bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mitigation of Injury from Myocardial Infarction by TH1834, an Inhibitor of the Acetyltransferase Tip60
Authors: Wang Xinrui , Wan Tina C. , Kulik Katherine , Lauth Amelia , Smith Brian C. , Lough John W. , Auchampach John A. 
Published: November 2021

ABSTRACTIt is estimated that up to one billion cardiomyocytes (CMs) can be lost during myocardial infarction (MI), which results in contractile dysfunction, adverse ventricular remodeling, and systolic heart failure. Pharmacologic strategies that target factors having both pro-apoptotic and anti-proliferative functions in CMs may be useful for the treatment of ischemic heart disease. One such multifunctional candidate for drug targeting is the acetyltransferase Tip60, which is a member of the MYST family of acetyltransferases known to acetylate both histone and non-histone protein targets that have been shown in cultured cancer cells to promote apoptosis and to initiate the DNA damage response (DDR) thereby limiting cellular expansion. Using a murine model, we recently published findings demonstrating that CM-specific disruption of the Kat5 gene encoding Tip60 markedly protected against the damaging effects of MI. In the experiments described here, in lieu of genetic targeting, we administered TH1834, an experimental drug designed to specifically inhibit the acetyltransferase domain of Tip60. We report that, similar to the effect of disrupting the Kat5 gene, daily systemic administration of TH1834 beginning 3 days after induction of MI and continuing for two weeks of a 4-week timeline resulted in improved systolic function assessed by echocardiography, reduced apoptosis and scarring, and increased activation of the CM cell-cycle. Our results support that idea that drugs that inhibit the acetyltransferase activity of Tip60 may be useful agents for the treatment of ischemic heart disease.
A vaccine targeting the L9 epitope of the malaria circumsporozoite protein confers protection from blood-stage infection in a mouse challenge model
Authors: Jelínková Lucie , Flores-Garcia Yevel , Shapiro Sarah , Roberts Bryce T. , Petrovsky Nikolai , Zavala Fidel , Chackerian Bryce 
Published: November 2021

AbstractPre-erythrocytic malaria vaccines that induce high-titer, durable antibody responses can potentially provide protection from infection. Here, we engineered a virus-like particle (VLP)-based vaccine targeting a recently described vulnerable epitope at the N-terminus of the central repeat region of the Plasmodium falciparum circumsporozoite protein (CSP) that is recognized by the potently inhibitory monoclonal antibody L9 and show that immunization with L9 VLPs induces strong antibody responses that provide protection from blood-stage malaria in a mouse infection model.
The dimensionality of plant–plant competition
Authors: Stouffer Daniel B. , Godoy Oscar , Dalla Riva Giulio V. , Mayfield Margaret M. 
Published: November 2021

AbstractTo avoid extinction, every species must be able to exploit available resources at least as well as the other species in its community. All else being equal, theory predicts that the more distinct the niches of such co-occurring and competing species, the more species that can persist in the long run. However, both theoretical and experimental studies define a priori the nature and number of resources over which species compete. It therefore remains unclear whether or not species in empirically realistic contexts are actually exploiting all or some of the niches available to them. Here we provide a mathematical solution to this long-standing problem. Specifically, we show how to use the interactions between sets of co-occurring plant species to quantify their implied “niche dimensionality”: the effective number of resources over which those species appear to be competing. We then apply this approach to quantify the niche dimensionality of 12 plant assemblages distributed across the globe. Contrary to conventional wisdom, we found that the niche dimensionality in these systems was much lower than the number of competing species. However, two high-resolution experiments also show that changes in the local environment induce a reshuffling of plant’s competitive roles and hence act to increase the assemblages’ effective niche dimensionality. Our results therefore indicate that homogeneous environments are unlikely to be able to maintain high diversity and also shows how environmental variation impacts species’ niches and hence their opportunities for long-term survival.
Conditional Generative Modeling for De Novo Protein Design with Hierarchical Functions
Authors: Kucera Tim , Togninalli Matteo , Meng-Papaxanthos Laetitia 
Published: November 2021

