tbuckley/cabot-search huggingface dataset:
Multiple Origins of Bioluminescence in Beetles and Evolution of Luciferase Function
Authors: Jinwu He, Jun Li, Ru Zhang, Zhiwei Dong, Guichun Liu, Zhou Chang, Wenxuan Bi, Yongying Ruan, Yuxia Yang, Haoyu Liu, Lu Qiu, Ruoping Zhao, Wenting Wan, Zihe Li, Lei Chen, Yuanning Li, Xueyan Li
Journal: Molecular Biology and Evolution (2024)

Abstract Bioluminescence in beetles has long fascinated biologists, with diverse applications in biotechnology. To date, however, our understanding of its evolutionary origin and functional variation mechanisms remains poor. To address these questions, we obtained high-quality reference genomes of luminous and nonluminous beetles in 6 Elateroidea families. We then reconstructed a robust phylogenetic relationship for all luminous families and related nonluminous families. Comparative genomic analyses and biochemical functional experiments suggested that gene evolution within Elateroidea played a crucial role in the origin of bioluminescence, with multiple parallel origins observed in the luminous beetle families. While most luciferase-like proteins exhibited a conserved nonluminous amino acid pattern (TLA346 to 348) in the luciferin-binding sites, luciferases in the different luminous beetle families showed divergent luminous patterns at these sites (TSA/CCA/CSA/LVA). Comparisons of the structural and enzymatic properties of ancestral, extant, and site-directed mutant luciferases further reinforced the important role of these sites in the trade-off between acyl-CoA synthetase and luciferase activities. Furthermore, the evolution of bioluminescent color demonstrated a tendency toward hypsochromic shifts and variations among the luminous families. Taken together, our results revealed multiple parallel origins of bioluminescence and functional divergence within the beetle bioluminescent system.
A compendium of genetic regulatory effects across pig tissues
Authors: Jinyan Teng, Yahui Gao, Hongwei Yin, Zhonghao Bai, Shuli Liu, Haonan Zeng, Lijing Bai, Zexi Cai, Bingru Zhao, Xiujin Li, Zhiting Xu, Qing Lin, Zhangyuan Pan, Wenjing Yang, Xiaoshan Yu, Dailu Guan, Yali Hou, Brittney N. Keel, Gary A. Rohrer, Amanda K. Lindholm-Perry, William T. Oliver, Maria Ballester, Daniel Crespo-Piazuelo, Raquel Quintanilla, Oriol Canela-Xandri, Konrad Rawlik, Charley Xia, Yuelin Yao, Qianyi Zhao, Wenye Yao, Liu Yang, Houcheng Li, Huicong Zhang, Wang Liao, Tianshuo Chen, Peter Karlskov-Mortensen, Merete Fredholm, Marcel Amills, Alex Clop, Elisabetta Giuffra, Jun Wu, Xiaodian Cai, Shuqi Diao, Xiangchun Pan, Chen Wei, Jinghui Li, Hao Cheng, Sheng Wang, Guosheng Su, Goutam Sahana, Mogens Sandø Lund, Jack C. M. Dekkers, Luke Kramer, Christopher K. Tuggle, Ryan Corbett, Martien A. M. Groenen, Ole Madsen, Marta Gòdia, Dominique Rocha, Mathieu Charles, Cong-jun Li, Hubert Pausch, Xiaoxiang Hu, Laurent Frantz, Yonglun Luo, Lin Lin, Zhongyin Zhou, Zhe Zhang, Zitao Chen, Leilei Cui, Ruidong Xiang, Xia Shen, Pinghua Li, Ruihua Huang, Guoqing Tang, Mingzhou Li, Yunxiang Zhao, Guoqiang Yi, Zhonglin Tang, Jicai Jiang, Fuping Zhao, Xiaolong Yuan, Xiaohong Liu, Yaosheng Chen, Xuewen Xu, Shuhong Zhao, Pengju Zhao, Chris Haley, Huaijun Zhou, Qishan Wang, Yuchun Pan, Xiangdong Ding, Li Ma, Jiaqi Li, Pau Navarro, Qin Zhang, Bingjie Li, Albert Tenesa, Kui Li, George E. Liu, Zhe Zhang, Lingzhao Fang
Journal: Nature Genetics (2024)

