bluuebunny/crossref_metadata_2025_split huggingface dataset:
Economic Evaluation of Hypertension screening in Iran using Markov model
Authors: Daroudi Rajabali , Akbari Sari Ali , Zamandi Mahmoud , Yousefi Elham 
Published: April 2024

AbstractIntroduction and purposeHypertension is one of the most common non-communicable diseases in the world. However, in LMCs, there is not enough evidence-based information about the cost-effectiveness of preventive interventions for hypertension. Therefore, the purpose of this study is to conduct an economic evaluation of high blood pressure screening strategies in Iran in 2020.MethodWe did an economic evaluation of 9 blood pressure screening strategies, including screening annually or every two or three years from the ages of 30, 40, or 50, using the Markov model. The Markov model was designed and implemented based on the natural history of cardiovascular disease in the 2020 TreeAge Pro software. The quality-adjusted life years and the average cost of high blood pressure screening and treatment per person were estimated from society’s perspective for the lifetime. Input data of the model were derived from published literature, expert opinion, and available data sourcesFindingsAll screening interventions were more costly and more effective compared to no screening. Five strategies, including screening every three years from the age of 50, 40, and 30 years and screening every two years and annually from the age of 30, were undominated. Incremental cost-effectiveness ratios for these strategies ranged from $90.5 to $38,289.57. Probabilistic sensitivity analysis indicated that, at a cost-effectiveness threshold close to one times the GDP per capita, screening every two or three years from age 30 had the highest cost-effectiveness, with probabilities of 0.589 and 0.361, respectively.ConclusionBased on the findings of the economic evaluation, all screening strategies are more cost-effective compared to no screening, and among the screening strategies, considering about one times the GDP per capita as the cost-effectiveness threshold, a screening strategy every two years, starting at the age of 30, is the most cost-effective strategy.
Molecular differences between neonatal and adult stria vascularis from organotypic explants and transcriptomics
Authors: Thulasiram Matsya Ruppari , Yamamoto Ryosuke , Olszewski Rafal T. , Gu Shoujun , Morell Robert J. , Hoa Michael , Dabdoub Alain 
Published: April 2024

SummaryThe stria vascularis (SV), part of the blood-labyrinth barrier, is an essential component of the inner ear that regulates the ionic environment required for hearing. SV degeneration disrupts cochlear homeostasis, leading to irreversible hearing loss, yet a comprehensive understanding of the SV, and consequently therapeutic availability for SV degeneration, is lacking. We developed a whole-tissue explant model from neonatal and adult mice to create a robust platform for SV research. We validated our model by demonstrating that the proliferative behaviour of the SVin vitromimics SVin vivo,providing a representative model and advancing high-throughput SV research. We also provided evidence for pharmacological intervention in our system by investigating the role of Wnt/β-catenin signaling in SV proliferation. Finally, we performed single-cell RNA sequencing fromin vivoneonatal and adult mouse SV and revealed key genes and pathways that may play a role in SV proliferation and maintenance. Together, our results contribute new insights into investigating biological solutions for SV-associated hearing loss.SignificanceHearing loss impairs our ability to communicate with people and interact with our environment. This can lead to social isolation, depression, cognitive deficits, and dementia. Inner ear degeneration is a primary cause of hearing loss, and our study provides an in depth look at one of the major sites of inner ear degeneration: the stria vascularis. The stria vascularis and associated blood-labyrinth barrier maintain the functional integrity of the auditory system, yet it is relatively understudied. By developing a newin vitromodel for the young and adult stria vascularis and using single cell RNA sequencing, our study provides a novel approach to studying this tissue, contributing new insights and widespread implications for auditory neuroscience and regenerative medicine.Highlights- We established an organotypic explant system of the neonatal and adult stria vascularis with an intact blood-labyrinth barrier.- Proliferation of the stria vascularis decreases with agein vitro, modelling its proliferative behaviourin vivo.- Pharmacological studies using ourin vitroSV model open possibilities for testing injury paradigms and therapeutic interventions.- Inhibition of Wnt signalling decreases proliferation in neonatal stria vascularis.- We identified key genes and transcription factors unique to developing and mature SV cell types using single cell RNA sequencing.
Expansion ofin vitro Toxoplasma gondiicysts using enzymatically enhanced ultrastructure expansion microscopy
Authors: Bondarenko Kseniia , Limoge Floriane , Pedram Kayvon , Gissot Mathieu , Young Joanna C. 
Published: April 2024

