bluuebunny/crossref_metadata_2025_split huggingface dataset:
ASO targeting temperature-controlledRBM3poison exon splicing prevents neurodegeneration in vivo
Authors: Preußner Marco , Smith Heather L , Zhang Min , Hughes Daniel , Emmerichs Ann-Kathrin , Scalzitti Silvia , Peretti Diego , Swinden Dean , Neumann Alexander , Haltenhof Tom , Mallucci Giovanna R , Heyd Florian 
Published: October 2022

SummaryNeurodegenerative diseases are increasingly prevalent in the aging population, yet currently no disease-modifying treatments are available. Increasing the expression of the cold-shock protein, RBM3, through therapeutic hypothermia is remarkably neuroprotective, but cooling poses a health risk itself, strongly limiting its clinical application. Selective upregulation of RBM3 at normothermia thus holds immense therapeutic potential. Here we identify a poison exon within the RBM3 gene that is solely responsible for cold-induced RBM3 expression. Genetic removal or ASO-mediated manipulation of this exon yields high RBM3 levels independent of cooling. Notably, a single administration of ASO to exclude the poison exon, using FDA-approved chemistry, results in long-lasting increase of RBM3 expression in mouse brains. In prion-diseased mice, this treatment leads to remarkable neuroprotection, with prevention of neuronal loss and spongiosis despite high levels of prion protein. RBM3-inducing ASOs could thus broadly deliver protection in humans in conditions ranging from acute brain injury to Alzheimer’s disease.One sentence summaryInducing cold shock protein RBM3 by modulating its alternative splicing at normothermia is neuroprotective in vivo
Examining the early distribution of the artemisinin-resistantPlasmodium falciparumkelch13 R561H mutation in Rwanda
Authors: Kirby Rebecca , Giesbrecht David , Karema Corine , Watson Oliver , Lewis Savannah , Munyaneza Tharcisse , de Dieu Butera Jean , Juliano Jonathan J , Bailey Jeffrey , Mazarati Jean Baptiste 
Published: October 2022

AbstractArtemisinin resistance mutations inPlasmodium falciparum kelch13(Pfk13) have begun to emerge in Africa.Pfk13-R561H was the first reported African mutation found in Rwanda in 2014, but limited sampling left questions about its early distribution and origin. We detected 476 parasitemias among 1873 residual blood spots from a 2014-15 Rwanda Demographic Health Survey. We sequenced 351 samples revealing 341/351 were wild type (97.03% weighted) and 4 samples (1.34% weighted) harbored R561H which were significantly spatially clustered. Our study better defines the early distribution of R561H in Rwanda and suggests that the origin may have involved higher-transmission regions.
In Silico Analysis of NovelVHLGermline Mutations in Iranian RCH Patients
Authors: Naseripour Masood , Bagherzadeh Kowsar , Khakpoor Golnaz , Sedaghat Ahad , Mirshahi Reza , Kasraee Hengameh , Kiaee Reza Afshar , Azimi Fatemeh 
Published: October 2022

AbstractVon Hippel-Lindau (VHL) syndrome is an autosomal dominant inherited multisystem neoplasia disorder caused by theVHLtumor suppressor gene, coding for VHL protein (pVHL), variants. Various types ofVHLvariants present different clinical phenotypes that later lead to events resulting in benign or malignant lesions including Retinal Capillary Hemangioblastoma (RCH). We reported on 3 novel mutation sites observed in 3 families (5 RCH patients), including c.511A>C, c.514C>T, and c.511A>T in exon 3 of theVHLgene. According to the ACMG classifications, c.514C>T and c.511A>T variations are likely pathogenic, and c.511A>C is a variant of uncertain significance (VUS) and in accordance with autosomal dominant inheritance. The location and impact of the incidence mutations on pVHL were computed using in silico analysis. The obtained structural information and computational analysis showed that the studied mutations induce conformational changes that limit the flexibility of the pVHL interaction interface with elonginB/C, elongin C/B, and cullin2, which is necessary for HIF1 alpha binding. The recently added gene variants and their related clinical phenotypes will improve the VHL diagnosis accuracy and the patients’ population carryingVHLgene mutations. These pioneering results could be a model for future functional studies.
AI-Enabled Classification of Head and Neck Tumors using Convolutional Neural Networks with Dynamic Optical Contrast Imaging
Authors: Odion Ren , Mukdad Laith , Alhiyari Yazeed , Tam Kenric , Shori Ramesh , Vo-Dinh Tuan , John Maie A. St. 
Published: October 2022

