tbuckley/cabot-search huggingface dataset:
Framework nucleic Acid-MicroRNA mediated hepatic differentiation and functional hepatic spheroid development for treating acute liver failure
Authors: Hongyan Wei, Tiantian Xue, Fenfang Li, Enguo Ju, Haixia Wang, Mingqiang Li, Yu Tao
Journal: Bioactive Materials (2024)

The specific induction of hepatic differentiation presents a significant challenge in developing alternative liver cell sources and viable strategies for clinical therapy of acute liver failure (ALF). The past decade has witnessed the blossom of microRNAs in regenerative medicine. Herein, microRNA 122-functionalized tetrahedral framework nucleic acid (FNA-miR-122) has emerged as an unprecedented and potential platform for directing the hepatic differentiation of adipose-derived mesenchymal stem cells (ADMSCs), which offers a straightforward and cost-effective method for generating functional hepatocyte-like cells (FNA-miR-122-iHep). Additionally, we have successfully established a liver organoid synthesis strategy by optimizing the co-culture of FNA-miR-122-iHep with endothelial cells (HUVECs), resulting in functional Hep:HUE-liver spheroids. Transcriptome analysis not only uncovered the potential molecular mechanisms through which miR-122 influences hepatic differentiation in ADMSCs, but also clarified that Hep:HUE-liver spheroids could further facilitate hepatocyte maturation and improved tissue-specific functions, which may provide new hints to be used to develop a hepatic organoid platform. Notably, compared to transplanted ADMSCs and Hep-liver spheroid, respectively, both FNA-miR-122-iHep-based single cell therapy and Hep:HUE-liver spheroid-based therapy showed high efficacy in treating ALF in vivo. Collectively, this research establishes a robust system using microRNA to induce ADMSCs into functional hepatocyte-like cells and to generate hepatic organoids in vitro, promising a highly efficient therapeutic approach for ALF.
Bacterial amyloid curli activates the host unfolded protein response via IRE1α in the presence of HLA-B27
Authors: Kaitlyn Grando, Shingo Bessho, Kayla Harrell, Kathrine Kyrylchuk, Alejandro M. Pantoja, Sophia Olubajo, Francisco J. Albicoro, Andres Klein-Szanto, Çagla Tükel
Journal: Gut Microbes (2024)

Salmonella enterica serovar Typhimurium (STm) causes gastroenteritis and can progress to reactive arthritis (ReA). STm forms biofilms in the gut that secrete the amyloid curli, which we previously demonstrated can trigger autoimmunity in mice. HLA-B27 is a genetic risk factor for ReA; activation of the unfolded protein response (UPR) due to HLA-B27 misfolding is thought to play a critical role in ReA pathogenesis. To determine whether curli exacerbates HLA-B27-induced UPR, bone marrow-derived macrophages (BMDMs) isolated from HLA-B27 transgenic (tg) mice were used. BMDMs treated with purified curli exhibited elevated UPR compared to C57BL/6, and curli-induced IL-6 was reduced by pre-treating macrophages with inhibitors of the IRE1α branch of the UPR. In BMDMs, intracellular curli colocalized with GRP78, a regulator of the UPR. In vivo, acute infection with wild-type STm increased UPR markers in the ceca of HLA-B27tg mice compared to C57BL/6. STm biofilms that contain curli were visible in the lumen of cecal tissue sections. Furthermore, curli was associated with macrophages in the lamina propria, colocalizing with GRP78. Together, these results suggest that UPR plays a role in the curli-induced inflammatory response, especially in the presence of HLA-B27, a possible mechanistic link between STm infection and genetic susceptibility to ReA.
Regulation of Ptbp1-controlled alternative splicing of pyruvate kinase muscle by Liver kinase b1 governs vascular smooth muscle cell plasticity <i>in vivo</i>
Authors: Zhaohua Cai, Ganesh Satyanarayana, Ping Song, Fujie Zhao, Shaojin You, Zhixue Liu, Jing Mu, Ye Ding, Ben He, Ming-Hui Zou
Journal: Cardiovascular Research (2024)

