bluuebunny/crossref_metadata_2025_split huggingface dataset:
mRNA-decapping associated DcpS enzyme controls critical steps of neuronal development
Authors: Salamon Iva , Palsule Geeta , Luo Xiaobing , Roque Alfonso , Tucai Shawn , Khosla Ishan , Volk Nicole , Liu Wendy , Cui Huijuan , Dal Pozzo Valentina , Zalamea Petronio , Jiao Xinfu , D’Arcangelo Gabriella , Hart Ronald P , Rasin Mladen-Roko , Kiledjian Megerditch 
Published: May 2021

AbstractHomozygous mutations in the gene encoding the scavenger mRNA-decapping enzyme, DcpS, have been shown to underlie developmental delay and intellectual disability. Intellectual disability is associated with both abnormal neocortical development and mRNA metabolism. However, the role of DcpS and its scavenger decapping activity in neuronal development is unknown. Here, we show that human neurons derived from patients with a DcpS mutation have compromised differentiation and neurite outgrowth. Moreover, in the developing mouse neocortex, DcpS is required for the radial migration, polarity, neurite outgrowth and identity of developing glutamatergic neurons. Collectively, these findings demonstrate that the scavenger mRNA decapping activity contributes to multiple pivotal roles in neural development, and further corroborate that mRNA metabolism and neocortical pathologies are associated with intellectual disability.
Cortical alpha-synuclein preformed fibrils do not affect interval timing in mice
Authors: Zhang Qiang , Abdelmotilib Hisham , Larson Travis , Keomanivong Cameron , Conlon Mackenzie , Aldridge Georgina M. , Narayanan Nandakumar S. 
Published: May 2021

AbstractOne hallmark feature of Parkinson’s disease (PD) is Lewy body pathology associated with misfolded alpha-synuclein. Previous studies have shown that striatal injection of alpha-synuclein preformed fibrils (PFF) can induce misfolding and aggregation of native alpha-synuclein in a prion-like manner, leading to cell death and motor dysfunction in mouse models. Here, we tested whether alpha-synuclein PFFs injected into the medial prefrontal cortex results in cognitive deficits in mouse models as measured by interval timing, which is reliably disrupted in PD patients and in rodent models. We injected human alpha-synuclein PFF or monomers in the medial prefrontal cortex pre-injected with adeno-associated virus (AAV) overexpressing human alpha-synuclein. Despite notable medial prefrontal cortical synucleinopathy, we did not observe consistent deficits in fixed-interval timing. These results suggest that cortical alpha-synuclein does not reliably disrupt interval timing in rodent models.HighlightsCortical injection of alpha-synuclein preformed fibrils (PFF) induces diffuse synucleinopathyCortical injection of PFFs does not affect interval timing in miceMedial prefrontal cortical synucleinopathy does not reliably disrupt interval timing
Absence of muricholic acid due to Cyp2c-deficiency protects against high fat diet-induced obesity in male mice but promotes liver damage
Authors: Oteng Antwi-Boasiako , Higuchi Sei , Banks Alexander S. , Haeusler Rebecca A. 
Published: May 2021

ABSTRACTObjectiveMurine-specific muricholic acids (MCAs) are reported to protect against obesity and associated metabolic disorders. However, the response of mice with genetic depletion of MCA to an obesogenic diet has not been evaluated. We used Cyp2c-deficient (Cyp2c−/−) mice, which lack MCAs and thus have a human-like bile acid (BA) profile, to directly investigate the potential role of MCAs in diet-induced obesity.MethodsMale and female Cyp2c−/− mice and wild-type controls were fed a standard chow diet or a high fat diet (HFD) for 18 weeks. We measured BA composition from a pool of liver, gallbladder, and intestine, as well as weekly body weight, food intake, lean and fat mass, systemic glucose homeostasis, energy expenditure, intestinal lipid absorption, fecal lipid, and energy content.ResultsCyp2c deficiency depleted MCAs and caused other changes in BA composition, namely a decrease in the ratio of 12α-hydroxylated (12α-OH) BAs to non-12α-OH BAs, without altering the total BA levels. While wild-type male mice became obese after HFD-feeding, Cyp2c−/− male mice were protected from obesity and associated metabolic dysfunctions. Cyp2c−/− male mice also showed reduced intestinal lipid absorption and increased lipid excretion, which was reversed by oral gavage with the 12α-OH BA, taurocholic acid. Cyp2c−/− mice also showed increased liver damage, which appeared stronger in females.ConclusionMCA does not protect against diet-induced obesity but may protect against liver injury. Reduced lipid absorption in Cyp2c-deficient male mice is potentially due to a reduced ratio of 12α-OH/non-12α-OH BAs.
HelR is a helicase-like protein that protects RNA polymerase from rifamycin antibiotics
Authors: Surette Matthew D. , Waglechner Nick , Koteva Kalinka , Wright Gerard D. 
Published: May 2021

