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Circadian Clocks, Daily Stress, and Neurodegenerative Disease Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2024-10-18 Eugene Nyamugenda, Clark Rosensweig, Ravi Allada
Disrupted circadian or 24-h rhythms are among the most common early findings in a wide range of neurodegenerative disorders. Once thought to be a mere consequence of the disease process, increasing evidence points toward a causal or contributory role of the circadian clock in neurodegenerative disease. Circadian clocks control many aspects of cellular biochemistry, including stress pathways implicated
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Multiple System Atrophy: Pathology, Pathogenesis, and Path Forward Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2024-10-15 Alain Ndayisaba, Glenda M. Halliday, Vikram Khurana
Multiple system atrophy (MSA) is a fatal neurodegenerative disease characterized by autonomic failure and motor impairment. The hallmark pathologic finding in MSA is widespread oligodendroglial cytoplasmic inclusions rich in aggregated α-synuclein (αSyn). MSA is widely held to be an oligodendroglial synucleinopathy, and we outline lines of evidence to support this assertion, including the presence
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Pathogenesis of Germinal Matrix Hemorrhage: Insights from Single-Cell Transcriptomics Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2024-10-15 Jiapei Chen, Jennifer Ja-Yoon Choi, Pin-Yeh Lin, Eric J. Huang
The germinal matrix harbors neurogenic niches in the subpallium of the prenatal human brain that produce abundant GABAergic neurons. In preterm infants, the germinal matrix is particularly vulnerable to developing hemorrhage, which disrupts neurogenesis and causes severe neurodevelopmental sequelae. However, the disease mechanisms that promote germinal matrix hemorrhage remain unclear. Here, we review
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Epigenetic regulation by polycomb repressive complex 1 promotes cerebral cavernous malformations. EMBO Mol. Med. (IF 9.0) Pub Date : 2024-10-14 Van-Cuong Pham,Claudia Jasmin Rödel,Mariaelena Valentino,Matteo Malinverno,Alessio Paolini,Juliane Münch,Candice Pasquier,Favour C Onyeogaziri,Bojana Lazovic,Romuald Girard,Janne Koskimäki,Melina Hußmann,Benjamin Keith,Daniel Jachimowicz,Franziska Kohl,Astrid Hagelkruys,Josef M Penninger,Stefan Schulte-Merker,Issam A Awad,Ryan Hicks,Peetra U Magnusson,Eva Faurobert,Massimiliano Pagani,Salim Abdelilah-Seyfried
Cerebral cavernous malformations (CCMs) are anomalies of the cerebral vasculature. Loss of the CCM proteins CCM1/KRIT1, CCM2, or CCM3/PDCD10 trigger a MAPK-Krüppel-like factor 2 (KLF2) signaling cascade, which induces a pathophysiological pattern of gene expression. The downstream target genes that are activated by KLF2 are mostly unknown. Here we show that Chromobox Protein Homolog 7 (CBX7), component
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Unraveling autophagic imbalances and therapeutic insights in Mecp2-deficient models. EMBO Mol. Med. (IF 9.0) Pub Date : 2024-10-14 Alessandro Esposito,Tommaso Seri,Martina Breccia,Marzia Indrigo,Giuseppina De Rocco,Francesca Nuzzolillo,Vanna Denti,Francesca Pappacena,Gaia Tartaglione,Simone Serrao,Giuseppe Paglia,Luca Murru,Stefano de Pretis,Jean-Michel Cioni,Nicoletta Landsberger,Fabrizia Claudia Guarnieri,Michela Palmieri
Loss-of-function mutations in MECP2 are associated to Rett syndrome (RTT), a severe neurodevelopmental disease. Mainly working as a transcriptional regulator, MeCP2 absence leads to gene expression perturbations resulting in deficits of synaptic function and neuronal activity. In addition, RTT patients and mouse models suffer from a complex metabolic syndrome, suggesting that related cellular pathways
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Targeting USP11 regulation by a novel lithium-organic coordination compound improves neuropathologies and cognitive functions in Alzheimer transgenic mice. EMBO Mol. Med. (IF 9.0) Pub Date : 2024-10-11 Yi Guo,Chuanbin Cai,Bingjie Zhang,Bo Tan,Qinmin Tang,Zhifeng Lei,Xiaolan Qi,Jiang Chen,Xiaojiang Zheng,Dan Zi,Song Li,Jun Tan
Alzheimer's Disease (AD), as the most common neurodegenerative disease worldwide, severely impairs patients' cognitive functions. Although its exact etiology remains unclear, the abnormal aggregations of misfolded β-amyloid peptide and tau protein are considered pivotal in its pathological progression. Recent studies identify ubiquitin-specific protease 11 (USP11) as the key regulator of tau deubiquitination
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Choroid Plexus Pathophysiology Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2024-10-09 Ya'el Courtney, Alexandra Hochstetler, Maria K. Lehtinen
This review examines the crucial roles of the choroid plexus (ChP) in central nervous system (CNS) pathology, emphasizing its involvement in disease mechanisms and therapeutic potential. Structural changes in the human ChP have been reported across various diseases in case reports and descriptive work, but studies have yet to pin down the physiological relevance of these changes. We highlight primary
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Cysteinyl Leukotrienes in Allergic Inflammation Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2024-10-07 Minkyu Lee, Joshua A. Boyce, Nora A. Barrett
