bluuebunny/crossref_metadata_2025_split huggingface dataset:
Condensate formation of the human RNA-binding protein SMAUG1 is controlled by its intrinsically disordered regions and interactions with 14-3-3 proteins
Authors: Fehilly John , Carey Olivia , O’Leary Eoghan Thomas , O’Shea Stephen , Juda Klaudia , Fitzel Rahel , Selvaraj Pooja , Lindsay Andrew J. , Mészáros Bálint , Dean Kellie 
Published: February 2023

AbstractSMAUG1 is a human RNA-binding protein that is known to be dysregulated in a wide range of diseases. It is evolutionarily conserved and has been shown to form condensates containing translationally repressed RNAs. This indicates that condensation is central to proper SMAUG1 function; however, the factors governing condensation are largely unknown. In this work, we show that SMAUG1 drives the formation of liquid-like condensates in cells through its non-conventional C-terminal prion-like disordered region. We use biochemical assays to show that this liquid-liquid phase separation is independent of RNA binding and does not depend on other large, disordered regions that potentially harbor several binding sites for partner proteins. Using a combination of computational predictions, structural modeling,in vitroand in cell measurements, we also show that SMAUG1-driven condensation is negatively regulated by direct interactions with members of the 14-3-3 protein family. These interactions are mediated by four distinct phospho-regulated short linear motifs embedded in the disordered regions of SMAUG1, working synergistically. Interactions between SMAUG1 and 14-3-3 proteins drive the dissolution of condensates, alter the dynamics of the condensed state, and are likely to be intertwined with currently unknown regulatory mechanisms. Our results provide information on how SMAUG1 phase separation is regulated and the first known instance of 14-3-3 proteins being able to completely dissolve condensates by directly interacting with a phase separation driver, which might be a general mechanism in cells to regulate biological condensation.Graphical abstractHighlightsSMAUG1 is a human RNA-binding protein capable of condensation with unknown regulationA prion-like domain of SMAUG1 drives condensation via liquid-liquid phase separationSMAUG1 interacts with 14-3-3 proteins via four phospho-regulated short linear motifs14-3-3 interactions change the dynamics of SMAUG1 condensates, promoting their dissolutionThis is the first described regulatory mechanism for SMAUG1-driven condensation
Telomerase reverse transcriptase (TERT)-expressing cells mark a novel stem cell population in the adult mouse brain
Authors: Jensen Gabriel S. , Beaulieu Ashleigh N. , Curtis Caroline D. , Passarelli Joshua , Blaszkiewicz Magdalena , Thomas Seth , Morin Trevor , Willows Jake W. , Greco Callie W. , Brennan Ciara J. , Aniapam Christopher , Caron Lydia , Alves Michele J. , Lynes Matthew D. , Carlone Diana L. , Breault David T. , Townsend Kristy L. 
Published: February 2023

AbstractTelomerase reverse transcriptase (TERT) is expressed by quiescent adult stem cells (ASC) in numerous adult murine and human tissues, but has never been explored in the adult brain. Here, we demonstrate that TERT+ cells in the adult mouse brain represent a novel population of multipotent ASCs that are localized to numerous classical neuro/gliogenic niches (including the ventricular-subventricular zone, hypothalamus, and olfactory bulb), as well as more recently described regions of adult brain plasticity such as the meninges and choroid plexus. Using a direct-reporter mouse line, we found that TERT+ cells expressed known neural stem cell markers such as Nestin and Sox2, but not markers of committed stem/progenitor cells, nor markers of mature neuronal or glial cells. TERT+ ASCs rarely expressed the proliferation marker Ki67, andin vitroTERT+ cells lost TERT expression when activated by growth factors, together indicating a quiescent phenotype similar to what has been observed in other tissues. When cultured, TERT+ cells behaved like neural stem cells by forming neurospheres, which could proliferate and become more metabolically active once stimulated by growth factors. TERT+ cells were observed in numerous brain niches, particularly near the ventricles and cerebrospinal fluid barriers, but notably, TERT+ cells were never observed in the hippocampus. Lineage tracing of TERT+ cells in adult transgenic mice (mTERTrtTA::oTET-Cre::RosamTmG) revealed large-scale expansion of TERT+ progeny and differentiation to diverse cell types in multiple brain regions. For example, lineage-traced cells expressed markers of mature neurons, oligodendrocytes, astrocytes, ependymal cells, and choroid epithelial cells, thus demonstrating the striking multipotency of this stem cell population in basal tissue turnover of the adult brain. Together, these data demonstrate that TERT+ cells represent a novel population of multipotent stem cells that contribute to basal plasticity and regeneration in the adult mouse brain.Graphical Abstract
A kinetic dichotomy between mitochondrial and nuclear gene expression drives OXPHOS biogenesis
Authors: McShane Erik , Couvillion Mary , Ietswaart Robert , Prakash Gyan , Smalec Brendan M. , Soto Iliana , Baxter-Koenigs Autum R. , Choquet Karine , Churchman L. Stirling 
Published: February 2023

