ArborSim: Articulated, branching, OpenSim routing for constructing models of multi-jointed appendages with complex muscle-tendon architecture.

Computational models of musculoskeletal systems are essential tools for understanding how muscles, tendons, bones, and actuation signals generate motion. In particular, the OpenSim family of models has facilitated a wide range of studies on diverse human motions, clinical studies of gait, and even non-human locomotion. However, biological structures with many joints, such as fingers, necks, tails, and spines, have been a longstanding challenge to the OpenSim modeling community, especially because these structures comprise numerous bones and are frequently actuated by extrinsic muscles that span multiple joints-often more than three-and act through a complex network of branching tendons. Existing model building software, typically optimized for limb structures, makes it difficult to build OpenSim models that accurately reflect these intricacies. Here, we introduce ArborSim, customized software that efficiently creates musculoskeletal models of highly jointed structures and can build branched muscle-tendon architectures. We used ArborSim to construct toy models of articulated structures to determine which morphological features make a structure most sensitive to branching. By comparing the joint kinematics of models constructed with branched and parallel muscle-tendon units, we found that among various parameters-the number of tendon branches, the number of joints between branches, and the ratio of muscle fiber length to muscle tendon unit length-the number of tendon branches and the number of joints between branches are most sensitive to branching modeling method. Notably, the differences between these models showed no predictable pattern with increased complexity. As the proportion of muscle increased, the kinematic differences between branched and parallel models units also increased. Our findings suggest that stress and strain interactions between distal tendon branches and proximal tendon and muscle greatly affect the overall kinematics of a musculoskeletal system. By incorporating complex muscle-tendon branching into OpenSim models using ArborSim, we can gain deeper insight into the interactions between the axial and appendicular skeleton, model the evolution and function of diverse animal tails, and understand the mechanics of more complex motions and tasks.

Genomic Characteristics of Emerging Intraerythrocytic Anaplasma capra and High Prevalence in Goats, China.

Anaplasma capra is an emerging tickborne human pathogen initially recognized in China in 2015; it has been reported in ticks and in a wide range of domestic and wild animals worldwide. We describe whole-genome sequences of 2 A. capra strains from metagenomic sequencing of purified erythrocytes from infected goats in China. The genome of A. capra was the smallest among members of the genus Anaplasma. The genomes of the 2 A. capra strains contained comparable G+C content and numbers of pseudogenes with intraerythrocytic Anaplasma species. The 2 A. capra strains had 54 unique genes. The prevalence of A. capra was high among goats in the 2 endemic areas. Phylogenetic analyses revealed that the A. capra strains detected in this study were basically classified into 2 subclusters with those previously detected in Asia. Our findings clarify details of the genomic characteristics of A. capra and shed light on its genetic diversity.

Mechanism of RhoA regulating benign prostatic hyperplasia: RhoA-ROCK-ß-catenin signaling axis and static & dynamic dual roles.

