tbuckley/cabot-search huggingface dataset:
Human-induced pluripotent stem cell–based hepatic modeling of lipid metabolism–associated TM6SF2-E167K variant
Authors: Lanuza A.P. Faccioli, Yiyue Sun, Olamide Animasahun, Takashi Motomura, Zhenghao Liu, Takeshi Kurihara, Zhiping Hu, Bo Yang, Zeliha Cetin, Annalisa M. Baratta, Ajay Shankaran, Minal Nenwani, Leyla Nurcihan Altay, Linqi Huang, Noah Meurs, Jonathan Franks, Donna Stolz, Dillon C. Gavlock, Mark T. Miedel, Alina Ostrowska, Rodrigo M. Florentino, Ira J. Fox, Deepak Nagrath, Alejandro Soto-Gutierrez
Journal: Hepatology (2024)

Background and Aims: TM6SF2 rs58542926 (E167K) is related to an increased prevalence of metabolic dysfunction–associated steatotic liver disease. Conflicting mouse study results highlight the need for a human model to understand this mutation’s impact. This study aims to create and characterize a reliable human in vitro model to mimic the effects of the TM6SF2-E167K mutation for future studies. Approach and Results: We used gene editing on human-induced pluripotent stem cells from a healthy individual to create cells with the TM6SF2-E167K mutation. After hepatocyte-directed differentiation, we observed decreased TM6SF2 protein expression, increased intracellular lipid droplets, and total cholesterol, in addition to reduced VLDL secretion. Transcriptomics revealed the upregulation of genes involved in lipid, fatty acid, and cholesterol transport, flux, and oxidation. Global lipidomics showed increased lipid classes associated with endoplasmic reticulum (ER) stress, mitochondrial dysfunction, apoptosis, and lipid metabolism. In addition, the TM6SF2-E167K mutation conferred a proinflammatory phenotype with signs of mitochondria and ER stress. Importantly, by facilitating protein folding within the ER of hepatocytes carrying TM6SF2-E167K mutation, VLDL secretion and ER stress markers improved. Conclusions: Our findings indicate that induced hepatocytes generated from human-induced pluripotent stem cells carrying the TM6SF2-E167K recapitulate the effects observed in human hepatocytes from individuals with the TM6SF2 mutation. This study characterizes an in vitro model that can be used as a platform to identify potential clinical targets and highlights the therapeutic potential of targeting protein misfolding to alleviate ER stress and mitigate the detrimental effects of the TM6SF2-E167K mutation on hepatic lipid metabolism.
A functional genomic framework to elucidate novel causal metabolic dysfunction-associated fatty liver disease genes
Authors: Peter Saliba-Gustafsson, Johanne M. Justesen, Amanda Ranta, Disha Sharma, Ewa Bielczyk-Maczynska, Jiehan Li, Laeya A. Najmi, Maider Apodaka, Patricia Aspichueta, Hanna M. Björck, Per Eriksson, Theresia M. Schurr, Anders Franco-Cereceda, Mike Gloudemans, Endrina Mujica, Marcel den Hoed, Themistocles L. Assimes, Thomas Quertermous, Ivan Carcamo-Orive, Chong Y. Park, Joshua W. Knowles
Journal: Hepatology (2024)

Metabolic dysfunction-associated fatty liver disease (MASLD) is the most prevalent chronic liver pathology in western countries, with serious public health consequences. Efforts to identify causal genes for MASLD have been hampered by the relative paucity of human data from gold standard magnetic resonance quantification of hepatic fat. To overcome insufficient sample size, genome-wide association studies using MASLD surrogate phenotypes have been used, but only a small number of loci have been identified to date. In this study, we combined genome-wide association studies of MASLD composite surrogate phenotypes with genetic colocalization studies followed by functional in vitro screens to identify bona fide causal genes for MASLD.
Functional humoral immunity is crucial to outcomes in severe alcohol-associated hepatitis
Authors: Brett M. McGettigan, Natalia A. Osna
Journal: Hepatology (2024)

