tbuckley/cabot-search huggingface dataset:
Structured 3′ UTRs destabilize mRNAs in plants
Authors: Tianru Zhang, Changhao Li, Jiaying Zhu, Yanjun Li, Zhiye Wang, Chun-Yip Tong, Yu Xi, Yi Han, Hisashi Koiwa, Xu Peng, Xiuren Zhang
Journal: Genome biology (2024)

Abstract Background RNA secondary structure (RSS) can influence the regulation of transcription, RNA processing, and protein synthesis, among other processes. 3′ untranslated regions (3′ UTRs) of mRNA also hold the key for many aspects of gene regulation. However, there are often contradictory results regarding the roles of RSS in 3′ UTRs in gene expression in different organisms and/or contexts. Results Here, we incidentally observe that the primary substrate of miR159a (pri-miR159a), when embedded in a 3′ UTR, could promote mRNA accumulation. The enhanced expression is attributed to the earlier polyadenylation of the transcript within the hybrid pri-miR159a-3′ UTR and, resultantly, a poorly structured 3′ UTR. RNA decay assays indicate that poorly structured 3′ UTRs could promote mRNA stability, whereas highly structured 3′ UTRs destabilize mRNA in vivo. Genome-wide DMS-MaPseq also reveals the prevailing inverse relationship between 3′ UTRs’ RSS and transcript accumulation in the transcriptomes of Arabidopsis , rice, and even human. Mechanistically, transcripts with highly structured 3′ UTRs are preferentially degraded by 3′–5′ exoribonuclease SOV and 5′–3′ exoribonuclease XRN4, leading to decreased expression in Arabidopsis . Finally, we engineer different structured 3′ UTRs to an endogenous FT gene and alter the FT -regulated flowering time in Arabidopsis . Conclusions We conclude that highly structured 3′ UTRs typically cause reduced accumulation of the harbored transcripts in Arabidopsis . This pattern extends to rice and even mammals. Furthermore, our study provides a new strategy of engineering the 3′ UTRs’ RSS to modify plant traits in agricultural production and mRNA stability in biotechnology.
Integrative Analyses of Tumor and Peripheral Biomarkers in the Treatment of Advanced Renal Cell Carcinoma
Authors: Toni K. Choueiri, Amber C. Donahue, David A. Braun, Brian I. Rini, Thomas Powles, John B.A.G. Haanen, James Larkin, Xinmeng Jasmine Mu, Jie Pu, Rosemary E. Teresi, Alessandra di Pietro, Paul B. Robbins, Robert J. Motzer
Journal: Cancer Discovery (2023)

