bluuebunny/crossref_metadata_2025_split huggingface dataset:
The human-specific miR-6762-5p is an activator of RhoA GTPase enhancingShigella flexneriintercellular spreading
Authors: Reisacher Caroline , Saifi Estelle , Ageron-Ardila Elisabeth , Mallmann Robert Theodor , Klugbauer Norbert , Skurnik David , Arbibe Laurence 
Published: November 2022

AbstractMicroRNAs have recently emerged as major players in host-bacterial pathogens interaction, either as part of the host defense mechanism to neutralize infection or as a bacterial arsenal aimed at subverting host cell functions. Here we identify the newly evolutionary emerged human microRNA miR-6762-5p as a new player in the host-Shigellainterplay. A microarray analysis in infected epithelial cells allowed the detection of this miRNA exclusively during the late phase of infection. Conditional expression of miR-6762-5p combined with a transcriptome analysis indicated a role in cytoskeleton remodeling. Likewise, miR-6762-5p enhanced stress fibers formation through RhoA activation andin silicoanalysis identified several regulators of RhoA activity as potential direct transcriptional targets. We further showed that miR-6762-5p expression induces an increase inShigellaintercellular spreading, while miR-6762-5p inhibition reduced bacterial dissemination. Overall, we have identified a human-specific miR-6762-5p acting specifically at theShigelladissemination step. We propose a model in which the expression of miR-6762-5p induces cytoskeleton modifications through RhoA activation to achieve a successful dissemination ofShigellain the host.
Remembering the “When”: Hebbian Memory Models for the Time of Past Events
Authors: Brea Johanni , Modirshanechi Alireza , Iatropoulos Georgios , Gerstner Wulfram 
Published: November 2022

AbstractHumans and animals can remember how long ago specific events happened. In contrast to interval-timing on the order of seconds and minutes, little is known about the neural mechanisms that enable remembering the “when” of autobiographical memories stored in the episodic memory system. Based on a systematic exploration of neural coding, association and retrieval schemes, we develop a family of hypotheses about the reconstruction of the time of past events, consistent with Hebbian plasticity in neural networks. We compare several plausible candidate mechanism in simulated experiments and, propose how combined behavioral and physiological experiments can be used to pin down the actual neural implementation of the memory for the time of past events.
Acquisition, co-option, and duplication of thertxtoxin system and the emergence of virulence inKingella
Authors: Morreale Daniel P. , Porsch Eric A. , Kern Brad K. , Geme Joseph W. St , Planet Paul J. 
Published: November 2022

AbstractTheKingellagenus includes two pathogenic species, namelyK. kingaeandK. negevensis, as well as strictly commensal species. BothK. kingaeandK. negevensissecrete a toxin called RtxA that is absent in the commensal species. Phylogenetic analysis demonstrates that the toxin-encoding operonrtxCrtxAtolCwas acquired by a common ancestor of the pathogenicKingellaspecies and that a preexisting type I secretion system was co-opted for toxin export. Subsequent genomic reorganization distributed the toxin machinery across two loci, with 30-35% ofK. kingaestrains containing two copies of thertxAtoxin gene. ThertxAduplication is largely clonal and strongly associated with invasive disease. In assays with isogenic strains, a single copy ofrtxAwas associated with reduced virulencein vitro. This study establishes the critical steps in the evolutionary transition from commensal to pathogen, including horizontal gene transfer, co-option of an existing secretion system, and gene duplication.
Cis-regulatory effect of HPV integration is constrained by host chromatin architecture in cervical cancers
Authors: Singh Anurag Kumar , Walavalkar Kaivalya , Tavernari Daniele , Ciriello Giovanni , Notani Dimple , Sabarinathan Radhakrishnan 
Published: November 2022

