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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

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 H 1 receptor; however, the role of the H 2 receptor (H 2 R) is not quite clear, especially in schizophrenia. Here, we found that expression of H 2 R in glutamatergic neurons of the frontal cortex was decreased in schizophrenia patients. Selective knockout of the H 2 R 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 H 2 R in glutamatergic neurons in the mPFC but not those in the hippocampus also mimicked these schizophrenia-like phenotypes. Furthermore, electrophysiology experiments established that H 2 R deficiency decreased the firing of glutamatergic neurons by enhancing the current through hyperpolarization-activated cyclic nucleotide-gated channels. In addition, either H 2 R overexpression in glutamatergic neurons or H 2 R 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 H 2 R in mPFC glutamatergic neurons may be pivotal to the pathogenesis of schizophrenia and that H 2 R 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 H 2 R in the brain, especially in glutamatergic neurons.

We propose a feasible scenario to directly polarize a relativistic electron beam and obtain overall polarization in various directions through a filter mechanism for single-shot collision between an ultrarelativistic unpolarized electron beam and an ultraintense circularly polarized laser pulse. The electrons are scattered to a large angular range of several degrees and the polarization states of the electrons are connected with their spatial position after the collision. Therefore, we can employ a filter to filter out a part of the scattered electrons based on their position and obtain high-degree overall polarization for the filtered beam. Through spin-considered Monte-Carlo simulations, polarization with a degree up to 62% in arbitrary transverse directions and longitudinal polarization up to 10% are obtained for the filtered beams at currently achievable laser intensity. We theoretically analyze the distribution formation of the scattered electrons and investigate the influence of different initial parameters through simulations to demonstrate the robustness of our scheme. This scenario provides a simple and flexible way to produce relativistic polarized electron beams for various polarization directions., 9 pages, 5 figures

The construction of robust (quasi)-solid-state electrolyte (SSE) for flexible lithium-metal batteries is desirable but extremely challenging. Herein, a novel, flexible, and robust quasi-solid-state electrolyte (QSSE) with a "tree-trunk" design is reported for ultralong-life lithium-metal batteries (LMBs). An in-situ-grown metal-organic framework (MOF) layer covers the cellulose-based framework to form hierarchical ion-channels, enabling rapid ionic transfer kinetics and excellent durability. A conductivity of 1.36 × 10

Myh6-Cre transgenic mouse line was known to express Cre recombinase only in the heart. Nevertheless, during breeding Myh6-Cre to Rosa26

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

Fallopian tube (FT) homeostasis requires dynamic regulation of heterogeneous cell populations and is disrupted in infertility and ovarian cancer. Here, we applied single-cell RNA-seq to profile 59,738 FT cells from four healthy, pre-menopausal subjects. The resulting cell atlas contains 12 major cell types representing epithelial, stromal, and immune compartments. Re-clustering of epithelial cells identified four ciliated and six non-ciliated secretory epithelial subtypes, two of which represent potential progenitor pools: one leading to mature secretory cells and the other contributing to either ciliated cells or one of the stromal cell types. To understand how FT cell numbers and states change in a disease state, we analyzed 17,798 cells from two hydrosalpinx samples and observed shifts in epithelial and stromal populations and cell-type-specific changes in extracellular matrix and TGF-β signaling; this underscores fibrosis pathophysiology. This resource is expected to facilitate future studies aimed at expanding understanding of fallopian tube homeostasis in normal development and disease.