The phase III JAVELIN Renal 101 trial demonstrated prolonged progression-free survival (PFS) in patients (N = 886) with advanced renal cell carcinoma treated with first-line avelumab + axitinib (A+Ax) versus sunitinib. We report novel findings from integrated analyses of longitudinal blood samples and baseline tumor tissue. PFS was associated with elevated lymphocyte levels in the sunitinib arm and an abundance of innate immune subsets in the A+Ax arm. Treatment with A+Ax led to greater T-cell repertoire modulation and less change in T-cell numbers versus sunitinib. In the A+Ax arm, patients with tumors harboring mutations in ≥2 of 10 previously identified PFS-associated genes (double mutants) had distinct circulating and tumor-infiltrating immunologic profiles versus those with wild-type or single-mutant tumors, suggesting a role for non-T-cell-mediated and non-natural killer cell-mediated mechanisms in double-mutant tumors. We provide evidence for different immunomodulatory mechanisms based on treatment (A+Ax vs. sunitinib) and tumor molecular subtypes. Our findings provide novel insights into the different immunomodulatory mechanisms governing responses in patients treated with avelumab (PD-L1 inhibitor) + axitinib or sunitinib (both VEGF inhibitors), highlighting the contribution of tumor biology to the complexity of the roles and interactions of infiltrating immune cells in response to these treatment regimens. This article is featured in Selected Articles from This Issue, p. 384.
To do no harm — and the most good — with AI in health care
Authors: Carey Beth Goldberg, Laura Adams, David Blumenthal, Patricia Flatley Brennan, Noah Brown, Atul J. Butte, Morgan Cheatham, Dave deBronkart, Jennifer Dixon, Jeffrey Drazen, Barbara J. Evans, Sara M. Hoffman, Chris Holmes, Peter Lee, Arjun Kumar Manrai, Gilbert S. Omenn, Jonathan B. Perlin, Rachel Ramoni, Guillermo Sapiro, Rupa Sarkar, Harpreet Sood, Effy Vayena, Isaac S. Kohane, Emily Alsentzer, Brian Anderson, Ran D. Balicer, Andrew L. Beam, Erwin Bottinger, Rebecca W. Brendel, Payal Chandak, Arnaub Chatterjee, Michael Chernew, Antoine Duclos, Lee A. Fleisher, William Gordon, Elizabeth Healey, Alejandro Hernández-Arango, Michele Kathleen Herndon, Alexander Hoffmann, Edward M. Hundert, Indra Joshi, Tobias Kowatsch, Stephen Kraus, Lisa Soleymani Lehmann, Karim Lekadir, Vincent X. Liu, Daniel J. Nigrin, Reut Ohana, Nigam H. Shah, Haris Shuaib, Tania Simoncelli, Amelia Li Min Tan, Donrich Thaldar, Eugene Tunik, Tommy Wang, John Wilbanks, Yuchen Xu, Jianfei Zhao
Journal: Nature Medicine (2024)
Discovery of Two Novel Immunoepitopes and Development of a Peptide-based Sarcoidosis Immunoassay
Authors: Changya Peng, Jaya Talreja, Brennen Steinbauer, Kazuhiko Shinki, Laura L. Koth, Lobelia Samavati
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

Sarcoidosis is a systemic granulomatous disorder associated with hypergammaglobulinemia and the presence of autoantibodies. The specific antigens initiating granulomatous inflammation in sarcoidosis are unknown, and there is no specific test available to diagnose sarcoidosis. To discover novel sarcoidosis antigens, we developed a high-throughput T7 phage display library derived from the sarcoidosis cDNA and identified numerous clones differentiating sarcoidosis from other respiratory diseases. After clone sequencing and a homology search, we identified two epitopes (cofilin μ and chain A) that specifically bind to serum IgGs of patients with sarcoidosis.
<scp>COVID</scp>‐19 vaccine safety and immunogenicity in patients with cold agglutinin disease receiving concomitant sutimlimab
Authors: Bruno Fattizzo, Alexander Röth, Catherine M. Broome, Umer Khan, Marek Wardęcki, Matias Cordoba, Wilma Barcellini
Journal: American Journal of Hematology (2024)

Patients with cold agglutinin disease (CAD) are more vulnerable to infectious agents, thus the COVID-19 pandemic has posed a particular risk to this population. Sutimlimab Phase 3 studies CARDINAL and CADENZA spanned the period before and during the pandemic; investigators were advised to vaccinate enrolled patients without stopping treatment. Of 61 completers from both studies, 47 received ≥1 dose of a COVID-19 vaccine. In the immunogenicity analysis (n = 27) all patients developed an immune response post-COVID-19 vaccination, with detectable immunoglobulin G anti-spike antibodies. Analysis of six patients with booster vaccinations demonstrated increased immune responses pre- to post-booster. COVID-19 vaccines were well tolerated in patients with CAD receiving sutimlimab treatment, and no signs of hemolytic exacerbations were observed post-vaccination.
GMC says sorry to LGBTQ+ doctors, but wider persecution continues in medicine: Video 1
Authors: Abi Rimmer
Journal: BMJ (2024)

