bluuebunny/crossref_metadata_2025_split huggingface dataset:
Operative dimensions in unconstrained connectivity of recurrent neural networks
Authors: Krause Renate , Cook Matthew , Kollmorgen Sepp , Mante Valerio , Indiveri Giacomo 
Published: June 2022

AbstractRecurrent Neural Networks (RNNs) are commonly used models to study neural computation. However, a comprehensive understanding of how dynamics in RNNs emerge from the underlying connectivity is largely lacking. Previous work derived such an understanding for RNNs fulfilling very specific constraints on their connectivity, but it is unclear whether the resulting insights apply more generally. Here we study how network dynamics are related to network connectivity in RNNs trained without any specific constraints on several tasks previously employed in neuroscience. Despite the apparent high-dimensional connectivity of these RNNs, we show that a low-dimensional, functionally relevant subspace of the weight matrix can be found through the identification ofoperativedimensions, which we define as components of the connectivity whose removal has a large influence on local RNN dynamics. We find that a weight matrix built from only a few operative dimensions is sufficient for the RNNs to operate with the original performance, implying that much of the high-dimensional structure of the trained connectivity is functionally irrelevant. The existence of a low-dimensional, operative subspace in the weight matrix simplifies the challenge of linking connectivity to network dynamics and suggests that independent network functions may be placed in specific, separate subspaces of the weight matrix to avoid catastrophic forgetting in continual learning.
RPG acts as a central determinant for infectosome formation and cellular polarization during intracellular rhizobial infections
Authors: Lace Beatrice , Su Chao , Perez Daniel Invernot , Rodriguez-Franco Marta , Vernié Tatiana , Batzenschlager Morgane , Egli Sabrina , Liu Cheng-Wu , Ott Thomas 
Published: June 2022

ABSTRACTHost-controlled intracellular accommodation of nitrogen-fixing bacteria is essential for the establishment of a functional Root Nodule Symbiosis (RNS). In many host plants, this occurs via transcellular tubular-structures (infection threads - ITs) that extend across cell layers via polar tip- growth. Comparative phylogenomic studies have identified RPG (RHIZOBIUM-DIRECTED POLAR GROWTH) among the critical genetic determinants for bacterial infection. In Medicago truncatula, RPG is required for effective IT progression within root hairs but the cellular and molecular function of the encoded protein remain elusive. Here, we show that RPG resides in the protein complex formed by the core endosymbiotic components VAPYRIN (VPY) and LUMPY INFECTION (LIN) required for IT polar growth, co- localizes with both VPY and LIN in IT tip- and perinuclear-associated puncta of M. truncatula root hairs undergoing infection and is necessary for VPY recruitment to puncta. Fluorescence Lifetime Imaging Microscopy (FLIM) of phosphoinositide species during bacterial infection revealed that functional RPG is required to sustain strong membrane polarization at the advancing tip of the IT. In addition, loss of RPG functionality alters the cytoskeleton-mediated connectivity between the IT tip and the nucleus and affects polar secretion of the cell wall modifying enzyme NODULE PECTATE LYASE (NPL). Our results integrate RPG into a core host machinery required to support symbiont accommodation, suggesting that its occurrence in plant host genomes is essential to co-opt a multimeric protein module committed to endosymbiosis to sustain IT-mediated bacterial infection.
Zyxin and non-muscle myosin are required for single fibroblast durotaxis, but Rho-kinase activity and the Arp2/3 complex are dispensable
Authors: Hakeem Reem M. , Subramanian Bhagawat C. , Hockenberry Max A. , King Zayna T. , Butler Mitchell T. , Legant Wesley R. , Bear James E. 
Published: June 2022

AbstractDurotaxis, migration of cells directed by stiffness gradient, is critical in development and disease. To study the molecular determinants of single cell durotaxis, we developed an all-in-one photopolymerized hydrogel system containing areas of stiffness gradients with different slopes, along with uniform stiffness (soft and stiff) regions. We find that fibroblasts rely on non-muscle myosin II (NMII) activity and the LIM-domain protein zyxin for durotaxis on both steep and shallow stiffness gradients. Importantly, unlike haptotaxis, the Arp2/3 complex is dispensable for durotaxis on both stiffness gradients. Lack of Arp2/3 results in a filopodia-based durotactic migration that is equally efficient as that of lamellipodia-based durotactic migration. Finally, we reveal an essential role for the actin-bundler fascin in the formation and asymmetric distribution of filopodia during filopodia-based durotaxis in shallow, but not steep, stiffness gradient. Together, our all-in-one hydrogel system can serve as a platform to identify, discriminate, and characterize stiffness gradient specific molecular mechanisms that cells employ to efficiently durotax.
Spatiotemporal recruitment of inhibition and excitation in the mammalian cortex during electrical stimulation
Authors: Dadarlat Maria C. , Sun Yujiao Jennifer , Stryker Michael P. 
Published: June 2022