The cysteinyl leukotrienes (CysLTs), LTC4, LTD4, and LTE4, are potent lipid mediators derived from arachidonic acid through the 5-lipoxygenase pathway. These mediators produce both inflammation and bronchoconstriction through three distinct G protein–coupled receptors (GPCRs)—CysLT1, CysLT2, and OXGR1 (also known as CysLT3 or GPR99). While CysLT-mediated functions in the effector phase of allergic
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Troubling bonds: lipid unsaturation promotes selenium dependency and sensitivity to ferroptosis. EMBO Mol. Med. (IF 9.0) Pub Date : 2024-10-07 Ancély Ferreira Dos Santos,José Pedro Friedmann-Angeli
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Contributions of Inflammation to Cardiometabolic Heart Failure with Preserved Ejection Fraction Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2024-10-02 Edward B. Thorp, Mallory Filipp
The most common form of heart failure is heart failure with preserved ejection fraction (HFpEF). While heterogeneous in origin, the most common form of HFpEF is the cardiometabolic manifestation. Obesity and aging promote systemic inflammation that appears integral to cardiometabolic HFpEF pathophysiology. Accumulation of immune cells within the heart, fueled by an altered metabolome, contribute to
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Inherited Predispositions to Myeloid Neoplasms: Pathogenesis and Clinical Implications Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2024-10-02 Yen-Chun Liu, Mohammad K. Eldomery, Jamie L. Maciaszek, Jeffery M. Klco
Myeloid neoplasms with and without preexisting platelet disorders frequently develop in association with an underlying germline predisposition. Germline alterations affecting ANKRD26, CEBPA, DDX41, ETV6, and RUNX1 are associated with nonsyndromic predisposition to the development of myeloid neoplasms including acute myeloid leukemia and myelodysplastic syndrome. However, germline predisposition to
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Jag1 insufficiency alters liver fibrosis via T cell and hepatocyte differentiation defects. EMBO Mol. Med. (IF 9.0) Pub Date : 2024-10-02 Jan Mašek,Iva Filipovic,Noémi Van Hul,Lenka Belicová,Markéta Jiroušková,Daniel V Oliveira,Anna Maria Frontino,Simona Hankeova,Jingyan He,Fabio Turetti,Afshan Iqbal,Igor Červenka,Lenka Sarnová,Elisabeth Verboven,Tomáš Brabec,Niklas K Björkström,Martin Gregor,Jan Dobeš,Emma R Andersson
Fibrosis contributes to tissue repair, but excessive fibrosis disrupts organ function. Alagille syndrome (ALGS, caused by mutations in JAGGED1) results in liver disease and characteristic fibrosis. Here, we show that Jag1Ndr/Ndr mice, a model for ALGS, recapitulate ALGS-like fibrosis. Single-cell RNA-seq and multi-color flow cytometry of the liver revealed immature hepatocytes and paradoxically low
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Pre-clinical development of AP4B1 gene replacement therapy for hereditary spastic paraplegia type 47. EMBO Mol. Med. (IF 9.0) Pub Date : 2024-10-02 Jessica P Wiseman,Joseph M Scarrott,João Alves-Cruzeiro,Afshin Saffari,Cedric Böger,Evangelia Karyka,Emily Dawes,Alexandra K Davies,Paolo M Marchi,Emily Graves,Fiona Fernandes,Zih-Liang Yang,Ian Coldicott,Jennifer Hirst,Christopher P Webster,J Robin Highley,Neil Hackett,Adrienn Angyal,Thushan de Silva,Adrian Higginbottom,Pamela J Shaw,Laura Ferraiuolo,Darius Ebrahimi-Fakhari,Mimoun Azzouz
Spastic paraplegia 47 (SPG47) is a neurological disorder caused by mutations in the adaptor protein complex 4 β1 subunit (AP4B1) gene leading to AP-4 complex deficiency. SPG47 is characterised by progressive spastic paraplegia, global developmental delay, intellectual disability and epilepsy. Gene therapy aimed at restoring functional AP4B1 protein levels is a rational therapeutic strategy to ameliorate
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A new class of capsid-targeting inhibitors that specifically block HIV-1 nuclear import. EMBO Mol. Med. (IF 9.0) Pub Date : 2024-10-02 Aude Boulay,Emmanuel Quevarec,Isabelle Malet,Giuseppe Nicastro,Célia Chamontin,Suzon Perrin,Corinne Henriquet,Martine Pugnière,Valérie Courgnaud,Mickaël Blaise,Anne-Geneviève Marcelin,Ian A Taylor,Laurent Chaloin,Nathalie J Arhel
HIV-1 capsids cross nuclear pore complexes (NPCs) by engaging with the nuclear import machinery. To identify compounds that inhibit HIV-1 nuclear import, we screened drugs in silico on a three-dimensional model of a CA hexamer bound by Transportin-1 (TRN-1). Among hits, compound H27 inhibited HIV-1 with a low micromolar IC50. Unlike other CA-targeting compounds, H27 did not alter CA assembly or disassembly
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Mutation in the mitochondrial chaperone TRAP1 leads to autism with more severe symptoms in males. EMBO Mol. Med. (IF 9.0) Pub Date : 2024-09-27 Małgorzata Rydzanicz,Bozena Kuzniewska,Marta Magnowska,Tomasz Wójtowicz,Aleksandra Stawikowska,Anna Hojka,Ewa Borsuk,Ksenia Meyza,Olga Gewartowska,Jakub Gruchota,Jacek Miłek,Patrycja Wardaszka,Izabela Chojnicka,Ludwika Kondrakiewicz,Dorota Dymkowska,Alicja Puścian,Ewelina Knapska,Andrzej Dziembowski,Rafał Płoski,Magdalena Dziembowska
