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Raman studies of the adipose tissue: Current state-of-art and future perspectives in diagnostics Prog. Lipid. Res. (IF 14.673) Pub Date : 2022-08-09 Krzysztof Czamara, Zuzanna Majka, Ewa Stanek, Natalia Hachlica, Agnieszka Kaczor
The last decades revealed that the adipose tissue shows an unexplored therapeutic potential. In particular, targeting the perivascular adipose tissue (PVAT), that surrounds blood vessels, can prevent cardiovascular pathologies and browning of the adipose tissue can become an effective strategy against obesity. Therefore, new analytical tools are necessary to analyze this tissue. This review reports
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Dendritic cell cross-dressing and tumor immunity EMBO Mol. Med. (IF 14.26) Pub Date : 2022-08-12 Amaia Martinez-Usatorre, Michele De Palma
In addition to direct and cross-presentation, dendritic cells (DCs) can present tumor antigens (TAs) to T cells via a hitherto poorly understood mechanism called “cross-dressing.” DC cross-dressing involves the acquisition of preformed peptide-major histocompatibility class I/II (p-MHC) complexes from cancer cells. This process has been documented both in cell culture and in tumor models; may occur
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TPC2 rescues lysosomal storage in mucolipidosis type IV, Niemann–Pick type C1, and Batten disease EMBO Mol. Med. (IF 14.26) Pub Date : 2022-08-05 Anna Scotto Rosato, Einar K Krogsaeter, Dawid Jaślan, Carla Abrahamian, Sandro Montefusco, Chiara Soldati, Barbara Spix, Maria Teresa Pizzo, Giuseppina Grieco, Julia Böck, Amanda Wyatt, Daniela Wünkhaus, Marcel Passon, Marc Stieglitz, Marco Keller, Guido Hermey, Sandra Markmann, Doris Gruber-Schoffnegger, Susan Cotman, Ludger Johannes, Dennis Crusius, Ulrich Boehm, Christian Wahl-Schott, Martin Biel
Lysosomes are cell organelles that degrade macromolecules to recycle their components. If lysosomal degradative function is impaired, e.g., due to mutations in lysosomal enzymes or membrane proteins, lysosomal storage diseases (LSDs) can develop. LSDs manifest often with neurodegenerative symptoms, typically starting in early childhood, and going along with a strongly reduced life expectancy and quality
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TOP3A amplification and ATRX inactivation are mutually exclusive events in pediatric osteosarcomas using ALT EMBO Mol. Med. (IF 14.26) Pub Date : 2022-08-03 Alexandre de Nonneville, Sébastien Salas, François Bertucci, Alexander P Sobinoff, José Adélaïde, Arnaud Guille, Pascal Finetti, Jane R Noble, Dimitri Churikov, Max Chaffanet, Elise Lavit, Hilda A Pickett, Corinne Bouvier, Daniel Birnbaum, Roger R Reddel, Vincent Géli
In some types of cancer, telomere length is maintained by the alternative lengthening of telomeres (ALT) mechanism. In many ALT cancers, the α-thalassemia/mental retardation syndrome X-linked (ATRX) gene is mutated leading to the conclusion that the ATRX complex represses ALT. Here, we report that most high-grade pediatric osteosarcomas maintain their telomeres by ALT, and that the majority of these
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Store-operated calcium entry controls innate and adaptive immune cell function in inflammatory bowel disease EMBO Mol. Med. (IF 14.26) Pub Date : 2022-08-02 Marilena Letizia, Yin-Hu Wang, Ulrike Kaufmann, Lorenz Gerbeth, Annegret Sand, Max Brunkhorst, Patrick Weidner, Jörn Felix Ziegler, Chotima Böttcher, Stephan Schlickeiser, Camila Fernández, Megumi Yamashita, Kenneth Stauderman, Katherine Sun, Désirée Kunkel, Murali Prakriya, , Ashley D Sanders, Britta Siegmund, Stefan Feske, Carl Weidinger
Inflammatory bowel disease (IBD) is characterized by dysregulated intestinal immune responses. Using mass cytometry (CyTOF) to analyze the immune cell composition in the lamina propria (LP) of patients with ulcerative colitis (UC) and Crohn's disease (CD), we observed an enrichment of CD4+ effector T cells producing IL-17A and TNF, CD8+ T cells producing IFNγ, T regulatory (Treg) cells, and innate
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FIBCD1 is an endocytic GAG receptor associated with a novel neurodevelopmental disorder EMBO Mol. Med. (IF 14.26) Pub Date : 2022-08-02 Christopher W Fell, Astrid Hagelkruys, Ana Cicvaric, Marion Horrer, Lucy Liu, Joshua Shing Shun Li, Johannes Stadlmann, Anton A Polyansky, Stefan Mereiter, Miguel Angel Tejada, Tomislav Kokotović, Venkat Swaroop Achuta, Angelica Scaramuzza, Kimberly A Twyman, Michelle M Morrow, Jane Juusola, Huifang Yan, Jingmin Wang, Margit Burmeister, Biswa Choudhury, Thomas Levin Andersen, Gerald Wirnsberger, Uffe
Whole-exome sequencing of two patients with idiopathic complex neurodevelopmental disorder (NDD) identified biallelic variants of unknown significance within FIBCD1, encoding an endocytic acetyl group-binding transmembrane receptor with no known function in the central nervous system. We found that FIBCD1 preferentially binds and endocytoses glycosaminoglycan (GAG) chondroitin sulphate-4S (CS-4S) and
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Mesenchymal tumor organoid models recapitulate rhabdomyosarcoma subtypes EMBO Mol. Med. (IF 14.26) Pub Date : 2022-08-02 Michael T Meister, Marian J A Groot Koerkamp, Terezinha de Souza, Willemijn B Breunis, Ewa Frazer-Mendelewska, Mariël Brok, Jeff DeMartino, Freek Manders, Camilla Calandrini, Hinri H D Kerstens, Alex Janse, M Emmy M Dolman, Selma Eising, Karin P S Langenberg, Marc van Tuil, Rutger R G Knops, Sheila Terwisscha van Scheltinga, Laura S Hiemcke-Jiwa, Uta Flucke, Johannes H M Merks, Max M van Noesel, Bastiaan
