tbuckley/cabot-search huggingface dataset:
Genetic Causes and Genomic Consequences of Breakdown of Distyly in <i>Linum trigynum</i>
Authors: Juanita Gutiérrez-Valencia, Panagiotis-Ioannis Zervakis, Zoé Postel, Marco Fracassetti, Aleksandra Losvik, Sara Mehrabi, Ignas Bunikis, Lucile Soler, P William Hughes, Aurélie Désamoré, Benjamin Laenen, Mohamed Abdelaziz, Olga Vinnere Pettersson, Juan Arroyo, Tanja Slotte
Journal: Molecular Biology and Evolution (2024)

Abstract Distyly is an iconic floral polymorphism governed by a supergene, which promotes efficient pollen transfer and outcrossing through reciprocal differences in the position of sexual organs in flowers, often coupled with heteromorphic self-incompatibility. Distyly has evolved convergently in multiple flowering plant lineages, but has also broken down repeatedly, often resulting in homostylous, self-compatible populations with elevated rates of self-fertilization. Here, we aimed to study the genetic causes and genomic consequences of the shift to homostyly in Linum trigynum, which is closely related to distylous Linum tenue. Building on a high-quality genome assembly, we show that L. trigynum harbors a genomic region homologous to the dominant haplotype of the distyly supergene conferring long stamens and short styles in L. tenue, suggesting that loss of distyly first occurred in a short-styled individual. In contrast to homostylous Primula and Fagopyrum, L. trigynum harbors no fixed loss-of-function mutations in coding sequences of S-linked distyly candidate genes. Instead, floral gene expression analyses and controlled crosses suggest that mutations downregulating the S-linked LtWDR-44 candidate gene for male self-incompatibility and/or anther height could underlie homostyly and self-compatibility in L. trigynum. Population genomic analyses of 224 whole-genome sequences further demonstrate that L. trigynum is highly self-fertilizing, exhibits significantly lower genetic diversity genome-wide, and is experiencing relaxed purifying selection and less frequent positive selection on nonsynonymous mutations relative to L. tenue. Our analyses shed light on the loss of distyly in L. trigynum, and advance our understanding of a common evolutionary transition in flowering plants.
Impact of age at ivacaftor initiation on pulmonary outcomes among people with cystic fibrosis
Authors: Christian A Merlo, Lisa J McGarry, Teja Thorat, Catherine Nguyen, Maral DerSarkissian, Aruna Muthukumar, Joe Healy, M Alan Brookhart, Jaime L Rubin
Journal: Thorax (2024)

Background Ivacaftor (IVA) improves lung function and other extrapulmonary outcomes in people with cystic fibrosis (CF). However, the effect of initiating IVA at earlier versus later ages has not been studied. Methods We conducted an observational cohort study of people in the US CF Foundation Patient Registry aged ≥6 years with ≥1 CF transmembrane conductance regulator–gating mutation to compare the effects of initiating IVA at earlier ages on per cent predicted forced expiratory volume in 1 s (ppFEV 1 ) and pulmonary exacerbation (PEx) outcomes. People with CF were grouped by age at IVA initiation (ages 6–10, 11–15, 16–20 and 21–25 years) to perform three analyses of younger versus older IVA initiation (6–10 vs 11–15, 11–15 vs 16–20 and 16–20 vs 21–25 years). For each analysis, baseline characteristics assessed over 1-year periods at the same age prior to IVA initiation were balanced by standardised mortality/morbidity ratio (SMR) weighting. For each analysis, outcomes were compared over a 5-year outcome assessment period when both groups were in the same age range and receiving IVA. Findings Baseline characteristics were well balanced between younger and older IVA initiator groups after SMR weighting. In the outcome assessment period, younger IVA initiators had significantly higher mean ppFEV 1 than older initiators across all comparisons, and those initiating IVA between ages 6–10 and 11–15 years had significantly lower PEx rates. Interpretation Study findings showed the importance of early IVA initiation in people with CF.
Comprehensive single-cell analysis deciphered microenvironmental dynamics and immune regulator olfactomedin 4 in pathogenesis of gallbladder cancer
Authors: Huisi He, Shuzhen Chen, Yong Yu, Zhecai Fan, Youwen Qian, Yaping Dong, Yuting Song, Caiming Zhong, Xiaojuan Sun, Qiqi Cao, Shiyao Li, Weihan Huang, Wenxin Li, Mingzhu Zhuang, Jinxian Yang, Xianming Wang, Jiaqian Wang, Dongfang Wu, Hongyang Wang, Wen Wen
Journal: Gut (2024)