SummaryRifamycin antibiotics such as rifampin are widely used for the management of tuberculosis and other bacterial infections. These drugs inhibit prokaryotic RNA polymerase (RNAP) by preventing elongation of mRNA resulting in cell death. Rifamycin resistance in the clinic is manifested primarily through amino acid substitutions in RNAP that decrease target affinity for the antibiotics. In contrast, environmental bacteria possess a wide variety of highly specific rifamycin enzyme-mediated resistance mechanisms that modify and inactivate the antibiotics by glycosylation, phosphorylation, ADP-ribosylation, or hydroxylation. Expression of rifamycin resistance is controlled by a common 19bp cis-acting rifamycin associated element (RAE) upstream of inactivating genes. Guided by the presence of RAE sequences, we identify an unprecedented ATP-dependent mechanism of rifamycin resistance that acts not by antibiotic inactivation but by protecting the RNAP target. We show that Streptomyces venezuelae encodes a helicase-like protein, HelR, which confers broad spectrum rifamycin resistance. Furthermore, HelR is essential for promoting rifamycin tolerance at inhibitory concentrations, enabling bacterial evasion of the toxic properties of these antibiotics. HelR forms a complex with RNAP in vivo and rescues transcription inhibition by rifampin in vitro. We synthesized a rifamycin photoprobe and demonstrated that HelR directly displaces rifamycins from RNAP. HelR-encoding genes associated with RAEs are broadly distributed in actinobacteria, including many opportunistic Mycobacterial pathogens, which cannot currently be treated with rifamycins. This first report of an RNAP protection protein conferring antibiotic resistance and offers guidance for developing new rifamycin antibiotics that can avoid this mechanism.
Expanding the Potential Genes of Inborn Errors of Immunity through Protein Interactions
Authors: Khan Humza A. , Butte Manish J. 
Published: May 2021

AbstractInborn errors of immunity (IEI) are a group of genetic disorders that impair the immune system, with over 400 genes described so far, and hundreds more to be discovered. To facilitate the search for new genes, we need a way to prioritize among all the genes in the genome those most likely to play an important role in immunity. Here we identify a new list of genes by linking known IEI genes to new ones by using open-source databases of protein-protein interactions, post-translational modifications, and transcriptional regulation. We analyze this new set of 2,530 IEI-related genes for their tolerance of genetic variation and by their expression levels in various immune cell types.
Phyllosphere-inhabiting endophytic bacteria feature a stationary phase-like lifestyle
Authors: Velásquez André C. , Huguet-Tapia José C. , He Sheng Yang 
Published: May 2021