Rhabdomyosarcomas (RMS) are mesenchyme-derived tumors and the most common childhood soft tissue sarcomas. Treatment is intense, with a nevertheless poor prognosis for high-risk patients. Discovery of new therapies would benefit from additional preclinical models. Here, we describe the generation of a collection of 19 pediatric RMS tumor organoid (tumoroid) models (success rate of 41%) comprising all
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Lipid-protein interactions regulating the canonical and the non-canonical NLRP3 inflammasome Prog. Lipid. Res. (IF 14.673) Pub Date : 2022-07-25 Malvina Pizzuto, Pablo Pelegrin, Jean-Marie Ruysschaert
The inflammatory response is a complex regulated effector mechanism of the innate immune system that is initiated after tissue injury or infection. The NLRP3 inflammasome is an important initiator of inflammation by regulating the activation of caspase-1, the maturation of pro-inflammatory cytokines and the induction of pyroptotic cell death. Numerous studies demonstrate that the NLRP3 inflammasome
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Liquid biopsy: blood-based analyses of circulating cell-free DNA in xenografts EMBO Mol. Med. (IF 14.26) Pub Date : 2022-07-29 Isabel Heidrich, Klaus Pantel
The liquid biopsy concept has been introduced for circulating tumor cells more than 10 years ago (Pantel & Alix-Panabieres, 2010) and rapidly extended to cell-free DNA released from tumor cells (ctDNA; Lo et al, 2021) and other tumor-derived products such as circulating cell-free RNA (noncoding and messenger RNA), extracellular vesicles, or tumor-educated platelets (Alix-Panabières & Pantel, 2021)
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SARS-CoV-2 spike protein enhances MAP4K3/GLK-induced ACE2 stability in COVID-19 EMBO Mol. Med. (IF 14.26) Pub Date : 2022-07-27 Huai-Chia Chuang, Chia-Hsin Hsueh, Pu-Ming Hsu, Rou-Huei Huang, Ching-Yi Tsai, Nai-Hsiang Chung, Yen-Hung Chow, Tse-Hua Tan
ACE2 on epithelial cells is the SARS-CoV-2 entry receptor. Single-cell RNA-sequencing data derived from two COVID-19 cohorts revealed that MAP4K3/GLK-positive epithelial cells were increased in patients. SARS-CoV-2-induced GLK overexpression in epithelial cells was correlated with COVID-19 severity and vesicle secretion. GLK overexpression induced the epithelial cell-derived exosomes containing ACE2;
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Activation of the integrated stress response is a vulnerability for multidrug-resistant FBXW7-deficient cells EMBO Mol. Med. (IF 14.26) Pub Date : 2022-07-21 Laura Sanchez-Burgos, Belén Navarro-González, Santiago García-Martín, Oleksandra Sirozh, Jorge Mota-Pino, Elena Fueyo-Marcos, Héctor Tejero, Marta Elena Antón, Matilde Murga, Fátima Al-Shahrour, Oscar Fernandez-Capetillo
FBXW7 is one of the most frequently mutated tumor suppressors, deficiency of which has been associated with resistance to some anticancer therapies. Through bioinformatics and genome-wide CRISPR screens, we here reveal that FBXW7 deficiency leads to multidrug resistance (MDR). Proteomic analyses found an upregulation of mitochondrial factors as a hallmark of FBXW7 deficiency, which has been previously
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A type IV Autotaxin inhibitor ameliorates acute liver injury and nonalcoholic steatohepatitis EMBO Mol. Med. (IF 14.26) Pub Date : 2022-07-14 Richell Booijink, Fernando Salgado-Polo, Craig Jamieson, Anastassis Perrakis, Ruchi Bansal
The lysophosphatidic acid (LPA) signaling axis is an important but rather underexplored pathway in liver disease. LPA is predominantly produced by Autotaxin (ATX) that has gained significant attention with an impressive number of ATX inhibitors (type I-IV) reported. Here, we evaluated the therapeutic potential of a (yet unexplored) type IV inhibitor, Cpd17, in liver injury. We first confirmed the involvement
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Is there an unmet medical need for improved hearing restoration? EMBO Mol. Med. (IF 14.26) Pub Date : 2022-07-14 Bettina Julia Wolf, Kathrin Kusch, Victoria Hunniford, Barbara Vona, Robert Kühler, Daniel Keppeler, Nicola Strenzke, Tobias Moser
Hearing impairment, the most prevalent sensory deficit, affects more than 466 million people worldwide (WHO). We presently lack causative treatment for the most common form, sensorineural hearing impairment; hearing aids and cochlear implants (CI) remain the only means of hearing restoration. We engaged with CI users to learn about their expectations and their willingness to collaborate with health
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A novel platform for attenuating immune hyperactivity using EXO-CD24 in COVID-19 and beyond EMBO Mol. Med. (IF 14.26) Pub Date : 2022-07-13 Shiran Shapira, Marina Ben Shimon, Mori Hay-Levi, Gil Shenberg, Guy Choshen, Lian Bannon, Michael Tepper, Dina Kazanov, Jonathan Seni, Shahar Lev-Ari, Michael Peer, Dimitrios Boubas, Justin Stebbing, Sotirios Tsiodras, Nadir Arber
A small but significant proportion of COVID-19 patients develop life-threatening cytokine storm. We have developed a new anti-inflammatory drug, EXO-CD24, a combination of an immune checkpoint (CD24) and a delivery platform (exosomes). CD24 inhibits the NF-kB pathway and the production of cytokines/chemokines. EXO-CD24 discriminates damage-from pathogen-associated molecular patterns (DAMPs and PAMPs)
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Genetically modified macrophages accelerate myelin repair EMBO Mol. Med. (IF 14.26) Pub Date : 2022-07-13 Marie-Stéphane Aigrot, Clara Barthelemy, Sarah Moyon, Gaelle Dufayet-Chaffaud, Leire Izagirre-Urizar, Beatrix Gillet-Legrand, Satoru Tada, Laura Bayón-Cordero, Juan-Carlos Chara, Carlos Matute, Nathalie Cartier, Catherine Lubetzki, Vanja Tepavčević
