bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immunological factors, but not clinical features, predict visceral leishmaniasis relapse in patients co-infected with HIV
Authors: Takele Yegnasew , Mulaw Tadele , Adem Emebet , Shaw Caroline Jayne , Franssen Susanne Ursula , Womersley Rebecca , Kaforou Myrsini , Taylor Graham Philip , Levin Michael , Müller Ingrid , Cotton James Anthony , Kropf Pascale 
Published: March 2021

ABSTRACTVisceral leishmaniasis (VL) has emerged as a clinically important opportunistic infection in HIV patients, as VL/HIV co-infected patients suffer from frequent VL relapse. Here, we followed cohorts of VL patients with or without HIV co-infections in Ethiopia and collected detailed clinical and immunological data during 12 months of follow-up. By the end of the study 78.1% of VL/HIV patients, but none of the VL only patients, had relapsed. Despite clinically defined cure, VL/HIV patients maintained high parasite loads, low BMI, hepatosplenomegaly and pancytopenia throughout follow-up. During detailed immunological study throughout the follow-up period, we identified three markers associated with VL relapse: i) failure to restore antigen-specific production of IFNγ, ii) persistently low CD4+T cell counts, and iii) high expression of PD1 on CD4+T cells. We show that these three markers combine well in predicting VL relapse, and that all three measurements are needed for optimal predictive power. These three immunological markers can be measured in primary hospital settings in Ethiopia and can predict VL relapse after anti-leishmanial therapy. The use of our prediction model has the potential to improve disease management and patient care.
Acitretin mitigates uroporphyrin-induced bone defects in congenital erythropoietic porphyria models
Authors: Cunha Juliana Bragazzi , Elenbaas Jared S , Maitra Dhiman , Kuo Ning , Azuero-Dajud Rodrigo , Ferguson Allison C , Griffin Megan S , Lentz Stephen I , Shavit Jordan A , Omary M Bishr 
Published: March 2021

ABSTRACTCongenital erythropoietic porphyria (CEP) is a rare genetic disorder leading to accumulation of uro/coproporphyrin-I in tissues due to inhibition of uroporphyrinogen-III synthase. Clinical manifestations of CEP include bone fragility, severe photosensitivity and photomutilation. Currently there is no specific treatment for CEP, except bone marrow transplantation, and there is an unmet need for treating this orphan disease. Fluorescent porphyrins cause protein aggregation, which led us to hypothesize that uroporphyrin-I accumulation leads to protein aggregation and CEP-related bone phenotype. We developed a zebrafish model that phenocopies features of CEP. As in human patients, uroporphyrin-I accumulated in the bones of zebrafish, leading to impaired bone development. Furthermore, in an osteoblast-like cell line, uroporphyrin-I decreased mineralization, aggregated bone matrix proteins, activated endoplasmic reticulum stress and disrupted autophagy. Using high-throughput drug screening, we identified acitretin, a second-generation retinoid, and showed that it reduced uroporphyrin-I accumulation and its deleterious effects on bones. Our findings provide a new CEP experimental model and a potential repurposed therapeutic.
Evolution of the insect PPK gene family
Authors: Latorre-Estivalis Jose Manuel , Almeida Francisca Cunha , Pontes Gina , Dopazo Hernán , Barrozo Romina , Lorenzo Marcelo Gustavo 
Published: March 2021