ABSTRACTBackgroundRecent advances in artificial intelligence (AI) in the field of imaging have resulted in new opportunities for automated tumor detection and margin assessment. In particular, AI deep learning techniques such as the Convolutional Neural Network (CNN) have greatly advanced the field of computer vision. Here we introduce the application of a CNN model for use with Dynamic Optical Contrast Imaging (DOCI), an imaging technique developed by our group that creates a unique molecular signature on tissue targets by obtaining the autofluorescence decay of several spectral bands in the UV-Vis range.Methods21 patients undergoing surgical resection for tonsillar squamous cell carcinoma (SCC) were identified on a prospective basis. DOCI images were analyzed and compared to the pathology results as ground truth. A CNN model was used to segment sections of DOCI images and provide a percentage chance of tumor presence, allowing for automated tumor margin delineation without a-priori knowledge of the tumor tissue composition.ResultsCNN outputs yielded a 99.98% confidence in classifying non-tumor tissue and 76.02% confidence in classifying tumor tissue.ConclusionsOur results indicate that a CNN-based classification model for DOCI allows for real-time analysis of tissue, providing improved sensitivity and accuracy of determining true margins and thus enabling the head and neck cancer surgeon to save healthy tissue and improve patient outcomes.
Transcription factor HSFA7b controls ethylene signaling and meristem maintenance at the shoot apical meristem during thermomemory
Authors: John Sheeba , Apelt Federico , Kumar Amit , Bents Dominik , Annunziata Maria Grazia , Fichtner Franziska , Mueller-Roeber Bernd , Olas Justyna J. 
Published: October 2022

AbstractThe shoot apical meristem (SAM) is responsible for overall shoot growth by generating all above-ground structures. Recent research identified that the SAM displays an autonomous heat stress (HS) memory of a previous non-lethal HS event. Considering the importance of the SAM for plant growth it is essential to unlock how its thermomemory is mechanistically controlled. Here, we report thatHEAT SHOCK TRANSCRIPTION FACTOR A7b(HSFA7b) plays a crucial role in this process in Arabidopsis. We found that HSFA7b directly regulates ethylene response at the SAM by binding to promoters of key regulators of ethylene signaling includingETHYLENE-INSENSITIVE 3to establish thermotolerance. Moreover, HSFA7b controls maintenance of the SAM stem cell pool during thermomemory by regulating the expression of the master regulatorWUSCHELthrough direct transcriptional activation of theSPLAYEDchromatin remodelling factor.
Prior information differentially affects discrimination decisions and subjective confidence reports
Authors: Constant Marika , Pereira Michael , Faivre Nathan , Filevich Elisa 
Published: October 2022

AbstractAccording to Bayesian models, both decisions and confidence are based on the same precision-weighted integration of prior expectations (“priors”) and incoming information (“likelihoods”). This assumes that priors are integrated optimally and equally in decisions and confidence, which has not been tested. In two experiments, we quantitatively assessed how priors inform both decisions and confidence. With a gamified dual-decision task we controlled the strength of priors and likelihoods to create pairs of conditions that were matched in posterior information, but differed on whether the prior or likelihood was more informative. We found that priors were underweighted in discrimination decisions, but used to a greater extent in confidence about those decisions, and this was not due to differences in processing time. With a Bayesian model we quantified the weighting parameters for the prior at both levels, and confirmed that priors are more optimally used in explicit confidence, even when underused in decisions.
Genomic Changes During the Evolution of theCoxiellaGenus Along the Parasitism-Mutualism Continuum
Authors: Santos-Garcia Diego , Morel Olivier , Henri Hélène , Filali Adil El , Buysse Marie , Noël Valérie , McCoy Karen D. , Gottlieb Yuval , Klasson Lisa , Zenner Lionel , Duron Olivier , Vavre Fabrice 
Published: October 2022

