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Failure of oocyte activation, including polyspermy and defects in pronuclear (PN) formation, triggers early embryonic developmental arrest. Many studies have shown that phospholipase C zeta 1 (PLCZ1) mutations cause failure of PN formation following intracytoplasmic sperm injection (ICSI); however, whether PLCZ1 mutation is associated with polyspermy during in vitro fertilization (IVF) remains unknown. Whole-exome sequencing (WES) was performed to identify candidate mutations in couples with primary infertility. Sanger sequencing was used to validate the mutations. Multiple PLCZ1 -mutated sperm were injected into human and mouse oocytes to explore whether PN formation was induced. Assisted oocyte activation (AOA) after ICSI was performed to overcome the failure of oocyte activation. We identified three PLCZ1 mutations in three patients who experienced polyspermy during IVF cycles, including a novel missense mutation c.1154C>T, p.R385Q. PN formation failure was observed during the ICSI cycle. However, injection of multiple PLCZ1 - mutated sperm induced PN formation, suggesting that the Ca2+ oscillations induced by the sperm exceeded the necessary threshold for PN formation. AOA after ICSI enabled normal fertilization, and all patients achieved successful pregnancies. These findings expand the mutational spectrum of PLCZ1 and suggest an important role for PLCZ1 in terms of blocking polyspermy. Furthermore, this study may benefit genetic diagnoses in cases of abnormal fertilization and provide potential appropriate therapeutic measures for these patients with sperm-derived polyspermy. [ABSTRACT FROM AUTHOR]

Linker histones are essential components of chromatin, but the distributions and functions of many during cellular differentiation are not well understood. Here, we show that H1.5 binds to genic and intergenic regions, forming blocks of enrichment, in differentiated human cells from all three embryonic germ layers but not in embryonic stem cells. In differentiated cells, H1.5, but not H1.3, binds preferentially to genes that encode membrane and membrane-related proteins. Strikingly, 37% of H1.5 target genes belong to gene family clusters, groups of homologous genes that are located in proximity to each other on chromosomes. H1.5 binding is associated with gene repression and is required for SIRT1 binding, H3K9me2 enrichment, and chromatin compaction. Depletion of H1.5 results in loss of SIRT1 and H3K9me2, increased chromatin accessibility, deregulation of gene expression, and decreased cell growth. Our data reveal for the first time a specific and novel function for linker histone subtype H1.5 in maintenance of condensed chromatin at defined gene families in differentiated human cells.

The ubiquity of solid–liquid interfaces in nature and the significant role of their atomic-scale structure in determining interfacial properties have led to intensive research. Particularly in electrocatalysis, however, a molecular-level picture that clearly describes the dynamic interfacial structures and organizations with their correlation to preferred reaction pathways in electrochemical reactions remains poorly understood. In this review, CO2 electroreduction reaction (CO2RR) is spatially and temporally understood as a result of intricate interactions at the interface, in which the interfacial features are highly relevant. We start with the discussion of current understandings and model development associated with the charged electrochemical interface as well as its dynamic landscape. We further highlight the interactive dynamics from the interfacial field, catalyst surface charges and various gradients in electrolyte and interfacial water structures at interfaces under CO2RR working conditions, with emphasis on the interfacial-structure dependence of catalytic reactivity/selectivity. Significantly, a probing energy-dependent "in situ characterization map" for dynamic interfaces based on various complementary in situ/operando techniques is proposed, aiming to present a comprehensive picture of interfacial electrocatalysis and to provide a more unified research framework. Moreover, recent milestones in both experimental and theoretical aspects to establish the correct profile of electrochemical interfaces are stressed. Finally, we present key scientific challenges with related perspectives toward future opportunities for this exciting frontier. [ABSTRACT FROM AUTHOR]