ABSTRACTInsectPickpocket(PPK) receptors mediate the detection of stimuli of diverse sensory modalities, therefore having a relevant role for environmental sounding. Notwithstanding their relevance, studies on their evolution are scarce. We have analyzed the genomes of 26 species belonging to 8 insect orders (Blattodea, Orthoptera, Hemiptera, Phthiraptera, Hymenoptera, Lepidoptera, Coleoptera, and Diptera) to identify their PPK repertoires and study the evolution of this gene family. PPKs were detected in all genomes analyzed, with a total of 578 genes identified that distributed in 7 subfamilies. Our phylogenetic analysis allowed clarifying that theppk17gene appears to be the most divergent family member, composing a new group designed as subfamily VII. According to our analysis, PPKs evolved under a birth-and-death model that generated lineage-specific expansions usually located in clusters and the effect of strong purifying selection was seen for several orthogroups. Subfamily V was the largest one, presenting half of all PPKs studied, including a mosquito-specific expansion that can be considered a new target for pest control. Consistently with their sensory role, PPKs present a high gene turnover that generated considerable variation in the size of insect repertoires:Musca domestica(59),Blattella germanica(41),Culex quinquefasciatus(48), andAedes albopictus(51) presented the largest PPK repertoires, whilePediculus humanus(onlyppk17), bees and ants (6-9) had the smallest ones. The expansions identified inM. domesticaandBl. germanicaalso show promise as specific targets for controlling these nuisance insects. Our phylogenetic analysis revealed a subset of prevalent PPKs across insect genomes, suggesting a very conserved function that resembles the case ofantennalionotropic receptors. Finally, we identified new highly conserved residues in the second transmembrane domain that may be key for receptor function. Besides, more than a hundred PPK sequences presented calmodulin binding motifs, suggesting that at least some members of this family may amplify sensory responses as previously proposed forD. melanogaster ppk25. Overall, our study is a first attempt to characterize the evolutionary history of this family of sensory receptors, revealing relevant unknown features and clade-specific expansions.
A stochastic model of hippocampal synaptic plasticity with geometrical readout of enzyme dynamics
Authors: Rodrigues Yuri Elias , Tigaret Cezar , Marie Hélène , O’Donnell Cian , Veltz Romain 
Published: March 2021

AbstractDiscovering the rules of synaptic plasticity is an important step for understanding brain learning. Existing plasticity models are either 1) top-down and interpretable, but not flexible enough to account for experimental data, or 2) bottom-up and biologically realistic, but too intricate to interpret and hard to fit to data. To avoid the shortcomings of these approaches, we present a new plasticity rule based on a geometrical readout mechanism that flexibly maps synaptic enzyme dynamics to predict plasticity outcomes. We apply this readout to a multi-timescale model of hippocampal synaptic plasticity induction that includes electrical dynamics, calcium, CaMKII and calcineurin, and accurate representation of intrinsic noise sources. Using a single set of model parameters, we demonstrate the robustness of this plasticity rule by reproducing nine publishedex vivoexperiments covering various spike-timing and frequency-dependent plasticity induction protocols, animal ages, and experimental conditions. Our model also predicts thatin vivo-like spike timing irregularity strongly shapes plasticity outcome. This geometrical readout modelling approach can be readily applied to other excitatory or inhibitory synapses to discover their synaptic plasticity rules.
Can good broiler flock welfare prevent colonization byCampylobacter?
Authors: Rawson Thomas , Colles Frances M. , Smith Adrian L. , Dawkins Marian Stamp , Bonsall Michael B. 
Published: March 2021

ABSTRACTUsing data on rearing and welfare metrics of multiple commercial broiler flocks from the last ten years, we investigate how welfare measures such as hock burn, mortality, weight, and pododermatitis, among others, impact the likelihood of a flock becoming colonized byCampylobacter. Using both logistic regression and Bayesian networks, we show that, while some welfare metrics were weakly related toCampylobactercolonization, evidence could not be found to suggest that these metrics actively exacerbatedCampylobactercolonization, rather that they were both symptoms of the same underlying cause. Instead, observed dependency on the management of the flock suggested that yet-undiscovered differences in rearing practise were the principal cause of both poor bird welfare and increased risk ofCampylobacter, suggesting that action can be taken to improve both these factors simultaneously.
Plant Metabolic Network: A multi-species resource of plant metabolic information
Authors: Hawkins Charles , Ginzburg Daniel , Zhao Kangmei , Dwyer William , Xue Bo , Xu Angela , Rice Selena , Cole Benjamin , Paley Suzanne , Karp Peter , Rhee Seung Yon 
Published: March 2021

