bluuebunny/crossref_metadata_2025_split huggingface dataset:
5’ tRNA halves are highly expressed in the primate hippocampus and sequence-specifically regulate gene expression
Authors: Jehn Julia , Treml Jana , Wulsch Svenja , Ottum Benjamin , Erb Verena , Hewel Charlotte , Kooijmans Roxana N. , Wester Laura , Fast Isabel , Rosenkranz David 
Published: September 2019

AbstractFragments of mature tRNAs have long been considered as mere degradation products without physiological function. However, recent reports show that tRNA fragments (tRFs) play prominent roles in diverse cellular processes across a wide spectrum of species. Contrasting the situation in other small RNA pathways the mechanisms behind these effects appear more diverse, more complex and are generally less well understood. In addition, surprisingly little is known about the expression profiles of tRFs across different tissues and species. Here, we provide an initial overview of tRF expression in different species and tissues, revealing very high tRF-levels particularly in the primate hippocampus. We further modulated the regulation capacity of selected tRFs in human cells by transfecting synthetic tRF mimics (“overexpression”) or antisense-RNAs (“inhibition”) and identified differentially expressed transcripts based on RNAseq. We then used a novel k-mer mapping approach to dissect the underlying targeting rules, demonstrating that 5’ tRNA halves (5’ tRHs) silence genes in a sequence-specific manner, while the most efficient target sites align to the mid-region of the 5’ tRH and are located within the CDS or 3’ UTR of the target. This amends previous observations that tRFs guide Argonaut proteins to silence their targets via a miRNA-like 5’ seed match and suggests a yet unknown mechanism of regulation. Finally, our data suggests that some 5’ tRHs are also able to sequence-specifically stabilize mRNAs as upregulated mRNAs are also significantly enriched for 5’ tRH target sites.
Loss of Piccolo function in rats induces Pontocerebellar Hypoplasia type 3-like phenotypes
Authors: Falck Joanne , Bruns Christine , Hoffmann Sheila , Straub Isabelle , Plautz Erik J. , Orlando Marta , Munawar Humaira , Rivalan Marion , Winter York , Izsvák Zsuzsanna , Schmitz Dietmar , Hamra F. Kent , Hallermann Stefan , Garner Craig , Ackermann Frauke 
Published: September 2019

AbstractPiccolo, a presynaptic active zone protein, is best known for its role in the regulated assembly and function of vertebrate synapses. Genetic studies suggest a further link to several psychiatric disorders as well as Pontocerebellar Hypoplasia type 3 (PCH3), although a causal relationship is lacking. We have characterized recently generated knockout (Pclogt/gt) rats. Analysis revealed a dramatic reduction in brain size compared to wildtype (Pclowt/wt) animals, attributed to a decrease in the size of the cerebral cortical, cerebellar and pontine regions. Analysis of the cerebellum and brainstem revealed a reduced granule cell (GC) layer and a reduction in size of pontine nuclei. Moreover, the maturation of mossy fiber (MF) afferents from pontine neurons and the expression of the α6 GABAA receptor subunit at the MF-GC synapse are perturbed, as well as the innervation of Purkinje cells by cerebellar climbing fibers (CFs). Ultrastructural and functional studies revealed a reduced size of MF boutons, with fewer synaptic vesicles and altered synaptic transmission. These data imply that Piccolo is required for the normal development, maturation and function of neuronal networks formed between the brainstem and cerebellum. Consistently, behavioral studies demonstrated that adult Pclogt/gt rats display impaired motor coordination, despite adequate performance in tasks that reflect muscle strength and locomotion. Together these data suggest that loss of Piccolo function in patients with PCH3 could be causal for many of the observed anatomical and behavioral symptoms, and that the further analysis of these animals could provide fundamental mechanistic insights into this devastating disorder.Significance StatementPontocerebellar Hypoplasia type 3 is a devastating developmental disorder associated with severe developmental delay, progressive microcephaly with brachycephaly, optic atrophy, seizures and hypertonia with hyperreflexia. Recent genetic studies have identified non-sense mutations in the coding region of the Piccolo gene, suggesting a functional link between this disorder and the presynaptic active zone. Our analysis of Piccolo knockout rats supports this hypothesis, formally demonstrating that anatomical and behavioral phenotypes seen in patients with PCH3 are also exhibited by these Piccolo deficient animals.
An agent-based model of molecular aggregation at the cell membrane
Authors: Griffié Juliette , Peters Ruby , Owen Dylan M. 
Published: September 2019

