A new insight on evaluation of the fertility and pregnancy outcome in patients with primary Sjögren syndrome: a propensity score matched study in multi-IVF centers.

BACKGROUND: Primary Sjögren syndrome (pSS) is often related to adverse neonatal outcomes. But it's currently controversial whether pSS has an adverse effect on female fertility and clinical pregnancy condition. More importantly, it's unclear regarding the role of pSS in oocyte and embryonic development. There is a lack of comprehensive understanding and evaluation of fertility in pSS patients. OBJECTIVE: This study aimed to investigate oocyte and embryonic development, ovarian reserve, and clinical pregnancy outcomes in Primary Sjögren syndrome (pSS) patients during in vitro fertilization (IVF) treatment from multi-IVF centers. METHODS: We performed a muti-central retrospective cohort study overall evaluating the baseline characteristics, ovarian reserve, IVF laboratory outcomes, and clinical pregnancy outcomes between the pSS patients and control patients who were matched by Propensity Score Matching. RESULTS: Following PSM matching, baseline characteristics generally coincided between the two groups. Ovarian reserve including anti-müllerian hormone (AMH) and antral follicle counting (AFC) were significantly lower in the pSS group vs comparison (0.8 vs. 2.9 ng/mL, P < 0.001; 6.0 vs. 10.0, P < 0.001, respectively). The pSS group performed significant reductions in numbers of large follicles, oocytes retrieved and MII oocytes. Additionally, pSS patients exhibited obviously deteriorate rates of oocyte maturation, 2PN cleavage, D3 good-quality embryo, and blastocyst formation compared to comparison. As for clinical pregnancy, notable decrease was found in implantation rate (37.9% vs. 54.9%, P = 0.022). The cumulative live birth rate (CLBR) following every embryo-transfer procedure was distinctly lower in the pSS group, and the conservative and optimal CLBRs following every complete cycle procedure were also significantly reduced in the pSS group. Lastly, the gestational weeks of the newborns in pSS group were distinctly early vs comparison. CONCLUSION: Patients with pSS exhibit worse conditions in terms of female fertility and clinical pregnancy, notably accompanied with deteriorate oocyte and embryo development. Individualized fertility evaluation and early fertility guidance are essential for these special patients.

Smooth endoplasmic reticulum aggregates in oocytes associated with increased risk of neonatal birth defects: A meta-analysis.

INTRODUCTION: Previous studies have indicated the association between smooth endoplasmic reticulum aggregates (SERa+) and poorer medically assisted reproduction outcomes. However, the link between SERa+ and neonatal outcomes remains controversial and open for debate. A comprehensive meta-analysis on the relation between SERa+ and the risk of birth defects is needed. MATERIAL AND METHODS: The literature search was conducted using the following databases: PubMed, Embase, Cochrane Libraries, Web of Science, and Chinese databases including China National Knowledge Infrastructure (CNKI) and Wan Fang from inception until July 2023. Risk ratio (RR) and 95% confidence interval (CI) were calculated by a fixed-effected model, while heterogeneity was assessed by forest plots and I2 statistic. Funnel plot was produced to assess publication bias. This meta-analysis has been registered on PROSPERO (CRD42022313387). RESULTS: The search resulted in 122 studies, 14 of which met the inclusion criteria. The analysis of birth defects revealed a higher risk (RR = 2.17, 95%CI 1.24 to 3.81, p = 0.007) in children derived from SERa+ cycle compared to SERa- cycles (711 vs. 4633). Meanwhile, in a subgroup analysis, the risk of birth defects was significantly increased in the SERa+ oocytes group as compared with the sibling SERa- oocytes group (RR = 3.53, 95%CI 1.21 to 10.24, p = 0.02). CONCLUSIONS: To conclude, our analysis indicated that SERa+ cycles/oocytes may have a potential risk of increased additional major birth defects comparing with SERa- cycles/oocytes. This conclusion may provide evidence-based support for clinicians in IVF clinical guidance and embryologists in prudent embryo selection strategy.