AbstractPlant metabolism is a pillar of our ecosystem, food security, and economy. To understand and engineer plant metabolism, we first need a comprehensive and accurate annotation of all metabolic information across plant species. As a step towards this goal, we previously created the Plant Metabolic Network (PMN), an online resource of curated and computationally predicted information about the enzymes, compounds, reactions, and pathways that make up plant metabolism. Here we report PMN 15, which contains genome-scale metabolic pathway databases of 126 algal and plant genomes, ranging from model organisms to crops to medicinal plants, and new tools for analyzing and viewing metabolism information across species and integrating omics data in a metabolic context. We systematically evaluated the quality of the databases, which revealed that our semi-automated validation pipeline dramatically improves the quality. We then compared the metabolic content across the 126 organisms using multiple correspondence analysis and found that Brassicaceae, Poaceae, and Chlorophyta appeared as metabolically distinct groups. To demonstrate the utility of this resource, we used recently published sorghum transcriptomics data to discover previously unreported trends of metabolism underlying drought tolerance. We also used single-cell transcriptomics data from theArabidopsisroot to infer cell-type specific metabolic pathways. This work shows the continued growth and refinement of the PMN resource and demonstrates its wide-ranging utility in integrating metabolism with other areas of plant biology.One-sentence SummaryThe Plant Metabolic Network is a collection of databases containing experimentally-supported and predicted information about plant metabolism spanning many species.
Arrayed multicycle drug screens identify broadly acting chemical inhibitors for repurposing against SARS-CoV-2
Authors: Murer Luca , Volle Romain , Andriasyan Vardan , Meili Nicole , Yang Liliane , Sequeira Daniela , Gomez-Gonzalez Afonso , Petkidis Anthony , Olszewski Dominik , Bauer Michael , Suomalainen Maarit , Kuttler Fabien , Turcatti Gerardo , Greber Urs F. 
Published: March 2021

AbstractCoronaviruses (CoVs) circulate in humans and animals, and expand their host range by zoonotic and anthroponotic transmissions. Endemic human CoVs, such as 229E and OC43 cause limited respiratory disease, and elicit short term anti-viral immunity favoring recurrent infections. Yet, severe acute respir-atory syndrome (SARS)-CoV-2 spreads across the globe with unprecedented impact on societies and economics. The world lacks broadly effective and affordable anti-viral agents to fight the pandemic and reduce the death toll. Here, we developed an image-based multicycle replication assay for focus for-mation of α-coronavirus hCoV-229E-eGFP infected cells for screening with a chemical library of 5440 compounds arrayed in 384 well format. The library contained about 39% clinically used compounds, 26% in phase I, II or III clinical trials, and 34% in preclinical development. Hits were counter-selected against toxicity, and challenged with hCoV-OC43 and SARS-CoV-2 in tissue culture and human bronchial and nasal epithelial explant cultures from healthy donors. Fifty three compounds inhibited hCoV-229E-GFP, 39 of which at 50% effective concentrations (EC50) < 2μM, and were at least 2-fold separated from toxicity. Thirty nine of the 53 compounds inhibited the replication of hCoV-OC43, while SARS-CoV-2 was inhibited by 11 compounds in at least two of four tested cell lines. Six of the 11 compounds are FDA-approved, one of which is used in mouth wash formulations, and five are systemic and orally available. Here, we demonstrate that methylene blue (MB) and mycophenolic acid (MPA), two broadly available low cost compounds, strongly inhibited shedding of infectious SARS-CoV-2 at the apical side of the cultures, in either pre- or post-exposure regimens, with somewhat weaker effects on viral RNA release indicated by RT-qPCR measurements. Our study illustrates the power of full cycle screens in repurposing clinical compounds against SARS-CoV-2. Importantly, both MB and MPA reportedly act as immunosuppressants, making them interesting candidates to counteract the cytokine storms affecting COVID-19 patients.
The long non-coding RNAMaTAR20promotes mammary tumor growth by regulating angiogenesis pathways
Authors: Diermeier Sarah D. , Chang Kung-Chi , Frewen Ashleigh , Taaffe Padraig , Grans Joke C. , Xiong Haoyu , Benz Brian A. , Russo Suzanne , Nowak Dawid , Hearn Stephen , Yu Allen , Wilkinson John E. , Rigo Frank , Spector David L. 
Published: March 2021