BACKGROUND: The pathogenesis of benign prostatic hyperplasia (BPH) has not been fully elucidated. Ras homology family member A (RhoA) plays an important role in regulating cell cytoskeleton, growth and fibrosis. The role of RhoA in BPH remains unclear. METHODS: This study aimed to clarify the expression, functional activity and mechanism of RhoA in BPH. Human prostate tissues, human prostate cell lines, BPH rat model were used. Cell models of RhoA knockdown and overexpression were generated. Immunofluorescence staining, quantitative real time PCR (qRT-PCR), Western blotting, cell counting kit-8 (CCK-8), flow cytometry, phalloidine staining, organ bath study, gel contraction assay, protein stability analysis, isolation and extraction of nuclear protein and cytoplasmic protein were performed. RESULTS: In this study we found that RhoA was localized in prostate stroma and epithelial compartments and was up-regulated in both BPH patients and BPH rats. Functionally, RhoA knockdown induced cell apoptosis and inhibited cell proliferation, fibrosis, epithelial-mesenchymal transformation (EMT) and contraction. Consistently, overexpression of RhoA reversed all aforementioned processes. More importantly, we found that ß-catenin and the downstream of Wnt/ß-catenin signaling, including C-MYC, Survivin and Snail were up-regulated in BPH rats. Downregulation of RhoA significantly reduced the expression of these proteins. Rho kinase inhibitor Y-27632 also down-regulated ß-catenin protein in a concentration-dependent manner. However, overexpression of ß-catenin did not affect RhoA-ROCK levels, suggesting that ß-catenin was the downstream of RhoA-ROCK regulation. Further data suggested that RhoA increased nuclear translocation of ß-catenin and up-regulated ß-catenin expression by inhibiting its proteasomal degradation, thereby activating Wnt/ß-catenin signaling. Overexpression of ß-catenin partially reversed the changes in cell growth, fibrosis and EMT except cell contraction caused by RhoA downregulation. Finally, Y-27632 partially reversed prostatic hyperplasia in vivo, further suggesting the potential of RhoA-ROCK signaling in BPH treatment. CONCLUSION: Our novel data demonstrated that RhoA regulated both static and dynamic factors of BPH, RhoA-ROCK-ß-catenin signaling axis played an important role in the development of BPH and might provide more possibilities for the formulation of subsequent clinical treatment strategies.

The Emerging Role of Cell Adhesion Molecules on Benign Prostatic Hyperplasia.

Benign prostatic hyperplasia (BPH) is a common disease in elderly men. It is characterized by prostatic enlargement and urethral compression and often causes lower urinary tract symptoms (LUTs) such as urinary frequency, urgency, and nocturia. Existing studies have shown that the pathological process of prostate hyperplasia is mainly related to the imbalance of cell proliferation and apoptosis, inflammation, epithelial-mesenchymal transition (EMT), and growth factors. However, the exact molecular mechanisms remain incompletely elucidated. Cell adhesion molecules (CAMs) are a group of cell surface proteins that mediate cell-cell adhesion and cell migration. Modulating adhesion molecule expression can regulate cell proliferation, apoptosis, EMT, and fibrotic processes, engaged in the development of prostatic hyperplasia. In this review, we went over the important roles and molecular mechanisms of cell adhesion molecules (mainly integrins and cadherins) in both physiological and pathological processes. We also analyzed the mechanisms of CAMs in prostate hyperplasia and explored the potential value of targeting CAMs as a therapeutic strategy for BPH.

Changes in the Expression and Functional Activities of C-X-C Motif Chemokine Ligand 13 (CXCL13) in Hyperplastic Prostate.

BACKGROUND: C-X-C motif chemokine ligand 13 (CXCL13), a member of the CXC subtype in chemokine superfamily, affects numerous biological processes of various types of cells and the progress of a great number of clinical diseases. The purpose of the current study was to reveal the internal mechanism between CXCL13 and benign prostatic hyperplasia (BPH). METHODS: Human serum, prostate tissues and human prostate cell lines (BPH-1, WPMY-1) were utilized. The effect of recombinant human CXCL13 (rHuCXCL13) protein and the influences of the knockdown/overexpression of CXCL13 on two cell lines were studied. Rescue experiments by anti-CXCR5 were also conducted. In vivo, rHuCXCL13 was injected into the ventral prostate of rats. Additionally, a tissue microarray of hyperplastic prostate tissues was constructed to analyze the correlations between CXCL13 and clinical parameters. RESULTS: CXCL13 was highly expressed in the prostate tissues and upregulated in the BPH group. It was observed that CXCL13 modulated cell proliferation, apoptosis, and the epithelial-mesenchymal transition (EMT) through CXCR5 via AKT and the ERK1/2 pathway in BPH-1, while it contributed to inflammation and fibrosis through CXCR5 via the STAT3 pathway in WPMY-1. In vivo, rHuCXCL13 induced the development of rat BPH. Additionally, CXCL13 was positively correlated with the prostate volume and total prostate specific antigen. CONCLUSIONS: Our novel data demonstrated that CXCL13 modulated cell proliferation, cell cycle, the EMT of epithelial cells, and induced the fibrosis of prostatic stromal cells via a variety of inflammatory factors, suggesting that CXCL13 might be rediscovered as a potential therapeutic target for the treatment of BPH.