An overview of CFTR mutation profiles and assisted reproductive technology outcomes in Chinese patients with congenital obstructive azoospermia.

PURPOSE: The cystic fibrosis transmembrane conductance regulator (CFTR) is the most common causative gene attributed to congenital obstructive azoospermia (OA). The aim of this study was to conduct an epidemiological survey of congenital OA patients, to screen for CFTR mutations, and to follow their pregnancy outcomes in assisted reproductive technology (ART). METHODS: This cohort study enrolled congenital OA patients undergoing ART and whole-exome sequencing from January 2018 to September 2023. Semen parameters, sex hormones, and seminal plasma biochemistry were evaluated. CFTR mutations identified in OA patients were analyzed. In addition, the laboratory outcomes, clinical outcomes, and neonatal outcomes were compared between OA patients carrying two CFTR mutations and the others after surgical sperm extraction-intracytoplasmic sperm injection (ICSI) treatment. RESULTS: A total of 76 patients with congenital OA were enrolled. CFTR mutations were identified in 35 (46.1%) congenital OA patients. A total of 60 CFTR mutation sites of 27 types were identified, and 10 of them were novel. The average frequency was 1.71 (60/35) per person. The most common mutation was c.1210-11T > G (25%, 15/60). After ICSI treatment, there were no statistically significant differences in laboratory outcomes, clinical outcomes, and neonatal outcomes between OA patients carrying two CFTR mutations (n = 25) and other OA patients (n = 51). CONCLUSION: Apart from the IVS9-5T mutation, the genetic mutation pattern of CFTR in Chinese OA patients is heterogeneous, which is significantly different from that of Caucasians. Although carrying two CFTR mutations or not had no effect on the pregnancy outcomes in OA patients after ICSI, genetic counseling is still recommended for such patients.

Immunopathogenesis of patients with COVID-19: from the perspective of immune system 'evolution' and 'revolution'.

The pandemic caused by severe acute respiratory syndrome coronavirus 2 is sweeping the world, threatening millions of lives and drastically altering our ways of living. According to current studies, failure to either activate or eliminate inflammatory responses timely and properly at certain stages could result in the progression of the disease. In other words, robust immune responses to coronavirus disease 2019 (COVID-19) are critical. However, they do not theoretically present in some special groups of people, including the young, the aged, patients with autoimmunity or cancer. Differences also do occur between men and women. Our immune system evolves to ensure delicate coordination at different stages of life. The innate immune cells mainly consisted of myeloid lineage cells, including neutrophils, basophils, eosinophils, dendritic cells and mast cells; they possess phagocytic capacity to different degrees at different stages of life. They are firstly recruited upon infection and may activate the adaptive immunity when needed. The adaptive immune cells, on the other way, are comprised mainly of lymphoid lineages. As one grows up, the adaptive immunity matures and expands its memory repertoire, accompanied by an adjustment in quantity and quality. In this review, we would summarise and analyse the immunological characteristics of these groups from the perspective of the immune system 'evolution' as well as 'revolution' that has been studied and speculated so far, which would aid the comprehensive understanding of COVID-19 and personalised-treatment strategy.

Rapamycin improves the quality and developmental competence of mice oocytes by promoting DNA damage repair during in vitro maturation.

