Signatures of superconductivity near 80 K in a nickelate under high pressure.

Although high-transition-temperature (high-Tc) superconductivity in cuprates has been known for more than three decades, the underlying mechanism remains unknown1-4. Cuprates are the only unconventional superconductors that exhibit bulk superconductivity with Tc above the liquid-nitrogen boiling temperature of 77 K. Here we observe that high-pressure resistance and mutual inductive magnetic susceptibility measurements showed signatures of superconductivity in single crystals of La3Ni2O7 with maximum Tc of 80 K at pressures between 14.0 GPa and 43.5 GPa. The superconducting phase under high pressure has an orthorhombic structure of Fmmm space group with the [Formula: see text] and [Formula: see text] orbitals of Ni cations strongly mixing with oxygen 2p orbitals. Our density functional theory calculations indicate that the superconductivity emerges coincidently with the metallization of the σ-bonding bands under the Fermi level, consisting of the [Formula: see text] orbitals with the apical oxygen ions connecting the Ni-O bilayers. Thus, our discoveries provide not only important clues for the high-Tc superconductivity in this Ruddlesden-Popper double-layered perovskite nickelates but also a previously unknown family of compounds to investigate the high-Tc superconductivity mechanism.

Spem2, a novel testis-enriched gene, is required for spermiogenesis and fertilization in mice.

Spermiogenesis is considered to be crucial for the production of haploid spermatozoa with normal morphology, structure and function, but the mechanisms underlying this process remain largely unclear. Here, we demonstrate that SPEM family member 2 (Spem2), as a novel testis-enriched gene, is essential for spermiogenesis and male fertility. Spem2 is predominantly expressed in the haploid male germ cells and is highly conserved across mammals. Mice deficient for Spem2 develop male infertility associated with spermiogenesis impairment. Specifically, the insufficient sperm individualization, failure of excess cytoplasm shedding, and defects in acrosome formation are evident in Spem2-null sperm. Sperm counts and motility are also significantly reduced compared to controls. In vivo fertilization assays have shown that Spem2-null sperm are unable to fertilize oocytes, possibly due to their impaired ability to migrate from the uterus into the oviduct. However, the infertility of Spem2-/- males cannot be rescued by in vitro fertilization, suggesting that defective sperm-egg interaction may also be a contributing factor. Furthermore, SPEM2 is detected to interact with ZPBP, PRSS21, PRSS54, PRSS55, ADAM2 and ADAM3 and is also required for their processing and maturation in epididymal sperm. Our findings establish SPEM2 as an essential regulator of spermiogenesis and fertilization in mice, possibly in mammals including humans. Understanding the molecular role of SPEM2 could provide new insights into future therapeutic treatment of human male infertility and development of non-hormonal male contraceptives.

USP47 deficiency in mice modulates tumor infiltrating immune cells and enhances antitumor immune responses in prostate cancer.

This study investigates the role of USP47, a deubiquitinating enzyme, in the tumor microenvironment and its impact on antitumor immune responses. Analysis of TCGA database revealed distinct expression patterns of USP47 in various tumor tissues and normal tissues. Prostate adenocarcinoma showed significant downregulation of USP47 compared to normal tissue. Correlation analysis demonstrated a positive association between USP47 expression levels and infiltrating CD8+ T cells, neutrophils, and macrophages, while showing a negative correlation with NKT cells. Furthermore, using Usp47 knockout mice, we observed a slower tumor growth rate and reduced tumor burden. The absence of USP47 led to increased infiltration of immune cells, including neutrophils, macrophages, NK cells, NKT cells, and T cells. Additionally, USP47 deficiency resulted in enhanced activation of cytotoxic T lymphocytes (CTLs) and altered T cell subsets within the tumor microenvironment. These findings suggest that USP47 plays a critical role in modulating the tumor microenvironment and promoting antitumor immune responses, highlighting its potential as a therapeutic target in prostate cancer.

Dissecting the PRSS37 interactome and potential mechanisms leading to ADAM3 loss in PRSS37-null sperm.

