Molecular Insights into the Effects of F16L and F19L Substitutions on the Conformation and Aggregation Dynamics of Human Calcitonin.

Human calcitonin (hCT) regulates calcium-phosphorus metabolism, but its amyloid aggregation disrupts physiological activity, increases thyroid carcinoma risk, and hampers its clinical use for bone-related diseases like osteoporosis and Paget's disease. Improving hCT with targeted modifications to mitigate amyloid formation while maintaining its function holds promise as a strategy. Understanding how each residue in hCT's amyloidogenic core affects its structure and aggregation dynamics is crucial for designing effective analogues. Mutants F16L-hCT and F19L-hCT, where Phe residues in the core are replaced with Leu as in nonamyloidogenic salmon calcitonin, showed different aggregation kinetics. However, the molecular effects of these substitutions in hCT are still unclear. Here, we systematically investigated the folding and self-assembly conformational dynamics of hCT, F16L-hCT, and F19L-hCT through multiple long-time scale independent atomistic discrete molecular dynamics (DMD) simulations. Our results indicated that the hCT monomer primarily assumed unstructured conformations with dynamic helices around residues 4-12 and 14-21. During self-assembly, the amyloidogenic core of hCT14-21 converted from dynamic helices to ß-sheets. However, substituting F16L did not induce significant conformational changes, as F16L-hCT exhibited characteristics similar to those of wild-type hCT in both monomeric and oligomeric states. In contrast, F19L-hCT exhibited substantially more helices and fewer ß-sheets than did hCT, irrespective of their monomers or oligomers. The substitution of F19L significantly enhanced the stability of the helical conformation for hCT14-21, thereby suppressing the helix-to-ß-sheet conformational conversion. Overall, our findings elucidate the molecular mechanisms underlying hCT aggregation and the effects of F16L and F19L substitutions on the conformational dynamics of hCT, highlighting the critical role of F19 as an important target in the design of amyloid-resistant hCT analogs for future clinical applications.

Damage Severity Assessment of Multi-Layer Complex Structures Based on a Damage Information Extraction Method with Ladder Feature Mining.

Multi-layer complex structures are widely used in large-scale engineering structures because of their diverse combinations of properties and excellent overall performance. However, multi-layer complex structures are prone to interlaminar debonding damage during use. Therefore, it is necessary to monitor debonding damage in engineering applications to determine structural integrity. In this paper, a damage information extraction method with ladder feature mining for Lamb waves is proposed. The method is able to optimize and screen effective damage information through ladder-type damage extraction. It is suitable for evaluating the severity of debonding damage in aluminum-foamed silicone rubber, a novel multi-layer complex structure. The proposed method contains ladder feature mining stages of damage information selection and damage feature fusion, realizing a multi-level damage information extraction process from coarse to fine. The results show that the accuracy of damage severity assessment by the damage information extraction method with ladder feature mining is improved by more than 5% compared to other methods. The effectiveness and accuracy of the method in assessing the damage severity of multi-layer complex structures are demonstrated, providing a new perspective and solution for damage monitoring of multi-layer complex structures.

Protective effects of human urinary kallidinogenase against corticospinal tract damage in acute ischemic stroke patients.

This study aimed to assess the effects of human urinary kallidinogenase (HUK) on motor function outcome and corticospinal tract recovery in patients with acute ischemic stroke (AIS). This study was a randomized, controlled, single-blinded trial. Eighty AIS patients were split into two groups: the HUK and control groups. The HUK group was administered HUK and standard treatment, while the control group received standard treatment only. At admission and discharge, the National Institutes of Health Stroke Scale (NIHSS), Barthel Index (BI) and muscle strength were scored. The primary endpoint was the short-term outcomes of AIS patients under different treatments. The secondary endpoint was the degree of corticospinal tract fiber damage under different treatments. There was a significant improvement in the NIHSS Scale, BI and muscle strength scores in the HUK group compared with controls (Mann-Whitney U test; P  < 0.05). Diffusion tensor tractography classification and intracranial arterial stenosis were independent predictors of short-term recovery by linear regression analysis. The changes in fractional anisotropy (FA) and apparent diffusion coefficient (ADC) decline rate were significantly smaller in the HUK group than in the control group ( P <  0.05). Vascular endothelial growth factor (VEGF) increased significantly after HUK treatment ( P  < 0.05), and the VEGF change was negatively correlated with changes in ADC. HUK is beneficial for the outcome in AIS patients especially in motor function recovery. It may have protective effects on the corticospinal tract which is reflected by the reduction in the FA and ADC decline rates and increased VEGF expression. The study was registered on ClinicalTrials.gov (unique identifier: NCT04102956).