Objective Elucidating complex ecosystems and molecular features of gallbladder cancer (GBC) and benign gallbladder diseases is pivotal to proactive cancer prevention and optimal therapeutic intervention. Design We performed single-cell transcriptome analysis on 230 737 cells from 15 GBCs, 4 cholecystitis samples, 3 gallbladder polyps, 5 gallbladder adenomas and 16 adjacent normal tissues. Findings were validated through large-scale histological assays, digital spatial profiler multiplexed immunofluorescence (GeoMx), etc. Further molecular mechanism was demonstrated with in vitro and in vivo studies. Results The cell atlas unveiled an altered immune landscape across different pathological states of gallbladder diseases. GBC featured a more suppressive immune microenvironment with distinct T-cell proliferation patterns and macrophage attributions in different GBC subtypes. Notably, mutual exclusivity between stromal and immune cells was identified and remarkable stromal ecosystem (SC) heterogeneity during GBC progression was unveiled. Specifically, SC1 demonstrated active interaction between Fibro-iCAF and Endo-Tip cells, correlating with poor prognosis. Moreover, epithelium genetic variations within adenocarcinoma (AC) indicated an evolutionary similarity between adenoma and AC. Importantly, our study identified elevated olfactomedin 4 (OLFM4) in epithelial cells as a central player in GBC progression. OLFM4 was related to T-cell malfunction and tumour-associated macrophage infiltration, leading to a worse prognosis in GBC. Further investigations revealed that OLFM4 upregulated programmed death-ligand 1 (PD-L1) expression through the MAPK-AP1 axis, facilitating tumour cell immune evasion. Conclusion These findings offer a valuable resource for understanding the pathogenesis of gallbladder diseases and indicate OLFM4 as a potential biomarker and therapeutic target for GBC.
Development of an mRNA-based therapeutic vaccine mHTV-03E2 for high-risk HPV-related malignancies
Authors: Jing Wang, Qixin Wang, Ling Ma, Kai Lv, Lu Han, Yunfeng Chen, Rui Zhou, Haokun Zhou, Hua Chen, Yi Wang, Tingting Zhang, Dongrong Yi, Qian Liu, Yongxin Zhang, Xiaoyu Li, Tingting Cheng, Jinming Zhang, Chunjian Huang, Yijie Dong, Weiguo Zhang, Shan Cen
Journal: Molecular Therapy (2024)
Increasing Medication Use and Polypharmacy in Type 2 Diabetes: The Danish Experience From 2000 to 2020
Authors: Karl Sebastian Johansson, Espen Jimenez-Solem, Tonny Studsgaard Petersen, Mikkel Bring Christensen
Journal: Diabetes Care (2024)

OBJECTIVE Type 2 diabetes often coexists with other conditions that are amenable to pharmacological treatment. We hypothesized that polypharmacy among individuals with type 2 diabetes has increased since 2000. RESEARCH DESIGN AND METHODS Using Danish national registries, we established a cohort of all Danish individuals (aged ≥18 years) with type 2 diabetes between 2000 and 2020. We analyzed their medication use and prevalence of varying degrees of polypharmacy (≥5 or ≥10 medications), stratifying by age, sex, number of chronic diseases, and socioeconomic status. RESULTS The cohort grew from 84,917 patients in 2000 to 307,011 in 2020, totaling 461,849 unique patients. The number of daily medications used per patient increased from (mean ± SD) 3.7 ± 2.8 (in 2000) to 5.3 ± 3.2 (in 2020). The lifetime risk of polypharmacy was substantial, with 89% (n = 409,062 of 461,849) being exposed to ≥5 medications at some point and 47% (n = 217,467 of 461,849) to ≥10 medications. The increases were driven by an expanding group of medications, with analgesics, antihypertensives, proton pump inhibitors, and statins having the largest net increase. Advanced age, male sex, lower socioeconomic status, and Danish ethnicity positively correlated with polypharmacy but could not explain the overall increase in polypharmacy. CONCLUSIONS Medication use and polypharmacy have increased among patients with type 2 diabetes. Although the implications and appropriateness of this increased medication use are uncertain, the results stress the increasing need for health care personnel to understand the potential risks associated with polypharmacy, including medication interactions, adverse effects, and over- and underprescribing.
Urgent action is needed to confront artemisinin partial resistance in African malaria parasites
Authors: Deus S. Ishengoma, Roly Gosling, Rosario Martinez-Vega, Khalid B. Beshir, Jeffrey A. Bailey, John Chimumbwa, Colin Sutherland, Melissa D. Conrad, Fitsum G. Tadesse, Jonathan J. Juliano, Moses R. Kamya, Wilfred F. Mbacham, Didier Ménard, Philip J. Rosenthal, Jaishree Raman, Allison Tatarsky, Sofonias K. Tessema, David A. Fidock, Abdoulaye A. Djimde
Journal: Nature Medicine (2024)
Association between changes in cardiovascular health and the risk of multimorbidity: community-based cohort studies in the UK and Finland
Authors: Christof Prugger, Marie-Cécile Perier, Séverine Sabia, Aurore Fayosse, Thomas van Sloten, Xavier Jouven, Jaana Pentti, Mika Kivimäki, Jean-Philippe Empana
Journal: The Lancet Regional Health - Europe (2024)

