bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protocol summary and statistical analysis plan for the randomized trial of early detection of clinically significant prostate cancer (ProScreen)
Authors: Nevalainen Jaakko , Raitanen Jani , Natunen Kari , Kilpeläinen Tuomas , Rannikko Antti , Tammela Teuvo , Auvinen Anssi ,   the ProScreen Trial Team
Published: May 2023

ABSTRACTIntroductionEvidence on the effectiveness of prostate cancer screening based on prostate-specific antigen is inconclusive and suggests a questionable balance between benefits and harms due to overdiagnosis. However, diagnostic accuracy studies have shown that detection of clinically insignificant prostate cancer can be reduced by magnetic resonance imaging combined with targeted biopsies.The aim of the paper is to describe the analysis of the ProScreen randomized trial to assess the performance of the novel screening algorithm in terms of the primary outcome, prostate cancer mortality, and secondary outcomes as intermediate indicators of screening benefits and harms of screening.MethodsThe trial aims to recruit at least 111,000 men to achieve sufficient statistical power for the primary outcome. Men will be allocated in a 1:3 ratio to the screening and control arms. Interim analysis is planned at 10 years of follow-up, and the final analysis at 15 years. Difference between the trial arms in prostate cancer mortality will be assessed by Gray’s test using intention to screen analysis of randomized men. Secondary outcomes will be the incidence of prostate cancer by disease aggressiveness, progression to advanced prostate cancer, death due to any cause and cost-effectiveness of screening.Ethics and disseminationThe trial protocol was reviewed by the ethical committee of the Helsinki University Hospital (HUS 2910/2017). Results will be disseminated in an international peer-reviewed journal(s) and at scientific meetings.Trial RegistrationNCT03423303STRENGTHS AND LIMITATIONSThis population-based, randomized multicenter trial targeting at recruiting 111,000 men will provide high quality evidence on the effectiveness of a novel screening strategy for prostate cancer mortalityBroad eligibility criteria and pragmatic approach embedded in normal clinical practice enhances the external validity of the trial and provide evidence applicable to decision making in public health and health careChallenges for the trial include the maintenance of high compliance to screening and the extent of opportunistic PSA testing in the population
Sub-national estimates of vitamin A supplementation coverage in children: a geospatial analysis of 45 low and middle-income countries
Authors: Seufert Jacqueline , Krishnan Nandita , Darmstadt Gary L. , Wang Grace , Bärnighausen Till , Geldsetzer Pascal 
Published: May 2023

AbstractVitamin A supplementation (VAS) can protect children from the adverse health consequences of vitamin A deficiency. To inform the geographically precise targeting of VAS programs and provide a benchmark for monitoring progress in reducing geographic disparities in coverage over time, we created high resolution maps (5km x 5km) of the proportion of preschool-age children (6-59 months) covered by VAS in 45 UNICEF designated VAS priority countries using data from the Demographic and Health Surveys program. In addition to prevalence, we estimated absolute VAS coverage and exceedance probabilities using thresholds of 0.5 and 0.7. We found that most countries had coverage levels below 70%. Coverage varied substantially between and within countries. Inter-national variations were most notable in Latin America and the Caribbean, as well as Africa, whereas intra-national variations were greatest in some south Asian and west and central African countries. These maps, especially when used along with high-resolution data on indicators of VAS need, could help VAS programs improve equity.
Population Genetics Analysis ofSLC3A1andSLC7A9Revealed the Etiology of Cystine Stone May Be More Than What Our Current Genetic Knowledge Can Explain
Authors: Wu Chen-Han Wilfred , Badreddine Jad , Chang Joshua , Huang Yu-Ren Mike , Kim Fernando J. , Wild Trevor , Tsai Anne , Meeks Naomi , Da Silva Rodrigo Donalisio , Molina Wilson R. , Schumacher Fredrick R. 
Published: May 2023

