Histamine H2 receptor deficit in glutamatergic neurons contributes to the pathogenesis of schizophrenia.

Schizophrenia is a serious mental disorder, and existing antipsychotic drugs show limited efficacy and cause unwanted side effects. The development of glutamatergic drugs for schizophrenia is currently challenging. Most functions of histamine in the brain are mediated by the histamine H1 receptor; however, the role of the H2 receptor (H2R) is not quite clear, especially in schizophrenia. Here, we found that expression of H2R in glutamatergic neurons of the frontal cortex was decreased in schizophrenia patients. Selective knockout of the H2R gene (Hrh2) in glutamatergic neurons (CaMKIIα-Cre; Hrh2 fl/fl) induced schizophrenia-like phenotypes including sensorimotor gating deficits, increased susceptibility to hyperactivity, social withdrawal, anhedonia, and impaired working memory, as well as decreased firing of glutamatergic neurons in the medial prefrontal cortex (mPFC) in in vivo electrophysiological tests. Selective knockdown of H2R in glutamatergic neurons in the mPFC but not those in the hippocampus also mimicked these schizophrenia-like phenotypes. Furthermore, electrophysiology experiments established that H2R deficiency decreased the firing of glutamatergic neurons by enhancing the current through hyperpolarization-activated cyclic nucleotide-gated channels. In addition, either H2R overexpression in glutamatergic neurons or H2R agonism in the mPFC counteracted schizophrenia-like phenotypes in an MK-801-induced mouse model of schizophrenia. Taken together, our results suggest that deficit of H2R in mPFC glutamatergic neurons may be pivotal to the pathogenesis of schizophrenia and that H2R agonists can be regarded as potentially efficacious medications for schizophrenia therapy. The findings also provide evidence for enriching the conventional glutamate hypothesis for the pathogenesis of schizophrenia and improve the understanding of the functional role of H2R in the brain, especially in glutamatergic neurons.

Selective and Scalable CO2 Electrolysis Enabled by Conductive Zinc Ion-Implanted Zeolite-Supported Cadmium Oxide Nanoclusters.

Catalyst supports play an essential role in catalytic reactions, hinting at pronounced metal-support effects. Zeolites are a propitious support in heterogeneous catalysts, while their use in the electrocatalytic CO2 reduction reaction has been limited as yet because of their electrically insulating nature and serious competing hydrogen evolution reaction (HER). Enlightened by theoretical prediction, herein, we implant zinc ions into the structural skeleton of a zeolite Y to strategically tailor a favorable electrocatalytic platform with remarkably enhanced electronic conduction and strong HER inhibition capability, which incorporates ultrafine cadmium oxide nanoclusters as guest species into the supercages of the tailored 12-ring window framework. The metal d-bandwidth tuning of cadmium by skeletal zinc steers the extent of substrate-molecule orbital mixing, enhancing the stabilization of the key intermediate *COOH while weakening the CO poisoning effect. Furthermore, the strong cadmium-zinc interplay causes a considerable thermodynamic barrier for water dissociation in the conversion of H+ to *H, potently suppressing the competing HER. Therefore, we achieve an industrial-level partial current density of 335 mA cm-2 and remarkable Faradaic efficiency of 97.1% for CO production and stably maintain Faradaic efficiency above 90% at the industrially relevant current density for over 120 h. This work provides a proof of concept of tailored conductive zeolite as a favorable electrocatalytic support for industrial-level CO2 electrolysis and will significantly enhance the adaptability of conductive zeolite-based electrocatalysts in a variety of electrocatalysis and energy conversion applications.

High-throughput splicing assays identify missense and silent splice-disruptive POU1F1 variants underlying pituitary hormone deficiency.