AbstractMolecular clustering at the plasma membrane has long been identified as a key process and is associated with regulating signalling pathways across cell types. Recent advances in microscopy, in particular the rise of super-resolution, have allowed the experimental observation of nanoscale molecular clusters in the plasma membrane. However, modelling approaches capable of recapitulating these observations are in their infancy, partly because of the extremely complex array of biophysical factors which influence molecular distributions and dynamics in the plasma membrane. We propose here a highly abstracted approach: an agent-based model dedicated to the study of molecular aggregation at the plasma membrane. We show that when molecules are modelled as though they can act (diffuse) in a manner which is influenced by their molecular neighbourhood, many of the distributions observed in cells can be recapitulated, even though such sensing and response is not possible for real membrane molecules. As such, agent-based offers a unique platform which may lead to a new understanding of how molecular clustering in extremely complex molecular environments can be abstracted, simulated and interpreted using simple rules.Author summaryMolecular aggregation in cell membranes is a key component of cellular machinery, involved across cell types in inter-cellular communication and signalling pathway initiation. As such, understanding the underlying mechanisms and molecule cluster characteristics at a more theoretical level is a pre-requisite. Complete descriptive molecular models have proven impossible to realise due to the overall complexity of the processes involved, highlighting the need for novel approaches. While conceptual models have been shown to be powerful tools and are routinely used in other fields with high level of complexity such as social sciences or economics, they are overall lacking from the literature when it comes to cell studies. We suggest in this work that the same principle applies to cell biology and in particular, the study of molecular clustering. We propose here a general model, independent of cell types or signalling pathways: an agent-based model dedicated to molecular clustering in the plasma membrane. We show we are able to recapitulate molecular aggregation similar to observations in cells while new properties are highlighted by our model, for instance, clustering is a digitised process.
GSDMAdrives the most replicated association with asthma in naïve CD4+T cells
Authors: Madore Anne-Marie , Pain Lucile , Boucher-Lafleur Anne-Marie , Meloche Jolyane , Morin Andréanne , Simon Marie-Michelle , Ge Bing , Kwan Tony , Cheung Warren A. , Pastinen Tomi , Laprise Catherine 
Published: September 2019

AbstractBackgroundThe 17q12-21 locus is the most replicated association with asthma. However, no study had described the genetic mechanisms underlying this association considering all genes of the locus in immune cell samples isolated from asthmatic and non-asthmatic individuals.ObjectiveThis study takes benefit of samples from naïve CD4+T cells and eosinophils isolated from the same 200 individuals to describe specific interactions between genetic variants, gene expression and DNA methylation levels for the 17q12-21 asthma locus.Methods and ResultsAfter isolation of naïve CD4+T cells and eosinophils from blood samples, next generation sequencing was used to measure DNA methylation levels and gene expression counts. Genetic interactions were then evaluated considering genetic variants from imputed genotype data. In naïve CD4+T cells but not eosinophils, 20 SNPs in the fourth and fifth haplotype blocks modulated bothGSDMAexpression and methylation levels, showing an opposite pattern of allele frequencies and expression counts in asthmatics compared to controls. Moreover, negative correlations have been measured between methylation levels of CpG sites located within the 1.5 kb region from the transcription start site ofGSDMAand its expression counts.ConclusionAvailability of sequencing data from two key cell types isolated from asthmatic and non-asthmatic individuals allowed identifying a new gene in naïve CD4+T cells that drives the association with the 17q12-21 locus, leading to a better understanding of the genetic mechanisms taking place in it.
Diversity patterns of marine heterotrophic culturable bacteria along vertical and latitudinal gradients
Authors: Sanz-Sáez Isabel , Salazar Guillem , Lara Elena , Royo-Llonch Marta , Vaqué Dolors , Duarte Carlos M. , Gasol Josep M. , Pedrós-Alió Carlos , Sánchez Olga , Acinas Silvia G. 
Published: September 2019

