Hsa_circ_0081065 exacerbates IH-induced EndMT via regulating miR-665/HIF-1α signal axis and HIF-1α nuclear translocation.

CircRNAs play an important role in various physiological and pathological biological processes. Despite their widespread involvement, the function of circRNAs in intermittent hypoxia (IH) remain incompletely understood. This study aims to clarify the molecular mechanism of it in IH. Differentially expressed circRNAs were identified by transcriptome sequencing analysis in intermittent hypoxia (IH) model. GO and KEGG enrichment analys were performed on the identified differentially expressed circRNAs. The circular characteristics of hsa_circ_0081065 in human umbilical vein endothelial cells (HUVECs) were detected by RT-qPCR. The sublocalization of hsa_circ_0081065 was examined by FISH. The effect of hsa_circ_0081065 on endothelial to mesenchymal transition (EndMT) was estimated by detecting the expression of EndMT related markers. Various techniques, including RNA-pull down, RIP, EMSA, dual-luciferase reporter assay and immunofluorescence staining were used to investigate the relationship among hsa_circ_0081065, miR-665 and HIF-1α. A total of 13,304 circRNAs were identified in HUVECs treatment with IH, among which 73 were differentially expressed, including 24 upregulated circRNAs and 49 downregulated circRNAs. Notably, hsa_circ_0081065 demonstrated a significantly upregulation. Hsa_circ_0081065 exhibited the circular characteristics of circRNA and was predominantly localized in the cytoplasm. Knockdown of hsa_circ_0081065 inhibited EndMT. Mechanically, we demonstrated that hsa_circ_0081065 acts as a sponge for miR-665 to up-regulate HIF-1α and exacerbate HIF-1α nuclear translocation in HUVECs. We have demonstrated that hsa_circ_0081065 is significantly upregulated in HUVECs treated with IH. Our findings indicate that hsa_circ_0081065 exacerbates IH-induced EndMT through the regulation of the miR-665/HIF-1α signal axis and facilitating HIF-1α nuclear translocation. These results provide a theoretical basis for considering of EndMT as a potential therapeutic target for OSAHS intervention.

Prediction of Mild Cognitive Impairment Progression to Alzheimer's Disease Based on Diffusion Tensor Imaging-Derived Diffusion Parameters: Construction and Validation of a Nomogram.

INTRODUCTION: The aim of the study was to construct and validate a nomogram that combines diffusion tensor imaging (DTI) parameters and clinically relevant features for predicting the progression of mild cognitive impairment (MCI) to Alzheimer's disease (AD). METHOD: A retrospective analysis was conducted on the MRI and clinical data of 121 MCI patients, of whom 32 progressed to AD during a 4-year follow-up period. The MCI patients were divided into training and validation sets at a ratio of 7:3. DTI features were extracted from MCI patient data in the training set, and their dimensionality was reduced to construct a radiomics signature (RS). Then, combining the RS with independent predictors of MCI disease progression, a joint model was constructed, and a nomogram was generated. Finally, the area under the receiver operating characteristic curve (AUC) and decision curve analysis (DCA) were used to evaluate the diagnostic and clinical efficacy of the nomogram based on the data from the validation set. RESULT: The AUCs of the RS in the training and validation sets were 0.81 and 0.84, with sensitivities of 0.87 and 0.78 and specificities of 0.71 and 0.81, respectively. Multiple logistic regression analysis showed that the RS, clinical dementia rating scale score, and Alzheimer's disease assessment scale score were the independent predictors of progression and were thus used to construct the nomogram. The AUCs of the nomogram in the training and validation sets were 0.89 and 0.91, respectively, with sensitivities of 0.78 and 0.89 and specificities of 0.90 and 0.88, respectively. DCA showed that the nomogram was the most valuable model for predicting the progression of MCI to AD and that it provided greater net benefits than other analysed models. CONCLUSION: Changes in white matter fibre bundles can serve as predictive imaging markers for MCI disease progression, and the combination of white matter DTI features and relevant clinical features can be used to construct a nomogram with important predictive value for MCI disease progression.

