tbuckley/cabot-search huggingface dataset:
Phenotypic and pathomechanistic overlap between tapasin and TAP deficiencies
Authors: Abdulwahab Elsayed, Sandra von Hardenberg, Faranaz Atschekzei, Theresa Graalmann, Christine Jänke, Torsten Witte, Felix C. Ringshausen, Georgios Sogkas
Journal: Journal of Allergy and Clinical Immunology (2024)

BackgroundHuman tapasin deficiency is reported to cause an autosomal-recessive inborn error of immunity characterized by substantially reduced cell surface expression of major histocompatibility complex class I (MHC-I).ObjectiveWe evaluated the immunologic and clinical consequences of tapasin deficiency.MethodsA novel homozygous variant in TAPBP was identified by means of whole genome sequencing. The expression of tapasin and both subunits of the transporter associated with antigen presentation (TAP) were evaluated by Western blot analysis. Cell surface and intracellular expression of MHC-I were evaluated by flow cytometry. Small interfering RNAs were used for silencing TAPBP expression in HEK293T cells.ResultsWe identified a deletion in TAPBP (c.312del, p.(K104Nfs∗6)) causing tapasin deficiency in a patient with bronchiectasis and recurrent respiratory tract infections as well as herpes zoster. Besides substantial reduction in TAP1 and TAP2 expression, peripheral blood mononuclear cells from this patient and TAPBP-knockdown HEK293T cells, displayed reduced cell surface expression of MHC-I, while reduction in intracellular expression of MHC-I was less prominent, suggesting a defect in MHC-I trafficking to the plasma membrane. IFN-α improved cell surface expression of MHC-I in tapasin deficient lymphocytes and TAPBP-knockdown HEK293T cells, representing a possible therapeutic approach for tapasin deficiency.ConclusionTapasin deficiency is a very rare inborn error of immunity, the pathomechanism and clinical spectrum of which overlaps with TAP deficiencies.
Profiling Bacteria in the Lungs of Patients with Severe Influenza Versus COVID-19 with or without Aspergillosis
Authors: Simon Feys, Martina Cardinali-Benigni, Hanne Moon Lauwers, Cato Jacobs, Annelies Stevaert, Samuel M Gonçalves, Cristina Cunha, Yves Debaveye, Greet Hermans, Jannes Heylen, Stephanie Humblet-Baron, Katrien Lagrou, Lenn Maessen, Philippe Meersseman, Marijke Peetermans, Alvaro Redondo-Rios, Laura Seldeslachts, Marick R. Starick, Karin Thevissen, Greetje Vande Velde, Christophe Vandenbriele, Lore Vanderbeke, Alexander Wilmer, Lieve Naesens, Frank L van de Veerdonk, Johan Van Weyenbergh, Toni Gabaldón, Joost Wauters, Agostinho Carvalho
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

The influence of the lung bacterial microbiome, including potential pathogens, in patients with influenza- or COVID-19-associated pulmonary aspergillosis (IAPA or CAPA) is yet to be explored.
Analysis of Evolutionary Conservation, Expression Level, and Genetic Association at a Genome-wide Scale Reveals Heterogeneity in Traits Across Polygenic Phenotypes
Authors: Ann-Sophie Giel, Jessica Bigge, Johannes Schumacher, Carlo Maj, Pouria Dasmeh
Journal: Molecular Biology and Evolution (2024)