ABSTRACTNowadays, there is a significant gap in the knowledge of the diversity and patterns for marine heterotrophic culturable microorganisms. In addition, most of the bacterial isolation efforts have focused on the photic ocean leaving the deep ocean less explored. We have isolated 1561 bacterial strains covering both photic (817) and aphotic layers (744) including isolates from the oxygen minimum zone (362) and the bathypelagic (382) from a variety of oceanographic regions including the North Western Mediterranean Sea, the North and South Atlantic Oceans, the Indian, the Pacific, and the Arctic Oceans. The partial sequencing of the 16S rRNA gene of all isolates revealed that they mainly affiliate with the classesAlphaproteobacteria(35.9%) andGammaproteobacteria(38.6%), as well as, phylumBacteroidetes(16.5%). The generaAlteromonasandErythrobacterwere the most widespread heterotrophic bacteria in the ocean able to grow on solid agar media. When comparing the sequences of all isolates, 37% of them were 100% identical. In fact, we found that 59% of the total aphotic isolates were 100% identical to photic isolates, indicating the ubiquity of some bacterial isolates along the water column. Unweighted UniFrac distances did not show significant differences among stations regardless of their geographic distance or depth, reflecting the wide dispersion of the culturable bacterial assemblage. This isolates collection provides an overview of the distribution patterns of cosmopolitan marine culturable heterotrophic bacteria.
Structural and molecular insight into the pH-induced low-permeability of the voltage-gated potassium channel Kv1.2 through dewetting of the water cavity
Authors: Lee Juhwan , Kang Mooseok , Kim Sangyeol , Chang Iksoo 
Published: September 2019

AbstractUnderstanding the gating mechanism of ion channel proteins is key to understanding the regulation of cell signaling through these channels. Channel opening and closing are regulated by diverse environmental factors that include temperature, electrical voltage across the channel, and proton concentration. Low permeability in voltage-gated potassium ion channels (Kv) is intimately correlated with the prolonged action potential duration observed in many acidosis diseases. The Kv channels consist of voltage-sensing domains (S1–S4 helices) and central pore domains (S5–S6 helices) that include a selectivity filter and water-filled cavity. The voltage-sensing domain is responsible for the voltage-gating of Kv channels. While the low permeability of Kv channels to potassium ion is highly correlated with the cellular proton concentration, it is unclear how an intracellular acidic condition drives their closure, which may indicate an additional pH-dependent gating mechanism of the Kv family. Here, we show that two residues E327 and H418 in the proximity of the water cavity of Kv1.2 play crucial roles as a pH switch. In addition, we present a structural and molecular concept of the pH-dependent gating of Kv1.2 in atomic detail, showing that the protonation of E327 and H418 disrupts the electrostatic balance around the S6 helices, which leads to a straightening transition in the shape of their axes and causes dewetting of the water-filled cavity and closure of the channel. Our work offers a conceptual advancement to the regulation of the pH-dependent gating of various voltage-gated ion channels and their related biological functions.Author SummaryThe acid sensing ion channels are a biological machinery for maintaining the cell functional under the acidic or basic cellular environment. Understanding the pH-dependent gating mechanism of such channels provides the structural insight to design the molecular strategy in regulating the acidosis. Here, we studied the voltage-gated potassium ion channel Kv1.2 which senses not only the electrical voltage across the channels but also the cellular acidity. We uncovered that two key residues E327 and H418 in the pore domain of Kv1.2 channel play a role as pH-switch in that their protonation control the gating of the pore in Kv1.2 channel. It offered a molecular insight how the acidity reduces the ion permeability in voltage-gated potassium channels.
UMI-Gen: a UMI-based reads simulator for variant calling evaluation in paired-end sequencing NGS libraries
Authors: Sater Vincent , Viailly Pierre-Julien , Lecroq Thierry , Ruminy Philippe , Bérard Caroline , Prieur-Gaston Élise , Jardin Fabrice 
Published: September 2019

