bluuebunny/crossref_metadata_2025_split huggingface dataset:
HNF1α transcriptional activation and repression maintain human islet α and β cell function
Authors: Qian Mollie F. , Bevacqua Romina J. , Nguyen Vy M. , Liu Xiong , Zhao Weichen , Chang Charles A. , Gu Xueying , Dai Xiao-Qing , MacDonald Patrick E. , Kim Seung K. 
Published: September 2022

ABSTRACTHNF1A haploinsufficiency underlies the most common form of human monogenic diabetes (HNF1A-MODY) and hypomorphic HNF1A variants confer type 2 diabetes risk, but a lack of experimental systems has limited our understanding of how the transcription factor HNF1α regulates adult human islet function. Here, we combined human islet genetics, RNA sequencing, Cleavage Under Targets & Release Using Nuclease (CUT&RUN) chromatin mapping, patch-clamp electrophysiology and transplantation-based assays to elucidate HNF1α-regulated mechanisms in mature pancreatic α and β cells. shRNA-mediated suppression of HNF1A in primary human pseudoislets led to blunted insulin output and dysregulated glucagon secretion both in vitro and after transplantation into immunocompromised mice, recapitulating phenotypes observed in HNF1A-MODY patients. These deficits corresponded with altered expression of genes encoding factors critical for hormone secretion, including calcium channel subunits, ATP-transporters and extracellular matrix constituents. Additionally, HNF1A loss led to upregulation of transcriptional repressors, providing evidence for a mechanism of transcriptional de-repression through HNF1α. CUT&RUN mapping of HNF1α DNA-binding sites in primary human islets verified that a subset of HNF1α-regulated genes were direct targets. These data provide unprecedented mechanistic links between HNF1A loss and diabetic phenotypes in mature human α and β cells.
Single-nucleoid architecture reveals heterogeneous packaging of mitochondrial DNA
Authors: Isaac R. Stefan , Tullius Thomas W. , Hansen Katja G. , Dubocanin Danilo , Couvillion Mary , Stergachis Andrew B. , Churchman L. Stirling 
Published: September 2022

AbstractCellular metabolism relies on the regulation and maintenance of mitochondrial DNA (mtDNA). Hundreds to thousands of copies of mtDNA exist in each cell, yet because mitochondria lack histones or other machinery important for nuclear genome compaction, it remains unresolved how mtDNA is packaged into individual nucleoids. In this study, we used long-read single-molecule accessibility mapping to measure the compaction of individual full-length mtDNA molecules at nucleotide resolution. We found that, unlike the nuclear genome, human mtDNA largely undergoes all-or-none global compaction, with the majority of nucleoids existing in an inaccessible, inactive state. Highly accessible mitochondrial nucleoids are co-occupied by transcription and replication machinery and selectively form a triple-stranded D-loop structure. In addition, we showed that the primary nucleoid-associated protein TFAM directly modulates the fraction of inaccessible nucleoids both in vivo and in vitro and acts via a nucleation-and-spreading mechanism to coat and compact mitochondrial nucleoids. Together, these findings reveal the primary architecture of mtDNA packaging and regulation in human cells.
Disruptions in cell fate decisions and transformed enteroendocrine cells drive intestinal tumorigenesis in Drosophila
Authors: Quintero Maria , Bangi Erdem 
Published: September 2022