Abstract Understanding the expression level and evolutionary rate of associated genes with human polygenic diseases provides crucial insights into their disease-contributing roles. In this work, we leveraged genome-wide association studies (GWASs) to investigate the relationship between the genetic association and both the evolutionary rate (dN/dS) and expression level of human genes associated with the two polygenic diseases of schizophrenia and coronary artery disease. Our findings highlight a distinct variation in these relationships between the two diseases. Genes associated with both diseases exhibit a significantly greater variance in evolutionary rate compared to those implicated in monogenic diseases. Expanding our analyses to 4,756 complex traits in the GWAS atlas database, we unraveled distinct trait categories with a unique interplay among the evolutionary rate, expression level, and genetic association of human genes. In most polygenic traits, highly expressed genes were more associated with the polygenic phenotypes compared to lowly expressed genes. About 69% of polygenic traits displayed a negative correlation between genetic association and evolutionary rate, while approximately 30% of these traits showed a positive correlation between genetic association and evolutionary rate. Our results demonstrate the presence of a spectrum among complex traits, shaped by natural selection. Notably, at opposite ends of this spectrum, we find metabolic traits being more likely influenced by purifying selection, and immunological traits that are more likely shaped by positive selection. We further established the polygenic evolution portal (evopolygen.de) as a resource for investigating relationships and generating hypotheses in the field of human polygenic trait evolution.
The mitochondrial TSPO ligand Atriol mitigates metabolic-associated steatohepatitis by downregulating CXCL1
Authors: Yuchang Li, Liting Chen, Chantal Sottas, Mahima Chandrakant Raul, Nrupa Dinesh Patel, Janaki Ramulu Bijja, S Kaleem Ahmed, Audrey Kapelanski-Lamoureux, Anthoula Lazaris, Peter Metrakos, Alexander Zambidis, Shefali Chopra, Meng Li, Go Sugahara, Takeshi Saito, Vassilios Papadopoulos
Journal: Metabolism (2024)
Nutrient-sensitizing drug repurposing screen identifies lomerizine as a mitochondrial metabolism inhibitor of chronic myeloid leukemia
Authors: Ahmed Khalaf, Lucie de Beauchamp, Eric Kalkman, Kevin Rattigan, Ekaterini Himonas, Joe Jones, Daniel James, Engy Shokry Abd Shokry, Mary T. Scott, Karen Dunn, Saverio Tardito, Mhairi Copland, David Sumpton, Emma Shanks, G. Vignir Helgason
Journal: Science Translational Medicine (2024)

In chronic myeloid leukemia (CML), the persistence of leukemic stem cells (LSCs) after treatment with tyrosine kinase inhibitors (TKIs), such as imatinib, can lead to disease relapse. It is known that therapy-resistant LSCs rely on oxidative phosphorylation (OXPHOS) for their survival and that targeting mitochondrial respiration sensitizes CML LSCs to imatinib treatment. However, current OXPHOS inhibitors have demonstrated limited efficacy or have shown adverse effects in clinical trials, highlighting that identification of clinically safe oxidative pathway inhibitors is warranted. We performed a high-throughput drug repurposing screen designed to identify mitochondrial metabolism inhibitors in myeloid leukemia cells. This identified lomerizine, a US Food and Drug Administration (FDA)–approved voltage-gated Ca 2+ channel blocker now used for the treatment of migraines, as one of the top hits. Transcriptome analysis revealed increased expression of voltage-gated CACNA1D and receptor-activated TRPC6 Ca 2+ channels in CML LSCs (CD34 + CD38 − ) compared with normal counterparts. This correlated with increased endoplasmic reticulum (ER) mass and increased ER and mitochondrial Ca 2+ content in CML stem/progenitor cells. We demonstrate that lomerizine-mediated inhibition of Ca 2+ uptake leads to ER and mitochondrial Ca 2+ depletion, with similar effects seen after CACNA1D and TRPC6 knockdown. Through stable isotope-assisted metabolomics and functional assays, we observe that lomerizine treatment inhibits mitochondrial isocitrate dehydrogenase activity and mitochondrial oxidative metabolism and selectively sensitizes CML LSCs to imatinib treatment. In addition, combination treatment with imatinib and lomerizine reduced CML tumor burden, targeted CML LSCs, and extended survival in xenotransplantation model of human CML, suggesting this as a potential therapeutic strategy to prevent disease relapse in patients.
Recurrent duplication and diversification of a vital DNA repair gene family across Drosophila
Authors: Cara L Brand, Genevieve T Oliver, Isabella Z Farkas, Michael Buszczak, Mia T Levine
Journal: Molecular Biology and Evolution (2024)

