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C5aR plus MEK inhibition durably targets the tumor milieu and reveals tumor cell phagocytosis. Life Sci. Alliance (IF 4.4) Pub Date : 2024-03-08 Melissa R Perrino, Niousha Ahmari, Ashley Hall, Mark Jackson, Youjin Na, Jay Pundavela, Sara Szabo, Trent M Woodruff, Eva Dombi, Mi-Ok Kim, Jörg Köhl, Jianqiang Wu, Nancy Ratner
Plexiform neurofibromas (PNFs) are nerve tumors caused by loss of NF1 and dysregulation of RAS-MAPK signaling in Schwann cells. Most PNFs shrink in response to MEK inhibition, but targets with increased and durable effects are needed. We identified the anaphylatoxin C5a as increased in PNFs and expressed largely by PNF m acrophages. We defined pharmacokinetic and immunomodulatory properties of a C5aR1/2
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Altered myocardial lipid regulation in junctophilin-2-associated familial cardiomyopathies. Life Sci. Alliance (IF 4.4) Pub Date : 2024-03-04 Satadru K Lahiri, Feng Jin, Yue Zhou, Ann P Quick, Carlos F Kramm, Meng C Wang, Xander Ht Wehrens
Myocardial lipid metabolism is critical to normal heart function, whereas altered lipid regulation has been linked to cardiac diseases including cardiomyopathies. Genetic variants in the JPH2 gene can cause hypertrophic cardiomyopathy (HCM) and, in some cases, dilated cardiomyopathy (DCM). In this study, we tested the hypothesis that JPH2 variants identified in patients with HCM and DCM, respectively
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Pip5k1γ regulates axon formation by limiting Rap1 activity. Life Sci. Alliance (IF 4.4) Pub Date : 2024-03-04 Danila Di Meo, Trisha Kundu, Priyadarshini Ravindran, Bhavin Shah, Andreas W Püschel
During their differentiation, neurons establish a highly polarized morphology by forming axons and dendrites. Cortical and hippocampal neurons initially extend several short neurites that all have the potential to become an axon. One of these neurites is then selected as the axon by a combination of positive and negative feedback signals that promote axon formation and prevent the remaining neurites
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A comparative study of structural variant calling in WGS from Alzheimer's disease families. Life Sci. Alliance (IF 4.4) Pub Date : 2024-02-28 John S Malamon, John J Farrell, Li Charlie Xia, Beth A Dombroski, Rueben G Das, Jessica Way, Amanda B Kuzma, Otto Valladares, Yuk Yee Leung, Allison J Scanlon, Irving Antonio Barrera Lopez, Jack Brehony, Kim C Worley, Nancy R Zhang, Li-San Wang, Lindsay A Farrer, Gerard D Schellenberg, Wan-Ping Lee, Badri N Vardarajan
Detecting structural variants (SVs) in whole-genome sequencing poses significant challenges. We present a protocol for variant calling, merging, genotyping, sensitivity analysis, and laboratory validation for generating a high-quality SV call set in whole-genome sequencing from the Alzheimer's Disease Sequencing Project comprising 578 individuals from 111 families. Employing two complementary pipelines
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Stable structures or PABP1 loading protects cellular and viral RNAs against ISG20-mediated decay. Life Sci. Alliance (IF 4.4) Pub Date : 2024-02-28 Camille Louvat, Séverine Deymier, Xuan-Nhi Nguyen, Emmanuel Labaronne, Kodie Noy, Marie Cariou, Antoine Corbin, Mathieu Mateo, Emiliano P Ricci, Francesca Fiorini, Andrea Cimarelli
ISG20 is an IFN-induced 3'-5' RNA exonuclease that acts as a broad antiviral factor. At present, the features that expose RNA to ISG20 remain unclear, although recent studies have pointed to the modulatory role of epitranscriptomic modifications in the susceptibility of target RNAs to ISG20. These findings raise the question as to how cellular RNAs, on which these modifications are abundant, cope with
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Lipotype acquisition during neural development is not recapitulated in stem cell-derived neurons. Life Sci. Alliance (IF 4.4) Pub Date : 2024-02-28 Anusha B Gopalan, Lisa van Uden, Richard R Sprenger, Nadine Fernandez-Novel Marx, Helle Bogetofte, Pierre A Neveu, Morten Meyer, Kyung-Min Noh, Alba Diz-Muñoz, Christer S Ejsing
During development, different tissues acquire distinct lipotypes that are coupled to tissue function and homeostasis. In the brain, where complex membrane trafficking systems are required for neural function, specific glycerophospholipids, sphingolipids, and cholesterol are highly abundant, and defective lipid metabolism is associated with abnormal neural development and neurodegenerative disease.
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Metabolic and circadian inputs encode anticipatory biogenesis of hepatic fed microRNAs. Life Sci. Alliance (IF 4.4) Pub Date : 2024-02-26 Sandra Usha Satheesan, Shreyam Chowdhury, Ullas Kolthur-Seetharam
Starvation and refeeding are mostly unanticipated in the wild in terms of duration, frequency, and nutritional value of the refed state. Notwithstanding this, organisms mount efficient and reproducible responses to restore metabolic homeostasis. Hence, it is intuitive to invoke expectant molecular mechanisms that build anticipatory responses to enable physiological toggling during fed-fast cycles.
