bluuebunny/crossref_metadata_2025_split huggingface dataset:
Patterns of evolution of TRIM genes highlight the evolutionary plasticity of antiviral effectors in mammals
Authors: Fernandes Alexandre P. , OhAinle Molly , Esteves Pedro J. 
Published: May 2023

AbstractThe innate immune system of mammals is formed by a complex web of interacting proteins, which together constitute the first barrier of entry for infectious pathogens. Genes from the E3-ubiquitin ligase tripartite motif (TRIM) family have been shown to play an important role in the innate immune system by restricting the activity of different retrovirus species. For example, TRIM5 and TRIM22, have both been associated with HIV restriction, and are regarded as crucial parts of the antiretroviral machinery of mammals. Our analyses of positive selection corroborate the great significance of these genes for some groups of mammals. However, we also show that many organisms lack TRIM5 and TRIM22 altogether. By analyzing a large number of mammalian genomes, here we provide the first comprehensive view of the evolution of these genes in eutherians, showcasing that the pattern of accumulation of TRIM genes has been dissimilar across mammalian orders. Our data suggests that these differences are caused by evolutionary plasticity of the immune system of eutherians, which have adapted to use different strategies to combat retrovirus infections. Altogether, our results provide insights into the dissimilar evolution of a representative family of restriction factors, highlighting a great example of adaptive and idiosyncratic evolution in the innate immune system.
Orphan Drugs and Rare Diseases: Unveiling Biological Patterns through Drug Repurposing
Authors: Otero-Carrasco Belén , Romero-Brufau Santiago , Álvarez-Pérez Andrea , Ayuso-Muñoz Adrián , Prieto-Santamaría Lucía , Hernández Juan Pedro Caraça-Valente , Rodríguez-González Alejandro 
Published: May 2023

AbstractRare diseases are a collection of unusual pathologies that afflict millions of individuals globally. However, the creation of treatments for these conditions is frequently limited due to the high expenses and lack of profitability associated with drug development. Orphan drugs, which are medications specifically designed for rare diseases, have played a pivotal role in treating these diseases over the past several years. Nevertheless, their creation remains challenging, and many rare diseases lack approved therapies. Therefore, drug repurposing has emerged as a viable strategy for identifying potential new treatments for these pathologies, a technique consists in using existing drugs to treat a new disease different from the one that they were developed for. This approach can significantly reduce the time and cost of drug development while increasing the likelihood of success. In this paper, we examined the temporal progression of orphan drugs since their introduction and assess the impact of drug repositioning on treatments for rare diseases. Additionally, we aim to identify biological patterns that may be unique to rare diseases treated with repurposed orphan drugs. To this end, we analyzed various biological components associated with these diseases, categorized linked diseases, and obtained the type of orphan drug associated with them. Lastly, we evaluated the phenotypic similarity between diseases treated with an orphan drug through repurposing. Through these findings, we have gained insight into the evolution of orphan drug development in recent years and identified specific patterns that characterize rare diseases associated with them.
Comparison of online and offline applications of dual-site transcranial alternating current stimulation (tACS) on functional connectivity between pre-supplementary motor area (preSMA) and right inferior frontal gyrus (rIFG) for improving response inhibition
Authors: Fujiyama Hakuei , Williams Alexandra G. , Tan Jane , Levin Oron , Hinder Mark R. 
Published: May 2023

AbstractBackgroundThe efficacy of transcranial alternating current stimulation (tACS) is thought to be brain state-dependent, such that tACS during task performance would be hypothesised to offer greater potential for inducing beneficial electrophysiological changes in the brain and associated behavioural improvement compared to tACS at rest. However, to date, no empirical study has directly tested this postulation.ObjectiveHere we compared the effects of tACS applied during a stop signal task (online) to the effects of the same tACS protocol applied prior to the task (offline) and a sham control stimulation.MethodsA total of 53 young, healthy adults (32 female; 18-35 yrs) received dual-site beta tACS over the right inferior frontal gyrus (rIFG) and pre-supplementary motor area (preSMA), which are thought to play critical roles in action cancellation, with phase-synchronised stimulation for 15 min with the aim of increasing functional connectivity.ResultsEEG connectivity analysis revealed significantly increased task-related functional connectivity following online but not offline tACS. Correlation analyses suggested that an increase in functional connectivity in the beta band at rest following online tACS was associated with an improvement in response inhibition. Interestingly, despite the lack of changes in functional connectivity at the target frequency range following offline tACS, significant improvements in response inhibition were still observed, suggesting offline tACS may still be efficacious in inducing behavioural changes, likely via a post-stimulation early plasticity mechanism.ConclusionOverall, the results indicate that online and offline dual-site beta tACS are beneficial in improving inhibitory control via distinct underlying mechanisms.
Concordance of weight status between mothers and children: A secondary analysis of the Pakistan Demographic and Health Survey VII
Authors: Alam Faiz , Ali Mohammed K. , Patel Shivani A. , Iqbal Romaina 
Published: May 2023