WDR38, a novel equatorial segment protein, interacts with the GTPase protein RAB19 and Golgi protein GM130 to play roles in acrosome biogenesis.

The WD40-repeat containing (WDR) proteins are enriched in the testis and play important roles in spermatogenesis. In the present study, we investigate the expression profile of WDR38, a novel member of the WDR protein family, in humans and mice. RT-qPCR (reverse transcription-quantitative polymerase chain reaction) results demonstrate that WDR38 mRNA is abundantly expressed in both the human and mouse testis. The expression of mouse Wdr38 is strictly regulated during development. Further immunofluorescence staining results show that WDR38 is located in the equatorial segment of the acrosome in human and mouse mature spermatozoa and is involved in acrosome biogenesis. Subcellular localization analysis reveals that the mouse Wdr38 protein is distributed in the perinuclear cytoplasm of transfected cells and colocalizes with the GTPase protein Rab19 and Golgi protein GM130. Coimmunoprecipitation (co-IP) assays demonstrate that Wdr38, Rab19 and GM130 interact with each other in the mouse testis and in HEK293T cells. In acrosome biogenesis, Wdr38, Rab19 and GM130 aggregate at the nuclear membrane to form large vesicles, and GM130 then detaches and moves towards the caudal region of the nucleus, whereas the Wdr38/Rab19 complex spreads along the dorsal nuclear edge and finally docks to the equatorial segment. These results indicate that WDR38 is a novel equatorial segment protein that interacts with the GTPase protein RAB19 and Golgi protein GM130 to play roles in acrosome biogenesis.

Efficient adsorption and reduction of Cr(VI) from aqueous solution by Santa Barbara Amorphous-15 (SBA-15) supported Fe/Ni bimetallic nanoparticles.

Nanoscale zero-valent iron (nZVI or Fe0) can rapidly reduce Cr(VI) contaminants in the water environment, but the agglomeration and passivation of the Fe0 system have adverse effects on its application. In this study, a novel mesoporous Santa Barbara Amorphous-15 supported Fe/Ni bimetallic composite (SBA-15@Fe/Ni) is proposed to remove Cr(VI). The proposed material can enhance the stability and removal capacity of the nZVI system. The results show that the unique six-way through-hole structure of SBA-15 provides a place for the dispersion of Fe0 particles. Meanwhile, SBA-15 effectively alleviates the accumulation of Fe0 particles. The removal efficiency of SBA-15@Fe/Ni is better than two single systems (SBA-15 and Fe/Ni). The removal efficiency of SBA-15@Fe/Ni towards Cr(VI) can reach 97.62% after 60 min at pH 4.0. SBA-15@Fe/Ni still maintains excellent performance in the presence of various competitive ions (Cl-, SO42-, CO32-, NO3-). At 298 K, the maximum removal capacity of SBA-15@Fe/Ni towards Cr(VI) is 180.99 mg/g. The possible removal process of SBA-15@Fe/Ni towards Cr(VI) is divided into the following steps: First, Cr(VI) is attracted into the vicinity of the SBA-15@Fe/Ni channel by the electrostatic attraction; Second, the reduction of Cr(VI) occurs after contacting with the Fe/Ni system, and its driving force mainly comes from nZVI and Fe(II); Furthermore, the introduction of Ni can promote Cr(VI) reduction through electron transfer and catalytic hydrogenation. In conclusion, adopting SBA-15@Fe/Ni to treat chromium contamination is an effective and promising approach.

Hepatocyte leukotriene B4 receptor 1 promotes NAFLD development in obesity.

