NVP-BHG712 alleviates ovariectomy-induced osteoporosis by modulating osteoclastogenesis.

Postmenopausal osteoporosis (PMOP) is closely related to the pathogenesis of osteoclasts, with the Cathepsin K (CTSK) protein playing a crucial role. Our study aimed to screen small molecule compounds targeting CTSK and evaluate their impact on PMOP. Through molecular docking, we identified NVP-BHG712 as significantly inhibiting osteoclast differentiation and bone resorption. NVP-BHG712 also effectively suppressed CTSK activity and exhibited strong binding affinity to CTSK protein. Furthermore, NVP-BHG712 regulated the expression of inflammatory factors and modulated the balance between M1 and M2 macrophage polarization. In the mouse model of ovariectomy-induced osteoporosis, NVP-BHG712 rescued bone loss by inhibiting excessive osteoclast activation. These findings suggest that NVP-BHG712 may be a promising treatment for pathological osteoporosis by alleviating osteoclast function.

Exposure to polystyrene microplastics during lactational period alters immune status in both male mice and their offspring.

The widespread use of microplastics and their harmful effects on the environment have emerged as serious concerns. However, the effect of microplastics on the immune system of mammals, particularly their offspring, has received little attention. In this study, polystyrene microplastics (PS-MPs) were orally administered to male mice during lactation. Flow cytometry was used to assess the immune cells in the spleens of both adult male mice and their offspring. The results showed that mice exposed to PS-MPs exhibited an increase in spleen weight and an elevated number of B and regulatory T cells (Tregs), irrespective of dosage. Furthermore, the F1 male offspring of the PS-MPs-exposed group had enlarged spleens; an increased number of B cells, T helper cells (Th cells), and Tregs; and an elevated ratio of T helper cells 17 (Th17 cells) to Tregs and T helper cells 1 (Th1 cells) to T helper cells 2 (Th2 cells). These results suggested a pro-inflammatory state in the spleen. In contrast, in the F1 female offspring exposed to PS-MPs, the changes in splenic immune cells were less pronounced. In the F2 generation of mice with exposed to PS-MPs, minimal alterations were observed in spleen immune cells and morphology. In conclusion, our study demonstrated that exposure to real human doses of PS-MPs during lactation in male mice altered the immune status, which can be passed on to F1 offspring but is not inherited across generations.

Reversible Electrochemical Swelling of Straight Carbon Nanotube Yarns for High-Performance Linear Actuation.

Coiled artificial muscle yarns outperform their straight counterparts in contractile strokes. However, challenges persist in the fabrication complexity and the susceptibility of the coiled yarns to becoming stuck by surrounding objects during contraction and recovery. Additionally, torsional stability remains a concern. In this study, it is reported that straight carbon nanotube (CNT) yarns when driven by a low-voltage electrochemical approach, can achieve a contractile stroke that surpasses even NiTi shape memory alloy fibers. The key lies in the suitable match between a yarn consisting of randomly aligned CNTs and the reversible and substantial electrochemical swelling induced by solvated ions. Wrinkled structures are formed on the surface of the CNT yarn to adapt to the swelling process. This not only assures torsional stability but also enhances the surface area for improved electrode-electrolyte interaction during electrochemical actuation. Remarkably, the CNT artificial muscle yarn generates a contractile stroke of 8.8% and an isometric stress of 7.5 MPa under 2.5 V actuation voltages, demonstrating its potential for applications requiring low energy consumption while maintaining high operational efficiency. This study highlights the crucial impact of CNT orientation on the effectiveness of electrochemically-driven artificial muscles, signaling new possibilities in smart material and biomechanical system development.

Lactating exposure to microplastics at the dose of infants ingested during artificial feeding induced reproductive toxicity in female mice and their offspring.