Upregulated bone morphogenetic protein 5 enhances proliferation and epithelial-mesenchymal transition process in benign prostatic hyperplasia via BMP/Smad signaling pathway.

BACKGROUND: Benign prostatic hyperplasia (BPH) is one of the most common illnesses in aging men. Recent studies found that bone morphogenetic protein 5 (BMP5) is upregulated in BPH tissues, however, the role of BMP5 in the development of BPH has not been examined. The current study aims to elucidate the potential roles of BMP5 and related signaling pathways in BPH. METHODS: Human prostate cell lines (BPH-1, WPMY-1) and human/rat hyperplastic prostate tissues were utilized. Western blot, quantitative real-time polymerase chain reaction, immunofluorescent staining, and immunohistochemical staining were performed. BMP5-silenced and -overexpressed cell models were generated and then cell cycle progression, apoptosis, and proliferation were determined. The epithelial-mesenchymal transition (EMT) was also quantitated. And rescue experiments by BMP/Smad signaling pathway agonist or antagonist were accomplished. Moreover, BPH-related tissue microarray analysis was performed and associations between clinical parameters and expression of BMP5 were analyzed. RESULTS: Our study demonstrated that BMP5 was upregulated in human and rat hyperplastic tissues and localized both in the epithelial and stromal compartments of the prostate tissues. E-cadherin was downregulated in hyperplastic tissues, while N-cadherin and vimentin were upregulated. Overexpression of BMP5 enhanced cell proliferation and the EMT process via phosphorylation of Smad1/5/8, while knockdown of BMP5 induced cell cycle arrest at G0/G1 phase and blocked the EMT process. Moreover, a BMP/Smad signaling pathway agonist and antagonist reversed the effects of BMP5 silencing and overexpression, respectively. In addition, BMP5 expression positively correlated with prostate volume and total prostate-specific antigen. CONCLUSION: Our novel data suggest that BMP5 modulated cell proliferation and the EMT process through the BMP/Smad signaling pathway which could contribute to the development of BPH. However, further studies are required to determine the exact mechanism. Our study also indicated that BMP/Smad signaling may be rediscovered as a promising new therapeutic target for the treatment of BPH.

Changes in the expression and functional activities of Myosin II isoforms in human hyperplastic prostate.

Benign prostatic hyperplasia (BPH) is a common disease among aging males with the etiology remaining unclear. We recently found myosin II was abundantly expressed in rat and cultured human prostate cells with permissive roles in the dynamic and static components. The present study aimed to explore the expression and functional activities of myosin II isoforms including smooth muscle (SM) myosin II (SMM II) and non-muscle myosin II (NMM II) in the hyperplastic prostate. Human prostate cell lines and tissues from normal human and BPH patients were used. Hematoxylin and Eosin (H&E), Masson's trichrome, immunohistochemical staining, in vitro organ bath, RT-polymerase chain reaction (PCR) and Western-blotting were performed. We further created cell models with NMM II isoforms silenced and proliferation, cycle, and apoptosis of prostate cells were determined by cell counting kit-8 (CCK-8) assay and flow cytometry. Hyperplastic prostate SM expressed more SM1 and LC17b isoforms compared with their alternatively spliced counterparts, favoring a slower more tonic-type contraction and greater force generation. For BPH group, blebbistatin (BLEB, a selective myosin II inhibitor), exhibited a stronger effect on relaxing phenylephrine (PE) pre-contracted prostate strips and inhibiting PE-induced contraction. Additionally, NMMHC-A and NMMHC-B were up-regulated in hyperplastic prostate with no change in NMMHC-C. Knockdown of NMMHC-A or NMMHC-B inhibited prostate cell proliferation and induced apoptosis, with no changes in cell cycle. Our novel data demonstrate that expression and functional activities of myosin II isoforms are altered in human hyperplastic prostate, suggesting a new pathological mechanism for BPH. Thus, the myosin II system may provide potential new therapeutic targets for BPH/lower urinary tract symptoms (LUTS).