AbstractBackgroundCystine stone is a Mendelian genetic disease caused bySLC3A1orSLC7A9. In this study, we aimed to estimate the genetic prevalence of cystine stones and compare it with the clinical prevalence to better understand the disease etiology.MethodsWe analyzed genetic variants in the general population using the 1000 Genomes project and the Human Gene Mutation Database to extract allSLC3A1andSLC7A9pathogenic variants. All variants procured from both databases were intersected. Pathogenic allele frequency, carrier rate, and affected rate were calculated and estimated based on Hardy-Weinberg equilibrium.ResultsWe found that 9 uniqueSLC3A1pathogenic variants were carried by 26 people and 5 uniqueSLC7A9pathogenic variants were carried by 12 people, all of whom were heterozygote carriers. No homozygote, compound heterozygote, or double heterozygote was identified in the 1000 Genome database. Based on the Hardy-Weinberg equilibrium, the calculated genetic prevalence of cystine stone disease is 1 in 30,585.ConclusionThe clinical prevalence of cystine stone has been previously reported as 1 in 7,000, a notably higher figure than the genetic prevalence of 1 in 30,585 calculated in this study. This suggests that the etiology of cystine stone is more complex than what our current genetic knowledge can explain. Possible factors that may contribute to this difference include novel causal genes, undiscovered pathogenic variants, alternative inheritance models, founder effects, epigenetic modifications, environmental factors, or other modifying factors. Further investigation is needed to fully understand the etiology of cystine stone.
Influence of endosymbionts on the reproductive fitness of the tickOrnithodoros moubata
Authors: Florian Taraveau , Thomas Pollet , Maxime Duhayon , Laëtitia Gardès , Hélène Jourdan-Pineau 
Published: May 2023

AbstractOver the past decade, many studies have demonstrated the crucial role of the tick microbiome in tick biology. The soft tickOrnithodoros moubatais a hematophagous ectoparasite ofSuidae, best known for transmitting theAfrican swine fever virus. Its bacterial microbiota is characterized by a high prevalence ofFrancisella-like andRickettsiaendosymbionts. The present study aims to better understand the potential influence of these two major members of the tick microbiota on the reproductive fitness ofO. moubata. A total of 132 adult female ticks were treated with antibiotics using gentamycin or rifampicin added to the blood meal. Half of the ticks were also supplemented with B vitamins to address the nutritional role of endosymbionts. Over two periods of 50 days, several traits related to the reproductive fitness were monitored to investigate the importance ofFrancisellaandRickettsiafor these traits. It appeared that most of the reproductive parameters considered were not affected. However, antibiotic treatments induced an increase in the tick survival, indicating a potential fitness cost of harboring endosymbionts during the tick reproductive cycle. Similarly, 366 first stage nymphs ofOrnithodoros moubatawere exposed to the same treatments for molecular quantification of both endosymbionts. Results from qPCR suggested that the treatments had a bacteriostatic effect on endosymbionts without completely eliminating neitherFrancisella-like endosymbiont norRickettsia.
Directed-evolution mutations of adenine base editor ABE8e improve its DNA-binding affinity and protein stability
Authors: Zhu Haixia , Jiang Xinyi , Wang Lei , Qin Qin , Song Menghua , Huang Qiang 
Published: May 2023

AbstractAdenine base editors (ABEs), consisting of CRISPR-associated (Cas) nickase and deaminase, can convert the A:T base pair to G:C. Previous studies have shown that ABE8e, a directed-evolution variant of ABE7.10 with eight amino-acid mutations in its deaminase TadA-8e, has higher base editing activity than ABE7.10. However, it remains unclear how the directed-evolution mutations of ABE8e increase its editing activity. Here, we combined molecular dynamics (MD) simulations and experimental measurements to elucidate the molecular origin of the activity enhancement by these mutations. MD simulations and microscale thermophoresis measurements showed that TadA-8e has a higher DNA-binding affinity than TadA-7.10, and the main driving force is electrostatic interactions. The directed-evolution mutations increase the positive charge density in the DNA-binding region, thereby enhancing the electrostatic attractions with DNA. We showed that R111 is the key mutation for the enhanced binding to DNA, which explains why the ABE-8e activity was dramatically reduced when R111 was mutated back to the original T. Unexpectedly, we also found that these mutations improve the thermal stability of TadA-8e by ∼12°C (Tm). Our results indicate that the editing activities of ABEs are closely related to their DNA-binding affinity and protein stability, thus providing a rational basis for their optimization.Author SummaryAdenine-to-guanine mutations account for 47% of known disease-causing point mutations in humans. Adenine base editors (ABEs), which can restore the guanine mutation to adenine, are a promising tool for precision gene therapy. ABE8e is the most widely used editor today due to its high editing efficacy and was derived from the first-generation base editor ABE7.10 by directed evolution. Compared to ABE7.10, ABE8e contains 8 directed-evolution amino-acid mutations. Understanding how these mutations affect the efficiency of ABE8e is important for the development of efficient base editors. In this study, we combined computational and experimental approaches to investigate how these mutations affect the editing activity of ABE8e. Our results showed that these directed-evolution mutations improve the DNA binding affinity and the protein stability of ABE8e, by enhancing electrostatic and hydrogen bonding interactions. Therefore, our study provides valuable insights for the design of more efficient base editors.
Regulatory mechanisms in multiple vascular diseases locusLRP1involve repression by SNAIL and extracellular matrix remodeling
Authors: Liu Lu , Henry Joséphine , Liu Yingwei , Jouve Charlène , Georges Adrien , Bouatia-Naji Nabila 
Published: May 2023

