bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of a throat spray with lactobacilli in COVID-19 outpatients in a randomized, double-blind, placebo-controlled trial for symptom and viral load reduction
Authors: De Boeck Ilke , Cauwenberghs Eline , Spacova Irina , Gehrmann Thies , Eilers Tom , Delanghe Lize , Wittouck Stijn , Bron Peter A. , Henkens Tim , Gamgami Imane , Simons Alix , Claes Ingmar , Mariën Joachim , Ariën Kevin K. , Bakokimi Diana , Loens Katherine , Jacobs Kevin , Ieven Margareta , Bruijning-Verhagen Patricia , Delputte Peter , Coenen Samuel , Verhoeven Veronique , Lebeer Sarah 
Published: March 2022

AbstractObjectivesPrimary care urgently needs treatments for COVID-19 patients because current options are limited, while these patients account for more than 90% of the people infected with SARS-CoV-2.MethodsWe evaluated a throat spray containing three Lactobacillaceae strains with broad antiviral properties in a randomized double-blind placebo-controlled trial. Seventy-eight eligible COVID-19 patients were randomized to verum (n=41) and placebo (n=37) within 96 hours of positive PCR-based SARS-CoV-2 diagnosis and per-protocol analysis was performed. Symptoms and severity were reported daily via an online diary. Combined nose-throat swabs and dried blood spots were collected at regular time points in the study.ResultsThe daily reported symptoms were highly variable, with no added benefit for symptom resolution in the verum group. Specific monitoring of the applied lactobacilli strains showed that they were detectable via microbiome (27%) and qPCR analysis (82%) of the verum group. Their relative abundances were also negatively correlated with the acute symptom score. At the end of the trial, a trend towards lower SARS-CoV-2 viral loads was observed for the verum group (2/30, 6.7% positive) compared to the placebo group (7/27, 26% positive) (p = 0.07).ConclusionsDespite a trend towards lower SARS-CoV-2 viral loads at the end of the trial and a negative correlation between relative abundances of the applied lactobacilli in the microbiome and acute symptoms, we did not observe a significant effect on overall symptom score for the verum group. This suggests that studies with earlier application of the spray in larger study populations are needed to further assess application potential.
Effectiveness of a positive deviant intervention to improve appropriate feeding practices and nutritional outcomes in West Omo Zone, Maji District: South West Region, Ethiopia: A study protocol for a cluster randomized control trial
Authors: Gizaw Abraham Tamirat , Sopory Pradeep , Sudhakar Morankar 
Published: March 2022

AbstractBackgroundNon-optimal infant and young child feeding practices (IYCFP) are linked to malnutrition and infant mortality in poor countries, notably in Ethiopia. The majority of growth stalls occur within the first two years of life; hence, there is a need to discover interventions that enhance appropriate IYCFP for improving nutritional outcomes during this critical period. Using the experience of mothers who have come up with solutions to their IYCFP problems to educate others is is a potential pathway to initiate and sustain behavioral changes in resource-limited areas. However, such interventions are not widely implemented in Ethiopia.ObjectiveThis study aims to assess the effectiveness of a positive deviant (hearth nutrition education) intervention to improve appropriate feeding practices and nutritional outcomes in West Omo Zone, Maji District: South West region, Ethiopia.MethodsA cluster randomized controlled trial will be conducted to compare the effect of positive deviant intervention versus routine health educationa. The intervention will be provided by positive deviant mothers who are members of the community using WHO infant and young child feeding guidelines, and “training of the trainers manual on counseling and supporting non-positive deviant mothers, infant and young child feeding” in the local language. Culturally appropriate and scientifically acceptable operational packages of information will be developed. Using preset criteria, 516 mothers will be recruited from 36 zones. The intervention arm will receive 12 demonstration (hearth) session in groups and every 15th day home visit by positive deviant mothers. Data will be entered into epi-data version 3.1 and analyzed using STATA version 13.0. All analyses will be done as intention-to-treat. We will fit mixed effects linear regression models for the continuous outcomes and mixed effects linear probability models for the binary outcomes with the study zone as random intercept to estimate study arm difference (intervention vs. routine health education) adjusted for baseline value of the outcome and additional relevant covariates.The protocol was developed in collaboration with the West Omo Zone and Maji Woreda Health Office. Ethical approval (Ref no: IHRPG/938/2020) was obtained from Jimma University, Institute of Health Research and Postgraduate Office. This study is funded by Jimma University research and postgraduate office.DiscussionWe expect that the trial will generate findings informing IYCFP and nutritional policies and practices in Ethiopia.Trial registrationRegistry: PACTR202108880303760 (30/08/2021); www.pactr.org, URL : https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=16081
Remote virtual reality assessment elucidates self-blame-related action tendencies in depression
Authors: Duan Suqian , Valmaggia Lucia , Fennema Diede , Moll Jorge , Zahn Roland 
Published: March 2022