1The Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA 2The Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, USA Abbreviations: ACLF, acute-on-chronic liver failure; AH, alcohol-associated hepatitis; AUD, alcohol use disorder. Correspondence Brett M. McGettigan, 200 1st Street SW, Rochester, MN 55905. Email: [email protected]
The senescence-associated secretome of hedgehog-deficient hepatocytes drives MASLD progression
Authors: Ji Hye Jun, Kuo Du, Rajesh Kumar Dutta, Raquel Maeso-Diaz, Seh Hoon Oh, Liuyang Wang, Guannan Gao, Ana Ferreira, Jon Hill, Steven S. Pullen, Anna Mae Diehl
Journal: Journal of Clinical Investigation (2024)

The burden of senescent hepatocytes correlates with the severity of metabolic dysfunction-associated steatotic liver disease (MASLD), but the mechanisms driving senescence and how it exacerbates MASLD are poorly understood. Hepatocytes experience lipotoxicity and become senescent when Smoothened (Smo) is deleted to disrupt Hedgehog signaling. We aimed to determine whether the secretomes of Smo-deficient hepatocytes perpetuate senescence to drive MASLD progression. RNA-Seq analysis of liver samples from human and murine cohorts with MASLD confirmed that hepatocyte populations in MASLD livers were depleted of Smo+ cells and enriched with senescent cells. When fed a choline-deficient, amino acid-restricted high-fat diet (CDA-HFD) to induce MASLD, Smo- mice had lower antioxidant markers and developed worse DNA damage, senescence, steatohepatitis, and fibrosis than did Smo+ mice. Sera and hepatocyte-conditioned medium from Smo- mice were depleted of thymidine phosphorylase (TP), a protein that maintains mitochondrial fitness. Treating Smo- hepatocytes with TP reduced senescence and lipotoxicity, whereas inhibiting TP in Smo+ hepatocytes had the opposite effect and exacerbated hepatocyte senescence, steatohepatitis, and fibrosis in CDA-HFD-fed mice. We conclude that inhibition of Hedgehog signaling in hepatocytes promoted MASLD by suppressing hepatocyte production of proteins that prevent lipotoxicity and senescence.
Single-cell multiomic analysis identifies macrophage subpopulations in promoting cardiac repair
Authors: Mingzhu Fu, Shengtao Jia, Longhui Xu, Xin Li, Yufang Lv, Yulong Zhong, Shanshan Ai
Journal: Journal of Clinical Investigation (2024)

Cardiac macrophages/monocytes participate in maintaining homeostasis and orchestrating cardiac responses upon injury. However, the function of specific macrophage/monocyte subtypes and the related cell fate commitment mechanisms remain elusive in regenerative and nonregenerative hearts due to their cellular heterogeneities. Using spatiotemporal single-cell epigenomic analysis of cardiac macrophages/monocytes in regenerative (P1) and nonregenerative (P10) mouse hearts post injury, we found that P1 hearts accumulate reparative Arg1+ macrophages, while proinflammatory S100a9+Ly6c+ monocytes are uniquely abundant during nonregenerative remodeling. Moreover, blocking chemokine CXCR2 to inhibit the specification of the S100a9+Ly6c+-biased inflammatory fate in P10 hearts resulted in elevated wound repair responses and marked improvements in cardiac function after injury. Single-cell RNA-seq further confirmed an increased Arg1+ macrophage subpopulation after CXCR2 blockade, which was accomplished by increased expression of wound repair-related genes and reduced expression of proinflammatory genes. Collectively, our findings provide instructive insights into the molecular mechanisms underlying the function and fate specification of heterogeneous macrophages/monocytes during cardiac repair and identify potential therapeutic targets for myocardial infarction.
A trust based framework for the envelopment of medical AI
Authors: Lena Christine Zuchowski, Matthias Lukas Zuchowski, Eckhard Nagel
Journal: npj Digital Medicine (2024)

The importance of a trust-based relationship between patients and medical professionals has been recognized as one of the most important predictors of treatment success and patients' satisfaction. We have developed a novel legal, social and regulatory envelopment of medical AI that is explicitly based on the preservation of trust between patients and medical professionals. We require that the envelopment fosters reliance on the medical AI by both patients and medical professionals. Focusing on this triangle of desirable attitudes allows us to develop eight envelopment components that will support, strengthen and preserve these attitudes. We then demonstrate how each envelopment component can be enacted during different stages of the systems development life cycle and demonstrate that this requires the involvement of medical professionals and patients at the earliest stages of the life cycle. Therefore, this framework requires medical AI start-ups to cooperate with medical professionals and patients throughout.
The Role of Malnutrition and Psychiatric Illnesses in Olfactory Dysfunction Post-Kidney Transplantation
Authors: Chia-Ter Chao
Journal: Journal of the American Society of Nephrology (2024)

