Top read articles in the last 30 days
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Abstract
Parkinson’s disease (PD) is a neurodegenerative disorder with both genetic and environmental factors contributing to pathogenesis. Viral infections are potential environmental triggers that influence PD pathology. Using ViroFind, an unbiased platform for whole virome sequencing, along with quantitative PCR (qPCR), we identified human pegivirus (HPgV) in 5 of 10 (50%) of PD brains, confirmed by IHC in 2 of 2 cases, suggesting an association with PD. All 14 age- and sex-matched controls were HPgV negative. HPgV-brain positive patients with PD showed increased neuropathology by Braak stage and Complexin-2 levels, while those positive in the blood had higher IGF-1 and lower pS65-ubiquitin, supporting disruption in metabolism or mitophagy in response to HPgV. RNA-Seq revealed altered immune signaling in HPgV-infected PD samples, including consistent suppression of IL-4 signaling in both the brain and blood. Longitudinal analysis of blood samples showed a genotype-dependent viral response, with HPgV titers correlating directly with IL-4 signaling in a LRRK2 genotype–dependent manner. YWHAB was a key hub gene in the LRRK2 genotypic response, which exhibited an altered relationship with immune-related factors, including NFKB1, ITPR2, and LRRK2 itself, in patients with PD who are positive for HPgV. These results suggest a role for HPgV in shaping PD pathology and highlight the complex interplay between viral infection, immunity, and neuropathogenesis.
Authors
Barbara A. Hanson, Xin Dang, Pouya Jamshidi, Alicia Steffens, Kaleigh Copenhaver, Zachary S. Orban, Bernabe Bustos, Steven J. Lubbe, Rudolph J. Castellani, Igor J. Koralnik
Total views: 6528
Abstract
Hypertrophic cardiomyopathy (HCM) is a hereditary heart condition characterized by either preserved or reduced ejection fraction without any underlying secondary causes. The primary cause of HCM is sarcomeric gene mutations, which account for only 40%–50% of the total cases. Here, we identified a pathogenic missense variant in tubulin tyrosine ligase (TTL p.G219S) in a patient with HCM. We used clinical, genetics, computational, and protein biochemistry approaches, as well as patient-specific and CRISPR gene-edited induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs), to demonstrate that the TTL pathogenic variant results in a reduced enzymatic activity and the accumulation of detyrosinated tubulin leading to the disruption of redox signaling, ultimately leading to HCM. Our findings highlight — for the first time to our knowledge — the crucial roles of the TTL variant in cardiac remodeling resulting in disease.
Authors
Pratul Kumar Jain, Susobhan Mahanty, Harshil Chittora, Veronique Henriot, Carsten Janke, Minhajuddin Sirajuddin, Perundurai S. Dhandapany
Total views: 1616
Abstract
The widespread uptake of COVID-19 vaccines by women provided a unique opportunity to study the effects of pregnancy and lactation on immune responses to vaccination. Leveraging a cohort with well-defined SARS-CoV-2 exposure history, we found that the magnitude of humoral and cellular immune responses to vaccine-delivered SARS-CoV-2 spike was not affected by pregnancy or lactation status. However, vaccination during pregnancy elicited more stem-like SARS-CoV-2–specific CD4+ T cells. Moreover, breakthrough infection promoted spike-specific IgG in pregnant individuals in contrast with IgA in those lactating, suggesting that the pregnancy-to-lactation transition favors mucosal antibody responses. Breakthrough infection also reduced peripheral cytolytic SARS-CoV-2–specific CD8+ T cell frequencies during lactation but not pregnancy, which may reflect trafficking of the cells to mammary glands. Our study also uncovered an impact of pregnancy and lactation on global T cell phenotypes. In particular, lactating individuals preferentially exhibited a state of diminished T cell activation. Furthermore, breakthrough infection during pregnancy, but not lactation, diminished frequencies of activated CD8+ T cells, tissue-homing CD8+ T cells, and γδ T cells. Our findings support the notion that immunity during pregnancy and lactation adapts to benefit the fetus or breastfed infant, with implications for eliciting effective long-term immunity for these uniquely vulnerable groups.