AbstractDarwin stated that humans have a strong and involuntary tendency to perform certain actions when a specific state of mind is induced. Such “action tendencies” are key to understanding the maladaptive impact of self-blame-related feelings in depression. For example, feeling like “hiding” and “creating a distance from oneself” in a text-based task were previously associated with recurrence risk in remitted depression. Despite their functional importance, action tendencies have not been systematically investigated in current depression, which was the aim of this pre-registered study. To this end, we developed the first virtual reality (VR) assessment of blame-related action tendencies and compared current depression (n=98) with control participants (n=40). The immersive VR-task, pre-programmed on devices sent to participants’ homes, used hypothetical social interactions, in which either participants (self-agency) or their friend (other-agency) were described to have acted inappropriately. Good concurrent validity was demonstrated for VR-versus the text-based task. As predicted, compared with controls, people with depression showed a maladaptive profile: Particularly in the other-agency condition, rather than feeling like verbally attacking their friend, they were prone to feeling like hiding, and punishing themselves. The depression group showed a more pronounced slowing of response times in the other-versus the self-agency condition, which may reflect a stronger ambivalence about externalising blame in depression. Interestingly, feeling like punishing oneself was associated with a history of self-harm but not suicide attempts. Current depression and self-harm history were thus linked with distinctive motivational signatures, paving the way for remote VR-based stratification and treatment.General Scientific SummaryAs precursors of social actions, action tendencies, such as feeling like hiding when experiencing shame or guilt, provide the key link between depressive emotions and behaviour. Here, we developed a novel virtual reality task and used it in a large sample of people with depression to unveil a distinctive pattern of such action tendencies. As predicted, we found a maladaptive pattern of action tendencies in people with depression that were specifically associated with self-harm. Our findings thereby elucidate a so far unexplored key aspect of psychopathology in depression and provide important targets for the development of novel future psychological interventions tackling self-harm-related motivations and depression.
Spatio-temporal clusters and patterns of spread of dengue, chikungunya, and Zika in Colombia
Authors: Freitas Laís Picinini , Carabali Mabel , Yuan Mengru , Jaramillo-Ramirez Gloria I. , Balaguera Cesar Garcia , Restrepo Berta N. , Zinszer Kate 
Published: March 2022

AbstractBackgroundColombia has one of the highest burdens of arboviruses in South America. The country was in a state of hyperendemicity between 2014 and 2016, with co-circulation of severalAedes-borne viruses, including a syndemic of dengue, chikungunya, and Zika in 2015.Methodology/Principal FindingsWe analyzed the cases of dengue, chikungunya, and Zika notified in Colombia from January 2014 to December 2018 by municipality and week. The trajectory and velocity of spread was studied using trend surface analysis, and spatio-temporal high-risk clusters for each disease in separate and for the three diseases simultaneously (multivariate) were identified using Kulldorff’s scan statistics. During the study period, there were 66,628, 77,345 and 74,793 cases of dengue, chikungunya, and Zika, respectively, in Colombia. The spread patterns for chikungunya and Zika were similar, although Zika’s spread was accelerated. Both chikungunya and Zika mainly spread from the regions on the Atlantic coast and the south-west to the rest of the country. We identified 21, 16, and 13 spatio-temporal clusters of dengue, chikungunya and Zika, respectively, and, from the multivariate analysis, 20 spatio-temporal clusters, among which 7 were simultaneous for the three diseases. For all disease-specific analyses and the multivariate analysis, the most-likely cluster was identified in the south-western region of Colombia, including the Valle del Cauca department.Conclusions/SignificanceThe results further our understanding of emergingAedes-borne diseases’ trajectory in Colombia and provide useful information on the identified spatio-temporal disease-specific and multivariate clusters of dengue, chikungunya, and Zika, that can be used to target interventions. To our knowledge, this is the first time that the co-occurrence of all three diseases in Colombia was explored using multivariate scan statistics.
Comparative developmental genomics of sex-biased gene expression in early embryogenesis across mammals
Authors: Richardson Victorya , Zhang Kai , Engel Nora , Kulathinal Rob J 
Published: March 2022