SUMMARYMost epithelial tissues are maintained by stem cells that produce the different cell lineages required for proper tissue function. Constant communication between different cell types that make up a tissue is essential to ensure that all cell lineages are produced at appropriate numbers and to mount regenerative responses to injury, infection, and other environmental stresses. Cancer-driving alterations change the intrinsic properties of transformed cells and disrupt stem cell regulation, cell fate decisions, and cell-cell communication within transformed tissue. However, mechanisms by which these processes are disrupted and co-opted to support tumorigenesis are not well understood. Here, we report a novel genetic platform, PromoterSwitch, that allows targeting of genetic manipulations to a small subset of cells of any tissue or cell type of interest and all their subsequent progeny. We use this technology to generate large, transformed clones derived from individual stem/progenitor cells in the adult Drosophila intestine. We show that cancer-driving genetic alterations representing common colon tumor genome landscapes drive disruptions in cell fate decisions within transformed clones and changes in the relative abundance of different intestinal cell lineages. We also uncover a critical, context-dependent role for the differentiated, hormone-producing enteroendocrine (EE) cells in the growth and maintenance of transformed clones. Our analysis in different genetic contexts provides insights into how the intrinsic properties of transformed cells —dictated by the genetic alterations they carry— determine their response to their environment and dependence on niche signals. A better mechanistic understanding of disruptions of cell-cell communication, stem cell regulation, and cell fate decisions within tumors could reveal novel vulnerabilities and druggable regulatory nodes that can be exploited for therapy. Understanding how tissues respond to the emergence of cells with cancer-driving genetic alterations also provides insights into stem cell biology and epithelial homeostasis.
Top-down design of protein nanomaterials with reinforcement learning
Authors: Lutz Isaac D. , Wang Shunzhi , Norn Christoffer , Borst Andrew J. , Zhao Yan Ting , Dosey Annie , Cao Longxing , Li Zhe , Baek Minkyung , King Neil P. , Ruohola-Baker Hannele , Baker David 
Published: September 2022

AbstractThe multisubunit protein assemblies that play critical roles in biology are the result of evolutionary selection for function of the entire assembly, and hence the subunits in structures such as icosahedral viral capsids often fit together with remarkable shape complementarity1,2. In contrast, the large multisubunit assemblies that have been created byde novoprotein design, notably the icosahedral nanocages used in a new generation of potent vaccines3–7, have been built by first designing symmetric oligomers with cyclic symmetry and then assembling these into nanocages while keeping the internal structure fixed8–14, which results in more porous structures with less extensive shape matching between the components. Such hierarchical “bottom-up” design approaches have the advantage that one interface can be designed and validated in the context of the cyclic oligomer building block15,16, but the disadvantage that the structural and functional features of the assemblies are limited by the properties of the predesigned building blocks. To overcome this limitation, we set out to develop a “top-down” reinforcement learning based approach to protein nanomaterial design in which both the structures of the subunits and the interactions between them are built up coordinately in the context of the entire assembly. We developed a Monte Carlo tree search (MCTS) method17,18which assembles protein monomer structures in the context of an overall architecture guided by a loss function which enables specification of any desired overall structural properties such as shape and porosity. We demonstrate the power of the approach by designing hyperstable icosahedral assemblies more compact than any previously observed protein icosahedral structure (designed or naturally occurring), that have very low porosity and are robust to fusion and display of proteins as complex as influenza hemagglutinin. CryoEM structures of two designs are very close to the computational design models. Our top-down reinforcement learning approach should enable the design of a wide variety of complex protein nanomaterials by direct optimization of overall system properties.
MRCK controls myosin II activation in the polarized cortex of mouse oocytes and promotes spindle rotation and male pronucleus centration
Authors: Bourdais Anne , Dehapiot Benoit , Halet Guillaume 
Published: September 2022

AbstractAsymmetric meiotic divisions in oocytes rely on spindle positioning in close vicinity to the cortex. In mouse oocytes arrested at metaphase II, eccentric spindle positioning is associated with a chromatin-induced remodeling of the overlying cortex, including the build-up of an actin cap surrounded by a ring of activated myosin II. While the role of the actin cap in promoting polar body formation was demonstrated, the role of ring myosin II, and its mechanism of activation, have remained elusive. Here, we show that ring myosin II activation requires Myotonic dystrophy kinase-Related Cdc42-binding Kinase (MRCK), downstream of polarized Cdc42. During anaphase-II, inhibition of MRCK resulted in spindle rotation defects and a decreased rate of polar body emission. Remarkably, some oocytes eventually achieved spindle rotation by disengaging one cluster of chromatids from the anaphase spindle. We show that the MRCK/myosin II pathway also regulates the flattening of the fertilization cone to initiate male pronucleus centration. These findings provide novel insights into mammalian oocyte polarization and the role of cortical myosin II in orchestrating asymmetric division.
Impact of COVID-19 pandemic on the incidence of suicidal behaviors: a retrospective analysis of integrated electronic health records in a 7.5-million population
Authors: Valero-Bover Damià , Fradera Marc , Carot-Sans Gerard , Parra Isabel , Piera Jordi , Pontes Caridad , Palao Diego 
Published: September 2022