BACKGROUND: Increasing evidence has shown that the mammalian target of rapamycin (mTOR) pathway plays a critical role in oocyte meiosis and embryonic development, however, previous studies reporting the effects of rapamycin on oocyte IVM showed different or even opposite results, and the specific mechanisms were not clear. METHODS: The immature oocytes from female mice underwent IVM with rapamycin at different concentrations to select an optimal dose. The maturation rate, activation rate, subsequent cleavage and blastocyst formation rates, spindle assembly, chromosome alignment, mitochondrial membrane potential (MMP), ROS levels, and DNA damage levels were evaluated and compared in oocytes matured with or without rapamycin. In addition, the expression levels of genes associated with mTORC1 pathway, spindle assembly, antioxidant function, and DNA damage repair (DDR) were also assessed and compared. RESULTS: Rapamycin at 10 nM was selected as an optimal concentration based on the higher maturation and activation rate of IVM oocytes. Following subsequent culture, cleavage and blastocyst formation rates were elevated in activated embryos from the rapamycin group. Additionally, oocytes cultured with 10 nM rapamycin presented decreased ROS levels, reduced chromosome aberration, and attenuated levels of γ-H2AX. No significant effects on the percentages of abnormal spindle were observed. Correspondingly, the expressions of Nrf2, Atm, Atr, and Prkdc in IVM oocytes were markedly increased, following the inhibition of mTORC1 pathway by 10 nM rapamycin. CONCLUSION: Rapamycin at 10 nM could ameliorate the developmental competence and quality of IVM oocytes of mice, mainly by improving the chromosome alignments. The inhibition of mTORC1 pathway, which involved in activating DDR-associated genes may act as a potential mechanism for oocyte quality improvement by rapamycin.

Molecular cloning and tissue distribution of the leptin gene in gibel carp (Carassius auratus gibelio): Regulation by postprandial and long-term fasting treatment.

Leptin is a multifunctional hormone that serves as a feeding regulator in mammals. However, the effect of leptin on fish remains unclear. We sequenced the leptin gene from gibel carp (Carassius auratus gibelio) and designated it gLEP. The length of the gLEP cDNA sequence was 562 bp, including an open reading frame (ORF) of 516 bp. The ORF putatively encodes a peptide of 171 amino acids, including a signal peptide of 20 amino acids. gLEP shared low primary amino acid sequence homology with leptin genes in vertebrates, whereas three-dimensional (3D) structural modeling revealed strong identity with the structures in other vertebrates. gLEP mRNA was widely distributed in all of the tissue that we examined, with the highest levels of expression in the hepatopancreas. Hepatopancreas gLEP mRNA expression levels showed no changes following postprandial treatment. However, hepatopancreas gLEP mRNA expression levels greatly decreased (P < 0.05) after fasting but substantially increased (P < 0.05) after refeeding in the long-term fasting treatment. In summary, these results indicate that leptin expression could be influenced by the regulation of food intake. These results provide the initial step toward elucidating the appetite regulatory systems associated with leptin in gibel carp.

T-17, a novel cyclin-dependent kinases/histone deacetylases dual inhibitor, induces cancer cells death through cell cycle arrest and apoptosis.

Combination of cyclin-dependent kinases (CDKs) and histone deacetylases (HDACs) inhibitors may have statistical synergy in suppressing cancer cell proliferation. Herein, a novel CDKs/HDACs dual inhibitor T-17 was rationally designed, synthesized, and evaluated. Our results demonstrated that T-17 concurrently exhibited potent and balanced inhibitory activity against CDKs (IC50 = 18.0 nM) and HDACs (IC50 = 6.6 nM) and also displayed good cell viability inhibitory effect on four cancer cell lines. Meanwhile, T-17 blocked the MDA-MB-231 and A549 cell cycle at G1 phase and S phase, respectively. In addition, T-17 induced MDA-MB-231 cells apoptosis and inhibited the HDACs and CDKs mediated signaling pathways. Finally, we also found that T-17 had good antitumor activity in vivo. In summary, these results indicated that T-17 would be a promising lead compound which deserves further research.

Application Prospect of Integrative Omics in Forensic Identification of Methamphetamine-Associated Psychosis.

