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Parthasarathy R, Hagglof T, Hadley JT, McLennan A, Mattke A, Dudley EA, Kumagai A, Dong LLQ, Leadbetter EA
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Receptor Interacting Protein Kinase Pathways Regulate Innate B Cell Developmental Checkpoints But Not Effector Function in Mice (opens in new window)

FRONTIERS IN IMMUNOLOGY 2021 DEC 9; 12(?):? Article 758407
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Mutations in the scaffolding domain of Receptor Interacting Protein kinases (RIP) underlie the recently described human autoimmune syndrome, CRIA, characterized by lymphadenopathy, splenomegaly, and autoantibody production. While disease mechanisms for CRIA remain undescribed, RIP kinases work together with caspase-8 to regulate cell death, which is critical for normal differentiation of many cell types. Here, we describe a key role for RIP1 in facilitating innate B cell differentiation and subsequent activation. By comparing RIP1, RIP3, and caspase-8 triple deficient and RIP3, caspase-8 double deficient mice, we identified selective contributions of RIP1 to an accumulation of murine splenic Marginal Zone (MZ) B cells and B1-b cells. We used mixed bone-marrow chimeras to determine that innate B cell commitment required B cell-intrinsic RIP1, RIP3, and caspase-8 sufficiency. RIP1 regulated MZ B cell development rather than differentiation and RIP1 mediates its innate immune effects independent of the RIP1 kinase domain. NP-KLH/alum and NP-Ficoll vaccination of mice doubly deficient in both caspase-8 and RIP3 or deficient in all three proteins (RIP3, caspase-8, and RIP1) revealed uniquely delayed T-dependent and T-independent IgG responses, abnormal splenic germinal center architecture, and reduced extrafollicular plasmablast formation compared to WT mice. Thus, RIP kinases and caspase-8 jointly orchestrate B cell fate and delayed effector function through a B cell-intrinsic mechanism.
Prakash R, Freyer L, Saiz N, Gavrilov S, Wang RQ, Romanienko PJ, Lacy E, Hadjantonakis AK, Jasin M
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XRCC3 loss leads to midgestational embryonic lethality in mice (opens in new window)

DNA REPAIR 2021 DEC; 108 Article 103227
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RAD51 paralogs are key components of the homologous recombination (HR) machinery. Mouse mutants have been reported for four of the canonical RAD51 paralogs, and each of these mutants exhibits embryonic lethality, although at different gestational stages. However, the phenotype of mice deficient in the fifth RAD51 paralog, XRCC3, has not been reported. Here we report that Xrcc3 knockout mice exhibit midgestational lethality, with mild phenotypes beginning at about E8.25 but severe developmental abnormalities evident by E9.0-9.5. The most obvious phenotypes are small size and a failure of the embryo to turn to a fetal position. A knockin mutation at a key ATPase residue in the Walker A box results in embryonic lethality at a similar stage. Death of knockout mice can be delayed a few days for some embryos by homozygous or heterozygous Trp53 mutation, in keeping with an important role for XRCC3 in promoting genome integrity. Given that XRCC3 is a unique member of one of two RAD51 paralog complexes with RAD51C, these results demonstrate that both RAD51 paralog complexes are required for mouse development.
Chen XQ, Barrero CA, Carpio RVD, Reddy EP, Fecchio C, Merali S, Deglincerti A, Fang C, Rogers J, Maccecchini ML
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Posiphen Reduces the Levels of Huntingtin Protein through Translation Suppression (opens in new window)