A disintegrin and metalloproteinase 3 (ADAM3) is a sperm membrane protein critical for sperm migration from the uterus into the oviduct and sperm-egg binding in mice. Disruption of PRSS37 results in male infertility concurrent with the absence of mature ADAM3 from cauda epididymal sperm. However, how PRSS37 modulates ADAM3 maturation remains largely unclear. Here, we determine the PRSS37 interactome by GFP immunoprecipitation coupled with mass spectrometry in PRSS37-EGFP knock-in mice. Three molecular chaperones (CLGN, CALR3 and PDILT) and three ADAM proteins (ADAM2, ADAM6B and ADAM4) were identified to be interacting with PRSS37. Coincidently, five of them (except ADAM4) have been reported to interact with ADAM3 precursor and regulate its maturation. We further demonstrated that PRSS37 also interacts directly with ADAM3 precursor and its deficiency impedes the association between PDILT and ADAM3. This could contribute to improper translocation of ADAM3 to the germ cell surface, leading to ADAM3 loss in PRSS37-null mature sperm. The understanding of the maturation mechanisms of pivotal sperm plasma membrane proteins will pave the way toward novel strategies for contraception and the treatment of unexplained male infertility.

Disruption of CD73-Derived and Equilibrative Nucleoside Transporter 1-Mediated Adenosine Signaling Exacerbates Oxygen-Induced Retinopathy.

Retinopathy of prematurity (ROP) is characterized by pathologic angiogenesis in retina, and remains a leading cause of blindness in children. Although enhanced extracellular adenosine is markedly increased in response to retinal hypoxia, adenosine acting at the A1 and A2A receptors has the opposite effect on pathologic angiogenesis. Herein, the oxygen-induced retinopathy (OIR) model of ROP was used to demonstrate that pharmacologic and genetic inactivation of CD73 (the key 5'-ectonucleotidase for extracellular generation of adenosine) did not affect normal retinal vasculature development but exacerbated intravitreal neovascularization at postnatal day (P) 17 and delayed revascularization at P21 of OIR. This exacerbated damage to retinal vessels by CD73 inactivation was associated with increased cellular apoptosis and microglial activation but decreased astrocyte function at P17 of OIR. Furthermore, pharmacologic blockade of equilibrative nucleoside transporter 1/2 (ENT1/2; bidirectional transport for controlling the balance of intracellular and extracellular adenosine) by 6-nitrobenzylthioinosine aggravated pathologic angiogenesis at P17 of OIR. Pharmacologic blockade of ENT1/2 and genetic inactivation of CD73 also aggravated avascular areas at the hyperoxia phase (P12) of OIR. Thus, disruption of CD73-derived extracellular adenosine or ENT1/2-mediated transport of adenosine flux across membrane aggravated the damage to retinal vessels. These findings support the role of adenosine as an endogenous protective regulator that limits oxygen-induced retinopathy. Thus, enhancing extracellular adenosine signaling represents a novel neuroprotection strategy for ROP by targeting CD73 and ENT1/2 activities.

Identification and validation of a CCL18-related signature for prediction of overall survival in patients with uveal melanoma.

Uveal melanoma (UM), the most frequent primary intraocular tumor in adults, has poor prognosis. High C-C motif chemokine ligand 18 (CCL18) has been detected in various tumors and is closely correlated with patients' clinicopathological characteristics. However, the essential role of CCL18 in UM remains unclear. Therefore, this study aimed to explore the prognostic value of CCL18 in UM. Uveal melanoma cells (M17) were transfected with pcDNA3.1-CCL18 si-RNA using Lipofectamine™ 2000. Cell growth and invasion abilities were measured through Cell Counting Kit-8 assay and invasion assay. RNA expression data and clinical and histopathological details were downloaded from the UM in The Cancer Genome Atlas (TCGA-UM) and GSE22138 datasets, which were defined as the training and validation cohorts, respectively. Univariate and multivariate Cox regression analyses were performed to identify significant prognostic biomarkers. The coefficients of these significant biomarkers generated by multivariate Cox proportional hazard regression analysis were used to establish a risk score formula. Functional enrichment analyses were also carried out. We found that downregulated CCL18 inhibits M17 cell growth and invasion in vitro. CCL18 may affect UM progression by altering C-C motif receptor 8 related pathways. Higher CCL18 expression was associated with worse clinical outcomes and tumor-specific death in the TCGA-UM dataset. Based on the coefficients obtained from the Cox proportional hazard regression analysis, a CCL18-related prognostic signature formula was constructed as follows: risk score = 0.05590 × age +2.43437 × chromosome 3 status +0.39496 × ExpressionCCL18. Notably, in this formula, the normal chromosome 3 was coded as 0, whereas the chromosome 3 loss was coded as 1. Each patient was assigned to either low-risk or high-risk groups using the median cut-off in the training cohort. High-risk patients survived for a shorter time than low-risk patients. The time-dependent and multivariate receiver operating characteristic curves showed promising diagnostic efficacy. Multivariate Cox regression analysis demonstrated the potential of this CCL18-related signature as an independent prognostic indicator. These results were validated using the GSE22138 dataset. In addition, in both TCGA-UM and GSE22138 datasets, stratification of clinical correlations and survival analyses based on this signature indicated the involvement of clinical progression and survival outcome in UM. In the high-risk group, Gene Ontology analyses mainly indicated the enrichment of immune response pathways, such as the T cell activation, response to interferon-gamma, antigen processing and presentation, interferon-gamma-mediated signaling pathway, MHC protein complex, MHC class II protein complex, antigen binding, and cytokine binding. Meanwhile, Kyoto Encyclopedia of Genes and Genomes analyses showed enrichments of pathways in cancer, cell adhesion, cytokine-cytokine receptor interaction, chemokine signaling pathway, Th1 and Th2 cell differentiation, and chemokine signaling pathway. Moreover, single-sample gene set enrichment analysis demonstrated the enrichment of almost all immune cells and immune functions in the high-risk group. In summary, a new prognostic CCL18-related signature was successfully established using the TCGA-UM dataset and validated using the GSE22138 dataset with meaningful predictive and diagnostic efficacies. This signature could serve as an independent and promising prognostic biomarker for patients with UM.