The clinical symptoms and signs of methamphetamine-associated psychosis (MAP) and schizophrenia are highly similar, but the situation is completely different when MAP and schizophrenia patients need to be assessed for criminal responsibility after they comitted a harmful behavior. Therefore, the distinction between the two psychoses is very important in forensic psychiatry. At present, the identification of these two psychoses is mainly dependent on the corresponding criteria such as the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) and the Chinese Classification of Mental Disorders Version 3 (CCMD-3). It's challenging to diagnose and distinguish between the two in practical cases due to their similar clinical symptoms and the lack of effective objective indexes. Different from the limitations of single omics, integrative omics intergrates data from multiple dimensions and has been extensively studied in the field of schizophrenia and has achieved some preliminary results. In view of the correlation between MAP and schizophrenia and the potential application value of integrative omics, this paper proposes an integrative omics strategy for MAP pathogenesis and forensic identification, aiming to improve the further understanding of the relationship between the two psychoses and the corresponding pathogenesis. It also provides references for the future exploration of integrative omics in forensic precise identification and effective monitoring and early warning methods.

The effect of polycystic ovary syndrome without hyperandrogenism on pregnancy-related outcomes: a retrospective cohort study.

OBJECTIVE: To evaluate the effect of polycystic ovary syndrome (PCOS) without hyperandrogenism on pregnancy-related outcomes. DESIGN: A retrospective cohort study. SETTING: Reproductive Medicine Centre of Tongji Hospital. POPULATION: Women without hyperandrogenism undergoing their first single blastocyst transfers in frozen-thawed cycles were divided into a PCOS group and a non-PCOS group according to the Rotterdam criteria. METHODS: The pregnancy-related outcomes of women with and without PCOS were compared. Propensity score matching and multiple logistic regression models were used to eliminate essential impacts on pregnancy-related outcomes. MAIN OUTCOME MEASURES: Pregnancy-related outcomes included pregnancy loss and abnormal perinatal outcomes. RESULTS: A total of 4083 women without hyperandrogenism met the study criteria, among whom 557 met the diagnostic criteria for PCOS. Women with PCOS had higher rates of clinical pregnancy (P = 0.035) and cumulative live births (P = 0.023). However, there were no significant differences in the rates of biochemical pregnancy, twins and pregnancy loss between the two groups. Among women with singleton pregnancies, the incidences of preterm birth, hypertensive disorders of pregnancy, gestational diabetes, placenta praevia, fetal malformation, macrosomia and low birthweight did not differ significantly between the two groups. The results remained unchanged even after adjustments were made for propensity score matching and multiple logistic regression analyses. CONCLUSION: Women with PCOS without hyperandrogenism may achieve higher rates of clinical pregnancy and cumulative live birth than those without PCOS, without increases in their rates of biochemical pregnancy, pregnancy loss or other abnormal perinatal outcomes. TWEETABLE ABSTRACT: PCOS without hyperandrogenism was not associated with abnormal pregnancy-related outcomes.

Pristimerin protects against inflammation and metabolic disorder in mice through inhibition of NLRP3 inflammasome activation.

Excessive activation of NLRP3 inflammasome is associated with the pathogenesis of inflammatory diseases. Pristimerin (Pri) is a quinonoid triterpene derived from traditional Chinese medical herb Celastraceae and Hippocrateaceae. Pri has shown antifungal, antibacterial, antioxidant, and anticancer activities. In this study we investigated whether NLRP3 inflammasome was associated with the anti-inflammatory activity of Pri. We showed that Pri (0.1-0.4 µM) dose-dependently blocked caspase-1 activation and IL-1ß maturation in LPS-primed mouse bone-marrow-derived macrophages (BMDMs). Pri specifically inhibited NLRP3 inflammasome activation, had no visible effects on NLRC4 and AIM2 inflammasome activation. Furthermore, we demonstrated that Pri blocked the assembly of the NLRP3 inflammasome via disturbing the interaction between NEK7 and NLRP3; the α, ß-unsaturated carbonyl moiety of Pri was essential for NLRP3 inflammasome inactivation. In LPS-induced systemic inflammation mouse model and MSU-induced mouse peritonitis model, preinjection of Pri (500 µg/kg, ip) produced remarkable therapeutic effects via inhibition of NLRP3 inflammasome in vivo. In HFD-induced diabetic mouse model, administration of Pri (100 µg· kg-1 ·d-1, ip, for 6 weeks) reversed HFD-induced metabolic disorders via suppression of NLRP3 inflammasome activation. Taken together, our results demonstrate that Pri acts as a NLRP3 inhibitor, suggesting that Pri might be useful for the treatment of NLRP3-associated diseases.