AbstractLong non-coding RNAs (lncRNAs) are an emerging class of regulatory molecules that have been shown to play important roles in tumorigenesis and cancer progression. Here, we studied the recently identified lncRNAMammary Tumor Associated RNA 20(MaTAR20) in mammary cancer progression. A CRISPR/Cas9 knockout ofMaTAR20in the metastatic 4T1 cell line led to reduced cancer cell proliferation and increased cell surface adhesion compared to control cells. Consistent with these knockout results antisense oligonucleotide (ASO) mediated knockdown ofMaTAR20resulted in reduced growth and invasion in 4T1 cells, and in primary mammary tumor organoids derived from the MMTV-PyMT mouse model of breast cancer. Injection ofMaTAR20-specific ASOs subcutaneously into tumor bearing MMTV-PyMT mice resulted in smaller and highly necrotic tumors in comparison to mice injected with a scrambled control ASO. To investigate the molecular mechanism by whichMaTAR20acts to advance mammary tumor progression, we applied a combination of RNA-sequencing and RNA-pulldown coupled to DNA-sequencing. These analyses demonstrated that the nuclear retained lncRNA is associated with several essential cancer signaling pathways such as VEGF signaling. In particular,MaTAR20directly binds to and regulates the expression ofTnfsf15. Our results indicate thatMaTAR20is an important driver of mammary tumor progression and represents a promising new therapeutic target.
Novel insights in the pathophysiology of α-synuclein dysregulation on D2 receptor activity contributing to the vulnerability of dopamine neurons
Authors: Dagra Abeer , Miller Douglas R. , Shaerzadeh Fatemeh , Lin Min , Gopinath Adithya , Harris Sharonda , Sorrentino Zachary A. , Velasco Sophia , Alonge Adetola R , Azar Janelle , Lebowitz Joe J , Ulm Brittany , Bu Anthea-Mengfei , Hansen Carissa A. , Urs Nikhil , Giasson Benoit I. , Khoshbouei Habibeh 
Published: March 2021

AbstractPathophysiological damages and loss of function of dopamine neurons precedes their demise and contributes to the early phases of Parkinson’s disease. The presence of aberrant intercellular pathological inclusions of the protein α-synuclein within ventral midbrain dopaminergic neurons is one of the cardinal features of Parkinson’s disease. We employed multiple complementary approaches in molecular biology, electrophysiology, and live-cell imaging to investigate how excessive α-synuclein levels alters multiple characteristics of dopaminergic neuronal dynamics and dopamine transmission prior to neuronal demise. These studies demonstrate that α-synuclein dysregulation of D2 receptor autoinhibition contributes to the vulnerability of dopaminergic neurons, and that modulation thereof can ameliorate the resulting pathophysiology. These novel findings provide mechanistic insights in the insidious loss of dopaminergic function and neurons that characterize Parkinson’s disease progression with significant therapeutic implications.
Dopamine facilitates fear memory formation in the human amygdala
Authors: Frick Andreas , Björkstrand Johannes , Lubberink Mark , Eriksson Allison , Fredrikson Mats , Åhs Fredrik 
Published: March 2021

ABSTRACTLearning which environmental cues that predict danger is crucial for survival and accomplished through Pavlovian fear conditioning. In humans and rodents alike, fear conditioning is amygdala-dependent and rests on similar neurocircuitry. Rodent studies have implicated a causative role for dopamine in the amygdala during fear memory formation, but the role of dopamine in aversive learning in humans is unclear. Here, we show dopamine release in the amygdala and striatum during fear learning in humans. Using simultaneous positron emission tomography and functional magnetic resonance imaging, we demonstrate that the amount of dopamine release is linked to strength of conditioned fear responses and linearly coupled to learning-induced memory trace activity in the amygdala. Thus, like in rodents, formation of amygdala-dependent fear memories in humans seems to be facilitated by endogenous dopamine release, supporting an evolutionary conserved neurochemical mechanism for aversive memory formation.
Estimating smooth and sparse neural receptive fields with a flexible spline basis
Authors: Huang Ziwei , Ran Yanli , Euler Thomas , Berens Philipp 
Published: March 2021