Microplastics (MPs) pollution poses a global environmental challenge with significant concerns regarding its potential impact on human health. Toxicological investigations have revealed multi-system impairments caused by MPs in various organisms. However, the specific reproductive hazards in human contexts remain elusive, and understanding the transgenerational reproductive toxicity of MPs remains limited. This study delves into the reproductive toxicity resulting from lactational exposure to polystyrene MPs (PS-MPs) in female mice, extending the inquiry to assess the reproductive effects on their offspring bred by rigorous natural mating. The MPs dosage corresponds to the detected concentration in infant formula prepared using plastic bottles. By systematically evaluating the reproductive phenotypes of F0 female mice from birth to adulthood, we found that female mice exposed to PS-MPs exhibited delayed puberty, disturbed estrous cyclicity, diminished fertility, elevated testosterone, abnormal follicle development, disrupted ovarian steroidogenesis, and ovarian inflammation. Importantly, the observed inheritable reproductive toxicity manifested with gender specificity, showcasing more pronounced abnormalities in male offspring. Specifically, reproductive disorders did not manifest in female offspring; however, a significant decrease in sperm count and viability was observed in PS-MPs-exposed F1 males. Testicular transcriptomics analysis of F1 males significantly enriched pathways associated with reproductive system development and epigenetic modification, such as male germ cell proliferation, DNA methylation, and histone modification. In summary, real-life exposure to PS-MPs impaired the reproductive function of female mice and threateningly disrupted the spermatogenesis of their F1 male offspring, which raises serious concerns about inter- and trans-generational reproductive toxicities of MPs in mammals. These findings underscore the potential threats of MPs to human reproductive health, emphasizing the need for continued vigilance and research in this critical area.

Growth differentiation factor 11 regulates high glucose-induced cardiomyocyte pyroptosis and diabetic cardiomyopathy by inhibiting inflammasome activation.

BACKGROUND: Diabetic cardiomyopathy (DCM) is a crucial complication of long-term chronic diabetes that can lead to myocardial hypertrophy, myocardial fibrosis, and heart failure. There is increasing evidence that DCM is associated with pyroptosis, a form of inflammation-related programmed cell death. Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor ß superfamily, which regulates oxidative stress, inflammation, and cell survival to mitigate myocardial hypertrophy, myocardial infarction, and vascular injury. However, the role of GDF11 in regulating pyroptosis in DCM remains to be elucidated. This research aims to investigate the role of GDF11 in regulating pyroptosis in DCM and the related mechanism. METHODS AND RESULTS: Mice were injected with streptozotocin (STZ) to induce a diabetes model. H9c2 cardiomyocytes were cultured in high glucose (50 mM) to establish an in vitro model of diabetes. C57BL/6J mice were preinjected with adeno-associated virus 9 (AAV9) intravenously via the tail vein to specifically overexpress myocardial GDF11. GDF11 attenuated pyroptosis in H9c2 cardiomyocytes after high-glucose treatment. In diabetic mice, GDF11 alleviated cardiomyocyte pyroptosis, reduced myocardial fibrosis, and improved cardiac function. Mechanistically, GDF11 inhibited pyroptosis by preventing inflammasome activation. GDF11 achieved this by specifically binding to apoptosis-associated speck-like protein containing a CARD (ASC) and preventing the assembly and activation of the inflammasome. Additionally, the expression of GDF11 during pyroptosis was regulated by peroxisome proliferator-activated receptor α (PPARα). CONCLUSION: These findings demonstrate that GDF11 can treat diabetic cardiomyopathy by alleviating pyroptosis and reveal the role of the PPARα-GDF11-ASC pathway in DCM, providing ideas for new strategies for cardioprotection.

Knittable Electrochemical Yarn Muscle for Morphing Textiles.

Morphing textiles, crafted using electrochemical artificial muscle yarns, boast features such as adaptive structural flexibility, programmable control, low operating voltage, and minimal thermal effect. However, the progression of these textiles is still impeded by the challenges in the continuous production of these yarn muscles and the necessity for proper structure designs that bypass operation in extensive electrolyte environments. Herein, a meters-long sheath-core structured carbon nanotube (CNT)/nylon composite yarn muscle is continuously prepared. The nylon core not only reduces the consumption of CNTs but also amplifies the surface area for interaction between the CNT yarn and the electrolyte, leading to an enhanced effective actuation volume. When driven electrochemically, the CNT@nylon yarn muscle demonstrates a maximum contractile stroke of 26.4%, a maximum contractile rate of 15.8% s-1, and a maximum power density of 0.37 W g-1, surpassing pure CNT yarn muscles by 1.59, 1.82, and 5.5 times, respectively. By knitting the electrochemical CNT@nylon artificial muscle yarns into a soft fabric that serves as both a soft scaffold and an electrolyte container, we achieved a morphing textile is achieved. This textile can perform programmable multiple motion modes in air such as contraction and sectional bending.

