journal
https://read.qxmd.com/read/39012714/radioproteomics-stratifies-molecular-response-to-antifibrotic-treatment-in-pulmonary-fibrosis
#1
JOURNAL ARTICLE
David Lauer, Cheryl Y Magnin, Luca R Kolly, Huijuan Wang, Matthias Brunner, Mamta Chabria, Grazia M Cereghetti, Hubert S Gabryś, Stephanie Tanadini-Lang, Anne-Christine Uldry, Manfred Heller, Stijn E Verleden, Kerstin Klein, Adela-Cristina Sarbu, Manuela Funke-Chambour, Lukas Ebner, Oliver Distler, Britta Maurer, Janine Gote-Schniering
Antifibrotic therapy with nintedanib is the clinical mainstay in the treatment of progressive fibrosing interstitial lung disease (ILD). High-dimensional medical image analysis, known as radiomics, provides quantitative insights into organ-scale pathophysiology, generating digital disease fingerprints. Here, we used an integrative analysis of radiomic and proteomic profiles (radioproteomics) to assess whether changes in radiomic signatures can stratify the degree of antifibrotic response to nintedanib in (experimental) fibrosing ILD...
July 16, 2024: JCI Insight
https://read.qxmd.com/read/39012710/targeting-cebpa-to-restore-cellular-identity-and-tissue-homeostasis-in-pulmonary-fibrosis
#2
JOURNAL ARTICLE
Qi Tan, Jack H Wellmerling, Shengren Song, Sara R Dresler, Jeffrey A Meridew, Kyoung M Choi, Yong Li, Y S Prakash, Daniel J Tschumperlin
Fibrosis in the lung is thought to be driven by epithelial cell dysfunction and aberrant cell-cell interactions. Unveiling the molecular mechanisms of cellular plasticity and cell-cell interactions is imperative to elucidate lung regenerative capacity and aberrant repair in pulmonary fibrosis. By mining publicly available RNA-seq datasets, we identified loss of CCAAT enhancer-binding protein alpha (CEBPA) as a candidate contributor to idiopathic pulmonary fibrosis (IPF). We used conditional knockout mice, scRNA-seq, lung organoids, small-molecule inhibition and novel gene manipulation methods to investigate the role of CEBPA in lung fibrosis and repair...
July 16, 2024: JCI Insight
https://read.qxmd.com/read/38990656/human-specific-elimination-of-epithelial-siglec-xii-suppresses-the-risk-of-inflammation-driven-colorectal-cancers
#3
JOURNAL ARTICLE
Hector A Cuello, Saptarshi Sinha, Andrea L Verhagen, Nissi Varki, Ajit Varki, Pradipta Ghosh
Carcinomas are common in humans but rare among closely related "great apes". Plausible explanations, including human-specific genomic alterations affecting the biology of sialic acids are proposed, but causality remains unproven. Here, an integrated evolutionary genetics-phenome-transcriptome approach studied the role of SIGLEC12 gene (encodes Siglec-XII) on epithelial transformation and cancer. Exogenous expression of the protein in cell lines and genetically engineered mice recapitulated ~30% of the human population in whom the protein is expressed in a form that cannot bind ligand due to a fixed, homozygous, human-universal missense mutation...
July 11, 2024: JCI Insight
https://read.qxmd.com/read/38990653/spatial-transcriptomics-implicates-impaired-bmp-signaling-in-nf1-fracture-pseudarthrosis-in-murine-and-patient-tissues
#4
JOURNAL ARTICLE
Jonathan J Rios, Conan Juan, John M Shelton, Nandina Paria, Ila Oxendine, Meghan Wassell, Yared H Kidane, Reuel Cornelia, Elise C Jeffery, David A Podeszwa, Simon J Conway, Carol A Wise, Robert J Tower
The Neurofibromatosis Type 1 (NF1) RASopathy is associated with persistent fibrotic nonunions (pseudarthrosis) in human and mouse skeletal tissue. Here, we first performed spatial transcriptomics to define the molecular signatures across normal endochondral healing following fracture in mice. Within the control fracture callus, we observed spatially restricted activation of morphogenetic pathways, such as TGF-β, WNT, and BMP. To investigate the molecular mechanisms contributing to Nf1-deficient delayed fracture healing, we performed spatial transcriptomic analysis on a Postn-cre;Nf1flox/- (Nf1Postn) fracture callus...