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Galectin-8 modulates human osteoclast activity partly through isoform-specific interactions. Life Sci. Alliance (IF 4.4) Pub Date : 2024-02-23 Michèle Roy, Léopold Mbous Nguimbus, Papa Yaya Badiane, Victor Goguen-Couture, Jade Degrandmaison, Jean-Luc Parent, Marie A Brunet, Sophie Roux
In overactive human osteoclasts, we previously identified an alternative splicing event in LGALS8, encoding galectin-8, resulting in decreased expression of the long isoform. Galectin-8, which modulates cell-matrix interactions and functions intracellularly as a danger recognition receptor, has never been associated with osteoclast biology. In human osteoclasts, inhibition of galectin-8 expression
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Cholesterol and COVID-19-therapeutic opportunities at the host/virus interface during cell entry. Life Sci. Alliance (IF 4.4) Pub Date : 2024-02-22 Thomas Grewal, Mai Khanh Linh Nguyen, Christa Buechler
The rapid development of vaccines to combat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections has been critical to reduce the severity of COVID-19. However, the continuous emergence of new SARS-CoV-2 subtypes highlights the need to develop additional approaches that oppose viral infections. Targeting host factors that support virus entry, replication, and propagation provide opportunities
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SHIP1 deficiency causes inflammation-dependent retardation in skeletal growth. Life Sci. Alliance (IF 4.4) Pub Date : 2024-02-22 Fatemeh Safari, Wen Jie Yeoh, Saskia Perret-Gentil, Frank Klenke, Silvia Dolder, Willy Hofstetter, Philippe Krebs
Inflammation and skeletal homeostasis are closely intertwined. Inflammatory diseases are associated with local and systemic bone loss, and post-menopausal osteoporosis is linked to low-level chronic inflammation. Phosphoinositide-3-kinase signalling is a pivotal pathway modulating immune responses and controlling skeletal health. Mice deficient in Src homology 2-containing inositol phosphatase 1 (SHIP1)
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Breast implant surface topography triggers a chronic-like inflammatory response. Life Sci. Alliance (IF 4.4) Pub Date : 2024-02-21 Valeriano Vinci, Cristina Belgiovine, Gerardus Janszen, Benedetta Agnelli, Luca Pellegrino, Francesca Calcaterra, Assunta Cancellara, Roberta Ciceri, Alessandra Benedetti, Cindy Cardenas, Federico Colombo, Domenico Supino, Alessia Lozito, Edoardo Caimi, Marta Monari, Francesco Maria Klinger, Giovanna Riccipetitoni, Alessandro Raffaele, Patrizia Comoli, Paola Allavena, Domenico Mavilio, Luca Di Landro
Breast implants are extensively employed for both reconstructive and esthetic purposes. However, the safety of breast implants with textured surfaces has been questioned, owing to a potential correlation with anaplastic large-cell lymphoma and the recurrence of breast cancer. This study investigates the immune response elicited by different prosthetic surfaces, focusing on the comparison between macrotextured
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Ageing-dependent thiol oxidation reveals early oxidation of proteins with core proteostasis functions. Life Sci. Alliance (IF 4.4) Pub Date : 2024-02-21 Katarzyna Jonak, Ida Suppanz, Julian Bender, Agnieszka Chacinska, Bettina Warscheid, Ulrike Topf
Oxidative post-translational modifications of protein thiols are well recognized as a readily occurring alteration of proteins, which can modify their function and thus control cellular processes. The development of techniques enabling the site-specific assessment of protein thiol oxidation on a proteome-wide scale significantly expanded the number of known oxidation-sensitive protein thiols. However
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The RNA-binding protein Msi2 regulates autophagy during myogenic differentiation. Life Sci. Alliance (IF 4.4) Pub Date : 2024-02-19 Ruochong Wang, Futaba Kato, Rio Yasui Watson, Aaron M Beedle, Jarrod A Call, Yugo Tsunoda, Takeshi Noda, Takaho Tsuchiya, Makoto Kashima, Ayuna Hattori, Takahiro Ito
Skeletal muscle development is a highly ordered process orchestrated transcriptionally by the myogenic regulatory factors. However, the downstream molecular mechanisms of myogenic regulatory factor functions in myogenesis are not fully understood. Here, we identified the RNA-binding protein Musashi2 (Msi2) as a myogenin target gene and a post-transcriptional regulator of myoblast differentiation. Msi2
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IFT88 maintains sensory function by localising signalling proteins along Drosophila cilia. Life Sci. Alliance (IF 4.4) Pub Date : 2024-02-19 Sascha Werner, Pilar Okenve-Ramos, Philip Hehlert, Sihem Zitouni, Pranjali Priya, Susana Mendonça, Anje Sporbert, Christian Spalthoff, Martin C Göpfert, Swadhin Chandra Jana, Mónica Bettencourt-Dias
Ciliary defects cause several ciliopathies, some of which have late onset, suggesting cilia are actively maintained. Still, we have a poor understanding of the mechanisms underlying their maintenance. Here, we show Drosophila melanogaster IFT88 (DmIFT88/nompB) continues to move along fully formed sensory cilia. We further identify Inactive, a TRPV channel subunit involved in Drosophila hearing and
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Oxidative phosphorylation is a pivotal therapeutic target of fibrodysplasia ossificans progressiva. Life Sci. Alliance (IF 4.4) Pub Date : 2024-02-16 Liping Sun, Yonghui Jin, Megumi Nishio, Makoto Watanabe, Takeshi Kamakura, Sanae Nagata, Masayuki Fukuda, Hirotsugu Maekawa, Shunsuke Kawai, Takuya Yamamoto, Junya Toguchida