Authors
Kailin Yin, Lin Li, Xiaoyu Luo, Jason Neidleman, Arianna G. Cassidy, Yarden Golan, Nida Ozarslan, Christine Y. Lin, Unurzul Jigmeddagva, Mikias Ilala, Megan A. Chidboy, Mary Prahl, Stephanie L. Gaw, Nadia R. Roan
Total views: 1249
Abstract
Recently, skeletal stem cells were shown to be present in the epiphyseal growth plate (epiphyseal skeletal stem cells, epSSCs), but their function in connection with linear bone growth remains unknown. Here, we explore the possibility that modulating the number of epSSCs can correct differences in leg length. First, we examined regulation of the number and activity of epSSCs by Hedgehog (Hh) signaling. Both systemic activation of Hh pathway with Smoothened agonist (SAG) and genetic activation of Hh pathway by Patched1 (Ptch1) ablation in Pthrp-creER Ptch1fl/fl tdTomato mice promoted proliferation of epSSCs and clonal enlargement. Transient intra-articular administration of SAG also elevated the number of epSSCs. When SAG-containing beads were implanted into the femoral secondary ossification center of 1 leg of rats, this leg was significantly longer 1 month later than the contralateral leg implanted with vehicle-containing beads, an effect that was even more pronounced 2 and 6 months after implantation. We conclude that Hh signaling activates growth plate epSSCs, which effectively leads to increased longitudinal growth of bones. This opens therapeutic possibilities for the treatment of differences in leg length.
Authors
Dana Trompet, Anastasiia D. Kurenkova, Baoyi Zhou, Lei Li, Ostap Dregval, Anna P. Usanova, Tsz Long Chu, Alexandra Are, Andrei A. Nedorubov, Maria Kasper, Andrei S. Chagin
Total views: 1173
Abstract
Immune checkpoint inhibitors (ICI) have revolutionized cancer therapy, but their use is limited by the development of autoimmunity in healthy tissues as a side effect of treatment. Such immune-related adverse events (IrAE) contribute to hospitalizations, cancer treatment interruption, and even premature death. ICI-induced autoimmune diabetes mellitus (ICI-T1DM) is a life-threatening IrAE that presents with rapid pancreatic β-islet cell destruction leading to hyperglycemia and life-long insulin dependence. While prior reports have focused on CD8+ T cells, the role for CD4+ T cells in ICI-T1DM is less understood. We identify expansion of CD4+ T follicular helper (Tfh) cells expressing IL-21 and IFN-γ as a hallmark of ICI-T1DM. Furthermore, we show that both IL-21 and IFN-γ are critical cytokines for autoimmune attack in ICI-T1DM. Because IL-21 and IFN-γ both signal through JAK/STAT pathways, we reasoned that JAK inhibitors (JAKi) may protect against ICI-T1DM. Indeed, JAKi provide robust in vivo protection against ICI-T1DM in a mouse model that is associated with decreased islet-infiltrating Tfh cells. Moreover, JAKi therapy impaired Tfh cell differentiation in patients with ICI-T1DM. These studies highlight CD4+ Tfh cells as underrecognized but critical mediators of ICI-T1DM that may be targeted with JAKi to prevent this grave IrAE.