Deciphering the influence of Y12L and N17H substitutions on the conformation and oligomerization of human calcitonin.

The abnormal aggregation of human calcitonin (hCT) hormone peptides impairs their physiological function, leading to harmful immune responses and cytotoxicity, which limits their clinical utility. Interestingly, a representative hCT analog incorporating Y12L and N17H substitutions (DM-hCT) has shown reduced aggregation tendencies while maintaining bioactivity. But the molecular mechanism of Y12L and N17H substitutions on the conformational dynamics of hCT remains unclear. Here, we systematically investigated the folding and self-assembly dynamics of hCT and DM-hCT using atomistic discrete molecular dynamics (DMD) simulations. Our findings revealed that hCT monomers predominantly adopted unstructured conformations with dynamic helices. Oligomerization of hCT resulted in the formation of ß-sheet-rich aggregates and ß-barrel intermediates. The Y12L and N17H substitutions enhanced helical conformations and suppressed ß-sheet formation in both monomers and oligomers. These substitutions stabilized the dynamic helices and disrupted aromatic interactions responsible for ß-sheet formation at residue 12. Notably, DM-hCT assemblies still exhibited ß-sheets in phenylalanine-rich and C-terminal hydrophobic regions, suggesting that future optimizations should focus on these areas. Our simulations provide insights into the molecular mechanisms underlying hCT aggregation and the amyloid-resistant effects of Y12L and N17H substitutions. These findings have valuable implications for the development of clinical hCT analogs.

SEVI Inhibits Aß Amyloid Aggregation by Capping the ß-Sheet Elongation Edges.

Inhibiting the aggregation of amyloid peptides with endogenous peptides has broad interest due to their intrinsically high biocompatibility and low immunogenicity. Here, we investigated the inhibition mechanism of the prostatic acidic phosphatase fragment SEVI (semen-derived enhancer of viral infection) against Aß42 fibrillization using atomistic discrete molecular dynamic simulations. Our result revealed that SEVI was intrinsically disordered with dynamic formation of residual helices. With a high positive net charge, the self-aggregation tendency of SEVI was weak. Aß42 had a strong aggregation propensity by readily self-assembling into ß-sheet-rich aggregates. SEVI preferred to interact with Aß42, rather than SEVI themselves. In the heteroaggregates, Aß42 mainly adopted ß-sheets buried inside and capped by SEVI in the outer layer. SEVI could bind to various Aß aggregation species─including monomers, dimers, and proto-fibrils─by capping the exposed ß-sheet elongation edges. The aggregation processes Aß42 from the formation of oligomers to conformational nucleation into fibrils and fibril growth should be inhibited as their ß-sheet elongation edges are being occupied by the highly charged SEVI. Overall, our computational study uncovered the molecular mechanism of experimentally observed inhibition of SEVI against Aß42 aggregation, providing novel insights into the development of therapeutic strategies against Alzheimer's disease.

The incidence of cytomegalovirus and BK polyomavirus infections in kidney transplant patients receiving mTOR inhibitors: A systematic review and meta-analysis.