AbstractThe COVID-19 pandemic has caused a remarkable psychological overwhelming and an increase of stressors that may trigger suicidal behaviors. However, its impact on the rate of suicidal behaviors has been poorly reported. We conducted a population-based retrospective analysis of all suicidal behaviors attended in healthcare centers of Catalonia (North-East Spain; 7.5-million inhabitants) between January 2017 and June 2022. We retrieved data from the episode, including an assessment of suicide risk and the individual’s socioeconomic and clinical characteristics. Data were summarized yearly and for the periods before and after the onset of the COVID-19 pandemic in Spain in March 2020. The analysis included 26,458 episodes of suicidal behavior (21,920 individuals); of them, 16,414 (62.0%) were suicide attempts. The monthly moving average ranged between 300 and 400 episodes until July 2020, and progressively increased to over 600 episodes monthly. In the post-pandemic period, suicidal ideation increased at the expense of suicidal attempts. Cases showed a lower suicide risk; the percentage of females and younger individuals increased, whereas the prevalence of classical risk factors, such as living alone or lacking a family network and a history of psychiatric diagnosis, decreased. In summary, suicidal behaviors have increased during the COVID-19 pandemic, with more episodes of suicidal ideations without attempt and younger and lower risk profiles.
Activity-based directed evolution of a membrane editor in mammalian cells
Authors: Tei Reika , Bagde Saket R. , Fromme J. Christopher , Baskin Jeremy M. 
Published: September 2022

ABSTRACTCellular membranes contain numerous lipid species, and efforts to understand the biological functions of individual lipids have been stymied by a lack of approaches for controlled modulation of membrane composition in situ. Here, we present a strategy for editing phospholipids, the most abundant lipids in biological membranes. Our membrane editor is based upon a bacterial phospholipase D (PLD), which exchanges phospholipid head groups through hydrolysis or transphosphatidylation of phosphatidylcholine with water or exogenous alcohols. Exploiting activity-dependent directed enzyme evolution in mammalian cells, we developed and structurally characterized a family of “superPLDs” with up to 100-fold higher activity than wildtype PLD. We demonstrated the utility of superPLDs for both optogenetics-enabled editing of phospholipids within specific organelle membranes in live cells and biocatalytic synthesis of natural and unnatural designer phospholipidsin vitro. Beyond the superPLDs, activity-based directed enzyme evolution in mammalian cells is a generalizable approach to engineer additional chemoenzymatic biomolecule editors.
Intravenous administration of human umbilical cord mesenchymal stromal cells leads to an inflammatory response in the lung
Authors: Pichardo Alejandra Hernandez , Wilm Bettina , Liptrott Neill , Murray Patricia 
Published: September 2022