NELL2 modulates cell proliferation and apoptosis via ERK pathway in the development of benign prostatic hyperplasia.

Benign prostatic hyperplasia (BPH) is a quite common illness but its etiology and mechanism remain unclear. Neural epidermal growth factor-like like 2 (NELL2) plays multifunctional roles in neural cell growth and is strongly linked to the urinary tract disease. Current study aims to determine the expression, functional activities and underlying mechanism of NELL2 in BPH. Human prostate cell lines and tissues from normal human and BPH patients were utilized. Immunohistochemical staining, immunofluorescent staining, RT-polymerase chain reaction (PCR) and Western blotting were performed. We further generated cell models with NELL2 silenced or overexpressed. Subsequently, proliferation, cycle, and apoptosis of prostate cells were determined by cell counting kit-8 (CCK-8) assay and flow cytometry analysis. The epithelial-mesenchymal transition (EMT) and fibrosis process were also analyzed. Our study revealed that NELL2 was up-regulated in BPH samples and localized in the stroma and the epithelium compartments of human prostate tissues. NELL2 deficiency induced a mitochondria-dependent cell apoptosis, and inhibited cell proliferation via phosphorylating extracellular signal-regulated kinase 1/2 (ERK1/2) activation. Additionally, suppression of ERK1/2 with U0126 incubation could significantly reverse NELL2 deficiency triggered cell apoptosis. Consistently, overexpression of NELL2 promoted cell proliferation and inhibited cell apoptosis. However, NELL2 interference was observed no effect on EMT and fibrosis process. Our novel data demonstrated that up-regulation of NELL2 in the enlarged prostate could contribute to the development of BPH through enhancing cell proliferation and inhibited a mitochondria-dependent cell apoptosis via the ERK pathway. The NELL2-ERK system might represent an important target to facilitate the development of future therapeutic approaches in BPH.

Changes in the expression and function of the PDE5 pathway in the obstructed urinary bladder.

Our study aims to explore changes in bladder contractility and the phosphodiesterase type 5 (PDE5) signalling pathway in response to partial bladder outlet obstruction (PBOO). A surgically induced male rat PBOO model and human obstructed bladder tissues were used. Histological changes were examined by H&E and Masson's trichrome staining. Bladder strip contractility was measured via organ bath. The expressions of nitric oxide synthase (NOS) isoforms, PDE5, muscarinic cholinergic receptor (CHRM) isoforms and PDE4 isoforms in bladder were detected by RT-PCR and Western blotting. The immunolocalization of the PDE5 protein and its functional activity were also determined. PBOO bladder tissue exhibited significant SM hypertrophy and elevated responsiveness to KCl depolarization and the muscarinic receptor agonist carbachol. NOS isoforms, PDE5, CHRM2, CHRM3 and PDE4A were up-regulated in obstructed bladder tissue, whereas no change in PDE4B and PDE4D isoform expression was observed. With regard to PDE5, it was expressed in the SM bundles of bladder. Interestingly, obstructed bladder exhibited less relaxation responsiveness to sodium nitroprusside (SNP), but an exaggerated PDE5 inhibition effect. The up-regulation of PDE5 could contribute to the lack of effect on Qmax for benign prostatic hyperplasia/lower urinary tract symptom (BPH/LUTS) patients treated with PDE5 inhibitors. Moreover, PDE5 (with presence of NO) and PDE4 may serve as new therapeutic targets for bladder diseases such as BPH-induced LUTS and overactive bladder (OAB).

Immunotherapeutic effects of allogeneic mesenchymal stem cells on systemic lupus erythematosus.