Ovotesticular disorders of sex development in FGF9 mouse models of human synostosis syndromes.

In mice, male sex determination depends on FGF9 signalling via FGFR2c in the bipotential gonads to maintain the expression of the key testis gene SOX9. In humans, however, while FGFR2 mutations have been linked to 46,XY disorders of sex development (DSD), the role of FGF9 is unresolved. The only reported pathogenic mutations in human FGF9, FGF9S99N and FGF9R62G, are dominant and result in craniosynostosis (fusion of cranial sutures) or multiple synostoses (fusion of limb joints). Whether these synostosis-causing FGF9 mutations impact upon gonadal development and DSD etiology has not been explored. We therefore examined embryonic gonads in the well-characterized Fgf9 missense mouse mutants, Fgf9S99N and Fgf9N143T, which phenocopy the skeletal defects of FGF9S99N and FGF9R62G variants, respectively. XY Fgf9S99N/S99N and XY Fgf9N143T/N143T fetal mouse gonads showed severely disorganized testis cords and partial XY sex reversal at 12.5 days post coitum (dpc), suggesting loss of FGF9 function. By 15.5 dpc, testis development in both mutants had partly recovered. Mitotic analysis in vivo and in vitro suggested that the testicular phenotypes in these mutants arise in part through reduced proliferation of the gonadal supporting cells. These data raise the possibility that human FGF9 mutations causative for dominant skeletal conditions can also lead to loss of FGF9 function in the developing testis, at least in mice. Our data suggest that, in humans, testis development is largely tolerant of deleterious FGF9 mutations which lead to skeletal defects, thus offering an explanation as to why XY DSDs are rare in patients with pathogenic FGF9 variants.

Testis-specific serine protease PRSS54 regulates acrosomal granule localization and sperm head morphogenesis in mice†.

Serine proteases (PRSS) constitute nearly one-third of all proteases, and many of them have been identified to be testis-specific and play significant roles during sperm development and male reproduction. PRSS54 is one of the testis-specific PRSS in mouse and human but its physiological function remains largely unclear. In the present study, we demonstrate in detail that PRSS54 exists not only in testis but also in mature sperm, exhibiting a change in protein size from 50 kDa in testis to 42 kDa in sperm. Loss of PRSS54 in mice results in male subfertility, acrosome deformation, defective sperm-zona penetration, and phenotypes of male subfertility and acrosome deformation can be rescued by Prss54 transgene. Ultrastructure analyses by transmission electronic microscopy further reveal various morphological abnormalities of Prss54-/- spermatids during spermiogenesis, including unfused vacuoles in acrosome, detachment and eccentrical localization of the acrosomal granules, and asymmetrical elongation of the nucleus. Subcellular localization of PRSS54 display that it appears in the acrosomal granule at the early phase of acrosome biogenesis, then extends along the inner acrosomal membrane, and ultimately presents in the acrosome region of the mature sperm. PRSS54 interacts with acrosomal proteins ZPBP1, ZPBP2, ACRBP, and ZP3R, and loss of PRSS54 affects the distribution of these proteins in testis and sperm, although their protein levels are largely unaffected. Moreover, Prss54-/- sperm are more sensitive to acrosome reaction inducers.