Heterotopic ossification (HO) is a non-physiological bone formation where soft tissue progenitor cells differentiate into chondrogenic cells. In fibrodysplasia ossificans progressiva (FOP), a rare genetic disease characterized by progressive and systemic HO, the Activin A/mutated ACVR1/mTORC1 cascade induces HO in progenitors in muscle tissues. The relevant biological processes aberrantly regulated
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Variety in the USP deubiquitinase catalytic mechanism. Life Sci. Alliance (IF 4.4) Pub Date : 2024-02-14 Niels Keijzer, Anu Priyanka, Yvette Stijf-Bultsma, Alexander Fish, Malte Gersch, Titia K Sixma
The ubiquitin-specific protease (USP) family of deubiquitinases (DUBs) controls cellular ubiquitin-dependent signaling events. This generates therapeutic potential, with active-site inhibitors in preclinical and clinical studies. Understanding of the USP active site is primarily guided by USP7 data, where the catalytic triad consists of cysteine, histidine, and a third residue (third critical residue)
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Apical dehydration impairs the cystic fibrosis airway epithelium barrier via a β1-integrin/YAP1 pathway. Life Sci. Alliance (IF 4.4) Pub Date : 2024-02-09 Juliette L Simonin, Caterina Tomba, Vincent Mercier, Marc Bacchetta, Tahir Idris, Mehdi Badaoui, Aurélien Roux, Marc Chanson
Defective hydration of airway surface mucosa is associated with lung infection in cystic fibrosis (CF), partly caused by disruption of the epithelial barrier integrity. Although rehydration of the CF airway surface liquid (ASL) alleviates epithelium vulnerability to infection by junctional protein expression, the mechanisms linking ASL to barrier integrity are unknown. We show here the strong degradation
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Epigenomic states contribute to coordinated allelic transcriptional bursting in iPSC reprogramming. Life Sci. Alliance (IF 4.4) Pub Date : 2024-02-06 Parichitran Ayyamperumal, Hemant Chandru Naik, Amlan Jyoti Naskar, Lakshmi Sowjanya Bammidi, Srimonta Gayen
Two alleles of a gene can be transcribed independently or coordinatedly, which can lead to temporal expression heterogeneity with potentially distinct impacts on cell fate. Here, we profiled genome-wide allelic transcriptional burst kinetics during the reprogramming of MEF to induced pluripotent stem cells. We show that the degree of coordination of allelic bursting differs among genes, and alleles
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Knockout of PA200 improves proteasomal degradation and myelination in a proteotoxic neuropathy. Life Sci. Alliance (IF 4.4) Pub Date : 2024-02-06 Jordan Js VerPlank, Joseph M Gawron, Nicholas J Silvestri, Lawrence Wrabetz, Maria Laura Feltri
The cellular response to a decrease in protein degradation by 26S proteasomes in chronic diseases is poorly understood. Pharmacological inhibition of proteasomes increases the expression of proteasome subunits and Proteasome Activator 200 (PA200), an alternative proteasome activator. In the S63del mouse model of the peripheral neuropathy Charcot Marie Tooth 1B (CMT1B), proteasomal protein degradation
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Stability of gut microbiome after COVID-19 vaccination in healthy and immuno-compromised individuals. Life Sci. Alliance (IF 4.4) Pub Date : 2024-02-05 Rebecca H Boston, Rui Guan, Lajos Kalmar, Sina Beier, Emily C Horner, Nonantzin Beristain-Covarrubias, Juan Carlos Yam-Puc, Pehuén Pereyra Gerber, Luisa Faria, Anna Kuroshchenkova, Anna E Lindell, Sonja Blasche, Andrea Correa-Noguera, Anne Elmer, Caroline Saunders, Areti Bermperi, Sherly Jose, Nathalie Kingston, , Sofia Grigoriadou, Emily Staples, Matthew S Buckland, Sara Lear, Nicholas J Matheson
Bidirectional interactions between the immune system and the gut microbiota are key contributors to various physiological functions. Immune-associated diseases such as cancer and autoimmunity, and efficacy of immunomodulatory therapies, have been linked to microbiome variation. Although COVID-19 infection has been shown to cause microbial dysbiosis, it remains understudied whether the inflammatory
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Genome-wide CRISPR screen reveals the synthetic lethality between BCL2L1 inhibition and radiotherapy. Life Sci. Alliance (IF 4.4) Pub Date : 2024-02-05 Ling Yin, Xiaoding Hu, Guangsheng Pei, Mengfan Tang, You Zhou, Huimin Zhang, Min Huang, Siting Li, Jie Zhang, Citu Citu, Zhongming Zhao, Bisrat G Debeb, Xu Feng, Junjie Chen
Radiation therapy (RT) is one of the most commonly used anticancer therapies. However, the landscape of cellular response to irradiation, especially to a single high-dose irradiation, remains largely unknown. In this study, we performed a whole-genome CRISPR loss-of-function screen and revealed temporal inherent and acquired responses to RT. Specifically, we found that loss of the IL1R1 pathway led
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Targeting circulating labile heme as a defense strategy against malaria. Life Sci. Alliance (IF 4.4) Pub Date : 2024-02-02 Susana Ramos, Viktoria Jeney, Ana Figueiredo, Tiago Paixão, Maria Rosário Sambo, Vatúsia Quinhentos, Rui Martins, Zélia Gouveia, Ana Rita Carlos, Ana Ferreira, Teresa F Pais, Hugo Lainé, Pedro Faísca, Sofia Rebelo, Silvia Cardoso, Emanuela Tolosano, Carlos Penha-Gonçalves, Miguel P Soares
