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Found 37443 matches. Displaying 21-30
DeSpenza T Jr, Kiziltug E, Allington G, Barson DG, Mcgee S, O'Connor D, Rober...
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PTEN mutations impair CSF dynamics and cortical networks by dysregulating per...

NATURE NEUROSCIENCE 2025 MAR; 28(3):?
Enlargement of the cerebrospinal fluid (CSF)-filled brain ventricles (ventriculomegaly) is a defining feature of congenital hydrocephalus (CH) and an under-recognized concomitant of autism. Here, we show that de novo mutations in the autism risk gene PTEN are among the most frequent monogenic causes of CH and primary ventriculomegaly. Mouse Pten-mutant ventriculomegaly results from aqueductal stenosis due to hyperproliferation of periventricular Nkx2.1+ neural progenitor cells (NPCs) and increased CSF production from hyperplastic choroid plexus. Pten-mutant ventriculomegalic cortices exhibit network dysfunction from increased activity of Nkx2.1+ NPC-derived inhibitory interneurons. Raptor deletion or postnatal everolimus treatment corrects ventriculomegaly, rescues cortical deficits and increases survival by antagonizing mTORC1-dependent Nkx2.1+ NPC pathology. Thus, PTEN mutations concurrently alter CSF dynamics and cortical networks by dysregulating Nkx2.1+ NPCs. These results implicate a nonsurgical treatment for CH, demonstrate a genetic association of ventriculomegaly and ASD, and help explain neurodevelopmental phenotypes refractory to CSF shunting in select individuals with CH.
Tan BW, Hedbacker K, Kelly L, Zhang ZY, Moura-Assis A, Luo JD, Rabinowitz JD,...
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A cellular and molecular basis of leptin resistance

CELL METABOLISM 2025 MAR 4; 37(3):?
Similar to most humans with obesity, diet-induced obese (DIO) mice have high leptin levels and fail to respond to the exogenous hormone, suggesting that their obesity is caused by leptin resistance, the pathogenesis of which is unknown. We found that leptin treatment reduced plasma levels of leucine and methionine, mTOR-activating ligands, leading us to hypothesize that chronic mTOR activation might reduce leptin signaling. Rapamycin, an mTOR inhibitor, reduced fat mass and increased leptin sensitivity in DIO mice but not in mice with defects in leptin signaling. Rapamycin restored leptin's actions on POMC neurons and failed to reduce the weight of mice with defects in melanocortin signaling. mTOR activation in POMC neurons caused leptin resistance, whereas POMC-specific mutations in mTOR activators decreased weight gain of DIO mice. Thus, increased mTOR activity in POMC neurons is necessary and sufficient for the development of leptin resistance in DIO mice, establishing a key pathogenic mechanism leading to obesity.
Gleicher N, Mochizuki L, Barad DH
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Natural or artificial menstrual cycle for frozen embryo transfer

LANCET 2025 MAR 15; 405(10482):893-894
Gleicher N, Gayete-Lafuente S, Barad DH, Patrizio P, Albertini DF
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Why the hypothesis of embryo selection in IVF/ICSI must finally be reconsider...

HUMAN REPRODUCTION OPEN 2025 MAR 21; 2025(2):? Article hoaf011
Embryo selection (ES) during IVF is expected to select the 'best' embryo(s) from among a cycle's embryo cohort and has been a core concept of IVF for over 40 years. However, among 36 492 articles on ES in a recent PubMed search, we were unable to locate even a single one questioning the concept that, beyond standard oocyte and embryo morphology, ES has remained an unproven hypothesis. In unselected patient populations, attempts at ES have universally, indeed, failed to improve cumulative pregnancy and live birth rates. The only benefit ES appears to offer is a marginal shortening in time to pregnancy, and even this benefit manifests only in best-prognosis patients with large oocyte and embryo numbers. Excluding in vitro maturation efforts, oocytes, once retrieved, and their resulting embryos have predetermined finite cumulative pregnancy and live birth chances that cannot be further improved. The hypothesis of ES has, however, remained a driving force for research and the introduction of a multitude of 'add-ons' to IVF. Enormous investments over decades in ES, therefore, should be better redirected from post- to pre-retrieval efforts.
Le E, Moadab F, Wang XX, Najjar R, van den Bogaerde SJ, Bays A, Lacava J, Mus...
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Interferons and Cytokines Induce Transcriptional Activation of the Long-Inter...