July 11, 2024: JCI Insight
https://read.qxmd.com/read/38990647/explainable-deep-learning-and-biomechanical-modeling-for-tmj-disorder-morphological-risk-factors
#5
JOURNAL ARTICLE
Shuchun Sun, Pei Xu, Nathan Buchweitz, Cherice N Hill, Farhad Ahmadi, Marshall B Wilson, Angela Mei, Xin She, Benedikt Sagl, Elizabeth H Slate, Janice S Lee, Yongren Wu, Hai Yao
Clarifying multifactorial musculoskeletal disorder etiologies supports risk analysis and development of targeted prevention and treatment modalities. Deep learning enables comprehensive risk factor identification through systematic analysis of disease datasets but does not provide sufficient context for mechanistic understanding, limiting clinical applicability for etiological investigations. Conversely, multiscale biomechanical modeling can evaluate mechanistic etiology within the relevant biomechanical and physiological context...
July 11, 2024: JCI Insight
https://read.qxmd.com/read/38980725/vedolizumab-and-art-in-recent-hiv-1-infection-unveil-the-role-of-%C3%AE-4%C3%AE-7-in-reservoir-size
#6
JOURNAL ARTICLE
Maria Reyes Jimenez-Leon, Carmen Gasca-Capote, Cristina Roca-Oporto, Nuria Espinosa, Salvador Sobrino, Maria Fontillon-Alberdi, Ce Gao, Isabelle Roseto, Gregory Gladkov, Inmaculada Rivas-Jeremias, Karin Neukam, Jose German Sanchez-Hernandez, Raul Rigo-Bonnin, Antonio J Cervera-Barajas, Rosario Mesones, Federico García, Ana Isabel Alvarez-Rios, Sara Bachiller, Joana Vitalle, Alberto Perez-Gomez, María Inés Camacho-Sojo, Isabel Gallego, Christian Brander, Ian McGowan, Beatriz Mothe, Pompeyo Viciana, Xu Yu, Mathias Lichterfeld, Luis F Lopez-Cortes, Ezequiel Ruiz-Mateos
We evaluated the safety and viral rebound, after analytical treatment interruption (ATI), of vedolizumab and ART in recent HIV-1 infection. We used this model to analyze the impact of α4β7 on the HIV-1 reservoir size. Participants started ART with monthly Vedolizumab infusions and ATI was performed at week 24. Biopsies were obtained from ileum and caecum at baseline and week 24. Vedolizumab levels, HIV-1 reservoir, flow cytometry and cell-sorting and antibody competition experiments were assayed...
July 9, 2024: JCI Insight
https://read.qxmd.com/read/38980723/childhood-obesity-s-impact-on-cognition-and-brain-connectivity-worsens-with-low-family-income
#7
JOURNAL ARTICLE
Dardo Tomasi, Nora D Volkow
Childhood obesity and its adverse health consequences have risen worldwide, with low socioeconomic status increasing the risk in high-income countries like the US. Understanding the interplay between childhood obesity, cognition, socioeconomic factors, and the brain is crucial for prevention and treatment. Using data from the ABCD study, we investigated how body mass index (BMI) relates to brain structural and functional connectivity metrics. Obese/overweight children (n = 2,356) were more likely to live in poverty and exhibited lower cognitive performance compared to normal weight children (n = 4,754)...
July 9, 2024: JCI Insight
https://read.qxmd.com/read/38954484/brd7-as-key-factor-in-pbaf-complex-assembly-and-cd8-t-cell-differentiation
#8
JOURNAL ARTICLE
Feng Huang, Yingtong Lin, Yidan Qiao, Yaochang Yuan, Zhihan Zhong, Baohong Luo, Yating Wu, Jun Liu, Jingliang Chen, Wanying Zhang, Hui Zhang, Bingfeng Liu
Upon infection, naïve CD8+ T cells differentiate into cytotoxic effector cells to eliminate the pathogen-infected cells. Although many mechanisms underlying this process have been demonstrated, the regulatory role of chromatin remodel system in this process remains largely unknown. Here we showed that BRD7, a component of the polybromo-associated BRG1-associated factor complex (PBAF), was required for naïve CD8+ T cells to differentiate into functional short-lived effector cells (SLECs) in response to acute infections caused by influenza virus or lymphocytic choriomeningitis virus (LCMV)...