BackgroundBetter cardiovascular health is associated with lower risk of various chronic diseases, but its association with multimorbidity is poorly understood. We aimed to examine whether change in cardiovascular health is associated with multimorbidity risk.MethodsThe primary analysis was conducted in the Whitehall II multiwave prospective cohort study (UK) and the validation analysis in the Finnish Public Sector cohort study (Finland). Change in cardiovascular health was assessed using the American Heart Association Life's Simple 7 (LS7) and Life's Essential 8 (LE8) at baseline and re-assessments, using objective measures in Whitehall II and self-reports and pharmacy claims in the Finnish Public Sector cohort study, respectively. Multimorbidity was defined as the presence of two or more of 12 chronic diseases during follow-up. We estimated hazard ratios (HR) and 95% confidence intervals (CI) using Cox's proportional hazard models with age as time scale, adjusting for sex, education, occupation, marital status, and ethnicity.FindingsIn the primary analysis among 9715 participants, mean age was 44.8 (standard deviation 6.0) years and 67.6% participants were men at baseline. During the median follow-up of 31.4 (interquartile range 26.8–32.3) years, 2751 participants developed multimorbidity. The hazard of multimorbidity decreased by 8% (HR 0.92, 95% CI 0.88–0.96) per ideal LS7 metric increment over 5 years and by 14% (HR 0.86, 95% CI 0.80–0.93) per ten points increase in LE8 score over 10 years. These findings were replicated in the validation analysis among 75,377 participants in terms of 4-year change in cardiovascular health.InterpretationImprovement in cardiovascular health was associated with lower multimorbidity risk in two community-based cohort studies. Interventions improving cardiovascular health of the community may contribute to multimorbidity prevention.FundingNone.
Single-Cell Transcriptional Signatures of Glomerular Disease in Transgenic Mice with APOL1 Variants
Authors: Teruhiko Yoshida, Khun Zaw Latt, Briana A. Santo, Shashi Shrivastav, Yongmei Zhao, Paride Fenaroli, Joon-Yong Chung, Stephen M. Hewitt, Vincent M. Tutino, Pinaki Sarder, Avi Z. Rosenberg, Cheryl A. Winkler, Jeffrey B. Kopp
Journal: Journal of the American Society of Nephrology (2024)

Key Points Apolipoprotein L1 (APOL1)-G1 induced kidney disease in the two APOL1 transgenic mouse models, HIV-associated nephropathy and IFN- γ administration. Glomerular single-nuclear RNA-sequencing identified genes differentially expressed among mice with APOL1-G1 and G0 variants at single-cell resolution. Background Apolipoprotein L1 ( APOL1 ) high-risk variants contribute to kidney disease among individuals with African ancestry. We sought to describe cell-specific APOL1 variant–induced pathways using two mouse models. Methods We characterized bacterial artificial chromosome/APOL1 transgenic mice crossed with HIV-associated nephropathy (HIVAN) Tg26 mice and bacterial artificial chromosome/APOL1 transgenic mice given IFN- γ . Results Both mouse models showed more severe glomerular disease in APOL1-G1 compared with APOL1-G0 mice. Synergistic podocyte-damaging pathways activated by APOL1-G1 and by the HIV transgene were identified by glomerular bulk RNA sequencing (RNA-seq) of HIVAN model. Single-nuclear RNA-seq revealed podocyte-specific patterns of differentially expressed genes as a function of APOL1 alleles. Shared activated pathways, for example, mammalian target of rapamycin, and differentially expressed genes, for example, Ccn2 , in podocytes in both models suggest novel markers of APOL1-associated kidney disease. HIVAN mouse-model podocyte single-nuclear RNA-seq data showed similarity to human focal segmental glomerulosclerosis glomerular RNA-seq data. Differential effects of the APOL1 -G1 variant on the eukaryotic initiation factor 2 pathway highlighted differences between the two models. Conclusions These findings in two mouse models demonstrated both shared and distinct cell type–specific transcriptomic signatures induced by APOL1 variants. These findings suggest novel therapeutic opportunities for APOL1 glomerulopathies.
CBTRUS Statistical Report: American Brain Tumor Association &amp; NCI Neuro-Oncology Branch Adolescent and Young Adult Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2016–2020
Authors: Mackenzie Price, Corey Neff, Nitin Nagarajan, Carol Kruchko, Kristin A Waite, Gino Cioffi, Brittany B Cordeiro, Nicole Willmarth, Marta Penas-Prado, Mark R Gilbert, Terri S Armstrong, Jill S Barnholtz-Sloan, Quinn T Ostrom
Journal: Neuro-Oncology (2024)