PHARMACEUTICS 2021 DEC; 13(12):? Article 2109
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Posiphen tartrate (Posiphen) is an orally available small molecule that targets a conserved regulatory element in the mRNAs of amyloid precursor protein (APP) and alpha-synuclein (alpha SYN) and inhibits their translation. APP and alpha SYN can cause neurodegeneration when their aggregates induce neurotoxicity. Therefore, Posiphen is a promising drug candidate for neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Posiphen's safety has been demonstrated in three independent phase I clinical trials. Moreover, in a proof of concept study, Posiphen lowered neurotoxic proteins and inflammatory markers in cerebrospinal fluid of mild cognitive impaired patients. Herein we investigated whether Posiphen reduced the expression of other proteins, as assessed by stable isotope labeling with amino acids in cell culture (SILAC) followed by mass spectrometry (MS)-based proteomics. Neuroblastoma SH-SY5Y cells, an in vitro model of neuronal function, were used for the SILAC protein profiling response. Proteins whose expression was altered by Posiphen treatment were characterized for biological functions, pathways and networks analysis. The most significantly affected pathway was the Huntington's disease signaling pathway, which, along with huntingtin (HTT) protein, was down-regulated by Posiphen in the SH-SY5Y cells. The downregulation of HTT protein by Posiphen was confirmed by quantitative Western blotting and immunofluorescence. Unchanged mRNA levels of HTT and a comparable decay rate of HTT proteins after Posiphen treatment supported the coclusion that Posiphen reduced HTT via downregulation of the translation of HTT mRNA. Meanwhile, the downregulation of APP and alpha SYN proteins by Posiphen was also confirmed. The mRNAs encoding HTT, APP and alpha SYN contain an atypical iron response element (IRE) in their 5 '-untranslated regions (5 '-UTRs) that bind iron regulatory protein 1 (IRP1), and Posiphen specifically bound this complex. Conversely, Posiphen did not bind the IRP1/IRE complex of mRNAs with canonical IREs, and the translation of these mRNAs was not affected by Posiphen. Taken together, Posiphen shows high affinity binding to the IRE/IRP1 complex of mRNAs with an atypical IRE stem loop, inducing their translation suppression, including the mRNAs of neurotoxic proteins APP, alpha SYN and HTT.
Thakkar PV, Kita K, Del Castillo U, Galletti G, Madhukar N, Navarro EV, Barasoain I, Goodson HV, Sackett D, Diaz JF, Lu Y, RoyChoudhury A, Molina H, Elemento O, Shah MA, Giannakakou P
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CLIP-170S is a microtubule plus TIP variant that confers resistance to taxanes by impairing drug-target engagement (opens in new window)

DEVELOPMENTAL CELL 2021 DEC 6; 56(23):3264-+
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Taxanes are widely used cancer chemotherapeutics. However, intrinsic resistance limits their efficacy without any actionable resistance mechanism. We have discovered a microtubule (MT) plus-end-binding CLIP-170 protein variant, hereafter CLIP-170S, which we found enriched in taxane-resistant cell lines and patient samples. CLIP-170S lacks the first Cap-Gly motif, forms longer comets, and impairs taxane access to its MT luminal binding site. CLIP-170S knockdown reversed taxane resistance in cells and xenografts, whereas its re-expression led to resistance, suggesting causation. Using a computational approach in conjunction with the connectivity map, we unexpectedly discovered that Imatinib was predicted to reverse CLIP-170S mediated taxane resistance. Indeed, Imatinib treatment selectively depleted CLIP-170S, thus completely reversing taxane resistance. Other RTK inhibitors also depleted CLIP-170S, suggesting a class effect. Herein, we identify CLIP-170S as a clinically prevalent variant that confers taxane resistance, whereas the discovery of Imatinib as a CLIP-170S inhibitor provides novel therapeutic opportunities for future trials.
Arkin LM, Moon JJ, Tran JM, Asgan S, O'Farrelly C, Casanova JL, Cowen EW, Mays JW, Singh AM, Drolet BA
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From Your Nose to Your Toes: A Review of Severe Acute Respiratory Syndrome Coronavirus 2 Pandemic-Associated Pernio (opens in new window)

JOURNAL OF INVESTIGATIVE DERMATOLOGY 2021 DEC; 141(12):2791-2796
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Despite thousands of reported patients with pandemic-associated pernio, low rates of seroconversion and PCR positivity have defied causative linkage to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Pernio in uninfected children is associated with monogenic disorders of excessive IFN-1 immunity, whereas severe COVID-19 pneumonia can result from insufficient IFN-1. Moreover, SARS-CoV-2 spike protein and robust IFN-1 response are seen in the skin of patients with pandemicassociated pernio, suggesting an excessive innate immune skin response to SARS-CoV-2. Understanding the pathophysiology of this phenomenon may elucidate the host mechanisms that drive a resilient immune response to SARS-CoV-2 and could produce relevant therapeutic targets.
Abt I, Aggarwal R, Aushev V, Behnke O, Bertolin A, Bloch I, Brock I, Brook NH, Brugnera R, Bruni A, Bussey PJ, Caldwell A, Catterall CD, Chwastowski J, Ciborowski J, Ciesielski R, Cooper-Sarkar AM, Corradi M, Dementiev RK, Dusini S, Ferrando J, Floerchinger S, Foster B, Gallo E, Gangadharan D, Garfagnini A, Geiser A, Gladilin LK, Golubkov YA, Grzelak G, Gwenlan C, Hochman D, Jomhari NZ, Kadenko I, Karshon U, Kaur P, Klanner R, Klein U, Korzhavina IA, Kovalchuk N, Kuze M, Levchenko BB, Levy A, Lohr B, Lohrmann E, Longhin A, Lorkowski F, Lukina OY, Makarenko I, Malka J, Masciocchi S, Nagano K, Nam JD, Onderwaater J, Onishchuk Y, Paul E, Pidhurskyi I, Polini A, Przybycien M, Quintero A, Ruspa M, Schneekloth U, Schorner-Sadenius T, Selyuzhenkov I, Shchedrolosiev M, Shcheglova LM, Skillicorn IO, Slominski W, Solano A, Stanco L, Stefaniuk N, Surrow B, Tokushuku K, Turkot O, Tymieniecka T, Verbytskyi A, Abdullah WATW, Wichmann K, Wing M, Yamada S, Yamazaki Y, Zarnecki AF, Zenaiev O
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Azimuthal correlations in photoproduction and deep inelastic ep scattering at HERA (opens in new window)