Gupta et al. conducted an insightful study that was published in JASN, investigating changes in cognitive function and olfaction after kidney transplantation.1 They found that cognitive dysfunction significantly improved 3 months after transplantation, whereas olfactory function did not change. The authors propose that cognitive dysfunction in kidney disease might result from reversible metabolic perturbations, whereas olfactory defects, particularly those involving the central mechanisms, might be less reversible. We concur with these propositions but wish to supplement them by elaborating on the influences of malnutrition and occult psychiatric illnesses on olfactory function in patients with CKD. Existing studies suggest that in patients with ESKD undergoing chronic hemodialysis, olfactory and gustatory dysfunctions are significantly associated with malnutrition.2 A recently published systematic review summarized the impact of several nutritional aberrancies on olfactory disorders in patients with CKD.3 Electrolyte imbalances, nutritional levels (assessed via subjective global assessment scores), and greater inflammation severity have all been implicated as exacerbating factors of olfactory alteration in these patients. Olfactory disorders are frequently accompanied by gustatory dysfunction, another major contributor to poor intake and malnutrition, in patients with CKD. Given that nutritional improvement varies with the duration after kidney transplantation, graft function, and the effects of immunosuppressive therapies, it is plausible that graft recipients in this study still experience a degree of nutritional compromise, precluding early olfactory function recovery. Olfactory dysfunction has also been correlated with depressive symptoms and loneliness. Depression may lead to a decreased activation of secondary olfactory areas and alter olfactory processing, interfering with sensory integration.4 As the prevalence of depression and other psychiatric disorders is high in patients with both nondialysis and dialysis-dependent CKD and remains elevated even after kidney transplantation, it is possible that these illnesses may partly contribute to poorer olfactory function recovery shortly after transplantation. This provides another possible explanation for the olfactory assessment findings in the study by Gupta et al.
68Ga-Trivehexin PET/CT in Metastatic Non–Small Cell Lung Cancer to the Brain
Authors: Fahad Marafi, Abdulredha A. Esmail, Mahmoud A. Alfeeli, Alyaa Sadeq
Journal: Clinical Nuclear Medicine (2024)

In the era of molecular imaging and eager to study tumor tissues' microenvironment with noninvasive means, the search and development of new radiotracer targeted molecule continue. αvβ6-Integrin is a heterodimeric glycoprotein transmembrane receptor that is unique in that it is expressed exclusively in epithelial cells. It is upregulated in varieties of carcinomas such of the lung, breast, and colon. It plays a role in facilitating invasion, inhibiting apoptosis, regulating expression of matrix metalloproteases, and activating TGF-β in carcinoma. Expression of αvβ6 indicates poor prognosis and can help in development of targeted therapy. 68 Ga-Trivehexin has affinity of 85%-88% of this integrin.
Association of Genetically Predicted Skipping of COL4A4 Exon 27 with Hematuria and Albuminuria
Authors: Frida Lona-Durazo, Kohei Omachi, Damian Fermin, Felix Eichinger, Jonathan P. Troost, Meei-Hua Lin, Ian R. Dinsmore, Tooraj Mirshahi, Alexander R. Chang, Jeffrey H. Miner, Andrew D. Paterson, Moumita Barua, Sarah A. Gagliano Taliun
Journal: Journal of the American Society of Nephrology (2024)

