tbuckley/cabot-search huggingface dataset:
Salt Responsive Gut Microbiota Induces Sex Specific Blood Pressure Changes
Authors: Pritam Bardhan, Xue Mei, Ngoc Khanh Lai, Blair Mell, Ramakumar Tummala, Sachin Aryal, Ishan Manandhar, Hyeongu Hwang, Tania Akter Jhuma, Rohit R. Atluri, Jun Kyoung, Ying Li, Bina Joe, Hong-Bao Li, Tao Yang
Journal: Circulation Research (2024)

BACKGROUND: Tryptophan metabolism is important in blood pressure regulation. The tryptophan-indole pathway is exclusively mediated by the gut microbiota. ACE2 (angiotensin-converting enzyme 2) participates in tryptophan absorption, and a lack of ACE2 leads to changes in the gut microbiota. The gut microbiota has been recognized as a regulator of blood pressure. Furthermore, there is ample evidence for sex differences in the gut microbiota. However, it is unclear whether such sex differences impact blood pressure differentially through the tryptophan-indole pathway. METHODS: To study the sex-specific mechanisms of gut microbiota-mediated tryptophan-indole pathway in hypertension, we generated a novel rat model with Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats–associated protein 9)–targeted deletion of Ace2 in the Dahl salt-sensitive rat. Cecal microbiota transfers from donors of both sexes to female S recipients were performed. Also, Dahl salt-sensitive rats of both sexes were orally gavaged with indole to investigate blood pressure response. RESULTS: The female gut microbiota and its tryptophan-indole pathway exhibited greater buffering capacity when exposed to tryptophan, due to Ace2 deficiency, and salt. In contrast, the male gut microbiota and its tryptophan-indole pathway were more vulnerable. Female rats with male cecal microbiota responded to salt with a higher blood pressure increase. Indole, a tryptophan-derived metabolite produced by gut bacteria, increased blood pressure in male but not in female rats. Moreover, salt altered host-mediated tryptophan metabolism, characterized by reduced serum serotonin of both sexes and higher levels of kynurenine derivatives in the females. CONCLUSIONS: We uncovered a novel sex-specific mechanism in the gut microbiota-mediated tryptophan-indole pathway in blood pressure regulation. Salt tipped the tryptophan metabolism between the host and gut microbiota in a sex-dependent manner. Our study provides evidence for a novel concept that gut microbiota and its metabolism play sex-specific roles in the development of salt-sensitive hypertension.
Long-term Outcomes and Risk Modifiers of MASLD Between Lean and Non-Lean Populations
Authors: Pojsakorn Danpanichkul, Kanokphong Suparan, Vitchapong Prasitsumrit, Aijaz Ahmed, Karn Wijarnpreecha, Donghee Kim
Journal: Clinical and Molecular Hepatology (2024)

One-third of adults across the globe exhibit metabolic dysfunction-associated steatotic liver disease (MASLD) - formerly known as nonalcoholic fatty liver disease (NAFLD). To date, MASLD is the fastest-growing etiology of chronic liver disease and hepatocellular carcinoma (HCC). Besides the population with obesity, MASLD can also be found in lean populations, accounting for 13% of the global population, especially Asians. Notably, individuals with lean MASLD face equal or higher overall mortality rates compared to their non-lean counterparts. Risk modifiers encompass advanced age, hepatic fibrosis, and type 2 diabetes mellitus (T2DM). Moreover, the population with lean MASLD is associated with an increased risk of HCC, while their non-lean counterparts are more prone to cardiovascular outcomes and T2DM. Existing evidence indicates a similar risk of liver-related events and extrahepatic cancer between the two groups. However, MASLD-related genetic variants, such as PNPLA3 and TM6SF2, did not significantly affect mortality between the two populations. Still, underreporting alcohol consumption and regional representation limits the study's comprehensiveness. Longitudinal studies and mechanistic explorations are needed to understand differences in lean versus non-lean MASLD populations. This review highlights the need for awareness and tailored interventions in managing MASLD, considering lean individuals' unique risks.
Membrane-bound IL-7 immobilized by the CD8 transmembrane region improves efficacy of CD19 CAR-T cell therapy
Authors: Chaoting Zhang, Ting Liu, Shance Li, Xia Teng, Yuge Zhu, Guanyu Zhang, Huimin Xie, Kang Sun, Jiaxin Tu, Wenjun Yang, Zheming Lu
Journal: Molecular Cancer (2024)