Severe presentations of malaria emerge as Plasmodium (P.) spp. parasites invade and lyse red blood cells (RBC), producing extracellular hemoglobin (HB), from which labile heme is released. Here, we tested whether scavenging of extracellular HB and/or labile heme, by haptoglobin (HP) and/or hemopexin (HPX), respectively, counter the pathogenesis of severe presentations of malaria. We found that circulating
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Zebrafish tsc1 and cxcl12a increase susceptibility to mycobacterial infection. Life Sci. Alliance (IF 4.4) Pub Date : 2024-02-02 Kathryn Wright, Darryl Jy Han, Renhua Song, Kumudika de Silva, Karren M Plain, Auriol C Purdie, Ava Shepherd, Maegan Chin, Elinor Hortle, Justin J-L Wong, Warwick J Britton, Stefan H Oehlers
Regulation of host miRNA expression is a contested node that controls the host immune response to mycobacterial infection. The host must counter subversive efforts of pathogenic mycobacteria to launch a protective immune response. Here, we examine the role of miR-126 in the zebrafish-Mycobacterium marinum infection model and identify a protective role for infection-induced miR-126 through multiple
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Micronucleus is not a potent inducer of the cGAS/STING pathway. Life Sci. Alliance (IF 4.4) Pub Date : 2024-02-02 Yuki Sato, Makoto T Hayashi
Micronuclei (MN) have been associated with the innate immune response. The abrupt rupture of MN membranes results in the accumulation of cGAS, potentially activating STING and downstream interferon-responsive genes. However, direct evidence connecting MN and cGAS activation has been lacking. We have developed the FuVis2 reporter system, which enables the visualization of the cell nucleus carrying a
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A feedback loop that drives cell death and proliferation and its defect in intestinal stem cells. Life Sci. Alliance (IF 4.4) Pub Date : 2024-01-31 Shivakshi Sulekh, Yuko Ikegawa, Saki Naito, Asami Oji, Ichiro Hiratani, Sa Kan Yoo
Cell death and proliferation are at a glance dichotomic events, but occasionally coupled. Caspases, traditionally known to execute apoptosis, play non-apoptotic roles, but their exact mechanism remains elusive. Here, using Drosophila intestinal stem cells (ISCs), we discovered that activation of caspases induces massive cell proliferation rather than cell death. We elucidate that a positive feedback
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FERM domain-containing proteins are active components of the cell nucleus. Life Sci. Alliance (IF 4.4) Pub Date : 2024-01-31 Péter Borkúti, Ildikó Kristó, Anikó Szabó, Zoltán Kovács, Péter Vilmos
The FERM domain is a conserved and widespread protein module that appeared in the common ancestor of amoebae, fungi, and animals, and is therefore now found in a wide variety of species. The primary function of the FERM domain is localizing to the plasma membrane through binding lipids and proteins of the membrane; thus, for a long time, FERM domain-containing proteins (FDCPs) were considered exclusively
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NeoMUST: an accurate and efficient multi-task learning model for neoantigen presentation. Life Sci. Alliance (IF 4.4) Pub Date : 2024-01-30 Wang Ma, Jiawei Zhang, Hui Yao
Accurate identification of neoantigens is important for advancing cancer immunotherapies. This study introduces Neoantigen MUlti-taSk Tower (NeoMUST), a model employing multi-task learning to effectively capture task-specific information across related tasks. Our results show that NeoMUST rivals existing algorithms in predicting the presentation of neoantigens via MHC-I molecules, while demonstrating
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Mapping parental DMRs predictive of local and distal methylome remodeling in epigenetic F1 hybrids. Life Sci. Alliance (IF 4.4) Pub Date : 2024-01-30 Ioanna Kakoulidou, Robert S Piecyk, Rhonda C Meyer, Markus Kuhlmann, Caroline Gutjahr, Thomas Altmann, Frank Johannes
F1 hybrids derived from a cross between two inbred parental lines often display widespread changes in DNA methylation and gene expression patterns relative to their parents. An emerging challenge is to understand how parental epigenomic differences contribute to these events. Here, we generated a large mapping panel of F1 epigenetic hybrids, whose parents are isogenic but variable in their DNA methylation
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Integrated analysis of RNA-seq datasets reveals novel targets and regulators of COVID-19 severity. Life Sci. Alliance (IF 4.4) Pub Date : 2024-01-23 Thais Teixeira Oliveira, Júlia Firme Freitas, Viviane Priscila Barros de Medeiros, Thiago Jesus da Silva Xavier, Lucymara Fassarella Agnez-Lima
During the COVID-19 pandemic, RNA-seq datasets were produced to investigate the virus-host relationship. However, much of these data remains underexplored. To improve the search for molecular targets and biomarkers, we performed an integrated analysis of multiple RNA-seq datasets, expanding the cohort and including patients from different countries, encompassing severe and mild COVID-19 patients. Our
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Drosophila MIC10b can polymerize into cristae-shaping filaments. Life Sci. Alliance (IF 4.4) Pub Date : 2024-01-22 Till Stephan, Stefan Stoldt, Mariam Barbot, Travis D Carney, Felix Lange, Mark Bates, Peter Bou Dib, Kaushik Inamdar, Halyna R Shcherbata, Michael Meinecke, Dietmar Riedel, Sven Dennerlein, Peter Rehling, Stefan Jakobs
Cristae are invaginations of the mitochondrial inner membrane that are crucial for cellular energy metabolism. The formation of cristae requires the presence of a protein complex known as MICOS, which is conserved across eukaryotic species. One of the subunits of this complex, MIC10, is a transmembrane protein that supports cristae formation by oligomerization. In Drosophila melanogaster, three MIC10-like