Key Points Using transcriptome-wide association studies, we identified an association between splicing out of exon 27 of COL4A4 and hematuria. We confirmed the presence of COL4A4 exon 27 splicing in an independent cohort. Functional assays revealed that the COL4A4 transcript with exon 27 spliced out affects collagen IV trimer assembly and secretion. Background Hematuria is an established sign of glomerular disease and can be associated with kidney failure, but there has been limited scientific study of this trait. Methods Here, we combined genetic data from the UK Biobank with predicted gene expression and splicing from Genotype Tissue Expression kidney cortex samples ( n =65) in a transcriptome-wide association study to identify additional potential biological mechanisms influencing hematuria. Results The transcriptome-wide association study using kidney cortex identified significant associations for five genes in expression and three significant splicing events. Notably, we identified an association between the skipping of COL4A4 exon 27, which is genetically predicted by intronic rs11898094 (minor allele frequency 13%), and hematuria. Association between this variant was also found with urinary albumin excretion. We found independent evidence supporting the same variant predicting this skipping event in glomeruli-derived mRNA transcriptomics data ( n =245) from the Nephrotic Syndrome Study Network. The functional significance of loss of exon 27 was demonstrated using the split NanoLuc-based α 3 α 4 α 5(IV) heterotrimer assay, in which type IV collagen heterotrimer formation was quantified by luminescence. The causal splicing variant for this skipping event is yet to be identified. Conclusions In summary, by integrating multiple data types, we identified a potential splicing event associated with hematuria and albuminuria.
Authors' Reply: The Role of Malnutrition and Psychiatric Illnesses in Olfactory Dysfunction Post-Kidney Transplantation
Authors: Aditi Gupta
Journal: Journal of the American Society of Nephrology (2024)

We found the letter to the editor by Dr. Chao1 on our article in JASN, "Changes in Olfactory and Cognitive Function after Kidney Transplantation,"2 insightful. Olfactory dysfunction in CKD is indeed multifactorial and associated with malnutrition, gustatory dysfunction, and psychiatric illnesses including depression. Depression is common in patients with CKD but improves with kidney transplantation.3 In response to this letter, we analyzed the Beck Depression Inventory scores in the 24 participants in our study2 and noted a significant improvement in depression after transplantation. The mean Beck Depression Inventory score pretransplant was 12.0±7.8, which improved to 5.5±5.7 after transplant (P value for change in score = 0.004). Similar to depression, malnutrition is also common in patients with CKD and in those on the transplant list awaiting transplant and improves after transplantation.4 Some patients may have malnutrition and weight loss after transplantation, often due to post-transplant complications, but most experience improved appetite and gain weight. While we did not assess gustatory function or nutritional status in our study, we did assess post-transplant graft function and changes in weight. All participants had a functioning allograft at the 3-month post-transplant visit with a mean post-transplant eGFR of 45±16 ml/min per 1.73 m2. In addition, most patients gained weight after transplant, and only a third of the patients experienced weight loss. We however acknowledge that change in weight is not an accurate measurement of change in nutritional status in this population, with large changes in volume status before and after transplantation. In summary, these data on depression, allograft function, and body weight suggest that these factors do not explain the lack of improvement in olfactory function after transplantation. Future studies on olfactory function in CKD should include assessment of psychiatric illnesses, gustatory function, and nutritional status.
Mapping the regulatory landscape for artificial intelligence in health within the European Union
Authors: Jelena Schmidt, Nienke M. Schutte, Stefan Buttigieg, David Novillo-Ortiz, Eric Sutherland, Michael Anderson, Bart de Witte, Michael Peolsson, Brigid Unim, Milena Pavlova, Ariel Dora Stern, Elias Mossialos, Robin van Kessel
Journal: npj Digital Medicine (2024)

Abstract Regulatory frameworks for artificial intelligence (AI) are needed to mitigate risks while ensuring the ethical, secure, and effective implementation of AI technology in healthcare and population health. In this article, we present a synthesis of 141 binding policies applicable to AI in healthcare and population health in the EU and 10 European countries. The EU AI Act sets the overall regulatory framework for AI, while other legislations set social, health, and human rights standards, address the safety of technologies and the implementation of innovation, and ensure the protection and safe use of data. Regulation specifically pertaining to AI is still nascent and scarce, though a combination of data, technology, innovation, and health and human rights policy has already formed a baseline regulatory framework for AI in health. Future work should explore specific regulatory challenges, especially with respect to AI medical devices, data protection, and data enablement.
Feeding into cardiometabolic health
Journal: Nature Metabolism (2024)