Cytomegalovirus (CMV) and BK polyomavirus (BKPyV) infections after kidney transplant have become increasingly prevalent. Based on previous studies, the mammalian target of rapamycin (mTOR) inhibitors seem like attractive alternatives with antiviral activity. The objective of this systematic review and meta-analysis was to investigate the incidence of CMV and BKPyV infections in kidney transplantation recipients receiving mTOR inhibitors. This meta-analysis included three comparisons of immunosuppressant regimens commonly used after kidney transplantation: Comparison 1: mTOR inhibitors versus calcineurin inhibitors (CNI); Comparison 2: mTOR inhibitors versus antimetabolites (AM); and Comparison 3: mTOR inhibitors plus a reduced-dose of CNI versus AM plus a standard-dose of CNI. The group containing mTOR inhibitors was the study group and the remaining one was the control group. The incidence of CMV or BKPyV infection defined by positive culture, serology, or polymerase chain reaction testing was the primary outcome. A total of 61 studies involving 13,609 patients were included. As compared with the control group, a significantly decreased risk of CMV and BKPyV infections favoring the mTOR inhibitors-based group was shown in comparisons 1, 2, and 3 (p < 0.05). Compared with the control group in all three comparisons, mTOR inhibitors made no difference in regard to death and graft loss (p > 0.05). Compared with CNI, the incidence of biopsy-proven acute rejection (BPAR) and anemia was higher with mTOR inhibitors (p < 0.05). In comparisons 2 and 3, the risk of new-onset diabetes mellitus (NODM) was higher with mTOR inhibitors (p < 0.05). Early introduction of mTOR inhibitors reduced more CMV infections in comparisons 1 and 2 (p < 0.05). The mTOR inhibitor-based regimen is an attractive alternative with lower risk of CMV and BKPyV infections in kidney transplant recipients. The combination regimen is more appropriate and acceptable than the mTOR-inhibitor monotherapy-based regimen. Early introduction of mTOR inhibitors is recommended, although it is worth noting that attention should be paid to wound healing when mTOR inhibitors are introduced early.

Identification of avian polyomavirus and its pathogenicity to SPF chickens.

The research aimed to study an Avian polyomavirus strain that was isolated in Shandong, China. To study the pathogenicity of APV in SPF chickens, and provide references for epidemiological research and disease prevention and control of APV. The genetic characterization of APV strain (termed APV-20) was analyzed and the pathogenicity of APV was investigated from two aspects: different age SPF chickens, and different infection doses. The results revealed that the APV-20 exhibits a nucleotide homology of 99% with the other three APV strains, and the evolution of APV In China was slow. In addition, the APV-20 infection in chickens caused depression, drowsiness, clustering, and fluffy feathers, but no deaths occurred in the infected chickens. The main manifestations of necropsy, and Hematoxylin and Eosin staining (HE) showed that one-day-old SPF chickens were the most susceptible, and there was a positive correlation between viral load and infection dose in the same tissue. This study showed that SPF chickens were susceptible to APV, and an experimental animal model was established. This study can provide a reference for the pathogenic mechanism of immune prevention and control of APV.

A drug utilization study of oral anticoagulants in five representative cities of China between 2015 and 2019.