ABSTRACTSpatio-temporal receptive field (STRF) models are frequently used to approximate the computation implemented by a sensory neuron. Typically, such STRFs are assumed to be smooth and sparse. Current state-of-the-art approaches for estimating STRFs based empirical Bayes estimation encode such prior knowledge into a prior covariance matrix, whose hyperparameters are learned from the data, and thus provide STRF estimates with the desired properties even with little or noisy data. However, empirical Bayes methods are often not computationally efficient in high-dimensional settings, as encountered in sensory neuroscience. Here we pursued an alternative approach and encode prior knowledge for estimation of STRFs by choosing a set of basis function with the desired properties: a natural cubic spline basis. Our method is computationally efficient, and can be easily applied to Linear-Gaussian and Linear-Nonlinear-Poisson models as well as more complicated Linear-Nonlinear-Linear-Nonlinear cascade model or spike-triggered clustering methods. We compared the performance of spline-based methods to no-spline ones on simulated and experimental data, showing that spline-based methods consistently outperformed the no-spline versions. We provide a Python toolbox for all suggested methods (https://github.com/berenslab/RFEst/).
Perceptual and Semantic Representations at Encoding Contribute to True and False Recognition of Objects
Authors: Naspi Loris , Hoffman Paul , Devereux Barry , Morcom Alexa 
Published: March 2021

AbstractWhen encoding new episodic memories, visual and semantic processing are proposed to make distinct contributions to accurate memory and memory distortions. Here, we used functional magnetic resonance imaging (fMRI) and representational similarity analysis to uncover the representations that predict true and false recognition of unfamiliar objects. Two semantic models captured coarse-grained taxonomic categories and specific object features, respectively, while two perceptual models embodied low-level visual properties. Twenty-eight female and male participants encoded images of objects during fMRI scanning, and later had to discriminate studied objects from similar lures and novel objects in a recognition memory test. Both perceptual and semantic models predicted true memory. When studied objects were later identified correctly, neural patterns corresponded to low-level visual representations of these object images in the early visual cortex, lingual, and fusiform gyri. In a similar fashion, alignment of neural patterns with fine-grained semantic feature representations in the fusiform gyrus also predicted true recognition. However, emphasis on coarser taxonomic representations predicted forgetting more anteriorly in ventral anterior temporal lobe, left perirhinal cortex, and left inferior frontal gyrus. In contrast, false recognition of similar lure objects was associated with weaker visual analysis posteriorly in early visual and left occipitotemporal cortex. The results implicate multiple perceptual and semantic representations in successful memory encoding and suggest that fine-grained semantic as well as visual analysis contributes to accurate later recognition, while processing visual image detail is critical for avoiding false recognition errors.Significance StatementPeople are able to store detailed memories of many similar objects. We offer new insights into the encoding of these specific memories by combining fMRI with explicit models of how image properties and object knowledge are represented in the brain. When people processed fine-grained visual properties in occipital and inferior temporal cortex, they were more likely to be recognize the objects later, and less likely to falsely recognize similar objects. In contrast, while object-specific feature representations in fusiform predicted accurate memory, coarse-grained categorical representations in frontal and temporal regions predicted forgetting. The data provide the first direct tests of theoretical assumptions about encoding true and false memories, suggesting that semantic representations contribute to specific memories as well as errors.
An ammonium transporter is a non-canonical olfactory receptor for ammonia
Authors: Vulpe Alina , Kim Hyong S. , Ballou Sydney , Wu Shiuan-Tze , Grabe Veit , Gonzales Cesar Nava , Sachse Silke , Jeanne James M , Su Chih-Ying , Menuz Karen 
Published: March 2021

SummaryTwo families of ligand-gated ion channels function as olfactory receptors in insects. Here, we show that these canonical olfactory receptors are not necessary for responses to ammonia, a key ecological odor that is attractive to many insects including disease vectors and agricultural pests. Instead, we show that a member of the ancient electrogenic ammonium transporter family, Amt, is a new type of olfactory receptor. We report two hitherto unidentified olfactory neuron populations that mediate neuronal and behavioral responses to ammonia. Their endogenous ammonia responses are Amt-dependent, and ectopic expression of eitherDrosophilaorAnophelesAmt confers ammonia sensitivity. Amt is the first transporter known to function as an olfactory receptor in animals, and its role may be conserved across insect species.