AbstractBackgroundGenome-wide association studies (GWAS) implicate common genetic variations in the low-density lipoprotein receptor-related protein 1 locus(LRP1)in risk for multiple vascular diseases and traits. However, the underlying biological mechanisms are unknown.MethodsFine mapping analyses included Bayesian colocalization to identify the most likely causal variant. Human induced pluripotent stem cells (iPSC) were genome-edited using CRISPR-Cas9 to delete or modify candidate enhancer regions, and generateLRP1knockout cell lines (KO). Cells were differentiated into smooth muscle cells (SMCs) through a mesodermal lineage. Transcription regulation was assessed using luciferase reporter assay, transcription factor knockdown and chromatin immunoprecipitation. Phenotype changes in cells were conducted using cellular assays, bulk RNA-sequencing and mass spectrometry.ResultsMulti-trait co-localization analyses pointed at rs11172113 as the most likely causal variant inLRP1for fibromuscular dysplasia, migraine, pulse pressure and pulmonary function trait. We found rs11172113-T allele to associate with higherLRP1expression. Genomic deletion in iPSC-derived SMCs supported rs11172113 to locate in an enhancer region regulatingLRP1expression. We found transcription factors MECP2 and SNAIL to repressLRP1expression through an allele-specific mechanism, involving SNAIL interaction with disease risk allele.LRP1KO decreased iPSC-derived SMCs proliferation and migration. Differentially expressed genes were enriched for collagen-containing extracellular matrix, connective tissue and lung development.LRP1KO showed potentiated canonical TGF-β signaling through enhanced phosphorylation of SMAD2/3. Analyses of protein content of decellularized extracts indicated partial extracellular matrix (ECM) remodeling involving enhanced secretion of CYR61, a known LRP1 ligand involved in vascular integrity and TIMP3, implicated in extracellular matrix maintenance and also known to interact with LRP1.ConclusionsOur findings support allele specificLRP1gene repression by the endothelial-to-mesenchymal transition regulator SNAIL. We propose decreasedLRP1expression in SMCs to remodel the ECM enhanced by TGF- β as a potential mechanism of this pleiotropic locus for vascular diseases.Graphical abstract
iFlpMosaics enable the multispectral barcoding and high-throughput comparative analysis of mutant and wildtype cells
Authors: Garcia-Gonzalez Irene , Gambera Stefano , Regano Alvaro , Rocha Susana F. , Garcia-Ortega Lourdes , Lytvyn Mariya , Diago-Domingo Luis , Sanchez-Muñoz Maria S. , Garcia-Cabero Aroa , Zagorac Ivana , Luo Wen , Fernández-Chacón Macarena , Casquero-Garcia Verónica , Lunella Federica Francesca , Benedito Rui 
Published: May 2023