BACKGROUND AND AIMS: NAFLD is the most prevalent chronic liver disease worldwide and has emerged as a serious public health issue with no approved treatment. The development of NAFLD is strongly associated with hepatic lipid content, and patients with NAFLD have significantly higher rates of hepatic de novo lipogenesis (DNL) than lean individuals. Leukotriene B4 (LTB4), a metabolite of arachidonic acid, is dramatically increased in obesity and plays important role in proinflammatory cytokine production and insulin resistance. But the role of liver LTB4/LTB4 receptor 1 (Ltb4r1) in lipid metabolism is unclear. APPROACH AND RESULTS: Hepatocyte-specific knockout (HKO) of Ltb4r1 improved hepatic steatosis and systemic insulin resistance in both diet-induced and genetically induced obese mice. The mRNA level of key enzymes involved in DNL and fatty acid esterification decreased in Ltb4r1 HKO obese mice. LTB4/Ltb4r1 directly promoted lipogenesis in HepG2 cells and primary hepatocytes. Mechanically, LTB4/Ltb4r1 promoted lipogenesis by activating the cAMP-protein kinase A (PKA)-inositol-requiring enzyme 1α (IRE1α)-spliced X-box-binding protein 1 (XBP1s) axis in hepatocytes, which in turn promoted the expression of lipogenesis genes regulated by XBP1s. In addition, Ltb4r1 suppression through the Ltb4r1 inhibitor or lentivirus-short hairpin RNA delivery alleviated the fatty liver phenotype in obese mice. CONCLUSIONS: LTB4/Ltb4r1 promotes hepatocyte lipogenesis directly by activating PKA-IRE1α-XBP1s to promote lipogenic gene expression. Inhibition of hepatocyte Ltb4r1 improved hepatic steatosis and insulin resistance. Ltb4r1 is a potential therapeutic target for NAFLD.

Predictive value of platelet-related hematological markers in indicating the outcomes after laparoscopic intraperitoneal onlay mesh repair (IPOM).

BACKGROUND: The predictive value of hematological markers in the outcomes after laparoscopic intraperitoneal onlay mesh repair (IPOM) remains to be investigated. We aim to evaluate the role of platelet-related parameters after laparoscopic IPOM in patients with incisional hernias. METHODS: The data of 95 patients who underwent laparoscopic IPOM for appendicectomy-related incisional hernias were retrospectively analyzed. The complete blood count analyses were measured preoperatively, and the outcomes were obtained from hospital records and follow-up calls to patients. Platelet-multiple-lymphocyte index (PLM), neutrophil-leukocyte ratio (NLR), lymphocyte-monocyte ratio (LMR), platelet-lymphocyte ratio (PLR) and systemic immune-inflammation index (SII) values were calculated. The patients were grouped based on the recurrence and the postoperative complications after surgery. RESULTS: Using cutoff values acquired by the Youden Index, we found platelet levels < 212.0 × 1000/µl, NLR > 2.33, LMR < 3.17, and PLM < 365.5 were revealed to be statistically significant in the recurrence of hernias based on univariant or multivariant analysis (p = < 0.05). We further divided the patients into two groups based on the cutoff value of PLM and found that a PLM value < 365.5 was significantly associated with the recurrence of incisional hernia (p = 0.018), the occurrence of postoperative seroma (p = 0.044), and there is a tendency that patients with PLM < 365.5 may suffer from other postoperative complications such as cardiopathy, respiratory infection, and hypoproteinemia (p = 0.089). CONCLUSION: The preoperative hematological values, especially PLM, may indicate the outcomes in incisional hernias after laparoscopic IPOM.

Association of genetic variants in Leptin, leptin receptor and adiponectin with hypertension risk and circulating Leptin/Adiponectin changes.