Abstract The Farm Animal Genotype-Tissue Expression (FarmGTEx) project has been established to develop a public resource of genetic regulatory variants in livestock, which is essential for linking genetic polymorphisms to variation in phenotypes, helping fundamental biological discovery and exploitation in animal breeding and human biomedicine. Here we show results from the pilot phase of PigGTEx by processing 5,457 RNA-sequencing and 1,602 whole-genome sequencing samples passing quality control from pigs. We build a pig genotype imputation panel and associate millions of genetic variants with five types of transcriptomic phenotypes in 34 tissues. We evaluate tissue specificity of regulatory effects and elucidate molecular mechanisms of their action using multi-omics data. Leveraging this resource, we decipher regulatory mechanisms underlying 207 pig complex phenotypes and demonstrate the similarity of pigs to humans in gene expression and the genetic regulation behind complex phenotypes, supporting the importance of pigs as a human biomedical model.
A systematic review and meta‐analysis on nutritional and dietary interventions for the treatment of acute respiratory infection in pediatric patients: An <scp>EAACI</scp> taskforce
Authors: Gregorio P. Milani, Ilaria Alberti, Martina Abodi, John Lakoumentas, George N. Konstantinou, Nikolaos G. Papadopoulos, Raluca M. Pop, Ioana C. Bocsan, Dimitrios Cassimos, Inger Kull, Silvia Bettocchi, Antonio Corsello, Marco Cugliari, Letizia Ciliberti, Giulia C. I. Spolidoro, Carlo Agostoni, Berber Vlieg Boerstra, Carina Venter, Liam O'Mahony, Emilia Vassilopoulou
Journal: Allergy (2024)

Abstract Acute respiratory infections are a major cause of morbidity and mortality in children worldwide. Dietary and nutritional interventions, including minerals and vitamin supplementation, have been explored as potential treatments for these infections. However, the evidence on their efficacy is limited and inconclusive. This systematic review and meta‐analysis aim to provide a comprehensive summary of the available evidence on the effectiveness of dietary and nutritional interventions for treating acute respiratory tract infections in children. A systematic review was conducted according to the PRISMA 2020 guidelines in April 2022 and updated in April 2023. Clinical trials focusing on dietary or nutritional interventions, including supplementations, in children with acute respiratory tract infections were included. The selection of interventions and outcomes was based on biological plausibility. Data were extracted using a standardized form, and the risk of bias was assessed using the Cochrane Risk of Bias Tool. Meta‐analysis was performed using random‐effect models. A total of 50 studies were included in the review. Four trials were conducted in low, 32 in lower‐middle, 12 in upper‐middle, and only two in high‐income countries. The studies evaluated various dietary interventions, including zinc, vitamin A, vitamin E, vitamin D, and probiotics. The results of individual studies on the efficacy of these interventions were mixed, with some showing positive effects on clinical outcomes such as duration of symptoms, while others showed no significant impact. Meta‐analysis was conducted for zinc supplementation in children with pneumonia, and the pooled results suggested a potential limited benefit in terms of reduced hospital length of stay but not time to recovery. Meta‐analyses on vitamin D did not show any effect in children with pneumonia. This systematic review fills a critical gap in the literature by synthesizing the available evidence on the efficacy and safety of nutritional or dietary interventions for acute respiratory tract infections in children. The findings indicate no dietary or nutritional intervention can currently be recommended for the routine treatment of respiratory tract infections in children based on single supplement studies. The metanalysis suggests that zinc supplementation might have a beneficial effect on length of hospitalization in children with pneumonia. New studies are needed to establish more conclusive evidence for pediatric acute respiratory diseases especially for children living in a context of high‐income countries.
Inhibition of NF-κB signaling unveils novel strategies to overcome drug resistance in cancers
Authors: Yuanfang Li, Baiwei Zhao, Juzheng Peng, Hailin Tang, Sicheng Wang, Sicheng Peng, Feng Ye, Junye Wang, Kai Ouyang, Jianjun Li, Manbo Cai, Yongming Chen
Journal: Drug Resistance Updates (2024)