Feeding into cardiometabolic health Although Western societies are mesmerized by the power of new anti-obesity drugs, we must not forget how diet can affect metabolic outcomes.In this Focus issue, and accompanying web collection, we showcase a series of Reviews, Comments and original research articles that present up-to-date evidence on how dietary interventions can affect cardiometabolic health.
The unique catalytic properties of PSAT1 mediate metabolic adaptation to glutamine blockade
Authors: Yijian Qiu, Olivia T. Stamatatos, Qingting Hu, Jed Ruiter Swain, Suzanne Russo, Ava Sann, Ana S. H. Costa, Sara Violante, David L. Spector, Justin R. Cross, Michael J. Lukey
Journal: Nature Metabolism (2024)
Author Correction: International consensus statement on the diagnosis and management of phaeochromocytoma and paraganglioma in children and adolescents
Authors: Ruth T. Casey, Emile Hendriks, Cheri Deal, Steven G. Waguespack, Verena Wiegering, Antje Redlich, Scott Akker, Rathi Prasad, Martin Fassnacht, Roderick Clifton-Bligh, Laurence Amar, Stefan Bornstein, Letizia Canu, Evangelia Charmandari, Alexandra Chrisoulidou, Maria Currás Freixes, Ronald de Krijger, Luisa de Sanctis, Antonio Fojo, Amol J. Ghia, Angela Huebner, Vasilis Kosmoliaptsis, Michaela Kuhlen, Marco Raffaelli, Charlotte Lussey-Lepoutre, Stephen D. Marks, Naris Nilubol, Mirko Parasiliti-Caprino, Henri H.J.L.M. Timmers, Anna Lena Zietlow, Mercedes Robledo, Anne-Paule Gimenez-Roqueplo, Ashley B. Grossman, David Taïeb, Eamonn R. Maher, Jacques W. M. Lenders, Graeme Eisenhofer, Camilo Jimenez, Karel Pacak, Christina Pamporaki
Journal: Nature Reviews Endocrinology (2024)
Oropouche Virus Disease Among U.S. Travelers — United States, 2024
Authors: Andrea Morrison, Jennifer L. White, Holly R. Hughes, Sarah Anne J. Guagliardo, Jason O. Velez, Kelly A. Fitzpatrick, Emily H. Davis, Danielle Stanek, Edgar Kopp, Peter Dumoulin, Timothy Locksmith, Lea Heberlein, Rebecca Zimler, Joshua Lassen, Carolina Bestard, Edhelene Rico, Alvaro Mejia-Echeverri, Kay-Anna Edwards-Taylor, Douglas Holt, Dionisia Halphen, Kaitlynn Peters, Cheryl Adams, Amanda M. Nichols, Alexander T. Ciota, Alan P. Dupuis, P. Bryon Backenson, Jennifer A. Lehman, Shelby Lyons, Hannah Padda, Roxanne C. Connelly, Van T. Tong, Stacey W. Martin, Amy J. Lambert, Aaron C. Brault, Carina Blackmore, J. Erin Staples, Carolyn V. Gould
Journal: MMWR Morbidity and Mortality Weekly Report (2024)

Beginning in late 2023, Oropouche virus was identified as the cause of large outbreaks in Amazon regions with known endemic transmission and in new areas in South America and the Caribbean. The virus is spread to humans by infected biting midges and some mosquito species. Although infection typically causes a self-limited febrile illness, reports of two deaths in patients with Oropouche virus infection and vertical transmission associated with adverse pregnancy outcomes have raised concerns about the threat of this virus to human health. In addition to approximately 8,000 locally acquired cases in the Americas, travel-associated Oropouche virus disease cases have recently been identified in European travelers returning from Cuba and Brazil. As of August 16, 2024, a total of 21 Oropouche virus disease cases were identified among U.S. travelers returning from Cuba. Most patients initially experienced fever, myalgia, and headache, often with other symptoms including arthralgia, diarrhea, nausea or vomiting, and rash. At least three patients had recurrent symptoms after the initial illness, a common characteristic of Oropouche virus disease. Clinicians and public health jurisdictions should be aware of the occurrence of Oropouche virus disease in U.S. travelers and request testing for suspected cases. Travelers should prevent insect bites when traveling, and pregnant persons should consider deferring travel to areas experiencing outbreaks of Oropouche virus disease.
Tumour mutational burden: clinical utility, challenges and emerging improvements
Authors: Jan Budczies, Daniel Kazdal, Michael Menzel, Susanne Beck, Klaus Kluck, Christian Altbürger, Constantin Schwab, Michael Allgäuer, Aysel Ahadova, Matthias Kloor, Peter Schirmacher, Solange Peters, Alwin Krämer, Petros Christopoulos, Albrecht Stenzinger
Journal: Nature Reviews Clinical Oncology (2024)