AbstractMotivationProtein design has become increasingly important for medical and biotechnological applications. Because of the complex mechanisms underlying protein formation, the creation of a novel protein requires tedious and time-consuming computational or experimental protocols. At the same time, machine learning has enabled the solving of complex problems by leveraging large amounts of available data, more recently with great improvements on the domain of generative modeling. Yet, generative models have mainly been applied to specific sub-problems of protein design.ResultsHere we approach the problem of general purpose protein design conditioned on functional labels of the hierarchical Gene Ontology. Since a canonical way to evaluate generative models in this domain is missing, we devise an evaluation scheme of several biologically and statistically inspired metrics. We then develop the conditional generative adversarial network ProteoGAN and show that it outperforms several classic and more recent deep learning baselines for protein sequence generation. We further give insights into the model by analysing hyperparameters and ablation baselines. Lastly, we hypothesize that a functionally conditional model could generate proteins with novel functions by combining labels and provide first steps into this direction of research.AvailabilityCode and data is available at https://github.com/timkucera/proteoganContacttim.kucera@bsse.ethz.ch, mt@visium.ch, lpapaxanthos@google.com
ODGI: understanding pangenome graphs
Authors: Guarracino Andrea , Heumos Simon , Nahnsen Sven , Prins Pjotr , Garrison Erik 
Published: November 2021

AbstractMotivationPangenome graphs provide a complete representation of the mutual alignment of collections of genomes. These models offer the opportunity to study the entire genomic diversity of a population, including structurally complex regions. Nevertheless, analyzing hundreds of gigabase-scale genomes using pangenome graphs is difficult as it is not well-supported by existing tools. Hence, fast and versatile software is required to ask advanced questions to such data in an efficient way.ResultsWe wrote ODGI, a novel suite of tools that implements scalable algorithms and has an efficient in-memory representation of DNA pangenome graphs in the form of variation graphs. ODGI supports pre-built graphs in the Graphical Fragment Assembly format. ODGI includes tools for detecting complex regions, extracting pangenomic loci, removing artifacts, exploratory analysis, manipulation, validation, and visualization. Its fast parallel execution facilitates routine pangenomic tasks, as well as pipelines that can quickly answer complex biological questions of gigabase-scale pangenome graphs.AvailabilityODGI is published as free software under the MIT open source license. Source code can be downloaded fromhttps://github.com/pangenome/odgiand documentation is available athttps://odgi.readthedocs.io. ODGI can be installed via Biocondahttps://bioconda.github.io/recipes/odgi/README.htmlor GNU Guixhttps://github.com/pangenome/odgi/blob/master/guix.scm.Contactegarris5@uthsc.edu
Lipophorin receptors regulate mushroom bodies development and participate in learning, memory and sleep in flies
Authors: Rojo-Cortés Francisca , Tapia-Valladares Victoria , Fuenzalida-Uribe Nicolás , Hidalgo Sergio , Roa Candy B. , González-Ramírez María-Constanza , Oliva Carlos , Campusano Jorge M. , Marzolo María-Paz 
Published: November 2021

AbstractBackgroundDrosophila melanogaster Lipophorin Receptors (LpRs), LpR1 and LpR2, mediate lipid uptake. The orthologs of these receptors in vertebrates, ApoER2 and VLDL-R, bind Reelin, a glycoprotein not present in flies. These receptors are associated with the development and function of the hippocampus and cerebral cortex, important association areas in the mammalian brain. It is currently unknown whether LpRs play similar roles in the Drosophila brain.ResultsWe report that LpR-deficient flies exhibit impaired olfactory memory and sleep patterns, which seem to reflect anatomical defects found in a critical brain association area, the Mushroom Bodies (MB). Moreover, cultured MB neurons respond to mammalian Reelin by increasing the complexity of their neurites. This effect depends on LpRs and Dab, the Drosophila ortholog of the reelin signaling adaptor protein Dab1. In vitro, two of the long isoforms of LpRs allow the internalization of Reelin.ConclusionsThese findings demonstrate that LpRs contribute to MB development and function, supporting the existence of LpR-dependent signaling in Drosophila.
Human Sex Matters: Y-linked lysine demethylase 5D drives accelerated male osteogenic differentiation
Authors: Merten Madlen , Greiner Johannes F.W. , Niemann Tarek , Venhaus Meike Grosse , Kronenberg Daniel , Stange Richard , Wähnert Dirk , Kaltschmidt Christian , Vordemvenne Thomas , Kaltschmidt Barbara 
Published: November 2021