10,11-dehydrocurvularin exerts antitumor effect against human breast cancer by suppressing STAT3 activation.

Aberrant activation of signal transducer and activator of transcription 3 (STAT3) plays a critical role in many types of cancers. As a result, STAT3 has been identified as a potential target for cancer therapy. In this study we identified 10,11-dehydrocurvularin (DCV), a natural-product macrolide derived from marine fungus, as a selective STAT3 inhibitor. We showed that DCV (2-8 µM) dose-dependently inhibited the proliferation, migration and invasion of human breast cancer cell lines MDA-MB-231 and MDA-MB-468, and induced cell apoptosis. In the two breast cancer cell lines, DCV selectively inhibited the phosphorylation of STAT3 Tyr-705, but did not affect the upstream components JAK1 and JAK2, as well as dephosphorylation of STAT3. Furthermore, DCV treatment strongly inhibited IFN-γ-induced STAT3 phosphorylation but had no significant effect on IFN-γ-induced STAT1 and STAT5 phosphorylation in the two breast cancer cell lines. We demonstrated that the α, ß-unsaturated carbonyl moiety of DCV was essential for STAT3 inactivation. Cellular thermal shift assay (CETSA) further revealed the direct engagement of DCV with STAT3. In nude mice bearing breast cancer cell line MDA-MB-231 xenografts, treatment with DCV (30 mg·kg-1·d-1, ip, for 14 days) markedly suppressed the tumor growth via inhibition of STAT3 activation without observed toxicity. Our results demonstrate that DCV acts as a selective STAT3 inhibitor for breast cancer intervention.

Application of CD83 and HSF5 to Identify Antemortem and Postmortem Skin Burns. / 应用CD83和HSF5鉴别生前与死后皮肤烧伤.

OBJECTIVES: To explore the forensic application value of cluster of differentiation 83 (CD83) and heat shock transcription factor 5(HSF5) in identifying antemortem and postmortem skin burns. METHODS: Through reverse transcription real-time quantitative polymerase chain reaction (RT-qPCR), CD83 and HSF5 mRNA levels in the skin tissues of antemortem and postmortem burned mice and human samples were detected quantitatively. RESULTS: Compared with the control group and the postmortem burned group, the mRNA levels of CD83 and HSF5 in antemortem burned mice were higher. The high mRNA expressions of CD83 could be detected 96 h after death, and the mRNA expressions of HSF5 could be observed 72 h after death. Compared with undamaged skin, increased CD83 and HSF5 mRNA levels were detected in 11 out of 15 cases(P<0.05). CONCLUSIONS: CD83 and HSF5 can be used in forensic practice as indicators for vital reaction in antemortem burn identification.

Risk of birth defects in children conceived by artificial oocyte activation and intracytoplasmic sperm injection: a meta-analysis.

BACKGROUND: Whether artificial oocyte activation (ICSI-AOA) will increase the risk of birth defects remains controversial. Thus, we performed this study to evaluate the risk of birth defects and further compare the incidence of different birth defects types (chromosomal aberrations and non-chromosomal aberrations) in children conceived by ICSI-AOA and conventional intracytoplasmic sperm injection (ICSI) in an enlarged sample size. METHOD: A comprehensive review of the literatures comparing birth defects in children conceived by ICSI-AOA and conventional ICSI by October 2020 was performed in PubMed, Embase, Cochrane Libraries, Web of Science, and Chinese databases including China National Knowledge Infrastructure, China Biology Medicine disc and Wan Fang. Risk ratios (RR) and 95% confidence intervals (CI) were calculated. RESULTS: Five studies were included in the final analysis. Compared with conventional ICSI, ICSI-AOA did not increase the birth defects rate (RR = 1.27, 95%CI 0.70-2.28) of children. Furthermore, in a subgroup analysis, birth defects were classified into two types (chromosomal aberrations and non-chromosomal aberrations) in four studies and no statistical difference were revealed. CONCLUSION: Our analysis indicates that ICSI-AOA represents no significant difference in the prevalence of major birth defects or types of birth defects (chromosomal aberrations and non-chromosomal aberrations) comparing with conventional ICSI. This conclusion may provide clinicians evidence-based support in patient counseling and instruction of the application and safety concern about ICSI-AOA.