1DisclaimerThe author has withdrawn version 2 of this manuscript due to a duplicate posting of manuscript number 027532. Therefore, the author does not wish this work to be cited as reference for the project. 775817v1 is the appropriate submission and the published version of the appropriate preprint can be found in the published article link. If you have any questions, please contact the corresponding author.
Influencing factors of telephone-cardiopulmonary resuscitation in China: a qualitative exploration based on managerial perspectives
Authors: Zhu Xuehua , Gui Li , Chen Ying , Lin Yin 
Published: September 2019

AbstractBackgroundTelephone-cardiopulmonary resuscitation(T-CPR) has been proven to systematically improve bystander CPR implementation and thus improve the survival rate of out-of-hospital cardiac arrest (OHCA) patients on a large scale. However, China has a lower proportion of cities that provide T-CPR than other countries.This study aimed to explore the factors affecting the providing of T-CPR based on managerial perspectives and promote the implementation of T-CPR in China to Protect human health.MethodsThis study adopted a descriptive qualitative method.The managers from health bureau and first-aid Center were recruited to participate through purposive sampling. Data were collected using semi-structured interviews and Colaizzi 7-step analysis method was adopted to summarize and conclude the theme.ResultsA total of 10 managers were interviewed.Five main themes were identified: (a) bystander factors, (b) dispatching factors, (c) legal factors, (d) guiding factors, and (e) financial factors.ConclusionIt is urgent to promote the implementation of T-CPR in China.We can promote it by strengthening the training of bystanders in CPR knowledge and skills, developing T-CPR guidance process suitable for Chines national conditions, building an intelligent prehospital emergency system, promoting the legislation of first aid exemption, and providing financial support from various channels.
Relevance of screening for Chagas and viral hepatitis in Bolivian migrants
Authors: Galván Irene Losada , Gariup Giuseppe , Casellas Aina , Subirà Carme , Almuedo-Riera Alex , Camprubí Daniel , Rodríguez-Valero Natalia , Gascón Joaquim , Muñoz Jose , Pinazo María Jesús 
Published: September 2019

AbstractObjectivesgiven the scarcity of data regarding prevalence of various infectious diseases in Latin-American countries, our study aims to assess the burden of T.cruzi, S.stercoralis, HIV and viral hepatitis in Latin-American migrants, with a focus on Bolivian migrants.Methodswe performed a retrospective observational study of 565 screening evaluations on adults (≥ 18 years) carried out at our referral International Healthcare service in Barcelona. We reviewed structured clinical records and microbiological results of patients attended between February 2012 and April 2015.Resultsthe median 35 years old and 74% were women. Bolivian origin accounted for 87% of the screened population. We found a 48% prevalence of T.cruzi, 16% of S.stercoralis, 0.2% of HIV, 92% of HAV, 0.2% HBV and 0.2% HCV.Conclusionsthese results support the relevance of the screening of T. cruzi and S. stercoralis in Bolivian migrants, but challenge the pertinence of systematic screening of HBV in this population.Author summaryIn response to the challenge of detecting diseases not previously present in host countries, screening programs have been implemented for migrants based on the probability of having certain diseases depending on their country of origin and / or migratory route. This increased risk is very clearly established in some cases such as Trypanosoma cruzi infection (the cause of Chagas disease) in people from Latin America; especially from Bolivia. In recent years screening recommendations for Strongyloides stercoralis in this population was proven necessary. Current recommendations regarding systematic screening for hepatitis B establish the relevance of screening based on the probability of the disease in the 2% population of origin. Since there are no reliable and up to date data regarding prevalence of hepatitis B virus in Bolivia, we aimed to analyze data available for migrants from Bolivia in Spain.Our results support the importance of screening for T. cruzi and S.stercoralis in patients from Bolivia. However, our data show a much lower prevalence of this hepatitis B virus (0.2%) than the 2% threshold that would justify systematic screening, so we question the relevance of screening for hepatitis B virus in this population in the absence of other risk factors.
Synaptic and intrinsic mechanisms underlying development of cortical direction selectivity
Authors: Roy Arani , Osik Jason J. , Meschede-Krasa Benyamin , Alford Wesley , Leman Daniel P. , Van Hooser Stephen D. 
Published: September 2019