AbstractTo understand gene function, it is necessary to compare cells carrying the mutated target gene with normal cells. In most biomedical studies, the cells being compared are in different mutant and control animals and therefore do not experience the same epigenetic changes and tissue microenvironment. The experimental induction of genetic mosaics is essential to determine a gene cell-autonomous function and to model the etiology of diseases caused by somatic mutations. Current technologies used to induce genetic mosaics in mice lack either accuracy, throughput or barcoding diversity. Here, we present a large set of new genetic tools and mouse lines that enable Flp recombinase-dependent ratiometric induction and single-cell clonal tracking of multiple fluorescently labeled wildtype and Cre-mutant cells within the same time window and tissue microenvironment. The labeled cells can be profiled by multispectral imaging or by FACS and scRNA-seq. This technology facilitates the induction and analysis of genetic mosaics in any cell type and for any given single or combination of floxed genes. iFlpMosaics enables a more accurate understanding of how induced genetic mutations affect the biology of single cells during tissue development, homeostasis, and disease.
Metabolic flux regulates growth transitions and antibiotic tolerance in uropathogenicEscherichia coli
Authors: Morrison Josiah J. , Banas Daniel A. , Madden Ellen K. , DiBiasio Eric C. , Rowley David C. , Cohen Paul S , Camberg Jodi L. 
Published: May 2023

AbstractReducing growth and limiting metabolism are strategies that allow bacteria to survive exposure to environmental stress and antibiotics. During infection, uropathogenicEscherichia coli(UPEC) may enter a quiescent state that enables them to reemerge after completion of successful antibiotic treatment. Many clinical isolates, including the well characterized UPEC strain CFT073, also enter a metabolite-dependent, quiescent state in vitro that is reversible with cues, including peptidoglycan-derived peptides and amino acids. Here, we show that quiescent UPEC is antibiotic tolerant and demonstrate that metabolic flux in the tricarboxylic acid (TCA) cycle regulates the UPEC quiescent state via succinyl-CoA. We also demonstrate that the transcriptional regulator complex IHF and the FtsZ-interacting protein ZapE, which is important forE. colidivision during stress, are essential for UPEC to enter the quiescent state. Notably, in addition to engaging FtsZ and late-stage cell division proteins, ZapE also interacts directly with TCA cycle enzymes in bacterial two hybrid assays. We report direct interactions between succinate dehydrogenase complex subunit SdhC, the late-stage cell division protein FtsN, and ZapE. These interactions likely enable communication between oxidative metabolism and the cell division machinery in UPEC. Moreover, these interactions are conserved in anE. coliK-12 strain. This work suggests that there is coordination among the two fundamental and essential pathways that regulate overall growth, quiescence, and antibiotic susceptibility.ImportanceUropathogenicEscherichia coli(UPEC) are the leading cause of urinary tract infections (UTIs). Upon invasion into bladder epithelial cells, UPEC establish quiescent intracellular reservoirs that may lead to antibiotic tolerance and recurrent UTIs. Here, we demonstrate using an in vitro system that quiescent UPEC cells are tolerant to ampicillin and have decreased metabolism characterized by succinyl-CoA limitation. We identify the global regulator the IHF complex and the cell division protein ZapE as critical regulators of quiescence and antibiotic tolerance. Lastly, we show ZapE interacts with components of both the cell division machinery and the TCA cycle, and this interaction is conserved in non-pathogenicE. coli, establishing a novel link between cell division and metabolism.
Ischemia/Reperfusion Injury and Oxidative Stress Impair Cardiac Desmin Proteostasis
Authors: Li Zixiao , Jun Seungho , Singh Krishna K. , Calhoun Patrick J. , Keceli Gizem , Patel Krishna , Kadioglu Hikmet , Paolocci Nazareno , Agnetti Giulio 
Published: May 2023