AbstractExpansion microscopy (ExM) is an innovative approach to achieve super-resolution images without using super-resolution microscopes, based on the physical expansion of the sample. The advent of ExM has unlocked super-resolution imaging for a broader scientific circle, lowering the cost and entry skill requirements to the field. One of its branches, ultrastructure ExM (U-ExM), has become popular among research groups studying Apicomplexan parasites, including the acute stage ofToxoplasma gondiiinfection. The chronic cyst-forming stage ofToxoplasma, however, resists U-ExM expansion, impeding precise protein localisation. Here, we solve thein vitrocyst’s resistance to denaturation required for successful U-ExM of the encapsulated parasites. As the cyst’s main structural protein CST1 contains a mucin domain, we added an enzymatic digestion step using the pan-mucinase StcE prior to the expansion protocol. This allowed full expansion of the cysts in fibroblasts and primary neuronal cell culture without interference with the epitopes of the cyst-wall associated proteins. Using StcE-enhanced U-ExM, we clarified the shape and location of the GRA2 protein important for establishing a normal cyst. Expanded cysts revealed GRA2 granules spanning across the cyst wall, with a notable presence observed outside on both sides of the CST1-positive layer.ImportanceToxoplasma gondiiis an intracellular parasite capable of establishing long-term chronic infection in nearly all warm-blooded animals. During the chronic stage, parasites encapsulate into cysts in a wide range of tissues but particularly in neurons of the central nervous system and in skeletal muscle. Current anti-Toxoplasma drugs do not eradicate chronic parasites and leave behind a reservoir of infection. As the cyst is critical for both transmission and pathology of the disease, we need to understand more fully the biology of the cyst and its vulnerabilities.The advent of a new super-resolution approach called ultrastructure expansion microscopy allowed in-depth studies of the acute stage ofToxoplasmainfection but not the cyst-forming stage, which resists protocol-specific denaturation. Here, we show that an additional step of enzymatic digestion using mucinase StcE allows full expansion of theToxoplasmacysts, offering a new avenue for a comprehensive examination of the chronic stage of infection using an accessible super-resolution technique.
Improved mouse models of the small intestine microbiota using region-specific sampling from humans
Authors: Culver Rebecca N. , Spencer Sean Paul , Violette Arvie , Lemus Silva Evelyn Giselle , Takeuchi Tadashi , Nafarzadegan Ceena , Higginbottom Steven K. , Shalon Dari , Sonnenburg Justin , Huang Kerwyn Casey 
Published: April 2024

AbstractOur understanding of region-specific microbial function within the gut is limited due to reliance on stool. Using a recently developed capsule device, we exploit regional sampling from the human intestines to develop models for interrogating small intestine (SI) microbiota composition and function.In vitroculturing of human intestinal contents produced stable, representative communities that robustly colonize the SI of germ-free mice. During mouse colonization, the combination of SI and stool microbes altered gut microbiota composition, functional capacity, and response to diet, resulting in increased diversity and reproducibility of SI colonization relative to stool microbes alone. Using a diverse strain library representative of the human SI microbiota, we constructed defined communities with taxa that largely exhibited the expected regional preferences. Response to a fiber-deficient diet was region-specific and reflected strain-specific fiber-processing and host mucus-degrading capabilities, suggesting that dietary fiber is critical for maintaining SI microbiota homeostasis. These tools should advance mechanistic modeling of the human SI microbiota and its role in disease and dietary responses.
Cryo-EM Structure of HRSL Domain Reveals Activating Crossed Helices at the Core of GCN2
Authors: Solorio-Kirpichyan Kristina , Fan Xiao , Golovenko Dmitrij , Korostelev Andrei A. , Yan Nieng , Korennykh Alexei 
Published: April 2024