Preventing neurodegeneration-associated disability progression in patients with multiple sclerosis (MS) remains an unmet therapeutic need. As remyelination prevents axonal degeneration, promoting this process in patients might enhance neuroprotection. In demyelinating mouse lesions, local overexpression of semaphorin 3F (Sema3F), an oligodendrocyte progenitor cell (OPC) attractant, increases remyelination
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Therapeutic application of PPE2 protein of Mycobacterium tuberculosis in inhibiting tissue inflammation EMBO Mol. Med. (IF 14.26) Pub Date : 2022-07-11 Ravi Pal, Madhu Babu Battu, Sangita Mukhopadhyay
There is an increasing need to develop biological anti-inflammatory agents that are more targeted, effective, and with lesser side effects as compared to conventional chemical drugs. In the present study, we found that Mycobacterium tuberculosis protein PPE2 and a synthetic derivative peptide can suppress the mast cell population and inhibit several vasoactive and fibrogenic mediators and pro-inflammatory
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Acyl-CoA:diacylglycerol acyltransferase: Properties, physiological roles, metabolic engineering and intentional control Prog. Lipid. Res. (IF 14.673) Pub Date : 2022-07-09 Guanqun Chen, John L. Harwood, M. Joanne Lemieux, Scot J. Stone, Randall J. Weselake
Acyl-CoA:diacylglycerol acyltransferase (DGAT, EC 2.3.1.20) catalyzes the last reaction in the acyl-CoA-dependent biosynthesis of triacylglycerol (TAG). DGAT activity resides mainly in membrane-bound DGAT1 and DGAT2 in eukaryotes and bifunctional wax ester synthase-diacylglycerol acyltransferase (WSD) in bacteria, which are all membrane-bound proteins but exhibit no sequence homology to each other
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Long non-coding RNA mediated drug resistance in breast cancer Drug Resist. Updat. (IF 22.841) Pub Date : 2022-07-03 Deepshikha Singh, Yehuda G. Assaraf, Rajesh N. Gacche
Breast cancer is one of the most prevalent cancers in women and a leading cause of mortality. As per the GLOBCAN report of 2021, breast cancer has surpassed lung cancer which until recently was the most commonly diagnosed cancer. Despite significant efforts to improve early detection and therapeutic efficacy of breast cancer, the frequent emergence of drug resistance remains the predominant basis for
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Understanding ER homeostasis and the UPR to enhance treatment efficacy of acute myeloid leukemia Drug Resist. Updat. (IF 22.841) Pub Date : 2022-07-08 Martyna Śniegocka, Francesca Liccardo, Francesco Fazi, Silvia Masciarelli
Protein biogenesis, maturation and degradation are tightly regulated processes that are governed by a complex network of signaling pathways. The endoplasmic reticulum (ER) is responsible for biosynthesis and maturation of secretory proteins. Circumstances that alter cellular protein homeostasis, determine accumulation of misfolded and unfolded proteins in the ER, a condition defined as ER stress. In
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Very long chain fatty acids Prog. Lipid. Res. (IF 14.673) Pub Date : 2022-07-08 Lucie Kyselová, Milada Vítová, Tomáš Řezanka
Very long chain fatty acids (VLCFAs) are important components of various lipid classes in most organisms, from bacteria to higher plants and mammals, including humans. VLCFAs, or very long chain polyunsaturated fatty acids (VLCPUFAs), can be defined as fatty acids with 23 or more carbon atoms in the molecule. The main emphasis in this review is on the analysis of these acids, including obtaining standards
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The strategic roles of four enzymes in the interconnection between metabolism and oncogene activation in non-small cell lung cancer: therapeutic implications Drug Resist. Updat. (IF 22.841) Pub Date : 2022-07-06 Philippe Icard, Luca Simula, Ludovic Fournel, Karen Leroy, Audrey Lupo, Diane Damotte, Marie Christine Charpentier, Catherine Durdux, Mauro Loi, Olivier Schussler, Guillaume Chassagnon, Antoine Coquerel, Hubert Lincet, Vincent De Pauw, Marco Alifano
NSCLC is the leading cause of cancer mortality and represents a major challenge in cancer therapy. Intrinsic and acquired anticancer drug resistance are promoted by hypoxia and HIF-1α. Moreover, chemoresistance is sustained by the activation of key signaling pathways (such as RAS and its well-known downstream targets PI3K/AKT and MAPK) and several mutated oncogenes (including KRAS and EGFR among others)
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Intestinal fatty acid binding protein: A rising therapeutic target in lipid metabolism Prog. Lipid. Res. (IF 14.673) Pub Date : 2022-06-30 Xi Huang, Youci Zhou, Yunwei Sun, Qijun Wang
Fatty acid binding proteins (FABPs) are key proteins in lipid transport, and the isoforms are segregated according to their tissue origins. Several isoforms, such as adipose-FABP and epidermal-FABP, have been shown to participate in multiple pathologic processes due to their ubiquitous expression. Intestinal fatty acid binding protein, also termed FABP2 or I-FABP, is specifically expressed in the small
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Multiscale lipid membrane dynamics as revealed by neutron spectroscopy Prog. Lipid. Res. (IF 14.673) Pub Date : 2022-06-30 V.K. Sharma, E. Mamontov
The plasma membrane is one of the principal structural components of the cell and, therefore, one of the key components of the cellular life. Because the membrane's dynamics links the membrane's structure and function, the complexity and the broad range of the membrane's motions are essential for the enormously diverse functionality of the cell membrane. Even for the main membrane component, the lipid