AbstractMesenchymal stromal cells (MSCs) administered intravenously (IV) have shown efficacy in pre-clinical models of various diseases. This is despite the cells not reaching the site of injury due to entrapment in the lungs. The ability of MSCs to modulate immune responses has been proposed as one of the mechanisms by which these cells provide therapeutic benefits, irrespective of whether they are sourced from bone marrow, adipose tissue or umbilical cord. To better understand how MSCs affect innate immune cell populations in the lung, we evaluated the percentage, distribution and phenotype of neutrophils, monocytes and macrophages by flow cytometry and histological analyses after delivering human umbilical cord-derived MSCs (hUC-MSCs) IV into immunocompetent mice. After 2 h, we observed a sharp increase in neutrophils, and pro-inflammatory monocytes and macrophages. Moreover, these immune cells localised in the vicinity of the MSCs suggesting an active role in their clearance. By 24 h, we detected an increase in anti-inflammatory monocytes and macrophages. These results suggest that the IV injection of hUC-MSCs leads to an initial inflammatory phase in the lung shortly after injection, followed by a resolution phase 24 h later.
The development of digital thread: the relations to digital twin and its industrial applications
Authors: Zhang Yuxin , Dong Wei , Wang Junyan , Che Congcong , Li Lefei 
Published: September 2022

PurposeThrough this research study, the authors found that digital thread has made significant progress in the life cycle management of the US Air Force. The authors hope that by reviewing similar studies in the aerospace field, the meaning of digital thread can be summarized and applied to a wider range of fields. In addition, theoretically, the definition of digital twin and digital thread are not unified. The authors hope that the comparison of digital thread and digital twin will better enable scholars to distinguish between the two concepts. Besides, the authors are also looking forward that more people will realize the significance of digital thread and carry out future research.Design/methodology/approachComplete research about digital thread and the relevant concept of the digital twin is conducted. First, by searching in Google Scholar with the keyword “digital thread”, the authors filter results and save literature with high relevance to digital thread. The authors also track these papers’ references for more paper of digital thread and digital twin. After removing the duplicate and low-relevance literature, 72 digital thread-related literature studies are saved and further analyzed from the perspective of time development, application field and research directions.FindingsDigital thread application in industries other than the aviation manufacturing industry is still relatively few, and the research on the application of digital thread in real industrial scenarios is mainly at the stage of framework design and design-side decision optimization. In addition, the digital thread needs a new management mechanism and organizational structure to realize landing. The new management mechanism and the process can adapt to the whole life cycle management process based on the digital thread, manage the data security and data update, and promote the digital thread to play a better effect on the organizational management.Practical implicationsBased on a review of digital thread, future research directions and usage suggestions are given. The fault diagnosis of high-speed train bogie as an example shows the effectiveness of the method and also partially demonstrates the advantages and effects brought by the digital thread connecting the data models at various stages.Originality/valueThis paper first investigates and analyzes the theoretical connotation and research progress of digital thread and gives a complete definition of digital thread from the perspective of the combination of digital thread and digital twins. Next, the research process of digital thread is reviewed, and the application fields, research directions and achievements in recent years are summarized. Finally, taking the fault diagnosis of high-speed train bogie as an example partially demonstrates the advantages and effects brought by the digital thread connecting the data models at various stages.
How technological, environmental and managerial performance contribute to the productivity change of Malaysian construction firms
Authors: Azman Mohd Azrai , Abdul-Samad Zulkiflee , Lee Boon L. , Skitmore Martin , Rajendra Darmicka , Chuweni Nor Nazihah 
Published: September 2022

PurposeTotal factor productivity (TFP) change is an important driver of long-run economic growth in the construction sector. However, examining TFP alone is insufficient to identify the cause of TFP changes. Therefore, this paper employs the infrequently used Geometric Young Index (GYI) and stochastic frontier analysis (SFA) to measure and decompose the TFP Index (TFPI) at the firm-level from 2009 to 2018 based on Malaysian construction firms' data.Design/methodology/approachTo improve the TFPI estimation, normally unobserved environmental variables were included in the GYI-TFPI model. These are the physical operation of the firm (inland versus marine operation) and regional locality (West Malaysia versus East Malaysia). Consequently, the complete components of TFPI (i.e. technological, environmental, managerial, and statistical noise) can be accurately decomposed.FindingsThe results reveal that TFP change is affected by technological stagnation and improvements in technical efficiency but a decline in scale-mix efficiency. Moreover, the effect of environmental efficiency on TFP is most profound. In this case, being a marine construction firm and operating in East Malaysia can reduce TFPI by up to 38%. The result, therefore, indicates the need for progressive policies to improve long-term productivity.Practical implicationsMonitoring and evaluating productivity change allows an informed decision to be made by managers/policy makers to improve firms' competitiveness. Incentives and policies to improve innovation, competition, training, removing unnecessary taxes and regulation on outputs (inputs) could enhance the technological, technical and scale-mix of resources. Furthermore, improving public infrastructure, particularly in East Malaysia could improve regionality locality in relation to the environmental index.Originality/valueThis study contributes to knowledge by demonstrating how TFP components can be completely modelled using an aggregator index with good axiomatic properties and SFA. In addition, this paper is the first to apply and include the GYI and environmental variables in modelling construction productivity, which is of crucial importance in formulating appropriate policies.
Food start-ups: leveraging digital marketing and disruptive information systems innovations to survive in the post-COVID environment
Authors: Almansour Mohammed 
Published: September 2022