ABSTRACTPlants are in constant association with a variety of microbes, and although much is known about how symbiotic and pathogenic microbes interact with plants, less is known about the population dynamics, adaptive traits, and transcriptional features of endophytic commensal microbes that live inside leaves. In this study, we evaluated the long-term population and transcriptional dynamics of two bacterial microbiota endophytes and compared them to those of a commensal-simulating non-pathogenic mutant of the bacterial pathogen Pseudomonas syringae. We found that population densities of all three endophytic phyllosphere bacteria remained static over a long period of time, which was caused by a continual equilibrium between bacterial multiplication and death, as evidenced by treatment of plants with antibiotics that only targeted dividing bacteria or by in planta visualization of bacteria carrying a fluorescent division reporter. Population stasis could not be explained by a lack of resources, as Arabidopsis leaves could support population densities up to 100 times higher than the normal microbiota populations, nor was population stasis reversed by significantly quenching PAMP-triggered immunity. Long-term temporal in planta transcriptomic analysis of these three bacterial endophytes revealed up-regulation of protein translation, the generation of energy, and the response to stress, and interestingly, for the microbiota strains, the longer the bacteria remained inside plants, the greater the up-regulation of some of these processes. Further transcriptomic analysis of in planta populations of commensal-simulating Pseudomonas syringae revealed a remarkable resemblance to those of in vitro bacteria in stationary phase, a metabolically active physiological state in which the production of secondary metabolites and stress responses are induced. This study provides novel insight into how endophytic bacteria survive and thrive inside plant leaves, and reshapes our current understanding of what it means to be part of the endophytic microbiota in the phyllosphere.
Prodromal dysfunction of α5GABA-A receptor modulated hippocampal ripples in Alzheimer’s disease
Authors: Ratner Marcia H. , Downing Scott S. , Guo Ouyang , Odamah KathrynAnn E. , Stewart Tara M. , Kumaresan Vidhya , Robitsek R. Jonathan , Xia Weiming , Farb David H. 
Published: May 2021

AbstractDecades of research attempting to slow the onset of Alzheimer’s disease (AD) indicates that a better understanding of memory will be key to the discovery of effective therapeutic approaches. Here, we ask whether prodromal neural network dysfunction might occur in the hippocampal trisynaptic circuit by using α5IA as a selective negative modulator of extrasynaptic α5GABA-A receptors in TgF344-AD transgenic rats, a model for early onset AD. The results demonstrate that orally bioavailable α5IA, an established memory enhancer, increases CA1 pyramidal cell mean firing rates and peak CA1 ripple amplitude during wakeful immobility in wild type F344 rats resting in a familiar environment. We show that TgF344-AD rats, which express human amyloid-beta precursor protein (with the Swedish mutation) and human presenilin-1 (with a Δ exon 9 mutation), exhibit high serum Aβ42 and Aβ40 levels by 3 months of age. By 9 months of age, CA1 ripples in young adult TgF344-AD rats are nonresponsive to α5IA indicating network dysfunction prior to the onset of AD pathology and memory dysfunction. These results demonstrate, to the best of our knowledge, the first evidence for prodromal α5GABA-A receptor dysfunction in the AD hippocampal trisynaptic circuit. Moreover, as α5GABA-A receptors are located extrasynaptically and subserve the function of tonic inhibition we posit that an early stage of memory dysfunction involves the disruption of tonic inhibition in the hippocampus.
Multi-resolution deconvolution of spatial transcriptomics data reveals continuous patterns of inflammation
Authors: Lopez Romain , Li Baoguo , Keren-Shaul Hadas , Boyeau Pierre , Kedmi Merav , Pilzer David , Jelinski Adam , David Eyal , Wagner Allon , Addad Yoseph , Jordan Michael I. , Amit Ido , Yosef Nir 
Published: May 2021

AbstractThe function of mammalian cells is largely influenced by their tissue microenvironment. Advances in spatial transcriptomics open the way for studying these important determinants of cellular function by enabling a transcriptome-wide evaluation of gene expressionin situ. A critical limitation of the current technologies, however, is that their resolution is limited to niches (spots) of sizes well beyond that of a single cell, thus providing measurements for cell aggregates which may mask critical interactions between neighboring cells of different types. While joint analysis with single-cell RNA-sequencing (scRNA-seq) can be leveraged to alleviate this problem, current analyses are limited to a discrete view of cell type proportion inside every spot. This limitation becomes critical in the common case where, even within a cell type, there is a continuum of cell states that cannot be clearly demarcated but reflects important differences in the way cells function and interact with their surroundings. To address this, we developed Deconvolution of Spatial Transcriptomics profiles using Variational Inference (DestVI), a probabilistic method for multi-resolution analysis for spatial transcriptomics that explicitly models continuous variation within cell types. Using simulations, we demonstrate that DestVI is capable of providing higher resolution compared to the existing methods and that it can estimate gene expression by every cell type inside every spot. We then introduce an automated pipeline that uses DestVI for analysis of single tissue slices and comparison between tissues. We apply this pipeline to study the immune crosstalk within lymph nodes to infection and explore the spatial organization of a mouse tumor model. In both cases, we demonstrate that DestVI can provide a high resolution and accurate spatial characterization of the cellular organization of these tissues, and that it is capable of identifying important cell-type-specific changes in gene expression - between different tissue regions or between conditions. DestVI is available as an open-source software package in the scvi-tools codebase (https://scvi-tools.org).
Exosomal transmission of α-synuclein initiates Parkinson’s disease-like pathology
Authors: Howitt Jason , Low Ley Hian , Bouman Michelle , Yang Jeremy , Gordon Sarah , Hill Andrew , Tan Seong-Seng 
Published: May 2021