JOURNAL OF HIGH ENERGY PHYSICS 2021 DEC 16; ?(12):? Article 102
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Collective behaviour of final-state hadrons, and multiparton interactions are studied in high-multiplicity ep scattering at a centre-of-mass energy root s = 318 GeV with the ZEUS detector at HERA. Two- and four-particle azimuthal correlations, as well as multiplicity, transverse momentum, and pseudorapidity distributions for charged-particle multiplicities N-ch >= 20 are measured. The dependence of two-particle correlations on the virtuality of the exchanged photon shows a clear transition from photoproduction to neutral current deep inelastic scattering. For the multiplicities studied, neither the measurements in photoproduction processes nor those in neutral current deep inelastic scattering indicate significant collective behaviour of the kind observed in high-multiplicity hadronic collisions at RHIC and the LHC. Comparisons of PYTHIA predictions with the measurements in photoproduction strongly indicate the presence of multiparton interactions from hadronic fluctuations of the exchanged photon.
Martinot M, Korganow AS, Wald M, Second J, Birckel E, Mahe A, Souply L, Mohseni-Zadeh M, Droy L, Tarabeux J, Okada S, Migaud M, Puel A, Guffroy A
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Case Report: A New Gain-of-Function Mutation of STAT1 Identified in a Patient With Chronic Mucocutaneous Candidiasis and Rosacea-Like Demodicosis: An Emerging Association (opens in new window)

FRONTIERS IN IMMUNOLOGY 2021 DEC 20; 12(?):? Article 760019
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PurposeHeterozygous missense STAT1 mutations leading to a gain of function (GOF) are the most frequent genetic cause of chronic mucocutaneous candidiasis (CMC). We describe the case of a patient presenting a new GOF mutation of STAT1 with the clinical symptoms of CMC, recurrent pneumonia, and persistent central erythema with papulopustules with ocular involvement related to rosacea-like demodicosis. MethodsGenetic analysis via targeted next-generation sequencing (NGS; NGS panel DIPAI v.1) exploring the 98 genes most frequently involved in primary immunodeficiencies, including STAT1, was performed to identify an underlying genetic defect. ResultsNGS identified a novel variant of STAT1, c.884C>A (exon 10), p.T295Y, not previously described. This variant was found to be gain of function using an in vitro luciferase reporter assay. Rosacea-like demodicosis was confirmed by substantial Demodex proliferation observed via the microscopic examination of a cutaneous sample. A review of literature retrieved 20 other cases of STAT1 GOF mutations associated with early-onset rosacea-like demodicosis, most with ocular involvement. ConclusionWe describe a new STAT1 GOF mutation associated with a phenotype of CMC and rosacea-like demodicosis. Rosacea-like demodicosis appears as a novel and important clinical phenotype among patients with STAT1 GOF mutation.
Bayrak CS, Stein D, Jain A, Chaudhary K, Nadkarni GN, Van Vleck TT, Puel A, Boisson-Dupuis S, Okada S, Stenson PD, Cooper DN, Schlessinger A, Itan Y
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Identification of discriminative gene-level and protein-level features associated with pathogenic gain-of-function and loss-of-function variants (opens in new window)