AbstractOxidative phosphorylation (OXPHOS) complexes, encoded by both mitochondrial and nuclear DNA, are essential producers of cellular ATP, but how nuclear and mitochondrial gene expression steps are coordinated to achieve balanced OXPHOS biogenesis remains unresolved. Here, we present a parallel quantitative analysis of the human nuclear and mitochondrial messenger RNA (mt-mRNA) life cycles, including transcript production, processing, ribosome association, and degradation. The kinetic rates of nearly every stage of gene expression differed starkly across compartments. Compared to nuclear mRNAs, mt-mRNAs were produced 700-fold higher, degraded 5-fold faster, and accumulated to 170-fold higher levels. Quantitative modeling and depletion of mitochondrial factors, LRPPRC and FASTKD5, identified critical points of mitochondrial regulatory control, revealing that the mitonuclear expression disparities intrinsically arise from the highly polycistronic nature of human mitochondrial pre-mRNA. We propose that resolving these differences requires a100-fold slower mitochondrial translation rate, illuminating the mitoribosome as a nexus of mitonuclear co-regulation.
Interference with the HNF4-dependent gene regulatory network diminishes ER stress in hepatocytes
Authors: Shah Anit , Huck Ian , Duncan Kaylia , Gansemer Erica R. , Apte Udayan , Stamnes Mark A. , Rutkowski D. Thomas 
Published: February 2023

AbstractIn all eukaryotic cell types, the unfolded protein response (UPR) upregulates factors that promote protein folding and misfolded protein clearance to help alleviate endoplasmic reticulum (ER) stress. Yet ER stress in the liver is uniquely accompanied by the suppression of metabolic genes, the coordination and purpose of which is largely unknown. Here, we used unsupervised machine learning to identify a cluster of correlated genes that were profoundly suppressed by persistent ER stress in the liver. These genes, which encode diverse functions including metabolism, coagulation, drug detoxification, and bile synthesis, are likely targets of the master regulator of hepatocyte differentiation HNF4α. The response of these genes to ER stress was phenocopied by liver-specific deletion of HNF4α. Strikingly, while deletion of HNF4α exacerbated liver injury in response to an ER stress challenge, it also diminished UPR activation and partially preserved ER ultrastructure, suggesting attenuated ER stress. Conversely, pharmacological maintenance of hepatocyte identityin vitroenhanced sensitivity to stress. Several pathways potentially link HNF4α to ER stress sensitivity, including control of expression of the tunicamycin transporter MFSD2A; modulation of IRE1/XBP1 signaling; and regulation of Pyruvate Dehydrogenase. Together, these findings suggest that HNF4α activity is linked to hepatic ER homeostasis through multiple mechanisms.
Cell state transition analysis identifies interventions that improve control ofM. tuberculosisinfection by susceptible macrophages
Authors: Yabaji Shivraj M. , Rukhlenko Oleksii S. , Chatterjee Sujoy , Bhattacharya Bidisha , Wood Emily , Kasaikina Marina , Kholodenko Boris , Gimelbrant Alexander A. , Kramnik Igor 
Published: February 2023