BACKGROUNDS: Hypertension is inheritable, and some candidate genes such as leptin and adiponectin have drawn special concerns. OBJECTIVES: We performed a meta-analysis on the association of 7 genetic variants in genes encoding leptin, leptin receptor and adiponectin with hypertension risk and circulating leptin/adiponectin changes. METHODS: Literature search, report selection and data extraction were performed by two authors independently. Effect sizes are expressed as odds ratio (OR) or standard mean difference (SMD) with 95% confidence interval (CI). RESULTS: Total 32 reports (7432 cases with hypertension and 9218 controls) were meta-analyzed. Overall analyses indicated that rs7799039 (dominant model: OR = 1.67; 95 % CI: 1.03 to 2.71; P = 0.038) and (TTTC)n (allelic model: OR = 1.53; 95 % CI: 1.05 to 2.23; P = 0.028) were significantly associated with hypertension risk. Subgroup analyses indicated that hypertension type, race, diabetes, genotyping method and quality score might be potential causes for between-study heterogeneity. Besides rs2241766, no evidence of publication bias existed for the other variants. Carriers of rs7799039-AG genotype had significantly higher leptin concentrations than carriers of rs7799039-GG genotype (SMD = 1.98; 95 % CI: 0.07 to 3.89; P = 0.042). In Mendelian randomization analyses, an increment of leptin concentrations by 1 ng/mL was causally associated with a 25 % significantly increased risk of hypertension (95 % CI: 1.02 to 10+; P < 0.05). CONCLUSIONS: Our findings indicated that leptin gene rs7799039 and (TTTC)n were potential hypertension-candidacy loci, and importantly high circulating leptin concentrations causally precipitated the development of hypertension.

WDR87 interacts with CFAP47 protein in the middle piece of spermatozoa flagella to participate in sperm tail assembly.

Spermatogenesis is a complex process that includes spermatogonia self-renewal, spermatocyte meiosis and spermatozoa assembly. Recent studies have revealed that WD40-repeat domain-containing (WDR) proteins play important roles in spermatocyte division, spermatozoa flagella assembly and head shaping. In this study, we investigated the expression pattern of WDR87 and found that it was highly expressed in the testis of both humans and mice. Immunofluorescence staining revealed that mouse WDR87 was distributed in the perinuclear cytoplasm of primary spermatocytes, secondary spermatocytes and round spermatids. In the spermiogenesis stage, with extension of the nucleus, WDR87 migrated to the manchette and finally localized to the middle piece of the spermatozoa tail. Furthermore, we identified a cilia- and flagella-associated protein, CFAP47, which interacted with WDR87 in the flagellar midpiece of the spermatozoa, suggesting that WDR87 may be associated with multiple morphological abnormalities of the flagella (MMAF). Subsequently, we screened gene mutations in seven MMAF individuals and found two novel mutations in CFAP47 (c.706G>A, Val236Met; c.1337C>T, Thr446Met) in one case. Immunoblotting and immunofluorescence revealed that CFAP47 was dramatically reduced in spermatozoa from the CFAP47-mutated man. Meanwhile, the expression of WDR87 was also significantly decreased, and weak signals were detected adjacent to the spermatozoa nuclei, indicating that CFAP47 was necessary for WDR87 transportation during spermatozoa flagella biogenesis. These data indicate that WDR87 is located in the middle piece of the sperm tail and interacts with CFAP47 to form a complex which is involved in spermatozoa tail assembly.

Nuclear Membrane Protein SUN5 Is Highly Expressed and Promotes Proliferation and Migration in Colorectal Cancer by Regulating the ERK Pathway.

SUN5 was first identified as a nuclear envelope protein involved in spermatocyte division. We found that SUN5 was highly expressed in some cancers, but its function and mechanism in cancer development remain unclear. In the present study, we demonstrated that SUN5 was highly expressed in colorectal cancer (CRC) tissues and cells, as indicated by bioinformatics analysis, and SUN5 promoted cell proliferation and migration in vitro. Moreover, the overexpression of SUN5 upregulated phosphorylated ERK1/2 (pERK1/2), whereas the knockdown of SUN5 yielded the opposite results. PD0325901 decreased the level of pERK1/2 to inhibit cell proliferation and migration, which was partially reversed by SUN5 overexpression, indicating that drug resistance existed in patients with high SUN5 expression. The xenograft transplantation experiment showed that SUN5 accelerated tumor formation in vivo. Furthermore, we found that SUN5 regulated the ERK pathway via Nesprin2 mediation and promoted the nuclear translocation of pERK1/2 by interacting with Nup93. Thus, these findings indicated that highly expressed SUN5 promoted CRC proliferation and migration by regulating the ERK pathway, which may contribute to the clinical diagnosis and new treatment strategies for CRC.