AbstractHuman papillomavirus (HPV) infections are the primary drivers of cervical cancers, and often the HPV DNA gets integrated into the host genome. Although the oncogenic impact of HPV encoded genes (such as E6/E7) is well known, the cis-regulatory effect of integrated HPV DNA on host chromatin structure and gene regulation remains less understood. Here, we investigate the genome-wide patterns of HPV integrations and associated host gene expression changes in the context of chromatin states and topologically associating domains (TADs). We find that HPV integrations are significantly enriched and depleted in active and inactive chromatin regions, respectively. Interestingly, regardless of the chromatin state, the genomic regions flanking HPV integrations showed transcriptional upregulation. Nevertheless, the upregulation (both local and long-range) is mostly confined to the TADs with integration and does not affect the adjacent TADs. Few TADs showed recurrent integrations associated with overexpression of oncogenes within them (such asMYC, PVT1, TP63andERBB2), regardless of the proximity. To further understand the long-range effect, we performed HiC and 4C-seq analyses in HeLa and observed chromatin looping interaction between the integrated HPV andMYC/PVT1regions (situated ∼500 kb apart), leading to allele-specific overexpression of these genes. Again, these chromatin interactions involving integrated HPV are mostly observed within the same TAD. Together, these results suggest the cis-regulatory potential of integrated HPV DNA that drives host gene upregulation at intra-TAD level in cervical cancer. Based on this, we propose HPV integrations can trigger multimodal oncogenic activation to promote cancer progression.
Migration and the excess exposure of birds to human density in North America
Authors: Jackson Erin K. , Dakin Roslyn 
Published: November 2022

ABSTRACTMigratory species must cross a range of landscapes that are increasingly modified by humans. A key question is how migrating populations are responding to human-induced environmental change. Here, we model the spring migration dynamics of 63 bird species in North America to quantify their exposure to human population density. We find that most bird species have a negative navigational bias, suggesting that they attempt to avoid human-dense areas during migration, and yet they experience far greater human density during migration as compared to breeding. Species that experience excess human density during migration share several key traits: they tend to be nocturnal migrants, they start migrating through North America earlier in the year, and they tend to migrate longer distances. These findings underscore that birds are especially vulnerable to threats associated with human disturbance during migration, with predictable exposures that are often elevated by 2- to 3-fold during migration.
Attentional modulation is orthogonal to disinhibition by VIP interneurons in primary visual cortex
Authors: Myers-Joseph Dylan , Wilmes Katharina A. , Fernandez-Otero Marian , Clopath Claudia , Khan Adil G. 
Published: November 2022

AbstractAttentional modulation of sensory processing is a key feature of cognition, yet its neural circuit basis is poorly understood. A candidate mechanism is the disinhibition of pyramidal cells through vasoactive intestinal peptide (VIP) and somatostatin (SOM) positive interneurons. However, the interaction of attentional modulation and VIP-SOM disinhibition has never been directly tested. We used all-optical methods to bi-directionally manipulate VIP interneuron activity as mice performed an attention switching task. We measured the activity of VIP, SOM and parvalbumin (PV) positive interneurons and pyramidal neurons identified in the same tissue and found that although activity in all cell classes was modulated by both attention and VIP manipulation, their effects were orthogonal. Attention and VIP-SOM disinhibition relied on distinct patterns of changes in activity and reorganisation of interactions between inhibitory and excitatory cells. Circuit modelling revealed a precise network architecture consistent with multiplexing strong yet non-interacting modulations in the same neural population.
Inferring Cognitive State Underlying Conflict Choices in Verbal Stroop Task Using Heterogeneous Input Discriminative-Generative Decoder Model
Authors: Rezaei Mohammad R. , Jeoung Haseul , Gharamani Ayda , Saha Utpal , Bhat Venkat , Popovic Milos R. , Yousefi Ali , Chen Robert , Lankarany Milad 
Published: November 2022