AbstractFemale sex is increasingly associated to a loss of bone mass during aging and an increased risk for fractures developing nonunion. Hormonal factors and cell-intrinsic mechanisms are suggested to drive these sexual dimorphisms, although underlying molecular mechanisms are still a matter of debate. Here, we observed a decreased capacity of calvarial bone recovery in female rats and a profound sexually dimorphic osteogenic differentiation human adult neural crest-derived stem cells (NCSCs). Next to an elevated expression of pro-osteogenic regulators, global trancriptomics revealed Lysine Demethylase 5D (KDM5D) to be highly upregulated in differentiating male NCSCs. Loss of function by siRNA or pharmacological inhibition of KDM5D significantly reduced the osteogenic differentiation capacity of male NCSCs. In summary, we demonstrate craniofacial osteogenic differentiation to be sexually dimorphic with the expression of KDM5D as a prerequisite for accelerated male osteogenic differentiation, emphasizing the analysis of sex-specific differences as a crucial parameter for treating bone defects.
Necroptosis inhibition counteracts neurodegeneration, memory decline and key hallmarks of aging, promoting brain rejuvenation
Authors: Arrázola Macarena S. , Lira Matías , Quiroz Gabriel , Véliz-Valverde Felipe , Iqbal Somya , Eaton Samantha L , Kline Rachel A , Lamont Douglas J , Huerta Hernán , Ureta Gonzalo , Bernales Sebastián , Cárdenas J César , Cerpa Waldo , Wishart Thomas M. , Court Felipe A. 
Published: November 2021

AbstractAge is the main risk factor for the development of neurodegenerative diseases. In the aged brain, axonal degeneration is an early pathological event, preceding neuronal dysfunction, and cognitive disabilities in humans, primates, rodents, and invertebrates. Necroptosis mediates degeneration of injured axons, but whether necroptosis triggers neurodegeneration and cognitive impairment along aging is unknown. Here we show that the loss of the necroptotic effectorMlklwas sufficient to delay age-associated axonal degeneration and neuroinflammation, protecting against decreased synaptic transmission and memory decline in aged mice. Moreover, short-term pharmacologic inhibition of necroptosis in aged mice reverted structural and functional hippocampal impairment, both at the electrophysiological and behavioral level. Finally, a quantitative proteomic analysis revealed that necroptosis inhibition leads to an overall improvement of the aged hippocampal proteome, including a subclass of molecular biofunctions associated with brain rejuvenation, such as long-term potentiation and synaptic plasticity. Our results demonstrate that necroptosis contributes to the age-dependent brain degeneration, disturbing hippocampal neuronal connectivity, and cognitive function. Therefore, necroptosis inhibition constitutes a potential geroprotective strategy to treat age-related disabilities associated with memory impairment and cognitive decline.
X-linked palindromic gene families4930567H17RikandMageb5are dispensable for male mouse fertility
Authors: Stark-Dykema Evan R. , Dulka Eden A. , Gerlinger Emma R. , Mueller Jacob L. 
Published: November 2021

AbstractMammalian sex chromosomes are enriched for large, nearly-identical, palindromic sequences harboring genes expressed predominately in testicular germ cells. Discerning if individual palindrome-associated gene families are essential for male reproduction is difficult due to challenges in disrupting all copies within a gene family. Here we generate precise, independent, deletions to assess the reproductive roles of two X-linked palindromic gene families with spermatid-predominant expression,4930567H17RikorMageb5. Via sequence comparisons, we find mouse4930567H17RikandMageb5have human orthologs,4930567H17Rikis rapidly diverging in rodents and primates, and4930567H17Rikis harbored in a palindrome in humans and mice, whileMageb5is not. Mice lacking either4930567H17RikorMageb5gene families do not have detectable defects in male fertility, fecundity, spermatogenesis, or in gene regulation, but do show differences in sperm head morphology, suggesting a potential role in sperm function. We conclude that while all palindrome-associated gene families are not essential for male fertility, large palindromes influence the evolution of their associated gene families.Summary sentenceMice lacking X-palindromic gene families display normal male fertility, fecundity, spermatogenesis, and gene expression but exhibit differences in sperm head morphology, suggesting a potential role for these gene families in sperm development.
Legume plant defenses and nutrients mediate indirect interactions between soil rhizobia and chewing herbivores
Authors: Basu Saumik , Lee Benjamin W , Clark Robert E , Bera Sayanta , Casteel Clare L , Crowder David W. 
Published: November 2021