ABSTRACTMammalian gonadal sex is determined by the presence or absence of a Y chromosome. In males, the Y chromosome initiates male gonadogenesis and the subsequent production of male-specific hormones defines the male state of each cell in the organism. In females, the lack of a Y chromosome and the presence of two X chromosomes triggers the development of female gonads, hormones, and cellular identity. However, sex chromosome-linked genes encoding dosage-sensitive transcription and epigenetic factors are expressed well before gonad formation and have the potential to establish sex-biased expression. Here, we apply a comparative bioinformatics analysis on published single-cell datasets from mouse and human during very early embryogenesis–from two-cell to preimplantation stages–to characterize sex-specific signals and to assess the degree of conservation among early-acting sex-specific genes and pathways. Clustering and regression analyses of gene expression across samples reveal that sex initially plays a significant role in overall gene expression patterns at the earliest stages of embryogenesis. In addition, gene expression signals from male and female gametes during fertilization may still be present. Although these transcriptional sex effects rapidly diminish, the sex-biased expression of epigenetic enzymes has the potential to establish sex-specific patterns that persist beyond preimplantation. Sex-biased genes appear to form sex-specific protein-protein interaction networks across preimplantation stages in both mammals. While the distribution of sex-differentially expressed genes (sexDEGs) in early embryonic stages are similar in mice and humans, the genes involved are generally different. Non-negative matrix factorization (NMF) on male and female transcriptomes generated clusters of genes with similar expression patterns across sex and developmental stages including post-fertilization, epigenetic, and preimplantation ontologies conserved between mouse and human. This comparative study uncovers much earlier than expected sex-specific signals in mouse and human embryos that pre-date hormonal signaling from the gonads. These early signals are diverged with respect to orthologs yet conserved in terms of function with important implications in the use of genetic models for sex-specific disease.
Symbolic quantitative cognition in wild zebrafish (Danio rerio)
Authors: Majeed Nawaf Abdul , Singh Dhairrya , Gopal Akshita Baiju , Battiwala Tanya , Kulshreshtha Ninaad , Mishra Rahulraj , Sabharwal Shagun , Behera Madhusmita , Sahu Manisha , Menon Ameya , Bungsut Lalchhanhimi , Walia Amiya , Saraf Raksha , Mathew Susan , Shah Ashumi , Kochhar Suhaavi , Salar Nivedita , Thakuri Sushmita , Sharma Yashant , Rampuria Nishtha , Bhattacharjee Anubhab , Wagh Niharika , Hegde Sahana , Bulhan Indira , Singh Gurasheesh , Rajaraman Bittu Kaveri 
Published: March 2022

AbstractZebrafish (Danio rerio) constitute an excellent model system to investigate the neural and genetic basis of quantitative cognition because of the single neuron resolution of calcium imaging of awake, behaving fish. While nonsymbolic numerical cognition has been investigated across many taxa, symbolic numerical cognition has not been investigated among fish. We developed a novel quantitative symbolic test for zebrafish using an operant conditioning paradigm in which the number of horizontal lines zebrafish approached in a 2-alternative forced choice task predicted the number of food reward pellets they would receive. Zebrafish did not at the population level learn a preference for the 2-line stimulus predictive of receiving 2 food pellets. However, they performed significantly above chance in a nonsymbolic discrimination task with the same apparatus, in which the 2-line stimulus was associated with the same reward but the choice of the 1-line stimulus was not rewarded. We also explored the explanatory value of alternative spatial learning hypotheses such as a Win-Stay, Lose-Shift (WSLS) strategy at the individual level for fish in navigating these spatially randomised tasks. The implications of this for symbolic versus nonsymbolic quantitative cognition in this model system are discussed relative to reward type and stimulus modality.
Transcellular chaperone signaling is an intercellular stress-response distinct from the HSF-1 mediated HSR
Authors: Miles Jay , Townend Sarah , Smith William , Westhead David R. , van Oosten-Hawle Patricija 
Published: March 2022