July 2, 2024: JCI Insight
https://read.qxmd.com/read/38954480/single-cell-rna-seq-analysis-reveals-cell-subsets-and-gene-signatures-associated-with-rheumatoid-arthritis-disease-activity
#9
JOURNAL ARTICLE
Marie Binvignat, Brenda Y Miao, Camilla Wibrand, Monica M Yang, Dmitry Rychkov, Emily Flynn, Joanne Nititham, Whitney Tamaki, Umair Khan, Alexander Carvidi, Melissa Krueger, Erene C Niemi, Yang Sun, Gabriela K Fragiadakis, Jérémie Sellam, Encarnita Mariotti-Ferrandiz, David Klatzmann, Andrew J Gross, Chun Jimmie Ye, Atul J Butte, Lindsey A Criswell, Mary C Nakamura, Marina Sirota
Rheumatoid arthritis (RA) management lean toward achieving remission or low-disease activity. In this study, we conducted single-cell RNA sequencing (scRNAseq) of peripheral blood mononuclear cells (PBMCs) from 36 individuals (18 RA patients and 18 matched controls, accounting for age, sex, race, and ethnicity), to identify disease-relevant cell subsets and cell type-specific signatures associated with disease activity. Our analysis revealed 18 distinct PBMC subsets, including an IFITM3 overexpressing Interferon-activated (IFN-activated) monocyte subset...
July 2, 2024: JCI Insight
https://read.qxmd.com/read/38954474/iron-capture-through-cd71-drives-perinatal-and-tumor-associated-treg-expansion
#10
JOURNAL ARTICLE
Ilenia Pacella, Alessandra Pinzon Grimaldos, Alessandra Rossi, Gloria Tucci, Marta Zagaglioni, Elena Potenza, Valeria Pinna, Ivano Rotella, Ilenia Cammarata, Valeria Cancila, Beatrice Belmonte, Claudio Tripodo, Giuseppe Pietropaolo, Chiara Di Censo, Giuseppe Sciumè, Valerio Licursi, Giovanna Peruzzi, Ylenia Antonucci, Silvia Campello, Francesca Guerrieri, Valerio Iebba, Rita Prota, Maria Di Chiara, Gianluca Terrin, Valerio De Peppo, Gian Luca Grazi, Vincenzo Barnaba, Silvia Piconese
Beside suppressing immune responses, regulatory T cells (Tregs) maintain tissue homeostasis and control systemic metabolism. Whether iron is involved in Treg-mediated tolerance is completely unknown. Here, we showed that the transferrin receptor CD71 was upregulated on activated Tregs infiltrating human liver cancer. Mice with a Treg-restricted CD71 deficiency spontaneously developed a scurfy-like disease, caused by impaired perinatal Treg expansion. CD71-null Tregs displayed decreased proliferation and tissue-Treg signature loss...
July 2, 2024: JCI Insight
https://read.qxmd.com/read/38954467/thrombospondin-1-promotes-fibro-adipogenic-stromal-expansion-and-contractile-dysfunction-of-the-diaphragm-in-obesity
#11
JOURNAL ARTICLE
Eric D Buras, Moon-Sook Woo, Romil Kaul Verma, Sri Harshita Kondisetti, Carol S Davis, Dennis R Claflin, Kimber Converso-Baran, Daniel E Michele, Susan V Brooks, Tae-Hwa Chun
Pulmonary disorders impact 40% to 80% of individuals with obesity. Respiratory muscle dysfunction is linked to these conditions; however, its pathophysiology remains largely undefined. Mice subjected to diet-induced obesity (DIO) develop diaphragmatic weakness. Increased intra-diaphragmatic adiposity and extracellular matrix (ECM) content correlate with reductions in contractile force. Thrombospondin-1 (THBS1) is an obesity-associated matricellular protein linked with muscular damage in genetic myopathies. THBS1 induces proliferation of fibro-adipogenic progenitors (FAPs) - mesenchymal cells that differentiate into adipocytes and fibroblasts...