Regulatory action against doctors that was based on now repealed homophobic laws casts a long shadow, say campaigners. They welcome a formal apology issued by the medical regulator this week—but they say that LGBTQ+ doctors still face prejudice in the workplace, writes <b>Abi Rimmer</b>
Factors influencing overdose and misuse of gender-affirming medication in Chinese transgender and gender diverse individuals: a qualitative study of experience and perspectives
Authors: Liping Li, Huiqing Pan, Keling Wang, Muhua Yang, Ying He, Lu Cai, Yang Liu
Journal: International Journal of Transgender Health (2024)

Background The overdose and misuse (ODM) of gender-affirming hormone treatment (GAHT) medications is common among the Chinese transgender and gender diverse (TGD) population due to a unique sociocultural and healthcare basis. However, there is no existing publication providing descriptions and interpretations of this situation among Chinese TGD people.
Chromosome evolution screens recapitulate tissue-specific tumor aneuploidy patterns
Authors: Emma V. Watson, Jake June-Koo Lee, Doga C. Gulhan, Giorgio E. M. Melloni, Sergey V. Venev, Rayna Y. Magesh, Abdulrazak Frederick, Kunitoshi Chiba, Eric C. Wooten, Kamila Naxerova, Job Dekker, Peter J. Park, Stephen J. Elledge
Journal: Nature Genetics (2024)

Whole chromosome and arm-level copy number alterations occur at high frequencies in tumors, but their selective advantages, if any, are poorly understood. Here, utilizing unbiased whole chromosome genetic screens combined with in vitro evolution to generate arm- and subarm-level events, we iteratively selected the fittest karyotypes from aneuploidized human renal and mammary epithelial cells. Proliferation-based karyotype selection in these epithelial lines modeled tissue-specific tumor aneuploidy patterns in patient cohorts in the absence of driver mutations. Hi-C-based translocation mapping revealed that arm-level events usually emerged in multiples of two via centromeric translocations and occurred more frequently in tetraploids than diploids, contributing to the increased diversity in evolving tetraploid populations. Isogenic clonal lineages enabled elucidation of pro-tumorigenic mechanisms associated with common copy number alterations, revealing Notch signaling potentiation as a driver of 1q gain in breast cancer. We propose that intrinsic, tissue-specific proliferative effects underlie tumor copy number patterns in cancer.
Stress and the coping of Israeli trans students in higher education: a qualitative study
Authors: Maya Tsfati, Yochay Nadan
Journal: International Journal of Transgender Health (2024)

Trans students are underrepresented in institutions of higher education, and little is known about their experiences and the stressors they face in this context. This study aims to understand Israeli trans students' experiences in such institutions, with a focus on the unique stressors they face and the elements that reduce these stressors' impact on their mental health.
Neurodevelopmental Outcomes for Individuals With Congenital Heart Disease: Updates in Neuroprotection, Risk-Stratification, Evaluation, and Management: A Scientific Statement From the American Heart Association
Authors: Erica Sood, Jane W. Newburger, Julia S. Anixt, Adam R. Cassidy, Jamie L. Jackson, Richard A. Jonas, Amy J. Lisanti, Keila N. Lopez, Shabnam Peyvandi, Bradley S. Marino
Journal: Circulation (2024)