WHAT IS KNOWN AND OBJECTIVE: Oral anticoagulants (OACs), including warfarin and newer direct-acting OACs (DOACs), have been used for decades to prevent thromboembolic diseases. A drug utilization study was performed to determine the prescribing patterns of OACs. METHODS: Data were extracted from the Cooperation Project of Hospital Prescription Analysis in China. A total of 455,490 prescription records from 43 tertiary hospitals in five cities of China (Beijing, Shanghai, Guangzhou, Hangzhou and Chengdu) were selected for inclusion. Quarterly trends of defined daily doses (DDDs) and defined daily dose cost (DDDC) from 1 January 2015 to 31 December 2019 were calculated. RESULTS AND DISCUSSION: Warfarin was the most widely used OAC with DDDs between 189,982 and 176,323 from the first quarter (Q1) of 2015 to the fourth quarter (Q4) of 2019, whereas the use of DOACs increased rapidly during this period. DDDs of rivaroxaban increased from 5409 in Q1 of 2015 to 125,800 in Q4 of 2019, whereas the DDDC declined from 160.5 to 45.7. From Q1 of 2018, rivaroxaban became the most prescribed OAC, surpassing warfarin, in patients diagnosed with deep vein thrombosis. In addition, the DDDs of rivaroxaban exceeded those of warfarin in patients diagnosed with non-valvular atrial fibrillation since the second quarter (Q2) of 2019. DDDs in outpatients and inpatients increased by 80.6% and 71.4%, respectively, and the DDDC for outpatients in Q4 of 2019 was 6.7-fold higher than that in Q1 of 2015. Among patients of all ages, the DDDs in elderly patients increased from 36.8% in Q1 of 2015 to 59.4% in Q4 of 2019. Moreover, the departments of cardiology and cardiothoracic surgery prescribed the majority of the OACs. WHAT IS NEW AND CONCLUSION: In this study, we describe OAC prescription patterns in China. DOACs, especially rivaroxaban, contribute to the continuous increase in the use of OACs. In the investigated population of China, outpatients and elderly patients were observed to be administered the highest proportion of DOACs.

Real-Time Life-Cycle Monitoring of Composite Structures Using Piezoelectric-Fiber Hybrid Sensor Network.

In this paper, an in situ piezoelectric-fiber hybrid sensor network was developed to monitor the life-cycle of carbon fiber-reinforced plastics (CFRPs), from the manufacturing phase to the life in service. The piezoelectric lead-zirconate titanate (PZT) sensors were inserted inside the composite structures during the manufacturing process to monitor important curing parameters, including the storage modulus of resin and the progress of the reaction (POR). The strain that is related to the storage modulus and the state of resin was measured by embedded fiber Bragg grating (FBG) sensors, and the gelation moment identified by the FBG sensors was very close to those determined by dynamic mechanical analysis (DMA) and POR. After curing, experiments were conducted on the fabricated CFRP specimen to investigate the damage identification capability of the embedded piezoelectric sensor network. Furthermore, a modified probability diagnostic imaging (PDI) algorithm with a dynamically adaptive shape factor and fusion frequency was proposed to indicate the damage location in the tested sample and to greatly improve the position precision. The experimental results demonstrated that the average relative distance error (RDE) of the modified PDI method was 68.48% and 46.97% lower than those of the conventional PDI method and the PDI method, respectively, with an averaged shape factor and fusion frequency, indicating the effectiveness and applicability of the proposed damage imaging method. It is obvious that the whole life-cycle of CFRPs can be effectively monitored by the piezoelectric-fiber hybrid sensor network.

[Corrigendum] Synergistic cardioprotective effects of Danshensu and hydroxysafflor yellow A against myocardial ischemia-reperfusion injury are mediated through the Akt/Nrf2/HO-1 pathway.

Subsequently to the publication of the above article, an interested reader drew to the authors' attention that some of the data panels shown in Fig. 6A on p. 90 appeared to contain overlapping data, such that the data may have been derived from the same original source where different experimental conditions were portrayed in the figure. The data that appeared to be overlapping were featured in the H/R and H/R+DH+Z panels (both the merged and the unmerged data panels). The authors have re-examined their original data and realize that they made an inadvertent error during the assembly of this figure. The corrected version of Fig. 6A, showing the correct TUNEL staining data for the H/R+DH+Z experiment, is shown on the next page. Note that the errors made during the assembly of this figure did not affect the major conclusions reported in the paper. All the authors have agreed to this Corrigendum, and thank the Editor of International Journal of Molecular Medicine for allowing them the opportunity to publish this. The authors regret these errors went unnoticed during the compilation of the figure in question, and apologize to the readership for any confusion that this may have caused. [the original article was published in International Journal of Molecular Medicine 38: 83-94, 2016; DOI: 10.3892/ijmm.2016.2584].