AbstractElectrical stimulation has emerged as a powerful and precise treatment in which to modulate aberrant neural activity patterns common in neural dysfunction and disease; however, the physiological process involved in microstimulation is poorly understood, particularly regarding the contributions of inhibitory neurons to shaping stimulation-evoked activity. To address this issue, we used 2-photon imaging of transgenic mice to measure the widespread responses of inhibitory and excitatory neurons to electrical stimulation through a chronically-implanted cortical microelectrode. We found that increasing stimulation amplitude both raised the fraction of neurons that responded to a stimulus and increased the distance at which inhibitory and excitatory neurons were significantly modulated by stimulation; however, the lateral spread of inhibitory activity preceded that of excitatory activity. By 50 µA, a significantly larger fraction of inhibitory neurons vs. excitatory neurons were modulated by stimulation. Increasing amplitude also shifted the temporal response properties of the population — towards longer-latency excitation close to the electrode tip and strong inhibition of more distant neurons. Animal behavior, specifically their locomotion patterns, strongly correlated with trial-to-trial variability in stimulation-evoked responses. We conclude that changing electrical stimulation amplitude can shift the balance of excitation to inhibition in the brain in a manner that interact with ongoing animal behavior.
Screening the PRISM library against Staphylococcus aureus reveals a sesquiterpene lactone from Liriodendron tulipifera with inhibitory activity
Authors: Kirk Riley D. , Rosario Margaret E. , Oblie Nana , Jouaneh Terra Marie M. , Carro Marina A. , Wu Christine , Leibovitz Elizabeth , Hunter Elizabeth Sage , Literman Robert , Handy Sara M. , Rowley David C. , Bertin Matthew J. 
Published: June 2022

ABSTRACTInfections caused by the bacterium Staphylococcus aureus continue to pose threats to human health and put a financial burden on the healthcare system. The overuse of antibiotics has contributed to mutations leading to the emergence of methicillin-resistant Staphylococcus aureus, and there is a critical need for the discovery and development of new antibiotics to evade drug resistant bacteria. Medicinal plants have shown promise as sources of new small molecule therapeutics with potential uses against pathogenic infections. The Principal Rhode Island Secondary Metabolite (PRISM) library is a botanical extract library generated from specimens in the URI Heber W. Youngken Jr. Medicinal Garden by upper-division undergraduate students. PRISM extracts were screened for activity against strains of methicillin-susceptible S. aureus (MSSA). An extract generated from the tulip tree (Liriodendron tulipifera) demonstrated growth inhibition against MSSA, and a bioassay-guided approach identified a sesquiterpene lactone, laurenobiolide, as the active constituent. Intriguingly, its isomers tulipinolide and epi-tulipinolide lacked potent activity against MSSA. Laurenobiolide also proved to be more potent against MSSA than the structurally similar sesquiterpene lactones constunolide and dehydrocostus lactone. Laurenobioloide was most abundant in the twig bark of the tulip tree, supporting the historical and cultural usage of twig bark in poultices and teas.ABSTRACT GRAPHIC
Dose-dependent nuclear delivery and transcriptional repression with a cell-penetrant MeCP2
Authors: Zhang Xizi , Zoltek Madeline , Mozumdar Deepto , Schepartz Alanna 
Published: June 2022