Mesenchymal stem cells have been applied to treat graft versus host disease as they have immunosuppressive ability and can overcome the major histocompatibility complex-histocompatibility barrier. The potential of allogeneic mesenchymal stem cells in treating systemic lupus erythematosus (SLE) was investigated in this study. MRL/lpr mice which can develop acquired SLE-like phenotypes were selected as an animal model. Mesenchymal stem cells obtained from green fluorescent protein-transgenic ICR mice were infused into MRL/lpr mice at either the early or late stage of disease. The dosage was 1 × 106/mice per infusion. Mice were stratified into six groups including negative controls and those receiving one, two, three, four or five doses at 2-weekly intervals. The phenotypes were monitored regularly. After treatment, the spleen CD3+CD4-CD8- T and CD19+ B cells of two-dose mesenchymal stem cell-treated mice were significantly lower than those of the phosphate-buffered saline control. In terms of reducing the severity of SLE such as hair loss, skin ulcers, proteinuria and anti-dsDNA level, mesenchymal stem cells given at the early stage responded better and mice receiving two doses of mesenchymal stem cells performed better than those receiving either a lower dose (one dose) or higher doses (three, four or five doses). In conclusion, early treatment and an optimal dose of mesenchymal stem cells can effectively suppress the murine SLE model.

SNHG14 induces osteogenic differentiation of human stromal (mesenchymal) stem cells in vitro by downregulating miR-2861.

BACKGROUND: The differentiation of human stromal (mesenchymal) stem cells (hMSCs) is a critical procedure for the development of osteoblast. SNHG14 is a newly discovered lncRNA that has been barely studied. Our preliminary experiments showed that SNHG14 may be dysregulated in the differentiation of hMSCs. In this study, we focused on elucidating the relationships among SNGH14, miR-2861, and osteoblastic differentiation of hMSCs. METHOD: To investigate the roles of SNHG14 and miR2861 in hMSCs differentiation, qRT-PCR, luciferase activity, cell transfections, the detections of ALP activity, and Alizarin Red staining were performed. RESULT: We found that the expression of SNHG14 was enhanced, while the expression of miR-2861 was suppressed in serum and hMSCs from patients with osteoporosis. SNHG14 could target miR-2861, and shSNHG14 suppressed osteoblast differentiation of hMSC. MiR-2861 suppressed osteoblast differentiation of hMSC. In addition, the effects of SNHG14 on osteoblast differentiation of hMSC were attenuated by miR-2861. CONCLUSION: In conclusion, our experimental data showed that the induction effects of SNHG14 on osteoblast differentiation of hMSC were attenuated by miR-2861. SNHG14 could induce osteogenic differentiation of hMSC in vitro by targeting miR-2861.

Confirmation the optimal aeration parameters for nitrogen removal and nitrous oxide emission in wastewater ecological soil infiltration systems with brown earth.

Nitrogen removal is an obstacle for the wide application of wastewater ecological soil infiltration (WESI) system in domestic wastewater treatment. In this study, matrix dissolved oxygen (DO), nitrogen removal and nitrous oxide (N2O) emission in aerated pilot WESI systems were investigated under different aeration times (1, 2, 3, 4 and 6 h/d) and aeration rates (1, 2, 3 and 4 L/min). The results showed that aerobic conditions in upper matrix and anoxic or anaerobic conditions in the subsequent matrix were developed in an aerated/non-aerated cycle at the optimal aeration condition of aeration time of 4 h/d and aeration rate of 3 L/min. Simultaneously, high removal efficiency of chemical oxygen demand (COD) (97.9%), NH4 +-N (98.2%), total nitrogen (TN) (90.7%) and low N2O emission rate (13.2 mg/(m2 d)) were obtained. The results would provide optimal aeration parameters for application of intermittent aerated WESI systems.

Changes in Retinal Nerve Fiber Layer Thickness in Obstructive Sleep Apnea/Hypopnea Syndrome: A Meta-Analysis.