Abstract Aims Vascular smooth muscle cell (VSMC) plasticity is a state in which VSMCs undergo phenotypic switching from a quiescent contractile phenotype into other functionally distinct phenotypes. Although emerging evidence suggests that VSMC plasticity plays critical roles in the development of vascular diseases, little is known about the key determinant for controlling VSMC plasticity and fate. Methods and results We found that smooth muscle cell-specific deletion of Lkb1 in tamoxifen-inducible Lkb1flox/flox;Myh11-Cre/ERT2 mice spontaneously and progressively induced aortic/arterial dilation, aneurysm, rupture, and premature death. Single-cell RNA sequencing and imaging-based lineage tracing showed that Lkb1-deficient VSMCs transdifferentiated gradually from early modulated VSMCs to fibroblast-like and chondrocyte-like cells, leading to ossification and blood vessel rupture. Mechanistically, Lkb1 regulates polypyrimidine tract binding protein 1 (Ptbp1) expression and controls alternative splicing of pyruvate kinase muscle (PKM) isoforms 1 and 2. Lkb1 loss in VSMC results in an increased PKM2/PKM1 ratio and alters the metabolic profile by promoting aerobic glycolysis. Treatment with PKM2 activator TEPP-46 rescues VSMC transformation and aortic dilation in Lkb1flox/flox;Myh11-Cre/ERT2 mice. Furthermore, we found that Lkb1 expression decreased in human aortic aneurysm tissue compared to control tissue, along with changes in markers of VSMC fate. Conclusion Lkb1, via its regulation of Ptbp1-dependent alterative splicing of PKM, maintains VSMC in contractile states by suppressing VSMC plasticity.
RNA Shielding of p65 Is Required to Potentiate Oncogenic Inflammation in <i>TET2</i>-Mutated Clonal Hematopoiesis
Authors: Nana Adjoa Ben-Crentsil, Wazim Mohammed Ismail, Maria E. Balasis, Hannah Newman, Ariel Quintana, Moritz Binder, Traci Kruer, Surendra Neupane, Meghan C. Ferrall-Fairbanks, Jenna Fernandez, Terra L. Lasho, Christy M. Finke, Mohammed L. Ibrahim, Kathy L. McGraw, Michael Wysota, Amy L. Aldrich, Christopher B. Ryder, Christopher T. Letson, Joshua Traina, Amy F. McLemore, Nathalie Droin, Aditi Shastri, Seongseok Yun, Eric Solary, David A. Sallman, Amer A. Beg, Li Ma, Alexandre Gaspar-Maia, Mrinal M. Patnaik, Eric Padron
Journal: Cancer Discovery (2024)

Abstract TET2 mutations (mTET2) are common genetic events in myeloid malignancies and clonal hematopoiesis. These mutations arise in the founding clone and are implicated in many clinical sequelae associated with oncogenic feedforward inflammatory circuits. However, the direct downstream effector of mTET2 responsible for the potentiation of these inflammatory circuits is unknown. To address this, we performed scRNA-seq and scATAC-seq in patients with COVID-19 with and without TET2-mutated clonal hematopoiesis reasoning that inflammation from COVID-19 may highlight critical downstream transcriptional targets of mTET2. Using this approach, we identified metastasis-associated lung adenoma transcript 1 (MALAT1), a therapeutically tractable lncRNA, as a central downstream effector of mTET2 that is both necessary and sufficient to induce the oncogenic proinflammatory features of mTET2 in vivo. We also elucidate the mechanism by which mTET2 upregulate MALAT1 and describe an interaction between MALAT1 and p65, which leads to RNA “shielding” from protein phosphatase 2A dephosphorylation, thus preventing resolution of inflammatory signaling. Significance: This work identifies MALAT1 as a requisite downstream effector of oncogenic feedforward inflammatory circuits necessary for the development of TET2-mutated CH and fulminant myeloid malignancy. We elucidate a novel mechanism by which MALAT1 “shields” p65 from dephosphorylation to potentiate this circuit and nominate MALAT1 inhibition as a future therapeutic strategy.
Prevention and cure of murine <i>C. difficile</i> infection by a Lachnospiraceae strain
Authors: Juan Noriega Tejada, William A. Walters, Yanling Wang, Melissa Kordahi, Benoit Chassaing, Joseph Pickard, Gabriel Nunez, Ruth Ley, Andrew T. Gewirtz
Journal: Gut Microbes (2024)