Two novel testis-specific long noncoding RNAs produced by 1700121C10Rik are dispensable for male fertility in mice.

Testis-specific genes are prone to affect spermatogenesis or sperm fertility, and thus may play pivotal roles in male reproduction. However, whether a gene really affects male reproduction in vivo needs to be confirmed using a gene knock-out (KO) model, a 'gold standard' method. Increasing studies have found that some of the evolutionarily conserved testis-enriched genes are not essential for male fertility. In this study, we report that 1700121C10Rik, a previously uncharacterized gene, is specifically expressed in the testis and produces two long noncoding RNAs (lncRNAs) in mouse: Transcript 1 and Transcript 2. qRT-PCR, northern blotting, and in situ hybridization revealed that expression of both the lncRNAs commenced at the onset of sexual maturity and was predominant in round and elongating spermatids during spermiogenesis. Moreover, we found different subcellular localization of Transcript 1 and Transcript 2 that was predominant in the cytoplasm and nucleus, respectively. 1700121C10Rik-KO mouse model disrupting Transcript 1 and Transcript 2 expression was generated by CRISPR/Cas9 to determine their role in male reproduction. Results showed that 1700121C10Rik-KO male mice were fully fertile with approximately standard testis size, testicular histology, sperm production, sperm morphology, sperm motility, and induction of acrosome reaction. Thus, we conclude that both the testis-specific 1700121C10Rik-produced lncRNAs are dispensable for male fertility in mice under standard laboratory conditions.

A point mutation in Fgf9 impedes joint interzone formation leading to multiple synostoses syndrome.

Human multiple synostoses syndrome (SYNS) is an autosomal dominant disorder characterized by multiple joint fusions. We previously identified a point mutation (S99N) in FGF9 that causes human SYNS3. However, the physiological function of FGF9 during joint development and comprehensive molecular portraits of SYNS3 remain elusive. Here, we report that mice harboring the S99N mutation in Fgf9 develop the curly tail phenotype and partially or fully fused caudal vertebrae and limb joints, which mimic the major phenotypes of SYNS3 patients. Further study reveals that the S99N mutation in Fgf9 disrupts joint interzone formation by affecting the chondrogenic differentiation of mesenchymal cells at the early stage of joint development. Consistently, the limb bud micromass culture (LBMMC) assay shows that Fgf9 inhibits mesenchymal cell differentiation into chondrocytes by downregulating the expression of Sox6 and Sox9. However, the mutant protein does not exhibit the same inhibitory effect. We also show that Fgf9 is required for normal expression of Gdf5 in the prospective elbow and knee joints through its activation of Gdf5 promoter activity. Signal transduction assays indicate that the S99N mutation diminishes FGF signaling in developmental limb joints. Finally, we demonstrate that the conformational change in FGF9 resulting from the S99N mutation disrupts FGF9/FGFR/heparin interaction, which impedes FGF signaling in developmental joints. Taken together, we conclude that the S99N mutation in Fgf9 causes SYNS3 via the disturbance of joint interzone formation. These results further implicate the crucial role of Fgf9 during embryonic joint development.

Serine protease PRSS55 is crucial for male mouse fertility via affecting sperm migration and sperm-egg binding.

Testis-specific PRSS55 is a highly conserved chymotrypsin-like serine protease among mammalian species. So far, the physiological function of PRSS55 remains unknown. Here, we show that PRSS55 is a GPI-anchored membrane protein, specifically expressed in adult mouse testis and mainly observed in the luminal side of seminiferous tubules and sperm acrosome. Mice deficient for Prss55 develop male infertile with normal reproduction-related parameters observed. Interestingly, in vivo fertilization rate of Prss55-/- males is dramatically decreased, possibly due to incapable migration of Prss55-/- sperm from uterus into oviduct. However, in vitro fertilization rate has no difference between two genotypes although Prss55-/- sperm presents defective recognition/binding to zona-intact or zona-free oocytes. Further study reveals that mature ADAM3 is almost undetectable in Prss55-/- sperm, while precursor ADAM3 remains unchanged in the testis. However, it is shown that ADAM3 has no interaction with PRSS55 by immunoprecipitation with anti-PRSS55 antibody. The expression levels of several proteins known to be related to the observed phenotypes remain comparable between wt and Prss55-/- mice. Moreover, we found that Prss55 deficiency has no effect on PRSS37 or vice versa albeit two mutant males share almost the same phenotypes. Microarray analysis reveals a total of 72 differentially expressed genes in Prss55-/- testis, most of which are associated with cellular membrane and organelle organization, protein transport and complex assembly, and response to stimulus and signaling. In conclusion, we have demonstrated that PRSS55 plays vital roles in regulating male fertility of mice, including in vivo sperm migration and in vitro sperm-egg interaction, possibly by affecting the maturation of ADAM3 in sperm and the expression of multiple genes in testis.