There is increasing evidence of mitochondrial dysfunction in autism spectrum disorders (ASD), but the causal relationships are unclear. In an ASD patient whose identical twin was unaffected, we identified a postzygotic mosaic mutation p.Q639* in the TRAP1 gene, which encodes a mitochondrial chaperone of the HSP90 family. Additional screening of 176 unrelated ASD probands revealed an identical TRAP1
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Publisher Correction: Novel immunotherapeutics against LGR5 to target multiple cancer types. EMBO Mol. Med. (IF 9.0) Pub Date : 2024-09-25 Hung-Chang Chen,Nico Mueller,Katherine Stott,Chrysa Kapeni,Eilidh Rivers,Carolin M Sauer,Flavio Beke,Stephen J Walsh,Nicola Ashman,Louise O'Brien,Amir Rafati Fard,Arman Ghodsinia,Changtai Li,Fadwa Joud,Olivier Giger,Inti Zlobec,Ioana Olan,Sarah J Aitken,Matthew Hoare,Richard Mair,Eva Serrao,James D Brenton,Alicia Garcia-Gimenez,Simon E Richardson,Brian Huntly,David R Spring,Mikkel-Ole Skjoedt,Karsten
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RIG-I is an intracellular checkpoint that limits CD8+ T-cell antitumour immunity. EMBO Mol. Med. (IF 9.0) Pub Date : 2024-09-25 Xiaobing Duan,Jiali Hu,Yuncong Zhang,Xiaoguang Zhao,Mingqi Yang,Taoping Sun,Siya Liu,Xin Chen,Juan Feng,Wenting Li,Ze Yang,Yitian Zhang,Xiaowen Lin,Dingjie Liu,Ya Meng,Guang Yang,Qiuping Lin,Guihai Zhang,Haihong Lei,Zhengsheng Yi,Yanyan Liu,Xiaobing Liang,Yujuan Wu,Wenqing Diao,Zesong Li,Haihai Liang,Meixiao Zhan,Hong-Wei Sun,Xian-Yang Li,Ligong Lu
Retinoic acid-inducible gene I (RIG-I) is a pattern recognition receptor involved in innate immunity, but its role in adaptive immunity, specifically in the context of CD8+ T-cell antitumour immunity, remains unclear. Here, we demonstrate that RIG-I is upregulated in tumour-infiltrating CD8+ T cells, where it functions as an intracellular checkpoint to negatively regulate CD8+ T-cell function and limit
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Emergence of novel Klebsiella pneumoniae ST types with multidrug resistance in clinic Drug Resist. Updat. (IF 15.8) Pub Date : 2024-09-23 Zhenghao Lou, Xiaolu Yang, Yu Yang, Kexin Guo, Lu Gong, Hao Xu, Beiwen Zheng, Wenhong Liu, Mantao Chen, Xiawei Jiang
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Infection length and host environment influence on Plasmodium falciparum dry season reservoir. EMBO Mol. Med. (IF 9.0) Pub Date : 2024-09-16 Carolina M Andrade,Manuela Carrasquilla,Usama Dabbas,Jessica Briggs,Hannah van Dijk,Nikolay Sergeev,Awa Sissoko,Moussa Niangaly,Christina Ntalla,Emily LaVerriere,Jeff Skinner,Klara Golob,Jeremy Richter,Hamidou Cisse,Shanping Li,Jason A Hendry,Muhammad Asghar,Didier Doumtabe,Anna Farnert,Thomas Ruppert,Daniel E Neafsey,Kassoum Kayentao,Safiatou Doumbo,Aissata Ongoiba,Peter D Crompton,Boubacar Traore
Persistence of malaria parasites in asymptomatic hosts is crucial in areas of seasonally-interrupted transmission, where P. falciparum bridges wet seasons months apart. During the dry season, infected erythrocytes exhibit extended circulation with reduced cytoadherence, increasing the risk of splenic clearance of infected cells and hindering parasitaemia increase. However, what determines parasite
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Whole-sporozoite malaria vaccines: where we are, where we are going. EMBO Mol. Med. (IF 9.0) Pub Date : 2024-09-16 Diana Moita,Miguel Prudêncio
The malaria vaccination landscape has seen significant advancements with the recent endorsement of RTS,S/AS01 and R21/Matrix-M vaccines, which target the pre-erythrocytic stages of Plasmodium falciparum (Pf) infection. However, several challenges remain to be addressed, including the incomplete protection afforded by these vaccines, their dependence on a single Pf antigen, and the fact that they were
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7D, a small molecule inhibits dengue infection by increasing interferons and neutralizing-antibodies via CXCL4:CXCR3:p38:IRF3 and Sirt1:STAT3 axes respectively. EMBO Mol. Med. (IF 9.0) Pub Date : 2024-09-16 Kishan Kumar Gaur,Tejeswara Rao Asuru,Mitul Srivastava,Nitu Singh,Nikil Purushotham,Boja Poojary,Bhabatosh Das,Sankar Bhattacharyya,Shailendra Asthana,Prasenjit Guchhait
There are a limited number of effective vaccines against dengue virus (DENV) and significant efforts are being made to develop potent anti-virals. Previously, we described that platelet-chemokine CXCL4 negatively regulates interferon (IFN)-α/β synthesis and promotes DENV2 replication. An antagonist to CXCR3 (CXCL4 receptor) reversed it and inhibited viral replication. In a concurrent search, we identified
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An update of isoprostanoid nomenclature Prog. Lipid. Res. (IF 14.0) Pub Date : 2024-09-14 Camille Oger, Tereza Pavlíčková, Valérie Bultel-Poncé, Alexandre Guy, Jean-Marie Galano, Ullrich Jahn, Thierry Durand
Polyunsaturated fatty acids (PUFAs) play numerous roles in living organisms but are also prone to rapid aerobic oxidation, resulting in the production of a wide range of isomeric metabolites called oxylipins. Among these, isoprostanes, discovered in the 1990s, are formed non-enzymatically from ω–3 and ω–6 PUFAs with 16 to 22 carbon atoms. Over nearly 35 years of research, two nomenclature systems for