PBX3 as a biomarker for the early diagnosis and prediction of prognosis of glioma.

BACKGROUND: Increasing evidence have elucidated that PBX3 played a crucial role in cancer initiation and progression. PBX3 was differentially expressed in many cancer types. However, PBX3 potential involvement in gliomas remains to be explored. METHODS: The expression level of PBX3 in glioma tissues and glioma cells, and its correlation with clinical features were analyzed by data from TCGA, GEPIA, CGGA and CCLE. Univariable survival and Multivariate Cox analysis was used to compare several clinical characteristics with survival. We also analyzed the correlation between PBX3 expression level and survival outcome and survival time of LGG and GBM patients by using linear regression equation. GSEA was used to generate an ordered list of all genes related to PBX3 expression and screening of genes co-expressed with PBX3 mRNA by "limma" package. RESULTS: The results showed that PBX3 was highly expressed in gliomas and its expression increased with the increase of malignancy. Survival analysis found that PBX3 is more valuable in predicting the OS and PFI of LGG patients than that of GBM. For further study, TCGA and CGGA data were downloaded for univariate Cox analysis and multivariate Cox analysis which showed that the expression of PBX3 was independent influencing factors for poor prognosis of LGG patients. Meanwhile, Receiver operating characteristic (ROC) curve showed that PBX3 was a predictor of overall survival rate and progression-free survival rate of LGG. Linear regression model analysis indicated that the higher expression of PBX3 the higher the risk of death of LGG patients, and the higher expression of PBX3 the higher the risk of disease progression of LGG patients. Next, TCGA data were downloaded for GSEA and Co-expression analyses, which was performed to study the function of PBX3. CONCLUSION: PBX3 may be involved in the occurrence and development of glioma, and has potential reference value for the early diagnosis and prediction of prognosis of glioma.

Supraphysiologic doses of 17ß-estradiol aggravate depression-like behaviors in ovariectomized mice possibly via regulating microglial responses and brain glycerophospholipid metabolism.

BACKGROUND: 17ß-Estradiol (E2) is generally considered neuroprotective in humans. However, the current clinical use of estrogen replacement therapy (ERT) is based on the physiological dose of E2 to treat menopausal syndrome and has limited therapeutic efficacy. The efficacy and potential toxicity of superphysiological doses of ERT for menopausal neurodegeneration are unknown. METHODS: In this study, we investigated the effect of E2 with a supraphysiologic dose (0.5 mg/kg, sE2) on the treatment of menopausal mouse models established by ovariectomy. We performed the open field, Y-maze spontaneous alternation, forced swim tests, and sucrose preference test to investigate behavioral alterations. Subsequently, the status of microglia and neurons was detected by immunohistochemistry, HE staining, and Nissl staining, respectively. Real-time PCR was used to detect neuroinflammatory cytokines in the hippocampus and cerebral cortex. Using mass spectrometry proteomics platform and LC-MS/ MS-based metabolomics platform, proteins and metabolites in brain tissues were extracted and analyzed. BV2 and HT22 cell lines and primary neurons and microglia were used to explore the underlying molecular mechanisms in vitro. RESULTS: sE2 aggravated depression-like behavior in ovariectomized mice, caused microglia response, and increased proinflammatory cytokines in the cerebral cortex and hippocampus, as well as neuronal damage and glycerophospholipid metabolism imbalance. Subsequently, we demonstrated that sE2 induced the pro-inflammatory phenotype of microglia through ERα/NF-κB signaling pathway and downregulated the expression of cannabinoid receptor 1 in neuronal cells, which were important in the pathogenesis of depression. CONCLUSION: These data suggest that sE2 may be nonhelpful or even detrimental to menopause-related depression, at least partly, by regulating microglial responses and glycerophospholipid metabolism.

Dual-Ion Co-Regulation System Enabling High-Performance Electrochemical Artificial Yarn Muscles with Energy-Free Catch States.