Pituitary hormone deficiency occurs in ∼1:4,000 live births. Approximately 3% of the cases are due to mutations in the alpha isoform of POU1F1, a pituitary-specific transcriptional activator. We found four separate heterozygous missense variants in unrelated individuals with hypopituitarism that were predicted to affect a minor isoform, POU1F1 beta, which can act as a transcriptional repressor. These variants retain repressor activity, but they shift splicing to favor the expression of the beta isoform, resulting in dominant-negative loss of function. Using a high-throughput splicing reporter assay, we tested 1,070 single-nucleotide variants in POU1F1. We identified 96 splice-disruptive variants, including 14 synonymous variants. In separate cohorts, we found two additional synonymous variants nominated by this screen that co-segregate with hypopituitarism. This study underlines the importance of evaluating the impact of variants on splicing and provides a catalog for interpretation of variants of unknown significance in POU1F1.

Molybdenum-Doped Cobalt-Free Cathode Realizing the Electrochemical Stability by Enhanced Covalent Bonding.

The doping strategy effectively enhances the capacity and cycling stability of cobalt-free nickel-rich cathodes. Understanding the intrinsic contributions of dopants is of great importance to optimize the performances of cathodes. This study investigates the correlation between the structure modification and their performances of Mo-doped LiNi0.8Mn0.2O2 (NM82) cathode. The role of doped Mo's valence state has been proved functional in both lattice structural modification and electronic state adjustment. Although the high-valence of Mo at the cathode surface inevitably reduces Ni valence for electronic neutrality and thus causes ion mixing, the original Mo valence will influence its diffusion depth. Structural analyses reveal Mo doping leads to a mixed layer on the surface, where high-valence Mo forms a slender cation mixing layer, enhancing structural stability and Li-ion transport. In addition, it is found that the high-valence dopant of Mo6+ ions partially occupies the unfilled 4d orbitals, which may strengthen the Mo─O bond through increased covalency and therefore reduce the oxygen mobility. This results in an impressive capacity retention (90.0% after 200 cycles) for Mo-NM82 cathodes with a high Mo valence state. These findings underscore the valence effect of doping on layered oxide cathode performance, offering guidance for next-generation cathode development.

Steric-hindrance Effect Tuned Ion Solvation Enabling High Performance Aqueous Zinc Ion Batteries.

Despite many additives have been reported for aqueous zinc ion batteries, steric-hindrance effect of additives and its correlation with Zn2+ solvation structure have been rarely reported. Herein, large-sized sucrose biomolecule is selected as a paradigm additive, and steric-hindrance electrolytes (STEs) are developed to investigate the steric-hindrance effect for solvation structure regulation. Sucrose molecules do not participate in Zn2+ solvation shell, but significantly homogenize the distribution of solvated Zn2+ and enlarge Zn2+ solvation shell with weakened Zn2+-H2O interaction due to the steric-hindrance effect. More importantly, STEs afford the water-shielding electric double layer and in situ construct the organic and inorganic hybrid solid electrolyte interface, which effectively boost Zn anode reversibility. Remarkably, Zn//NVO battery presents high capacity of 3.9 mAh ⋅ cm-2 with long cycling stability for over 650 cycles at lean electrolyte of 4.5 µL ⋅ mg-1 and low N/P ratio of 1.5, and the stable operation at wide temperature (-20 °C~+40 °C).

Designing Cooperative Ion Transport Pathway in Ultra-Thin Solid-State Electrolytes toward Practical Lithium Metal Batteries.

Solid polymer electrolytes (SPEs) are promising for high-energy-density solid-state Li metal batteries due to their decent flexibility, safety, and interfacial stability. However, their development was seriously hindered by the interfacial instability and limited conductivity, leading to inferior electrochemical performance.  Herein, we proposed to design ultra-thin solid-state electrolyte with long-range cooperative ion transport pathway to effectively increase the ionic conductivity and stability. The impregnation of PVDF-HFP inside pores of  fluorinated covalent organic framework (CF3-COF) can disrupt its symmetry, rendering rapid ion transportation and inhibited anion imigration. The functional groups of CF3-COF can interact with PVDF-HFP to form fast Li+ transport channels, which enables the uniform and confined Li+ conduction within the electrolyte. The introduction of CF3-COF also enhances the mechanical strength and flexibility of SPEs, as well as ensures homogeneous Li deposition and inhibited dendrite growth.  Hence, a remarkably high conductivity of 1.21×10-3 S cm-1 can be achieved. Finally, the ultra-thin SPEs with an extremely long cycle life exceed 9000 h can be obtained (the longest cycle life reported until now) while the NCM523/Li pouch cell demonstrates a high capacity of 760 mAh and 96% capacity retention after cycling, holding great promises to be utilized for practical solid-state Li metal batteries.