AbstractThe Coxiellaceae family is composed of five genera showing lifestyles ranging from free-living to symbiosis. Among them,Coxiella burnetiiis a well-known pathogen causing Q fever in humans. This bacterium presents both intracellular (parasitic) and environmental (resistant) forms. Recently, several environmentalCoxiellagenomes have been reported, among which several have come from intracellular mutualistic symbionts of ticks, termedCoxiella-like endosymbionts. We sequenced two newCoxiella-LE genomes fromDermacentor marginatus(CLEDm) andOrnithodoros maritimus(CLEOmar) ticks, the latter belonging to theC. burnetiilineage. Using these newly sequencedCoxiella-LEs and 43 Coxiellaceae genomes, we conducted comparative genomic and phylogenomic analyses to increase our knowledge ofC. burnetiipathogenicity and the emergence ofCoxiella-LEs. Results highlight the probably parasitic nature of the common ancestor of the Coxiellaceae. Indeed, the virulence factor Dot/Icm T4 Secretion System is present in most, but not all, Coxiellaceae. Whereas it is part of a putative pathogenic island inC. burnetii, it has been entirely lost or inactivated inCoxiella-LEs, suggesting its importance in pathogenesis. Additionally, we found that a Sha/Mrp antiporter was laterally acquired in theC. burnetiilineage. This antiporter might be involved in alkali resistance and the development of the resistant form that is able to persist in the environment for long periods of time. The Sha operon is eroded or absent inCoxiella-LEs. Finally, we found that allCoxiellarepresentatives produce B vitamins and co-factors indicating a pre-adaptation ofCoxiellato mutualism with hematophagous arthropods. Accordingly, the ancestor ofC. burnetiiandCoxiella-LEs was likely a parasitic bacterium able to manipulate its host cell and to produce vitamins and co-factors for its own use.
A community genomics approach to natural hybridization
Authors: Zbinden Zachery D. , Douglas Marlis R. , Chafin Tyler K. , Douglas Michael E. 
Published: October 2022

AbstractHybridization is a complicated, oft-misunderstood process. Once deemed unnatural and uncommon, hybridization is now recognized as ubiquitous among species. But hybridization rates within and among communities are poorly understood despite the relevance to ecology, evolution, and conservation. To clarify, we examined hybridization across 75 freshwater fish communities within the Ozarks of the North American Interior Highlands (USA) by SNP genotyping 33 species (N=2,865 individuals; ddRAD). We found evidence of hybridization (70 putative hybrids; 2.4% of individuals) among 18 species-pairs involving 73% (24/33) of study species, with the majority being concentrated within one family (Leuciscidae/minnows; 15 species; 66 individuals). Interspecific genetic exchange— or introgression— was evident from 24 backcrossed individuals (10/18 species-pairs). Hybrids occurred within 42 of 75 communities (56%). Four selected environmental variables (species richness, protected area extent, precipitation [May and annually]) exhibited 73–78% accuracy in predicting hybrid occurrence via random forest classification. Our community-level assessment identified hybridization as spatially widespread and environmentally dependent (albeit predominantly within one large, diverse family). Our approach provides a more holistic survey of natural hybridization by testing a wide range of species-pairs, thus contrasting with more conventional evaluations.
Brain-inspired methods for achieving robust computation in heterogeneous mixed-signal neuromorphic processing systems
Authors: Zendrikov Dmitrii , Solinas Sergio , Indiveri Giacomo 
Published: October 2022

AbstractNeuromorphic processing systems implementing spiking neural networks with mixed signal analog/digital electronic circuits and/or memristive devices represent a promising technology for edge computing applications that require low power, low latency, and that cannot connect to the cloud for off-line processing, either due to lack of connectivity or for privacy concerns. However these circuits are typically noisy and imprecise, because they are affected by device to device variability, and operate with extremely small currents. So achieving reliable computation and high accuracy following this approach is still an open challenge that has hampered progress on one hand and limited widespread adoption of this technology on the other. By construction, these hardware processing systems have many constraints that are biologically plausible, such as heterogeneity and non-negativity of parameters. More and more evidence is showing that applying such constraints to artificial neural networks, including those used in artificial intelligence, promotes robustness in learning and improves their reliability. Here we delve even more in neuroscience and present network-level brain-inspired strategies that further improve reliability and robustness in these neuromorphic systems: we quantify, with chip measurements, to what extent population averaging is effective in reducing variability in neural responses, we demonstrate experimentally how the neural coding strategies of cortical models allow silicon neurons to produce reliable signal representations, and show how to robustly implement essential computational primitives, such as selective amplification, signal restoration, working memory, and relational networks, exploiting such strategies. We argue that these strategies can be instrumental for guiding the design of robust and reliable ultra-low power electronic neural processing systems implemented using noisy and imprecise computing substrates such as subthreshold neuromorphic circuits and emerging memory technologies.
Riverscape community genomics: A comparative analytical approach to identify common drivers of spatial structure
Authors: Zbinden Zachery D. , Douglas Marlis R. , Chafin Tyler K. , Douglas Michael E. 
Published: October 2022