Drug resistance in cancer remains a major challenge in oncology, impeding the effectiveness of various treatment modalities. The nuclear factor-kappa B (NF-κB) signaling pathway has emerged as a critical player in the development of drug resistance in cancer cells. This comprehensive review explores the intricate relationship between NF-κB and drug resistance in cancer. We delve into the molecular mechanisms through which NF-κB activation contributes to resistance against chemotherapeutic agents, targeted therapies, and immunotherapies. Additionally, we discuss potential strategies to overcome this resistance by targeting NF-κB signaling, such as small molecule inhibitors and combination therapies. Understanding the multifaceted interactions between NF-κB and drug resistance is crucial for the development of more effective cancer treatment strategies. By dissecting the complex signaling network of NF-κB, we hope to shed light on novel therapeutic approaches that can enhance treatment outcomes, ultimately improving the prognosis for cancer patients. This review aims to provide a comprehensive overview of the current state of knowledge on NF-κB and its role in drug resistance, offering insights that may guide future research and therapeutic interventions in the fight against cancer.
Therapeutic challenges in peripheral T-cell lymphoma
Authors: Yunpeng Luan, Xiang Li, Yunqi Luan, Junyu Luo, Qinzuo Dong, Shili Ye, Yuejin Li, Yanmei Li, Lu Jia, Jun Yang, Dong-Hua Yang
Journal: Molecular Cancer (2024)

Abstract Peripheral T-cell lymphoma (PTCL) is a rare and heterogeneous group of hematological malignancies. Compared to our knowledge of B-cell tumors, our understanding of T-cell leukemia and lymphoma remains less advanced, and a significant number of patients are diagnosed with advanced stages of the disease. Unfortunately, the development of drug resistance in tumors leads to relapsed or refractory peripheral T-Cell Lymphomas (r/r PTCL), resulting in highly unsatisfactory treatment outcomes for these patients. This review provides an overview of potential mechanisms contributing to PTCL treatment resistance, encompassing aspects such as tumor heterogeneity, tumor microenvironment, and abnormal signaling pathways in PTCL development. The existing drugs aimed at overcoming PTCL resistance and their potential resistance mechanisms are also discussed. Furthermore, a summary of ongoing clinical trials related to PTCL is presented, with the aim of aiding clinicians in making informed treatment decisions.
Treatment and outcomes for patients with relapsed or refractory diffuse large B-cell lymphoma: a contemporary, nationwide, population-based study in the Netherlands
Authors: Elise R. A. Pennings, Müjde Durmaz, Otto Visser, Eduardus F. M. Posthuma, Djamila E. Issa, Martine E. D. Chamuleau, Pieternella J. Lugtenburg, Marie José Kersten, Avinash G. Dinmohamed
Journal: Blood Cancer Journal (2024)
The emergence of machine learning force fields in drug design
Authors: Mingan Chen, Xinyu Jiang, Lehan Zhang, Xiaoxu Chen, Yiming Wen, Zhiyong Gu, Xutong Li, Mingyue Zheng
Journal: Medicinal Research Reviews (2024)

In the field of molecular simulation for drug design, traditional molecular mechanic force fields and quantum chemical theories have been instrumental but limited in terms of scalability and computational efficiency. To overcome these limitations, machine learning force fields (MLFFs) have emerged as a powerful tool capable of balancing accuracy with efficiency. MLFFs rely on the relationship between molecular structures and potential energy, bypassing the need for a preconceived notion of interaction representations. Their accuracy depends on the machine learning models used, and the quality and volume of training data sets. With recent advances in equivariant neural networks and high-quality datasets, MLFFs have significantly improved their performance. This review explores MLFFs, emphasizing their potential in drug design. It elucidates MLFF principles, provides development and validation guidelines, and highlights successful MLFF implementations. It also addresses potential challenges in developing and applying MLFFs. The review concludes by illuminating the path ahead for MLFFs, outlining the challenges to be overcome and the opportunities to be harnessed. This inspires researchers to embrace MLFFs in their investigations as a new tool to perform molecular simulations in drug design.
Immune system perturbations in patients with long COVID
Authors: Lucie Rodriguez, Petter Brodin
Journal: Trends in Molecular Medicine (2024)