We sought to better understand how intestinal microbiota confer protection against Clostridioides difficile (C. difficile) infection (CDI). We utilized gnotobiotic altered Schaedler flora (ASF) mice, which lack the abnormalities of germfree (GF) mice as well as the complexity and heterogeneity of antibiotic-treated mice. Like GF mice, ASF mice were highly prone to rapid lethal CDI, without antibiotics, while very low infectious doses resulted in chronic CDI. Administering such chronic CDI mice an undefined preparation of Clostridia lowered C. difficile levels by several logs. Importantly, such resolution of CDI was associated with colonization of Lachnospiraceae. Fractionation of the Clostridia population to enrich for Lachnospiraceae led to the appreciation that its CDI-impeding property strongly associated with a specific Lachnospiraceae strain, namely uncultured bacteria and archaea (UBA) 3401. UBA3401 was recalcitrant to being propagated as a pure culture but could be maintained in ASF mice, wherein it comprised up to about 50% of the intestinal microbiota, which was sufficient to generate a high-quality genomic sequence of this bacterium. Sequence analysis and ex vivo study of UBA3401 indicated that it had the ability to secrete substance(s) that directly impeded C. difficile growth. Moreover, in vivo administration of UBA3401/ASF feces provided strong protection to C. difficile challenge. Thus, UBA3401 may contribute to and/or provide a means to study microbiota-mediated CDI resistance.
Optical coherence tomography assessment of the impact of colchicine on non-culprit coronary plaque composition after myocardial infarction
Authors: Peter J Psaltis, Mau T Nguyen, Kuljit Singh, Ajay Sinhal, Dennis T L Wong, Richard Alcock, Sharmalar Rajendran, Rustem Dautov, Peter Barlis, Sanjay Patel, Thalia Salagaras, Jessica A Marathe, Christina A Bursill, Nicholas J Montarello, Stefan M Nidorf, Peter L Thompson, Julie Butters, Alana R Cuthbert, Lisa N Yelland, Juanita L Ottaway, Yu Kataoka, Giuseppe Di Giovanni, Stephen J Nicholls
Journal: Cardiovascular Research (2024)

Low-dose colchicine reduces the risk of cardiovascular events after myocardial infarction (MI). The purpose of this study was to assess the effect of colchicine post-MI on coronary plaque morphology in non-culprit segments by optical coherence tomography (OCT).
Gut microbiome profiles to exclude the diagnosis of hepatic encephalopathy in patients with cirrhosis
Authors: Jasmohan S Bajaj, Jacqueline G O’Leary, Sofia S Jakab, Andrew Fagan, Masoumeh Sikaroodi, Patrick M Gillevet
Journal: Gut Microbes (2024)

Patients with cirrhosis who have cognitive complaints are presumed to have hepatic encephalopathy (HE), which leads to unwarranted medications while ignoring the underlying disease process causing these complaints. Since neuropsychological testing, the current gold standard for HE diagnosis, is not readily available, an orderable test is needed. We aimed to develop and validate a rapid gut microbiota test to exclude HE and determine stakeholder input on this approach. Stool was collected from two cohorts: a two-center training cohort (n = 305, on/not on HE-related therapy) and a multicenter validation cohort (n = 30, on HE treatment). Stool microbiota was analyzed rapidly using nanopore analysis. Stakeholder (patients and clinicians) needs assessment was evaluated using semi-quantitative questionnaires. In the training cohort, machine learning using neural network identified a 20-species signature that differentiated HE vs no-HE with 84% specificity compared to the gold standard neuropsychological testing. This high specificity persisted regardless of whether patients were on HE-related therapy or not. In the validation cohort, application of this profile led to reevaluation of the HE diagnosis and treatment in > 40% of the patients. This approach was acceptable to patients (Veterans in the validation cohort) and clinician (n = 40 nationwide) stakeholders. We conclude that a machine learning stool signature based on 20 microbial species developed in a training set and validated in a separate multicenter prospective cohort differentiated those with vs. without HE, identified patients misdiagnosed with HE, and was acceptable to patients and clinician stakeholders.
Photodynamic therapy reduces the burden of small ultraviolet-induced epidermal clones in human and mouse skin
Authors: Lei Wei, Megan E Fitzgerald, Li Yan, Mitsuko Murakami, Sydney R Grant, Qiang Hu, Serena Fan, Bernard Okai, Divya Goyal, Prashant K Singh, Gal Shafirstein, Eva Remenyik, Emese Gellen, Barbara A Foster, Wendy J Huss, Gyorgy Paragh
Journal: British Journal of Dermatology (2024)