AbstractGCN2 is a conserved receptor kinase activating the Integrated Stress Response (ISR) in eukaryotic cells. The ISR kinases detect accumulation of stress molecules and reprogram translation from basal tasks to preferred production of cytoprotective proteins. GCN2 stands out evolutionarily among all protein kinases due to the presence of ahistidyl tRNAsynthetase-like (HRSL) domain, which arises only in GCN2 and is located next to the kinase domain. How HRSL contributes to GCN2 signaling remains unknown. Here we report a 3.2 Å cryo-EM structure of HRSL from thermotolerant yeastKluyveromyces marxianus. This structure shows a constitutive symmetrical homodimer featuring a compact helical-bundle structure at the junction between HRSL and kinase domains, in the core of the receptor. Mutagenesis demonstrates that this junction structure activates GCN2 and indicates that our cryo-EM structure captures the active signaling state of HRSL. Based on these results, we put forward a GCN2 regulation mechanism, where HRSL drives the formation of activated kinase dimers. Remaining domains of GCN2 have the opposite role and in the absence of stress they help keep GCN2 basally inactive. This autoinhibitory activity is relieved upon stress ligand binding. We propose that the opposing action of HRSL and additional GCN2 domains thus yields a regulated ISR receptor.Significance statementRegulation of protein synthesis (translation) is a central mechanism by which eukaryotic cells adapt to stressful conditions. In starving cells, this translational adaptation is achieved via the receptor kinase GCN2, which stays inactive under normal conditions, but is switched on under stress. The molecular mechanism of GCN2 switching is not well understood due to the presence of a structurally and biochemically uncharacterizedhistidyl tRNAsynthetase-like domain (HRSL) at the core of GCN2. Here we use single-particle cryo-EM and biochemistry to elucidate the structure and function of HRSL. We identify a structure at the kinase/HRSL interface, which forms crossed helices and helps position GCN2 kinase domains for activation. These data clarify the molecular mechanism of GCN2 regulation.
Reliability of self-reported risk factors for age-related brain disease
Authors: Tack Reinier W.P. , Senff Jasper R. , Kimball Tamara N. , Prapiadou Savvina , Yechoor Nirupama , Rosand Jonathan , Singh Sanjula D. , Anderson Christopher D. 
Published: April 2024

AbstractImportancemodifiable risk factors, including hypertension, hypercholesterolemia, diabetes, kidney disease, hearing impairment, and being overweight, increase risk of stroke, dementia, and late life depression (LLD), but may be poorly understood by patients.ObjectiveTo aid in the design of brain health risk stratification tools, we aimed to determine whether self-reported modifiable risk factors can identify at-risk patients on a population level.Designcohort study using cross-sectional data of ten iterations of the National Health and Examination Surveys (NHANES) from 1999 to 2018. Analyses were conducted between February and April of 2024.SettingUS population-based cohortsParticipantsall participants who had both questionnaire data and objective measurements available.Exposurewe collected data on answers to common questions and compared these to objectively measured risk factors for age-related brain disease.Main outcomes and measureswe compared answers to simple questions to objectively measured risk factors. We reported means and 95% confidence intervals of objective measurements, created confusion matrices to determine common metrics, and compared performance of individual questions. We defined a question reliable if performance, measured through F1 scores, was > 0.7, as moderately reliable if F1 score was 0.5-0.7 and as unreliable if F1 score was < 0.5.ResultsParticipants with both objective measurements and questionnaire data ranged from 16,966 (median age 32, 9,113 [20%] black, 19,993 [45%] white) in hearing impairment to 63,834 (median age 39, 14,156 [22%] black, 25,754 [40%] white) in diabetes. Mean values of objective measurements were significantly increased across all risk factors in patients that responded “Yes” to common questions on their presence compared to those who answered “No”. Performance of questions in identifying at-risk patients measured by F1 score was 0.25 in kidney disease, 0.44 in hypercholesterolemia, 0.56 in hypertension, 0.59 in hearing impairment, 0.71 in diabetes and 0.81 in being overweight.Conclusion and relevancein this study of multiple cohorts of up to 63,834 Americans, self-reported awareness of meeting clinical criteria for diabetes or being overweight were reliable, hypertension or hearing impairment were moderately reliable, and hypercholesterolemia or kidney disease were unreliable. These results could be used to guide construction of risk factor screening tools.
Plasmodium knowlesiinfection is associated with elevated circulating biomarkers of brain injury and endothelial activation
Authors: Bertran-Cobo Cesc , Dumont Elin , Noordin Naqib Rafieqin , Lai Meng-Yee , Stone William , Tetteh Kevin KA , Drakeley Chris , Krishna Sanjeev , Lau Yee-Ling , Wassmer Samuel C 
Published: April 2024