AbstractSoil bacteria that form mutualisms with plants, such as rhizobia, affects susceptibility of plants to herbivores and pathogens. Soil rhizobia also promote nitrogen fixation, which mediates host nutrient levels and defenses. However, whether aboveground herbivores affect the function of soil rhizobia remains poorly understood. We assessed reciprocal interactions betweenSitona lineatus, a chewing herbivore, and pea (Pisum sativum) plants grown with or without rhizobia (Rhizobium leguminosarumbiovarviciae). We also examined the underlying plant-defense and nutritional mechanisms of these interactions. In our experiments, soil rhizobia influenced feeding and herbivory by chewing herbivores. Leaf defoliation byS. lineatuswas lower on plants treated with rhizobia, but these insects had similar amino acid levels compared to those on un-inoculated plants. Plants grown with soil rhizobia had increased expression of gene transcripts associated with phytohormone-mediated defense, which may explain decreased susceptibility toS. lineatus. Rhizobia also induced expression of gene transcripts associated with physical and antioxidant-related defense pathways inP. sativum. Conversely,S. lineatusfeeding reduced the number of root nodules and nodule biomass, suggesting a disruption of the symbiosis between plants and rhizobia. Our study shows that aboveground herbivores can engage in mutually antagonistic interactions with soil microbes mediated through a multitude of plant-mediated pathways.
SARS-CoV-2 Envelope protein (E) binds and activates TLR2: A novel target for COVID-19 interventions
Authors: Planès Rémi , Bert Jean-Baptiste , Tairi Sofiane , Benmohamed Lbachir , Bahraoui Elmostafa 
Published: November 2021

AbstractIn this study, we present a molecular characterization of the interaction between the SARS-CoV-2 envelope protein E with TLR2. We demonstrated that E protein interacts physically with TLR2 receptor in a specific and dose-dependent manner. Furthermore, we showed that this interaction is able to engage TLR2 pathway as demonstrated by its capacity to activate NF-κB transcription factor and to stimulate the production of CXCL8 inflammatory chemokine in a TLR2-dependent manner. Furthermore, in agreement with the importance of NF-κB in TLR signaling pathway, we showed that the chemical inhibition of this transcription factor led to significant inhibition of CXCL8 production, while blockade of P38 and ERK1/2 MAP kinases resulted only in a partial CXCL8 inhibition. Overall, our findings suggest considering the envelope protein E as a novel target for COVID-19 interventions: (i) either by exploring the therapeutic effect of anti-E blocking/neutralizing antibodies in symptomatic COVID-19 patients, or (ii) as a promising non-Spike SARS-CoV-2 antigen candidate to include in the development of next generation prophylactic vaccines against COVID-19 infection and disease.ImportanceAlthough, the exact mechanisms of COVID-19 pathogenesis are unknown, recent data demonstrated that elevated levels of pro-inflammatory cytokines in serum is associated with enhanced disease pathogenesis and mortality. Thus, determining the molecular mechanisms responsible for inflammatory cytokine production in the course of SARS-CoV-2 infection could provide future therapeutic targets. In this context, to the best of our knowledge, our report is first to use a detailed molecular characterization to demonstrate that SARS-CoV-2 Envelope E protein binds to TLR2 receptor. Specifically, we showed that SARS-CoV-2 Envelope E protein binds to TLR2 in a direct, specific and dose-dependent manner. Investigating signalling events that control downstream activation of cytokine production show that E protein / TLR2 binding leads to the activation of NF-κB transcription factor that control the expression of multiple pro-inflammatory cytokines including CXCL8. Overall, our findings suggest considering the envelope protein E as a novel target for COVID-19 interventions.
Development of a core measurement set for research in degenerative cervical myelopathy: a study protocol (AO Spine RECODE-DCM CMS)
Authors: Davies Benjamin M. , Touzet Alvaro Yanez , Mowforth Oliver D. , Lee Keng Siang , Khan Danyal , Furlan Julio C. , Fehlings Michael G. , Harrop James , Zipser Carl M. , Rodrigues-Pinto Ricardo , Milligan James , Sarewitz Ellen , Curt Armin , Rahimi-Movaghar Vafa , Aarabi Bizhan , Boerger Timothy F. , Tetreault Lindsay , Chen Robert , Guest James D. , Kalsi-Ryan Sukhvinder , Sadler Iwan , Widdop Shirley , McNair Angus G. K. , Kotter Mark R. N. 
Published: November 2021