Over the past decade, new research has advanced scientific knowledge of neurodevelopmental trajectories, factors that increase neurodevelopmental risk, and neuroprotective strategies for individuals with congenital heart disease. In addition, best practices for evaluation and management of developmental delays and disorders in this high-risk patient population have been formulated based on literature review and expert consensus. This American Heart Association scientific statement serves as an update to the 2012 statement on the evaluation and management of neurodevelopmental outcomes in children with congenital heart disease. It includes revised risk categories for developmental delay or disorder and an updated list of factors that increase neurodevelopmental risk in individuals with congenital heart disease according to current evidence, including genetic predisposition, fetal and perinatal factors, surgical and perioperative factors, socioeconomic disadvantage, and parental psychological distress. It also includes an updated algorithm for referral, evaluation, and management of individuals at high risk. Risk stratification of individuals with congenital heart disease with the updated categories and risk factors will identify a large and growing population of survivors at high risk for developmental delay or disorder and associated impacts across the life span. Critical next steps must include efforts to prevent and mitigate developmental delays and disorders. The goal of this scientific statement is to inform health care professionals caring for patients with congenital heart disease and other key stakeholders about the current state of knowledge of neurodevelopmental outcomes for individuals with congenital heart disease and best practices for neuroprotection, risk stratification, evaluation, and management.
Tumor-resident microbes: the new kids on the microenvironment block
Authors: Le Li, Vidhi Chandra, Florencia McAllister
Journal: Trends in cancer (2024)

Tumor-resident microbes (TRM) are an integral component of the tumor microenvironment (TME). TRM can influence tumor growth, distant dissemination, and response to therapies by interfering with molecular pathways in tumor cells as well as with other components of the TME. Novel technologies are improving the identification and visualization of cell type-specific microbes in the TME. The mechanisms that mediate the role of TRM at the primary tumors and metastatic sites are being elucidated. This knowledge is providing novel perspectives for targeting microbes or using microbial interventions for cancer interception or therapy.
AGA Clinical Practice Update on High-Quality Upper Endoscopy: Expert Review
Authors: Satish Nagula, Sravanthi Parasa, Loren Laine, Shailja C. Shah
Journal: Clinical Gastroenterology and Hepatology (2024)

The purpose of this Clinical Practice Update (CPU) Expert Review is to provide clinicians with guidance on best practices for performing a high-quality upper endoscopic exam.
PRMT1 Sustains <i>De Novo</i> Fatty Acid Synthesis by Methylating PHGDH to Drive Chemoresistance in Triple-Negative Breast Cancer
Authors: Takehiro Yamamoto, Tetsu Hayashida, Yohei Masugi, Kiyotaka Oshikawa, Noriyo Hayakawa, Mai Itoh, Chiyoko Nishime, Masami Suzuki, Aiko Nagayama, Yuko Kawai, Takako Hishiki, Tomomi Matsuura, Yoshiko Naito, Akiko Kubo, Arisa Yamamoto, Yujiro Yoshioka, Tomokazu Kurahori, Misa Nagasaka, Minako Takizawa, Naoharu Takano, Koji Kawakami, Michiie Sakamoto, Masatoshi Wakui, Takushi Yamamoto, Yuko Kitagawa, Yasuaki Kabe, Kenichi Horisawa, Atsushi Suzuki, Masaki Matsumoto, Makoto Suematsu
Journal: Cancer Research (2024)