The field of brain organoid research is complicated by morphological variability with multiple neural rosette structures per organoid. We have developed a new human brain organoid technique that generates self-organizing, single-rosette spheroids (SOSRS) with reproducible size, cortical-like lamination, and cell diversity. Rather than patterning a 3-dimensional embryoid body, we initiate brain organoid formation from a 2-dimensional monolayer of human pluripotent stem cells (hPSCs) that is patterned with small molecules into neuroepithelium and differentiated to cells of the developing dorsal cerebral cortex. This approach recapitulates the 2D to 3D transition from neural plate to neural tube that occurs during neurodevelopment. The vast majority of monolayer fragments form spheres with a single central lumen and consistent growth rates. Over time, the SOSRS develop appropriately ordered lamination consistent with six cortical layers by immunocytochemistry and single cell RNA-sequencing. The reproducibility of this method has allowed us to demonstrate robust structural phenotypes arising from chemical teratogen exposure or when modeling a genetic neurodevelopmental epileptic disorder. This platform should advance studies of human cortical development, brain disorder mechanisms, and precision therapies.SUMMARY STATEMENTSimple procedure for generating reproducible single rosette cortical brain organoids used to identify robust structural phenotypes with neuroteratogen exposure and in a genetic neurodevelopmental disease model.

Manufacturing advanced solid-state electrolytes (SSEs) for flexible rechargeable batteries becomes increasingly important but remains grand challenge. The sophisticated structure of robust animal dermis and good water-retention of plant cell in nature grant germane inspirations for designing high-performance SSEs. Herein, tough bioinspired SSEs with intrinsic hydroxide ion (OH

Luteinizing hormone (LH) stimulates testosterone production from Leydig cells. Both LH and testosterone play important roles in spermatogenesis and male fertility. To identify LH - and testosterone - responsive transporter genes that play key roles in spermatogenesis, we performed large-scale gene expression analyses on testes obtained from adult control and Lhb knockout mice. We found a significant reduction in cystine/glutamate transporter encoding Slc7a11 mRNA in testes of Lhb null mice. We observed that Slc7a11/SLC7A11 expression was initiated pre-pubertally and developmentally regulated in mouse testis. Immunolocalization studies confirmed that SLC7A11 was mostly expressed in Sertoli cells in testes of control and germ cell-deficient mice. Western blot analyses indicated that SLC7A11 was significantly reduced in testes of mutant mice lacking either LH or androgen receptor selectively in Sertoli cells. Genetic and pharmacological rescue of Lhb knockout mice restored the testicular expression of Slc7a11 comparable to that observed in controls. Additionally, Slc7a11 mRNA was significantly suppressed upon Sertoli cell/testicular damage induced in mice by cadmium treatment. Knockdown of Slc7a11 in vitro in TM4 Sertoli cells or treatment of mice with sulfasalazine, a SLC7A11 inhibitor caused a significant reduction in intracellular cysteine and glutathione levels but glutamate content remained unchanged as determined by metabolomic analysis. Knockdown of Slc7a11 resulted in compensatory upregulation of other glutamate transporters belonging to the Slc1a family presumably to maintain intracellular glutamate levels. Collectively, our studies identified that SLC7A11 is an LH/testosterone-regulated transporter that is required for cysteine/glutathione but not glutamate homeostasis in mouse Sertoli cells.

Although one of the most mature battery technologies, lithium-ion batteries still have many aspects that have not reached the desired requirements, such as energy density, current density, safety, environmental compatibility, and price. To solve these problems, all-solid-state lithium batteries (ASSLB) based on lithium metal anodes with high energy density and safety have been proposed and become a research hotpot in recent years. Due to the advanced electrochemical properties of 2D materials (2DM), they have been applied to mitigate some of the current problems of ASSLBs, such as high interface impedance and low electrolyte ionic conductivity. In this work, the background and fabrication method of 2DMs are reviewed initially. The improvement strategies of 2DMs are categorized based on their application in the three main components of ASSLBs: The anode, cathode, and electrolyte. Finally, to elucidate the mechanisms of 2DMs in ASSLBs, the role of in situ characterization, synchrotron X-ray techniques, and other advanced characterization are discussed.