Abstract Recent analyses have shown that, whereas cancer survival overall has been improving, it has not improved for adolescents and young adults ages 15–39 years (AYA). The clinical care of AYA with primary brain and other central nervous system (CNS) tumors (BT) is complicated by the fact that the histopathologies of such tumors in AYA differ from their histopathologies in either children (ages 0–14 years) or older adults (ages 40+ years). The present report, as an update to a 2016 publication from the Central Brain Tumor Registry of the United States and the American Brain Tumor Association, provides in-depth analyses of the epidemiology of primary BT in AYA in the United States and is the first to provide biomolecular marker-specific statistics and prevalence by histopathology for both primary malignant and non-malignant BT in AYA. Between 2016 and 2020, the annual average age-specific incidence rate (AASIR) of primary malignant and non-malignant BT in AYA was 12.00 per 100,000 population, an average of 12,848 newly diagnosed cases per year. During the same period, an average of 1,018 AYA deaths per year were caused by primary malignant BT, representing an annual average age-specific mortality rate of 0.96 per 100,000 population. When primary BT were categorized by histopathology, pituitary tumors were the most common (36.6%), with an AASIR of 4.34 per 100,000 population. Total incidence increased with age overall; when stratified by sex, the incidence was higher in females than males at all ages. Incidence rates for all primary BT combined and for non-malignant tumors only were highest for non-Hispanic American Indian/Alaska Native individuals, whereas malignant tumors were more frequent in non-Hispanic White individuals, compared with other racial/ethnic groups. On the basis of histopathology, the most common molecularly defined tumor was diffuse glioma (an AASIR of 1.51 per 100,000). Primary malignant BT are the second most common cause of cancer death in the AYA population. Incidence rates of primary BT overall, as well as specific histopathologies, vary significantly by age. Accordingly, an accurate statistical assessment of primary BT in the AYA population is vital for better understanding the impact of these tumors on the US population and to serve as a reference for afflicted individuals, for researchers investigating new therapies, and for clinicians treating these patients.
Progranulin: A promising biomarker and therapeutic target for fibrotic diseases
Authors: Fan Yang, Ming-Han Cheng, Hai-Feng Pan, Jian Gao
Journal: Acta Pharmaceutica Sinica B (2024)

Progranulin (PGRN), a multifunctional growth factor-like protein expressed by a variety of cell types, serves an important function in the physiologic and pathologic processes of fibrotic diseases, including wound healing and the inflammatory response. PGRN was discovered to inhibit pro-inflammation effect by competing with tumor necrosis factor-alpha (TNF-α) binding to TNF receptors. Notably, excessive tissue repair in the development of inflammation causes tissue fibrosis. Previous investigations have indicated the significance of PGRN in regulating inflammatory responses. Recently, multiple studies have shown that PGRN was linked to fibrogenesis, and was considered to monitor the formation of fibrosis in multiple organs, including liver, cardiovascular, lung and skin. This paper is a comprehensive review summarizing our current knowledge of PGRN, from its discovery to the role in fibrosis. This is followed by an in-depth look at the characteristics of PGRN, consisting of its structure, basic function and intracellular signaling. Finally, we will discuss the potential of PGRN in the diagnosis and treatment of fibrosis.
The Role of Genetic Testing in Adult CKD
Authors: Nine V.A.M. Knoers, Albertien M. van Eerde
Journal: Journal of the American Society of Nephrology (2024)