Acute myocardial infarction therapy using calycosin and tanshinone co-loaded; mitochondrion-targeted tetrapeptide and cyclic arginyl-glycyl-aspartic acid peptide co-modified lipid-polymer hybrid nano-system: preparation, characterization, and anti myocardial infarction activity assessment.

Acute myocardial infarction (AMI) is one of the most common ischemic heart diseases. However, lack of sufficient drug concentration (in the ischemic heart) is the major factor of treatment failure. It is urgent for researchers to engineer novel drug delivery systems to enhance the targeted delivery of cardioprotective agents. The aim of the present study was to investigate the anti-AMI ability of calycosin (CAL) and tanshinone (TAN) co-loaded; mitochondrion-targeted tetrapeptide (MTP) and cyclic arginyl-glycyl-aspartic acid (RGD) peptide co-modified nano-system.: We prepared CAL and TAN combined lipid-polymer hybrid nano-system, and RGD was modified to the system to achieve RGD-CAL/TAN NS. MTP-131 was conjugated with PEG and modified onto the nanoparticles to achieve dual ligands co-modified MTP/RGD-CAL/TAN NS. The physicochemical properties of nano-systems were characterized. The AMI therapy ability of the systems was investigated in AMI rats' model. The size of MTP/RGD-CAL/TAN NS was 170.2 ± 5.6 nm, with a surface charge of -18.9 ± 1.9 mV. The area under the curve (AUC) and blood circulation half-life (T1/2) of MTP/RGD-CAL/TAN NS was 178.86 ± 6.62 µg·min/mL and 0.47 h, respectively. MTP/RGD-CAL/TAN NS exhibited the most significant infarct size reduction effect of 22.9%. MTP/RGD-CAL/TAN NS exhibited the highest heart accumulation and best infarct size reduction effect, which could be used as a promising system for efficient treatment of cardiovascular diseases.

A comparative study of three bone age assessment methods on Chinese preschool-aged children.

Background: Bone age assessment (BAA) is an essential tool utilized in outpatient pediatric clinics. Three major BAA methods, Greulich-Pyle (GP), Tanner-Whitehouse 3 (TW3), and China 05 RUS-CHN (RUS-CHN), were applied to comprehensively compare bone age (BA) and chronological age (CA) in a Chinese sample of preschool children. This study was designed to determine the most reliable method. Methods: The BAA sample consisted of 207 females and 183 males aged 3-6 years from the Zhejiang Province in China. The radiographs were estimated according to the GP, TW3, and RUS-CHN methods by two pediatric radiologists. The data was analyzed statistically using boxplots, the Wilcoxon rank test, and Student's t-test to explore the difference (D) between BA and CA. Results: According to the distributions of D, the boxplots showed that the median D of the TW3 method was close to zero for both male and female subjects. The TW3 and RUS-CHN methods overestimated the age of both genders. The TW3 method had the highest correct classification rate for males but a similar rate for females. The GP method did not show any significant difference between the BA and CA when applied to 3-year-old males and 4-year-old females while the TW3 method showed similar results when applied to 6-year-old females. The RUS-CHN method showed the least consistent results among the three methods. Conclusion: The TW3 method was superior to the GP and RUS-CHN methods but not reliable on its own. It should be noted that a precise age diagnosis for preschool children cannot be easily made if only one of the methods is utilized. Therefore, it is advantageous to combine multiple methods when assessing bone age.

Acute myocardial infarction therapy using calycosin and tanshinone co-loaded mitochondria targeted lipid-polymer hybrid nano-system: Preparation, characterization, and anti myocardial infarction activity assessment.