Myh6 promoter-driven Cre recombinase excises floxed DNA fragments in a subset of male germline cells.

Myh6-Cre transgenic mouse line was known to express Cre recombinase only in the heart. Nevertheless, during breeding Myh6-Cre to Rosa26fstdTom reporter (tdTom) mouse line, we observed that a significant part of their F2 tdTom/+ offspring had tdTom reporter gene universally activated. Our results show that Myh6-Cre transgenic mice have Cre recombinase activity in a subpopulation of the male germline cells, and that Myh6 gene transcripts are enriched in the interstitial Leydig cells and the undifferentiated spermatogonia stem cells. In summary, the current study confirms that the previously known "heart-specific" Myh6 promoter drives Cre expression in the testis.

Porous organic polymers for Li-chemistry-based batteries: functionalities and characterization studies.

Porous organic polymers (POPs), a versatile class of materials that possess many tunable properties such as high chemical absorptivity and ionic conductivity, are emerging candidate electrode materials, permselective membranes, ionic conductors, interfacial stabilizers and functional precursors to synthesize advanced porous carbon. Based on their crystal structure features, the emerging POPs can be classified into two subclasses: amorphous POPs (hyper cross-linked polymers, polymers with intrinsic microporosity, conjugated microporous polymers, porous aromatic frameworks, etc.) and crystalline POPs (covalent organic frameworks, etc.). This tutorial review provides a brief introduction of different types of POPs in terms of their classification and functions for tackling the remaining challenges in various types of Li-chemistry-based batteries. In situ and ex situ characterization studies are also discussed to highlight their importance and applicability for the structural investigation of POPs to reveal the underlying mechanism of POPs over the course of the electrochemical process. Although some revolutionary advances have been achieved, the development of POPs in Li-chemistry-based batteries is still in its infancy. Perspectives regarding future application and mechanistic insights of POPs in battery studies are outlined at the end.

Advanced Material Engineering to Tailor Nucleation and Growth towards Uniform Deposition for Anode-Less Lithium Metal Batteries.

Anode-less lithium metal batteries (ALMBs), whether employing liquid or solid electrolytes, have significant advantages such as lowered costs and increased energy density over lithium metal batteries (LMBs). Among many issues, dendrite growth and non-uniform plating which results in poor coulombic efficiency are the key issues that viciously decrease the longevity of the ALMBs. As a result, lowering the nucleation barrier and facilitating lithium growth towards uniform plating is even more critical in ALMBs. While extensive reviews have focused to describe strategies to achieve high performance in LMBs and ALMBs, this review focuses on strategies designed to directly facilitate nucleation and growth of dendrite-free ALMBs. The review begins with a discussion of the primary components of ALMBs, followed by a brief theoretical analysis of the nucleation and growth mechanism for ALMBs. The review then emphasizes key examples for each strategy in order to highlight the mechanisms and rationale that facilitate lithium plating. By comparing the structure and mechanisms of key materials, the review discusses their benefits and drawbacks. Finally, major trends and key findings are summarized, as well as an outlook on the scientific and economic gaps in ALMBs.

Hierarchically Nanostructured Solid-State Electrolyte for Flexible Rechargeable Zinc-Air Batteries.