Mounting evidence indicates that monogenic disorders are the underlying cause in a significant proportion of patients with CKD. In recent years, the diagnostic yield of genetic testing in these patients has increased significantly as a result of revolutionary developments in genetic sequencing techniques and sequencing data analysis. Identification of disease-causing genetic variant(s) in patients with CKD may facilitate prognostication and personalized management, including nephroprotection and decisions around kidney transplantation, and is crucial for genetic counseling and reproductive family planning. A genetic diagnosis in a patient with CKD allows for screening of at-risk family members, which is also important for determining their eligibility as kidney transplant donors. Despite evidence for clinical utility, increased availability, and data supporting the cost-effectiveness of genetic testing in CKD, especially when applied early in the diagnostic process, many nephrologists do not use genetic testing to its full potential because of multiple perceived barriers. Our aim in this article was to empower nephrologists to (further) implement genetic testing as a diagnostic means in their clinical practice, on the basis of the most recent insights and exemplified by patient vignettes. We stress why genetic testing is of significant clinical benefit to many patients with CKD, provide recommendations for which patients to test and which test(s) to order, give guidance about interpretation of genetic testing results, and highlight the necessity for and essential components of pretest and post-test genetic counseling.
Complement Terminal Pathway Activation and Intrarenal Immune Response in C3 Glomerulopathy
Authors: Marie-Sophie Meuleman, Florent Petitprez, Matthew C. Pickering, Moglie Le Quintrec, Mikel Rezola Artero, Anna Duval, Marion Rabant, Alyssa Gilmore, Olivia Boyer, Julien Hogan, Aude Servais, François Provot, Vivianne Gnemmi, Maeva Eloudzeri, Anne Grunenwald, David Buob, Jean-Jacques Boffa, Anissa Moktefi, Vincent Audard, Jean-Michel Goujon, Frank Bridoux F, Eric Thervet, Alexandre Karras, Lubka T. Roumenina, Véronique Frémeaux- Bacchi, Jean-Paul Duong Van Huyen, Sophie Chauvet
Journal: Journal of the American Society of Nephrology (2024)

Key Points We evidenced terminal pathway activation (C5b-9 deposits) in most of the glomeruli on kidney biopsy of C3 glomerulopathy. The amount of C5b-9 deposits correlated with disease prognosis in C3 glomerulopathy. Increased terminal pathway activation was found predominantly in a subgroup exhibiting an immuno-fibroblastic signature. Background C3 glomerulopathy is a rare disease resulting from an overactivation of the complement alternative pathway. Although there is also evidence of terminal pathway activation, its occurrence and consequences on the disease have been poorly studied. Methods We retrospectively studied a cohort of 42 patients diagnosed with C3 glomerulopathy. We performed centralized extensive characterization of histological parameters. Kidney C5b-9 staining was performed as a marker of terminal pathway activation; intrarenal immune response was characterized through transcriptomic analysis. Results Eighty-eight percent of biopsies showed C5b-9 deposits in glomeruli. Biopsies were grouped according to the amount of C5b-9 deposits (no or low n =15/42, 36%; intermediate n =15/42, 36%; and high n =12/42, 28%). Patients with high C5b-9 deposits significantly differed from the two other groups of patients and were characterized by a significant higher histological chronicity score ( P = 0.005) and lower outcome-free survival ( P = 0.001). In multivariable analysis, higher glomerular C5b-9 remained associated with poor kidney prognosis after adjustment. One third of the 847 studied immune genes were upregulated in C3 glomerulopathy biopsies compared with controls. Unsupervised clustering on differentially expressed genes identified a group of kidney biopsies enriched in high glomerular C5b-9 with high immune and fibroblastic signature and showed high chronicity scores on histological examination. Conclusions In a cohort of patients with C3 glomerulopathy, intrarenal terminal pathway activation was associated with specific histological phenotype and disease prognosis.
Transthoracic ultrasound localization microscopy of myocardial vasculature in patients
Authors: Jipeng Yan, Biao Huang, Johanna Tonko, Matthieu Toulemonde, Joseph Hansen-Shearer, Qingyuan Tan, Kai Riemer, Konstantinos Ntagiantas, Rasheda A. Chowdhury, Pier D. Lambiase, Roxy Senior, Meng-Xing Tang
Journal: Nature Biomedical Engineering (2024)

Myocardial microvasculature and haemodynamics are indicative of potential microvascular diseases for patients with symptoms of coronary heart disease in the absence of obstructive coronary arteries. However, imaging microvascular structure and flow within the myocardium is challenging owing to the small size of the vessels and the constant movement of the patient's heart. Here we show the feasibility of transthoracic ultrasound localization microscopy for imaging myocardial microvasculature and haemodynamics in explanted pig hearts and in patients in vivo. Through a customized data-acquisition and processing pipeline with a cardiac phased-array probe, we leveraged motion correction and tracking to reconstruct the dynamics of microcirculation. For four patients, two of whom had impaired myocardial function, we obtained super-resolution images of myocardial vascular structure and flow using data acquired within a breath hold. Myocardial ultrasound localization microscopy may facilitate the understanding of myocardial microcirculation and the management of patients with cardiac microvascular diseases.