BACKGROUND: Acute myocardial infarction (AMI) is one of the most common ischemic heart diseases. However, lack of sufficient drug concentrations in the ischemic heart may led to treatment failure. It is urgent for researchers to engineer novel drug delivery systems to enhance the targeted delivery of cardioprotective agents. OBJECTIVE: The aim of the present study was to investigate the anti-AMI ability of calycosin (CAL) and tanshinone (TAN) co-loaded mitochondria targeted lipid-polymer hybrid nano-system. METHODS: CAL and TAN combined lipid-polymer hybrid nano-systems were prepared and MTP-131 was conjugated with PEG and modified onto the nanoparticles to achieve MTP-CAL/TAN NS. The physicochemical properties of nano-systems were characterized, the AMI therapy ability of the systems was investigated in AMI rats' model. RESULTS: The size of MTP-CAL/TAN NS was 168.7 ±â€¯5.1 nm, with a surface charge of - 21.3 ±â€¯2.3 mV. The area under the curve (AUC) and blood circulation half-life (T1/2) of MTP-CAL/TAN NS was 178.86 ±â€¯6.62 µg·min/mL and 0.47 h, respectively. MTP-CAL/TAN NS exhibited the most significant infarct size reduction effect of 23.9 %. CONCLUSION: MTP-CAL/TAN NS exhibited the highest heart accumulation and best infarct size reduction effect, which could be used as a promising system for efficient treatment of cardiovascular diseases.

Correlation between apparent diffusion coefficient and tumor-stroma ratio in hybrid 18F-FDG PET/MRI: preliminary results of a rectal cancer cohort study.

Background: To explore possible correlations between the tumor-stroma ratio (TSR) and different imaging features of fluorine-18-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (18F-FDG PET/MRI) in untreated rectal cancer patients. Methods: A patients with rectal cancer were included in this study. All participants were examined preoperatively with whole-body 18F-FDG PET/MRI. Two pathologists evaluated the TSR of tumors together. Apparent diffusion coefficient (ADC) values and PET-related parameters of the primary lesions were measured and compared between the stroma-high and stroma-low groups. Pearson's correlation or Spearman's rank correlation were used to evaluate the correlation between the ADC values, PET-related parameters, and pathological indices. Results: Our results showed that in the untreated rectal cancer patients, the ADC mean values correlated with the TSR (r=0.327; P=0.007), and stroma-high (low TSR) rectal cancer corresponded to relatively lower ADC mean values (813.54±88.68 vs. 879.92±133.18; P=0.018). The ADC mean and ADC minimum (ADCmin) values were found to be negatively correlated with the pathological T stages (r=-0.384, P=0.001; r=-0.416, P=0.001, respectively) as well as the largest tumor diameters (r=-0.340, P=0.005; r=-0.314, P=0.010, respectively) of rectal cancer. In addition, the pathological T stages correlated with all PET-related metabolic parameters, including mean standard uptake value (SUV), maximum SUV (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) (r=0.338, P=0.006; r=0.350, P=0.004; r=0.326, P=0.007; and r=0.472, P<0.001, respectively). Our results also identified associations between the ADCmin values and SUVmean, SUVmax, and TLG (r=-0.335, P=0.006; r=-0.343, P=0.005; and r=-0.343, P=0.005, respectively). However, there were no statistical correlations between the PET/MRI parameters and the immunohistochemical (IHC) results. Conclusions: This study indicated that the intratumoral heterogeneity measured by PET/MRI may reflect characteristics of the tumor microenvironment. Hence, PET/MRI parameters might be helpful in predicting tumor aggressiveness and prognosis.