Klein et al. report multimodal analyses of immune cells, proteins, and physiological parameters in patients with long COVID (LC). At the group level, LC subjects exhibited elevated antibody responses to SARS-CoV-2, but also to herpes viruses, pointing to a general suppression of viral control mechanisms in LC.
Gene regulation in t(6;9) DEK::NUP214 Acute Myeloid Leukemia resembles that of FLT3-ITD/NPM1 Acute Myeloid Leukemia but with an altered HOX/MEIS axis
Authors: Sandeep Potluri, Sophie G. Kellaway, Daniel J. L. Coleman, Peter Keane, Maria Rosaria Imperato, Salam A. Assi, Peter N. Cockerill, Constanze Bonifer
Journal: Leukemia (2024)
Acellular scaffold-based approach for in situ genetic engineering of host T-cells in solid tumor immunotherapy
Authors: Hiren Y. Dandia, Mamatha M. Pillai, Deepak Sharma, Meghna Suvarna, Neha Dalal, Ayush Madhok, Arvind Ingle, Shubhada V. Chiplunkar, Sanjeev Galande, Prakriti Tayalia
Journal: Military Medical Research (2024)

Targeted T-cell therapy has emerged as a promising strategy for the treatment of hematological malignancies. However, its application to solid tumors presents significant challenges due to the limited accessibility and heterogeneity. Localized delivery of tumor-specific T-cells using biomaterials has shown promise, however, procedures required for genetic modification and generation of a sufficient number of tumor-specific T-cells ex vivo remain major obstacles due to cost and time constraints. Polyethylene glycol (PEG)-based three-dimensional (3D) scaffolds were developed and conjugated with positively charged poly-L-lysine (PLL) using carbamide chemistry for efficient loading of lentiviruses (LVs) carrying tumor antigen-specific T-cell receptors (TCRs). The physical and biological properties of the scaffold were extensively characterized. Further, the scaffold loaded with OVA-TCR LVs was implanted in B16F10 cells expressing ovalbumin (B16-OVA) tumor model to evaluate the anti-tumor response and the presence of transduced T-cells. Our findings demonstrate that the scaffolds do not induce any systemic inflammation upon subcutaneous implantation and effectively recruit T-cells to the site. In B16-OVA melanoma tumor-bearing mice, the scaffolds efficiently transduce host T-cells with OVA-specific TCRs. These genetically modified T-cells exhibit homing capability towards the tumor and secondary lymphoid organs, resulting in a significant reduction of tumor size and systemic increase in anti-tumor cytokines. Immune cell profiling revealed a significantly high percentage of transduced T-cells and a notable reduction in suppressor immune cells within the tumors of mice implanted with these scaffolds. Our scaffold-based T-cell therapy presents an innovative in situ localized approach for programming T-cells to target solid tumors. This approach offers a viable alternative to in vitro manipulation of T-cells, circumventing the need for large-scale in vitro generation and culture of tumor-specific T-cells. It offers an off-the-shelf alternative that facilitates the use of host cells instead of allogeneic cells, thereby, overcoming a major hurdle.
Exploring the Potential of Nanogels: From Drug Carriers to Radiopharmaceutical Agents (Adv. Healthcare Mater. 1/2024)
Authors: Manja Kubeil, Yota Suzuki, Maria Antonietta Casulli, Rozy Kamal, Takeshi Hashimoto, Michael Bachmann, Takashi Hayashita, Holger Stephan
Journal: Advanced Healthcare Materials (2024)
A MYC-rearrangement is a negative prognostic factor in stage II, but not in stage I diffuse large B-cell lymphoma
Authors: A. V. de Jonge, J. A. A. Bult, D. F. E. Karssing, M. Nijland, M. E. D. Chamuleau, M. Brink
Journal: Blood Cancer Journal (2024)