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Single variant, yet "double trouble": TSC and KBG syndrome because of a large de novo inversion. Life Sci. Alliance (IF 4.4) Pub Date : 2024-01-22 Victoria Rodrigues Alves Barbosa, Tatiana Maroilley, Catherine Diao, Leslie Colvin-James, Renee Perrier, Maja Tarailo-Graovac
Despite the advances in high-throughput sequencing, many rare disease patients remain undiagnosed. In particular, the patients with well-defined clinical phenotypes and established clinical diagnosis, yet missing or partial genetic diagnosis, may hold a clue to more complex genetic mechanisms of a disease that could be missed by available clinical tests. Here, we report a patient with a clinical diagnosis
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Absence of the RING domain in MID1 results in patterning defects in the developing human brain. Life Sci. Alliance (IF 4.4) Pub Date : 2024-01-18 Sarah Frank, Elisa Gabassi, Stephan Käseberg, Marco Bertin, Lea Zografidou, Daniela Pfeiffer, Heiko Brennenstuhl, Sven Falk, Marisa Karow, Susann Schweiger
The X-linked form of Opitz BBB/G syndrome (OS) is a monogenic disorder in which symptoms are established early during embryonic development. OS is caused by pathogenic variants in the X-linked gene MID1 Disease-associated variants are distributed across the entire gene locus, except for the N-terminal really interesting new gene (RING) domain that encompasses the E3 ubiquitin ligase activity. By using
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Reduced myeloid commitment and increased uptake by macrophages of stem cell-derived HPS2 neutrophils. Life Sci. Alliance (IF 4.4) Pub Date : 2024-01-18 Steven Ds Webbers, Cathelijn Em Aarts, Bart Klein, Dané Koops, Judy Geissler, Anton Tj Tool, Robin van Bruggen, Emile van den Akker, Taco W Kuijpers
Hermansky-Pudlak syndrome type 2 (HPS2) is a rare autosomal recessive disorder, caused by mutations in the AP3B1 gene, encoding the β3A subunit of the adapter protein complex 3. This results in mis-sorting of proteins within the cell. A clinical feature of HPS2 is severe neutropenia. Current HPS2 animal models do not recapitulate the human disease. Hence, we used induced pluripotent stem cells (iPSCs)
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Synaptobrevin2 monomers and dimers differentially engage to regulate the functional trans-SNARE assembly. Life Sci. Alliance (IF 4.4) Pub Date : 2024-01-18 Swapnali S Patil, Kinjal Sanghrajka, Malavika Sriram, Aritra Chakraborty, Sougata Majumdar, Bhavya R Bhaskar, Debasis Das
The precise cell-to-cell communication relies on SNARE-catalyzed membrane fusion. Among ∼70 copies of synaptobrevin2 (syb2) in synaptic vesicles, only ∼3 copies are sufficient to facilitate the fusion process at the presynaptic terminal. It is unclear what dictates the number of SNARE complexes that constitute the fusion pore assembly. The structure-function relation of these dynamic pores is also
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Spatiotemporal DNA methylation dynamics shape megabase-scale methylome landscapes. Life Sci. Alliance (IF 4.4) Pub Date : 2024-01-17 Hidehiro Toh, Hiroyuki Sasaki
DNA methylation is an essential epigenetic mechanism that regulates cellular reprogramming and development. Studies using whole-genome bisulfite sequencing have revealed distinct DNA methylome landscapes in human and mouse cells and tissues. However, the factors responsible for the differences in megabase-scale methylome patterns between cell types remain poorly understood. By analyzing publicly available
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Enhancer mutations modulate the severity of chemotherapy-induced myelosuppression. Life Sci. Alliance (IF 4.4) Pub Date : 2024-01-16 Artemy Zhigulev, Zandra Norberg, Julie Cordier, Rapolas Spalinskas, Hassan Bassereh, Niclas Björn, Sailendra Pradhananga, Henrik Gréen, Pelin Sahlén
Non-small cell lung cancer is often diagnosed at advanced stages, and many patients are still treated with classical chemotherapy. The unselective nature of chemotherapy often results in severe myelosuppression. Previous studies showed that protein-coding mutations could not fully explain the predisposition to myelosuppression. Here, we investigate the possible role of enhancer mutations in myelosuppression
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The origin, evolution, and molecular diversity of the chemokine system. Life Sci. Alliance (IF 4.4) Pub Date : 2024-01-16 Alessandra Aleotti, Matthew Goulty, Clifton Lewis, Flaviano Giorgini, Roberto Feuda
Chemokine signalling performs key functions in cell migration via chemoattraction, such as attracting leukocytes to the site of infection during host defence. The system consists of a ligand, the chemokine, usually secreted outside the cell, and a chemokine receptor on the surface of a target cell that recognises the ligand. Several noncanonical components interact with the system. These include a
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Nucleolar protein TAAP1/C22orf46 confers pro-survival signaling in non-small cell lung cancer. Life Sci. Alliance (IF 4.4) Pub Date : 2024-01-16 Marietta Döring, Melanie Brux, Maciej Paszkowski-Rogacz, Pedro M Guillem-Gloria, Frank Buchholz, M Teresa Pisabarro, Mirko Theis