Evaluation of a Pharmacist-Led Remote Warfarin Management Model Using a Smartphone Application (Yixing) in Improving Patients' Knowledge and Outcomes of Anticoagulation Therapy.

Background: The management of warfarin-treated patients has been recognized as a challenge due to narrow therapeutic range and food and drug interactions in warfarin therapy. We aim to evaluate the effect of a pharmacist-led remote warfarin management model using a smartphone application (app) on anticoagulation therapy. Methods: Eligible patients who had received warfarin therapy after mechanical heart valve replacement were enrolled. The intervention group was offered a pharmacist-led remote warfarin management model using the app named Yixing. Yixing incorporates functions including automatic daily reminder, personal health record, educational program, and online counseling. The control group received traditional pharmacy services without Yixing. Co-primary outcomes were patients' awareness score of warfarin therapy obtained from questionnaire, the medication adherence measured by the percentage of the correct-warfarin-taken days in the monitored period, the fraction of time in therapeutic range (FTTR), and the incidence of anticoagulation-related complications. The needed information of the patients was acquired via electronic medical records from the hospital, Yixing system and telephone follow-up when necessary. Results: 64 and 66 patients were initially in the intervention and control groups respectively. After propensity score matching, 50 patients were assigned in each group. The intervention group had a median age of 51.0 years, in which 27 (54%) were male. The control group had a median age of 50.5 years, in which 28 (56%) were male. Patient awareness score in the intervention group was 8.00 (2.00), which was higher than that in the control group, with score at 6.50 (2.50) (p = 0.001). No significant difference was found in the percentage of the correct-warfarin-taken days between the two groups (p = 0.520). The median (interquartile range) value of FTTR was 80.3% (21.9%) and 72.1% (17.7%) in the intervention and control groups respectively (p = 0.033), and no significant differences in the incidence of anticoagulation-related complications were observed (p = 0.514). Conclusion: The pharmacist-led remote warfarin management model using Yixing improves patients' awareness of warfarin therapy and increases FTTR, but may not have significant improvements on medication adherence and safety.

Quantitative defect inspection in the curved composite structure using the modified probabilistic tomography algorithm and fusion of damage index.

The curved composite structures are popularly used in the aerospace field for their superior properties. Complexity of structure and geometry generally limit the inspection or monitoring effect of different types of defects in the curved composite structure. A feasible damage probabilistic tomography algorithm combined with ultrasonic guided wave technology is necessary to be developed for the structural health monitoring of curved composite structures. In this paper, defect zones in a curved composite structure are characterized using the modified probabilistic tomography (MPT) method and fusion of damage index (DI). The MPT with the defect shape factor ßM at each damage-impaired path and hybrid DI schemes are proposed to indicate the location and propagation of defect zones in tested sample. The feasibility of proposed approaches is verified on the curved carbon/epoxy composite structure, experimentally. The results show that the MPT and fusion DI methods successfully represent the extension of defect zones in a quantitative manner. It is suggested that the accuracy and reliability of localization results of the MPT algorithm is better than those obtained by the probabilistic tomography (PT) algorithm with the averaged ß.

Pregnancy outcomes in female patients exposed to cyclosporin-based versus tacrolimus-based immunosuppressive regimens after liver/kidney transplantation: A systematic review and meta-analysis.