Actinic keratoses (AKs) and keratinocyte carcinomas (KCs) arise from prolonged UV exposure, with precursor UV-induced clonal mutations (CMs) appearing in sun-damaged skin. Photodynamic therapy (PDT) is a common field treatment for AKs and early KCs, but its impact on subclinical CMs is unknown. This study examines CMs using targeted ultra-deep sequencing on epidermal samples. By comparing skin before and after PDT in five patients and a mouse model of chronic UV carcinogenesis, a significant reduction in low-frequency mutations post-treatment was revealed. These findings highlight PDT’s potential in modifying subclinical damage and propose low-variant allele frequency CMs as biomarkers for field treatment efficacy.
Effects of postbiotics on chronic diarrhea in young adults: a randomized, double-blind, placebo-controlled crossover trial assessing clinical symptoms, gut microbiota, and metabolite profiles
Authors: Shuai Guo, Teng Ma, Lai-Yu Kwok, Keyu Quan, Bohai Li, Huan Wang, Heping Zhang, Bilige Menghe, Yongfu Chen
Journal: Gut Microbes (2024)

Chronic diarrhea has a considerable impact on quality of life. This randomized, double-blind, placebo-controlled crossover intervention trial was conducted with 69 participants (36 in Group A, 33 in Group B), aiming to investigate the potential of postbiotics in alleviating diarrhea-associated symptoms. Participants received postbiotic Probio-Eco® and placebo for 21 days each in alternating order, with a 14-day washout period between interventions. The results showed that postbiotic intake resulted in significant improvements in Bristol stool scale score, defecation frequency, urgency, and anxiety. Moreover, the postbiotic intervention increased beneficial intestinal bacteria, including Dysosmobacter welbionis and Faecalibacterium prausnitzii, while reducing potential pathogens like Megamonas funiformis. The levels of gut Microviridae notably increased. Non-targeted metabolomics analysis revealed postbiotic-driven enrichment of beneficial metabolites, including α-linolenic acid and p-methoxycinnamic acid, and reduction of diarrhea-associated metabolites, including theophylline, piperine, capsaicin, and phenylalanine. Targeted metabolomics confirmed a significant increase in fecal butyric acid after postbiotic intervention. The levels of aromatic amino acids, phenylalanine and tryptophan, and their related metabolites, 5-hydroxytryptophan and kynurenine, decreased after the postbiotic intervention, suggesting diarrhea alleviation was through modulating the tryptophan-5-hydroxytryptamine and tryptophan-kynurenine pathways. Additionally, chenodeoxycholic acid, a diarrhea-linked primary bile acid, decreased substantially. In conclusion, postbiotics have shown promise in relieving chronic diarrhea.
Personalized dose selection for the first Waldenström macroglobulinemia patient on the PRECISE CURATE.AI trial
Authors: Agata Blasiak, Lester W. J. Tan, Li Ming Chong, Xavier Tadeo, Anh T. L. Truong, Kirthika Senthil Kumar, Yoann Sapanel, Michelle Poon, Raghav Sundar, Sanjay de Mel, Dean Ho
Journal: npj Digital Medicine (2024)