AMERICAN JOURNAL OF HUMAN GENETICS 2021 DEC 2; 108(12):2301-2318
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Identifying whether a given genetic mutation results in a gene product with increased (gain-of-function; GOF) or diminished (loss-offunction; LOF) activity is an important step toward understanding disease mechanisms because they may result in markedly different clinical phenotypes. Here, we generated an extensive database of documented germline GOF and LOF pathogenic variants by employing natural language processing (NLP) on the available abstracts in the Human Gene Mutation Database. We then investigated various geneand protein-level features of GOF and LOF variants and applied machine learning and statistical analyses to identify discriminative features. We found that GOF variants were enriched in essential genes, for autosomal-dominant inheritance, and in protein binding and interaction domains, whereas LOF variants were enriched in singleton genes, for protein-truncating variants, and in protein core regions. We developed a user-friendly web-based interface that enables the extraction of selected subsets from the GOF/LOF database by a broad set of annotated features and downloading of up-to-date versions. These results improve our understanding of how variants affect gene/protein function and may ultimately guide future treatment options.
Ortuno MJ, Schneeberger M, Ilanges A, Marchildon F, Pellegrino K, Friedman JM, Ducy P
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Melanocortin 4 receptor stimulation prevents antidepressant-associated weight gain in mice caused fluoxetine (opens in new window)

JOURNAL OF CLINICAL INVESTIGATION 2021 DEC 15; 131(24):? Article e151976
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Contrasting with the predicted anorexigenic effect of increasing brain serotonin signaling, long-term use of selective serotonin reuptake inhibitor (SSRI) antidepressants correlates with body weight (BW) gain. This adverse outcome increases the risk of transitioning to obesity and interferes with treatment compliance. Here, we show that orally administered fluoxetine (Flx), a widely prescribed SSRI, increased BW by enhancing food intake in healthy mice at 2 different time points and through 2 distinct mechanisms. Within hours, Flx decreased the activity of a subset of brainstem serotonergic neurons by triggering autoinhibitory signaling through 5-hydroxytryptamine receptor 1a (Htr1a). Following a longer treatment period, Flx blunted 5-hydroxytryptamine receptor 2c (Htr2c) expression and signaling, decreased the phosphorylation of cAMP response element-binding protein (CREB) and STAT3, and dampened the production of pro-opiomelanocortin (POMC, the precursor of alpha-melanocyte stimulating hormone [alpha-MSH]) in hypothalamic neurons, thereby increasing food intake. Accordingly, exogenous stimulation of the melanocortin 4 receptor (Mc4r) by cotreating mice with Flx and lipocalin 2, an anorexigenic hormone signaling through this receptor, normalized feeding and BW. Flx and other SSRIs also inhibited CREB and STAT3 phosphorylation in a human neuronal cell line, suggesting that these noncanonical effects could also occur in individuals treated long term with SSRIs. By defining the molecular basis of long-term SSRI-associated weight gain, we propose a therapeutic strategy to counter this effect.
Myler LR, Kinzig CG, Sasi NK, Zakusilo G, Cai SRW, de Lange T
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The evolution of metazoan shelterin (opens in new window)

GENES & DEVELOPMENT 2021 DEC 1; 35(23-24):1625-1641
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The mammalian telomeric shelterin complex-comprised of TRF1, TRF2, Rap1, TIN2, TPP1, and POT1-blocks the DNA damage response at chromosome ends and interacts with telomerase and the CST complex to regulate telomere length. The evolutionary origins of shelterin are unclear, partly because unicellular organisms have distinct telomeric proteins. Here, we describe the evolution of metazoan shelterin, showing that TRF1 emerged in vertebrates upon duplication of a TRF2-like ancestor. TRF1 and TRF2 diverged rapidly during vertebrate evolution through the acquisition of new domains and interacting factors. Vertebrate shelterin is also distinguished by the presence of an HJRL domain in the split C-terminal OB fold of POT1, whereas invertebrate POT1s carry inserts of variable nature. Importantly, the data reveal that, apart from the primate and rodent POT1 orthologs, all metazoan POT1s are predicted to have a fourth OB fold at their N termini. Therefore, we propose that POT1 arose from a four-OB-fold ancestor, most likely an RPA70-like protein. This analysis provides insights into the biology of shelterin and its evolution from ancestral telomeric DNA-binding proteins. In this study, Myler et al. investigated the evolutionary origins of shelterin complex, which is comprised of TRF1, TRF2, Rap1, TIN2, TPP1, and POT1; blocks the DNA damage response at chromosome ends; and interacts with telomerase and the CST complex to regulate telomere length. They describe the evolution of metazoan shelterin, showing that TRF1 emerged in vertebrates upon duplication of a TRF2-like ancestor, and providing insights into the biology of shelterin and its evolution from ancestral telomeric DNA-binding proteins.