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ERK5 suppression overcomes FAK inhibitor resistance in mutant KRAS-driven non-small cell lung cancer. EMBO Mol. Med. (IF 9.0) Pub Date : 2024-09-13 Chiara Pozzato,Gonçalo Outeiro-Pinho,Mirco Galiè,Giorgio Ramadori,Georgia Konstantinidou
Mutated KRAS serves as the oncogenic driver in 30% of non-small cell lung cancers (NSCLCs) and is associated with metastatic and therapy-resistant tumors. Focal Adhesion Kinase (FAK) acts as a mediator in sustaining KRAS-driven lung tumors, and although FAK inhibitors are currently undergoing clinical development, clinical data indicated that their efficacy in producing long-term anti-tumor responses
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CRISPR-enabled point-of-care genotyping for APOL1 genetic risk assessment. EMBO Mol. Med. (IF 9.0) Pub Date : 2024-09-13 Robert Greensmith,Isadora T Lape,Cristian V Riella,Alexander J Schubert,Jakob J Metzger,Anand S Dighe,Xiao Tan,Bernhard Hemmer,Josefine Rau,Sarah Wendlinger,Nora Diederich,Anja Schütz,Leonardo V Riella,Michael M Kaminski
Detecting genetic variants enables risk factor identification, disease screening, and initiation of preventative therapeutics. However, current methods, relying on hybridization or sequencing, are unsuitable for point-of-care settings. In contrast, CRISPR-based-diagnostics offer high sensitivity and specificity for point-of-care applications. While these methods have predominantly been used for pathogen
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Multiomics reveals microbial metabolites as key actors in intestinal fibrosis in Crohn's disease. EMBO Mol. Med. (IF 9.0) Pub Date : 2024-09-13 Xuehua Li,Shixian Hu,Xiaodi Shen,Ruonan Zhang,Caiguang Liu,Lin Xiao,Jinjiang Lin,Li Huang,Weitao He,Xinyue Wang,Lili Huang,Qingzhu Zheng,Luyao Wu,Canhui Sun,Zhenpeng Peng,Minhu Chen,Ziping Li,Rui Feng,Yijun Zhu,Yangdi Wang,Zhoulei Li,Ren Mao,Shi-Ting Feng
Intestinal fibrosis is the primary cause of disability in patients with Crohn's disease (CD), yet effective therapeutic strategies are currently lacking. Here, we report a multiomics analysis of gut microbiota and fecal/blood metabolites of 278 CD patients and 28 healthy controls, identifying characteristic alterations in gut microbiota (e.g., Lachnospiraceae, Ruminococcaceae, Muribaculaceae, Saccharimonadales)
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An intrinsic mechanism of metabolic tuning promotes cardiac resilience to stress. EMBO Mol. Med. (IF 9.0) Pub Date : 2024-09-13 Matteo Sorge,Giulia Savoré,Andrea Gallo,Davide Acquarone,Mauro Sbroggiò,Silvia Velasco,Federica Zamporlini,Saveria Femminò,Enrico Moiso,Giampaolo Morciano,Elisa Balmas,Andrea Raimondi,Gabrielle Nattenberg,Rachele Stefania,Carlo Tacchetti,Angela Maria Rizzo,Paola Corsetto,Alessandra Ghigo,Emilia Turco,Fiorella Altruda,Lorenzo Silengo,Paolo Pinton,Nadia Raffaelli,Nathan J Sniadecki,Claudia Penna,Pasquale
Defining the molecular mechanisms underlying cardiac resilience is crucial to find effective approaches to protect the heart. A physiologic level of ROS is produced in the heart by fatty acid oxidation, but stressful events can boost ROS and cause mitochondrial dysfunction and cardiac functional impairment. Melusin is a muscle specific chaperone required for myocardial compensatory remodeling during
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B Cell Responses to the Placenta and Fetus Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2024-09-12 Gabrielle Rizzuto
Pregnancy has fascinated immunologists ever since Peter Medawar's observation that reproduction runs contrary to the founding tenets of immunology. During healthy pregnancy, maternal B cells interact with antigens of the foreign conceptus (placenta and fetus) yet do not elicit rejection. Instead, robust, and redundant fetomaternal tolerance pathways generally prevent maternal B cells and antibodies
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O-GlcNAcylation regulation of RIPK1-dependent apoptosis dictates sensitivity to sunitinib in renal cell carcinoma Drug Resist. Updat. (IF 15.8) Pub Date : 2024-09-12 Xiangbo Zeng, Zhiliang Chen, Yuanchao Zhu, Lei Liu, Zhiyong Zhang, Yongyuan Xiao, Qiong Wang, Shiyu Pang, Fengjin Zhao, Bihong Xu, Mengxin Leng, Xiaocen Liu, Chenxi Hu, Siying Zeng, Fei Li, Wenlian Xie, Wanlong Tan, Zaosong Zheng
Receptor interacting protein kinase 1 (RIPK1) has emerged as a key regulatory molecule that influences the balance between cell death and cell survival. Under external stress, RIPK1 determines whether a cell undergoes RIPK-dependent apoptosis (RDA) or survives by activating NF-κB signaling. However, the role and mechanisms of RIPK1 on sunitinib sensitivity in renal cell carcinoma (RCC) remain elusive
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Wnt/β-Catenin Signaling in Liver Pathobiology Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2024-09-11 Matthew D. Carson, Kari Nejak-Bowen
The liver has a critical role in regulating host metabolism, immunity, detoxification, and homeostasis. Proper liver function is essential for host health, and dysregulation of hepatic signaling pathways can lead to the onset of disease. The Wnt/β-catenin signaling pathway is an important regulator of liver homeostasis and function. Throughout life, hepatic Wnt/β-catenin signaling contributes to liver