July 2, 2024: JCI Insight
https://read.qxmd.com/read/38954463/lymphotoxin-%C3%AE-receptor-and-tertiary-lymphoid-organs-shape-acute-and-chronic-allograft-rejection
#12
JOURNAL ARTICLE
Gang Zhang, Neda Feizi, Daqiang Zhao, Latha Halesha, Amanda L Williams, Parmjeet S Randhawa, Khodor I Abou-Daya, Martin H Oberbarnscheidt
Solid organ transplantation remains the life-saving treatment for end-stage organ failure, but chronic rejection remains a major obstacle to long-term allograft outcomes and has not improved substantially. Tertiary lymphoid organs (TLO) are ectopic lymphoid structures that form under conditions of chronic inflammation, and evidence from human transplantation suggests that TLO regularly form in allografts undergoing chronic rejection. In this study, we utilized a mouse renal transplantation model and manipulation of the lymphotoxin alpha (LTα) - lymphotoxin beta receptor (LTβR) pathway, which is essential for TLO formation, to define the role of TLO in transplantation...
July 2, 2024: JCI Insight
https://read.qxmd.com/read/38935435/a-metabolic-redox-relay-supports-er-proinsulin-export-in-pancreatic-islet-%C3%AE-cells
#13
JOURNAL ARTICLE
Kristen E Rohli, Nicole J Stubbe, Emily M Walker, Gemma L Pearson, Scott A Soleimanpour, Samuel B Stephens
Endoplasmic reticulum (ER) stress and proinsulin misfolding are heralded as contributing factors to β-cell dysfunction in Type 2 diabetes (T2D), yet how ER function becomes compromised is not well understood. Recent data identifies altered ER redox homeostasis as a critical mechanism that contributes to insulin granule loss in diabetes. Hyperoxidation of the ER delays proinsulin export and limits the proinsulin supply available for insulin granule formation. In this report, we identified glucose metabolism as a critical determinant in the redox homeostasis of the ER...
June 27, 2024: JCI Insight
https://read.qxmd.com/read/38917318/dispelling-the-myth-comparable-duration-and-impact-of-research-training-for-md-phd-and-phd-graduates
#14
JOURNAL ARTICLE
Rory Vu Mather, Temperance R Rowell, Steve Obuchowski, Loren D Walensky
The average time-to-degree for completing a life sciences PhD in the U.S. is longer for single-degree than dual-degree trainees, supporting a perception that the PhD training of MD-PhDs is less rigorous or fulsome. To determine whether the duration and impact of graduate training is influenced by degree format, we analyzed data for the 2011-2016 graduates of three Harvard Medical School PhD programs. Linear mixed effects models were used to determine the association between degree type (MD-PhD vs. PhD) and research outcomes, including time-to-degree, time-to-thesis-defense, and publications submitted during the PhD...
June 25, 2024: JCI Insight
https://read.qxmd.com/read/38916964/identification-of-circular-rnas-regulating-cardiomyocyte-proliferation-in-neonatal-pig-hearts
#15
JOURNAL ARTICLE
Ling Tang, Nyarige Verah, Pengsheng Li, Junwen Wang, Wuqiang Zhu
Little is known about the expression patterns and functions of circular RNAs (circRNAs) in the heart of large mammals. In this study, we examined the expression profiles of circRNAs, microRNAs (miRNAs), and messenger RNAs (mRNAs) in neonatal pig hearts. Pig heart samples collected on postnatal days 1 (P1), 3 (P3), 7 (P7) and 28 (P28) were sent for total RNA sequencing. Our data revealed a total of 7000 circRNAs in the 24 pig hearts. Pathway enrichment analysis of hallmark gene sets demonstrated that differentially expressed circRNAs are engaged in different pathways...
June 25, 2024: JCI Insight
https://read.qxmd.com/read/38916963/hpv8-induced-stat3-activation-led-keratinocyte-stem-cell-expansion-in-human-actinic-keratoses
#16
JOURNAL ARTICLE
Huw J Morgan, Carlotta Olivero, Boris Y Shorning, Alex Gibbs, Alexandra L Phillips, Lokapriya Ananthan, Annabelle Xiao Hui Lim, Licia Martuscelli, Cinzia Borgogna, Marco De Andrea, Martin Hufbauer, Richard G Goodwin, Baki Akgül, Marisa Gariglio, Girish K Patel
Despite epidermal turnover, the skin is host to a complex array of microbes including viruses, such as the human papillomavirus (HPV), which must infect and manipulate skin keratinocyte stem cells (KSC) to survive. This crosstalk between the virome and KSC populations remains largely unknown. Here, we investigated the effect of HPV8 on KSCs using various mouse models. We observed that the HPV8 early region gene E6 specifically caused Lrig1+ hair follicle junctional zone KSC proliferation and expansion, which would facilitate viral transmission...