EUROPEAN JOURNAL OF IMMUNOLOGY 2025 MAR; 55(3):? Article 2451351
Approximately 17% of our genome consists of copies of the retrotransposon "long interspersed element-1" (LINE-1 or L1). Patients with systemic lupus erythematosus (SLE) frequently have autoantibodies against the L1-encoded ORF1 protein (ORF1p), which correlate with disease activity and interferon gene signature. ORF1p is present in neutrophils from patients with active disease in perinuclear ribonucleoprotein particles that also contain Ro60 and nucleic acid sensors. Here, we report that treatment of neutrophils or monocytes with the demethylating agent 5-aza-deoxycytidine, interferon-alpha, tumor necrosis factor-alpha, and other cytokines or toll-like receptor agonists, induce a rapid increase in L1 transcripts. This increase was greater in cells from patients with SLE or rheumatoid arthritis (RA) than in cells from healthy donors, except that cells from SLE did not respond to interferon-alpha, presumably because most SLE patients have elevated type I interferons in vivo. Interferon-alpha also induced ORF1p in RA neutrophils with a subcellular distribution like that of ORF1p in freshly isolated SLE neutrophils. A luciferase reporter gene driven by the 5' untranslated region of L1, which controls its transcription, was also stimulated by interferon-alpha. These new insights into L1 transcriptional regulation indicate that it may play a more active role in antiviral immune responses.
Sachen KL, Hammaker D, Sarabia I, Stoveken B, Hartman J, Leppard KL, Manieri ...
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Guselkumab binding to CD64+ IL-23-producing myeloid cells enhances...

FRONTIERS IN IMMUNOLOGY 2025 MAR 12; 16(?):? Article 1532852
IL-23 is implicated in the pathogenesis of immune-mediated inflammatory diseases, and myeloid cells that express Fc gamma receptor 1 (Fc gamma RI or CD64) on their surface have been recently identified as a primary source of IL-23 in inflamed tissue. Our complementary analyses of transcriptomic datasets from psoriasis and IBD showed increased expression of CD64 and IL-23 transcripts in inflamed tissue, and greater abundance of cell types with co-expression of CD64 and IL-23. These findings led us to explore potential implications of CD64 binding on the function of IL-23-targeting monoclonal antibodies (mAbs). Guselkumab and risankizumab are mAbs that target the IL-23p19 subunit. Guselkumab has a native Fc domain while risankizumab contains mutations that diminish binding to Fc gamma Rs. In flow cytometry assays, guselkumab, but not risankizumab, showed Fc-mediated binding to CD64 on IFN gamma-primed monocytes. Guselkumab bound CD64 on IL-23-producing inflammatory monocytes and simultaneously captured IL-23 secreted from these cells. Guselkumab binding to CD64 did not induce cytokine production. In live-cell confocal imaging of CD64+ macrophages, guselkumab, but not risankizumab, mediated IL-23 internalization to low-pH intracellular compartments. Guselkumab and risankizumab demonstrated similar potency for inhibition of IL-23 signaling in cellular assays with exogenous addition of IL-23. However, in a co-culture of IL-23-producing CD64+ THP-1 cells with an IL-23-responsive reporter cell line, guselkumab demonstrated Fc-dependent enhanced potency compared to risankizumab for inhibiting IL-23 signaling. These in vitro data highlight the potential for guselkumab binding to CD64 in inflamed tissue to contribute to the potent neutralization of IL-23 at its cellular source.
Boisson-Dupuis S, Bastard P, Béziat V, Bustamante J, Cobat A, Jouanguy E, Pue...
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The monogenic landscape of human infectious diseases

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 2025 MAR; 155(3):768-783
The spectrum of known monogenic inborn errors of immunity is growing, with certain disorders underlying a specific and narrow range of infectious diseases. These disorders reveal the core mechanisms by which these infections occur in various settings, including inherited and acquired immunodeficiencies, thereby delineating the essential mechanisms of protective immunity to the corresponding pathogens. These findings also have medical implications, facilitating diagnosis and improving the management of individuals at risk of disease. (J Allergy Clin Immunol 2025;155:768-83.)
Buitrago L, Menezes MR, Larson C, Li JH, Kartika T, Banerjee P, Glickman F, C...
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Unbiased high-throughput screening of drug-repurposing libraries identifies s...