Tumor cells subvert immune surveillance or lytic stress by harnessing inhibitory signals. Hence, bispecific antibodies have been developed to direct CTLs to the tumor site and foster immune-dependent cytotoxicity. Although applied with success, T cell-based immunotherapies are not universally effective partially because of the expression of pro-survival factors by tumor cells protecting them from apoptosis
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The LINC complex ensures accurate centrosome positioning during prophase. Life Sci. Alliance (IF 4.4) Pub Date : 2024-01-16 Joana T Lima, António J Pereira, Jorge G Ferreira
Accurate centrosome separation and positioning during early mitosis relies on force-generating mechanisms regulated by a combination of extracellular, cytoplasmic, and nuclear cues. The identity of the nuclear cues involved in this process remains largely unknown. Here, we investigate how the prophase nucleus contributes to centrosome positioning during the initial stages of mitosis, using a combination
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Accessory genes define species-specific routes to antibiotic resistance. Life Sci. Alliance (IF 4.4) Pub Date : 2024-01-16 Lucy Dillon, Nicholas J Dimonaco, Christopher J Creevey
A deeper understanding of the relationship between the antimicrobial resistance (AMR) gene carriage and phenotype is necessary to develop effective response strategies against this global burden. AMR phenotype is often a result of multi-gene interactions; therefore, we need approaches that go beyond current simple AMR gene identification tools. Machine-learning (ML) methods may meet this challenge
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CLN3 deficiency leads to neurological and metabolic perturbations during early development. Life Sci. Alliance (IF 4.4) Pub Date : 2024-01-09 Ursula Heins-Marroquin, Randolph R Singh, Simon Perathoner, Floriane Gavotto, Carla Merino Ruiz, Myrto Patraskaki, Gemma Gomez-Giro, Felix Kleine Borgmann, Melanie Meyer, Anaïs Carpentier, Marc O Warmoes, Christian Jäger, Michel Mittelbronn, Jens C Schwamborn, Maria Lorena Cordero-Maldonado, Alexander D Crawford, Emma L Schymanski, Carole L Linster
Juvenile neuronal ceroid lipofuscinosis (or Batten disease) is an autosomal recessive, rare neurodegenerative disorder that affects mainly children above the age of 5 yr and is most commonly caused by mutations in the highly conserved CLN3 gene. Here, we generated cln3 morphants and stable mutant lines in zebrafish. Although neither morphant nor mutant cln3 larvae showed any obvious developmental or
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Centriole and transition zone structures in photoreceptor cilia revealed by cryo-electron tomography. Life Sci. Alliance (IF 4.4) Pub Date : 2024-01-05 Zhixian Zhang, Abigail R Moye, Feng He, Muyuan Chen, Melina A Agosto, Theodore G Wensel
Primary cilia mediate sensory signaling in multiple organisms and cell types but have structures adapted for specific roles. Structural defects in them lead to devastating diseases known as ciliopathies in humans. Key to their functions are structures at their base: the basal body, the transition zone, the "Y-shaped links," and the "ciliary necklace." We have used cryo-electron tomography with subtomogram
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USP27X variants underlying X-linked intellectual disability disrupt protein function via distinct mechanisms. Life Sci. Alliance (IF 4.4) Pub Date : 2024-01-05 Intisar Koch, Maya Slovik, Yuling Zhang, Bingyu Liu, Martin Rennie, Emily Konz, Benjamin Cogne, Muhannad Daana, Laura Davids, Illja J Diets, Nina B Gold, Alexander M Holtz, Bertrand Isidor, Hagar Mor-Shaked, Juanita Neira Fresneda, Karen Y Niederhoffer, Mathilde Nizon, Rolph Pfundt, Meh Simon, Apa Stegmann, Maria J Guillen Sacoto, Marijke Wevers, Tahsin Stefan Barakat, Shira Yanovsky-Dagan, Boyko S
Neurodevelopmental disorders with intellectual disability (ND/ID) are a heterogeneous group of diseases driving lifelong deficits in cognition and behavior with no definitive cure. X-linked intellectual disability disorder 105 (XLID105, #300984; OMIM) is a ND/ID driven by hemizygous variants in the USP27X gene encoding a protein deubiquitylase with a role in cell proliferation and neural development
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Early Atf4 activity drives airway club and goblet cell differentiation. Life Sci. Alliance (IF 4.4) Pub Date : 2024-01-04 Juan F Barrera-Lopez, Guadalupe Cumplido-Laso, Marcos Olivera-Gomez, Sergio Garrido-Jimenez, Selene Diaz-Chamorro, Clara M Mateos-Quiros, Dixan A Benitez, Francisco Centeno, Sonia Mulero-Navarro, Angel C Roman, Jose M Carvajal-Gonzalez
Activating transcription factor 4 (Atf4), which is modulated by the protein kinase RNA-like ER kinase (PERK), is a stress-induced transcription factor responsible for controlling the expression of a wide range of adaptive genes, enabling cells to withstand stressful conditions. However, the impact of the Atf4 signaling pathway on airway regeneration remains poorly understood. In this study, we used
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Variable PD-1 glycosylation modulates the activity of immune checkpoint inhibitors. Life Sci. Alliance (IF 4.4) Pub Date : 2024-01-04 Chih-Wei Chu, Tomislav Čaval, Frederico Alisson-Silva, Akshaya Tankasala, Christina Guerrier, Gregg Czerwieniec, Heinz Läubli, Flavio Schwarz
Monoclonal antibodies targeting the immune checkpoint PD-1 have provided significant clinical benefit across a number of solid tumors, with differences in efficacy and toxicity profiles possibly related to their intrinsic molecular properties. Here, we report that camrelizumab and cemiplimab engage PD-1 through interactions with its fucosylated glycan. Using a combination of protein and cell glycoengineering