AbstractThe subthalamic nucleus (STN) of the basal ganglia interacts with the medial prefrontal cortex (mPFC) and shapes a control loop, specifically when the brain receives contradictory information from either different sensory systems or conflicting information from sensory inputs and prior knowledge that developed in the brain. Experimental studies demonstrated that significant increases in theta activities (2-8 Hz) in both the STN and mPFC as well as increased phase synchronization between mPFC and STN are prominent features of conflict processing. While these neural features reflect the importance of STN-mPFC circuitry in conflict processing, a low-dimensional representation of the mPFC-STN interaction referred to as a cognitive state, that links neural activities generated by these sub-regions to behavioral signals (e.g., the response time), remains to be identified. Here, we propose a new model, namely, the heterogeneous input discriminative-generative decoder (HI-DGD) model, to infer a cognitive state underlying decision-making based on neural activities (STN and mPFC) and behavioral signals (individuals’ response time) recorded in 10 Parkinson’s disease patients while they performed a Stroop task. PD patients may have conflict processing which is quantitatively (may be qualitative in some) different from healthy population. Using extensive synthetic and experimental data, we showed that the HI-DGD model can diffuse information from neural- and behavioral data simultaneously and estimate cognitive states underlying conflict and nonconflict trials significantly better than traditional methods. Additionally, the HI-DGD model identified which neural features made significant contributions to conflict and non-conflict choices. Interestingly, the estimated features match well with those reported in experimental studies. Finally, we highlight the capability of the HI-DGD model in estimating a cognitive state from a single trial of observation, which makes it appropriate to be utilized in closed-loop neuromodulation systems.HighlightsResearch highlight 1Research highlight 2
Profile of a flower: How rates of morphological evolution drive floral diversification in Ericales
Authors: Herting Julian , Schönenberger Jürg , Sauquet Hervé 
Published: November 2022

ABSTRACTPremise of the StudyRecent studies of floral disparity in the asterid order Ericales have shown that flowers vary strongly among families and that disparity is unequally distributed between the three flower modules (perianth, androecium, gynoecium). However, it remains unknown whether these patterns are driven by heterogeneous rates of morphological evolution or other factors.MethodsHere, we compiled a dataset of 33 floral characters scored for 414 extant ericalean species sampled from 346 genera and all 22 families. We conducted ancestral state reconstructions using an equal rates Markov models for each trait. We used the rates estimated during the ancestral state reconstruction for comparing evolutionary rates between flower modules, creating a “rate profile” of ericalean flowers.Key ResultsThe androecium exhibits the highest evolutionary rates across most characters, whereas most perianth and gynoecium characters evolve slower. High and low rates of morphological evolution can result in high floral disparity in Ericales. Analyses of an angiosperm-wide floral dataset reveal that this pattern appears to be conserved across most major angiosperm clades.ConclusionsElevated rates of morphological evolution in the androecium of Ericales may explain the higher disparity reported for this floral module. We discuss the implications of heterogenous morphological rates of evolution among floral modules from a functional perspective. Comparing rates of morphological evolution through rate profiles proves to be a powerful tool in understanding floral evolution.
Extensive somatic nuclear exchanges shape global populations of the wheat leaf rust pathogenPuccinia triticina
Authors: Sperschneider Jana , Hewitt Tim , Lewis David C. , Periyannan Sambasivam , Milgate Andrew W. , Hickey Lee T. , Mago Rohit , Dodds Peter N. , Figueroa Melania 
Published: November 2022

AbstractNon-sexual processes such as somatic nuclear exchange are postulated to play a role in the diversity of clonally reproducing dikaryotic rust fungi but have been difficult to detect due to the lack of genome resolution between the two haploid nuclei. We examined three nuclear-phased genome assemblies ofPuccinia triticina, which causes wheat leaf rust disease. We found that the most recently emerged Australian lineage is derived by nuclear exchange between two pre-existing lineages, which originated in Europe and North America. Haplotype-specific phylogenetic analysis reveal that repeated somatic exchange events have shuffled haploid nuclei between long-term clonal lineages, leading to a global population representing different combinations of a limited number of haploid genomes. Thus, nuclear exchange seems to be the predominant mechanism generating diversity and the emergence of new strains in this otherwise clonal pathogen. Such genomics-accelerated surveillance of pathogen evolution paves the way for more accurate global disease monitoring.
AATF Inhibition Exerts Antiangiogenic Effects Against Human Hepatocellular Carcinoma
Authors: Suresh Diwakar , Srinivas Akshatha N. , Prashant Akila , Satish Suchitha , Vishwanath Prashant , Santhekadur Prasanna K. , Kumar Divya P. 
Published: November 2022