Abstract MYC oncogene rearrangements ( MYC -R) negatively affect survival in patients with Ann Arbor stage III–IV diffuse large B-cell lymphoma (DLBCL), but their impact in limited stage (LS) I–II is unclear. Therefore, we assessed the impact of MYC -R on progression-free survival (PFS) and overall survival (OS) in LS DLBCL patients at the population level. We identified 1,434 LS DLBCL patients with known MYC -R status diagnosed between 2014 and 2020, who received R-CHOP(-like) regimens using the Netherlands Cancer Registry, with survival follow-up until February 2022. Stage I patients with ( n = 83, 11%) and without ( n = 650, 89%) a MYC -R had similar 2-years PFS (89% and 93%, p = 0.63) and OS (both 95%, p = 0.22). Conversely, stage II DLBCL patients with a MYC -R ( n = 90, 13%) had inferior survival outcomes compared to stage II patients without a MYC -R ( n = 611, 87%) (PFS 70% vs. 89%, p = 0.001; OS 79% vs. 94%, p &lt; 0.0001). Both single MYC -R (single hit, n = 36) and concurrent BCL2 and/or BCL6 rearrangements (double/triple hit, n = 39) were associated with increased mortality and relapse risk. In conclusion, in stage II DLBCL a MYC -R is negatively associated with survival. In stage I DLBCL, however, survival outcomes are excellent irrespective of MYC -R status. This challenges the diagnostic assessment of MYC -R in stage I DLBCL patients.
Genomic and functional impact of Trp53 inactivation in JAK2V617F myeloproliferative neoplasms
Authors: Panhong Gou, Duanya Liu, Saravanan Ganesan, Evelyne Lauret, Nabih Maslah, Veronique Parietti, Wenchao Zhang, Véronique Meignin, Jean-Jacques Kiladjian, Bruno Cassinat, Stephane Giraudier
Journal: Blood Cancer Journal (2024)

Abstract Classical myeloproliferative neoplasms (MPNs) are characterized by the proliferation of myeloid cells and the risk of transformation into myelofibrosis or acute myeloid leukemia (AML) and TP53 mutations in MPN patients are linked to AML. However, JAK2V617F has been reported to impact the TP53 response to DNA damage, suggesting potential overlapping role of TP53 inactivation in MPN. We established a mouse model showing that JAK2V617F/Vav-Cre/Trp53 −/− mice displayed a similar phenotype to JAK2V617F/Vav-Cre mice, but their proliferation was outcompeted in competitive grafts. RNA-Seq revealed that half of the genes affected by JAK2V617F were affected by p53-inactivation, including the interferon pathway. To validate this finding, mice were repopulated with a mixture of wild-type and JAK2V617F (or JAK2V617F/Vav-Cre/Trp53 −/− ) cells and treated with pegylated interferonα. JAK2V617F-reconstituted mice entered complete hematological remission, while JAK2V617F/Vav-Cre /Trp53 −/− -reconstituted mice did not, confirming that p53 loss induced interferon-α resistance. KEGG and Gene Ontology analyses of common deregulated genes showed that these genes were mainly implicated in cytokine response, proliferation, and leukemia evolution, illustrating that in this mouse model, the development of MPN is not affected by TP53 inactivation. Taken together, our results show that many genetic modifications induced by JAK2V617F are influenced by TP53, the MPN phenotype may not be. Trp53 loss alone is insufficient to induce rapid leukemic transformation in steady-state hematopoiesis in JAK2V617F MPN, and Trp53 loss may contribute to interferon resistance in MPN.
Repurposing lansoprazole to alleviate metabolic syndrome via PHOSPHO1 inhibition
Authors: Yingting Wu, Jiaqi Xin, Xinyu Li, Ting Yang, Yi Liu, Yongsheng Zhao, Wen Xie, Mengxi Jiang
Journal: Acta Pharmaceutica Sinica B (2024)