PURPOSE: To evaluate and compare changes in retinal nerve fiber layer (RNFL) thickness in patients with obstructive sleep apnea/hypopnea syndrome (OSAHS). METHODS: The Cochrane Library, Medline, and Embase were screened using our key words. Results were carefully reviewed to ensure that the included studies met the inclusion/exclusion criteria, and the quality of the studies was assessed using the Newcastle-Ottawa Scale. All included studies categorized patients with OSAHS into 3 groups (mild, moderate, and severe), and measured average and 4-quadrant (temporal, superior, nasal, and inferior) RNFL thickness. All studies included a healthy control group. The weighted mean differences and 95% confidence intervals were calculated for the continuous outcomes. RESULTS: Ten case-control studies were included in the meta-analysis, consisting of a total of 811 OSAHS group and 868 healthy eyes. A meta-analysis of the data showed that the average RNFL thicknesses in the mild, moderate, and severe OSAHS groups were significantly decreased compared to healthy controls. Additionally, RNFL thickness was significantly reduced in all but the temporal quadrant in the moderate and severe OSAHS groups when compared to healthy controls. CONCLUSIONS: On the basis of these results, we suggest that peripapillary RNFL thickness as measured by optical coherence tomography could be a useful tool to monitor and assess the severity of OSAHS in patients. Further studies are required in order to differentiate these RNFL changes from glaucomatous changes. This has not been properly examined in any of the studies we were able to identify.

Jointed tails enhance control of three-dimensional body rotation.

Tails used as inertial appendages induce body rotations of animals and robots-a phenomenon that is governed largely by the ratio of the body and tail moments of inertia. However, vertebrate tails have more degrees of freedom (e.g., number of joints, rotational axes) than most current theoretical models and robotic tails. To understand how morphology affects inertial appendage function, we developed an optimization-based approach that finds the maximally effective tail trajectory and measures error from a target trajectory. For tails of equal total length and mass, increasing the number of equal-length joints increased the complexity of maximally effective tail motions. When we optimized the relative lengths of tail bones while keeping the total tail length, mass, and number of joints the same, this optimization-based approach found that the lengths match the pattern found in the tail bones of mammals specialized for inertial maneuvering. In both experiments, adding joints enhanced the performance of the inertial appendage, but with diminishing returns, largely due to the total control effort constraint. This optimization-based simulation can compare the maximum performance of diverse inertial appendages that dynamically vary in moment of inertia in 3D space, predict inertial capabilities from skeletal data, and inform the design of robotic inertial appendages.

Screening of 152 Veterinary Drug Residues in Animal Source Foods by LC-MS/MS, Multilaboratory Validation Study: Final Action 2020.04.

BACKGROUND: The presence of veterinary drug residues in food-producing animals and animal products is regulated through the enforcement of maximum residue limits (MRLs). To answer the need of the food sector to monitor these substances in a wide range of food commodities, stakeholders at AOAC INTERNATIONAL identified the need for a reliable confirmatory screening method. Such a qualitative approach is required for compliance checking and to support product release in manufacturing. OBJECTIVE: Data were collected from five independent laboratories that applied the First Action Official Method 2020.04 to demonstrate adequate performance under reproducibility conditions. The probability of detection (POD) was calculated in blank test samples and test samples spiked at the screening target concentration (STC) level, with the objective to achieve PODs ≤10% and ≥90%, respectively. Additionally, the effectiveness of the screening method was evaluated by participating in 92 proficiency tests. METHODS: Four streams were optimized to screen for 152 veterinary drug residues by LC-MS/MS in a wide variety of food commodities including milk-based ingredients and related products (e.g., milk fractions, infant formula, infant cereals, and baby foods), meat- and fish-based ingredients and related products (fresh, powdered, cooked, infant cereals, and baby foods), and other ingredients based on eggs, animal fat, and animal byproducts. The four streams covered 105 antibiotic residues, anti-inflammatory and antiparasitic agents (stream A), 23 beta-lactams (stream B), 14 aminoglycosides (stream C), and 10 tetracyclines (Stream D). RESULTS: The multilaboratory validation led to PODs at the STC ≥94% and PODs in the blank ≤9%. Further application of the multilaboratory validated method to 92 proficiency tests provided more than 99% satisfactory submitted results (n = 784). CONCLUSION: The interlaboratory reproducibility determined for this method met the acceptance criteria defined in AOAC Standard Method Performance Requirement (SMPR®) 2018.010. HIGHLIGHTS: AOAC has approved the method for Final Action status.