ABSTRACTHepatocellular carcinoma (HCC), a highly fatal cancer with a mortality rate proportional to its incidence, continues to pose a global health care challenge. Angiogenesis is a key factor in the growth and metastasis of hepatic tumors and thus a potential therapeutic target in HCC. We previously showed that the apoptosis antagonizing transcription factor (AATF) affects tumor growth and metastasis in a mouse xenograft model. However, the regulatory role of AATF in tumor angiogenesis and its underlying mechanisms in HCC remain unknown. In the current study, we identified high levels of AATF in human HCC tissues compared to adjacent normal liver tissues, and the expression was found to be correlated with the stages and tumor grades of HCC. Inhibition of AATF in human HCC cells showed high levels of pigment epithelium-derived factor (PEDF) compared to controls as a resultant of reduced matric metalloproteinases activity. Conditioned media from AATF knockdown (KD) cells inhibited the proliferation, migration, and invasion of human umbilical vein endothelial cells as well as the vascularization of the chick chorioallantoic membrane. Furthermore, the VEGF-mediated downstream signaling pathway responsible for endothelial cell survival and vascular permeability, cell proliferation, and migration favoring angiogenesis was suppressed by AATF inhibition. Of note, PEDF inhibition by its respective antibody profoundly reversed the anti-angiogenic effect of AATF KD. In conclusion, our study demonstrates that inhibition of AATF suppresses angiogenesis in HCC via PEDF. Thus, a therapeutic strategy based on the inhibition of AATF to disrupt tumor angiogenesis may be a promising approach for HCC treatment.
Review and further developments in statistical corrections for Winner’s Curse in genetic association studies
Authors: Forde Amanda , Hemani Gibran , Ferguson John 
Published: November 2022

AbstractGenome-wide association studies (GWAS) are commonly used to identify genomic variants that are associated with complex traits, and estimate the magnitude of this association for each variant. However, it has been widely observed that the association estimates of variants tend to be lower in a replication study than in the study that discovered those associations. A phenomenon known asWinner’s Curseis responsible for this upward bias present in association estimates of significant variants in the discovery study. We review existingWinner’s Cursecorrection methods which require only GWAS summary statistics in order to make adjustments. In addition, we propose modifications to improve existing methods and propose a novel approach which uses the parametric bootstrap. We evaluate and compare methods, first using a wide variety of simulated data sets and then, using real data sets for three different traits. The metric, estimated mean squared error (MSE) over significant SNPs, was primarily used for method assessment. Our results indicate that widely used conditional likelihood based methods tend to perform poorly. The other considered methods behave much more similarly, with our proposed bootstrap method demonstrating very competitive performance. To complement this review, we have developed an R package, ‘winnerscurse’ which can be used to implement these variousWinner’s Curseadjustment methods to GWAS summary statistics.Author SummaryA genome-wide association study is designed to analyse many common genetic variants in thousands of samples and identify which variants are associated with a trait of interest. It provides estimates of association strength for each variant and variants are classified as associated if their test statistics obtained in the study pass a chosen significance threshold. However, due to a phenomenon known asWinner’s Curse,the association estimates of these significant variants tend to be upward biased and greater in magnitude than their true values. Naturally, this bias has adverse consequences for downstream statistical techniques which use these estimates. In this paper, we look at current methods which have been designed to combatWinner’s Curseand propose modifications to these methods in order to improve performance. Using a wide variety of simulated data sets as well as real data, we perform a thorough evaluation of these methods. We use a metric which allows us to identify which methods, on average, produce adjusted estimates for significant variants that are closest to the true values. To accompany our work, we have created an R package, ‘winnerscurse’, which allows users to easily applyWinner’s Cursecorrection methods to their data sets.
Limited oxygen availability in standard cell culture alters metabolism and function in terminally-differentiated cells
Authors: Tan Joycelyn , Virtue Sam , Norris Dougall M. , Conway Olivia J. , Yang Ming , Gribben Christopher , Lugtu Fatima , Kamzolas Ioannis , Krycer James R. , Mills Richard J. , Pereira Conceição , Dale Martin , Shun-Shion Amber S. , Baird Harry J. M. , Horscroft James A. , Sowton Alice P. , Ma Marcella , Carobbio Stefania , Petsalaki Evangelia , Murray Andrew J. , Gershlick David C. , Hudson James E. , Vallier Ludovic , Fisher-Wellman Kelsey H , Frezza Christian , Vidal-Puig Antonio , Fazakerley Daniel J. 
Published: November 2022