Enhancing the efficacy of CD19 CAR-T cell therapy can significantly improve patient outcomes by reducing relapse rates in CD19 + B cell malignancies. Exogenous or transgenic cytokines are often used to boost the expansion and durability of CAR-T cells but pose risks of severe toxicities. A promising approach to address these limitations is to immobilize cytokines on the surface of CAR-T cells using transmembrane (TM) anchor domains. Given IL-7 can enhance T-cell proliferation and antitumor activity, our study developed membrane-bound IL-7 constructs using different TM anchor domains (CD8, CD28 and B7-1). We primarily found that the CD8 TM provided superior anchoring for IL-7 compared to CD28 and B7-1. Moreover, the IL-7 construct with a CD8 TM (IL7/CD8) enhanced naïve T cell proliferation and effector functions, and improved the in vitro and in vivo antitumor activity of CD19 CAR-T cells. Importantly, although IL7/CD8 could promote T-cell proliferation, it did not sustain long-term autonomous expansion, which could ensure the safety of CD19 CAR-T cells expressing IL7/CD8 in clinical applications. Collectively, the IL7/CD8 construct represents a promising strategy for enhancing the therapeutic potential of CD19 CAR-T cell therapy.
The Journey of Antibody–Drug Conjugates: Lessons Learned from 40 Years of Development
Authors: Raffaele Colombo, Paolo Tarantino, Jamie R. Rich, Patricia M. LoRusso, Elisabeth G.E. de Vries
Journal: Cancer Discovery (2024)

Abstract Antibody–drug conjugates (ADC) represent one of the most rapidly expanding treatment modalities in oncology, with 11 ADCs approved by the FDA and more than 210 currently being tested in clinical trials. Spanning over 40 years, ADC clinical development has enhanced our understanding of the multifaceted mechanisms of action for this class of therapeutics. In this article, we discuss key insights into the toxicity, efficacy, stability, distribution, and fate of ADCs. Furthermore, we highlight ongoing challenges related to their clinical optimization, the development of rational sequencing strategies, and the identification of predictive biomarkers. Significance: The development and utilization of ADCs have allowed for relevant improvements in the prognosis of multiple cancer types. Concomitantly, the rise of ADCs in oncology has produced several challenges, including the prediction of their activity, their utilization in sequence, and minimization of their side effects, that still too often resemble those of the cytotoxic molecule that they carry. In this review, we retrace 40 years of development in the field of ADCs and delve deep into the mechanisms of action of these complex therapeutics and reasons behind the many achievements and failures observed in the field to date.
The dysfunction of complement and coagulation in diseases: the implications for the therapeutic interventions
Authors: Honghong Jiang, Yiming Guo, Qihang Wang, Yiran Wang, Dingchuan Peng, Yigong Fang, Lei Yan, Zhuolin Ruan, Sheng Zhang, Yong Zhao, Wendan Zhang, Wei Shang, Zhichun Feng
Journal: MedComm (2024)