Adenosine A2A receptor antagonists act at the hyperoxic phase to confer protection against retinopathy.

BACKGROUND: Retinopathy of prematurity (ROP) remains a major cause of childhood blindness and current laser photocoagulation and anti-VEGF antibody treatments are associated with reduced peripheral vision and possible delayed development of retinal vasculatures and neurons. In this study, we advanced the translational potential of adenosine A2A receptor (A2AR) antagonists as a novel therapeutic strategy for selectively controlling pathological retinal neovascularization in oxygen-induced retinopathy (OIR) model of ROP. METHODS: Developing C57BL/6 mice were exposed to 75% oxygen from postnatal (P) day 7 to P12 and to room air from P12 to P17 and treated with KW6002 or vehicle at different postnatal developmental stages. Retinal vascularization was examined by whole-mount fluorescence and cross-sectional hematoxylin-eosin staining. Cellular proliferation, astrocyte and microglial activation, and tip cell function were investigated by isolectin staining and immunohistochemistry. Apoptosis was analyzed by TUNEL assay. The effects of oxygen exposure and KW6002 treatment were analyzed by two-way ANOVA or Kruskal-Wallis test or independent Student's t-test or Mann-Whitney U test. RESULTS: The A2AR antagonist KW6002 (P7-P17) did not affect normal postnatal development of retinal vasculature, but selectively reduced avascular areas and neovascularization, with the reduced cellular apoptosis and proliferation, and enhanced astrocyte and tip cell functions in OIR. Importantly, contrary to our prediction that A2AR antagonists were most effective at the hypoxic phase with aberrantly increased adenosine-A2AR signaling, we discovered that the A2AR antagonist KW6002 mainly acted at the hyperoxic phase to confer protection against OIR as KW6002 treatment at P7-P12 (but not P12-P17) conferred protection against OIR; this protection was observed as early as P9 with reduced avascular areas and reduced cellular apoptosis and reversal of eNOS mRNA down-regulation in retina of OIR. CONCLUSIONS: As ROP being a biphasic disease, our identification of the hyperoxic phase as the effective window, together with selective and robust protection against pathological (but not physiological) angiogenesis, elevates A2AR antagonists as a novel therapeutic strategy for ROP treatment.

Caffeine preferentially protects against oxygen-induced retinopathy.

Retinopathy of prematurity (ROP) is the leading cause of childhood blindness, but current anti-VEGF therapy is concerned with delayed retinal vasculature, eye, and brain development of preterm infants. The clinical observation of reduced ROP severity in premature infants after caffeine treatment for apnea suggests that caffeine may protect against ROP. Here, we demonstrate that caffeine did not interfere with normal retinal vascularization development but selectively protected against oxygen-induced retinopathy (OIR) in mice. Moreover, caffeine attenuated not only hypoxia-induced pathologic angiogenesis, but also hyperoxia-induced vaso-obliteration, which suggests a novel protection window by caffeine. At the hyperoxic phase, caffeine reduced oxygen-induced neural apoptosis by adenosine A2A receptor (A2AR)-dependent mechanism, as revealed by combined caffeine and A2AR-knockout treatment. At the hypoxic phase, caffeine reduced microglial activation and enhanced tip cell formation by A2AR-dependent and -independent mechanisms, as combined caffeine and A2AR knockout produced additive and nearly full protection against OIR. Together with clinical use of caffeine in neonates, our demonstration of the selective protection against OIR, effective therapeutic window, adenosine receptor mechanisms, and neuroglial involvement provide the direct evidence of the novel effects of caffeine therapy in the prevention and treatment of ROP.-Zhang, S., Zhou, R., Li, B., Li, H., Wang, Y., Gu, X., Tang, L., Wang, C., Zhong, D., Ge, Y., Huo, Y., Lin, J., Liu, X.-L., Chen, J.-F. Caffeine preferentially protects against oxygen-induced retinopathy.