AbstractBackgroundThough acute mortality by myocardial infarction (MI) has declined in past decades, MI still represents one of the leading causes of heart failure (HF) development. We recently demonstrated the accumulation of toxic desmin aggregates in patients with HF of ischemic origin. Since desmin aggregates are toxic for the heart we aimed to test whether their formation can be induced by oxidative stress as a proxy for reperfusion injury, as well as addressing the effects of therapeutic strategies aimed at reducing desmin aggregation with cardiac oxidative stress.Methods and ResultsWe demonstrate here that oxidative stress is able to induce desmin aggregation, acutely, in a cell-specific and dose-dependent fashion. We also show that elevation ofO-linked β-N-acetylglucosamine (O-GlcNAc) prior to or after oxidative stress reduces the formation of toxic desmin aggregates and its pro-aggregating desmin post-translational modifications (PTM). In addition, we show for the first time a role for the transmembrane protease serine 13 (TMPRSS13) with desmin cleavage in response to oxidative stress while desmin’s single cysteine plays a protective role from I/R injury, which is independent of gain or loss of desmin function.ConclusionsThe proliferation of desmin PTM-forms (i.e., proteoforms) and its aggregation hallmark acute and chronic cardiac stress and result in both loss of and gain of desmin function. We report here two novel mechanisms that could be targeted for therapy to preserve desmin homeostasis and cardiac function in the acute settings of oxidative stress and reperfusion injury.
TGFβ controls alveolar type 1 epithelial cell plasticity and alveolar matrisome gene transcription
Authors: Callaway Danielle A. , Penkala Ian J. , Zhou Su , Cardenas-Diaz Fabian , Babu Apoorva , Morley Michael P. , Lopes Mariana , Garcia Benjamin A. , Morrisey Edward E. 
Published: May 2023

ABSTRACTPremature birth disrupts normal lung development and places infants at risk for bronchopulmonary dysplasia (BPD), a disease increasing in incidence which disrupts lung health throughout the lifespan. The TGFβ superfamily has been implicated in BPD pathogenesis, however, what cell lineage it impacts remains unclear. We show thatTgfbr2is critical for AT1 cell fate maintenance and function. Loss ofTgfbr2in AT1 cells during late lung development leads to AT1-AT2 cell reprogramming and altered pulmonary architecture, which persists into adulthood. Restriction of fetal lung stretch and associated AT1 cell spreading through a model of oligohydramnios enhances AT1-AT2 reprogramming.Transcriptomic and proteomic analysis reveal the necessity ofTgfbr2expression in AT1 cells for extracellular matrix production. Moreover, TGFβ signaling regulates integrin transcription to alter AT1 cell morphology, which further impacts ECM expression through changes in mechanotransduction. These data reveal the cell intrinsic necessity of TGFβ signaling in maintaining AT1 cell fate and reveal this cell lineage as a major orchestrator of the alveolar matrisome.
Serine arginine-rich splicing factor (SRSF7) cooperates with the histone methyltransferase KMT5a to promote the type I interferon response via transcriptional activation of IRF7
Authors: Scott Haley M. , Smith Mackenzie H. , Coleman Aja K. , Apostalo Summer L. , Wagner Allison R. , Watson Robert O. , Patrick Kristin L. 
Published: May 2023

SUMMARYTight regulation of macrophage immune gene expression is required to fight infection without risking harmful inflammation. The contribution of RNA binding proteins (RBPs) to shaping the macrophage response to pathogens remains poorly understood. Transcriptomic analysis revealed that a member of the serine/arginine-rich (SR) family of mRNA processing factors, SRSF7, is required for optimal expression of a cohort of interferon stimulated genes (ISGs) in macrophages. Using genetic and biochemical assays, we discovered that in addition to its canonical role in regulating alternative splicing, SRSF7 drives transcription of interferon regulatory transcription factor 7 (IRF7) to promote antiviral immunity. At theIrf7promoter, SRSF7 maximizes STAT1 transcription factor binding and RNA polymerase II elongation via cooperation with the H4K20me1 histone methyltransferase KMT5a (SET8). These studies define an unorthodox role for an SR protein in activating transcription and reveal an unappreciated RNA binding protein-chromatin network that orchestrates macrophage antiviral gene expression.
Organizational change strategies: the role of leaders, change agents, and firm structures
Authors: Leventhal Emily 
Published: May 2023

Purpose
This paper aims to review the latest management developments across the globe and pinpoint practical implications from cutting-edge research and case studies.

Design/methodology/approach
This briefing is prepared by an independent writer who adds their own impartial comments and places the articles in context.

Findings
Organizational development strategies must be carefully considered before they are enacted, based on involvement, the issue at hand, the existing structures of the firm, and managerial structures.

Originality/value
The briefing saves busy executives, strategists and researchers hours of reading time by selecting only the very best, most pertinent information and presenting it in a condensed and easy-to-digest format.