STEAP4 modulates cell proliferation and oxidative stress in benign prostatic hyperplasia.

Benign prostatic hyperplasia (BPH) is a quite common chronic disease plagued elderly men and its etiology remains unclear. It was reported that the six-transmembrane epithelial antigen of prostate 4 (STEAP4) could modulate cell proliferation/apoptosis ratio and oxidative stress in cancers. Our current study aimed to explore the expression, biological function, and underlying mechanism of STEAP4 in BPH progress. Human prostate tissues and cell lines were utilized. qRT-PCR and immunofluorescence staining were employed. STEAP4 knockdown (STEAP4-KD) or STEAP4 overexpression (STEAP4-OE) cell models were established. Cell proliferation, cell cycle, apoptosis, and reactive oxygen species (ROS) were determined by cell counting kit-8 (CCK-8) assay and flow cytometry. Apoptosis-related proteins and antioxidant enzymes were identified by Western Blot. In addition, the epithelial-mesenchymal transition (EMT) process and fibrosis biomarker (collagen I and α-SMA) were analyzed. It was indicated that STEAP4 was mainly located in the prostate epithelium and upregulated in BPH tissues. STEAP4 deficiency induced apoptosis and inhibited cell survival, but had no effect on the cell cycle, fibrosis, and EMT process. In addition, ROS changes were observed in the STEAP4-KD model. Consistently, overproduction of STEAP4 suppressed apoptosis and promoted cell proliferation, as well as facilitated ROS production. We further examined AKT / mTOR, p38MAPK / p-p38MAPK, and WNT/ ß-Catenin signaling pathway and demonstrated that STEAP4 regulated the proliferation and apoptosis of prostate cells through AKT / mTOR signaling, rather than p38MAPK / p-p38MAPK and WNT/ ß-Catenin pathways. Furthermore, activating AKT / mTOR signaling with SC79 significantly reversed apoptosis triggered by STEAP4 deficiency, whereas suppressing AKT / mTOR signaling with MK2206 reduced the increase of cell viability triggered by STEAP4 overproduction. Our original data demonstrated that STEAP4 is crucial in the onset and progression of prostate hyperplasia and may become a new target for the treatment of BPH.

Human pluripotent stem cell-derived kidney organoids: Current progress and challenges.

Human pluripotent stem cell (hPSC)-derived kidney organoids share similarities with the fetal kidney. However, the current hPSC-derived kidney organoids have some limitations, including the inability to perform nephrogenesis and lack of a corticomedullary definition, uniform vascular system, and coordinated exit pathway for urinary filtrate. Therefore, further studies are required to produce hPSC-derived kidney organoids that accurately mimic human kidneys to facilitate research on kidney development, regeneration, disease modeling, and drug screening. In this review, we discussed recent advances in the generation of hPSC-derived kidney organoids, how these organoids contribute to the understanding of human kidney development and research in disease modeling. Additionally, the limitations, future research focus, and applications of hPSC-derived kidney organoids were highlighted.

Fibronectin-1: A Predictive Immunotherapy Response Biomarker for Muscle­Invasive Bladder Cancer.