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Alteration of microbiota antibody-mediated immune selection contributes to dysbiosis in inflammatory bowel diseases EMBO Mol. Med. (IF 14.26) Pub Date : 2022-07-04 Eva Michaud, Louis Waeckel, Rémi Gayet, Roman Goguyer-Deschaumes, Blandine Chanut, Fabienne Jospin, Katell Bathany, Magali Monnoye, Coraline Genet, Amelie Prier, Caroline Tokarski, Philippe Gérard, Xavier Roblin, Nicolas Rochereau, Stéphane Paul
Human secretory immunoglobulins (SIg) A1 and SIgA2 guide mucosal responses toward tolerance or inflammation, notably through reverse-transcytosis, the apical-to-basal transport of IgA2 immune complexes via M cells of gut Peyer's patches. As such, the maintenance of a diverse gut microbiota requires broad affinity IgA and glycan–glycan interaction. Here, we asked whether IgA1 and IgA2-microbiota interactions
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Clinical grade ACE2 as a universal agent to block SARS-CoV-2 variants EMBO Mol. Med. (IF 14.26) Pub Date : 2022-07-04 Vanessa Monteil, Brett Eaton, Elena Postnikova, Michael Murphy, Benedict Braunsfeld, Ian Crozier, Franz Kricek, Janine Niederhöfer, Alice Schwarzböck, Helene Breid, Stephanie Devignot, Jonas Klingström, Charlotte Thålin, Max J Kellner, Wanda Christ, Sebastian Havervall, Stefan Mereiter, Sylvia Knapp, Anna Sanchez Jimenez, Agnes Bugajska-Schretter, Alexander Dohnal, Christine Ruf, Romana Gugenberger
The recent emergence of multiple SARS-CoV-2 variants has caused considerable concern due to both reduced vaccine efficacy and escape from neutralizing antibody therapeutics. It is, therefore, paramount to develop therapeutic strategies that inhibit all known and future SARS-CoV-2 variants. Here, we report that all SARS-CoV-2 variants analyzed, including variants of concern (VOC) Alpha, Beta, Gamma
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Spleen tyrosine kinase mediates innate and adaptive immune crosstalk in SARS-CoV-2 mRNA vaccination EMBO Mol. Med. (IF 14.26) Pub Date : 2022-07-04 Sebastian J Theobald, Alexander Simonis, Julie M Mudler, Ulrike Göbel, Richard Acton, Viktoria Kohlhas, Marie-Christine Albert, Anna-Maria Hellmann, Jakob J Malin, Sandra Winter, Michael Hallek, Henning Walczak, Phuong-Hien Nguyen, Manuel Koch, Jan Rybniker
Durable cell-mediated immune responses require efficient innate immune signaling and the release of pro-inflammatory cytokines. How precisely mRNA vaccines trigger innate immune cells for shaping antigen specific adaptive immunity remains unknown. Here, we show that SARS-CoV-2 mRNA vaccination primes human monocyte-derived macrophages for activation of the NLRP3 inflammasome. Spike protein exposed
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Single-cell transcriptomics reveals a senescence-associated IL-6/CCR6 axis driving radiodermatitis EMBO Mol. Med. (IF 14.26) Pub Date : 2022-07-04 Mor Paldor, Orr Levkovitch-Siany, Dana Eidelshtein, Revital Adar, Claes D Enk, Yitzhak Marmary, Sharona Elgavish, Yuval Nevo, Hadar Benyamini, Inbar Plaschkes, Shiri Klein, Alex Mali, Stefan Rose-John, Amnon Peled, Eithan Galun, Jonathan H Axelrod
Irradiation-induced alopecia and dermatitis (IRIAD) are two of the most visually recognized complications of radiotherapy, of which the molecular and cellular basis remains largely unclear. By combining scRNA-seq analysis of whole skin-derived irradiated cells with genetic ablation and molecular inhibition studies, we show that senescence-associated IL-6 and IL-1 signaling, together with IL-17 upregulation
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New insights into antiangiogenic therapy resistance in cancer: Mechanisms and therapeutic aspects Drug Resist. Updat. (IF 22.841) Pub Date : 2022-06-30 Maohua Huang, Yuning Lin, Chenran Wang, Lijuan Deng, Minfeng Chen, Yehuda G. Assaraf, Zhe-Sheng Chen, Wencai Ye, Dongmei Zhang
Angiogenesis is a hallmark of cancer and is required for tumor growth and progression. Antiangiogenic therapy has been revolutionarily developing and was approved for the treatment of various types of cancer for nearly two decades, among which bevacizumab and sorafenib continue to be the two most frequently used antiangiogenic drugs. Although antiangiogenic therapy has brought substantial survival
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Challenges and opportunities for prevention and removal of unwanted variation in lipidomic studies Prog. Lipid. Res. (IF 14.673) Pub Date : 2022-06-30 Gavriel Olshansky, Corey Giles, Agus Salim, Peter J. Meikle
Large ‘omics studies are of particular interest to population and clinical research as they allow elucidation of biological pathways that are often out of reach of other methodologies. Typically, these information rich datasets are produced from multiple coordinated profiling studies that may include lipidomics, metabolomics, proteomics or other strategies to generate high dimensional data. In lipidomics
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Strengthening vaccines and medicines manufacturing capabilities in Africa: challenges and perspectives EMBO Mol. Med. (IF 14.26) Pub Date : 2022-06-27 AbdulRahman A Saied, Asmaa A Metwally, Manish Dhawan, Om Prakash Choudhary, Hani Aiash
Africa carries a high burden of infectious diseases. Every year, millions of Africans contract tuberculosis, malaria, and many other diseases. Malaria kills hundreds of thousands of children under the age of five years annually. More than 11,000 people died during the 2014–2016 Ebola outbreak in West Africa; still, occasional cases of Ebola, as well as monkeypox, periodically appear in the Democratic