AbstractThe intercellular transmission of α-synuclein is proposed to be involved in the pathogenesis of Parkinson’s disease (PD)1. Supporting this transmission hypothesis, α-synuclein has been identified to act as a prion2 and has been found in cerebrospinal fluid (CSF), blood, and saliva3. However, the mechanism required to initiate the pathogenic spread of α-synuclein in the body that results in PD remains unclear. Here we identify a mechanism for the loading of α-synuclein into exosomes, resulting in prion-like transmission that is mediated by the ubiquitin ligase activator, Ndfip1. Risk factors associated with PD, including metal toxicity, lysosome dysfunction and pesticide exposure,4 stimulate the upregulation of Ndfip1 and increase the loading of α-synuclein into exosomes. We used this pathway to promote the loading of endogenous α-synuclein into exosomes, that when intranasally delivered to either wild type or M83 transgenic mice, resulted in Parkinson’s-like pathology including motor impairments and brain amyloids. Recipient cells require α-synuclein for pathogenesis, as delivery of exosomes containing α-synuclein to Snca knockout mice did not generate brain amyloids or Parkinson’s-like motor impairments. Our results demonstrate a novel mechanism to initiate the prion-like spread of α-synuclein in exosomes, following exposure to risk factors for PD.
Educators' self-esteem: the effect of perceived occupational stress and the role of organizational support
Authors: Masoom Muhammad Rehan 
Published: May 2021

PurposeThis research investigates the mediation effect of perceived organizational support on the relationship between organization-based self-esteem and perceived occupational stress of teachers.Design/methodology/approachThe present quantitative venture follows a causal research design to unveil the relationship among organization based self-esteem (independent variable), perceived occupational stress (dependent variable) and perceived organizational support (intervening variable). The research surveys 813 educators from nineteen selected distinct areas of Dhaka city; the survey instrument has twenty-six items apart from some general inquires about the respondents. To address the dynamic interplay among these variables, a confirmatory factor analysis (CFA) is conducted within a structural equation modeling (SEM) framework.FindingsTeachers with low self-esteem perceived a high level of occupational stress, whereas teachers who perceived high organizational support feel low occupational stress. Increasing organizational support not only increases organization-based self-esteem but also mediates the relationship between self-esteem and occupational stress.Practical implicationsTeachers' stress is not only an increasing problem over the years but also it was one of the top six most stressful professions. The present study outlines the possible organizational initiatives that can reduce the stresses of the teaching profession.Originality/valueThe findings of the present study square with several theoretical frameworks such as the job demands–resources (JD–R) model and conservation of resources (COR) theory. The results highlight the fact that allowing school teachers to express their ideas and points of view makes them feel esteemed. Likewise, good relations with the school head and getting positive feedback are found to be contributing factors. The teachers feel lesson planning overburdensome and undue office inspections hurt their self-esteem. Any school can increase the self-esteem of the teachers by providing support and training to adjust to changes.
The use of m-government applications: empirical evidence from the smartest cities of Brazil
Authors: de Oliveira Malaquias Fernanda Francielle , da Silva Júnior Romes Jorge 
Published: May 2021