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Pridopidine subtly ameliorates motor skills in a mouse model for vanishing white matter. Life Sci. Alliance (IF 4.4) Pub Date : 2024-01-03 Ellen Oudejans, Diede Witkamp, Gino V Hu-A-Ng, Leoni Hoogterp, Gemma van Rooijen-van Leeuwen, Iris Kruijff, Pleun Schonewille, Zeinab Lalaoui El Mouttalibi, Imke Bartelink, Marjo S van der Knaap, Truus Em Abbink
The leukodystrophy vanishing white matter (VWM) is characterized by chronic and episodic acute neurological deterioration. Curative treatment is presently unavailable. Pathogenic variants in the genes encoding eukaryotic initiation factor 2B (eIF2B) cause VWM and deregulate the integrated stress response (ISR). Previous studies in VWM mouse models showed that several ISR-targeting compounds ameliorate
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Tmprss2 maintains epithelial barrier integrity and transepithelial sodium transport. Life Sci. Alliance (IF 4.4) Pub Date : 2024-01-03 Olivia J Rickman, Emma Guignard, Thomas Chabanon, Giovanni Bertoldi, Muriel Auberson, Edith Hummler
The mouse cortical collecting duct cell line presents a tight epithelium with regulated ion and water transport. The epithelial sodium channel (ENaC) is localized in the apical membrane and constitutes the rate-limiting step for sodium entry, thereby enabling transepithelial transport of sodium ions. The membrane-bound serine protease Tmprss2 is co-expressed with the alpha subunit of ENaC. αENaC gene
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VE-cadherin junction dynamics in initial lymphatic vessels promotes lymph node metastasis. Life Sci. Alliance (IF 4.4) Pub Date : 2023-12-26 Miguel Sáinz-Jaspeado, Sarah Ring, Steven T Proulx, Mark Richards, Pernilla Martinsson, Xiujuan Li, Lena Claesson-Welsh, Maria H Ulvmar, Yi Jin
The endothelial junction component vascular endothelial (VE)-cadherin governs junctional dynamics in the blood and lymphatic vasculature. Here, we explored how lymphatic junction stability is modulated by elevated VEGFA signaling to facilitate metastasis to sentinel lymph nodes. Zippering of VE-cadherin junctions was established in dermal initial lymphatic vessels after VEGFA injection and in tumor-proximal
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Extreme trait GWAS (Et-GWAS): Unraveling rare variants in the 3,000 rice genome. Life Sci. Alliance (IF 4.4) Pub Date : 2023-12-26 Niranjani Gnanapragasam, Vinukonda Vishnu Prasanth, Krishna Tesman Sundaram, Ajay Kumar, Bandana Pahi, Anoop Gurjar, Challa Venkateshwarlu, Sanjay Kalia, Arvind Kumar, Shalabh Dixit, Ajay Kohli, Uma Maheshwer Singh, Vikas Kumar Singh, Pallavi Sinha
Identifying high-impact, rare genetic variants associated with specific traits is crucial for crop improvement. The 3,010 rice genome (3K RG) dataset offers a valuable resource for discovering genomic regions with potential applications in crop breeding. We used Extreme Trait GWAS (Et-GWAS), employing bulk pooling and allele frequency measurement to efficiently extract rare variants from the 3K RG
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Loss-of-function cancer-linked mutations in the EIF4G2 non-canonical translation initiation factor. Life Sci. Alliance (IF 4.4) Pub Date : 2023-12-21 Sara Meril, Marcela Bahlsen, Miriam Eisenstein, Alon Savidor, Yishai Levin, Shani Bialik, Shmuel Pietrokovski, Adi Kimchi
Tumor cells often exploit the protein translation machinery, resulting in enhanced protein expression essential for tumor growth. Since canonical translation initiation is often suppressed because of cell stress in the tumor microenvironment, non-canonical translation initiation mechanisms become particularly important for shaping the tumor proteome. EIF4G2 is a non-canonical translation initiation
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Single-cell time series analysis reveals the dynamics of HSPC response to inflammation. Life Sci. Alliance (IF 4.4) Pub Date : 2023-12-18 Brigitte J Bouman, Yasmin Demerdash, Shubhankar Sood, Florian Grünschläger, Franziska Pilz, Abdul R Itani, Andrea Kuck, Valérie Marot-Lassauzaie, Simon Haas, Laleh Haghverdi, Marieke Ag Essers
Hematopoietic stem and progenitor cells (HSPCs) are known to respond to acute inflammation; however, little is understood about the dynamics and heterogeneity of these stress responses in HSPCs. Here, we performed single-cell sequencing during the sensing, response, and recovery phases of the inflammatory response of HSPCs to treatment (a total of 10,046 cells from four time points spanning the first
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Changes in searching behaviour of CSL transcription complexes in Notch active conditions. Life Sci. Alliance (IF 4.4) Pub Date : 2023-12-14 Sarah Baloul, Charalambos Roussos, Maria Gomez-Lamarca, Leila Muresan, Sarah Bray
During development cells receive a variety of signals, which are of crucial importance to their fate determination. One such source of signal is the Notch signalling pathway, where Notch activity regulates expression of target genes through the core transcription factor CSL. To understand changes in transcription factor behaviour that lead to transcriptional changes in Notch active cells, we have probed
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Mitochondria isolated from lipid droplets of white adipose tissue reveal functional differences based on lipid droplet size. Life Sci. Alliance (IF 4.4) Pub Date : 2023-12-06 Alexandra J Brownstein, Michaela Veliova, Rebeca Acin-Perez, Frankie Villalobos, Anton Petcherski, Alberto Tombolato, Marc Liesa, Orian S Shirihai