Abstract Triple-negative breast cancer (TNBC) chemoresistance hampers the ability to effectively treat patients. Identification of mechanisms driving chemoresistance can lead to strategies to improve treatment. Here, we revealed that protein arginine methyltransferase-1 (PRMT1) simultaneously methylates D-3-phosphoglycerate dehydrogenase (PHGDH), a critical enzyme in serine synthesis, and the glycolytic enzymes PFKFB3 and PKM2 in TNBC cells. 13C metabolic flux analyses showed that PRMT1-dependent methylation of these three enzymes diverts glucose toward intermediates in the serine-synthesizing and serine/glycine cleavage pathways, thereby accelerating the production of methyl donors in TNBC cells. Mechanistically, PRMT1-dependent methylation of PHGDH at R54 or R20 activated its enzymatic activity by stabilizing 3-phosphoglycerate binding and suppressing polyubiquitination. PRMT1-mediated PHGDH methylation drove chemoresistance independently of glutathione synthesis. Rather, activation of the serine synthesis pathway supplied α-ketoglutarate and citrate to increase palmitate levels through activation of fatty acid synthase (FASN). Increased palmitate induced protein S-palmitoylation of PHGDH and FASN to further enhance fatty acid synthesis in a PRMT1-dependent manner. Loss of PRMT1 or pharmacologic inhibition of FASN or protein S-palmitoyltransferase reversed chemoresistance in TNBC. Furthermore, IHC coupled with imaging MS in clinical TNBC specimens substantiated that PRMT1-mediated methylation of PHGDH, PFKFB3, and PKM2 correlates with chemoresistance and that metabolites required for methylation and fatty acid synthesis are enriched in TNBC. Together, these results suggest that enhanced de novo fatty acid synthesis mediated by coordinated protein arginine methylation and protein S-palmitoylation is a therapeutic target for overcoming chemoresistance in TNBC. Significance: PRMT1 promotes chemoresistance in TNBC by methylating metabolic enzymes PFKFB3, PKM2, and PHGDH to augment de novo fatty acid synthesis, indicating that targeting this axis is a potential treatment strategy.
The therapeutically actionable long non-coding RNA ‘T-RECS’ is essential to cancer cells’ survival in NRAS/MAPK-driven melanoma
Authors: Valentin Feichtenschlager, Linan Chen, Yixuan James Zheng, Wilson Ho, Martina Sanlorenzo, Igor Vujic, Eleanor Fewings, Albert Lee, Christopher Chen, Ciara Callanan, Kevin Lin, Tiange Qu, Dasha Hohlova, Marin Vujic, Yeonjoo Hwang, Kevin Lai, Stephanie Chen, Thuan Nguyen, Denise P Muñoz, Yoshinori Kohwi, Christian Posch, Adil Daud, Klemens Rappersberger, Terumi Kohwi-Shigematsu, Jean-Philippe Coppé, Susana Ortiz-Urda
Journal: Molecular Cancer (2024)

Abstract Finding effective therapeutic targets to treat NRAS-mutated melanoma remains a challenge. Long non-coding RNAs (lncRNAs) recently emerged as essential regulators of tumorigenesis. Using a discovery approach combining experimental models and unbiased computational analysis complemented by validation in patient biospecimens, we identified a nuclear-enriched lncRNA ( AC004540.4 ) that is upregulated in NRAS/MAPK-dependent melanoma, and that we named T-RECS . Considering potential innovative treatment strategies, we designed antisense oligonucleotides (ASOs) to target T-RECS . T-RECS ASOs reduced the growth of melanoma cells and induced apoptotic cell death, while having minimal impact on normal primary melanocytes. Mechanistically, treatment with T-RECS ASOs downregulated the activity of pro-survival kinases and reduced the protein stability of hnRNPA2/B1, a pro-oncogenic regulator of MAPK signaling. Using patient- and cell line- derived tumor xenograft mouse models, we demonstrated that systemic treatment with T-RECS ASOs significantly suppressed the growth of melanoma tumors, with no noticeable toxicity. ASO-mediated T-RECS inhibition represents a promising RNA-targeting approach to improve the outcome of MAPK pathway-activated melanoma.
Optimal timing of influenza vaccination in young children: population based cohort study
Authors: Christopher M Worsham, Charles F Bray, Anupam B Jena
Journal: BMJ (2024)