The construction of safe and environmentally-benign solid-state electrolytes (SSEs) with intrinsic hydroxide ion-conduction for flexible zinc-air batteries is highly desirable yet extremely challenging. Herein, hierarchically nanostructured CCNF-PDIL SSEs with reinforced concrete architecture are constructed by nanoconfined polymerization of dual-cation ionic liquid (PDIL, concrete) within a robust three-dimensional porous cationic cellulose nanofiber matrix (CCNF, reinforcing steel), where plenty of penetrating ion-conductive channels are formed and undergo dynamic self-rearrangement under different hydrated levels. The CCNF-PDIL SSEs synchronously exhibit good flexibility, mechanical robustness, superhigh ion conductivity of 286.5 mS cm-1 , and decent water uptake. The resultant flexible solid-state zinc-air batteries deliver a high-power density of 135 mW cm-2 , a specific capacity of 775 mAh g-1 and an ultralong cycling stability with continuous operation of 240 hours for 720 cycles, far outperforming those of the state-of-the-art solid-state batteries. The marriage of biomaterials with the diversity of ionic liquids creates enormous opportunities to construct advanced SSEs for solid-state batteries.

Genetic variants in PLG, LPA, and SIGLEC 14 as well as smoking contribute to plasma plasminogen levels.

Plasminogen is the precursor of the serine protease plasmin, a central enzyme of the fibrinolytic system. Plasma levels of plasminogen vary by almost 2-fold among healthy individuals, yet little is known about its heritability or genetic determinants in the general population. In order to identify genetic factors affecting the natural variation of plasminogen levels, we performed a genome-wide association study and linkage analysis in a sample of 3456 young healthy individuals who participated in the Genes and Blood Clotting Study (GABC) or the Trinity Student Study (TSS). Heritability of plasminogen levels was 48.1% to 60.0%. Tobacco smoking and female sex were associated with higher levels of plasminogen. In the meta-analysis, 11 single-nucleotide polymorphisms (SNPs) in 2 regions reached genome-wide significance (P < 5.0E-8). Of these, 9 SNPs were near the PLG or LPA genes on Chr6q26, whereas 2 were on Chr19q13 and 5' upstream of SIGLEC14. These 11 SNPs represented 4 independent signals and collectively explained 6.8% of plasminogen level variation in the study populations. The strongest association was observed for a nonsynonymous SNP in the PLG gene (R523W). Individuals bearing an additional copy of this allele had an average decrease of 13.4% in plasma plasminogen level.

HESX1 mutations in patients with congenital hypopituitarism: variable phenotypes with the same genotype.

INTRODUCTION: Mutations in the transcription factor HESX1 can cause isolated growth hormone deficiency (IGHD) or combined pituitary hormone deficiency (CPHD) with or without septo-optic dysplasia (SOD). So far there is no clear genotype-phenotype correlation. PATIENTS AND RESULTS: We report four different recessive loss-of-function mutations in three unrelated families with CPHD and no midline defects or SOD. A homozygous p.R160C mutation was found by Sanger sequencing in two siblings from a consanguineous family. These patients presented with ACTH, TSH and GH deficiencies, severe anterior pituitary hypoplasia (APH) or pituitary aplasia (PA) and normal posterior pituitary. The p.R160C mutation was previously reported in a case with SOD, CPHD and ectopic posterior pituitary (EPP). Using exome sequencing, a homozygous p.I26T mutation was found in a Brazilian patient born to consanguineous parents. This patient had evolving CPHD, normal ACTH, APH and normal posterior pituitary (NPP). A previously reported patient homozygous for p.I26T had evolving CPHD and EPP. Finally, we identified compound heterozygous mutations in HESX1, p.[R159W];[R160H], in a patient with PA and CPHD. We showed that both of these mutations abrogate the ability of HESX1 to repress PROP1-mediated transcriptional activation. A patient homozygous for p.R160H was previously reported in a patient with CPHD, EPP, APH. CONCLUSION: These three examples demonstrate that HESX1 mutations cause variable clinical features in patients, which suggests an influence of modifier genes or environmental factors on the phenotype.