PurposeThis paper aims to investigate the use of m-government applications for public services providing in Brazil. As a secondary objective, the paper aims to analyze the relationship between the use of m-government applications and development.Design/methodology/approachTo achieve the objective of this research, the 100 smartest cities of Brazil were selected and the mobile apps provided by their local governments were identified. Both qualitative and quantitative methods were adopted, including content analysis technique, chi-square test and regression analysis.FindingsThe results show that mobile apps developed by local governments of Brazilian smart cities include information and public services access, health, education, security, tourism, water supply system, environment, among others. The results also show a positive relationship between apps downloads and development indexes.Social implicationsThis paper emphasizes the social side of information technology, showing that it can contribute to the implementation of more inclusive cities that respond to the needs and interests of their citizens.Originality/valueThis paper presents empirical evidences of the potential benefits of m-government technologies for development in an emerging country. Moreover, it highlights how mobile applications developed by local governments may lead to a better quality of life of the population, considering a comprehensive approach of development that involves its economic, social and human dimensions.
Transcoding authenticity: preserving unreleased gaming software outside of memory institutions
Authors: Hodges James A. 
Published: May 2021

PurposeThis paper aims to introduce new criteria for evaluating authenticity in digital preservation, particularly in cases related to unreleased software projects and preservation work that occurs in non-institutional settings.Design/methodology/approachInterpretive visual and formal analysis of image files is performed on three overlapping preservation efforts to understand the ways that self-appointed preservationists reframe content in varied settings. The unreleased mid-1990s console game Sonic X-Treme is used as a case study because assets from the development process have been widely preserved among former developers and enthusiasts alike.FindingsThe findings indicate that non-professional preservationists transcode original production files into a variety of formats, ranging from lossy compressed images to contemporary three-dimensional (3D) modeling files. Materials are presented in settings that range from colorful webpages mimicking the appearance of commercial software to browsable file systems. These results show that non-institutional preservation practices embody notions of authenticity that diverge significantly from those of professional archivists.Research limitations/implicationsThe study is limited by its focus on a single case study, but helps to facilitate ongoing research concerning preservation of unreleased projects insofar as it surveys the current status of existing projects.Originality/valueExisting studies within preservation literature have established the need for increased attention paid to unfinished digital works. This study introduces new data and interpretative findings that outline such preservation efforts as they already occur in non-institutional settings.
Self-injurious behaviour in forensic mental health care: a study into the prevalence and characteristics of incidents of self-injury
Authors: de Vogel Vivienne , Verstegen Nienke 
Published: May 2021

Purpose
Incidents of self-injury by forensic psychiatric patients often have a deleterious impact on all those involved. Moreover, self-injurious behaviour is an important predictor for violence towards others during treatment. The aim of this study is to analyse methods and severity of incidents of self-injury of patients admitted to forensic psychiatry, as well as the diagnoses of self-injuring patients.

Design/methodology/approach
All incidents of self-injury during treatment in a forensic psychiatric centre recorded between 2008 and 2019 were analysed and the severity was coded with the modified observed aggression scale+ (MOAS+).

Findings
In this period, 299 incidents of self-injury were recorded, displayed by 106 patients. Most of these incidents (87.6%) were classified as non-suicidal. Methods most often used were skin cutting with glass, broken plates, a razor or knife and swallowing dangerous objects or liquids. Ten patients died by suicide, almost all by suffocation with a rope or belt. The majority of the incidents was coded as severe or extreme with the MOAS+. Female patients were overrepresented and they caused on average three times more incidents than male patients.

Practical implications
More attention is warranted for self-injurious behaviour during forensic treatment considering the distressing consequences for both patients themselves, supervisors and witnesses. Adequate screening for risk of self-injurious behaviour could help to prevent this behaviour. Further research is needed in different forensic settings into predictors of self-injurious behaviour, more specifically, if there are distinct predictors for aggression to others versus to the self.

Originality/value
Incidents of self-injury occur with some regularity in forensic mental health care and are usually classified as severe. The impact of suicide (attempts) and incidents of self-injurious behaviour on all those involved can be enormous. More research is needed into the impact on all those involved, motivations, precipitants and functions of self-injurious behaviour and effective treatment of it.