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Systemically targeted cancer immunotherapy and gene delivery using transmorphic particles EMBO Mol. Med. (IF 14.26) Pub Date : 2022-06-27 Paladd Asavarut, Sajee Waramit, Keittisak Suwan, Gert J K Marais, Aitthiphon Chongchai, Surachet Benjathummarak, Mariam Al-Bahrani, Paula Vila-Gomez, Matthew Williams, Prachya Kongtawelert, Teerapong Yata, Amin Hajitou
Immunotherapy is a powerful tool for cancer treatment, but the pleiotropic nature of cytokines and immunological agents strongly limits clinical translation and safety. To address this unmet need, we designed and characterised a systemically targeted cytokine gene delivery system through transmorphic encapsidation of human recombinant adeno-associated virus DNA using coat proteins from a tumour-targeted
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Longitudinal monitoring of disease burden and response using ctDNA from dried blood spots in xenograft models EMBO Mol. Med. (IF 14.26) Pub Date : 2022-06-13 Carolin M Sauer, Katrin Heider, Jelena Belic, Samantha E Boyle, James A Hall, Dominique-Laurent Couturier, Angela An, Aadhitthya Vijayaraghavan, Marika AV Reinius, Karen Hosking, Maria Vias, Nitzan Rosenfeld, James D Brenton
Whole-genome sequencing (WGS) of circulating tumour DNA (ctDNA) is now a clinically important biomarker for predicting therapy response, disease burden and disease progression. However, the translation of ctDNA monitoring into vital preclinical PDX models has not been possible owing to low circulating blood volumes in small rodents. Here, we describe the longitudinal detection and monitoring of ctDNA
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Functional divergence of the two Elongator subcomplexes during neurodevelopment EMBO Mol. Med. (IF 14.26) Pub Date : 2022-06-13 Monika Gaik, Marija Kojic, Megan R Stegeman, Tülay Öncü-Öner, Anna Kościelniak, Alun Jones, Ahmed Mohamed, Pak Yan Stefanie Chau, Sazia Sharmin, Andrzej Chramiec-Głąbik, Paulina Indyka, Michał Rawski, Anna Biela, Dominika Dobosz, Amanda Millar, Vann Chau, Aycan Ünalp, Michael Piper, Mark C Bellingham, Evan E Eichler, Deborah A Nickerson, Handan Güleryüz, Nour El Hana Abbassi, Konrad Jazgar, Melissa
The highly conserved Elongator complex is a translational regulator that plays a critical role in neurodevelopment, neurological diseases, and brain tumors. Numerous clinically relevant variants have been reported in the catalytic Elp123 subcomplex, while no missense mutations in the accessory subcomplex Elp456 have been described. Here, we identify ELP4 and ELP6 variants in patients with developmental
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The onset of PI3K-related vascular malformations occurs during angiogenesis and is prevented by the AKT inhibitor miransertib EMBO Mol. Med. (IF 14.26) Pub Date : 2022-06-13 Piotr Kobialka, Helena Sabata, Odena Vilalta, Leonor Gouveia, Ana Angulo-Urarte, Laia Muixí, Jasmina Zanoncello, Oscar Muñoz-Aznar, Nagore G Olaciregui, Lucia Fanlo, Anna Esteve-Codina, Cinzia Lavarino, Biola M Javierre, Veronica Celis, Carlota Rovira, Susana López-Fernández, Eulàlia Baselga, Jaume Mora, Sandra D Castillo, Mariona Graupera
Low-flow vascular malformations are congenital overgrowths composed of abnormal blood vessels potentially causing pain, bleeding and obstruction of different organs. These diseases are caused by oncogenic mutations in the endothelium, which result in overactivation of the PI3K/AKT pathway. Lack of robust in vivo preclinical data has prevented the development and translation into clinical trials of
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Targeting the Leukemic stem cell protein machinery by inhibition of mitochondrial pyrimidine synthesis EMBO Mol. Med. (IF 14.26) Pub Date : 2022-06-13 Elisa Donato, Andreas Trumpp
Acute Myeloid Leukemia is one of the most aggressive blood cancers with a high frequency of relapse. While standard chemotherapy is able to target rapidly proliferating immature blasts, it fails to eradicate slowly proliferating Leukemic Stem Cells. Therefore, new therapeutic strategies that efficiently target LSCs are urgently needed. Recent studies suggest that LSCs have particular metabolic vulnerabilities
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Mitochondrial HSF1 triggers mitochondrial dysfunction and neurodegeneration in Huntington's disease EMBO Mol. Med. (IF 14.26) Pub Date : 2022-06-07 Chunyue Liu, Zixing Fu, Shanshan Wu, Xiaosong Wang, Shengrong Zhang, Chu Chu, Yuan Hong, Wenbo Wu, Shengqi Chen, Yueqing Jiang, Yang Wu, Yongbo Song, Yan Liu, Xing Guo
Aberrant localization of proteins to mitochondria disturbs mitochondrial function and contributes to the pathogenesis of Huntington’s disease (HD). However, the crucial factors and the molecular mechanisms remain elusive. Here, we found that heat shock transcription factor 1 (HSF1) accumulates in the mitochondria of HD cell models, a YAC128 mouse model, and human striatal organoids derived from HD
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Understanding the nitrolipidome: From chemistry to mass spectrometry and biological significance of modified complex lipids Prog. Lipid. Res. (IF 14.673) Pub Date : 2022-05-27 Bruna Neves, Dolores Pérez-Sala, Helena Beatriz Ferreira, Inês M.S. Guerra, Ana S.P. Moreira, Pedro Domingues, M. Rosário Domingues, Tânia Melo
Complex lipids, phospholipids (PLs) and triacylglycerides (TAGs), are prone to modifications induced by reactive nitrated species and reactive oxygen species, generating a range of nitrated, nitrosated or nitroxidized derivatives, as nitro PLs and nitro TAGs. These modified lipids (epilipids) have been reported in vitro and in vivo using lipidomics approaches. However, their detection in living systems