Bioinformatics Methods Reveal the Biomarkers and the miRNA-mRNA Network in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) has threatened the health of humans, and few therapeutic strategies can completely uproot this illness. Bioinformatics methods have been widely used for investigating the pathological mechanisms of disease. In this study, datasets including GSE20077 and GSE108724, obtained from the Gene Expression Omnibus (GEO) database, were used for investigating the biomarker and molecular mechanism of HCC. The differentially expressed genes (DEGs) in the datasets were identified, and the targets of the miRNAs were searched in the miRDIP and miRNET databases. Enrichment analysis was performed for delving the molecular mechanism of DEGs, and protein-protein interaction (PPI) networks and miRNA-mRNA networks were used to reveal the hub nodes and the related interaction relationships. Moreover, the expression and diagnostic values of hub nodes were analyzed with the GEPIA2 database. The results showed that 53 upregulated miRNAs and 48 downregulated miRNAs were found in GSE20077, and 55 upregulated miRNAs and 69 downregulated miRNAs were found in GSE108724. Moreover, seven common miRNAs including miR-146b-5p, miR-338-3p, miR-375, miR-502-3p, miR-532-3p, miR-532-5p, and miR-557 were found in the datasets. The targets of the common miRNAs were related with the P53, HIF1, Wnt, and NF-κB pathways. Besides, YWHAZ and CDC42 were identified as the hub nodes and served as the downstream targets of miR-375-3p. The GEPIA2 database showed that YWHAZ and CDC42 were related with the survival rate of the patients. In conclusion, this study suggests that miR-375-3p functions as a tumor suppressor which could inhibit the progression of HCC via targeting YWHAZ and CDC42.

The effect of flipped classroom in multiple clinical skills training for clinical interns on Objective Structured Clinical Examinations (OSCE).

AIMS: The flipped classroom (FC) is a hybrid approach, combining online learning and face-to-face classroom activities. To comprehensively evaluate the role of the Flipped Classroom (FC) model in clinical skills teaching of medical interns and investigate the acceptance and recognition of FC and Objective Structured Clinical Examinations (OSCE). METHODS: In the teaching of clinical skills, the students were further grouped into two groups- A and B (A = 37, B = 42), using a computer-based random digital method. group A adopted the traditional classroom (TC) model, and group B adopted the FC model. OSCE was used to assess the clinical skills of the two groups of interns. Two independent sample t-test was used to analyze the difference of participant's demographic data and OSCE scores between the two different teaching model. We sent FC questionnaires to group A and OSCE questionnaires to groups A and B. RESULTS: The score of OSCE in group B was higher than that in group A (P = 0.024), especially in the heart physical examination (P < 0.050), lung physical examination (P < 0.050), and abdominal physical examination (P < 0.050). The result of the FC questionnaires showed that regarding online courses, most students in group B thought watching videos was a good way to prepare for class (97.6%), For offline courses, most medical interns said that it enhanced their learning ability (88.1%), and they could accept this form of teaching (85.7%). As for the form of OSCE questionnaires, most people in group A and B said that they knew more about this form of assessment (81.0%), that it truly reflected the clinical ability (82.3%). CONCLUSIONS: FC model has shown good results in clinical skills training, while FC and OSCE can be further promoted in future teaching and assessment.

Saxagliptin protects against diabetic nephropathy by inhibiting caspase 3/PARP-1-dependent nephrocyte apoptosis.

Saxagliptin (SAX) can protect against tissue damage caused by diabetic nephropathy. However, whether this compound can restore kidney function, and its specific mechanism of action remain unclear. The present study explored the therapeutic effects and mechanisms of SAX. Male Wistar rats (8 weeks old) were randomly divided into the following groups: A control group (n=10); a group with streptozocin-induced diabetes mellitus (DM) treated with saline (n=20); and a group with streptozocin-induced DM treated with SAX (n=20). Following 20 weeks of treatment, renal function and the extent of renal damage were assessed based on histological staining using hematoxylin and eosin, periodic acid-Schiff and Masson's trichrome staining. The experimental results indicated that Streptozocin induction of DM led to thicker basement membranes in mesangial cells and a more abundant extracellular matrix. These changes were ameliorated following treatment with SAX. The data demonstrated that renal tissue and renal cell apoptosis were ameliorated significantly following treatment with SAX. Furthermore, the expression levels of the apoptotic genes poly (ADP-ribose) polymerase-1 (PARP-1) and caspase 3 were significantly decreased following treatment with SAX. Therefore, SAX may reduce the extent of renal apoptosis and pathological outcomes in diabetic nephropathy by downregulating the expression of caspase 3 and PARP-1 in the death receptor pathway of apoptosis.