Abstract Maintaining genome integrity is vital for organismal survival and reproduction. Essential, broadly conserved DNA repair pathways actively preserve genome integrity. However, many DNA repair proteins evolve adaptively. Ecological forces like UV exposure are classically cited drivers of DNA repair evolution. Intrinsic forces like repetitive DNA, which also imperil genome integrity, have received less attention. We recently reported that a Drosophila melanogaster-specific DNA satellite array triggered species-specific, adaptive evolution of a DNA repair protein called Spartan/MH. The Spartan family of proteases cleave hazardous, covalent crosslinks that form between DNA and proteins (“DNA–protein crosslink repair”). Appreciating that DNA satellites are both ubiquitous and universally fast-evolving, we hypothesized that satellite DNA turnover spurs adaptive evolution of DNA–protein crosslink repair beyond a single gene and beyond the D. melanogaster lineage. This hypothesis predicts pervasive Spartan gene family diversification across Drosophila species. To study the evolutionary history of the Drosophila Spartan gene family, we conducted population genetic, molecular evolution, phylogenomic, and tissue-specific expression analyses. We uncovered widespread signals of positive selection across multiple Spartan family genes and across multiple evolutionary timescales. We also detected recurrent Spartan family gene duplication, divergence, and gene loss. Finally, we found that ovary-enriched parent genes consistently birthed functionally diverged, testis-enriched daughter genes. To account for Spartan family diversification, we introduce a novel mechanistic model of antagonistic coevolution that links DNA satellite evolution and adaptive regulation of Spartan protease activity. This framework promises to accelerate our understanding of how DNA repeats drive recurrent evolutionary innovation to preserve genome integrity.
Heterotypic immunity from prior SARS-CoV-2 infection but not COVID-19 vaccination associates with lower endemic coronavirus incidence
Authors: David J. Bean, Janet Monroe, Yan Mei Liang, Ella Borberg, Yasmeen Senussi, Zoe Swank, Sujata Chalise, David Walt, Janice Weinberg, Manish Sagar
Journal: Science Translational Medicine (2024)

Immune responses from prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and COVID-19 vaccination mitigate disease severity, but they do not fully prevent subsequent infections, especially from genetically divergent strains. We examined the incidence of and immune differences against human endemic coronaviruses (eCoVs) as a proxy for response against future genetically heterologous coronaviruses (CoVs). We assessed differences in symptomatic eCoV and non-CoV respiratory disease incidence among those with known prior SARS-CoV-2 infection or previous COVID-19 vaccination but no documented SARS-CoV-2 infection or neither exposure. Retrospective cohort analyses suggest that prior SARS-CoV-2 infection, but not previous COVID-19 vaccination alone, associates with a lower incidence of subsequent symptomatic eCoV infection. There was no difference in non-CoV incidence, implying that the observed difference was eCoV specific. In a second cohort where both cellular and humoral immunity were measured, those with prior SARS-CoV-2 spike protein exposure had lower eCoV-directed neutralizing antibodies, suggesting that neutralization is not responsible for the observed decreased eCoV disease. The three groups had similar cellular responses against the eCoV spike protein and nucleocapsid antigens. However, CD8
Microglia promote maladaptive plasticity in autonomic circuitry after spinal cord injury in mice
Authors: Faith H. Brennan, Emily A. Swarts, Kristina A. Kigerl, Katherine A. Mifflin, Zhen Guan, Benjamin T. Noble, Yan Wang, Kristina G. Witcher, Jonathan P. Godbout, Phillip G. Popovich
Journal: Science Translational Medicine (2024)