Artificial yarn muscles show great potential in applications requiring low-energy consumption while maintaining high performance. However, conventional designs have been limited by weak ion-yarn muscle interactions and inefficient "rocking-chair" ion migration. To address these limitations, we present an electrochemical artificial yarn muscle design driven by a dual-ion co-regulation system. By utilizing two reaction channels, this system shortens ion migration pathways, leading to faster and more efficient actuation. During the charging/discharging process, [Formula: see text] ions react with carbon nanotube yarn, while Li+ ions react with an Al foil. The intercalation reaction between [Formula: see text] and collapsed carbon nanotubes allows the yarn muscle to achieve an energy-free high-tension catch state. The dual-ion coordinated yarn muscles exhibit superior contractile stroke, maximum contractile rate, and maximum power densities, exceeding those of "rocking-chair" type ion migration yarn muscles. The dual-ion co-regulation system enhances the ion migration rate during actuation, resulting in improved performance. Moreover, the yarn muscles can withstand high levels of isometric stress, displaying a stress of 61 times that of skeletal muscles and 8 times that of "rocking-chair" type yarn muscles at higher frequencies. This technology holds significant potential for various applications, including prosthetics and robotics.

Pretension-Free and Self-Recoverable Coiled Artificial Muscle Fibers with Powerful Cyclic Work Capability.

Similar to natural muscle fibers, coiled artificial muscle fibers provide a straightforward contraction. However, unlike natural muscle fibers, their recovery from the contracted state to the initial state requires high stress, resulting in almost zero work during a full actuation cycle. Herein, a self-recoverable coiled artificial muscle fiber was prepared by conformally coating an elastic carbon nanotube (CNT) fiber with a very thin liquid crystal elastomer (LCE) sheath. The as-obtained muscle fiber demonstrated excellent actuation properties comprising 56.9% contractile stroke, 1522%/s contraction rate, 7.03 kW kg-1 power density, and 32,000 stable cycles. The LCE chains were helically aligned in a nematic phase, and the phase change of the LCE caused by Joule heating drove the actuation process. Moreover, the LCE/CNT fiber had a well-separated, torsionally stable, and elastic coiled structure, which permitted large contractile strokes and acted as an elastic template for external-stress-free recovery. Thus, the use of self-recoverable muscle fibers to mimic the natural muscles for object dragging, multidirectional bending, and quick striking was demonstrated.

The radiomics features of the temporal lobe region related to menopause based on MR-T2WI can be used as potential biomarkers for AD.

Menopause may be an important pathogenic factor for Alzheimer's disease (AD). The M1 polarization of microglia and neuroinflammatory responses occur in the early pathogenetic stages of AD. Currently, no effective monitoring markers are available for AD's early pathological manifestations. Radiomics is an automated feature generation method for the extraction of hundreds of quantitative phenotypes (radiomics features) from radiology images. In this study, we retrospectively analyzed the magnetic resonance T2-weighted imaging (MR-T2WI) on the temporal lobe region and clinical data of both premenopausal and postmenopausal women. There were three significant differences were identified for select radiomic features in the temporal lobe between premenopausal and postmenopausal women, i.e. the texture feature Original-glcm-Idn (OI) based on the Original image, the filter-based first-order feature Log-firstorder-Mean (LM), and the texture feature Wavelet-LHH-glrlm-Run Length Nonuniformity (WLR). In humans, these three features were significantly correlated with the timing of menopause. In mice, these features were also different between the sham and ovariectomy (OVX) groups and were significantly associated with neuronal damage, microglial M1 polarization, neuroinflammation, and cognitive decline in the OVX groups. In AD patients, OI was significantly associated with cognitive decline, while LM was associated with anxiety and depression. OI and WLR could distinguish AD from healthy controls. In conclusion, radiomics features based on brain MR-T2WI scans have the potential to serve as biomarkers for AD and noninvasive monitoring of pathological progression in the temporal lobe of the brain in women undergoing menopause.

RBM46 is essential for gametogenesis and functions in post-transcriptional roles affecting meiotic cohesin subunits.