AbstractMethyl-CpG-binding-protein 2 (MeCP2) is a nuclear protein expressed in all cell types, especially neurons1. Mutations in the MECP2 gene cause Rett syndrome (RTT), an incurable neurological disorder that disproportionately affects young girls2. Strategies to restore MeCP2 expression phenotypically reverse RTT-like symptoms in male and female MeCP2-deficient mice3–5, suggesting that direct nuclear delivery of functional MeCP2 could restore MeCP2 activity. We report that ZF-tMeCP2, a conjugate of MeCP2(Δaa13-71, 313-484)6 and the cell-permeant mini-protein ZF5.37–11, both binds DNA in a methylation-dependent manner and reaches the nucleus of model cell lines intact at concentrations above 700 nM. When delivered to live cells, ZF-tMeCP2 engages the NCoR/SMRT co-repressor complex and selectively represses transcription from methylated promoters. Efficient nuclear delivery of ZF-tMeCP2 relies on a unique endosomal escape portal provided by HOPS-dependent endosomal fusion. The Tat conjugate of MeCP2 (Tat-tMeCP2), evaluated for comparison, is degraded within the nucleus, is not selective for methylated promoters, and trafficks in a HOPS-independent manner. These results support the feasibility of a HOPS-dependent portal for delivering functional macromolecules to the cell interior using the cell-penetrant mini-protein ZF5.3. Such a strategy could broaden the impact of multiple families of protein-derived therapeutics.
Evaluating the breadth of neutralizing antibody responses elicited by infectious bursal disease virus (IBDV) genogroup A1 strains using a novel chicken B-cell rescue system and neutralization assay
Authors: Reddy Vishwanatha R. A. P. , Nazki Salik , Brodrick Andrew J. , Asfor Amin , Urbaniec Joanna , Morris Yasmin , Broadbent Andrew J. 
Published: June 2022

AbstractEight infectious bursal disease virus (IBDV) genogroups have been identified based on the sequence of the capsid hypervariable region (HVR) (A1-8), yet many vaccines are based on A1 strains. Given reported vaccine failures, there is a need to evaluate the ability of vaccines to neutralize the different genogroups. To address this, we used a reverse genetics system and the chicken B-cell line DT40 to rescue a panel of chimeric IBDVs and perform neutralization assays. Chimeric viruses had the backbone of a lab-adapted strain (PBG98) and the HVRs from diverse field strains: classical F52-70 (A1), US-variant Del-E (A2), Chinese-variant SHG19 (A2), very-virulent UK661 (A3), M04/09 distinct (A4), Italian ITA-04 (A6), and Australian-variant Vic-01/94 (A8). Rescued viruses showed no substitutions at amino-acid positions 253, 284, or 330, previously associated with cell-culture adaptation. Sera from chickens inoculated with wt (F52-70) or vaccine (228E) A1 strains had the highest mean virus neutralization (VN) titers against the A1 virus (log2 15.41 and 12.66), and the lowest against A2 viruses (log2 7.41-7.91, p=0.0001-0.0274), consistent with A1 viruses being most antigenically distant from A2 strains, which correlated with the extent of differences in the predicted HVR structure. VN titers against the other genogroups ranged from log2 9.32-13.32, and A1 strains were likely more closely antigenically related to genogroups A3 and A4 than A6 and A8. Our data are consistent with field observations, validating our method, which can used to screen future vaccine candidates for breadth of neutralizing antibodies, and evaluate the antigenic relatedness of different genogroups.ImportanceThere is a need to evaluate the ability of vaccines to neutralize diverse IBDV genogroups, and to better understand the relationship between HVR sequence, structure, and antigenicity. Here, we used a chicken B cell-line to rescue a panel of chimeric IBDVs with the HVR from seven diverse IBDV field strains, and conduct neutralization assays and protein modelling. We evaluated the ability of serum from vaccinated or infected birds to neutralize the different genogroups. Our novel chicken B-cell rescue system and neutralization assay can be used to screen IBDV vaccine candidates, platforms, and regimens for the breadth of neutralizing antibody responses elicited, evaluate the antigenic relatedness of diverse IBDV strains, and when coupled with structural modelling, elucidate immunodominant and conserved epitopes to strategically design novel IBDV vaccines in the future.
Calcitonin Gene-Related Peptide (CGRP) Receptor Antagonism Reduces Motion Sickness Indicators in Mouse Migraine Models
Authors: Rahman Shafaqat M. , Luebke Anne E. 
Published: June 2022