Recent studies in brown adipose tissue (BAT) described a unique subpopulation of mitochondria bound to lipid droplets (LDs), which were termed PeriDroplet Mitochondria (PDM). PDM can be isolated from BAT by differential centrifugation and salt washes. Contrary to BAT, this approach has so far not led to the successful isolation of PDM from white adipose tissue (WAT). Here, we developed a method to
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Structural maintenance of chromosomes (SMC) proteins are required for DNA elimination in Paramecium. Life Sci. Alliance (IF 4.4) Pub Date : 2023-12-06 Fukai Zhang, Sebastian Bechara, Mariusz Nowacki
Chromosome (SMC) proteins are a large family of ATPases that play important roles in the organization and dynamics of chromatin. They are central regulators of chromosome dynamics and the core component of condensin. DNA elimination during zygotic somatic genome development is a characteristic feature of ciliated protozoa such as Paramecium This process occurs after meiosis, mitosis, karyogamy, and
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IMPA1 dependent regulation of phosphatidylinositol 4,5-bisphosphate and calcium signalling by lithium. Life Sci. Alliance (IF 4.4) Pub Date : 2023-12-06 Sankhanil Saha, Harini Krishnan, Padinjat Raghu
Lithium (Li) is widely used as a mood stabilizer to treat bipolar affective disorder. However, the molecular targets of Li that underpin its therapeutic effect remain unresolved. Inositol monophosphatase (IMPA1) is an enzyme involved in phosphatidylinositol 4,5-bisphosphate (PIP2) resynthesis after PLC signaling. In vitro, Li inhibits IMPA1, but the relevance of this inhibition within neural cells
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Proteomic-based stratification of intermediate-risk prostate cancer patients. Life Sci. Alliance (IF 4.4) Pub Date : 2023-12-04 Qing Zhong, Rui Sun, Adel T Aref, Zainab Noor, Asim Anees, Yi Zhu, Natasha Lucas, Rebecca C Poulos, Mengge Lyu, Tiansheng Zhu, Guo-Bo Chen, Yingrui Wang, Xuan Ding, Dorothea Rutishauser, Niels J Rupp, Jan H Rueschoff, Cédric Poyet, Thomas Hermanns, Christian Fankhauser, María Rodríguez Martínez, Wenguang Shao, Marija Buljan, Janis Frederick Neumann, Andreas Beyer, Peter G Hains, Roger R Reddel, Phillip
Gleason grading is an important prognostic indicator for prostate adenocarcinoma and is crucial for patient treatment decisions. However, intermediate-risk patients diagnosed in the Gleason grade group (GG) 2 and GG3 can harbour either aggressive or non-aggressive disease, resulting in under- or overtreatment of a significant number of patients. Here, we performed proteomic, differential expression
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Common analysis of direct RNA sequencinG CUrrently leads to misidentification of m5C at GCU motifs. Life Sci. Alliance (IF 4.4) Pub Date : 2023-11-29 Kaylee J Watson, Robin E Bromley, Benjamin C Sparklin, Mark T Gasser, Tamanash Bhattacharya, Jarrett F Lebov, Tyonna Tyson, Nan Dai, Laura E Teigen, Karen T Graf, Jeremy M Foster, Michelle Michalski, Vincent M Bruno, Amelia Ri Lindsey, Ivan R Corrêa, Richard W Hardy, Irene Lg Newton, Julie C Dunning Hotopp
RNA modifications, such as methylation, can be detected with Oxford Nanopore Technologies direct RNA sequencing. One commonly used tool for detecting 5-methylcytosine (m5C) modifications is Tombo, which uses an "Alternative Model" to detect putative modifications from a single sample. We examined direct RNA sequencing data from diverse taxa including viruses, bacteria, fungi, and animals. The algorithm
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Analysis of the indispensable RAD51 cofactor BRCA2 in Naganishia liquefaciens, a Basidiomycota yeast. Life Sci. Alliance (IF 4.4) Pub Date : 2023-11-28 Maierdan Palihati,Hiroshi Iwasaki,Hideo Tsubouchi
The BRCA2 tumor suppressor plays a critical role in homologous recombination by regulating RAD51, the eukaryotic homologous recombinase. We identified the BRCA2 homolog in a Basidiomycota yeast, Naganishia liquefaciens BRCA2 homologs are found in many Basidiomycota species but not in Ascomycota species. Naganishia BRCA2 (Brh2, for BRCA2 homolog) is about one-third the size of human BRCA2. Brh2 carries
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A dual-targeted drug inhibits cardiac ryanodine receptor Ca2+ leak but activates SERCA2a Ca2+ uptake. Life Sci. Alliance (IF 4.4) Pub Date : 2023-11-27 Jörg W Wegener,Gyuzel Y Mitronova,Lina ElShareif,Christine Quentin,Vladimir Belov,Tatiana Pochechueva,Gerd Hasenfuss,Lutz Ackermann,Stephan E Lehnart
In the heart, genetic or acquired mishandling of diastolic [Ca2+] by ryanodine receptor type 2 (RyR2) overactivity correlates with risks of arrhythmia and sudden cardiac death. Strategies to avoid these risks include decrease of Ca2+ release by drugs modulating RyR2 activity or increase in Ca2+ uptake by drugs modulating SR Ca2+ ATPase (SERCA2a) activity. Here, we combine these strategies by developing
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PARP-1 is a transcriptional rheostat of metabolic and bivalent genes during development. Life Sci. Alliance (IF 4.4) Pub Date : 2023-11-27 Gbolahan Bamgbose,Alexei Tulin
PARP-1 participates in various cellular processes, including gene regulation. In Drosophila, PARP-1 mutants undergo developmental arrest during larval-to-pupal transition. In this study, we investigated PARP-1 binding and its transcriptional regulatory role at this stage. Our findings revealed that PARP-1 binds and represses active metabolic genes, including glycolytic genes, whereas activating low-expression