AbstractIntroductionMalaria remains a major public health concern with substantial morbidity and mortality worldwide. In Malaysia, the emergence ofPlasmodium knowlesihas led to a surge in zoonotic malaria cases and deaths in recent years. Signs of cerebral involvement have been observed in a non-comatose, fatal case of severe knowlesi infection, but the potential impact of this malaria species on the brain remains underexplored. To address this gap, we investigated circulating levels of brain injury, inflammation, and vascular biomarkers in a cohort of knowlesi-infected patients and controls.MethodsArchived plasma samples from 19 patients with confirmed symptomatic knowlesi infection and 19 healthy, age-matched controls from Peninsular Malaysia were analysed. A total of 52 plasma biomarkers of brain injury, inflammation, and vascular activation were measured using Luminex and SIMOA assays. Wilcoxon tests were used to examine group differences, and biomarker profiles were explored through hierarchical clustering heatmap analysis.ResultsBonferroni-corrected analyses revealed significantly elevated brain injury biomarker levels in knowlesi-infected patients, including S100B (p<0.0001), Tau (p=0.0007), UCH-L1 (p<0.0001), αSyn (p<0.0001), Park7 (p=0.0006), NRGN (p=0.0022), and TDP-43 (p=0.005). Compared to controls, levels were lower in the infected group for BDNF (p<0.0001), CaBD (p<0.0001), CNTN1 (p<0.0001), NCAM-1 (p<0.0001), GFAP (p=0.0013), and KLK6 (p=0.0126). Hierarchical clustering revealed distinct group profiles for circulating levels of brain injury and vascular activation biomarkers.ConclusionsOur findings highlight for the first time the impact ofPlasmodium knowlesiinfection on the brain, with distinct alterations in cerebral injury and endothelial activation biomarker profiles compared to healthy controls. Further studies are warranted to investigate the pathophysiology and clinical significance of these altered surrogate markers, through both neuroimaging and long-term neurocognitive assessments.
Unveiling the threat: Characterization ofClostridioides difficileInfection in the Northwest Region of Buenos Aires between 2019-2023 and Associated Risk Factors redefined through a Meta-Analysis
Authors: Barbero Angela María , Moriconi Nicolás Diego , Palma Sabina , Celano Josefina , Balbi María Gracia , Morro Lorenzo Sebastián , Calvo Zarlenga María Martina , Suárez Jorgelina , Martínez María Guadalupe , Machain Mónica Graciela , Altamiranda Carlos Gabriel , Erbiti Gabriel , Hernández Del Pino Rodrigo Emanuel , Pasquinelli Virginia 
Published: April 2024

AbstractClostridioides difficilestands as the leading cause of hospital acquired enteric infection in developed countries. In Argentina, the epidemiology ofClostridioides difficileinfection (CDI) is currently poorly characterized. Therefore, we conducted a retrospective case-control study evaluating the prevalence of CDI in 249 stool samples collected between 2019 and 2023 in the Northwest region of Buenos Aires. The presence ofC. difficilewas detected by combining three techniques (EIA, PCR and toxigenic culture) in a diagnostic algorithm. Clinical and demographic data from patients was also analyzed to identify CDI-associated risk factors. 1 in 5 patients presentedC. difficileas the etiological agent of diarrhea and the 80% of CDI+ cases carried toxigenic strains, with a third of cases acquired in the community. Age ≥69 years, previous use of antibiotics, previous hospitalization and previous episodes of CDI emerged as predisposing factors for CDI in our study cohort. Blood parameters such as an elevated number of leukocytes and platelets, a decreased basophil count, and an increased urea concentration were identified as indicators of CDI. We also carried out a systematic review and a meta-analysis where we contrasted our results with 39 studies selected from different countries around the world. At the global level, the meta-analysis highlighted advanced age, previous consumption of antibiotics and previous hospitalization as CDI risk factors and the leukocyte count as an indicator of CDI. These results emphasize the importance of epidemiological studies and reveal crucial information for healthcare decision-making regarding CDI.
PSMAx-Guided PROTAC Degraders for Tumor-Specific Protein Degradation in Prostate Cancer
Authors: Meng Xiaolei , Hu Xiaolin , Zhang Siqi , Zhang Sai , Wang Xiao , Ma Shumin , Qin Chong 
Published: April 2024