AbstractUnderstanding cell state transitions and purposefully controlling them to improve therapies is a longstanding challenge in biological research and medicine. Here, we identify a transcriptional signature that distinguishes activated macrophages from TB-susceptible and TB-resistant mice. We then apply the cSTAR (cell State Transition Assessment and Regulation) approach to data from screening-by-RNA sequencing to identify chemical perturbations that shift the. transcriptional state of the TB-susceptible macrophages towards that of TB-resistant cells. Finally, we demonstrate that the compounds identified with this approach enhance resistance of the TB-susceptible mouse macrophages to virulentM. tuberculosis.
Interrogating the function of bicistronic translational control elements to improve consistency of gene expression
Authors: Jansen Zachary , Reilly Sophia R. , Lieber-Kotz Matan , Li Andrew Z. , Wei Qiyao , Kulhanek Devon L. , Gilmour Andrew R. , Thyer Ross 
Published: February 2023

AbstractContext independent gene expression is required for genetic circuits to maintain consistent and predicable behavior. Previous efforts to develop context independent translation have leveraged the helicase activity of translating ribosomes via bicistronic design translational control elements (BCDs) located within an efficiently translated leader peptide. We have developed a series of bicistronic translational control elements with strengths that span several orders of magnitude, maintain consistent expression levels across diverse sequence contexts, and are agnostic to common ligation sequences used in modular cloning systems. We have used this series of BCDs to investigate several features of this design, including the spacing of the start and stop codons, the nucleotide identity upstream of the start codon, and factors affecting translation of the leader peptide. To demonstrate the flexibility of this architecture and their value as a generic modular expression control cassette for synthetic biology, we have developed a set of robust BCDs for use in severalRhodococcusspecies.
TidyGEO: Preparing analysis-ready datasets from Gene Expression Omnibus
Authors: Mecham Avery , Stephenson Ashlie , Quinteros Badi I. , Salmons Grace , Piccolo Stephen R. 
Published: February 2023

AbstractTidyGEO is a Web-based tool for downloading, tidying, and reformatting data series from Gene Expression Omnibus (GEO). As a freely accessible repository with data from over 4 million biological samples across more than 4,000 organisms, GEO provides diverse opportunities for secondary research. Transcriptomic data are most common in GEO, but other measurement types are also prevalent, including DNA methylation levels, genotypes, and chromatin-accessibility profiles. GEO’s diversity and expansiveness present opportunities and challenges. Although scientists may find assay data relevant to a given research question, most analyses require sample annotations, such as a sample’s treatment group, disease subtype, or age. In GEO, such annotations are stored alongside assay data in delimited, text-based files. However, the structure and semantics of the annotations vary widely from one series to another, and many annotations are not useful for analysis purposes. Thus, every GEO series must be tidied before it can be analyzed. Manual approaches may be used, but these are error prone and take time away from other research tasks. Custom computer scripts can be written, but many scientists lack the computational expertise to create such scripts. To address these challenges, we created TidyGEO, which supports essential data-cleaning tasks for sample-level annotations, such as selecting informative columns, renaming columns, splitting or merging columns, standardizing data values, and filtering samples. Additionally, users can integrate annotations with assay data, restructure assay data, and generate code that enables others to reproduce these steps. The source code for TidyGEO is athttps://github.com/srp33/TidyGEO.
A Potent and Selective CDKL5/GSK3 Chemical Probe is Neuroprotective
Authors: Ong Han Wee , Liang Yi , Richardson William , Lowry Emily R. , Wells Carrow I. , Chen Xiangrong , Silvestre Margaux , Dempster Kelvin , Silvaroli Josie A. , Smith Jeffery L. , Wichterle Hynek , Pabla Navjot S. , Ultanir Sila K. , Bullock Alex N. , Drewry David H. , Axtman Alison D. 
Published: February 2023