AbstractFamilial concordance of nutritional status is an emerging field of study that may guide the development of interventions that operate beyond the individual and within the family context. Little published data exist for concordance of nutritional status within Pakistani households. We assessed the associations between weight status of mothers and their children in a nationally representative sample of households in Pakistan using Demographic and Health Survey data. Our analysis included 3465 mother-child dyads, restricting to children under-five years of age with body mass index (BMI) information on their mothers. We used linear regression models to assess the associations between maternal BMI category (underweight, normal weight, overweight, obese) and child’s weight-for-height z-score (WHZ), accounting for socio-demographic characteristics of mothers and children. We assessed these relationships in all children under-five and also stratified by age of children (younger than 2 years and 2 to 5 years). In all children under-five and in children 2 to 5 years, maternal BMI was positively associated with child’s WHZ, while there was no association between maternal BMI and child WHZ for children under-two. The findings indicate that the weight status of mother’s is positively associated with that of their children. These associations have implications for interventions aimed at healthy weights of families.
Exploring Factors Affecting the Adoption and Continuance Usage of Drone in Healthcare: The Role of the Environment
Authors: Marfo John Serbe , Asamoah Pasty , Owusu-Bio Matilda Kokui , Asare Marfo Afia Frimpomaa , Kyeremeh Kwadwo 
Published: May 2023

ABSTRACTDrone technologies and healthcare delivery have attracted scholarly attention over the years. Studies have acknowledged the positive impact of the adoption and usage of drone technologies for healthcare delivery. We argue however that, knowledge is lacking on the role of the environment in drone technologies adoption, usage and continuance usage. An examination of 330 health facilities that engage in the use of drone services from Zipline Ghana showed that the environment inversely moderates the relationship between actual usage and intention to continue usage, suggesting that reducing the influence of environmental factors will increase the impact actual usage has on the continuance usage of drone technology in healthcare delivery.
Long-read sequencing and profiling of RNA-binding proteins reveals the pathogenic mechanism of aberrant splicing of anSCN1Apoison exon in epilepsy
Authors: Happ Hannah C , Schneider Patricia N , Hong Jung Hwa , Goes Eleanor , Bandouil Masha , Biar Carina G. , Ramamurthy Aishwarya , Reese Fairlie , Engel Krysta , Weckhuysen Sarah , Scheffer Ingrid E , Mefford Heather C , Calhoun Jeffrey D , Carvill Gemma L 
Published: May 2023

AbstractPathogenic loss-of-functionSCN1Avariants cause a spectrum of seizure disorders. We previously identified variants in individuals withSCN1A-related epilepsy that fall in or near a poison exon (PE) inSCN1Aintron 20 (20N). We hypothesized these variants lead to increased PE inclusion, which introduces a premature stop codon, and, therefore, reduced abundance of the full-lengthSCN1Atranscript and Nav1.1 protein. We used a splicing reporter assay to interrogate PE inclusion in HEK293T cells. In addition, we used patient-specific induced pluripotent stem cells (iPSCs) differentiated into neurons to quantify 20N inclusion by long and short-read sequencing and Nav1.1 abundance by western blot. We performed RNA-antisense purification with mass spectrometry to identify RNA-binding proteins (RBPs) that could account for the aberrant PE splicing. We demonstrate that variants in/near 20N lead to increased 20N inclusion by long-read sequencing or splicing reporter assay and decreased Nav1.1 abundance. We also identified 28 RBPs that differentially interact with variant constructs compared to wild-type, including SRSF1 and HNRNPL. We propose a model whereby 20N variants disrupt RBP binding to splicing enhancers (SRSF1) and suppressors (HNRNPL), to favor PE inclusion. Overall, we demonstrate thatSCN1A20N variants cause haploinsufficiency andSCN1A-related epilepsies. This work provides insights into the complex control of RBP-mediated PE alternative splicing, with broader implications for PE discovery and identification of pathogenic PE variants in other genetic conditions.
Sex differences in the relationship between maternal and foetal glucocorticoids in a free-ranging large mammal
Authors: Amin Bawan , Fishman Ruth , Quinn Matthew , Matas Devorah , Palme Rupert , Koren Lee , Ciuti Simone 
Published: May 2023