ABSTRACTGenetic differentiation among local groups of individuals, i.e., genetic β-diversity, is a key component of population persistence related to connectivity and isolation. However, most genetic investigations of natural populations focus on a single species, overlooking opportunities for multispecies conservation plans to benefit entire communities in an ecosystem. We present an approach to evaluate genetic β-diversity within and among many species and demonstrate how thisriverscape community genomicsapproach can be applied to identify common drivers of genetic structure. Our study evaluated genetic β-diversity in 31 co-distributed native stream fishes sampled from 75 sites across the White River Basin (Ozarks, USA) using SNP genotyping (ddRAD). Despite variance among species in the degree of genetic divergence, general spatial patterns were identified corresponding to river network architecture. Most species (N=24) were partitioned into discrete sub-populations (K=2–7). We used partial redundancy analysis to compare species-specific genetic β-diversity across four models of genetic structure: Isolation by distance (IBD), isolation by barrier (IBB), isolation by stream hierarchy (IBH), and isolation by environment (IBE). A significant proportion of intraspecific genetic variation was explained by IBH (x□ =62%), with the remaining models generally redundant. We found evidence for consistent spatial modularity in that gene flow is higher within rather than between hierarchical units (i.e., catchments, watersheds, basins), supporting the generalization of the Stream Hierarchy Model. We discuss our conclusions regarding conservation and management and identify the 8-digit Hydrologic Unit (HUC) as the most relevant spatial scale for managing genetic diversity across riverine networks.
Genome assembly of three AmazonianMorphobutterfly species reveals Z-chromosome rearrangements between closely-related species living in sympatry
Authors: Bastide Héloïse , López-Villavicencio Manuela , Ogereau David , Lledo Joanna , Dutrillaux Anne-Marie , Debat Vincent , Llaurens Violaine 
Published: October 2022

AbstractThe genomic processes enabling speciation and the coexistence of species in sympatry are still largely unknown. Here we describe the whole genome sequencing and assembly of three closely-related species from the butterfly genusMorpho:Morpho achilles(Linnaeus, 1758),M. helenor(Cramer, 1776) andM. deidamia(Hübner, 1819). These large blue butterflies are emblematic species of the Amazonian rainforest. They live in sympatry in a wide range of their geographical distribution and display parallel diversification of dorsal wing colour pattern, suggesting local mimicry. By sequencing, assembling and annotating their genomes, we aim at uncovering pre-zygotic barriers preventing gene flow between these sympatric species. We found a genome size of 480 Mb for the three species and a chromosomal number ranging from 2n = 54 forM. deidamiato 2n = 56 forM. achillesandM. helenor. We also detected inversions on the sex chromosome Z that were differentially fixed between species, suggesting that chromosomal rearrangements may contribute to their reproductive isolation. The annotation of their genomes allowed us to recover in each species at least 12,000 protein-coding genes and to discover duplications of genes potentially involved in pre-zygotic isolation like genes controlling colour discrimination (L-opsin). Altogether, the assembly and the annotation of these three new reference genomes open new research avenues into the genomic architecture of speciation and reinforcement in sympatry, establishingMorphobutterflies as a new eco-evolutionary model.
Novel EGFR-Mutant Mouse Models of Lung Adenocarcinoma Reveal Adaptive Immunity Requirement for Durable Osimertinib Response
Authors: Kleczko Emily K , Le Anh T , Hinz Trista K , Nguyen Teresa T , Navarro Andre , Hu Cheng-Jun , Clambey Eric T , Merrick Daniel T , Weiser-Evans Mary , Nemenoff Raphael A , Heasley Lynn E 
Published: October 2022