WHAT IS KNOWN AND OBJECTIVE: Pregnancy after transplantation is a challenge owing to the high risk of adverse maternal and foetal outcomes, and immunosuppressants may further impact these outcomes. There are no head-to-head randomized controlled trials comparing influences of cyclosporin and tacrolimus on pregnancy outcomes. Thus, we systematically reviewed and meta-analysed observational studies assessing the comparative influences of these two drugs on pregnancy outcomes in liver/kidney transplant recipients. METHODS: Relevant studies comparing pregnancy outcomes with tacrolimus and cyclosporin head-to-head were searched in PubMed, EMBASE and Web of Science (from 1 January 2000 to 20 March 2020). The weighted mean difference and odds ratio (OR) were calculated to compare continuous and dichotomous variables, respectively, with 95% confidence intervals (CIs). Publication bias was estimated using funnel plots. The study quality was assessed according to the modified Newcastle-Ottawa scale. RESULTS AND DISCUSSION: Overall, 10 observational studies of low quality, including a total of 1080 post-liver or kidney transplant pregnancies, were identified. Tacrolimus-treated recipients experienced a lower risk of gestational hypertension (28.0%; OR: 1.74; 95% CI: 1.27-2.39; p < 0.01). Cyclosporin-treated recipients showed a lower incidence of caesarean section (40.3%; OR: 0.62; 95% CI: 0.46-0.82; p < 0.01). Additionally, cyclosporin performed better in terms of the live birth rate (78.0%; OR: 1.38; 95% CI: 1.02-1.88; p = 0.04). No significant differences in the incidences of pre-eclampsia, gestational diabetes, preterm delivery and birth weight were observed. WHAT IS NEW AND CONCLUSION: Tacrolimus performed better in patients with gestational hypertension, while cyclosporin was associated with a lower incidence of caesarean section and a higher incidence of live birth. The findings are based on relatively low-quality evidence, but may provide a reference for clinicians in their clinical monitoring and obstetric care for post-transplant pregnancies.

Genetic and clinical determinants of mizoribine pharmacokinetics in renal transplant recipients.

AIM: Mizoribine (MZR) is an immunosuppressant for the prevention of allograft rejection in Asian countries, but the great variability in pharmacokinetics (PK) limits its clinical use. This study was to explore genetic and clinical factors that affect the MZR PK process. METHODS: Blood samples and clinical data were collected from 60 Chinese renal transplant recipients. MZR plasma concentration was measured at pre-dose (0 h) and 0.5, 1, 2, 3, 4, 5, 6, 8, and 12 h post-dose by high performance liquid chromatography with an ultraviolet detector. PK parameters were calculated by non-compartmental analysis. High-throughput sequenced single nucleotide polymorphism was applied screening possible genetic factors. RESULTS: Extensive inter-individual MZR PK differences were reflected in the process of elimination (ke, CL/F, MRT and t1/2) and intestinal absorption (Cmax and Tmax), as well as in the dose-normalized exposure (AUC0-12h/D). From 146 SNPs within 39 genes screened, AUC0-12h/D was found higher in recipients with CREB1 rs11904814 TT than with G allele carriers (3.135 ± 0.928 versus 2.084 ± 0.379 µg h ml-1 mg-1, p = 0.007). Recipients with SLC28A3 rs10868138 TT had lower t1/2 as compared to C allele carriers (0.728 ± 0.189 versus 0.951 ± 0.196 h, p = 0.001). Serum creatinine (SCr) explained 35.5% of C0/D variability (p < 0.001). Pure effects of genotypes CREB1 and SLC28A3 were 13.7% (p = 0.004) and 17.5% (p = 0.001) for AUC0-12h/D and t1/2, respectively. When additionally taking SCr into models, CREB1 and SLC28A3 genotypes explained 20.0% (p = 0.038) and 46.5% (p < 0.001) of AUC0-12h/D and t1/2 variability, respectively. CONCLUSION: CREB1 and SLC28A3 genotypes, as well as SCr, are identified as determinants in predicting inter-individual MZR PK differences in renal transplant recipients.

Active Monitoring of Fatigue Crack in the Weld Zone of Bogie Frames Using Ultrasonic Guided Waves.