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Trained immunity of intestinal tuft cells during infancy enhances host defense against enteroviral infections in mice. EMBO Mol. Med. (IF 9.0) Pub Date : 2024-09-11 Deyan Chen,Jing Wu,Fang Zhang,Ruining Lyu,Qiao You,Yajie Qian,Yurong Cai,Xiaoyan Tian,Hongji Tao,Yating He,Waqas Nawaz,Zhiwei Wu
Innate immune cells have been acknowledged as trainable in recent years. While intestinal tuft cells are recognized for their crucial roles in the host defense against intestinal pathogens, there remains uncertainty regarding their trainability. Enterovirus 71 (EV71), a prevalent enterovirus that primarily infects children but rarely infects adults. At present, there is a significant expansion of intestinal
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A critical role for HNF4α in polymicrobial sepsis-associated metabolic reprogramming and death. EMBO Mol. Med. (IF 9.0) Pub Date : 2024-09-11 Céline Van Dender,Steven Timmermans,Ville Paakinaho,Tineke Vanderhaeghen,Jolien Vandewalle,Maarten Claes,Bruno Garcia,Bart Roman,Jan De Waele,Siska Croubels,Karolien De Bosscher,Philip Meuleman,Antoine Herpain,Jorma J Palvimo,Claude Libert
In sepsis, limited food intake and increased energy expenditure induce a starvation response, which is compromised by a quick decline in the expression of hepatic PPARα, a transcription factor essential in intracellular catabolism of free fatty acids. The mechanism upstream of this PPARα downregulation is unknown. We found that sepsis causes a progressive hepatic loss-of-function of HNF4α, which has
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RGS5+ lymphatic endothelial cells facilitate metastasis and acquired drug resistance of breast cancer through oxidative stress-sensing mechanism Drug Resist. Updat. (IF 15.8) Pub Date : 2024-09-06 Caixin Qiu, Chaoyi Tang, Yujun Tang, Ka Su, Xiao Chai, Zexu Zhan, Xing Niu, Jiehua Li
Oxidative stress reflected by elevated reactive oxygen species (ROS) in the tumor ecosystem, is a hallmark of human cancers. The mechanisms by which oxidative stress regulate the metastatic ecosystem and resistance remain elusive. This study aimed to dissect the oxidative stress-sensing machinery during the evolvement of early dissemination and acquired drug resistance in breast cancer.
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The important role of lactylation in regulating DNA damage repair and tumor chemotherapy resistance Drug Resist. Updat. (IF 15.8) Pub Date : 2024-09-06 Jia Li, Zhe-Sheng Chen, Yihang Pan, Leli Zeng
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The influence of AHR on immune and tissue biology. EMBO Mol. Med. (IF 9.0) Pub Date : 2024-09-06 Brigitta Stockinger,Oscar E Diaz,Emma Wincent
The aryl hydrocarbon receptor is a ligand dependent transcription factor which functions as an environmental sensor. Originally discovered as the sensor for man made pollutants such as 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) it has recently gained prominence as an important mediator for environmental triggers via the diet or microbiota which influences many physiological functions in different cell
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Next generation of "magic bullets", solutions from the microbial pangenome. EMBO Mol. Med. (IF 9.0) Pub Date : 2024-09-06 Vega Masignani,Rino Rappuoli,Mariagrazia Pizza
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Somatic Mosaicism in Brain Disorders Ann. Review Paleopathol. Mech. Disease (IF 28.4) Pub Date : 2024-09-04 Rachel R. Corrigan, Lauren M. Mashburn-Warren, Hyojung Yoon, Tracy A. Bedrosian
Research efforts over the past decade have defined the genetic landscape of somatic variation in the brain. Neurons accumulate somatic mutations from development through aging with potentially profound functional consequences. Recent studies have revealed the contribution of somatic mosaicism to various brain disorders including focal epilepsy, neuropsychiatric disease, and neurodegeneration. One notable
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Can we manipulate the ovary's own metabolism to protect it from chemotherapy-induced damage? EMBO Mol. Med. (IF 9.0) Pub Date : 2024-09-03 Adomas Liugaila,Agnes Stefansdottir,Norah Spears
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Plasmid-borne tigecycline resistance gene tet(X4) in Salmonella enterica and Escherichia coli isolates from a pediatric patient with diarrhea Drug Resist. Updat. (IF 15.8) Pub Date : 2024-09-02 Zelin Yan, Yan Li, Yingling Ni, Xiaoni Xia, Yanyan Zhang, Yuchen Wu, Jing Zhang, Gongxiang Chen, Ruichao Li, Rong Zhang
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Mechanism of staphylococcal resistance to clinically relevant antibiotics Drug Resist. Updat. (IF 15.8) Pub Date : 2024-08-31 Daniela Brdová, Tomáš Ruml, Jitka Viktorová
, a notorious pathogen with versatile virulence, poses a significant challenge to current antibiotic treatments due to its ability to develop resistance mechanisms against a variety of clinically relevant antibiotics. In this comprehensive review, we carefully dissect the resistance mechanisms employed by against various antibiotics commonly used in clinical settings. The article navigates through
