (NE) and acetylcholine (ACh), two neuromodulators known to modulate low frequency oscillations. NE increased the frequency of the GDPs by enhancing β-adrenergic receptor activity while ACh decreased GDP frequency through M4muscarinic receptor-activation. Multi-electrode array (MEA) recordings demonstrated that NE promoted synchronous oscillatory network activity while the application of ACh led to a desynchronization of neuronal activity. Our data indicate that the human neocortex is more prone to generate slow wave activity, which was reflected by more pronounced GDPs in L2/3 large basket cells. The distinct modulation of GDPs and slow wave activity by NE and ACh exerts a specific modulatory control over the human neocortex.
The statistics of natural shapes predict high-level aftereffects in human vision
Authors: Morgenstern Yaniv , Storrs Katherine R. , Schmidt Filipp , Hartmann Frieder , Tiedemann Henning , Wagemans Johan , Fleming Roland W. 
Published: January 2023

AbstractShape perception is essential for numerous everyday behaviors from object recognition to grasping and handling objects. Yet how the brain encodes shape remains poorly understood. Here, we probed shape representations using visual aftereffects—perceptual distortions that occur following extended exposure to a stimulus—to resolve a long-standing debate about shape encoding. We implemented contrasting low-level and high-level computational models of neural adaptation, which made precise and distinct predictions about the illusory shape distortions the observers experience following adaptation. Directly pitting the predictions of the two models against one another revealed that the perceptual distortions are driven by high-level shape attributes derived from the statistics of natural shapes. Our findings suggest that the diverse shape attributes thought to underlie shape encoding (e.g., curvature distributions, ‘skeletons’, aspect ratio) are the result of a visual system that learns to encode natural shape geometries based on observing many objects.
Real time mobilization of a novel diatomMutator-Like Element(MULE) transposon to inactivate the uridine monophosphate synthase (UMPS) locus inPhaeodactylum tricornutum
Authors: Abbriano Raffaela M. , George Jestin , Kahlke Tim , Commault Audrey S. , Fabris Michele 
Published: January 2023

SummaryDiatoms are photosynthetic unicellular microalgae that drive global ecological phenomena in the biosphere and are emerging sustainable feedstock for an increasing number of industrial applications. Diatoms exhibit enormous taxonomic and genetic diversity, which often result in peculiar biochemical and biological traits. Transposable elements (TE) represent a substantial portion of diatom genomes and have been hypothesized to exert a relevant role in enriching genetic diversity and centrally contribute to genome evolution. Here, through long-read whole genome sequencing, we identified a novel Mutator-Like Element (MULE) in the model diatomPhaeodactylum tricornutum,and we report the direct observation of its mobilization within the course of one single laboratory experiment. Under selective conditions, this novel TE inactivated theuridine monophosphate synthase(UMPS) geneof P. tricornutum,one of the two only endogenous genetic loci currently targeted for selectable auxotrophy in functional genetics and genome editing applications.We report the first, real-time observation of the mobilization of a transposon in diatoms that possesses novel peculiar features. These include the combined presence of a MULE transposase domain with Zinc finger, SWIM-type domains, and of a diatom-specific E3 ubiquitin ligase of the zinc finger UBR type, which indicate a novel mobilization mechanism. Our findings provide new elements for the understanding of the role of TEs in diatom genome evolution and in the enrichment of intraspecific genetic variability. Ultimately, this raises relevant concerns on the targeting of loci such asUMPSas selectable markers for functional genetics and biotechnological applications in diatoms.Significance StatementWe identified a novel DNA transposon in the diatomPhaeodactylum tricornutum. This new Mutator-Like Element encodes a transposase and a diatom-specific E3 ubiquitin ligase, which suggest a novel mobilization mechanism. We documented independent insertions in real-time, which spontaneously inactivated theuridine monophosphate synthase(UMPS) locus, a common selectable marker. We provide new insights on the role of transposons in diatom genome dynamics and evolution and on the unsuitability ofUMPSas selection locus in diatoms.
DISCO+QR: Rooting Species Trees in the Presence of GDL and ILS
Authors: Willson James , Tabatabaee Yasamin , Liu Baqiao , Warnow Tandy 
Published: January 2023

AbstractGenes evolve under processes such as gene duplication and loss (GDL), so that gene family trees are multi-copy, as well as incomplete lineage sorting (ILS); both processes produce gene trees that differ from the species tree. The estimation of species trees from sets of gene family trees is challenging, and the estimation of rooted species trees presents additional analytical challenges. Two of the methods developed for this problem are STRIDE (Emms and Kelly, MBE 2017), which roots species trees by considering GDL events, and Quintet Rooting (Tabatabaee et al., ISMB 2022 and Bioinformatics 2022), which roots species trees by considering ILS. We present DISCO+QR, a new method for rooting species trees in the presence of both GDL and ILS. DISCO+QR, operates by taking the input gene family trees and decomposing them into single-copy trees using DISCO (Willson et al., Systematic Biology 2022) and then roots the given species tree using the information in the single-copy gene trees using Quintet Rooting (QR). We show that the relative accuracy of STRIDE and DISCO+QR depend on properties of the dataset (number of species, genes, rate of gene duplication, degree of ILS, and gene tree estimation error), and that each provides advantages over the other under some conditions. Availability: DISCO and QR are available in GitHub. The supplementary materials are available athttp://tandy.cs.illinois.edu/discoqr-suppl.pdf.
Temperature Sensitive Contact Modes Allosterically Gate TRPV3
Authors: Burns Daniel , Venditti Vincenzo , Potoyan Davit A 
Published: January 2023

AbstractTRPV Ion channels are sophisticated molecular sensors designed to respond to distinct temperature thresholds. The recent surge in cryo-EM structures has provided numerous insights into the structural rearrangements accompanying their opening and closing; however, the molecular mechanisms by which TRPV channels establish precise and robust temperature sensing remain elusive. In this work we employ molecular simulations, multi-ensemble contact analysis, graph theory, and machine learning techniques to reveal the temperature-sensitive residue-residue interactions driving allostery in TRPV3. We find that groups of residues exhibiting similar temperature-dependent contact frequency profiles cluster at specific regions of the channel. The dominant mode clusters on the ankyrin repeat domain and displays a linear melting trend while others display non-linear trends. These modes describe the residue-level temperature response patterns that underlie the channel’s functional dynamics. With network analysis, we find that the community structure of the channel changes with temperature. And that a network of high centrality contacts connects distant regions of the protomer to the gate, serving as a means for the temperature-sensitive contact modes to allosterically regulate channel gating. Using a random forest model, we show that the contact states of specific temperature-sensitive modes are indeed predictive of the channel gate’s state. Supporting the physical validity of these modes and networks are several residues identified with our analyses that are reported in literature to be functionally critical. Our results offer high resolution insight into thermo-TRP channel function and demonstrate the utility of temperature-sensitive contact analysis.