Lithium sulfur (Li-S) batteries have been considered as one of the most promising next-generation rechargeable batteries owing to its high energy density and cost-effectiveness. However, the sluggish kinetics of the sulfur reduction reaction process, which is so far insufficiently explored, still impedes its practical application. Metal organic frameworks (MOF) are widely investigated as sulfur immobilizer, but the interactions and catalytic activity of lithium polysulfides (LiPs) on metal nodes are weak due to the presence of organic ligands. Herein, we present a strategy to design Quasi-MOF nanospheres, which has a transition-state structure between MOF and metal oxide, via controlled ligand exchange strategy to serve as sulfur electrocatalyst. The Quasi-MOF not only inherits the porous structure of MOF, but also exposes abundant metal nodes to act as active sites, rendering strong LiPs absorbability. The reversible deligandation/ligandation of Quasi-MOF and its impact on the durability of catalyst over the course of electrochemical process has been acknowledged, which confers a remarkable catalytic activity. Attributed to these structural advantages, Quasi-MOF delivers a decent discharge capacity and low capacity fading rate over long-term cycling. This work not only offers insight into the rational design of Quasi-MOF based composite, but also provides guidance for the application in Li-S batteries. This article is protected by copyright. All rights reserved.

Lithium anode‐based batteries (LBs) are highly demanded in society owing to the high theoretical capacity and low reduction potential of metallic lithium. They are expected to see increasing deployment in performance critical areas including electric vehicles, grid storage, space, and sea vehicle operations. Unfortunately, competitive performance cannot be achieved when LBs operating under extreme temperature conditions where the lithium‐ion chemistry fail to perform optimally. In this review, a brief overview of the challenges in developing LBs for low temperature (60 °C) operation are provided followed by electrolyte design strategies involving Li salt modification, solvation structure optimization, additive introduction, and solid‐state electrolyte utilization for LBs are introduced. Specifically, the prospects of using lithium metal batteries (LMBs), lithium sulfur (Li‐S) batteries, and lithium oxygen (Li‐O2) batteries for performance under low and high temperature applications are evaluated. These three chemistries are presented as prototypical examples of how the conventional low temperature charge transfer resistances and high temperature side reactions can be overcome. This review also points out the research direction of extreme temperature electrolyte design toward practical applications., This review introduces current progress of electrolyte design in lithium metal batteries to realize improved performance under extremely low and high temperature applications. By reviewing the scientific issues related to the current electrolyte design strategy, including Li salt modification, solvent component optimization, electrolyte additive introduction and solid‐state electrolyte utilization, this review points out the research direction toward practical applications.

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.

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We report four allelic variants (three novel) in three genes previously established as causal for hypopituitarism or related disorders. A novel homozygous variant in the growth hormone gene, GH1 c.171delT (p.Phe 57Leufs*43), was found in a male patient with severe isolated growth hormone deficiency (IGHD) born to consanguineous parents. A hemizygous SOX3 allelic variant (p.Met304Ile) was found in a male patient with IGHD and hypoplastic anterior pituitary. YASARA, a tool to evaluate protein stability, suggests that p.Met304Ile destabilizes the SOX3 protein (ΔΔG = 2.49 kcal/mol). A rare, heterozygous missense variant in the TALE homeobox protein gene, TGIF1 (c.268C&gt, T:p.Arg90Cys) was found in a patient with combined pituitary hormone deficiency (CPHD), diabetes insipidus, and syndromic features of holoprosencephaly (HPE). This variant was previously reported in a patient with severe holoprosencephaly and shown to affect TGIF1 function. A novel heterozygous TGIF1 variant (c.82T&gt, C:p.Ser28Pro) was identified in a patient with CPHD, pituitary aplasia and ectopic posterior lobe. Both TGIF1 variants have an autosomal dominant pattern of inheritance with incomplete penetrance. In conclusion, we have found allelic variants in three genes in hypopituitarism patients. We discuss these variants and associated patient phenotypes in relation to previously reported variants in these genes, expanding our knowledge of the phenotypic spectrum in patient populations.

International audience; 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.