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Biological foundations of successful bacteriophage therapy EMBO Mol. Med. (IF 14.26) Pub Date : 2022-05-27 Carola Venturini, Aleksandra Petrovic Fabijan, Alicia Fajardo Lubian, Stefanie Barbirz, Jonathan Iredell
Bacteriophages (phages) are selective viral predators of bacteria. Abundant and ubiquitous in nature, phages can be used to treat bacterial infections (phage therapy), including refractory infections and those resistant to antibiotics. However, despite an abundance of anecdotal evidence of efficacy, significant hurdles remain before routine implementation of phage therapy into medical practice, including
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Sigma-1 receptor attenuates osteoclastogenesis by promoting ER-associated degradation of SERCA2 EMBO Mol. Med. (IF 14.26) Pub Date : 2022-05-25 Xiaoan Wei, Zeyu Zheng, Zhenhua Feng, Lin Zheng, Siyue Tao, Bingjie Zheng, Bao Huang, Xuyang Zhang, Junhui Liu, Yilei Chen, Wentian Zong, Zhi Shan, Shunwu Fan, Jian Chen, Fengdong Zhao
Sigma-1 receptor (Sigmar1) is a specific chaperone located in the mitochondria-associated endoplasmic reticulum membrane (MAM) and plays a role in several physiological processes. However, the role of Sigmar1 in bone homeostasis remains unknown. Here, we show that mice lacking Sigmar1 exhibited severe osteoporosis in an ovariectomized model. In contrast, overexpression of Sigmar1 locally alleviated
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Olverembatinib inhibits SARS-CoV-2-Omicron variant-mediated cytokine release in human peripheral blood mononuclear cells. EMBO Mol. Med. (IF 14.26) Pub Date : 2022-05-17 Marina Chan,Eric C Holland,Taranjit S Gujral
The N-terminus domain (NTD) of the SARS-CoV-2 Omicron variant spike protien strongly induces multiple inflammatory molecules in human peripheral blood mononuclear cells, unaffected by the mutations observed in the NTD. Olverembatinib, a clinical-stage multi-kinase inhibitor, potently inhibits Omicron NTD-mediated cytokine release.
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ASC nanobodies to counteract the consequences of inflammasome activation EMBO Mol. Med. (IF 14.26) Pub Date : 2022-05-16 Sahil Adriouch, Pablo Pelegrin
Inflammasomes are multiprotein complexes that signal by oligomerizing the apoptosis speck-like protein with caspase recruitment and activator domain (ASC) and are involved in multiple inflammatory, metabolic and degenerative diseases. Pharmacological targeting of specific inflammasomes with small molecules is leading to the development of novel drugs for most common diseases. The targeting of ASC oligomers
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The constellation of cholesterol-dependent processes associated with SARS-CoV-2 infection Prog. Lipid. Res. (IF 14.673) Pub Date : 2022-05-02 Francisco J. Barrantes
The role of cholesterol in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other coronavirus-host cell interactions is currently being discussed in the context of two main scenarios: i) the presence of the neutral lipid in cholesterol-rich lipid domains involved in different steps of the viral infection and ii) the alteration of metabolic pathways by the virus over the course of infection
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Inhibition of pyrimidine biosynthesis targets protein translation in acute myeloid leukemia EMBO Mol. Med. (IF 14.26) Pub Date : 2022-05-06 Joan So, Alexander C Lewis, Lorey K Smith, Kym Stanley, Rheana Franich, David Yoannidis, Lizzy Pijpers, Pilar Dominguez, Simon J Hogg, Stephin J Vervoort, Fiona C Brown, Ricky W Johnstone, Gabrielle McDonald, Danielle B Ulanet, Josh Murtie, Emily Gruber, Lev M Kats
The mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) catalyzes one of the rate-limiting steps in de novo pyrimidine biosynthesis, a pathway that provides essential metabolic precursors for nucleic acids, glycoproteins, and phospholipids. DHODH inhibitors (DHODHi) are clinically used for autoimmune diseases and are emerging as a novel class of anticancer agents, especially in acute myeloid
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A preclinical model of peripheral T-cell lymphoma GATA3 reveals DNA damage response pathway vulnerability EMBO Mol. Med. (IF 14.26) Pub Date : 2022-05-05 Elizabeth A Kuczynski, Giulia Morlino, Alison Peter, Anna M L Coenen-Stass, Jennifer I Moss, Neha Wali, Oona Delpuech, Avinash Reddy, Anisha Solanki, Charles Sinclair, Dinis P Calado, Larissa S Carnevalli
Peripheral T-cell lymphoma (PTCL) represents a rare group of heterogeneous diseases in urgent need of effective treatments. A scarcity of disease-relevant preclinical models hinders research advances. Here, we isolated a novel mouse (m)PTCL by serially transplanting a lymphoma from a germinal center B-cell hyperplasia model (Cγ1-Cre Blimp1fl/fl) through immune-competent mice. Lymphoma cells were identified
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Feed-forward loops between metastatic cancer cells and their microenvironment—the stage of escalation EMBO Mol. Med. (IF 14.26) Pub Date : 2022-05-04 Zora Baumann, Priska Auf der Maur, Mohamed Bentires-Alj
Breast cancer is the most frequent cancer among women, and metastases in distant organs are the leading cause of the cancer-related deaths. While survival of early-stage breast cancer patients has increased dramatically, the 5-year survival rate of metastatic patients has barely improved in the last 20 years. Metastases can arise up to decades after primary tumor resection, hinting at microenvironmental