June 25, 2024: JCI Insight
https://read.qxmd.com/read/38916962/fibroblast-growth-factor-receptors-mediate-cellular-senescence-in-the-cystic-fibrosis-airway-epithelium
#17
JOURNAL ARTICLE
Molly Easter, Meghan June Hirsch, Elex Harris, Patrick Henry Howze Iv, Emma Lea Matthews, Luke I Jones, Seth Bollenbecker, Shia Vang, Daniel J Tyrrell, Yan Y Sanders, Susan E Birket, Jarrod W Barnes, Stefanie Krick
The number of adults living with cystic fibrosis (CF) has already increased significantly due to drastic improvements in life expectancy attributable to advances in treatment including the development of highly effective modulator therapy. Chronic airway inflammation in cystic fibrosis (CF) contributes to morbidity and mortality and aging processes like 'inflammaging' and cell senescence impact CF pathology. Our results show that single cell RNA sequencing data, human primary bronchial epithelial cells from non-CF and CF donors, a CF bronchial epithelial cell line, and Cftr knockout (Cftr-/-) rats all demonstrated increased cell senescence markers in the CF bronchial epithelium...
June 25, 2024: JCI Insight
https://read.qxmd.com/read/38916959/injury-induced-foxm1-expression-in-mouse-kidney-drives-epithelial-proliferation-by-a-cyclin-f-dependent-mechanism
#18
JOURNAL ARTICLE
Megan L Noonan, Yoshiharu Muto, Yasuhiro Yoshimura, Aidan Leckie-Harre, Haojia Wu, Vladimir V Kalinichenko, Benjamin D Humphreys, Monica Chang-Panesso
Acute kidney injury strongly upregulates the transcription factor Foxm1 in proximal tubule in vivo and Foxm1 drives epithelial proliferation in vitro. Here we report that deletion of Foxm1 either with a nephron specific Cre driver or by inducible global deletion reduces proximal tubule proliferation after ischemic injury in vivo. Foxm1 deletion led to increased AKI-to-CKD transition with enhanced fibrosis and ongoing tubule injury 6 weeks after injury. We report extracellular signal-regulated kinase (ERK) mediates FOXM1 induction downstream of the epidermal growth factor receptor (EGFR) in primary proximal tubule cells...
June 25, 2024: JCI Insight
https://read.qxmd.com/read/38916957/spatial-detection-and-consequences-of-nonrenal-calcitriol-production-as-assessed-by-targeted-mass-spectrometry-imaging
#19
JOURNAL ARTICLE
Mark B Meyer, Seong Min Lee, Shannon R Cichanski, Diego F Cobice, J Wesley Pike
The immune benefits of vitamin D3 supplementation beyond calcium and phosphate maintenance are highly clinically debated. Kidney expression of CYP27B1 is the source of endocrine, circulating 1,25(OH)2D3 (active form of vitamin D) that maintains serum calcium and phosphate. 1,25(OH)2D3 may also be made by the CYP27B1 enzyme in non-renal cells, like immune cells, in a process driven by cellular availability of 25(OH)D3 and inflammation. Due to the endocrine nature of 1,25(OH)2D3 in circulation, it is difficult to discern between these two sources...
June 25, 2024: JCI Insight
https://read.qxmd.com/read/38916953/targeting-drp1-with-mdivi-1-to-correct-mitochondrial-abnormalities-in-adoa-plus-syndrome
#20
JOURNAL ARTICLE
Yan Lin, Dongdong Wang, Busu Li, Jiayin Wang, Ling Xu, Xiaohan Sun, Kunqian Ji, Chuanzhu Yan, Fuchen Liu, Yuying Zhao
Autosomal dominant optic atrophy plus (ADOA+) is characterized by primary optic nerve atrophy accompanied by a spectrum of degenerative neurological symptoms. Despite ongoing research, no effective treatments are currently available for this condition. Our study provided evidence for the pathogenicity of an unreported c.1780T>C variant in the OPA1 gene through patient-derived skin fibroblasts and an engineered HEK293T cell line with OPA1 downregulation. We demonstrated that OPA1 insufficiency promoted mitochondrial fragmentation and increased DRP1 expression, disrupting mitochondrial dynamics...
June 25, 2024: JCI Insight
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