The bogie frame is an important structure of railway vehicles, transmitting the traction, braking force, lateral force, and vertical force during the traction operation. With the development of high speeds and heavy loads, the appearance of fatigue cracks in the bogie frames is increasing, which reduces the driving life of railway vehicles and even causes serious traffic accidents. Real-time monitoring on the integrity of the bogie is an inevitable requirement for ensuring the safe operation of railway vehicles. In this paper, ultrasonic guided wave-based active structural health monitoring (SHM) was developed to identify the fatigue crack of the bogie frame. Experiments were conducted on a welded T-shape specimen with a thickness of 12 mm. A total of 10 piezoelectric lead zirconate titanate (PZT) disks were mounted around the weld zone of the specimen, five of which were used as actuators, and the other five were used as sensors. Five-peak modulation narrow-band sine waves were input into the actuators to excite the specimen. From the sensor signals, the advanced damage index (DI) was calculated to identify the propagation of the crack. The experimental results demonstrate that crack damage as small as 2 mm in the weld zone of the bogie frame can be successfully detected. Some practical issues for implementing the SHM in real applications, such as crack quantification and environmental compensation, were also discussed.

The lncRNA small nucleolar RNA host gene 5 regulates trophoblast cell proliferation, invasion, and migration via modulating miR-26a-5p/N-cadherin axis.

Pre-eclampsia (PE) is a pregnancy-specific disease characterized by the occurrence of hypertension and proteinuria after two weeks of gestation. Long noncoding RNAs (lncRNAs) are emerging as key regulators in PE development. This study aims to investigate the role of lncRNA, small nucleolar RNA host gene 5 (SNHG5), in the pathogenesis of PE. The expression of SNHG5 was significantly downregulated in placental tissues from patients with severe PE compared normal controls. Overexpression of SNHG5 promoted trophoblast (HTR-8/SVneo) cell proliferation, invasion, and migration, and flow cytometry results showed that SNHG5 overexpression inhibited apoptosis and caused a decrease of cell population at the G 0 /G 1 phase and an increase of cell population at the S phase, while knockdown of SNHG5 had the opposite effects. The interaction between SNHG5 and miR-26a-5p was predicted by bioinformatics analysis and confirmed by luciferase reporter assay and RNA immunoprecipitation, and miR-26a-5p was negatively regulated by SNHG5; miR-26a-5p expression was upregulated in PE placental tissues and was inversely correlated with SNHG5 expression. Furthermore, miR-26a-5p was predicted to target the 3' untranslated region of N-cadherin, which was confirmed by luciferase reporter assay, and miR-26a-5p overexpression suppressed N-cadherin expression in HTR-8/SVneo cells. N-cadherin mRNA expression was downregulated in PE placental tissues and was positively correlated with SNHG5 expression. Both overexpression of miR-26a-5p and knockdown of N-cadherin suppressed HTR-8/SVneo cell invasion and migration, and also attenuated the effects of SNHG5 on the cellular functions of HTR-8/SVneo cells. In conclusion, our study suggested that SNHG5 promotes trophoblast cell proliferation, invasion, and migration at least partly via regulating the miR-26a-5p/N-cadherin axis.

Designing robust underwater superoleophobic microstructures on copper substrates.

Recently, surfaces with a robust underwater superoleophobicity have attracted much attention. Although it is recognized that stable microstructures are significant for such surfaces, a clear picture of how microstructural features such as morphology, size, etc. influence their own stability and related wettability is still missing. Herein, three low adhesive underwater superoleophobic copper surfaces with different microstructures (hemispheric, pinecone-like, and honeycomb) were first prepared, and then the stability of these microstructures was examined by a series of physical and chemical damage experiments (sand grain abrasion, corrosion in acid/base solutions, etc.). The results indicate that the hemispheric microstructure is more stable than the other two microstructures and the corresponding surface has a robust underwater superoleophobicity. Theoretical simulation analysis further confirms the experimental results and reveals that different stabilities are ascribed to different stress distributions on these microstructures under an external force due to distinct microstructure shapes. Furthermore, based on the same design strategy, a robust underwater superoleophobic oil/water separation copper mesh film was also prepared. This work provides an insight into the effect of microstructural features on the stability and related underwater oil-repellent properties of superoleophobic copper surfaces, and could provide us with some fresh design ideas for robust superwetting surfaces.