Structured AbstractBackgroundMigraine and especially vestibular migraine are associated with enhanced motion sickness and motion-induced nausea. Murine models of migraine have used injections of Calcitonin Gene-Related Peptide (CGRP) or other migraine triggers [i.e., sodium nitroprusside (SNP)] to induce migraine sensitivities to touch and light. Yet, there is limited research on whether these triggers increase motion-induced nausea, and if migraine blockers can reduce these migraine symptoms. We hypothesized that systemic delivery of CGRP or SNP will increase motion sickness susceptibility and motion-induced nausea in mouse models, and that migraine blockers can block these changes induced by systemically delivered CGRP or SNP.MethodsWe investigated two measures of motion sickness assessment [motion sickness index (MSI) scoring and motion-induced thermoregulation] after intraperitoneal injections of either CGRP or SNP in C57B6/J mice. The drugs olcegepant, sumatriptan, and rizatriptan were used to assess the efficacy of migraine blockers.ResultsMSI measures were confounded by CGRP’s effect on gastric distress. However, analysis of tail vasodilations as a surrogate for motion-induced nausea was robust forbothmigraine triggers. Only olcegepant treatment rescued tail vasodilations.ConclusionThese preclinical findings support the use of small molecule CGRP receptor antagonists for the treatment of motion-induced nausea of migraine, and show that triptan therapeutics are ineffective against motion-induced nausea of migraine.
A lack of distinct cell identities in single-cell measurements: revisiting Waddington’s landscape
Authors: Sparta Breanne , Hamilton Timothy , Hughes Serena , Natesan Gunalan , Deeds Eric J. 
Published: June 2022

AbstractThe prevailing interpretation of Waddington’s landscape is that attractors in gene expression space produce and stabilize distinct cell types. This notion is often applied in single-cell omics data, where groups of cells are clustered for analysis. Here we apply graph theory to characterize the distribution of cells in epigenetic space, using data from various tissues and organisms as well as various single-cell omics technologies. We found that cell types exist in the same regions of epigenetic space, with highly heterogeneous density distributions that are inconsistent with expected densities near an attractor. The lack of attractor structure could not be explained by technical noise, scale variance among genes, nor the subset of genes that were used; nor could it be rescued by any standard set of transformations. These findings pose a challenge for the robust analysis of single-cell data and open the possibility for alternative explanations of canalization during development.
Molecular epidemiology of carbapenemase-producing Acinetobacter spp. from Israel, 2001-2006: earliest report of blaNDM predating the oldest known blaNDM-positive strains
Authors: Grenier Frédéric , Baby Vincent , Allard Sarah , Heynemand Félix , Lévesque Simon , Sullivan Richard , Landecker Hannah L. , Higgins Paul G. , Rodrigue Sébastien , Haraoui Louis-Patrick 
Published: June 2022

AbstractBackgroundCarbapenem-resistant Acinetobacter baumannii (CRAb) is a WHO priority 1 critical pathogen. Despite early emergence of elevated CRAb rates in Israel, limited molecular data from this location are available. We searched for carbapenemases among 198 clinical Acinetobacter spp. from Israel between 2001 and 2006.MethodsStrains from 3 archives underwent whole-genome sequencing (Illumina NovaSeq on all, MinION on a subset) and computational analyses: assembly (Unicycler), annotation (prokka), identification (Kraken, rpoB similarity), search for carbapenemases (ResFinder, BLDB curation).FindingsA. baumannii (Ab) represented 179 (90·4%) Acinetobacter spp. Eighty-four Ab (46·9%) carried a carbapenemase: 38 (45·2%) blaOXA-72 (blaOXA-24-like); 28 (33·3%) blaOXA-23-like (20 blaOXA-23 and 8 blaOXA-225); 18 (21·5%) blaOXA-58 (16 from 2001-2). Carbapenemase rates increased yearly from 2002 (32%) to 2006 (67%). Eight species of non-baumannii Acinetobacter (NbA) accounted for 19 isolates (9·6%). Two of three A. junii contained blaOXA-58, one of which, Ajun-H1-3, isolated in January 2004, also possessed blaNDM-1. The pNDM-Ajun-H1-3 plasmid matched numerous NDM-positive plasmids reported from 2005 onwards in Acinetobacter spp. as well as Enterobacterales.InterpretationWe assessed carbapenemase diversity among Acinetobacter spp. in Israel from 2001-2006. Findings in Ab predate observations elsewhere: rapidly rising carbapenemase rates, driven by blaOXA-23-like and blaOXA-24-like genes replacing blaOXA-58. Among NbA, an A. junii isolated in 2004 carried blaNDM-1, making it the earliest NDM-positive isolate reported to date, preceding those from 2005 in India. Further research into blaNDM’s emergence is warranted, in order to shed light on the evolution and spread of this and other antibiotic-resistance genes.FundingCentre de recherche Charles-Le Moyne; Department of Microbiology and Infectious Diseases, Faculty of Medicine and Health Sciences, Université de Sherbrooke; Fonds de recherche du Québec – Santé; New Frontiers in Research Fund Grant NFRFE-2019-00444; CIFAR-Azrieli Global Scholars Program.
HIRA loss transforms FH-deficient cells
Authors: Valcarcel-Jimenez Lorea , Rogerson Connor , Yong Cissy , Schmidt Christina , Yang Ming , Harle Victoria , Offord Victoria , Wong Kim , Mora Ariane , Speed Alyson , Caraffini Veronica , Tran Maxine Gia Binh , Maher Eamonn R. , Stewart Grant D. , Vanharanta Sakari , Adams David J. , Frezza Christian 
Published: June 2022