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Polyunsaturated fatty acids and fatty acid-derived lipid mediators: Recent advances in the understanding of their biosynthesis, structures, and functions Prog. Lipid. Res. (IF 14.673) Pub Date : 2022-05-01 Simon C. Dyall, Laurence Balas, Nicolas G. Bazan, J. Thomas Brenna, Nan Chiang, Felipe da Costa Souza, Jesmond Dalli, Thierry Durand, Jean-Marie Galano, Pamela J. Lein, Charles N. Serhan, Ameer Y. Taha
Polyunsaturated fatty acids (PUFAs) are structural components of membrane phospholipids, and influence cellular function via effects on membrane properties, and also by acting as a precursor pool for lipid mediators. These lipid mediators are formed via activation of pathways involving at least one step of dioxygen-dependent oxidation, and are consequently called oxylipins. Their biosynthesis can be
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Selenium and tellurium in the development of novel small molecules and nanoparticles as cancer multidrug resistance reversal agents Drug Resist. Updat. (IF 22.841) Pub Date : 2022-05-02 Enrique Domínguez-Álvarez, Bálint Rácz, Małgorzata Anna Marć, Muhammad Jawad Nasim, Nikoletta Szemerédi, Jitka Viktorová, Claus Jacob, Gabriella Spengler
Selenium is an essential trace element that is crucial for cellular antioxidant defense against reactive oxygen species (ROS). Recently, many selenium-containing compounds have exhibited a wide spectrum of biological activities that make them promising scaffolds in Medicinal Chemistry, and, in particular, in the search for novel compounds with anticancer activity. Similarly, certain tellurium-containing
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Liver gene therapy with intein-mediated F8 trans-splicing corrects mouse haemophilia A EMBO Mol. Med. (IF 14.26) Pub Date : 2022-05-02 Federica Esposito, Hristiana Lyubenova, Patrizia Tornabene, Stefano Auricchio, Antonella Iuliano, Edoardo Nusco, Simone Merlin, Cristina Olgasi, Giorgia Manni, Marco Gargaro, Francesca Fallarino, Antonia Follenzi, Alberto Auricchio
Liver gene therapy with adeno-associated viral (AAV) vectors is under clinical investigation for haemophilia A (HemA), the most common inherited X-linked bleeding disorder. Major limitations are the large size of the F8 transgene, which makes packaging in a single AAV vector a challenge, as well as the development of circulating anti-F8 antibodies which neutralise F8 activity. Taking advantage of
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Caspase-8 in endothelial cells maintains gut homeostasis and prevents small bowel inflammation in mice EMBO Mol. Med. (IF 14.26) Pub Date : 2022-05-02 Nathalie Tisch, Carolin Mogler, Ana Stojanovic, Robert Luck, Emilia A Korhonen, Alexander Ellerkmann, Heike Adler, Mahak Singhal, Géza Schermann, Lena Erkert, Jay V Patankar, Andromachi Karakatsani, Anna-Lena Scherr, Yaron Fuchs, Adelheid Cerwenka, Stefan Wirtz, Bruno Christian Köhler, Hellmut G Augustin, Christoph Becker, Thomas Schmidt, Carmen Ruiz de Almodóvar
The gut has a specific vascular barrier that controls trafficking of antigens and microbiota into the bloodstream. However, the molecular mechanisms regulating the maintenance of this vascular barrier remain elusive. Here, we identified Caspase-8 as a pro-survival factor in mature intestinal endothelial cells that is required to actively maintain vascular homeostasis in the small intestine in an organ-specific
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Nanobodies dismantle post-pyroptotic ASC specks and counteract inflammation in vivo EMBO Mol. Med. (IF 14.26) Pub Date : 2022-04-19 Damien Bertheloot, Carlos WS Wanderley, Ayda H Schneider, Lisa DJ Schiffelers, Jennifer D Wuerth, Jan MP Tödtmann, Salie Maasewerd, Ibrahim Hawwari, Fraser Duthie, Cornelia Rohland, Lucas S Ribeiro, Lea-Marie Jenster, Nathalia Rosero, Yonas M Tesfamariam, Fernando Q Cunha, Florian I Schmidt, Bernardo S Franklin
Inflammasomes sense intracellular clues of infection, damage, or metabolic imbalances. Activated inflammasome sensors polymerize the adaptor ASC into micron-sized “specks” to maximize caspase-1 activation and the maturation of IL-1 cytokines. Caspase-1 also drives pyroptosis, a lytic cell death characterized by leakage of intracellular content to the extracellular space. ASC specks are released among
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When fat meets the gut-focus on intestinal lipid handling in metabolic health and disease. EMBO Mol. Med. (IF 14.26) Pub Date : 2022-04-19 Magdalena Wit,Jonathan Trujillo-Viera,Akim Strohmeyer,Martin Klingenspor,Mohammed Hankir,Grzegorz Sumara
The regular overconsumption of energy-dense foods (rich in lipids and sugars) results in elevated intestinal nutrient absorption and consequently excessive accumulation of lipids in the liver, adipose tissue, skeletal muscles, and other organs. This can eventually lead to obesity and obesity-associated diseases such as type 2 diabetes (T2D), non-alcoholic fatty liver disease (NAFLD), cardiovascular
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BNT162b2 vaccine induces antibody release in saliva: a possible role for mucosal viral protection? EMBO Mol. Med. (IF 14.26) Pub Date : 2022-04-19 Abbass Darwich,Chiara Pozzi,Giulia Fornasa,Michela Lizier,Elena Azzolini,Ilaria Spadoni,Francesco Carli,Antonio Voza,Antonio Desai,Carlo Ferrero,Luca Germagnoli,,Alberto Mantovani,Maria Rescigno
Vaccination against an airborne pathogen is very effective if it induces also the development of mucosal antibodies that can protect against infection. The mRNA-based vaccine-encoding SARS-CoV-2 full-length spike protein (BNT162b2, Pfizer/BioNTech) protects also against infection despite being administered systemically. Here, we show that upon vaccination, cognate IgG molecules are also found in the