Robust structural remodeling and synaptic plasticity occurs within spinal autonomic circuitry after severe high-level spinal cord injury (SCI). As a result, normally innocuous visceral or somatic stimuli elicit uncontrolled activation of spinal sympathetic reflexes that contribute to systemic disease and organ-specific pathology. How hyperexcitable sympathetic circuitry forms is unknown, but local cues from neighboring glia likely help mold these maladaptive neuronal networks. Here, we used a mouse model of SCI to show that microglia surrounded active glutamatergic interneurons and subsequently coordinated multi-segmental excitatory synaptogenesis and expansion of sympathetic networks that control immune, neuroendocrine, and cardiovascular functions. Depleting microglia during critical periods of circuit remodeling after SCI prevented maladaptive synaptic and structural plasticity in autonomic networks, decreased the frequency and severity of autonomic dysreflexia, and prevented SCI-induced immunosuppression. Forced turnover of microglia in microglia-depleted mice restored structural and functional indices of pathological dysautonomia, providing further evidence that microglia are key effectors of autonomic plasticity. Additional data show that microglia-dependent autonomic plasticity required expression of triggering receptor expressed on myeloid cells 2 (Trem2) and α2δ-1-dependent synaptogenesis. These data suggest that microglia are primary effectors of autonomic neuroplasticity and dysautonomia after SCI in mice. Manipulating microglia may be a strategy to limit autonomic complications after SCI or other forms of neurologic disease.
Metformin-induced changes in the gut microbiome and plasma metabolome are associated with cognition in men
Authors: Marisel Rosell-Díaz, Anna Petit-Gay, Clàudia Molas-Prat, Laura Gallardo-Nuell, Lluís Ramió-Torrentà, Josep Garre-Olmo, Vicente Pérez-Brocal, Andrés Moya, Mariona Jové, Reinald Pamplona, Josep Puig, Rafael Ramos, Fredrik Bäckhed, Jordi Mayneris-Perxachs, José Manuel Fernández-Real
Journal: Metabolism (2024)
Towards a roadmap for COSEB: the next steps in harmonization of outcomes for epidermolysis bullosa
Authors: Eva W H Korte, Anna M G Pasmooij, Maria C Bolling, Sinéad Hickey, Sagair Hussain, Dimitra Kiritsi, Jan Kottner, Cecilia A C Prinsen, Angélique Sauvestre, Gaston Sendin, Phyllis I Spuls, Núria Tarrats, Verena Wally, Tobias Welponer, Martin Laimer, Peter C van den Akker, Ajoy Bardhan, Pauline Bataille, Christine Bodemer, Marieke Bolling, Anna Bruckner, Christine Chiaverini, Victoria Clemett, Caroline Collins, Caroline Colmant, Laura De Rosa, José Duipmans, Christen Ebens, María Florencia Fernandez, Emily Gorell, Sophie Guez, Cristina Has, Sinéad Hickey, Chao-Kai Hsu, Sagair Hussain, Ritu Jain, Tom Kenny, Johannes S Kern, Divya Khanna, Dimitra Kiritsi, Sophie Kitzmüller, Eva Korte, Jan Kottner, Martin Laimer, Irene Lara-Corrales, Michelle Lee, Wei Li, Lucia Lospalluti, M Peter Marinkovich, Anna Martinez, Jemima Mellerio, Celia Moss, Olivia Mullins, Dédée Murrell, Hagen Ott, Francis Palisson, Amy Paller, Marjon Pasmooij, Gabriela Petrof, Elena Pope, Cecilia Prinsen, Gudrun Salamon, Julio Salas-Alanis, Carmen Salavastru, Angélique Sauvestre, Sabine Scherer, Nicholas Schräder, Gaston Sendin, Eli Sprecher, Corina Spreitzer, Phyllis Spuls, Núria Tarrats, Peter van den Akker, Verena Wally, Tobias Welponer, Katarzyna Wertheim-Tysarowska, Tobias Zahn
Journal: British Journal of Dermatology (2024)

The COSEB initiative aims for standardized and uniform measurement by developing core outcome sets for epidermolysis bullosa. This report describes the COSEB workshop organized in December 2023, which led to a broad stakeholder consensus-based roadmap. Moreover, it highlights novel features of COSEB, including the pro-active engagement of stakeholders from the very beginning and the appointment of a multi-stakeholder advisory panel.
Longitudinal Assessment of Left Atrial Remodeling in Patients With Chronic Severe Aortic Regurgitation
Authors: Emmanuel Akintoye, Joseph El Dahdah, M Marwan Dabbagh, Hardik Patel, Osamah Badwan, Lorenzo Braghieri, Michel Chedid El Helou, Joseph Kassab, Christine L. Jellis, Milind Y. Desai, L. Leonardo Rodriguez, Richard A. Grimm, Eric E. Roselli, Brian P. Griffin, Zoran B. Popovic
Journal: JACC. Cardiovascular imaging (2024)
Identification and potential clinical applications of novel autophagy/mitophagy proteins in the biofluids of Alzheimer’s disease patients
Authors: Jianying Zhang, He-Ling Wang, Kateřina Veverová, Martin Vyhnálek, Evandro Fei Fang
Journal: Ageing Research Reviews (2024)