AbstractSome neural circuits are constructed through an overproduction of initial connections followed by activity-dependent refinement. Under this paradigm, functional receptive fields would be expected to be narrowed from a diffuse immature condition to a sharper mature condition. Alternatively, neural activity might lead to formation of new connections, leading to expansion of an initially compact receptive field. In the simple cells of the ferret visual cortex undergoing developmental enhancement of direction selectivity, we found evidence for a mixed mechanism: an expansion of the spatiotemporal receptive fields along the temporal dimension combined with a narrowing in space-time through a marked loss of inputs with certain space-time selectivities. Further, the resulting increase in subthreshold direction selectivity was accompanied by increases in near-spike-threshold excitability and input-output gain that resulted in dramatically increased spiking responses. Increases in subthreshold membrane responses and the increased input-output spiking gain were both necessary to explain firing rates in experienced ferrets. These results demonstrate that cortical direction selectivity develops through a combination of plasticity in synaptic and cell-intrinsic properties.
In situdissection of domain boundaries affect genome topology and gene transcription inDrosophila
Authors: Arzate-Mejía Rodrigo G. , Cerecedo-Castillo Angel Josué , Guerrero Georgina , Furlan-Magaril Mayra , Recillas-Targa Félix 
Published: September 2019

AbstractThe molecular mechanisms responsible for Topologically Associated Domains (TADs) formation are not yet fully understood. InDrosophila, it has been proposed that transcription is fundamental for TAD organization while the participation of genetic sequences bound by Architectural Proteins (APs) remains controversial. Here, we investigate the contribution of domain boundaries to TAD organization and the regulation of gene expression at theNotchgene locus inDrosophila. We find that deletion of domain boundaries results in TAD fusion and long-range topological defects that are accompanied by loss of APs and RNA Pol II chromatin binding as well as defects in transcription. Together, our results provide compelling evidence on the contribution of discrete genetic sequences bound by APs and RNA Pol II in the partition of the genome into TADs and in the regulation of gene expression inDrosophila.
Gene-by-environmental modulation of longevity and weight gain in the murine BXD family
Authors: Roy Suheeta , Sleiman Maroun Bou , Jha Pooja , Williams Evan G. , Ingels Jesse F. , Chapman Casey J. , McCarty Melinda S. , Hook Michael , Sun Anna , Zhao Wenyuan , Huang Jinsong , Neuner Sarah M. , Wilmott Lynda A. , Shapaker Thomas M. , Centeno Arthur G. , Mozhui Khyobeni , Mulligan Megan K. , Kaczorowski Catherine C. , Makowski Liza , Lu Lu , Read Robert W. , Sen Saunak , Miller Richard A. , Auwerx Johan , Williams Robert W. 
Published: September 2019

SummaryDiet and environment profoundly modulate lifespan. We measured longevity as a function of diet and weight gain across a genetically diverse family of mice. We followed 1348 females from two parental strains—C57BL/6J and DBA/2J—and 146 cohorts of BXD isogenic progeny strains (n= 73) across their lifespan on a low fat chow diet (CD, 18% calories from fat) and on a high fat diet (HFD, 60% calories from fat). On average, HFD shortens lifespan by 85 days or 12%, roughly equivalent to an 8–10 year decrease in humans. However, strain variation in the response of diet on longevity is remarkably high, ranging from a longevity loss of 54% in BXD65 to a gain of 37% in BXD8. Baseline weights and early weight gain are both associated with a mean decrease in longevity of ∼4 days/g. By 500 days-of-age, cases fed HFD gained four times as much weight as control on average. However, strain-specific variation was substantial, thus weight gain did not correlate well with lifespan. In summary, high fat had a strong negative effect on longevity, but genetic interactions effects were even stronger. This highlights the unequivocal importance of genetic differences in making dietary recommendations.