AbstractOrganismal proteostasis is maintained by intercellular signaling processes including cell nonautonomous stress responses such as transcellular chaperone signaling (TCS). When TCS is activated upon tissue-specific knockdown of hsp-90 in the C. elegans intestine, heat-inducible hsp-70 is induced in muscle cells at the permissive temperature resulting in increased heat stress resistance and lifespan extension. However, our understanding of the molecular mechanism and signaling factors mediating transcellular activation of hsp-70 expression from one tissue to another is still in its infancy. Here we conducted a combinatorial approach using transcriptome RNA-Seq profiling and a forward genetic mutagenesis screen to elucidate how stress-signaling from the intestine to the muscle is regulated. We find that the TCS-mediated “gut-to-muscle” induction of hsp-70 expression is suppressed by HSF-1 and instead relies on transcellular-X-cross-tissue (txt) genes. We identify a key role for the PDZ-domain guanylate cyclase txt-1 and the homeobox transcription factor ceh-58 as signaling hubs in the stress receiving muscle cells to initiate hsp-70 expression and facilitate TCS-mediated heat stress resistance and lifespan extension. Our results provide a new view on cell-nonautonomous regulation of “inter-tissue” stress responses in an organism that highlight a key role for the gut. Our data suggest that the HSF-1-mediated HSR is switched off upon TCS activation, in favor of an intercellular stress-signaling-route to safeguard survival.
DENVIS: scalable and high-throughput virtual screening using graph neural networks with atomic and surface protein pocket features
Authors: Krasoulis Agamemnon , Antonopoulos Nick , Pitsikalis Vassilis , Theodorakis Stavros 
Published: March 2022

AbstractComputational methods for virtual screening can dramatically accelerate early-stage drug discovery by identifying potential hits for a specified target. Docking algorithms traditionally use physics-based simulations to address this challenge by estimating the binding orientation of a query protein-ligand pair and a corresponding binding affinity score. Over the recent years, classical and modern machine learning architectures have shown potential for outperforming traditional docking algorithms. Nevertheless, most learning-based algorithms still rely on the availability of the protein-ligand complex binding pose, typically estimated via docking simulations, which leads to a severe slowdown of the overall virtual screening process. A family of algorithms processing target information at the amino acid sequence level avoid this requirement, however at the cost of processing protein data at a higher representation level. We introduce deep neural virtual screening (DENVIS), an end-to-end pipeline for virtual screening using graph neural networks (GNNs). By performing experiments on two benchmark databases, we show that our method performs competitively to several docking-based, machine learning-based, and hybrid docking/machine learning-based algorithms. By avoiding the intermediate docking step, DENVIS exhibits several orders of magnitude faster screening times (i.e., higher throughput) than both docking-based and hybrid models. When compared to an amino acid sequence-based machine learning model with comparable screening times, DENVIS achieves dramatically better performance. Some key elements of our approach include protein pocket modelling using a combination of atomic and surface features, the use of model ensembles, and data augmentation via artificial negative sampling during model training. In summary, DENVIS achieves competitive to state-of-the-art virtual screening performance, while offering the potential to scale to billions of molecules using minimal computational resources.Graphical TOC Entry
EXONIZATION BY THE EMERGENCE OF A CLEAVAGE-POLYADENYLATION SITE
Authors: Méreau Agnès , Lerivray Hubert , Viet Justine , Hardy Serge , Paillard Luc , Audic Yann 
Published: March 2022