RBM46 is a germ cell-specific RNA-binding protein required for gametogenesis, but the targets and molecular functions of RBM46 remain unknown. Here, we demonstrate that RBM46 binds at specific motifs in the 3'UTRs of mRNAs encoding multiple meiotic cohesin subunits and show that RBM46 is required for normal synaptonemal complex formation during meiosis initiation. Using a recently reported, high-resolution technique known as LACE-seq and working with low-input cells, we profiled the targets of RBM46 at single-nucleotide resolution in leptotene and zygotene stage gametes. We found that RBM46 preferentially binds target mRNAs containing GCCUAU/GUUCGA motifs in their 3'UTRs regions. In Rbm46 knockout mice, the RBM46-target cohesin subunits displayed unaltered mRNA levels but had reduced translation, resulting in the failed assembly of axial elements, synapsis disruption, and meiotic arrest. Our study thus provides mechanistic insights into the molecular functions of RBM46 in gametogenesis and illustrates the power of LACE-seq for investigations of RNA-binding protein functions when working with low-abundance input materials.

Air pollution exposure and ovarian reserve impairment in Shandong province, China: The effects of particulate matter size and exposure window.

BACKGROUND: Lack of evidence exists on whether air pollution exposure may affect ovarian reserve, especially for Chinese women. OBJECTIVES: To explore the association between exposure to various air pollutants and anti-Müllerian hormone (AMH), a predictor of ovarian reserve, over different exposure windows in Shandong Province, China. METHODS: We enrolled 18,878 women who had AMH measurements in the Center for Reproductive Medicine, Shandong University during 2010-2019. Daily average concentrations of ambient particulate matter with diameters ≤1 µm/2.5 µm/10 µm (PM1, PM2.5, and PM10), nitrogen dioxide (NO2) and ozone (O3) were developed at a spatial resolution of 0.01° × 0.01°, and assigned to the residential addresses. Three exposure windows were considered, i.e., the process from primary to small antral follicle stage (W1), from primary to secondary follicle stage (W2), and from secondary to small antral follicle stage (W3). The air pollution-AMH association was fitted using the multivariable linear mixed effect model with adjustment for potential confounders. Stratified analyses were performed by age group, overweight status, residential region, and educational level. RESULTS: The level of AMH changed by -8.8% (95% confidence interval (CI): -12.1%, -5.3%), -2.1% (95% CI: -3.5%, -0.6%), -1.9% (95% CI: -3.3%, -0.5%), and -4.5% (95% CI: -7.1%, -1.9%) per 10 µg/m3 increase in PM1, PM2.5, PM10, and NO2, respectively, during W1. The effect estimates were significant during W2 for PM1, PM2.5 and NO2 while minimal association was observed in W3. Greater vulnerability for certain air pollutants were observed for women who lived in inland areas and were less educated. CONCLUSIONS: We found that ovarian reserve was negatively associated with air pollution exposure for women, particularly from the primary to secondary follicle stage. The effect estimate increased by the reduction in the diameter of PMs, which also varied across population sub-groups.

Artificial neuromuscular fibers by multilayered coaxial integration with dynamic adaption.

Integrating sense in a thin artificial muscle fiber for environmental adaption and actuation path tracing, as a snail tentacle does, is highly needed but still challenging because of the interfacing mismatch between the fiber's actuation and sensing components. Here, we report an artificial neuromuscular fiber by wrapping a carbon nanotube (CNT) fiber core in sequence with an elastomer layer, a nanofiber network, and an MXene/CNT thin sheath, achieving the ingenious sense-judge-act intelligent system in an elastic fiber. The CNT/elastomer components provide actuation, and the sheath enables touch/stretch perception and hysteresis-free cyclic actuation tracing due to its strain-dependent resistance. As a whole, the coaxial structure builds a dielectric capacitor that enables sensitive touchless perception. The key to seamless integration is to use a nanofiber interface that allows the sensing layer to adaptively trace but not restrict actuation. This work provides promising solutions for closed-loop control for future intelligent soft robots.

Metformin promotes in vitro maturation of oocytes from aged mice by attenuating mitochondrial oxidative stress via SIRT3-dependent SOD2ac.