PurposeThe COVID-19 pandemic impacted the food and beverage sector very severely. The complete breakdown of the supply chain and lack of customers was particularly challenging for start-ups in the industry. Those that survived were the ones who made a timely and smooth transition in business models to become more technology driven. However, the issues faced and the ground realities of the extent of struggle that these start-ups went through are less understood in the scholarly literature, with most accounts being anecdotal. The purpose of this paper is to address these issues.Design/methodology/approachThe present study attempts to bridge this gap by conducting a qualitative study to collect data from 35 owners/employees of food and beverage start-ups and using the grounded theory approach to code it and identify key themes.FindingsContent analysis of the 35 responses revealed three main themes: the impact of the COVID-19 pandemic on operations of food and beverage start-ups, challenges due to the onset of the COVID-19 pandemic and combating the pandemic, divided into seven subthemes: differences in operations pre- and post-COVID, key changes experienced in operations post-COVID, problems arising in operations due to the pandemic, problems in the use of digital marketing due to the pandemic, problems in the use of technological platforms due to the pandemic, using innovative approaches and technological innovations and using disruptive technologies.Originality/valueThe study contributes novel insights by investigating the changes experienced by food and beverage start-ups due to the pandemic, the innovations introduced by them and the perception about the role of disruptive technologies in their postpandemic operations of food and beverage start-ups.
A field study of age discrimination in the workplace: the importance of gender and race‒pay the gap
Authors: Drydakis Nick , Paraskevopoulou Anna , Bozani Vasiliki 
Published: September 2022

PurposeThe study examines whether age intersects with gender and race during the initial stage of the hiring process and affects access to vacancies outcomes and wage sorting.Design/methodology/approachIn order to answer the research question, the study collects data from four simultaneous field experiments in England. The study compares the labour market outcomes of younger White British men with those of older White British men and women, and with those of older Black British men and women. The study concentrates on low-skilled vacancies in hospitality and sales in the private sector.FindingsThe results of this study indicate that older White British men and women, as well as older Black British men and women, experience occupational access constraints and are sorted into lower-paid jobs than younger White British men. The level of age discrimination is found to be higher for Black British men and women. In addition, Black British women experience the highest level of age discrimination. These patterns may well be in line with prejudices against racial minority groups and stereotypical sexist beliefs that the physical strengths and job performance of women decline earlier than those do for men.Practical implicationsIf prejudices against older individuals are present, then anti-discrimination legislation may be the appropriate response, especially for racial minorities and women. Eliminating age discrimination in selection requires firms to adopt inclusive human resources (HR) policies at the earliest stages of the recruitment process.Originality/valueThis research presents for the first-time comparisons of access to vacancies and wage sorting between younger male racial majorities and older male racial majorities, older female racial majorities, older male racial minorities, and older female racial minorities. In addition, the driven mechanism of the assigned differences is explored. Because the study has attempted to minimise the negative employer stereotypesvis-à-visolder employees, with respect to the employees' motivation, productivity, and health, such prejudices against older individuals may be considered taste-based discrimination.