BACKGROUND: Muscle-invasive bladder cancer (MIBC) is characterized as bladder tumors that infiltrate into the muscle layer, along with multiple metastasis and poor prognosis. Numerous research studies have been performed to identify the underlying clinical and pathological alterations that occur. However, few studies have revealed the molecular mechanism of its progression based upon the immunotherapy response. Our present study was designed to identify biomarkers which may predict the immunotherapy response by investigating the tumor microenvironment (TME) in MIBC. METHODS: The transcriptome and clinical data of MIBC patients were obtained and analyzed with R version 4.0.3 (POSIT Software, Boston, MA, USA) ESTIMATE package. Differentially expressed immune-related genes (DEIRGs) were identified and further analyzed via the protein-protein interaction network (PPI). Meanwhile, univariate Cox analysis was utilized to screen out the prognostic DEIRGs (PDEIRGs). Then, the PPI core gene was matched with PDEIRGs to obtain the target gene-fibronectin-1 (FN1). Human MIBC and control tissues were collected and FN1 was measured with Quantitative Reverse Transcription PCR (qRT-PCR) and Western-Blot. Finally, the relationship between FN1 expression level and MIBC was validated through survival, univariate Cox, multivariate Cox, Gene Set Enrichment Analysis (GSEA) and correlation analysis of tumor infiltrating immune cells. RESULTS: TME DEIRGs were identified and the target gene FN1 was obtained. The higher expression of FN1 was confirmed in MIBC tissues via bioinformatics analysis, qRT-PCR and Western-Blot. Moreover, higher FN1 expression correlated with reduced survival time and FN1 expression was further favorably correlated with clinic-pathological features (grade, TNM stage, invasion, lymphatic and distant metastasis). Additionally, the genes in the high FN1 expression group were mainly enriched in immune-related activities and macrophage M2, T cell CD4, T cell CD8 and T cell follicular helper cells were correlated with FN1. Finally, it was observed that FN1 was closely related to key immune checkpoints. CONCLUSIONS: FN1 was identified as a novel and independent prognostic factor for MIBC. Our data also suggests FN1 can predict MIBC patients' response to immune checkpoints inhibitors.

Genetically predicted insomnia causally increases the risk of erectile dysfunction.

Sleep has attracted extensive attention due to its significance in health. However, its association with erectile dysfunction (ED) is insufficiently investigated. To investigate the potential causal links between sleep traits (insomnia, sleep duration, and chronotype) and ED, this study was performed. The single-nucleotide polymorphisms (SNPs) associated with insomnia, sleep duration, and chronotype were retrieved from previous genome-wide association studies (GWAS). A conventional two-sample Mendelian randomization (MR) was used to estimate the causal links between sleep traits and ED. The summary statistics of ED were from individuals of European ancestry (6175 cases vs 217 630 controls). As shown by the random effect inverse-variance-weighting (IVW) estimator, genetically predicted insomnia was causally associated with a 1.15-fold risk of ED (95% confidence interval: 1.07-1.23, P < 0.001). Sleep duration and morningness were not causally associated with ED, as indicated by the IVW (all P > 0.05). These findings were consistent with the results of sensitivity analyses. Based on genetic data, this study provides causal evidence that genetically predicted insomnia increases the risk of ED, whereas sleep duration and chronotype do not.

DHCR7 promotes tumorigenesis via activating PI3K/AKT/mTOR signalling pathway in bladder cancer.

Bladder cancer (BCa) is a common malignancy with uncertain molecular mechanism. 7-dehydrocholesterol reductase (DHCR7), the enzyme of mammalian sterol biosynthesis, plays important roles in several types of cancers but its specific function in BCa is still unknown. The current study aimed to determine the bioinformatic characteristics and biological functions of DHCR7 in BCa. Sequencing results and clinical data from online public databases, human BCa tissues and matched noncancerous tissues, xenograft nude mice, DHCR7 deficiency and overexpression BCa cell (T24 and EJ) models were used. Several bioinformatics analyses were made, qRT-PCR, Western-blotting, flow cytometry, immunohistochemistry (IHC), MTT assay, wound healing and cell invasion assays were performed. It was found that DHCR7 was upregulated in BCa as an independent risk factor, and the expression of DHCR7 was associated with BCa grade and stage, finally resulted in poor prognosis. We further demonstrated that DHCR7 overexpression could accelerate the G0/G1 phase to accelerate the growth of tumor cells, antagonize cell apoptosis, and enhance the invasion and migration capacity, as well as EMT process via PI3K/AKT/mTOR signalling pathway, which could be completely reversed by DHCR7 knockdown. Finally, DHCR7 deficiency significantly decreased tumorigenesis in vivo. Our novel data demonstrated that DHCR7 could modulate BCa tumorigenesis in vitro and in vivo via PI3K/AKT/mTOR signalling pathway. It is suggested that DHCR7 might become a molecular target for the diagnosis and treatment of BCa.