Human female fecundity decreases irreversibly as chronological age rises, adversely affecting oocyte quality, consequently worsening pregnancy outcomes and increasing the extent of birth defects. The first-line type 2 diabetes treatment metformin has been associated with delayed aging and reduction of oxidative stress; yet it remains unclear if metformin confers any benefits for oocytes from aged mice, particularly in the context of the assisted human reproductive technology (ART) known as in vitro maturation (IVM). Here, we found that adding metformin into the M16 culture medium of oocytes from aged mice significantly improved both oocyte maturation and early embryonic development. This study showed that metformin reduced the extent of meiotic defects and maintained a normal distribution of cortical granules (CGs). RNA-seq analysis of metformin-treated oocytes revealed genes apparently involved in the reduction of mitochondrial ROS. Further, the results supported that the metformin improved mitochondrial function, reduced apoptosis, increased the extent of autophagy, and reduced mitochondrial ROS via SIRT3-mediated acetylation status of SOD2K68 in oocytes from aged mice. Thus, this finding demonstrated a protective effect for metformin against the decreased quality of oocytes from aged mice to potentially improve ART success rates and illustrated a potential strategy to prevent or delay reproductive aging.

Dexamethasone Sensitizes Acute Monocytic Leukemia Cells to Ara-C by Upregulating FKBP51.

In this study, we demonstrated that the expression of FK506 binding protein 51 (FKBP51) is upregulated in acute monocytic leukemia (AML-M5) cells by dexamethasone and aimed to investigate the possible effects of FKBP51 on the growth and cytarabine sensitivity of AML-M5 cells. THP-1 and U937cells were used to establish AML-M5 cell models with FKBP51 overexpression and knockdown, respectively. Cell proliferation, apoptosis and response to cytarabine were investigated by cell cycle, CCK-8 and Flow cytometry analyses. The mice experiment was conducted to detect the role of FKBP51 on AML-M5 cells proliferation and antileukemia effect of Ara-C/Dexamethasone co-therapy in vivo. Western blots were employed to determine protein expression levels. FKBP51 upregulation significantly attenuated THP-1 cell proliferation and sensitized the cells to cytarabine treatment which was further enhanced by dexamethasone. These effects were indicated by decreases in cell viability, S-G2/M phase cell cycle distribution, cytarabine 50% inhibitory concentration (IC50) values and increases in apoptosis and were supported by decreased phosphorylation levels of AKT, GSK3ß and FOXO1A and decreased levels of BCL-2 and increased levels of P21 and P27. In contrast, FKBP51 knockdown led to excessive U937 cell proliferation and cytarabine resistance, as indicated by increased cell viability and S-G2/M phase cell cycle distribution, decreased apoptosis, increased phosphorylation levels of AKT, GSK3ß and FOXO1A, and increased BCL-2 and decreased P21 and P27 expression. In addition, an AKT inhibitor blocked cell cycle progression and reduced cell viability in all groups of cells. Furthermore, SAFit2, a specific FKBP51 inhibitor, increased U937 cell viability and cytarabine resistance as well as AKT phosphorylation. In conclusion, FKBP51 decelerates proliferation and improves the cytarabine sensitivity of AML-M5 cells by inhibiting AKT pathways, and dexamethasone in combination with Ara-C improves the chemosensitivity of AML-M5.

Association of SNPs in the FK-506 binding protein (FKBP5) gene among Han Chinese women with polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrine disorder in premenopausal women, whose etiology remains uncertain, although it is known to be highly heterogeneous and genetically complex. PCOS often presents with hyperandrogenism symptoms. The present study aimed to determine whether polymorphisms in the FK-506 binding protein 5 (FKBP5) gene (androgen target gene) are associated with an association for PCOS and hyperandrogenism. METHODS: This is a case-control study, and association analyses were conducted. A total of 13 single-nucleotide polymorphisms (SNPs) in the FKBP5 gene were evaluated in 775 PCOS patients who were diagnosed based on the Rotterdam Standard and 783 healthy Chinese Han women. Associations between FKBP5 SNPs and hormone levels were investigated. These 13 SNPs were genotyped using the Sequenom MassARRAY system, and an association analysis between the phenotype and alleles and genotypes were conducted. RESULTS: The genotype frequencies for the rs1360780 and rs3800373 SNPs differed significantly between the PCOS cases and healthy controls (p = 0.025, OR is 1.63 (1.05-2.53) and p = 0.029, OR is 1.59 (1.03-2.45) respectively under co-dominant model). Moreover, the genotype frequencies and genetic model analysis for the SNPs rs1360780, rs9470080, rs9296158, rs1043805 and rs7757037 differed significantly between the hyperandrogenism and non-hyperandrogenism groups of PCOS patients. The TT genotype of rs1360780, the TT genotype of rs9470080, the TT genotype of rs1043805 or the GG genotype of rs7705037 (ORs are 2.13 (1.03-4.39), 1.81 (1.03-3.17), 2.94 (1.32-6.53) and 1.72 (1.04-2.84) respectively) were correlated with androgen level of PCOS patients. CONCLUSION: Our study showed that FKBP5 gene polymorphisms are associated with PCOS generally (rs1360780 and rs3800373) and with the hyperandrogenism subtype specifically (rs1360780, rs9470080, rs9296158, rs1043805 and rs7757037).