AbstractMaternal phenotypes can have long-term effects on offspring phenotypes. These maternal effects may begin during gestation, when maternal glucocorticoid (GC) levels may affect foetal GC levels, thereby having an organizational effect on the offspring phenotype. Recent studies have showed that maternal effects may be different between the sexes. However, how maternal GC levels relate to foetal levels is still not completely understood. Here we related, for the first time in a free-ranging large mammal, the fallow deer (Dama dama), maternal GC levels with foetalin uteroGC levels. We did this in a non-invasive way by quantifying cortisol metabolites from faecal samples collected from pregnant does during late gestation, as proxy for maternal GC level. These were then related to GC levels from hair of their neonate offspring (n = 40). We have shown that maternal GC levels were positively associated with foetal GC levels, but only in female offspring. These findings highlight sex differences, which may have evolved to optimize male growth at the cost of survival.
Genetic basis of expression and splicing underlying spike architecture in wheat (Triticum aestivumL.)
Authors: Yang Guang , Pan Yan , Cui Licao , Chen Mingxun , Zeng Qingdong , Pan Wenqiu , Liang Zhe , Edwards Dave , Batley Jacqueline , Han Dejun , Deng Pingcheng , Yu Hao , Henry Robert J , Song Weining , Nie Xiaojun 
Published: May 2023

AbstractIntroductionWheat is one of the most important staple crops worldwide, and an important source of human protein and mineral element intake. Continuously increasing stable production of wheat is critical for global food security under the challenge of population growth and limited resource input.ObjectiveSpike architecture determines the potential grain yield of wheat. However, the mechanisms of transcriptional regulation of spike architecture in wheat remain largely unknown, limiting further genetic improvement of wheat yield. In this study we explored the genetic basis of spike architecture in wheat.MethodsPopulation RNA-seq methods were used to identify the eQTLs and sQTLs associated with spike architecture and applied this to dissection of the genetic basis of gene expression and splicing controlling these complex yield-related traits.ResultsIn total, 4,143 expression quantitative trait loci (eQTLs) and 12,933 splice QTLs (sQTLs) were identified in wheat based on 178 RNA-seq samples, revealing 774 cis-eQTLs and 321 cis-sQTLs for 86 eGenes and 73 sGenes, respectively. Integration of eQTLs and sQTLs with genome-wide association study (GWAS) identified dozens of additional novel candidate genes that may contribute to spike-related traits. Gene network analysis showed that eQTLs and sQTLs were widely involved in the co-expression modules that regulate wheat spike architecture. Notably, the eQTL locusAX-108754757regulated the expression of 5 eGenes that negatively controled grain number per spike.AX-111592099regulated both the splicing and expression ofTraesCS7B02G442100,encoding an E3 ubiquitin ligase, and playing a central role in regulating spike length.ConclusionThis study provides new insights into the genetic basis of spike architecture. This improved understanding of spike-related traits in wheat will contribute to more rapid genetic improvement.
Active and Allosteric Site Binding MOLECULAR MECHANICS-QUANTUM MECHANICS studies of STEVIOSIDE Derivative in PCSK9 Protein Intended to provide a safe Antilipidemic agent
Authors: Irfan N , Vaithyanathan Prakash , Anandaram Harishchander , Zaidh S Mohammed , Varshini S Priya , Puratchikody A 
Published: May 2023