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Unveiling the resistance to therapies in pancreatic ductal adenocarcinoma Drug Resist. Updat. (IF 15.8) Pub Date : 2024-08-30 Ashu Shah, Koelina Ganguly, Sanchita Rauth, Shamema S. Sheree, Imran Khan, Apar K. Ganti, Moorthy P. Ponnusamy, Sushil Kumar, Maneesh Jain, Surinder K. Batra
Despite the ongoing advances in interventional strategies (surgery, chemotherapy, radiotherapy, and immunotherapy) for managing pancreatic ductal adenocarcinoma (PDAC), the development of therapy refractory phenotypes remains a significant challenge. Resistance to various therapeutic modalities in PDAC emanates from a combination of inherent and acquired factors and is attributable to cancer cell-intrinsic
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The gray boundaries of aberrant shortening of the cellular timekeepers' edges. EMBO Mol. Med. (IF 9.0) Pub Date : 2024-08-28 Guillermo Guenechea,Nestor W Meza
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The evolving genetic landscape of telomere biology disorder dyskeratosis congenita. EMBO Mol. Med. (IF 9.0) Pub Date : 2024-08-28 Hemanth Tummala,Amanda J Walne,Mohsin Badat,Manthan Patel,Abigail M Walne,Jenna Alnajar,Chi Ching Chow,Ibtehal Albursan,Jennifer M Frost,David Ballard,Sally Killick,Peter Szitányi,Anne M Kelly,Manoj Raghavan,Corrina Powell,Reinier Raymakers,Tony Todd,Elpis Mantadakis,Sophia Polychronopoulou,Nikolas Pontikos,Tianyi Liao,Pradeep Madapura,Upal Hossain,Tom Vulliamy,Inderjeet Dokal
Dyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome, caused by genetic mutations that principally affect telomere biology. Approximately 35% of cases remain uncharacterised at the genetic level. To explore the genetic landscape, we conducted genetic studies on a large collection of clinically diagnosed cases of DC as well as cases exhibiting features resembling DC, referred
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Un-methylation of NUDT21 represses docosahexaenoic acid biosynthesis contributing to enzalutamide resistance in prostate cancer Drug Resist. Updat. (IF 15.8) Pub Date : 2024-08-24 Shin-Chih Lin, Ya-Chuan Tsai, Ying-Lan Chen, Hui-Kuan Lin, Yun-Chen Huang, Yi-Syuan Lin, Yu-Sheng Cheng, Hsing-Yi Chen, Chia-Jung Li, Tsung-Yen Lin, Shih-Chieh Lin
The recent approval of enzalutamide for metastatic castration-sensitive prostate cancer underscores its growing clinical significance, raising concerns about emerging resistance and limited treatment options. While the reactivation of the androgen receptor (AR) and other genes plays a role in enzalutamide resistance, identifications of novel underlying mechanism with therapeutic potential in enzalutamide-resistant
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CRISPR-AMRtracker: A novel toolkit to monitor the antimicrobial resistance gene transfer in fecal microbiota Drug Resist. Updat. (IF 15.8) Pub Date : 2024-08-24 Gong Li, Teng-Fei Long, Shi-Ying Zhou, Li-Juan Xia, Ang Gao, Lei Wan, Xiao-Yuan Diao, Yu-Zhang He, Ruan-Yang Sun, Jin-Tao Yang, Sheng-Qiu Tang, Hao Ren, Liang-Xing Fang, Xiao-Ping Liao, Ya-Hong Liu, Liang Chen, Jian Sun
The spread of antibiotic resistance genes (ARGs), particularly those carried on plasmids, poses a major risk to global health. However, the extent and frequency of ARGs transfer in microbial communities among human, animal, and environmental sectors is not well understood due to a lack of effective tracking tools. We have developed a novel fluorescent tracing tool, CRISPR-AMRtracker, to study ARG transfer
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Human breast tissue engineering in health and disease. EMBO Mol. Med. (IF 9.0) Pub Date : 2024-08-23 Maj-Britt Buchholz,Demi I Scheerman,Riccardo Levato,Ellen J Wehrens,Anne C Rios
The human mammary gland represents a highly organized and dynamic tissue, uniquely characterized by postnatal developmental cycles. During pregnancy and lactation, it undergoes extensive hormone-stimulated architectural remodeling, culminating in the formation of specialized structures for milk production to nourish offspring. Moreover, it carries significant health implications, due to the high prevalence
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Revolutionising infection control: building the next generation of phage banks Drug Resist. Updat. (IF 15.8) Pub Date : 2024-08-22 Braira Wahid, Muhammad Salman Tiwana, Akhtar Ali
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Novel immunotherapeutics against LGR5 to target multiple cancer types. EMBO Mol. Med. (IF 9.0) Pub Date : 2024-08-21 Hung-Chang Chen,Nico Mueller,Katherine Stott,Chrysa Kapeni,Eilidh Rivers,Carolin M Sauer,Flavio Beke,Stephen J Walsh,Nicola Ashman,Louise O'Brien,Amir Rafati Fard,Arman Ghodsinia,Changtai Li,Fadwa Joud,Olivier Giger,Inti Zlobec,Ioana Olan,Sarah J Aitken,Matthew Hoare,Richard Mair,Eva Serrao,James D Brenton,Alicia Garcia-Gimenez,Simon E Richardson,Brian Huntly,David R Spring,Mikkel-Ole Skjoedt,Karsten
We have developed and validated a highly specific, versatile antibody to the extracellular domain of human LGR5 (α-LGR5). α-LGR5 detects LGR5 overexpression in >90% of colorectal cancer (CRC), hepatocellular carcinoma (HCC) and pre-B-ALL tumour cells and was used to generate an Antibody-Drug Conjugate (α-LGR5-ADC), Bispecific T-cell Engager (α-LGR5-BiTE) and Chimeric Antigen Receptor (α-LGR5-CAR).