Citrate-capped gold nanoparticles (AuNPs) are highly important for sensing, drug delivery, and materials design. Many of their reactions take place in various buffers such as phosphate and Good's buffers. The effect of buffer on the surface properties of AuNPs is critical, yet this topic has not been systematically explored. Herein, we used halides such as fluoride, chloride, and bromide as probes to measure the relative adsorption strength of six common buffers. Among them, HEPES had the highest adsorption affinity, while MES, citrate and phosphate were weakly adsorbed with an overall ranking of HEPES > PIPES > MOPS > MES > citrate, phosphate. The adsorption strength was reflected from the inhibited adsorption of DNA and from the displacement of pre-adsorbed DNA. This conclusion is also supported by surface enhanced Raman spectroscopy. Furthermore, some buffer molecules did not get adsorbed instantaneously, and the MOPS buffer took up to 1 h to reach equilibrium. Finally, a classic label-free AuNP-based colorimetric sensor was tested. Its sensitivity increased by 15.7-fold when performed in a MES buffer compared to a HEPES buffer. This study has articulated the importance of buffer for AuNP-based studies and how it can improve sensors and yield more reproducible experimental systems., Aside from maintaining pH, Good's buffers can be adsorbed on gold nanoparticles with different affinities, affecting the stability and its fluorescent and colorimetric sensing performance.

Testicular development and function rely on interactions between somatic cells and the germline, but similar to other organs, regenerative capacity declines in aging and disease. Whether the adult testis maintains a reserve progenitor population remains uncertain. Here, we characterize a recently identified mouse testis interstitial population expressing the transcription factor Tcf21. We found that TCF21lin cells are bipotential somatic progenitors present in fetal testis and ovary, maintain adult testis homeostasis during aging, and act as potential reserve somatic progenitors following injury. In vitro, TCF21lin cells are multipotent mesenchymal progenitors which form multiple somatic lineages including Leydig and myoid cells. Additionally, TCF21+ cells resemble resident fibroblast populations reported in other organs having roles in tissue homeostasis, fibrosis, and regeneration. Our findings reveal that the testis, like other organs, maintains multipotent mesenchymal progenitors that can be potentially leveraged in development of future therapies for hypoandrogenism and/or infertility., Whether the adult testis harbours a somatic progenitor population is unknown. Here, the authors provide evidence that the testis interstitial cells expressing the transcription factor Tcf21 maintain adult testis homeostasis during aging, and act as potential reserve somatic progenitors following injury.

Loss of function mutations in COQ4 lead to fatal neonatal mitochondrial disorders with CoQ10 deficiency. In two siblings with childhood-onset, slowly progressive ataxia from a consanguineous mating from Turkey, whole exome sequencing identified homozygous missense mutations in COQ4 (Gly55Val). Blood levels of CoQ10 were either below or at the low end of the normal range. The more severely affected of the siblings was given a high dose of CoQ10 (2000 mg/day) for one month, following which significant improvement in neurological signs and symptoms was noted. Our report indicates that COQ4 mutations are a rare cause of ataxia and that CoQ10 supplementation is a personalized treatment for this form of ataxia.

We report four allelic variants (3 novel) in three genes previously established as causal for hypopituitarism or related disorders. A novel homozygous variant in the growth hormone gene, GH1 c.171delT (p. Phe 57Leufs * 43), was found in a male patient with severe isolated growth hormone deficiency (IGHD) born to consanguineous parents. A SOX3 allelic variant (p.Met304Ile) was found in a male patient with IGHD and hypoplastic anterior pituitary. YASARA, a tool to evaluate protein stability, suggests that p.Met304Ile destabilizes the SOX3 protein (ΔΔG = 2.49 kcal/mol). A rare, heterozygous missense variant in the TALE homeobox protein gene, TGIF1 (c.268C>T:p.Arg90Cys) was found in a patient with combined pituitary hormone deficiency (CPHD), diabetes insipidus, and syndromic features of holoprosencephaly (HPE). A novel heterozygous TGIF1 variant (c.82T>C:p.Ser28Pro) was identified in a patient with CPHD, pituitary aplasia and ectopic posterior lobe. Both TGIF1 variants have an autosomal dominant pattern of inheritance with incomplete penetrance. In conclusion, we have found allelic variants in 3 genes in hypopituitarism patients. We discuss these variants and associated patient phenotypes in relation to previously reported variants in these genes, expanding our knowledge of the phenotypic spectrum in patient populations.