Abstract The complement system, comprising over 30 proteins, is integral to the immune system, and the coagulation system is critical for vascular homeostasis. The activation of the complement and coagulation systems involves an organized proteolytic cascade, and the overactivation of these systems is a central pathogenic mechanism in several diseases. This review describes the role of complement and coagulation system activation in critical illness, particularly sepsis. The complexities of sepsis reveal significant knowledge gaps that can be compared to a profound abyss, highlighting the urgent need for further investigation and exploration. It is well recognized that the inflammatory network, coagulation, and complement systems are integral mechanisms through which multiple factors contribute to increased susceptibility to infection and may result in a disordered immune response during septic events in patients. Given the overlapping pathogenic mechanisms in sepsis, immunomodulatory therapies currently under development may be particularly beneficial for patients with sepsis who have concurrent infections. Herein, we present recent findings regarding the molecular relationships between the coagulation and complement pathways in the advancement of sepsis, and propose potential intervention targets related to the crosstalk between coagulation and complement, aiming to provide more valuable treatment of sepsis.
RNA modification in normal hematopoiesis and hematologic malignancies
Authors: Xi Chen, Yixiao Yuan, Fan Zhou, Lihua Li, Jun Pu, Xiulin Jiang
Journal: MedComm (2024)

Abstract N6‐methyladenosine (m6A) is the most abundant RNA modification in eukaryotic cells. Previous studies have shown that m6A plays a critical role under both normal physiological and pathological conditions. Hematopoiesis and differentiation are highly regulated processes, and recent studies on m6A mRNA methylation have revealed how this modification controls cell fate in both normal and malignant hematopoietic states. However, despite these insights, a comprehensive understanding of its complex roles between normal hematopoietic development and malignant hematopoietic diseases remains elusive. This review first provides an overview of the components and biological functions of m6A modification regulators. Additionally, it highlights the origin, differentiation process, biological characteristics, and regulatory mechanisms of hematopoietic stem cells, as well as the features, immune properties, and self‐renewal pathways of leukemia stem cells. Last, the article systematically reviews the latest research advancements on the roles and mechanisms of m6A regulatory factors in normal hematopoiesis and related malignant diseases. More importantly, this review explores how targeting m6A regulators and various signaling pathways could effectively intervene in the development of leukemia, providing new insights and potential therapeutic targets. Targeting m6A modification may hold promise for achieving more precise and effective leukemia treatments.
NPM1-fusion proteins promote myeloid leukemogenesis through XPO1-dependent HOX activation
Authors: Yuko Shimosato, Keita Yamamoto, Yuhan Jia, Wenyu Zhang, Norio Shiba, Yasuhide Hayashi, Shuichi Ito, Toshio Kitamura, Susumu Goyama
Journal: Leukemia (2024)

Abstract Nucleophosmin ( NPM1 ) is a nucleolar protein and one of the most frequently mutated genes in acute myeloid leukemia (AML). In addition to the commonly detected frameshift mutations in exon12 (NPM1c), previous studies have identified NPM1 gene rearrangements leading to the expression of NPM1-fusion proteins in pediatric AML. However, whether the NPM1-fusions are indeed oncogenic and how the NPM1-fusions cause AML have been largely unknown. In this study, we investigated the subcellular localization and leukemogenic potential of two rare NPM1-fusion proteins, NPM1::MLF1 and NPM1::CCDC28A. NPM1::MLF1 is present in both the nucleus and cytoplasm and occasionally induces AML in the mouse transplantation assay. NPM1::CCDC28A is more localized to the cytoplasm, immortalizes mouse bone marrow cells in vitro and efficiently induces AML in vivo. Mechanistically, both NPM1-fusions bind to the HOX gene cluster and, like NPM1c, cause aberrant upregulation of HOX genes in cooperation with XPO1. The XPO1 inhibitor selinexor suppressed HOX activation and colony formation driven by the NPM1-fusions. NPM1::CCDC28A cells were also sensitive to menin inhibition. Thus, our study provides experimental evidence that both NPM1::MLF1 and NPM1::CCDC28A are oncogenes with functions similar to NPM1c. Inhibition of XPO1 and menin may be a promising strategy for the NPM1-rearranged AML.
Agreement between antigen-based skin test and interferon-gamma release assay in elderly individuals aged ≥ 65 years in China
Authors: Yijun He, Lingyu Shen, Jiang Du, Xuefang Cao, Bin Zhang, Dakuan Wang, Boxuan Feng, Zihan Li, Yuanzhi Di, Juanjuan Huang, Tonglei Guo, Jianguo Liang, Jiaoxia Yan, Zisen Liu, Qi Jin, Weitao Duan, Henan Xin, Lei Gao
Journal: Clinical Microbiology and Infection (2024)
Feedback loop LINC00511–YTHDF2–SOX2 regulatory network drives cholangiocarcinoma progression and stemness
Authors: Canghai Guan, Xinlei Zou, Xin Gao, Sidi Liu, Jianjun Gao, Wujiang Shi, Qingfu Dong, Xingming Jiang, Xiangyu Zhong
Journal: MedComm (2024)