ABSTRACTDespite mediating several essential processes in the brain, including during development, cyclin-dependent kinase-like 5 (CDKL5) remains a poorly characterized human protein kinase. Accordingly, its substrates, functions, and regulatory mechanisms have not been fully described. We realized that availability of a potent and selective small molecule probe targeting CDKL5 could enable illumination of its roles in normal development as well as in diseases where it has become aberrant due to mutation. We prepared analogs of AT-7519, a known inhibitor of several cyclin dependent and cyclin-dependent kinase-like kinases that has been advanced into Phase II clinical trials. We identified analog2as a highly potent and cell-active chemical probe for CDKL5/GSK3 (glycogen synthase kinase 3). Evaluation of its kinome-wide selectivity confirmed that analog2demonstrates excellent selectivity and only retains GSK3α/β affinity. As confirmation that our chemical probe is a high-quality tool to use in directed biological studies, we demonstrated inhibition of downstream CDKL5 and GSK3α/β signaling and solved a co-crystal structure of analog2bound to CDKL5. A structurally similar analog (4) proved to lack CDKL5 affinity and maintain potent and selective inhibition of GSK3α/β. Finally, we used our chemical probe pair (2and4) to demonstrate that inhibition of CDKL5 and/or GSK3α/β promotes the survival of human motor neurons exposed to endoplasmic reticulum (ER) stress. We have demonstrated a neuroprotective phenotype elicited by our chemical probe pair and exemplified the utility of our compounds to characterize the role of CDKL5/GSK3 in neurons and beyond.
Health vulnerability and health poverty of rice farmers: evidence from Hubei province in China
Authors: Li Wenjing , Zhang Lu , Yue Meng , Ruiz-Menjivar Jorge , Zhang Junbiao 
Published: February 2023

PurposeThe purpose of this study was threefold: (1) to measure farmers' health poverty, (2) to examine the effect of health vulnerability on health poverty and (3) to identify countermeasures that may alleviate health poverty in rural China.Design/methodology/approachThis study built a health poverty measurement model based on the multi-dimensional poverty framework to evaluate farmers' health vulnerability. Further, this paper used an econometric model to assess the impact of health vulnerability on health poverty. The sample for this study comprised 1,115 rice farmers from Hubei province, China.FindingsThe medical affordability poverty ratio was 17.95%, where farmers in the low-income group faced severe medical affordability poverty (27.46%). Results from the multi-dimensional analysis showed that, the health poverty ratios were 17.95 and 30.50%, respectively. Our results indicated that climate change vulnerabilities, living habits, medical facilities and medical accessibility were positively related to health poverty, whereas the regular physical examinations reduced mental health poverty.Research limitations/implicationsBased on this study's findings, we proposed that: (1) to address illness-induced poverty among members of the agricultural community, national and provincial strategies and programs grounded on a multi-dimensional health poverty framework ought to be formulated and implemented, (2) mechanisms of health knowledge exchange may facilitate the improvement of farmers' health status, (3) robust and comprehensive metrics should be employed to understand and improve farmers' ability to absorb and mitigate the negative health impacts and (4) the improvement in both quality and quantity for medical facilities and medical affordability in the rural areas should be key priorities in governmental-wide initiatives.Originality/valueExisting studies for alleviating poverty caused by disease mainly focus on medical service support to those economic vulnerabilities after a disease happens. However, few studies have focused on the root causes of poverty caused by disease, particularly from the preventive perspective of health vulnerability. To fill this gap, this study, therefore, proposes the health poverty index and analyzes the impact of health vulnerability on health poverty.
Transforming construction health and safety management during COVID-19 pandemic using innovative technologies: PLS-SEM approach
Authors: Kum Yi Tong , Yap Jeffrey Boon Hui , Lew Yoke-Lian , Lee Wah Peng 
Published: February 2023