AbstractLung cancers bearing oncogenically-mutated EGFR represent a significant fraction of lung adenocarcinomas (LUADs) for which EGFR-targeting tyrosine kinase inhibitors (TKIs) provide a highly effective therapeutic approach. However, these lung cancers eventually acquire resistance and undergo progression within a characteristically broad treatment duration range. Our previous study of EGFR mutant lung cancer biopsies highlighted the positive association of a TKI-induced interferon γ transcriptional response with increased time to treatment progression. To test the hypothesis that host immunity contributes to the TKI response, we developed novel genetically-engineered mouse models of EGFR mutant lung cancer bearing exon 19 deletions (del19) or the L860R missense mutation. Both oncogenic EGFR mouse models developed multifocal LUADs from which transplantable cancer cell lines sensitive to the EGFR-specific TKIs, gefitinib and osimertinib, were derived. When propagated orthotopically in the left lungs of syngeneic C57BL/6 mice, deep and durable shrinkage of the cell line-derived tumors was observed in response to daily treatment with osimertinib. By contrast, orthotopic tumors propagated in immune deficientnu/numice exhibited modest tumor shrinkage followed by rapid progression on continuous osimertinib treatment. Importantly, osimertinib treatment significantly increased intratumoral CD3+ T cell content relative to diluent treatment. The findings provide strong evidence supporting the requirement for adaptive immunity in the durable therapeutic control of EGFR mutant lung cancer.
Re-examining supposed correlations between synonymous codon usage and protein bond angles inE. coli
Authors: Akeju Opetunde J. , Cope Alexander L. 
Published: October 2022

AbstractA recent paper by Rosenberg et al. [2022] found a surprising correlation between synonymous codon usage and the dihedral bond angles of the resulting amino acid. However, their analysis did not account for the strongest known correlate of codon usage: gene expression. We applied the approach of Rosenberg et al. [2022] to simulated protein-coding sequences that (1) maintain the general relationship between codon usage and gene expression and (2) completely random codon usage. The analysis of the simulated data assuming a general relationship between gene expression and codon usage returned results remarkably similar to the real data. More concerning was the large number of significant results detected when sequences with random codon usage were analyzed. We believe that the specific results of Rosenberg et al. [2022] were confounded by the relationship between codon usage and gene expression, but also that their method is generally prone to detecting noise in protein bond angle distributions.
CXCL4 signaling and gene induction in human monocytes involve a TLR4 response divergent from LPS
Authors: Yang Chao , Yuan Ruoxi , Mishra Bikash , Bell Richard D. , Zhang Yaxia , Du Yong , Ah Kioon Marie Dominique , Barrat Franck J. , Ivashkiv Lionel B. 
Published: October 2022

AbstractThe chemokine CXCL4 activates myeloid cells and contributes to the pathogenesis of inflammatory and fibrotic diseases. One mechanism of CXCL4 action is binding of nucleic acids to promote their internalization and activation of endosomal TLRs. However, the signaling pathways and receptors that mediate myeloid cell responses to CXCL4 alone are not well characterized. Here, we report that in primary human monocytes, CXCL4 activated NF-κB and a TBK1-JNK signaling axis that drive the expression of inflammatory, fibrotic and neutrophil chemokine genes, and also RIPK3-dependent necroptosis. Surprisingly, six distinct lines of evidence targeting TLR4 expression and function suggested a role for TLR4 in CXCL4 responses. However, in contrast to the canonical TLR4 agonist LPS, CXCL4 did not effectively activate an autocrine IFN response or IL-12 family genes, even after IFN-γ priming of monocytes. In accord with its role in inducing chemokine and inflammatory gene expression, CXCL4 regulated neutrophil and macrophage infiltration into skin wounds, and promoted wound healing in a mouse model. Our findings suggest that CXCL4 modulates the profile of TLR4 responses to induce a macrophage phenotype divergent from LPS-activated cells, provide new insights into mechanisms by which CXCL4 activates human monocytes, and implicate CXCL4 in regulation of skin wound healing.