Tafa-2 plays an essential role in neuronal survival and neurobiological function in mice.

Tafa is a family of small secreted proteins with conserved cysteine residues and restricted expression in the brain. It is composed of five highly homologous genes referred to as Tafa-1 to -5. Among them, Tafa-2 is identified as one of the potential genes responsible for intellectual deficiency in a patient with mild mental retardation. To investigate the biological function of Tafa-2 in vivo, Tafa-2 knockout mice were generated. The mutant mice grew and developed normally but exhibited impairments in spatial learning and memory in Morris water maze test and impairments in short- and long-term memory in novel object recognition test, accompanied with increased level of anxiety-like behaviors in open-field test and elevated plus maze test, and decreased level of depression-like behaviors in forced-swim test and tail-suspension test. Further examinations revealed that Tafa-2 deficiency causes severe neuronal reduction and increased apoptosis in the brain of Tafa-2-/- mice via downregulation of PI3K/Akt and MAPK/Erk pathways. Conformably, the expression levels of CREB target genes including BDNF, c-fos and NF1, and CBP were found to be reduced in the brain of Tafa-2-/- mice. Taken together, our data indicate that Tafa-2 may function as a neurotrophic factor essential for neuronal survival and neurobiological functions.

Nhe5 deficiency enhances learning and memory via upregulating Bdnf/TrkB signaling in mice.

Nhe5, a Na+ /H+ exchanger, is predominantly expressed in brain tissue and is proposed to act as a negative regulator of dendritic spine growth. Up to now, its physiological function in vivo remains unclear. Here we show that Nhe5-deficient mice exhibit markedly enhanced learning and memory in Morris water maze, novel object recognition, and passive avoidance task. Meanwhile, the pre- and post-synaptic components, synaptophysin (Syn) and post-synaptic density 95 (PSD95) expression levels were found increased in hippocampal regions lacking of Nhe5, suggesting a possible alterations in neuronal synaptic structure and function in Nhe5-/- mice. Further study reveals that Nhe5 deficiency leads to higher Bdnf expression levels, followed by increased phosphorylated TrkB and PLCγ levels, indicating that Bdnf/TrkB signaling is activated due to Nhe5 deficiency. Moreover, the corresponding brain regions of Nhe5-/- mice display elevated ERK/CaMKII/CREB phosphorylation levels. Taken together, these findings uncover a novel physiological function of Nhe5 in regulating learning and memory, further implying Nhe5 as a potential therapeutic target for improving cognition.

Pressure-Induced Structural and Electronic Transition in Sr2ZnWO6 Double Perovskite.

High-pressure structural and electrical properties of Sr2ZnWO6 double perovskite were investigated using in situ angle-dispersive synchrotron X-ray diffraction (XRD), Raman, and alternating current (AC) impedance spectroscopy. A structural transition from monoclinic (P21/n) to triclinic (P1̅) phase around 9 GPa was observed due to the pressure-induced distortion of (W, Zn)O6 octahedron. In situ high-pressure Raman spectroscopy showed the increasing interaction among O-W-O in WO6 octahedron with pressure and a transition pressure consistent with the XRD results. From the AC impedance spectroscopy measurements, the resistivity increased steeply by ∼1 order of magnitude around 11 GPa, indicating an electronic transition accompanying the symmetry change. The increase in the interaction among O-W-O enhances the attraction of O(2-) electrons toward W(6+), thus increasing the covalence, which in turn lowers the charge transfer energy between O(2-) and W(6+) and induces the resistivity increase under high pressure.

Re-emerging magnetic order in correlated van der Waals antiferromagnet NiPS3.