Abstract Cholangiocarcinoma (CCA) was identified as a malignant tumor with rising incidence and mortality rates, and the roles of long noncoding RNA (lncRNA) in CCA remained not entirely clear. In this study, LINC00511 had high expression in CCA, which was closely related to poor prognosis. Knockdown of LINC00511 significantly inhibited cell malignant biological behaviors. It also affected the stemness of CCA, evidenced by decreased SOX2 protein expression. Moreover, the study revealed the interaction of LINC00511, YTHDF2, and SOX2 in CCA. Specifically, LINC00511 facilitated the formation of a complex with YTHDF2 on SOX2 mRNA, which uniquely enhances the mRNA's stability through m6A methylation sites. This stabilization appears crucial for maintaining malignant behaviors in CCA cells. Additionally, LINC00511 modulated SOX2 expression via the PI3K/AKT signaling pathway. Meanwhile, SOX2 can also promote LINC00511 expression as an upstream transcription factor, thereby confirming a positive feedback loop formed by LINC00511, YTHDF2, and SOX2, which plays a significant role in the occurrence and development of CCA. Finally, the study successfully constructed two patient‐derived xenograft models, revealing the vital role of LINC00511 in CCA development. In summary, this research provides a comprehensive understanding of the role of LINC00511 in the pathogenesis of CCA.
Long‐term exposure to fine particulate matter constituents, genetic susceptibility, and incident heart failure among 411 807 adults
Authors: Feipeng Cui, Lei Zheng, Jing Zhang, Linxi Tang, Yudiyang Ma, Dankang Li, Jianing Wang, Meiqi Xing, Junqing Xie, Jian Yang, Yaohua Tian
Journal: European Journal of Heart Failure (2024)
Visit‐to‐visit changes in heart rate in heart failure: A pooled participant‐level analysis of the <scp>PARADIGM</scp>‐<scp>HF</scp> and <scp>PARAGON</scp>‐<scp>HF</scp> trials
Authors: Henri Lu, Brian L. Claggett, Milton Packer, Marc A. Pfeffer, Karl Swedberg, Jean Rouleau, Michael R. Zile, Martin Lefkowitz, Akshay S. Desai, Pardeep S. Jhund, John J.V. McMurray, Scott D. Solomon, Muthiah Vaduganathan
Journal: European Journal of Heart Failure (2024)
Neurodevelopmental outcomes of infants after in utero exposure to SARS-CoV-2 or mRNA COVID-19 vaccine compared to unexposed infants: a COVI-PREG prospective cohort study
Authors: Guillaume Favre, Rebecca L Bromley, Matthew Bluett-Duncan, Emeline Maisonneuve, Léo Pomar, Charlotte Daire, Anda-Petronela Radan, Luigi Raio, Daniel Surbek, Carolin Blume, Stylianos Kalimeris, Yoann Madec, Juliane Schneider, Myriam Bickle Graz, Ursula Winterfeld, Alice Panchaud, David Baud
Journal: Clinical Microbiology and Infection (2024)
Priming of Cancer-Immunity Cycle by Alleviating Hypoxia-induced Ferroptosis Resistance and Immunosuppression
Authors: Yun Chen, Mengxuan Zuo, Deblin Jana, Wenbin Zhong, Brynne Shu Ni Tan, Xiaodong Zhang, Xiaokai Chen, Yanli Zhao
Journal: Biomaterials (2024)
A retrospective multicenter cohort study of differences in clinical characteristics of Infantile Hemangiomas in preterm and term infants: Prematurity increases risk of permanent cutaneous sequelae
Authors: Flora E Bradley, Esteban Fernández Faith, Sonal D Shah, Mitchell Braun, Elena Pope, Irene Lara-Corrales, Patricia M Witman, Katya Harfmann, Amy Buros Stein, Ilona J Frieden
Journal: Journal of the American Academy of Dermatology (2024)
The global, regional, and national burden of myocarditis in 204 countries and territories, 1990–2021: Results from the Global Burden of Disease Study 2021
Authors: Le Li, Ligang Ding, Lingmin Wu, Zhicheng Hu, Limin Liu, Minghao Zhao, Tao Zhang, Lihui Zheng, Yan Yao
Journal: European Journal of Heart Failure (2024)
Fecal samples and rectal swabs adequately reflect the human colonic luminal microbiota
Authors: Julia Rode, Linnea Brengesjö Johnson, Julia König, Ignacio Rangel, Lars Engstrand, Dirk Repsilber, Robert J Brummer
Journal: Gut Microbes (2024)