ABSTRACTIntroductionProgress in degenerative cervical myelopathy (DCM) is hindered by inconsistent measurement and reporting of outcomes. This can, for example, impede the aggregation of data and comparison of outcomes between studies. This limitation can be reversed by developing a core measurement set (CMS) for use in DCM research. Previously, the AO Spine Research Objectives and Common Data Elements for DCM (AO Spine RECODE-DCM) defined ‘what’ should be measured in DCM: specifically, the core data elements and core outcome set of the disease. The next step of this initiative is to determine ‘how’ to measure these features. The current protocol outlines the steps necessary for the development of a CMS for DCM research and audit.Methods and analysisThe CMS will be developed in accordance with the guidance developed by the Core Outcome Measures in Effectiveness Trials (COMET) and the Consensus-based Standards for the selection of health Measurement Instruments (COSMIN). The process will involve five phases: (1) agreement on the measurement constructs and approaches to their evaluation; (2) the formation of a long list of potential measurement instruments, by identifying existing instruments and assessing their psychometric properties; (3) the aggregation of evidence concerning ‘when’ measurements should be taken; (4) consensus about which instruments to include in the CMS; and (5) implementation.Ethics and disseminationEthical approval was obtained from the University of Cambridge. Dissemination strategies to promote awareness and adoption of the CMS include peer-reviewed scientific publications; conference presentations; podcasts; the identification of AO Spine RECODE-DCM ambassadors; and engagement with relevant journals, funders, and the DCM community.Impact of this workThe proposed project will enable standardised and comprehensive measurement in DCM clinical trials. The CMS will be established using a robust, global, and multi-stakeholder consensus process, with broad representation of healthcare professionals and individuals living with the disease. It will focus on measurement instruments currently in use. This ensures that the CMS will be immediately usable and suited for widespread adoption. The development of better outcome instruments in DCM remains a top 10 research priority and this work will hence facilitate knowledge generation for this important disease.
Intraoperative localization and preservation of reading in ventral occipitotemporal cortex
Authors: Woolnough Oscar , Snyder Kathryn M. , Morse Cale W. , McCarty Meredith J. , Lhatoo Samden D. , Tandon Nitin 
Published: November 2021

AbstractResective surgery in language-dominant ventral occipitotemporal cortex (vOTC) carries the risk of causing impairment to reading. As it is not on the lateral surface, it is not easily accessible for intraoperative mapping and extensive stimulation mapping can be time consuming. Here we assess the feasibility of using task-based electrocorticography (ECoG) recordings intraoperatively to help guide stimulation mapping of reading in vOTC.In 11 patients undergoing extraoperative, intracranial seizure mapping we recorded induced broadband gamma activation (70 – 150 Hz) during a visual category localizer. Word-responsive cortex localized in this manner showed a high sensitivity (72%) to stimulation-induced reading deficits, and the confluence of ECoG and stimulation positive sites appears to demarcate the visual word form area.In two additional patients, with pathologies necessitating resections in language-dominant vOTC, task-based functional mapping was performed intraoperatively using subdural ECoG, alongside direct cortical stimulation. Cortical areas critical for reading were mapped and successfully preserved, while enabling pathological tissue to be completely removed. Data collection is possible in <3 minutes and initial intraoperative data analysis takes <3 minutes, allowing for rapid assessment of broad areas of cortex.Eloquent cortex in ventral visual cortex can be rapidly mapped intraoperatively using ECoG. This method acts to guide high-probability targets for stimulation, with limited patient participation, and can be used to avoid iatrogenic dyslexia following surgery.