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 hypopituitarism patients 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 1,080 single nucleotide variants inPOU1F1. We identified 113 splice disruptive variants, including 23 synonymous variants. We evaluated separate cohorts of hypopituitarism patients and found two different synonymous splice disruptive variants 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 thePOU1F1gene.

Objective The transcription factor OTX2is implicated in ocular, craniofacial, and pituitary development. Design We aimed to establish the contribution of OTX2 mutations in congenital hypopituitarism patients with/without eye abnormalities, study functional consequences, and establish OTX2 expression in the human brain, with a view to investigate the mechanism of action. Methods We screened patients from the UK (n = 103), international centres (n = 24), and Brazil (n = 282); 145 were within the septo-optic dysplasia spectrum, and 264 had no eye phenotype. Transactivation ability of OTX2 variants was analysed in murine hypothalamic GT1-7 neurons. In situ hybridization was performed on human embryonic brain sections. Genetically engineered mice were generated with a series of C-terminal OTX2 variants. Results Two chromosomal deletions and six haploinsufficient mutations were identified in individuals with eye abnormalities; an affected relative of one patient harboured the same mutation without an ocular phenotype. OTX2 truncations led to significant transactivation reduction. A missense variant was identified in another patient without eye abnormalities; however, studies revealed it was most likely not causative. In the mouse, truncations proximal to aa219 caused anophthalmia, while distal truncations and the missense variant were tolerated. During human embryogenesis, OTX2 was expressed in the posterior pituitary, retina, ear, thalamus, choroid plexus, and partially in the hypothalamus, but not in the anterior pituitary. Conclusions OTX2 mutations are rarely associated with hypopituitarism in isolation without eye abnormalities, and may be variably penetrant, even within the same pedigree. Our data suggest that the endocrine phenotypes in patients with OTX2 mutations are of hypothalamic origin.

Fallopian tube (FT) homeostasis requires dynamic regulation of heterogeneous cell populations and is disrupted in infertility and ovarian cancer. Here we applied single-cell RNAseq to profile 53,376 FT cells from 3 healthy pre-menopausal subjects. The resulting cell atlas contains 12 major cell types representing epithelial, stromal and immune compartments. Re-clustering of epithelial cells identified 4 ciliated and 6 non-ciliated secretory epithelial subtypes, two of which represent potential progenitor pools: one leading to mature secretory cells, while the other contributing to either ciliated cells or one of the stromal cell types. To understand how FT cell numbers and states change in a disease state, we analyzed ~15,000 cells from a hydrosalpinx sample and observed shifts in epithelial and stromal populations, and cell type-specific changes in extracellular matrix and TGF-β signaling, underscoring fibrosis pathophysiology. This resource is expected to facilitate future studies to understand fallopian tube homeostasis in normal development and disease.

The field of brain organoid research is complicated by morphological variability with multiple rosette structures per organoid. We have developed a new human brain organoid technique that generates self-organizing, single-rosette spheroids (SOSRS) with reproducible size, cortical-like lamination, and cell diversity. Rather than patterning a 3-dimensional embryoid body, we initiate brain organoid formation from a 2-dimensional monolayer of human pluripotent stem cells (hPSCs) that is patterned with small molecules into neuroepithelium and differentiated to cells of the developing dorsal cerebral cortex. This approach recapitulates the 2D to 3D transition from neural plate to neural tube that occurs during neurodevelopment. The vast majority of monolayer fragments form spheres with a single central lumen. The reproducibility of this method has allowed us to demonstrate robust structural phenotypes arising from chemical teratogen exposure or when modeling a genetic neurodevelopmental epileptic disorder. This platform should advance studies of human cortical development, brain disorder mechanisms, and precision therapies.