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Fertility protection during chemotherapy treatment by boosting the NAD(P)+ metabolome. EMBO Mol. Med. (IF 9.0) Pub Date : 2024-08-21 Wing-Hong Jonathan Ho,Maria B Marinova,Dave R Listijono,Michael J Bertoldo,Dulama Richani,Lynn-Jee Kim,Amelia Brown,Angelique H Riepsamen,Safaa Cabot,Emily R Frost,Sonia Bustamante,Ling Zhong,Kaisa Selesniemi,Derek Wong,Romanthi Madawala,Maria Marchante,Dale M Goss,Catherine Li,Toshiyuki Araki,David J Livingston,Nigel Turner,David A Sinclair,Kirsty A Walters,Hayden A Homer,Robert B Gilchrist,Lindsay
Chemotherapy induced ovarian failure and infertility is an important concern in female cancer patients of reproductive age or younger, and non-invasive, pharmacological approaches to maintain ovarian function are urgently needed. Given the role of reduced nicotinamide adenine dinucleotide phosphate (NADPH) as an essential cofactor for drug detoxification, we sought to test whether boosting the NAD(P)+
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Restoration of defective oxidative phosphorylation to a subset of neurons prevents mitochondrial encephalopathy. EMBO Mol. Med. (IF 9.0) Pub Date : 2024-08-21 Brittni R Walker,Lise-Michelle Theard,Milena Pinto,Monica Rodriguez-Silva,Sandra R Bacman,Carlos T Moraes
Oxidative Phosphorylation (OXPHOS) defects can cause severe encephalopathies and no effective treatment exists for these disorders. To assess the ability of gene replacement to prevent disease progression, we subjected two different CNS-deficient mouse models (Ndufs3/complex I or Cox10/complex IV conditional knockouts) to gene therapy. We used retro-orbitally injected AAV-PHP.eB to deliver the missing
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Immunotherapies targeting the oncogenic fusion gene CLDN18-ARHGAP in gastric cancer. EMBO Mol. Med. (IF 9.0) Pub Date : 2024-08-20 Yue Wang,Hanbing Wang,Tao Shi,Xueru Song,Xin Zhang,Yue Zhang,Xuan Wang,Keying Che,Yuting Luo,Lixia Yu,Baorui Liu,Jia Wei
The CLDN18-ARHGAP fusion gene is an oncogenic driver newly discovered in gastric cancer. It was detected in 9% (8/87) of gastric cancer patients in our center. An immunogenic peptide specifically targeting CLDN18-ARHGAP fusion gene was generated to induce neoantigen-reactive T cells, which was proved to have specific and robust anti-tumor capacity both in in vitro coculture models and in vivo xenograft
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An enhanced intracellular delivery platform based on a distant diphtheria toxin homolog that evades pre-existing antitoxin antibodies. EMBO Mol. Med. (IF 9.0) Pub Date : 2024-08-19 Shivneet K Gill,Seiji N Sugiman-Marangos,Greg L Beilhartz,Elizabeth Mei,Mikko Taipale,Roman A Melnyk
Targeted intracellular delivery of therapeutic proteins remains a significant unmet challenge in biotechnology. A promising approach is to leverage the intrinsic capabilities of bacterial toxins like diphtheria toxin (DT) to deliver a potent cytotoxic enzyme into cells with an associated membrane translocation moiety. Despite showing promising clinical efficacy, widespread deployment of DT-based therapeutics
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Fusion event mediated by IS903B between chromosome and plasmid in two MCR-9- and KPC-2-co-producing Klebsiella pneumoniae isolates Drug Resist. Updat. (IF 15.8) Pub Date : 2024-08-17 Ruishan Liu, Yingying Chen, Hao Xu, Huanran Zhang, Yi Liu, Xiaojing Liu, Haowei Ye, Mantao Chen, Beiwen Zheng
Herein, we first isolated two MCR-9- and KPC-2-co-producing isolates. Notably, we observed a fusion event between the chromosome and plasmid, mediated by IS, in these two strains. This cointegration of chromosomes and plasmids introduces a new mode of transmission for antimicrobial resistance genes.
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Unraveling the secrets: Evolution of resistance mediated by membrane proteins Drug Resist. Updat. (IF 15.8) Pub Date : 2024-08-16 Xue Yang, Min Li, Zi-Chang Jia, Yan Liu, Shun-Fan Wu, Mo-Xian Chen, Ge-Fei Hao, Qing Yang
Membrane protein-mediated resistance is a multidisciplinary challenge that spans fields such as medicine, agriculture, and environmental science. Understanding its complexity and devising innovative strategies are crucial for treating diseases like cancer and managing resistant pests in agriculture. This paper explores the dual nature of resistance mechanisms across different organisms: On one hand
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Folylpolyglutamate synthetase inactivation in relapsed ALL induces a druggable folate metabolic vulnerability Drug Resist. Updat. (IF 15.8) Pub Date : 2024-08-16 Hui Li, Yao Chen, Ming Ding, Jingjing Liu, Huiying Sun, Houshun Fang, Samuel W. Brady, Yan Xu, Fabian Glaser, Xiaotu Ma, Yabin Tang, Liang Du, Xiaoyu Wu, Shuxuan Wang, Liang Zhu, Benshang Li, Shuhong Shen, Jinghui Zhang, Liang Zheng, Jiyang Yu, Yehuda G. Assaraf, Bin-Bing S. Zhou
The antifolate methotrexate (MTX) is an anchor drug used in acute lymphoblastic leukemia (ALL) with poorly understood chemoresistance mechanisms in relapse. Herein we find decreased folate polyglutamylation network activities and inactivating FPGS mutations, both of which could induce MTX resistance and folate metabolic vulnerability in relapsed ALL.