The appropriateness of the fecal microbiota to adequately reflect the gut microbiota composition from more difficult to access luminal content at different colonic locations has been debated. Here, in a healthy population, luminal samples were collected from terminal ileum to rectum using an unique sampling technique without the need of prior bowel cleansing/preparation. Rectal swabs were collected immediately prior colonoscopy by an experienced physician, and fecal samples were collected at home by the participants themselves. Microbiota composition was evaluated as relative abundance, α-diversity and Bray-Curtis dissimilarities. Our data suggest that fecal samples and rectal swabs present noninvasive, easily accessible, low-cost sampling tools that are accurate proxies to characterize luminal large intestinal microbiota composition.
Muropeptides and muropeptide transporters impact on host immune response
Authors: Maria Lucia Orsini Delgado, Joao Gamelas Magalhaes, Rachel Morra, Antonietta Cultrone
Journal: Gut Microbes (2024)

In bacteria, the cell envelope is the key element surrounding and protecting the bacterial content from mechanical or osmotic damages. It allows the selective interchanges of solutes, ions, cellular debris, and drugs between the cellular compartments and the external environment, thanks to the presence of transmembrane proteins called transporters. The major component of the cell envelope is the peptidoglycan, consisting of long linear glycan strands cross-linked by short peptide stems. During cell growth or under stress conditions, peptidoglycan fragments, the muropeptides, are released by bacteria and recognized by the host Pattern Recognition Receptor, promoting the activation of their innate defense mechanisms. The review sums up the salient aspects of microbiota-host interaction with a focus on the NOD-dependent immune response to bacterial peptidoglycan and on the accountability of muropeptide transporters in the crosstalk with the host and in antibiotic resistance. Furthermore, it retraces the discoveries and applications of microorganisms-derived components such as vaccines or vaccine adjuvants.
The Population History of Domestic Sheep Revealed by Paleogenomes
Authors: Damla Kaptan, Gözde Atağ, Kıvılcım Başak Vural, Pedro Morell Miranda, Ali Akbaba, Eren Yüncü, Aleksey Buluktaev, Mohammad Foad Abazari, Sevgi Yorulmaz, Duygu Deniz Kazancı, Ayça Küçükakdağ Doğu, Yasin Gökhan Çakan, Rana Özbal, Fokke Gerritsen, Bea De Cupere, Refik Duru, Gülsün Umurtak, Benjamin S Arbuckle, Douglas Baird, Özlem Çevik, Erhan Bıçakçı, Can Yumni Gündem, Evangelia Pişkin, Lamys Hachem, Kayra Canpolat, Zohre Fakhari, Maria Ochir-Goryaeva, Viktoria Kukanova, Hamid Reza Valipour, Javad Hoseinzadeh, Fatma Küçük Baloğlu, Anders Götherström, Eleftherios Hadjisterkotis, Thierry Grange, Eva-Maria Geigl, İnci Z Togan, Torsten Günther, Mehmet Somel, Füsun Özer
Journal: Molecular Biology and Evolution (2024)