AbstractPROTACs, degrading target protein to treat diseases, represent a highly promising drug design strategy. However, the degradation of target proteins by PROTACs in non-disease tissues may lead to systemic toxicity. Herein, capitalizing on the characteristic overexpression of PSMA in prostate cancer tumor tissues, we devised a PSMA-guided PROTACs specific targeting to prostate cancer. By conjugating AR degraders and BET degraders separately with PSMA ligands via cleavable linkers, two classes of PSMA-guided PROTACs were obtained.In vitroexperiments demonstrated that PSMA-guided PROTAC molecules selectively degraded target proteins in PSMA-overexpressing prostate cancer cells, without affecting target proteins in non-PSMA-overexpressing cells.In vivostudies revealed that compared to conventional PROTACs, PSMA-guided PROTACs enhanced drug exposure in prostate cancer tumor tissues, prolonged half-life, and consequently achieved stronger and more sustained therapeutic effects. The PSMA-guided PROTAC strategy provides a novel avenue for disease tissue-specific PROTAC research, holding significant implications for targeted therapy in prostate cancer.
A human forebrain organoid model reveals the essential function of GTF2IRD1-TTR-ERK axis for the neurodevelopmental deficits of Williams Syndrome
Authors: Zhao Xingsen , Sun Qihang , Shou Yikai , Chen Weijun , Wang Mengxuan , Qu Wenzheng , Huang Xiaoli , Li Ying , Wang Chao , Gu Yan , Ji Chai , Shu Qiang , Li Xuekun 
Published: April 2024

AbstractWilliams Syndrome (WS; OMIM#194050) is a rare disorder, which is caused by the microdeletion of one copy of 25-27 genes, and WS patients display diverse neuronal deficits. Although remarkable progresses have been achieved, the mechanisms for these distinct deficits are still largely unknown. Here, we have shown that neural progenitor cells (NPCs) in WS forebrain organoids display abnormal proliferation and differentiation capabilities, and synapse formation. Genes with altered expression are related to neuronal development and neurogenesis. Single cell RNA-seq (scRNA-seq) data analysis revealed 13 clusters in healthy control and WS organoids. WS organoids show an aberrant generation of excitatory neurons. Mechanistically, the expression of transthyretin (TTR) are remarkably decreased in WS forebrain organoids. We have found that GTF2IRD1 encoded by one WS associated geneGTF2IRD1binds toTTRpromoter regions and regulates the expression ofTTR. In addition, exogenous TTR can activate ERK signaling and rescue neurogenic deficits of WS forebrain organoids.Gtf2ird1deficient mice display similar neurodevelopmental deficits as observed in WS organoids. Collectively, our study reveals critical function of GTF2IRD1 in regulating neurodevelopment of WS forebrain organoids and mice through regulating TTR-ERK pathway.
Multiple direct and indirect roles of Paf1C in elongation, splicing, and histone post-translational modifications
Authors: Francette Alex M. , Arndt Karen M. 
Published: April 2024

SUMMARYPaf1C is a highly conserved protein complex with critical functions during eukaryotic transcription. Previous studies have shown that Paf1C is multi-functional, controlling specific aspects of transcription, ranging from RNAPII processivity to histone modifications. However, it is unclear how specific Paf1C subunits directly impact transcription and coupled processes. We have compared conditional depletion to steady-state deletion for each Paf1C subunit to determine the direct and indirect contributions to gene expression inSaccharomyces cerevisiae. Using nascent transcript sequencing, RNAPII profiling, and modeling of transcription elongation dynamics, we have demonstrated direct effects of Paf1C subunits on RNAPII processivity and elongation rate and indirect effects on transcript splicing and repression of antisense transcripts. Further, our results suggest that the direct transcriptional effects of Paf1C cannot be readily assigned to any particular histone modification. This work comprehensively analyzes both the immediate and extended roles of each Paf1C subunit in transcription elongation and transcript regulation.