Capturing 3D Chromatin Maps of Human Primary Monocytes: Insights From High-Resolution Hi-C.

Although the variation in chromatin architecture during adaptive immune responses has been thoroughly investigated, the 3D landscape of innate immunity is still unknown. Herein, chromatin regulation and heterogeneity among human primary monocytes were investigated. Peripheral blood was collected from two healthy persons and two patients with systemic lupus erythematosus (SLE), and CD14+ monocytes were selected to perform Hi-C, RNA-seq, ATAC-seq and ChIP-seq analyses. Raw data from the THP1 cell line Hi-C library were used for comparison. For each sample, we constructed three Hi-C libraries and obtained approximately 3 billion paired-end reads in total. Resolution analysis showed that more than 80% of bins presented depths greater than 1000 at a 5 kb resolution. The constructed high-resolution chromatin interaction maps presented similar landscapes in the four individuals, which showed significant divergence from the THP1 cell line chromatin structure. The variability in chromatin interactions around HLA-D genes in the HLA complex region was notable within individuals. We further found that the CD16-encoding gene (FCGR3A) is located at a variable topologically associating domain (TAD) boundary and that chromatin loop dynamics might modulate CD16 expression. Our results indicate both the stability and variability of high-resolution chromatin interaction maps among human primary monocytes. This work sheds light on the potential mechanisms by which the complex interplay of epigenetics and spatial 3D architecture regulates chromatin in innate immunity.

FKBP51 promotes invasion and migration by increasing the autophagic degradation of TIMP3 in clear cell renal cell carcinoma.

The occurrence of metastasis is a serious risk for renal cell carcinoma (RCC) patients. In order to develop novel therapeutic approaches to control the progression of metastatic RCC, it is of urgent need to understand the molecular mechanisms underlying RCC metastasis and identify prognostic markers of metastatic risk. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) have been known to be closely associated with extracellular matrix (ECM) turnover, which plays a highly active role in tumor metastasis. Recent studies have shown that immunophilin FK-506-binding protein 51 (FKBP51) may be important for the regulation of ECM function, and exert effects on the invasion and migration of tumor cells. However, the mechanisms underlying these activities remain unclear. The present study detected the role of FKBP51 in clear cell renal cell carcinoma (ccRCC), the most common subtype of RCC, and found that FKBP51 significantly promotes ccRCC invasion and migration by binding with the TIMP3, connecting TIMP3 with Beclin1 complex and increasing autophagic degradation of TIMP3. Given the important roles that TIMPs/MMPs play in ECM regulation and remodeling, our findings will provide new perspective for future investigation of the regulation of metastasis of kidney cancer and other types of cancer.

Protocatechualdehyde Inhibits the Osteoclast Differentiation of RAW264.7 and BMM Cells by Regulating NF-κB and MAPK Activity.

Protocatechualdehyde (PCA), an important component of Salvia miltiorrhiza, has many activities, such as anti-inflammatory and antisepsis activities. However, the role of PCA in osteoclasts is not clear. We used RAW264.7 cells (a mouse leukemic monocyte/macrophage cell line) and bone marrow macrophages (BMMs) to probe the role of PCA in osteoclasts and the underlying mechanism. The effects of PCA on cell activity were evaluated with CCK-8 assays. TRAP staining detected mature osteoclasts. Corning Osteo Assay Surface plates were used to examine absorption. The levels of RNA and protein were analyzed, respectively, using RT-PCR and Western blotting. PCA (5 µg/ml) was not toxic to the two cell types but reduced the formation of osteoclasts and bone absorption. Furthermore, PCA restrained the expression of mRNAs encoding proteins associated with osteoclasts and reduced the phosphorylation of proteins in important signaling pathways. The results indicate that PCA inhibits osteoclast differentiation by suppressing NF-κB and MAPK activity.