Abstract The digital revolution in healthcare, amplified by the COVID-19 pandemic and artificial intelligence (AI) advances, has led to a surge in the development of digital technologies. However, integrating digital health solutions, especially AI-based ones, in rare diseases like Waldenström macroglobulinemia (WM) remains challenging due to limited data, among other factors. CURATE.AI, a clinical decision support system, offers an alternative to big data approaches by calibrating individual treatment profiles based on that individual’s data alone. We present a case study from the PRECISE CURATE.AI trial with a WM patient, where, over two years, CURATE.AI provided dynamic Ibrutinib dose recommendations to clinicians (users) aimed at achieving optimal IgM levels. An 80-year-old male with newly diagnosed WM requiring treatment due to anemia was recruited to the trial for CURATE.AI-based dosing of the Bruton tyrosine kinase inhibitor Ibrutinib. The primary and secondary outcome measures were focused on scientific and logistical feasibility. Preliminary results underscore the platform’s potential in enhancing user and patient engagement, in addition to clinical efficacy. Based on a two-year-long patient enrollment into the CURATE.AI-augmented treatment, this study showcases how AI-enabled tools can support the management of rare diseases, emphasizing the integration of AI to enhance personalized therapy.
Homozygosity for a stop-gain variant in CCDC201 causes primary ovarian insufficiency
Authors: Asmundur Oddsson, Valgerdur Steinthorsdottir, Gudjon R. Oskarsson, Unnur Styrkarsdottir, Kristjan H. S. Moore, Salvor Isberg, Gisli H. Halldorsson, Gardar Sveinbjornsson, David Westergaard, Henriette Svarre Nielsen, Run Fridriksdottir, Brynjar O. Jensson, Gudny A. Arnadottir, Hakon Jonsson, Arni Sturluson, Audunn S. Snaebjarnarson, Ole A. Andreassen, G. Bragi Walters, Mette Nyegaard, Christian Erikstrup, Thora Steingrimsdottir, Rolv T. Lie, Pall Melsted, Ingileif Jonsdottir, Bjarni V. Halldorsson, Gudmar Thorleifsson, Jona Saemundsdottir, Olafur Th. Magnusson, Hreinn Stefansson, Karina Banasik, Erik Sorensen, Gisli Masson, Ole Birger Pedersen, Laufey Tryggvadottir, Jan Haavik, Sisse Rye Ostrowski, Hreinn Stefansson, Hilma Holm, Thorunn Rafnar, Daniel F. Gudbjartsson, Patrick Sulem, Kari Stefansson
Journal: Nature Genetics (2024)

Age at menopause (AOM) has a substantial impact on fertility and disease risk. While many loci with variants that associate with AOM have been identified through genome-wide association studies (GWAS) under an additive model, other genetic models are rarely considered
Genetic architecture of telomere length in 462,666 UK Biobank whole-genome sequences
Authors: Oliver S. Burren, Ryan S. Dhindsa, Sri V. V. Deevi, Sean Wen, Abhishek Nag, Jonathan Mitchell, Fengyuan Hu, Douglas P. Loesch, Katherine R. Smith, Neetu Razdan, Henric Olsson, Adam Platt, Dimitrios Vitsios, Qiang Wu, Rasmus Ågren, Lauren Anderson-Dring, Santosh Atanur, David Baker, Maria Belvisi, Mohammad Bohlooly-Y, Lisa Buvall, Sophia Cameron-Christie, Suzanne Cohen, Regina F. Danielson, Shikta Das, Andrew Davis, Guillermo del Angel, Wei Ding, Brian Dougherty, Zammy Fairhurst-Hunter, Manik Garg, Benjamin Georgi, Carmen Guerrero Rangel, Andrew Harper, Carolina Haefliger, Mårten Hammar, Richard N. Hanna, Pernille B. L. Hansen, Jennifer Harrow, Ian Henry, Sonja Hess, Ben Hollis, Xiao Jiang, Kousik Kundu, Zhongwu Lai, Mark Lal, Glenda Lassi, Yupu Liang, Margarida Lopes, Eagle Lou, Kieren Lythgow, Stewart MacArthur, Meeta Maisuria-Armer, Ruth March, Carla Martins, Dorota Matelska, Karine Megy, Rob Menzies, Erik Michaëlsson, Fiona Middleton, Bill Mowrey, Daniel Muthas, Sean O’Dell, Erin Oerton, Yoichiro Ohne, Henric Olsson, Amanda O’Neill, Kristoffer Ostridge, Dirk Paul, Bram Prins, Benjamin Pullman, William Rae, Arwa Raies, Anna Reznichenko, Xavier Romero Ros, Hitesh Sanganee, None Ben Sidders, Mike Snowden, Stasa Stankovic, Helen Stevens, Ioanna Tachmazidou, Haeyam Taiy, Lifeng Tian, Christina Underwood, Coralie Viollet, Anna Walentinsson, Lily Wang, Qing-Dong Wang, Eleanor Wheeler, Ahmet Zehir, Zoe Zou, Veryan Codd, Christopher P. Nelson, Nilesh J. Samani, Ruth E. March, Sebastian Wasilewski, Keren Carss, Margarete Fabre, Quanli Wang, Menelas N. Pangalos, Slavé Petrovski
Journal: Nature Genetics (2024)