SUMMARYCell culture is generally considered to be hyperoxic. However, the importance of cellular oxygen consumption is often underappreciated, with rates of oxygen consumption often sufficient to cause hypoxia at cell monolayers. We initially focused on cultured adipocytes as a terminally differentiated cell-type with substantial oxygen consumption rates to support diverse cellular functions. Under standard conditions, cultured adipocytes are hypoxic and highly glycolytic. Increasing oxygen diverted glucose flux toward mitochondria and resulted in thousands of gene expression changes that pointed toward alleviated physiological transcriptional responses to hypoxia. Phenotypically, providing more oxygen increased adipokine secretion and rendered adipocytes more sensitive to insulin and lipolytic stimuli. The functional benefits of increasing pericellular oxygen were transferable to other cellular systems including hPSC-derived hepatocytes and cardiac organoids. Our findings suggest that oxygen is limiting in many terminally-differentiated cell culture systems, and that controlling oxygen availability can improve the quality and translatability of cell models.
Utilization of anArtery-on-a-chipto unravel novel regulators and therapeutic targets in vascular diseases
Authors: Paloschi Valentina , Pauli Jessica , Winski Greg , Wu Zhiyuan , Li Zhaolong , Glukha Nadiya , Hummel Nora , Rogowitz Felix , Meucci Sandro , Botti Lorenzo , Busch Albert , Chernogubova Ekaterina , Jin Hong , Sachs Nadja , Eckstein Hans-Henning , Dueck Anne , Boon Reinier A. , Bausch Andreas R. , Maegdefessel Lars 
Published: November 2022

AbstractIntroductionOrgans-on-chips represent novelin vitromodels that have the capacity to emulate aspects of human physiology and pathophysiology by incorporating features like tissue-multicellularity and exposure to organ-relevant physical environment. We developed anartery-on-a-chipwith the objective to recapitulate the structure of the arterial wall composed of intimal and medial layers and the relevant hemodynamic forces that affect luminal cells.ResultsBy comparingarteries-on-chipsexposed either toin vivo-like shear stress values or kept in static conditions, we identified a panel of novel genes modulated by shear stress. We next measured the expression pattern of shear stress-modulated genes in areas of the vascular tree affected by atherosclerotic plaques and aortic aneurysms, where disease development and progression are induced by alterations of shear stress. We obtained biopsies from patients affected by carotid artery disease (CAD), comprising the atherosclerotic plaque (diseased artery) and the adjacent region (non-diseased artery). From patients with abdominal aortic aneurysms (AAA), we obtained the aneurysmal portion (diseased aorta) and non-dilated adjacent segment (non-diseased aorta). Genes modulated by shear stress followed the same expression pattern in non-diseased segments of human vessels and were expressed by endothelial and smooth muscle cells as evidenced by immunofluorescence analysis and single cell RNA sequencing. Using mice and porcine models of vascular CAD and AAA, we confirmed that shear stress mediated targets are important in discriminating diseased and non-diseased vessel portionsin vivo. Furthermore, we showed that ourartery-on-a-chipcan serve as a platform for drug-testing. We were able to reproduce the effects of a therapeutic agent previously used in AAA animal models inartery-on-a-chipsystems and extend our understanding of its therapeutic effect through a multicellular structure.ConclusionsOur novelin vitromodel is capable of mimicking important physiological aspects of human arteries, such as the response to shear stress, and can further shed light on the mechanism of action of potential therapeutics before they enter the clinical stage.TeaserTheartery-on-a-chipis a novelin vitroplatform that enables the mimicry of human arteries and can be used to gain insights into the development and therapeutic targeting of vascular diseases.