Abstract Objective To assess optimal timing of influenza vaccination in young children. Design Population based cohort study. Setting United States. Participants Commercially insured children aged 2-5 years who were vaccinated against influenza during 2011-18. Main outcome measure Rates of diagnosis of influenza among children who were vaccinated against influenza, by birth month. Results Overall, 819 223 children aged 2-5 received influenza vaccination. Children vaccinated in November and December were least likely to have a diagnosis of influenza, a finding that may be confounded by unmeasured factors that influence the timing of vaccination and risk of influenza. Vaccination commonly occurred on days of preventive care visits and during birth months. Children born in October were disproportionately vaccinated in October and were, on average, vaccinated later than children born in August and earlier than those born in December. Children born in October had the lowest rate of influenza diagnosis (for example, 2.7% (6016/224 540) versus 3.0% (6462/212 622) for those born in August; adjusted odds ratio 0.88, 95% confidence interval 0.85 to 0.92). Conclusions In a quasi-experimental analysis of young children vaccinated against influenza, birth month was associated with the timing of vaccination through its influence on the timing of preventive care visits. Children born in October were most likely to be vaccinated in October and least likely to have a diagnosis of influenza, consistent with recommendations promoting October vaccination.
Attention-deficit/hyperactivity disorder
Authors: Stephen V. Faraone, Mark A. Bellgrove, Isabell Brikell, Samuele Cortese, Catharina A. Hartman, Chris Hollis, Jeffrey H. Newcorn, Alexandra Philipsen, Guilherme V. Polanczyk, Katya Rubia, Margaret H. Sibley, Jan K. Buitelaar
Journal: Nature Reviews Disease Primers (2024)
Blood–brain barrier disruption and sustained systemic inflammation in individuals with long COVID-associated cognitive impairment
Authors: Chris Greene, Ruairi Connolly, Declan Brennan, Aoife Laffan, Eoin O’Keeffe, Lilia Zaporojan, Jeffrey O’Callaghan, Bennett Thomson, Emma Connolly, Ruth Argue, James F. M. Meaney, Ignacio Martin-Loeches, Aideen Long, Cliona Ni Cheallaigh, Niall Conlon, Colin P. Doherty, Matthew Campbell
Journal: Nature Neuroscience (2024)

Abstract Vascular disruption has been implicated in coronavirus disease 2019 (COVID-19) pathogenesis and may predispose to the neurological sequelae associated with long COVID, yet it is unclear how blood–brain barrier (BBB) function is affected in these conditions. Here we show that BBB disruption is evident during acute infection and in patients with long COVID with cognitive impairment, commonly referred to as brain fog. Using dynamic contrast-enhanced magnetic resonance imaging, we show BBB disruption in patients with long COVID-associated brain fog. Transcriptomic analysis of peripheral blood mononuclear cells revealed dysregulation of the coagulation system and a dampened adaptive immune response in individuals with brain fog. Accordingly, peripheral blood mononuclear cells showed increased adhesion to human brain endothelial cells in vitro, while exposure of brain endothelial cells to serum from patients with long COVID induced expression of inflammatory markers. Together, our data suggest that sustained systemic inflammation and persistent localized BBB dysfunction is a key feature of long COVID-associated brain fog.
Enteric and systemic postprandial lactate shuttle phases and dietary carbohydrate carbon flow in humans
Authors: Robert G. Leija, Casey C. Curl, Jose A. Arevalo, Adam D. Osmond, Justin J. Duong, Melvin J. Huie, Umesh Masharani, George A. Brooks
Journal: Nature Metabolism (2024)

Abstract Dietary glucose in excess is stored in the liver in the form of glycogen. As opposed to direct conversion of glucose into glycogen, the hypothesis of the postprandial lactate shuttle (PLS) proposes that dietary glucose uptake is metabolized to lactate in the gut, thereby being transferred to the liver for glycogen storage. In the present study, we provide evidence of a PLS in young healthy men and women. Overnight fasted participants underwent an oral glucose tolerance test, and arterialized lactate concentration and rate of appearance were determined. The concentration of lactate in the blood rose before the concentration of glucose, thus providing evidence of an enteric PLS. Secondary increments in the concentration of lactate in the blood and its rate of appearance coincided with those of glucose, which indicates the presence of a larger, secondary, systemic PLS phase driven by hepatic glucose release. The present study challenges the notion that lactate production is the result of hypoxia in skeletal muscles, because our work indicates that glycolysis proceeds to lactate in fully aerobic tissues and dietary carbohydrate is processed via lactate shuttling. Our study proposes that, in humans, lactate is a major vehicle for carbohydrate carbon distribution and metabolism.