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Clinical implications of germline variations for treatment outcome and drug resistance for small molecule kinase inhibitors in patients with non-small cell lung cancer Drug Resist. Updat. (IF 22.841) Pub Date : 2022-04-05 Niels Heersche, G.D. Marijn Veerman, Mirjam de With, Sander Bins, Yehuda G. Assaraf, Anne-Marie C. Dingemans, Ron H.N. van Schaik, Ron H.J. Mathijssen, Frank G.A. Jansman
Small-molecule kinase inhibitors (SMKIs) represent the cornerstone in the treatment of non-small cell lung cancer (NSCLC) patients harboring genetic driver mutations. Because of the introduction of SMKIs in the last decades, treatment outcomes have drastically improved. Their treatment efficacy, the development of drug resistance as well as untoward toxicity, all suffer from large patient variability
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The role of extracellular vesicles in the transfer of drug resistance competences to cancer cells Drug Resist. Updat. (IF 22.841) Pub Date : 2022-04-05 Cristina P.R. Xavier, Dimas Carolina Belisario, Rita Rebelo, Yehuda G. Assaraf, Elisa Giovannetti, Joanna Kopecka, M. Helena Vasconcelos
Drug resistance remains a major hurdle to successful cancer treatment, being accountable for approximately 90% of cancer-related deaths. In the past years, increasing attention has been given to the role of extracellular vesicles (EVs) in the horizontal transfer of drug resistance in cancer. Indeed, many studies have described the dissemination of therapy resistance traits mediated by EVs, which may
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Revolutionizing non-conventional wound healing using honey by simultaneously targeting multiple molecular mechanisms Drug Resist. Updat. (IF 22.841) Pub Date : 2022-04-05 Carlos C.F. Pleeging, Frank A.D.T.G. Wagener, Hilde de Rooster, Niels A.J. Cremers
Hospital-acquired infections and treatment-related wound complications constitute a tremendous burden for the health care system, particularly given the serious increase in multidrug resistant pathogens. Imagine that a large part of nosocomial infections can be prevented using a simple treatment. In this respect, honey is used mainly in topical cutaneous wound care because of its potent broad-spectrum
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Genetic variation and intestinal cholesterol absorption in humans: A systematic review and a gene network analysis Prog. Lipid. Res. (IF 14.673) Pub Date : 2022-04-04 Fatma B.A. Mokhtar, Jogchum Plat, Ronald P. Mensink
Intestinal cholesterol absorption varies widely between individuals, which may translate into differences in responsiveness to cholesterol-lowering drugs or diets. Therefore, understanding the importance of genetic variation on cholesterol absorption rates and the complex intestinal cholesterol network is important. Based on a systematic review, genetic variants in seven genes (ABCG5, ABCG8, ABO, APOE
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AAV-delivered diacylglycerol kinase DGKk achieves long-term rescue of fragile X syndrome mouse model. EMBO Mol. Med. (IF 14.26) Pub Date : 2022-04-04 Karima Habbas,Oktay Cakil,Boglárka Zámbó,Ricardos Tabet,Fabrice Riet,Doulaye Dembele,Jean-Louis Mandel,Michaël Hocquemiller,Ralph Laufer,Françoise Piguet,Hervé Moine
Fragile X syndrome (FXS) is the most frequent form of familial intellectual disability. FXS results from the lack of the RNA-binding protein FMRP and is associated with the deregulation of signaling pathways downstream of mGluRI receptors and upstream of mRNA translation. We previously found that diacylglycerol kinase kappa (DGKk), a main mRNA target of FMRP in cortical neurons and a master regulator
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The HSP40 chaperone Ydj1 drives amyloid beta 42 toxicity. EMBO Mol. Med. (IF 14.26) Pub Date : 2022-04-04 Julia Ring,Jelena Tadic,Selena Ristic,Michael Poglitsch,Martina Bergmann,Nemanja Radic,Dirk Mossmann,YongTian Liang,Marta Maglione,Andrea Jerkovic,Roozbeh Hajiraissi,Marcel Hanke,Victoria Küttner,Heimo Wolinski,Andreas Zimmermann,Lana Domuz Trifunović,Leonie Mikolasch,Daiana N Moretti,Filomena Broeskamp,Julia Westermayer,Claudia Abraham,Simon Schauer,Christopher Dammbrueck,Sebastian J Hofer,Mahmoud
Amyloid beta 42 (Abeta42) is the principal trigger of neurodegeneration during Alzheimer's disease (AD). However, the etiology of its noxious cellular effects remains elusive. In a combinatory genetic and proteomic approach using a yeast model to study aspects of intracellular Abeta42 toxicity, we here identify the HSP40 family member Ydj1, the yeast orthologue of human DnaJA1, as a crucial factor
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Parkinson's disease motor symptoms rescue by CRISPRa-reprogramming astrocytes into GABAergic neurons. EMBO Mol. Med. (IF 14.26) Pub Date : 2022-04-04 Jessica Giehrl-Schwab,Florian Giesert,Benedict Rauser,Chu Lan Lao,Sina Hembach,Sandrine Lefort,Ignacio L Ibarra,Christina Koupourtidou,Malte Daniel Luecken,Dong-Jiunn Jeffery Truong,Judith Fischer-Sternjak,Giacomo Masserdotti,Nilima Prakash,Jovica Ninkovic,Sabine M Hölter,Daniela M Vogt Weisenhorn,Fabian J Theis,Magdalena Götz,Wolfgang Wurst
Direct reprogramming based on genetic factors resembles a promising strategy to replace lost cells in degenerative diseases such as Parkinson's disease. For this, we developed a knock-in mouse line carrying a dual dCas9 transactivator system (dCAM) allowing the conditional in vivo activation of endogenous genes. To enable a translational application, we additionally established an AAV-based strategy