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Ultrastructural, metabolic and genetic characteristics of determinants facilitating the acquisition of macrolide resistance by Streptococcus pneumoniae Drug Resist. Updat. (IF 15.8) Pub Date : 2024-08-16 Xueqing Wu, Babek Alibayov, Xi Xiang, Santiago M. Lattar, Fuminori Sakai, Austin A. Medders, Brenda S. Antezana, Lance E. Keller, Ana G.J. Vidal, Yih-Ling Tzeng, D. Ashley Robinson, David S. Stephens, Yunsong Yu, Jorge E. Vidal
To investigate the molecular events associated with acquiring macrolide resistance genes [/ (Mega) or ] in () during nasopharyngeal colonization. Genomic analysis of 128 macrolide-resistant isolates revealed recombination events in genes of the conjugation apparatus, or the competence system, in strains carrying Tn-related elements. Studies using confocal and electron microscopy demonstrated that during
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Histidine-rich glycoprotein modulates neutrophils and thrombolysis-associated hemorrhagic transformation. EMBO Mol. Med. (IF 9.0) Pub Date : 2024-08-15 Wei Jiang,Yuexin Zhao,Rongrong Liu,Bohao Zhang,Yuhan Xie,Bin Gao,Kaibin Shi,Ming Zou,Dongmei Jia,Jiayue Ding,Xiaowei Hu,Yanli Duan,Ranran Han,DeRen Huang,Luc Van Kaer,Fu-Dong Shi
Intravenous thrombolysis using recombinant tissue plasminogen activator (tPA) remains the primary treatment for patients with acute ischemic stroke (AIS). However, the mechanism of tPA-related hemorrhagic transformation (HT) remains poorly understood. Elevation of histidine-rich glycoprotein (HRG) expression was detected by nano-liquid chromatography tandem mass spectrometry at 1 h following tPA infusion
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The key role of iroBCDN-lacking pLVPK-like plasmid in the evolution of the most prevalent hypervirulent carbapenem-resistant ST11-KL64 Klebsiella pneumoniae in China Drug Resist. Updat. (IF 15.8) Pub Date : 2024-08-14 Xinmiao Jia, Ying Zhu, Peiyao Jia, Cuidan Li, Xiaobing Chu, Tianshu Sun, Xiaoyu Liu, Wei Yu, Fei Chen, Yingchun Xu, Qiwen Yang
Hypervirulent carbapenem-resistant (hv-CRKP), coharboring hypervirulence and carbapenem-resistance genes mediated by plasmids, causes infections with extremely high mortality and seriously impacts public health. Exploring the transfer mechanisms of virulence/carbapenem-resistance plasmids, as well as the formation and evolution pathway of hv-CRKP is of great significance to the control of hv-CRKP infections
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CBX4 counteracts cellular senescence to desensitize gastric cancer cells to chemotherapy by inducing YAP1 SUMOylation Drug Resist. Updat. (IF 15.8) Pub Date : 2024-08-12 Yunru Gu, Tingting Xu, Yuan Fang, Jun Shao, Tong Hu, Xi Wu, Haoyang Shen, Yangyue Xu, Jingxin Zhang, Yu Song, Yang Xia, Yongqian Shu, Pei Ma
As our comprehension of the intricate relationship between cellular senescence and tumor biology continues to evolve, the therapeutic potential of cellular senescence is gaining increasing recognition. Here, we identify chromobox 4 (CBX4), a Small Ubiquitin-related Modifier (SUMO) E3 ligase, as an antagonist of cellular senescence and elucidate a novel mechanism by which CBX4 promotes drug resistance
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Editorial: ABC transporters and drug resistance Drug Resist. Updat. (IF 15.8) Pub Date : 2024-08-10 Qisi Lu, Suresh V. Ambudkar, Dong-Hua Yang
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Comprehensive molecular characterization of collecting duct carcinoma for therapeutic vulnerability. EMBO Mol. Med. (IF 9.0) Pub Date : 2024-08-09 Peiyong Guan,Jianfeng Chen,Chengqiang Mo,Tomoya Fukawa,Chao Zhang,Xiuyu Cai,Mei Li,Jing Han Hong,Jason Yongsheng Chan,Cedric Chuan Young Ng,Jing Yi Lee,Suet Far Wong,Wei Liu,Xian Zeng,Peili Wang,Rong Xiao,Vikneswari Rajasegaran,Swe Swe Myint,Abner Ming Sun Lim,Joe Poh Sheng Yeong,Puay Hoon Tan,Choon Kiat Ong,Tao Xu,Yiqing Du,Fan Bai,Xin Yao,Bin Tean Teh,Jing Tan
Collecting duct carcinoma (CDC) is an aggressive rare subtype of kidney cancer with unmet clinical needs. Little is known about its underlying molecular alterations and etiology, primarily due to its rarity, and lack of preclinical models. This study aims to comprehensively characterize molecular alterations in CDC and identify its therapeutic vulnerabilities. Through whole-exome and transcriptome