ABSTRACTInteraction of low-density lipoprotein receptors with proprotein convertase subtilisin/ kexin type 9 (PCSK9) plays a vital role in causing atherosclerosis. It is the hidden precursor of clinical myocardial infarction (MI), stroke, CVD and estimates 60% of deaths worldwide. The current need is to design small molecules to prevent the interaction between PCSK9 with LDL receptors. This study aims to evaluate the PCSK9 antagonistic effect of a derivative of Stevioside (also referred as Methylidene tetracyclo derivative) and atorvastatin. Also, a comparative study was performed to analyze the binding interaction of molecules inside the active and allosteric sites of PCSK9. The RCSB downloaded protein 7S5H and above said ligands were optimized to the local minima energy level and docked inside the active and allosteric sites. The stability of non-bonded interaction of complex was analyzed using Desmond MD simulation studies. The results of docking showed that the Methylidene tetracyclo molecule possesses a two-fold higher affinity of -10.159 kcal/mol in the active site and -10.824 kcal/mol in the allosteric site. The Phe377 amino acid made the Methylidene tetracyclo molecule orient inside the active site. Nine H-bonds with 5 amino acids of allosteric site increase the binding affinity compared to Atorvastatin. The MD simulation studies exposed that the nonbonded interaction of Methylidene tetracyclo molecule was stable throughout 100ns. This confirms the Methylidene tetracyclo molecule will be the better hit as well as the lead molecule to inhibit PCSK9 protein.
Sea-ice melt determines seasonal phytoplankton dynamics and delimits the habitat of temperate Atlantic taxa as the Arctic Ocean atlantifies
Authors: Oldenburg Ellen , Popa Ovidiu , Wietz Matthias , von Appen Wilken-Jon , Torres-Valdes Sinhue , Bienhold Christina , Ebenhöh Oliver , Metfies Katja 
Published: May 2023

AbstractThe Arctic Ocean is one of the regions where anthropogenic environmental change is progressing most rapidly and drastically. The impact of rising temperatures and decreasing sea ice on Arctic marine microbial communities is yet not well understood. Microbes form the basis of food webs in the Arctic Ocean, providing energy for larger organisms. Previous studies have shown that Atlantic taxa associated with low light are robust to more polar conditions. In this study, we compared to which extent sea ice melt influences light-associated phytoplankton dynamics and biodiversity over two years at two mooring locations in the Fram Strait. One mooring is deployed in pure Atlantic water, and the second in the intermittently ice-covered Marginal Ice Zone. Time-series analysis of amplicon sequence variants abundance over a two-year period, allowed us to identify communities of co-occurring taxa that exhibit similar patterns throughout the annual cycle. We then examined how alterations in environmental conditions affect the prevalence of species. During high abundance periods of diatoms, polar phytoplankton populations dominated, while temperate taxa were weakly represented. Generally, polar pelagic and ice-associated taxa (such asFragilariopsis cylindrusorMelosira arctica) were more prevalent in Atlantic conditions whereas temperate taxa (such asOdontella auritaorProboscia alata) have limited potential to persist in colder ice-impacted waters. In contrast to previous assumptions, we think that sea-ice melt acts as a barrier to the horizontal extent of temperate diatoms by preventing their succession at places strongly influenced by polar conditions such as the melting sea ice.
FOXM1 expression reverts aging chromatin profiles through repression of the senescence-associated pioneer factor AP-1
Authors: Ferreira Fábio J. , Galhardo Mafalda , Teixeira Joana , Logarinho Elsa , Bessa José 
Published: May 2023

ABSTRACTAging is characterized by changes in gene expression that drive deleterious cellular phenotypes leading to senescence. The transcriptional activation of senescence genes has been mainly attributed to epigenetic shifts, but the changes in chromatin accessibility and its underling mechanisms remain largely elusive in natural aging. Here, we profiled chromatin accessibility in human dermal fibroblasts (HDFs) from neonatal and octogenarian individuals. We found that AP-1 binding motifs are prevalent in elderly specific accessible regions of the chromatin while neonatal-specific regions are highly enriched for TEAD binding motifs. We further show thatTEAD4andFOXM1share a conserved transcriptional regulatory landscape controlled by an age-dependent enhancer that closes with aging and drives senescence when deleted. Finally, we demonstrate thatFOXM1ectopic expression in elderly cells partially resets chromatin accessibility to a youthful state due to FOXM1 repressive function in the promoters of several members of the AP-1 complex. These results placeFOXM1at a top hierarchical level in chromatin remodeling required to prevent senescence.
Can motional dynamics account for the cytotoxicity of beta amyloid oligomers?
Authors: Yeh Chen-Tsen , Chang Han-Wen , Hsu Wen-Hsin , Huang Shing-Jong , Wu Meng-Hsin , Tu Ling-Hsien , Lee Ming-Che , Chung Chan Jerry Chun 
Published: May 2023