Authors
Nicole L. Huang, Jessica G. Ortega, Kyleigh Kimbrell, Joah Lee, Lauren N. Scott, Esther M. Peluso, Sarah J. Wang, Ellie Y. Kao, Kristy Kim, Jarod Olay, Jaden N. Nguyen, Zoe Quandt, Trevor E. Angell, Maureen A. Su, Melissa G. Lechner
Total views: 1164
Abstract
The pathobiology of pulmonary hypertension (PH) is complex and multiple cell types contribute to disease pathogenesis. We sought to characterize the molecular crosstalk between endothelial and mesenchymal cells that promote PH in the tumor necrosis factor α–transgenic (TNF-Tg) model of PH. Pulmonary endothelial and mesenchymal cells were isolated from WT and TNF-Tg mice and underwent single-cell RNA sequencing. Data were analyzed using clustering, differential gene expression and pathway analysis, ligand-receptor interaction, transcription factor binding, and RNA velocity assessments. Significantly altered ligand-receptor interactions were confirmed with immunofluorescent staining. TNF-Tg mice had increases in smooth muscle cells and Col14+ fibroblasts, and reductions in general capillary (gCAP) endothelial cells, Col13+ fibroblasts, pericytes, and myofibroblasts. Pathway analysis demonstrated NF-κB–, JAK/STAT-, and interferon-mediated inflammation, endothelial apoptosis, loss of vasodilatory pathways, increased TGF-β signaling, and smooth muscle cell proliferation. Ligand-receptor analysis demonstrated a loss of BMPR2 signaling in TNF-Tg lungs and establishment of a maladaptive BMP signaling cascade, which functional studies revealed stemmed from endothelial NF-κB activation and subsequent endothelial SMAD2/3 signaling. This system highlights a complex set of changes in cellular composition, cell communication, and cell fate driven by TNF signaling that lead to aberrant BMP signaling that is critical for development of PH.
Authors
Maria de la Luz Garcia-Hernandez, Javier Rangel-Moreno, Qingfu Xu, YeJin Jeong, Soumyaroop Bhattacharya, Ravi Misra, Stacey Duemmel, Ke Yuan, Benjamin D. Korman
Total views: 1126
N6-methyladenosine (m6A) dysregulation contributes to network excitability in temporal lobe epilepsy
Abstract
Analogous to DNA methylation and protein phosphorylation, it is now well understood that RNA is also subject to extensive processing and modification. N6-methyladenosine (m6A) is the most abundant internal RNA modification and regulates RNA fate in several ways, including stability and translational efficiency. The role of m6A in both experimental and human epilepsy remains unknown. Here, we used transcriptome-wide m6A arrays to obtain a detailed analysis of the hippocampal m6A-ome from both mouse and human epilepsy samples. We combined this with human proteomic analyses and show that epileptic tissue displays disrupted metabolic and autophagic pathways that may be directly linked to m6A processing. Specifically, our results suggest that m6A levels inversely correlate with protein pathway activation. Finally, we show that elevated levels of m6A decrease seizure susceptibility and severity in mice. Together, our findings indicate that m6A represents an additional layer of gene regulation complexity in epilepsy and may contribute to the pathomechanisms that drive the development and maintenance of hyperexcitable brain networks.
Authors
Justine Mathoux, Marc-Michel Wilson, Sujithra Srinivas, Gabrielle Litovskich, Leticia Villalba Benito, Cindy Tran, Jaideep Kesavan, Aileen Harnett, Theresa Auer, Amaya Sanz-Rodriguez, Mohammad Kh. A.E. Alkhayyat, Mairéad Sullivan, Zining Liu, Yifan Huang, Austin Lacey, Norman Delanty, Jane Cryan, Francesca M. Brett, Michael A. Farrell, Donncha F. O’Brien, Pablo M. Casillas-Espinosa, Eva M. Jimenez-Mateos, Jeffrey C. Glennon, Mary Canavan, David C. Henshall, Gary P. Brennan
Total views: 1053
Abstract
Cellular metabolism plays a key role in T cell biology. Increased glycolysis and mitochondrial respiration have been identified in CD4+ helper T cells from both patients with systemic lupus erythematosus (SLE) and lupus mouse models. Inhibiting this metabolic activity can reduce T cell activation and ameliorate disease symptoms in lupus mice. However, the metabolic differences among circulating follicular helper T (cTfh) cell subsets in patients with SLE versus healthy controls (HCs) have not been thoroughly studied. While the frequencies of cTfh cells and their subsets were similar between patients with SLE and HCs, patients exhibited a higher proportion of activated ICOS+ programmed cell death 1–positive cells, which correlated with disease activity. cTfh17 cells from both patients with SLE and HCs demonstrated heightened glycolytic activity and expression of glycolysis-related genes compared with cTfh1 and cTfh2. Glucose deprivation significantly diminished costimulatory molecule expression and cytokine production, including IL-17A, IL-10, IL-2, and TNF-α. Glycolysis inhibition reduced the B cell activation capacity of cTfh17 cells. This glucose dependence was more pronounced in cTfh17 than cTfh2 from patients with SLE, but it similarly affected both cTfh2 and cTfh17 cells from HCs. These findings highlight distinct metabolic dependencies among cTfh subsets and the critical role of glycolysis in cTfh17-mediated B cell activation in SLE.