Complete Khoisan and Bantu genomes from southern Africa.

The genetic structure of the indigenous hunter-gatherer peoples of southern Africa, the oldest known lineage of modern human, is important for understanding human diversity. Studies based on mitochondrial and small sets of nuclear markers have shown that these hunter-gatherers, known as Khoisan, San, or Bushmen, are genetically divergent from other humans. However, until now, fully sequenced human genomes have been limited to recently diverged populations. Here we present the complete genome sequences of an indigenous hunter-gatherer from the Kalahari Desert and a Bantu from southern Africa, as well as protein-coding regions from an additional three hunter-gatherers from disparate regions of the Kalahari. We characterize the extent of whole-genome and exome diversity among the five men, reporting 1.3 million novel DNA differences genome-wide, including 13,146 novel amino acid variants. In terms of nucleotide substitutions, the Bushmen seem to be, on average, more different from each other than, for example, a European and an Asian. Observed genomic differences between the hunter-gatherers and others may help to pinpoint genetic adaptations to an agricultural lifestyle. Adding the described variants to current databases will facilitate inclusion of southern Africans in medical research efforts, particularly when family and medical histories can be correlated with genome-wide data.

Conductive Zeolite Supported Indium-Tin Alloy Nanoclusters for Selective and Scalable Formic Acid Electrosynthesis.

Upgrading excess CO2 toward the electrosynthesis of formic acid is of significant research and commercial interest. However, simultaneously achieving high selectivity and industrially relevant current densities of CO2-to-formate conversion remains a grand challenge for practical implementations. Here, an electrically conductive zeolite support is strategically designed by implanting Sn ions into the skeleton structure of a zeolite Y, which impregnates ultrasmall In0.2Sn0.8 alloy nanoclusters into the supercages of the tailored 12-ring framework. The prominent electronic and geometric interactions between In0.2Sn0.8 nanoalloy and zeolite support lead to the delocalization of electron density that enhances orbital hybridizations between In active site and *OCHO intermediate. Thus, the energy barrier for the rate-limiting *OCHO formation step is reduced, facilitating the electrocatalytic hydrogenation of CO2 to formic acid. Accordingly, the developed zeolite electrocatalyst achieves an industrial-level partial current density of 322 mA cm-2 and remarkable Faradaic efficiency of 98.2% for formate production and stably maintains Faradaic efficiency above 93% at an industrially relevant current density for over 102 h. This work opens up new opportunities of conductive zeolite-based electrocatalysts for industrial-level formic acid electrosynthesis from CO2 electrolysis and toward practically accessible electrocatalysis and energy conversion.

Design Unsaturated Selenium Coordinated NbSe2-x as Multifunctional Sulfur Electrocatalyst toward Fast and Durable Sulfur Reduction Reaction.

Lithium-sulfur (Li-S) battery are considered as the next generation energy storage system owing to their ultra-high theoretical specific capacity and energy density. However, the commercialization of Li-S battery is still hindered by the intrinsically low conductivity of sulfur, sluggish catalytic conversion and notorious shuttle effect of polysulfides. The implantation of defects in sulfur electrocatalyst can effectively increase its conductivity and catalytic efficiency of lithium polysulfides, but the current mainstream defective materials are limited and lack of in-depth research. Herein, a defective niobium selenide (NbSe2-x) nanosheet sulfur electrocatalyst is constructed with enriched selenium defects, which demonstrates strong interaction with sulfur species, endowing NbSe2-x with rapid and reliable sulfur reduction reaction. As a result, the Li-S cell with NbSe2-x exhibits excellent multiplicative performance in both coin cell and pouch cell, which maintains stable cycling for over 2000 cycles under 5 C, corresponding to a low-capacity fading rate of 0.024% per cycle. Ah level pouch cell is also fabricated, showing a decent energy density of 378 Wh kg-1. This creative strategy not only emphasizes the importance of selenium defect engineering in Li-S batterie toward practical application, but also enlightens the material engineering to realize superior performance in related energy storage and conversion area.