• Elevated PINK1 and reduced TFEB in CSF and serum samples of AD patients. • Correlations were found between levels of PINK1, TFEB, and clinical indicators of AD. • Changes of the fluid protein levels of mitophagy/autophagy proteins could be developed into markers in assisting diagnsosi and prognosis.
Artificial intelligence and radiologists in prostate cancer detection on MRI (PI-CAI): an international, paired, non-inferiority, confirmatory study
Authors: Anindo Saha, Joeran S Bosma, Jasper J Twilt, Bram van Ginneken, Anders Bjartell, Anwar R Padhani, David Bonekamp, Geert Villeirs, Georg Salomon, Gianluca Giannarini, Jayashree Kalpathy-Cramer, Jelle Barentsz, Klaus H Maier-Hein, Mirabela Rusu, Olivier Rouvière, Roderick van den Bergh, Valeria Panebianco, Veeru Kasivisvanathan, Nancy A Obuchowski, Derya Yakar, Mattijs Elschot, Jeroen Veltman, Jurgen J Fütterer, Maarten de Rooij, Henkjan Huisman
Journal: The Lancet Oncology (2024)
The “echo-free space” technique: A safe and reliable method for endoscopic ultrasound scope insertion into the esophagus
Authors: Shunsuke Omoto, Mamoru Takenaka, Kota Takashima, Yoriaki Komeda, Masatoshi Kudo
Journal: Endoscopy (2024)

In recent years, the use of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) and EUS-guided drainage has greatly expanded [1] [2] [3] [4]. However, inserting a linear EUS scope into the esophagus can be challenging, particularly in intubated or pediatric patients. This is because the scope is side-viewing, and the tip does not face the cervical esophagus. As a result, it can damage the laryngopharynx and lead to unsuccessful insertion if advanced, based on endoscopic imaging ([Fig. 1]).
Esophageal pneumatosis and hematomatosis concomitant with achalasia
Authors: Takashi Ueda, Ryuzo Deguchi, Masaya Sano, Hidekazu Suzuki
Journal: Endoscopy (2024)

Although pneumatosis affecting the large intestine, small intestine, and stomach has been documented in the gastrointestinal tract, cases of pneumatosis in the esophagus are infrequent. The patient in this case was an octogenarian man who presented to Tokai University Hospital with the chief complaint of persistent dysphagia. Achalasia was diagnosed using upper gastrointestinal endoscopy and upper gastrointestinal imaging ([Fig. 1]). Subsequently, hospitalization was deemed necessary due to compromised oral intake.
Gastric endoscopic submucosal dissection through a gastrostomy using a newly developed thin endoscope
Authors: Satoki Shichijo, Mori Hitoshi, Koji Higashino, Noriya Uedo, Tomoki Michida
Journal: Endoscopy (2024)

A 76-year-old man underwent follow-up endoscopy after undergoing curative endoscopic submucosal dissection (ESD) for esophageal cancer [1]. He had a past history of advanced pharyngeal cancer, which had been treated with chemoradiotherapy, and had a percutaneous endoscopic gastrostomy because of persistent trismus ([Fig. 1]). The follow-up endoscopy, performed via transnasal endoscopy, revealed a 6-mm depressed lesion in the lesser curvature of the antrum, and a biopsy confirmed adenocarcinoma ([Fig. 2]). ESD using a newly developed endoscope [2] [3] was performed to treat the gastric cancer.
A technique for preventing clip snagging during the use of a rotating function endoscopic clip
Authors: Koichiro Kawano, Mamoru Takenaka, Reiko Kawano, Tomonori Moriguchi, Koutaro Mine, Katsuhisa Nishi, Masatoshi Kudo
Journal: Endoscopy (2024)