The Pyk2/MCU pathway in the rat middle cerebral artery occlusion model of ischemic stroke.

Mitochondrial dysfunction caused by Ca2+ overload plays an important role in ischemia-induced brain damage. Mitochondrial calcium uniporter (MCU), located on the mitochondrial inner membrane, is the major channel responsible for mitochondrial Ca2+ uptake. Activated proline-rich tyrosine kinase 2 (Pyk2) can directly phosphorylate MCU, which enhances mitochondrial Ca2+ uptake in cardiomyocytes. It has been suggested that the Pyk2/MCU pathway may be a novel therapeutic target in stress-induced cellular apoptosis. In this study, we explored the role of the Pyk2/MCU pathway in the ischemic brain following a stroke injury. We found that the Pyk2/MCU pathway is activated in a rat cerebral ischemia model, and is responsible for mitochondrial dysfunction and neuronal apoptosis. Inhibiting the Pyk2/MCU pathway with a Pyk2 inhibitor (PF-431396) prevented mitochondrial Ca2+ overload, mitochondrial injury, proapoptotic protein release, and cell death. Interestingly, human urinary kallidinogenase (HUK) alleviated neuronal ischemic injury by inhibiting the Pyk2/MCU pathway, suggesting that the Pyk2/MCU pathway may be a protective target for ischemic stroke treatment.

Hypoxia stimulates proliferation of rat neural stem/progenitor cells by regulating mir-21: an in vitro study.

Neural stem/progenitor cells (NSPCs) reside not only in the developing brain, but also in the adult brain within specialized microenvironments that regulate their function. In vitro and in vivo studies have revealed strong regulatory links between hypoxic/ischemic insults and activation of NSCPs. However, the underlying mechanisms of this activation remain unclear. In this study, we found that cell proliferation is promoted by hypoxia, and accompanied by increasing expression of miR-21 in cultured rat NSPCs. Moreover, qRT-PCR analysis indicated that expression of miR-21 increases in a time-dependent manner. 5-Bromo-2-deoxyUridine (BrdU) staining and flow cytometry showed that overexpression of miR-21 further promoted proliferation of NSPCs in the presence of hypoxia. Knocking down of miR-21 partially abolished the proliferative effect of hypoxia treatment on cell proliferation. Western blot demonstrated that overexpression of miR-21 enhanced expression of cyclin D1, while knock down of miR-21 suppressed cyclin D1 expression under hypoxic conditions. Furthermore, overexpression of miR-21 also increased levels of p-AKT. These results demonstrate that miR-21 plays a role in regulating the proliferation of cultured rat NSPCs undergoing hypoxia, and the activation of the PI-3-K signaling pathway might be one of the underlying mechanisms. These findings prompt a molecular study investigating potential mechanisms for stem cell treatment of cerebral ischemia.

Influence of electromagnetic pulse on the offspring sex ratio of male BALB/c mice.

Public concern is growing about the exposure to electromagnetic fields (EMF) and its effect on male reproductive health. Detrimental effect of EMF exposure on sex hormones, reproductive performance and sex-ratio was reported. The present study was designed to clarify whether paternal exposure to electromagnetic pulse (EMP) affects offspring sex ratio in mice. 50 male BALB/c mice aged 5-6 weeks were exposed to EMP daily for 2 weeks before mated with non-exposed females at 0d, 7d, 14d, 21d and 28d after exposure. Sex hormones including total testosterone, LH, FSH, and GnRH were detected using radioimmunoassay. The sex ratio was examined by PCR and agarose gel electrophoresis. The results of D0, D21 and D28 showed significant increases compared with sham-exposed groups. The serum testosterone increased significantly in D0, D14, D21, and D28 compared with sham-exposed groups (p<0.05). Overall, this study suggested that EMP exposure may lead to the disturbance of reproductive hormone levels and affect the offspring sex ratio.