ABSTRACTFumarate Hydratase (FH) is a mitochondrial enzyme that catalyses the reversible hydration of fumarate to malate in the TCA cycle. Germline mutations of FH lead to HLRCC, a cancer syndrome characterised by a highly aggressive form of renal cancer(1). Although HLRCC tumours metastasise rapidly, FH-deficient mice develop premalignant cysts in the kidneys, rather than carcinomas (2). How Fh1-deficient cells overcome these tumour suppressive events during transformation is unknown. Here, we perform a genome-wide CRISPR/Cas9 screen to identify genes that, when ablated, enhance the proliferation of Fh1-deficient cells. We found that the depletion of HIRA enhances proliferation and invasion of Fh1-deficient cells in vitro and in vivo. Mechanistically, Hira loss enables the activation of MYC and its target genes, increasing nucleotide metabolism specifically in Fh1-deficient cells, independent of its histone chaperone activity. These results are instrumental for understanding mechanisms of tumorigenesis in HLRCC and the development of targeted treatments for patients.
Exceptional fossil preservation and evolution of the ray-finned fish brain
Authors: Figueroa Rodrigo T. , Goodvin Danielle , Kolmann Matthew A. , Coates Michael I. , Caron Abigail M. , Friedman Matt , Giles Sam 
Published: June 2022

SUMMARYBrain anatomy provides key evidence for ray-finned fish relationships1, but two key limitations obscure our understanding of neuroanatomical evolution in this major vertebrate group. First, the deepest branching living lineages are separated from the group’s common ancestor by hundreds of millions of years, with indications that aspects of their brain morphology–like other aspects of their anatomy2,3–are specialised relative to primitive conditions. Second, there are no direct constraints on brain morphology in the earliest ray-finned fishes beyond the coarse picture provided by cranial endocasts: natural or virtual infillings of void spaces within the skull4–8. Here we report brain and cranial nerve soft-tissue preservation in †Coccocephalichthys wildi, a ∼319-million-year-old (Myr) ray-finned fish. This oldest example of a well-preserved vertebrate brain provides a unique window into neural anatomy deep within ray-finned fish phylogeny. †Coccocephalichthys indicates a more complicated pattern of brain evolution than suggested by living species alone, highlighting cladistian apomorphies9 and providing temporal constraints on the origin of traits uniting all extant ray-finned fishes9–11. Our findings, along with a growing set of studies in other animal groups12–16, point to the significance of ancient soft tissue preservation in understanding the deep evolutionary assembly of major anatomical systems outside of the narrow subset of skeletal tissues17–20.
AdipoQ – a simple, open-source software to quantify adipocyte morphology and function in tissues and in vitro
Authors: Sieckmann Katharina , Winnerling Nora , Huebecker Mylene , Leyendecker Philipp , Ribeiro Dalila , Gnad Thorsten , Pfeifer Alexander , Wachten Dagmar , Hansen Jan N. 
Published: June 2022

AbstractThe different adipose tissues can be distinguished according to their function. For example, white adipose tissue (WAT) stores energy in form of lipids, whereas brown adipose tissue (BAT) dissipates energy in the form of heat. These functional differences are represented in the respective adipocyte morphology: whereas white adipocytes contain large, unilocular lipid droplets, brown adipocytes contain smaller, multilocular lipid droplets. However, an automated, image-analysis pipeline to comprehensively analyze adipocytes in vitro in cell culture as well as ex vivo in tissue sections is missing. We here present AdipoQ, an open-source software implemented as ImageJ plugins that allows to analyze adipocytes in tissue sections and in vitro after histological and/or immunofluorescent labelling. AdipoQ is compatible with different imaging modalities and staining methods, allows batch processing of large datasets and simple post-hoc analysis, provides a broad band of parameters, and allows combining multiple fluorescent read-outs. Thereby, AdipoQ is of immediate use not only for basic research but also for clinical diagnosis.