AbstractThe underlying biophysical principle governing the cytotoxicity of the oligomeric aggregates of β-amyloid (Aβ) peptides has long been an enigma. Here we show that the size of Aβ40oligomers can be actively controlled by incubating the peptides in reverse micelles. Our approach allowed for the first time a detailed comparison of the structures and dynamics of two Aβ40oligomers of different size, viz., 10 and 23 nm, by solid-state NMR. From the chemical shift data, we infer that the conformation of the residues from K16 to K28 are different between the 10-nm and 23-nm oligomers. We find that the 10-nm oligomers are more cytotoxic, and the molecular motions of their charged residues are more dynamic. Interestingly, the residue A21 exhibits an unusually high structural rigidity. Our data raise the interesting possibility that the cytotoxicity of Aβ40oligomers could also be correlated to the motional dynamics of the charged residues.
EXTRANEURAL RABIES VIRUS INFECTION LEADS TO TISSUE DAMAGE AND CELL DEATH IN MICE
Authors: Leal Rodrigues Érika D. , Pacheco da Silva Vinicius , Bastos Chaves Victor G. , de Sousa Moraes Cássia N. , de Souza Pereira Sara , Nogueira Lima André L. , Fernandes Barbosa Coelho Taciana , da Costa Vasconcelos Pedro F. , Ribeiro Cruz Ana C. , Medeiros Neves Casseb Livia 
Published: May 2023

ABSTRACTRabies, a fatal neurological disease caused byLyssavirus rabies(RABV), poses a significant threat to public health globally. Despite extensive studies on RABV-induced neuropathology, the involvement of extraneural organs during rabies pathogenesis and the tropisms of wild-type strains to different organs remain largely unknown. Here, we investigated the tropism of a dog and bat RABV variant to three different extraneural tissues (kidneys, lungs and liver) and characterized cellular and tissue damage associated with infection in mice over 30 days. Our results reveal that RABV may have a tropism for the kidneys and cause tissue-specific cellular damage. Furthermore, we propose that RABV spreads to extraneural tissues simultaneously with central nervous system (CNS) infection. Understanding the involvement of extraneural organs in rabies pathogenesis may contribute to the development of effective treatment strategies of this fatal disease.AUTHOR SUMMARYRabies is a lethal viral infection that targets the nervous system and generally can be transmitted to humans by bites of infected animals. While there has been significant research focused on how the virus damages the brain, little is known about how the infection affects other organs in the periphery. To address this knowledge gap, we conducted an experimental study to investigate the effects of two distinct wild strains of the virus, one isolated from dogs and the other from bats, on the lungs, liver, and kidneys in mice model of infection. Our findings suggest that the rabies virus infection leads to cell death and produces specific lesions in each of these organs, and we hypothesize that rabies virus may spread to these tissues at the same time as the brain, which possible contributes to the disease outcome. These findings enhance our understanding on how rabies virus targets organs outside the nervous system and its pathology in these different systems.
The salt-and-pepper pattern in mouse blastocysts is compatible with signalling beyond the nearest neighbours
Authors: Fischer Sabine C. , Schardt Simon , Lilao-Garzón Joaquín , Descalzo Silvia Muñoz 
Published: May 2023

SUMMARYEmbryos develop in a concerted sequence of spatio-temporal arrangements of cells. In the preimplantation mouse embryo, the distribution of the cells in the inner cell mass evolves from a salt-and-pepper pattern to spatial segregation of two distinct cell types. The exact properties of the salt-and-pepper pattern have not been analysed so far. We investigate the spatio-temporal distribution of NANOG and GATA6 expressing cells in the ICM of the mouse blastocysts with quantitative three-dimensional single cell-based neighbourhood analyses. A combination of spatial statistics and agent-based modelling reveals that the cell fate distribution follows a local clustering pattern. Using ordinary differential equations modelling, we show that this pattern can be established by a distance-based signalling mechanism enabling cells to integrate information from the whole inner cell mass into their cell fate decision. Our work highlights the importance of longer-range signalling to ensure coordinated decisions in groups of cells to successfully build embryos.