The Adaptive Dynamic Programming Toolbox.

The paper develops the adaptive dynamic programming toolbox (ADPT), which is a MATLAB-based software package and computationally solves optimal control problems for continuous-time control-affine systems. The ADPT produces approximate optimal feedback controls by employing the adaptive dynamic programming technique and solving the Hamilton-Jacobi-Bellman equation approximately. A novel implementation method is derived to optimize the memory consumption by the ADPT throughout its execution. The ADPT supports two working modes: model-based mode and model-free mode. In the former mode, the ADPT computes optimal feedback controls provided the system dynamics. In the latter mode, optimal feedback controls are generated from the measurements of system trajectories, without the requirement of knowledge of the system model. Multiple setting options are provided in the ADPT, such that various customized circumstances can be accommodated. Compared to other popular software toolboxes for optimal control, the ADPT features computational precision and time efficiency, which is illustrated with its applications to a highly non-linear satellite attitude control problem.

SUN5 Interacting With Nesprin3 Plays an Essential Role in Sperm Head-to-Tail Linkage: Research on Sun5 Gene Knockout Mice.

Acephalic spermatozoa syndrome is a rare genetic and reproductive disease. Recent studies have shown that approximately 33-47% of patients with acephalic spermatozoa syndrome have SUN5 mutations, but the molecular mechanism underlying this phenomenon has not been elucidated. In this study, we generated Sun5 knockout mice and found that the head-to-tail linkage was broken in Sun5-/- mice, which was similar to human acephalic spermatozoa syndrome. Furthermore, ultrastructural imaging revealed that the head-tail coupling apparatus (HTCA) and the centrosome were distant from the nucleus at steps 9-10 during spermatid elongation. With the manchette disappearing at steps 13-14, the head and the tail segregated. To explore the molecular mechanism underlying this process, bioinformatic analysis was performed and showed that Sun5 may interact with Nesprin3. Further coimmunoprecipitation (Co-IP) and immunofluorescence assays confirmed that Sun5 and Nesprin3 were indeed bona fide interaction partners that formed the linker of the nucleoskeleton and cytoskeleton (LINC) complex participating in the connection of the head and tail of spermatozoa. Nesprin3 was located posterior and anterior to the nucleus during spermiogenesis in wild-type mice, whereas it lost its localization at the implantation fossa of the posterior region in Sun5-/- mice. Without correct localization of Nesprin3 at the nuclear membrane, the centrosome, which is the originator of the flagellum, was distant from the nucleus, which led to the separation of the head and tail. In addition, isobaric tag for relative and absolute quantitation results showed that 47 proteins were upregulated, and 56 proteins were downregulated, in the testis in Sun5-/- mice, and the downregulation of spermatogenesis-related proteins (Odf1 and Odf2) may also contribute to the damage to the spermatozoa head-to-tail linkage. Our findings suggested that Sun5 is essential for the localization of Nesprin3 at the posterior nuclear membrane, which plays an essential role in the sperm head-tail connection.

Patients with acephalic spermatozoa syndrome linked to novel TSGA10/PMFBP1 variants have favorable pregnancy outcomes from intracytoplasmic sperm injection.

Acephalic spermatozoa syndrome is a rare form of teratozoospermia characterized by headless spermatozoa. Previous studies have found that variants in SUN5, PMFBP1, TSGA10, BRDT, and SPATC1L are associated with this phenotype. Many researchers have suggested that variants in TSGA10 without a proximal centriole might influence early embryonic development. This retrospective cohort study included 12 infertile men with severe acephalic spermatozoa in China. We identified six heterozygous variants and four homozygous variants in TSGA10/PMFBP1 in seven patients by whole-exome sequencing (WES). Acephalic spermatozoa defects due to different genetic variations may affect only spermatozoa morphology but do not reduce the chances of fertilization, affect embryo quality at early stages or impair intracytoplasmic sperm injection (ICSI) outcomes. Patients with TSGA10/PMFBP1 variations were all expected to have good prognoses with ICSI.