Drug repurposing offers an efficient approach to therapeutic development. In this study, our bioinformatic analysis first predicted an association between obesity and lansoprazole (LPZ), a commonly prescribed drug for gastrointestinal ulcers. We went on to show that LPZ treatment increased energy expenditure and alleviated the high-fat diet-induced obesity, insulin resistance, and hepatic steatosis in mice. Treatment with LPZ elicited thermogenic gene expression and mitochondrial respiration in primary adipocytes, and induced cold tolerance in cold-exposed mice, suggesting the activity of LPZ in promoting adipose thermogenesis and energy metabolism. Mechanistically, LPZ is an efficient inhibitor of adipose phosphocholine phosphatase 1 (PHOSPHO1) and produces metabolic benefits in a PHOSPHO1-dependent manner. Our results suggested that LPZ may stimulate adipose thermogenesis by inhibiting the conversion of 2-arachidonoylglycerol-lysophosphatidic acid (2-AG-LPA) to 2-arachidonoylglycerol (2-AG) and reduce the activity of the thermogenic-suppressive cannabinoid receptor signaling. In summary, we have uncovered a novel therapeutic indication and mechanism of LPZ in managing obesity and its related metabolic syndrome, and identified a potential metabolic basis by which LPZ improves energy metabolism.
Aggregated eosinophils and neutrophils characterize the properties of mucus in chronic rhinosinusitis
Authors: Yui Miyabe, Mineyo Fukuchi, Hiroki Tomizawa, Yuka Nakamura, Mitsutoshi Jikei, Yoshinori Matsuwaki, Misaki Arima, Yasunori Konno, Yuki Moritoki, Masahide Takeda, Naoya Tanabe, Hiroshi Shima, Yusuke Shiraishi, Toyohiro Hirai, Nobuo Ohta, Junko Takahata, Atsushi Matsubara, Takechiyo Yamada, Koichiro Asano, Isao Miyairi, Rossana C.N. Melo, Peter F. Weller, Shigeharu Ueki
Journal: Journal of Allergy and Clinical Immunology (2024)
Ileitis promotes MASLD progression via bile acid modulation and enhanced TGR5 signaling in ileal CD8+ T cells
Authors: Chang Zheng, Lei Wang, Tianhui Zou, Senlin Lian, Jiajing Luo, Yijun Lu, Hanbing Hao, Yuejie Xu, Ying Xiang, Xiaoqi Zhang, Guifang Xu, Xiaoping Zou, Runqiu Jiang
Journal: Journal of Hepatology (2024)
Using multi-scale genomics to associate poorly annotated genes with rare diseases
Authors: Christina Canavati, Dana Sherill-Rofe, Lara Kamal, Idit Bloch, Fouad Zahdeh, Elad Sharon, Batel Terespolsky, Islam Abu Allan, Grace Rabie, Mariana Kawas, Hanin Kassem, Karen B. Avraham, Paul Renbaum, Ephrat Levy-Lahad, Moien Kanaan, Yuval Tabach
Journal: Genome Medicine (2024)

Abstract Background Next-generation sequencing (NGS) has significantly transformed the landscape of identifying disease-causing genes associated with genetic disorders. However, a substantial portion of sequenced patients remains undiagnosed. This may be attributed not only to the challenges posed by harder-to-detect variants, such as non-coding and structural variations but also to the existence of variants in genes not previously associated with the patient’s clinical phenotype. This study introduces EvORanker, an algorithm that integrates unbiased data from 1,028 eukaryotic genomes to link mutated genes to clinical phenotypes. Methods EvORanker utilizes clinical data, multi-scale phylogenetic profiling, and other omics data to prioritize disease-associated genes. It was evaluated on solved exomes and simulated genomes, compared with existing methods, and applied to 6260 knockout genes with mouse phenotypes lacking human associations. Additionally, EvORanker was made accessible as a user-friendly web tool. Results In the analyzed exomic cohort, EvORanker accurately identified the “true” disease gene as the top candidate in 69% of cases and within the top 5 candidates in 95% of cases, consistent with results from the simulated dataset. Notably, EvORanker outperformed existing methods, particularly for poorly annotated genes. In the case of the 6260 knockout genes with mouse phenotypes, EvORanker linked 41% of these genes to observed human disease phenotypes. Furthermore, in two unsolved cases, EvORanker successfully identified DLGAP2 and LPCAT3 as disease candidates for previously uncharacterized genetic syndromes. Conclusions We highlight clade-based phylogenetic profiling as a powerful systematic approach for prioritizing potential disease genes. Our study showcases the efficacy of EvORanker in associating poorly annotated genes to disease phenotypes observed in patients. The EvORanker server is freely available at https://ccanavati.shinyapps.io/EvORanker/ .