Key Points: Question: Is dual antiplatelet therapy noninferior to intravenous thrombolysis in patients with minor nondisabling acute ischemic stroke? Findings: In this noninferiority randomized clinical trial that included 760 participants, excellent neurologic function at 90 days (modified Rankin Scale score of 0 or 1) occurred in 93.8% of those randomized to receive dual antiplatelet therapy and 91.4% of those randomized to receive intravenous alteplase, a difference greater than the prespecified noninferiority margin of −4.5%. Meaning: Among patients with minor nondisabling acute ischemic stroke, dual antiplatelet therapy, compared with intravenous alteplase, met the criteria for noninferiority with regard to excellent functional outcome at 90 days. Importance: Intravenous thrombolysis is increasingly used in patients with minor stroke, but its benefit in patients with minor nondisabling stroke is unknown. Objective: To investigate whether dual antiplatelet therapy (DAPT) is noninferior to intravenous thrombolysis among patients with minor nondisabling acute ischemic stroke. Design, Setting, and Participants: This multicenter, open-label, blinded end point, noninferiority randomized clinical trial included 760 patients with acute minor nondisabling stroke (National Institutes of Health Stroke Scale [NIHSS] score ≤5, with ≤1 point on the NIHSS in several key single-item scores; scale range, 0-42). The trial was conducted at 38 hospitals in China from October 2018 through April 2022. The final follow-up was on July 18, 2022. Interventions: Eligible patients were randomized within 4.5 hours of symptom onset to the DAPT group (n = 393), who received 300 mg of clopidogrel on the first day followed by 75 mg daily for 12 (±2) days, 100 mg of aspirin on the first day followed by 100 mg daily for 12 (±2) days, and guideline-based antiplatelet treatment until 90 days, or the alteplase group (n = 367), who received intravenous alteplase (0.9 mg/kg; maximum dose, 90 mg) followed by guideline-based antiplatelet treatment beginning 24 hours after receipt of alteplase. Main Outcomes and Measures: The primary end point was excellent functional outcome, defined as a modified Rankin Scale score of 0 or 1 (range, 0-6), at 90 days. The noninferiority of DAPT to alteplase was defined on the basis of a lower boundary of the 1-sided 97.5% CI of the risk difference greater than or equal to −4.5% (noninferiority margin) based on a full analysis set, which included all randomized participants with at least 1 efficacy evaluation, regardless of treatment group. The 90-day end points were assessed in a blinded manner. A safety end point was symptomatic intracerebral hemorrhage up to 90 days. Results: Among 760 eligible randomized patients (median [IQR] age, 64 [57-71] years; 223 [31.0%] women; median [IQR] NIHSS score, 2 [1-3]), 719 (94.6%) completed the trial. At 90 days, 93.8% of patients (346/369) in the DAPT group and 91.4% (320/350) in the alteplase group had an excellent functional outcome (risk difference, 2.3% [95% CI, −1.5% to 6.2%]; crude relative risk, 1.38 [95% CI, 0.81-2.32]). The unadjusted lower limit of the 1-sided 97.5% CI was −1.5%, which is larger than the −4.5% noninferiority margin (P for noninferiority <.001). Symptomatic intracerebral hemorrhage at 90 days occurred in 1 of 371 participants (0.3%) in the DAPT group and 3 of 351 (0.9%) in the alteplase group. Conclusions and Relevance: Among patients with minor nondisabling acute ischemic stroke presenting within 4.5 hours of symptom onset, DAPT was noninferior to intravenous alteplase with regard to excellent functional outcome at 90 days. Trial Registration: ClinicalTrials.gov Identifier: NCT03661411 This randomized trial examines whether dual antiplatelet therapy is noninferior to intravenous thrombolysis among patients with minor nondisabling acute ischemic stroke. [ABSTRACT FROM AUTHOR]

Photocatalytic epoxide alcoholysis through C−O bond cleavage and formation has emerged as an alternative to synthesizing anti‐tumoral pharmaceuticals and fine chemicals. However, the lack of crucial evidence to interpret the interaction between reactants and photocatalyst surface makes it challenging for photocatalytic epoxide alcoholysis with both high activity and regioselectivity. In this work, we report the hierarchical ZnIn2S4@CdS photocatalyst for epoxide alcoholysis with high regioselectivity nearly 100 %. Mechanistic studies unveil that the precise activation switch on exposed Zn acid sites for C−O bond polarization and cleavage has a critical significance for achieving efficient photocatalytic performance. Furthermore, the establishment of Z‐scheme heterojunction facilitates the interface charge separation and transfer. Remarkably, the underlying regioselective photocatalytic reaction pathway has been distinctly revealed. [ABSTRACT FROM AUTHOR]