PurposeThis study aims to investigate technology-based health and safety (H&S) management to control the spread of disease on construction sites using a partial least squares structural equation modelling (PLS-SEM) approach.Design/methodology/approachAn extensive literature review is conducted to develop a conceptual framework. The variables identified from the literature review are included in a cross-sectional survey which gathered a total of 203 valid feedback. The variables for challenges are grouped under their relevant construct using exploratory factor analysis. Then, a hypothesized model is developed for PLS-SEM analysis using Smart PLS software. Later, the outcome of the model is further validated by nine construction experts using a semi-structured questionnaire survey.FindingsThe results rationalized the relationships between the COVID-19 H&S measures, challenges in implementing COVID-19 H&S measures on construction sites and the innovative technologies in transforming construction H&S management during the COVID-19 pandemic. The possible challenges that obstruct the implementation of H&S measures are highlighted. The potential technologies which can significantly transform H&S management by reducing the impact of challenges are presented.Practical implicationsThe findings benefited the industry practitioners who are suffering disruption in construction operations due to the pneumonic plague.Originality/valueBy developing a conceptual model, this study reveals the contribution of technology-based H&S management for construction projects during the COVID-19 pandemic, which remains under-studied, especially in the context of the developing world.
Scoping review: understanding the barriers and drivers of risk management in local governments
Authors: Bourgeois Eve , Baril Pierre-Luc , Normandin Julie-Maude , Therrien Marie-Christine 
Published: February 2023

Purpose
This paper aims to provide scholars with a deep understanding of the field through the identification of strengths and weaknesses in the literature and support decision-makers in the development of new practices in local risk management based on scientific data. The specific question in this review asks: what are the drivers and barriers to local risk management?

Design/methodology/approach
This paper provides an overview of the scientific literature produce over the past 20 years of the divers and barriers to local risk management. This paper presents a scoping review of peer-reviewed articles published between 2000 and 2019 inclusively in the fields of public policy and public administration.

Findings
This paper makes three main observations regarding the state of the literature. First, this paper finds that scholars mainly focus on single risk and certain regions of the world. Second, there is multiple approached used by the literature to study risk management at the local level. Third, little attention is given to the political context in which local risk management takes place.

Originality/value
This paper is a complete literature review of more than 500 peer-reviewed articles published in academic journals regarding risk prevention policies over the past two decades. This paper analyzed the main findings of the current literature to provide a general view of the scholarship and improve the collective understanding of risk management at the local level by providing future research avenues.
The role of community leaders in the eradication of alms begging in Nima, Ghana
Authors: Salifu Adam , Abdul-Karim Abass Umar 
Published: February 2023

Purpose
While the causes and effects of begging are well known, solutions on how to eradicate begging are still elusive in many parts of the developing world. The purpose of this study is to examine the different ways through which community leaders at the local level can contribute to the eradication of begging in one of Ghana’s most densely populated suburbs in the city of Accra.

Design/methodology/approach
This study was undertaken using the qualitative approach, and primary data was collected through interviews, participants observation and focus group discussions with beggars, community leaders and officials of non-governmental organisations at Nima, a suburb of Accra.

Findings
Begging in the suburb of Nima is increasingly becoming a business venture. It is no more an activity that is the preserve of only the weak, the poor, the elderly, the physically challenged, the needy and the marginalised in society. This paper argues that the eradication of begging requires multiple approaches and that community-based leaders must play a central role. This paper identified the provision of alternative sources of livelihood, the naming, shaming and condemnation of unjustified begging in the community, strict boarder control, returning foreign beggars to their home countries, the formulation and enforcement of community anti-begging by-laws and regular sensitisation programs on begging as crucial in reducing or eliminating begging.

Research limitations/implications
While focusing on one Muslim-dominated suburb in Accra ensures a detailed discussion of strategies of eliminating begging from a cultural and religious perspective, the findings of this study may not be applicable to non-Islamic settings and communities where cultural or religious leadership structures do not exist.

Practical implications
This study has demonstrated that the eradication of begging in society cannot have one-size-fit all solution. This paper shows that in societies where cultural and religious leadership structures exist, they must play important roles in the design and implementation of strategies that seek to reduce or eliminate religious begging in society. This implies that formal government agencies and their associated laws alone will not be enough to eradicate or reduce begging under such contexts.

Originality/value
Measures to eradicate begging have often ignored the role of community leaders. This paper contributes to our understanding on this by specifically examining the phenomenon of begging at the micro level and exploring the different ways community leaders can contribute to the eradication of begging in society.