BLOOD ADVANCES 2025 MAR 11; 9(5):1049-1068
Platelet clot retraction, the ultimate phase of platelet thrombus formation, is critical for clot stabilization. It requires functional alpha IIb(33 receptors, fibrin, and the integrated actions of the actin-myosin contractile and cytoskeletal systems. Disturbances in clot retraction have been associated with both bleeding and thrombosis. We recently demonstrated that platelets treated with the alpha IIb(33 antagonist peptide Arg-Gly-Asp-Trp, which eliminates fibrinogen- mediated platelet aggregation, are still able to retract clots. We have exploited this observation to develop an unbiased, functional high-throughput assay to identify small- molecule inhibitors of fibrin-mediated clot retraction adapted for a 384-well plate format. We tested 9710 compounds from drug-repurposing libraries (DRLs). These libraries contain compounds that are either US Food and Drug Administration approved or have undergone preclinical/clinical development. We identified 27 compounds from the Library of Pharmacologically Active Compounds library as inhibitors of clot retraction, of which 14 are known inhibitors of platelet function. From the DRLs, we identified 135 compounds (1.6% hit rate). After extensive curation, these compounds were categorized based on the activity of their reported target. Multiple kinase and phosphodiesterase inhibitors with known antiplatelet effects were identified, along with multiple deubiquitination and receptor inhibitors, as well as compounds that have not previously been reported to have antiplatelet activity. Studies of 1 of the deubiquitination inhibitors (degrasyn) suggest that its effects are downstream of thrombin-induced platelet-fibrinogen interactions and thus may permit the separation of platelet thrombin-induced aggregation-mediated events from clot retraction. Additional studies of the identified compounds may lead to novel mechanisms of inhibiting thrombosis.
Renganathan B, Moore AS, Yeo WH, Petruncio A, Ackerman D, Weigel AV, Team TC,...
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Vimentin filament transport and organization revealed by single-particle trac...

JOURNAL OF CELL BIOLOGY 2025 MAR 10; 224(4):? Article e202406054
Vimentin intermediate filaments (VIFs) form complex, tightly packed networks; due to this density, traditional imaging approaches cannot discern single-filament behavior. To address this, we developed and validated a sparse vimentin-SunTag labeling strategy, enabling single-particle tracking of individual VIFs and providing a sensitive, unbiased, and quantitative method for measuring global VIF motility. Using this approach, we define the steady-state VIF motility rate, showing a constant similar to 8% of VIFs undergo directed microtubule-based motion irrespective of subcellular location or local filament density. Significantly, our single-particle tracking approach revealed uncorrelated motion of individual VIFs within bundles, an observation seemingly at odds with conventional models of tightly cross-linked bundles. To address this, we acquired high-resolution focused ion beam scanning electron microscopy volumes of vitreously frozen cells and reconstructed three-dimensional VIF bundles, finding that they form only loosely organized, semi-coherent structures from which single VIFs frequently emerge to locally engage neighboring microtubules. Overall, this work demonstrates single VIF dynamics and organization in the cellular milieu for the first time.
Rubio AA, Baharani VA, Dadonaite B, Parada M, Abernathy ME, Wang ZJ, Lee YE, ...
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Bispecific antibodies targeting the N-terminal and receptor binding domains p...

SCIENCE TRANSLATIONAL MEDICINE 2025 MAR 5; 17(788):? Article eadq5720
The ongoing emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) that reduce the effectiveness of antibody therapeutics necessitates development of next-generation antibody modalities that are resilient to viral evolution. Here, we characterized amino-terminal domain (NTD)- and receptor binding domain (RBD)-specific monoclonal antibodies previously isolated from coronavirus disease 2019 (COVID-19) convalescent donors for their activity against emergent SARS-CoV-2 VOCs. Among these, the NTD-specific antibody C1596 displayed the greatest breadth of binding to VOCs, with cryo-electron microscopy structural analysis revealing recognition of a distinct NTD epitope outside of the site i antigenic supersite. Given C1596's favorable binding profile, we designed a series of bispecific antibodies (bsAbs), termed CoV2-biRNs, that featured both NTD and RBD specificities. Two of the C1596-inclusive bsAbs, CoV2-biRN5 and CoV2-biRN7, retained potent in vitro neutralization activity against all Omicron variants tested, including XBB.1.5, BA.2.86, and JN.1, contrasting the diminished potency of parental antibodies delivered as monotherapies or as a cocktail. Furthermore, prophylactic delivery of CoV2-biRN5 reduced the viral load within the lungs of K18-hACE2 mice after challenge with SARS-CoV-2 XBB.1.5. In conclusion, NTD-RBD bsAbs offer promising potential for the design of resilient, next-generation antibody therapeutics against SARS-CoV-2 VOCs.