Telomeres protect chromosome ends from damage and their length is linked with human disease and aging. We developed a joint telomere length metric, combining quantitative PCR and whole-genome sequencing measurements from 462,666 UK Biobank participants. This metric increased SNP heritability, suggesting that it better captures genetic regulation of telomere length. Exome-wide rare-variant and gene-level collapsing association studies identified 64 variants and 30 genes significantly associated with telomere length, including allelic series in ACD and RTEL1. Notably, 16% of these genes are known drivers of clonal hematopoiesis-an age-related somatic mosaicism associated with myeloid cancers and several nonmalignant diseases. Somatic variant analyses revealed gene-specific associations with telomere length, including lengthened telomeres in individuals with large SRSF2-mutant clones, compared with shortened telomeres in individuals with clonal expansions driven by other genes. Collectively, our findings demonstrate the impact of rare variants on telomere length, with larger effects observed among genes also associated with clonal hematopoiesis.
A novel shockwave-driven nanomotor composite microneedle transdermal delivery system for the localized treatment of osteoporosis: a basic science study
Authors: Fan Hu, Haojun Liang, Jing Xie, Meng Yuan, Wanxia Huang, Yinze Lei, Hao Li, Linwen Lv, Qiuyang Liu, Junhui Zhang, Wenxi Su, Ranran Chen, Zhe Wang, Ya-nan Chang, Juan Li, Cunfeng Wei, Gengyan Xing, Gengmei Xing, Kui Chen
Journal: International Journal of Surgery (2024)

Background: Clinical protocols in osteoporosis treatment could not meet the requirement of increasing local bone mineral density. A local delivery system was brought in to fix this dilemma. The high-energy extracorporeal shock wave (ESW) can travel into the deep tissues with little heat loss. Hence, ESW-driven nanoparticles could be used for local treatment of osteoporosis. Materials and methods: An ESW-actuated nanomotor (NM) sealed into microneedles (MNs) (ESW-NM-MN) was constructed for localized osteoporosis protection. The NM was made of calcium phosphate nanoparticles with a high Young’s modulus, which allows it to absorb ESW energy efficiently and convert it into kinetic energy for solid tissue penetration. Zoledronic (ZOL), as an alternative phosphorus source, forms the backbone of the NM (ZOL-NM), leading to bone targeting and ESW-mediated drug release. Results: After the ZOL-NM is sealed into hyaluronic acid (HA)-made microneedles, the soluble MN tips could break through the stratum corneum, injecting the ZOL-NM into the skin. As soon as the ESW was applied, the ZOL-NM would absorb the ESW energy to move from the outer layer of skin into the deep tissue and be fragmented to release ZOL and Ca 2+ for anti-osteoclastogenesis and pro-osteogenesis. In vivo , the ZOL-NM increases localized bone parameters and reduces fracture risk, indicating its potential value in osteoporotic healing and other biomedical fields. Conclusion: The ESW-mediated transdermal delivery platform (ESW-NM-MN) could be used as a new strategy to improve local bone mineral density and protect local prone-fracture areas.
Variance Between Clinical Guidance and Real-world Management of Metabolic Dysfunction-associated Steatotic Liver Disease in US
Authors: Mary E. Rinella, Mark L. Hartman, Shraddha Shinde, David Schapiro, Victoria Higgins, Quentin M. Anstee
Journal: Clinical Gastroenterology and Hepatology (2024)

Clinical practice guidelines can facilitate diagnosis and management of patients with metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction associated steatohepatitis (MASH), although their implementation to date has been suboptimal.