The EZ clip series (Olympus, Tokyo, Japan) is widely recognized as a useful endoscopic clip with a rotating function [1] [2] [3]. This highly effective rotation function allows the clip to be oriented correctly relative to the target ([Fig. 1]). When employing this function, it is crucial to ensure that the coil sheath does not contact the end of the clip, as frictional resistance may impede proper rotation. Thus, separating the coil sheath from the clip is necessary before initiating rotation. The clip is then rotated to the proper angle and then retracted until the clip stopper contacts the coil sheath to allow for clipping. However, excessive bending of the endoscope during angle adjustment may cause the tip of the clip to collide with the coil sheath, leading to clip snagging ([Fig. 2]) and, consequently, imprecise clipping ([Fig. 3]).
Congenital gastric ectopic pylorus: a rare gastric malformation
Authors: Chang Wang, Shengwu Pan, Yaqi Zhai
Journal: Endoscopy (2024)

A 71-year-old man who presented with hematemesis and melena was admitted to our hospital. He denied any previous surgery history or recent use of alcohol and antithrombotic agents. Esophagogastroduodenoscopy (EGD) revealed an opening leading to the duodenum and the blind antrum without normal pylorus ([Fig. 1],[Fig. 2]). The ectopic pyloric opening was located in the lesser curvature of the upper gastric body, approximately 2 cm distal to the cardia. Multiple ulcers were also found near the opening without active bleeding ([Video 1]). The upper gastroenterography and computed tomography showed the teapot-like stomach, further confirming the ectopic pyloric opening in the upper gastric body ([Fig. 3],[Fig. 4]). With conservative medication, the patient gained a rapid recovery and was discharged uneventfully.
Mutational characteristics and clinical outcomes for lung adenocarcinoma with EGFR germline mutations
Authors: Kelsey Pan, Jennifer Owens, Yasir Elamin, Charles Lu, Mark Routbort, Jianjun Zhang, Frank Fossella, Marcelo V Negrao, Mehmet Altan, Jenny Pozadzides, Ferdinandos Skoulidis, Anne Tsao, Tina Cascone, John V Heymach, Edwin Ostrin, Xiuning Le
Journal: Journal of Thoracic Oncology (2024)
Pharmacology of Hydrogen Sulfide and Its Donors in Cardiometabolic Diseases
Authors: Hai-Jian Sun, Qing-Bo Lu, Xue-Xue Zhu, Zhang-Rong Ni, Jia-Bao Su, Xiao Fu, Guo Chen, Guan-Li Zheng, Xiao-Wei Nie, Jin-Song Bian
Journal: Pharmacological Reviews (2024)

Cardiometabolic diseases (CMDs) are major contributors to global mortality, emphasizing the critical need for novel therapeutic interventions. Hydrogen sulfide (H<sub>2</sub>S) has garnered enormous attention as a significant gasotransmitter with various physiological, pathophysiological, and pharmacological impacts within mammalian cardiometabolic systems. In addition to its roles in attenuating oxidative stress and inflammatory response, burgeoning research emphasizes the significance of H<sub>2</sub>S in regulating proteins via persulfidation, a well-known modification intricately associated with the pathogenesis of CMDs. This review seeks to investigate recent updates on the physiological actions of endogenous H<sub>2</sub>S and the pharmacological roles of various H<sub>2</sub>S donors in addressing diverse aspects of CMDs across cellular, animal, and clinical studies. Of note, advanced methodologies including multi-omics, intestinal microflora analysis, organoid and single-cell sequencing techniques are gaining traction due to their ability to offer comprehensive insights into biomedical research. These emerging approaches hold promise in characterizing the pharmacological roles of H<sub>2</sub>S in health and diseases. We will critically assesse the current literatures to clarify the roles of H<sub>2</sub>S in diseases while also delineating the opportunities and challenges they present in H<sub>2</sub>S-based pharmacotherapy for CMDs. <b>Significance Statement</b> The comprehensive review covers recent developments in H<sub>2</sub>S biology and pharmacology in CMDs. Endogenous H<sub>2</sub>S and its donors show great promise for the management of CMDs by regulating numerous proteins and signaling pathways. The emergence of new technologies will considerably advance the pharmacological research and clinical translation of H<sub>2</sub>S.