Abstract Sheep was one of the first domesticated animals in Neolithic West Eurasia. The zooarchaeological record suggests that domestication first took place in Southwest Asia, although much remains unresolved about the precise location(s) and timing(s) of earliest domestication, or the post-domestication history of sheep. Here, we present 24 new partial sheep paleogenomes, including a 13,000-year-old Epipaleolithic Central Anatolian wild sheep, as well as 14 domestic sheep from Neolithic Anatolia, two from Neolithic Iran, two from Neolithic Iberia, three from Neolithic France, and one each from Late Neolithic/Bronze Age Baltic and South Russia, in addition to five present-day Central Anatolian Mouflons and two present-day Cyprian Mouflons. We find that Neolithic European, as well as domestic sheep breeds, are genetically closer to the Anatolian Epipaleolithic sheep and the present-day Anatolian and Cyprian Mouflon than to the Iranian Mouflon. This supports a Central Anatolian source for domestication, presenting strong evidence for a domestication event in SW Asia outside the Fertile Crescent, although we cannot rule out multiple domestication events also within the Neolithic Fertile Crescent. We further find evidence for multiple admixture and replacement events, including one that parallels the Pontic Steppe-related ancestry expansion in Europe, as well as a post-Bronze Age event that appears to have further spread Asia-related alleles across global sheep breeds. Our findings mark the dynamism of past domestic sheep populations in their potential for dispersal and admixture, sometimes being paralleled by their shepherds and in other cases not.
Activation of Gs signaling in mouse enteroendocrine K cells greatly improves obesity- and diabetes-related metabolic deficits
Authors: Antwi-Boasiako Oteng, Liu Liu, Yinghong Cui, Oksana Gavrilova, Huiyan Lu, Min Chen, Lee S Weinstein, Jonathan E Campbell, Jo E Lewis, Fiona M Gribble, Frank Reimann, Jürgen Wess
Journal: Journal of Clinical Investigation (2024)

Following a meal, glucagon-like peptide-1 (GLP1) and glucose-dependent insulinotropic polypeptide (GIP), the two major incretins promoting insulin release, are secreted from specialized enteroendocrine cells (L- and K-cells, respectively). Although GIP is the dominant incretin in humans, the detailed molecular mechanisms governing its release remain to be explored. GIP secretion is regulated by the activity of G protein-coupled receptors (GPCRs) expressed by K-cells. GPCRs couple to one or more specific classes of heterotrimeric G proteins. In the present study, we focused on the potential metabolic roles of K-cell Gs. First, we generated a mouse model that allowed us to selectively stimulate K-cell Gs signaling. Second, we generated a mouse strain harboring an inactivating mutation of Gnas, the gene encoding the alpha-subunit of Gs, selectively in K-cells. Metabolic phenotyping studies showed that acute or chronic stimulation of K-cell Gs signaling greatly improved impaired glucose homeostasis in obese mice and in a mouse model of type 2 diabetes, due to enhanced GIP secretion. In contrast, K-cell-specific Gnas knockout mice displayed markedly reduced plasma GIP levels. These data strongly suggest that strategies aimed at enhancing K-cell Gs signaling may prove useful for the treatment of diabetes and related metabolic diseases.