Authors
Vera Kim, Takaya Misao, Hong Tian, Meggan Mackay, Cynthia Aranow, Sun Jung Kim
Total views: 922
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a poor survival rate due to late detection. PDAC arises from precursor microscopic lesions, termed pancreatic intraepithelial neoplasia (PanIN), that develop at least a decade before overt disease; this provides an opportunity to intercept PanIN-to-PDAC progression. However, immune interception strategies require full understanding of PanIN and PDAC cellular architecture. Surgical specimens containing PanIN and PDAC lesions from a unique cohort of 5 treatment-naive patients with PDAC were surveyed using spatial omics (proteomic and transcriptomic). Findings were corroborated by spatial proteomics of PanIN and PDAC from tamoxifen-inducible KPC mice. We uncovered the organization of lymphoid cells into tertiary lymphoid structures (TLSs) adjacent to PanIN lesions. These TLSs lacked CD21+CD23+ B cells compared with more mature TLSs near the PDAC border. PanINs harbored mostly CD4+ T cells, with fewer Tregs and exhausted T cells than PDAC. Peritumoral space was enriched with naive CD4+ and central memory T cells. These observations highlight the opportunity to modulate the immune microenvironment in PanINs before immune exclusion and immunosuppression emerge during progression into PDAC.
Authors
Melissa R. Lyman, Jacob T. Mitchell, Sidharth Raghavan, Luciane T. Kagohara, Amanda L. Huff, Saurav D. Haldar, Sarah M. Shin, Samantha Guinn, Benjamin Barrett, Gabriella Longway, Alexei Hernandez, Erin M. Coyne, Xuan Yuan, Lalitya Andaloori, Jiaying Lai, Yun Zhou Liu, Rachel Karchin, Anuj Gupta, Ashley L. Kiemen, André Forjaz, Denis Wirtz, Pei-Hsun Wu, Atul Deshpande, Jae W. Lee, Todd D. Armstrong, Nilofer S. Azad, Jacquelyn W. Zimmerman, Laura D. Wood, Robert A. Anders, Elizabeth D. Thompson, Elizabeth M. Jaffee, Elana J. Fertig, Won Jin Ho, Neeha Zaidi
Total views: 906
Abstract
Glycans are one of the 4 major macromolecules essential for life and are the most abundant family of organic molecules. However, in contrast with DNA and RNA, glycan structures have no template; this results in limited tools to study this challenging macromolecule with a diversity of glycan structures. A central bottleneck in studying glycosylation in vivo is that inhibitors and complete KOs are lethal. In a forward genetic screen, we identified a viable, hypomorphic mutation at a conserved site in mannose phosphate isomerase (Mpi) that causes a multisystemic phenotype affecting RBCs, liver, stomach, intestines, skin, size, fat, and fluid balance in mice. The phenotype could be rescued with mannose. Analyses of glycopeptides in mice with this mutation showed a 500% increase in unoccupied N-glycan sites. This is equivalent to a “glycan knockdown,” which would be useful for examining the role of glycans in biology and disease. Therefore, we report an in vivo tool to study global N-glycosylation deficiency with tissue-specific targeting and a rescue mechanism with mannose.
Authors
Elisa B. Lin, Steve Meregini, Zhao Zhang, Avishek Roy, Tandav Argula, James M. Mitchell, William J. Israelsen, Sara Ludwig, Jamie Russell, Jiexia Quan, Sara Hildebrand, Evan Nair-Gill, Bruce Beutler, Jeffrey A. SoRelle
Total views: 889