ABSTRACTExonization is the evolutionary process of recruitment of new exonic regions from previously intronic regions. It is a major contributor to the increased complexity of alternative splicing. Here, we explore exonization mediated by the emergence of a novel cleavage-polyadenylation site in an intron. In Xenopus laevis, the tpm1 gene, which encodes muscular tropomyosin, contains alternative terminal exons. In adult muscles and embryonic hearts, exon 9A is joined to the terminal exon 9B. In embryonic somites, it is joined to the exonic region 9’, which is transcribed from the intron immediately downstream of exon 9A. Consequently, exon 9A is either an internal exon when ligated to exon 9B, or a part of a terminal exon along with region 9’. We show here that region 9’ is present only in amphibians and coelacanths. This suggests that it emerged in sarcopterygians and was lost in amniotes. We used antisense morpholino oligonucleotides to mask the regions of tpm1 pre-mRNA that potentially regulate the inclusion of exon 9A9’. This revealed that the definition of exon 9A9’ relies on a weak cleavage-polyadenylation site and an intronic enhancer, but is independent of the 3’ splice site. We demonstrate that RNAs containing exon 9B are toxic in somites. This may have contributed to the evolutionary pressure that led to the exonization of region 9’ in sarcopterygians. These findings reveal the emergence of a novel cleavage-polyadenylation site that avoids the accumulation of a toxic RNA as a novel mechanism for exonization-mediated diversification of terminal exons.
Fate mapping melanoma persister cells through regression and into recurrent disease in adult zebrafish
Authors: Travnickova Jana , Muise Sarah , Wojciechowska Sonia , Brombin Alessandro , Zeng Zhiqiang , Young Adelaide I.J. , Wyatt Cameron , Patton E. Elizabeth 
Published: March 2022

AbstractMelanoma heterogeneity and plasticity underlie therapy resistance. Some tumour cells possess innate resistance, while others reprogramme during drug exposure and survive to form persister cells, a source of potential cancer cells for recurrent disease. Tracing individual melanoma cell populations through tumour regression and into recurrent disease remains largely unexplored, in part, because complex animal models are required for live imaging of cell populations over time. Here, we apply tamoxifen-inducible creERt2/loxP lineage tracing to a zebrafish model of MITF-dependent melanoma regression and recurrence to image and trace cell populations in vivo through disease stages. Using this strategy, we show that melanoma persister cells at the minimal residual disease site originate from the primary tumour. Next, we fate mapped rare MITF-independent persister cells and demonstrate that these cells directly contribute to progressive disease. Multiplex immunohistochemistry confirmed MITF-independent persister cells give rise to Mitfa+ cells in recurrent disease. Taken together, our work reveals a direct contribution of persister cell populations to recurrent disease, and provides a resource for lineage tracing methodology in adult zebrafish cancer models.Summary statementWe fate map melanoma cells from the primary tumour into a persister cell state and show that persister cells directly contribute to recurrent disease.
Identification of minor alleles associated with reduced lodging in tef (Eragrostis tef)
Authors: Ben-Zeev Shiran , Hellwig Timo , Demeile Muluken , Barak Vered , Vorobyova Sasha , Hübner Sariel , Saranga Yehoshua 
Published: March 2022

AbstractRationalUnderutilized species that are not widely cultivated (known as orphan crops) present opportunities to increase crop diversity and food security. Tef [Eragrostis tef (Zucc.) Trotter] is known for its high-quality grain and forage. Root-borne lodging is a major devastating problem in tef cultivation, leading to large economic losses and limiting its widespread adoption.ObjectiveThe aim of this study was to identify genomic regions that are associated with tef lodging.MethodsA tef diversity panel (TDP-300) comprised of 297 lines was assembled, genotyped, and phenotyped across 4 field environments. This unique panel, the first of its kind in tef, has the potential to facilitate tef research and breeding.ResultsGenome-wide association study identified 29 sites associated with lodging; in all cases with a minor allele conferring reduced lodging. The eleven sites of prime interest were located in or near genes, 5 of them with a putative role, of which 3 were found to be involved root development.ConclusionsThe identification of lodging-related sites in the current study may advance understanding of the mechanisms underlying tef lodging and crop improvement. The identification of genes related to root development support the importance of root traits in tef lodging, which should be targeted in future breeding.