Generation of attosecond gigawatt soft x-ray pulses through coherent Thomson backscattering.

Collision between relativistic electron sheets and counterpropagating laser pulses is recognized as a promising way to produce intense attosecond x rays through coherent Thomson backscattering (TBS). In a double-layer scheme, the electrons in an ultrathin solid foil are first pushed out by an intense laser driver and then interact with the laser reflected off a second foil to form a high-density relativistic electron sheet with vanishing transverse momentum. However, the repulsion between these concentrated electrons can increase the thickness of the layer, reducing both its density and subsequently the coherent TBS. Here, we present a systematic study on the evolution of the flying electron layer and find that its resulting thickness is determined by the interplay between the intrinsic space-charge expansion and the velocity compression induced by the drive laser. How the laser driver, the target areal density, the reflector, and the collision laser intensity affect the properties of the produced x rays is explored. Multidimensional particle-in-cell simulations indicate that employing this scheme in the nonlinear regime has the potential to stably produce soft x rays with several gigawatt peak power in hundreds of terawatt ultrafast laser facilities. The pulse duration can be tuned to tens of attoseconds. This compact and intense attosecond x-ray source may have broad applications in attosecond science.

Conformal Engineering of Both Electrodes Toward High-Performance Flexible Quasi-Solid-State Zn-Ion Micro-Supercapacitors.

The severe Zn-dendrite growth and insufficient carbon-based cathode performance are two critical issues that hinder the practical applications of flexible Zn-ion micro-ssupercapacitors (FZCs). Herein, a self-adaptive electrode design concept of the synchronous improvement on both the cathode and anode is proposed to enhance the overall performance of FZCs. Polypyrrole doped with anti-expansion graphene oxide and acrylamide (PPy/GO-AM) on the cathode side can exhibit remarkable electrochemical performance, including decent capacitance and cycling stability, as well as exceptional mechanical properties. Meanwhile, a robust protective polymeric layer containing reduced graphene oxide and polyacrylamide is self-assembled onto the Zn surface (rGO/PAM@Zn) at the anode side, by which the "tip effect" of Zn small protuberance can be effectively alleviated, the Zn-ion distribution homogenized, and dendrite growth restricted. Benefiting from these advantages, the FZCs deliver an excellent specific capacitance of 125 mF cm-2 (125 F cm-3) at 1 mA cm-2, along with a maximum energy density of 44.4 µWh cm-2, and outstanding long-term durability with 90.3% capacitance remained after 5000 cycles. This conformal electrode design strategy is believed to enlighten the practical design of high-performance in-plane flexible Zn-based electrochemical energy storage devices (EESDs) by simultaneously tackling the challenges faced by Zn anodes and capacitance-type cathodes.

Deletion of histamine H2 receptor in VTA dopaminergic neurons of mice induces behavior reminiscent of mania.

Hyperfunction of the dopamine system has been implicated in manic episodes in bipolar disorders. How dopaminergic neuronal function is regulated in the pathogenesis of mania remains unclear. Histaminergic neurons project dense efferents into the midbrain dopaminergic nuclei. Here, we present mice lacking dopaminergic histamine H2 receptor (H2R) in the ventral tegmental area (VTA) that exhibit a behavioral phenotype mirroring some of the symptoms of mania, including increased locomotor activity and reduced anxiety- and depression-like behavior. These behavioral deficits can be reversed by the mood stabilizers lithium and valproate. H2R deletion in dopaminergic neurons significantly enhances neuronal activity, concurrent with a decrease in the γ-aminobutyric acid (GABA) type A receptor (GABAAR) membrane presence and inhibitory transmission. Conversely, either overexpression of H2R in VTA dopaminergic neurons or treatment of H2R agonist amthamine within the VTA counteracts amphetamine-induced hyperactivity. Together, our results demonstrate the engagement of H2R in reducing VTA dopaminergic activity, shedding light on the role of H2R as a potential target for mania therapy.