Van der Waals (vdW) gap is a significant feature that distinguishes vdW magnets from traditional magnets. Manipulating the magnetic properties by changing the vdW gap has been hot topic in condensed matter research. Here we report a re-emerging magnetic order induced by pressure in a correlated vdW antiferromagnetic insulator NiPS3. It is found that the interlayer magnetoresistance (MR) nearly vanishes at the critical pressure where the crystal structure transforms fromC2/mphase to the slidingC2/mphase. On further compression within the slidingC2/mphase, a substantially enhanced MR emerges from low temperature associated with an insulator-to-metal transition, indicating a metallic antiferromagnetic phase. The enhanced re-emerging MR in slidingC2/mphase can be ascribed to the increasing magnetic interaction between neighboring layers due to the vdW gap narrowing. Our results provide important experimental clues for understanding the pressure effects on magnetism in correlated layered materials.

Fgf9 regulates bone marrow mesenchymal stem cell fate and bone-fat balance in osteoporosis by PI3K/AKT/Hippo and MEK/ERK signaling.

Bone-fat balance is crucial to maintain bone homeostasis. As common progenitor cells of osteoblasts and adipocytes, bone marrow mesenchymal stem cells (BMSCs) are delicately balanced for their differentiation commitment. However, the exact mechanisms governing BMSC cell fate are unclear. In this study, we discovered that fibroblast growth factor 9 (Fgf9), a cytokine expressed in the bone marrow niche, controlled bone-fat balance by influencing the cell fate of BMSCs. Histomorphology and cytodifferentiation analysis showed that Fgf9 loss-of-function mutation (S99N) notably inhibited bone marrow adipose tissue (BMAT) formation and alleviated ovariectomy-induced bone loss and BMAT accumulation in adult mice. Furthermore, in vitro and in vivo investigations demonstrated that Fgf9 altered the differentiation potential of BMSCs, shifting from osteogenesis to adipogenesis at the early stages of cell commitment. Transcriptomic and gene expression analyses demonstrated that FGF9 upregulated the expression of adipogenic genes while downregulating osteogenic gene expression at both mRNA and protein levels. Mechanistic studies revealed that FGF9, through FGFR1, promoted adipogenic gene expression via PI3K/AKT/Hippo pathways and inhibited osteogenic gene expression via MAPK/ERK pathway. This study underscores the crucial role of Fgf9 as a cytokine regulating the bone-fat balance in adult bone, suggesting that FGF9 is a potentially therapeutic target in the treatment of osteoporosis.

Prss37 is required for male fertility in the mouse.

In order to understand the mechanisms of mammalian fertilization, studies using genetically manipulated animals have provided us with plenty of interesting and valuable information on the genetic factors affecting male fertility. In the present work, we demonstrate for the first time that Prss37, a previously uncharacterized putative trypsin-like serine protease, is required for male fertility. Prss37 is highly and exclusively expressed in the testis of adult mice, especially in the elongating spermatids during spermiogenesis, and almost vanishes in the mature sperm of mice. Mice deficient for Prss37 show male infertility, but their mating activity, spermatogenesis, sperm morphology, and motility remain unaffected. In vivo fertilization assays revealed that Prss37(-/-) mice exhibited a markedly decreased fertilization rate (2.3% vs. 70% of that in control mice) accompanied by the defect in sperm migration from uterus into oviduct. In vitro study further showed sperm were incapable of sperm-egg recognition/binding when zona-intact eggs were exposed to Prss37(-/-) sperm, in which mature Adam3 was completely undetectable. Interestingly, however, Prss37(-/-) sperm were able to fertilize cumulus-intact oocytes in vitro. These data clearly indicate that Prss37 deficiency causes the absence of mature Adam3 in sperm and a defect in sperm migration from uterus into oviduct, which mainly accounts for male infertility of Prss37-null mice, while the defect in sperm-zona binding seems irrelevant to the fertilizing ability of Prss37(-/-) sperm.

Vibrational and structural properties of tetramethyltin under pressure.

The vibrational and structural properties of a hydrogen-rich group IVa hydride, Sn(CH(3))(4), have been investigated by combining Raman spectroscopy and synchrotron x-ray diffraction measurements at room temperature and at pressures up to 49.9 GPa. Both techniques allow the obtaining of complementary information on the high-pressure behaviors and yield consistent phase transitions at 0.9 GPa for the liquid to solid and 2.8, 10.4, 20.4, and 32.6 GPa for the solid to solid. The foregoing solid phases are identified to have the orthorhombic, tetragonal, monoclinic crystal structures with space groups of Pmmm for phase I, P4/mmm for phase II, P2/m for phase III, respectively. The phases IV and V coexist with phase III, resulting in complex analysis on the possible structures. These transitions suggest the variation in the inter- and intra-molecular bonding of this compound.