Pregnancy and perinatal outcomes in pregnancies resulting from time interval between a freeze-all cycle and a subsequent frozen-thawed single blastocyst transfer.

BACKGROUND: Adverse obstetric outcomes are correlated with altered circulating hormone levels at the time implantation by the trophectoderm. What' more, embryo freezing process may also have adverse effect on perinatal outcomes. This study aims to evaluate whether increasing interval time between a freeze-all cycle and a subsequent frozen-thawed single blastocyst transfer could have any effect on pregnancy and perinatal outcomes. METHODS: This was a retrospective cohort study included the first single blastocyst transfer in artificially cycles of all patients who underwent a freeze-all cycle between January 1st, 2016 and September 30th, 2018. All patients were divided into two groups according to the time interval between oocyte retrieval and the day of first frozen-thawed embryo transferred (FET): Group 1 (immediate FET cycles) and Group 2 (delayed FET cycles). RESULTS: No significant differences were reported between the two groups regarding the rates of clinical pregnancy, live birth, biochemical pregnancy and pregnancy loss even after adjusting for measured confounding. When accounting for perinatal outcomes, gestational age, birth weight, delivery mode, fetus gender, preterm birth, gestational hypertension, GDM, placenta previa, fetal malformation and low birthweight also did not vary significantly between the two groups. Only the incidence of macrosomia was more frequently in the Group 2 compared with the Group 1 (AOR 3.886, 95%CI 1.153-13.103, P = 0.029) after adjusting with a multiple logistic regression model. CONCLUSIONS: We found delayed FET cycles for blastocyst transfer following freeze-all cycles may not improve the pregnancy outcomes. On the contrary, postponement of FET cycles may increase the risk of macrosomia. Therefore, FET cycles for blastocyst transfer should be done immediately to avoid adverse effects of delayed time on perinatal outcomes.

[Effects of rapamycin on glucose-induced autophagy and apoptosis of corpus cavernosum smooth muscle cells in SD rats].

OBJECTIVE: To observe the effects of rapamycin on glucose-induced autophagy and apoptosis of corpus cavernosum smooth muscle cells (CCSMC) in SD rats. METHODS: After primary isolation, purification and identification, CCSMCs were treated with glucose at 5.6, 10, 20, 30 and 40 mmol/L for 48 hours. The autophagy flow was detected in the cells transfected with mCherry-GFP-LC3B double fluorescent adenovirus, the protein and mRNA expressions of autophagy-related gene 5 (ATG5), microtubule-associated protein 1 light chain 3 (LC3), P62 and Beclin-1 determined by Western blot and PCR and the apoptosis of the CCSMC measured by flow cytometry, followed by detection of the changes in the protein and mRNA levels of LC3, Beclin-1 and P62 and the apoptosis of the cells after 2-hour pretreatment with 600 nmol/L rapamycin and then 48-hour treatment with 40 mmol/L glucose. RESULTS: Autophagy was observed in the CCSMCs treated with different concentrations of glucose, the strongest in the 10 mmol/L group (P < 0.05) and then gradually decreasing with the increase of glucose concentration (P < 0.05). The apoptosis rate of the CCSMCs was remarkably increased in a concentration-dependent manner after treated with glucose (P < 0.01) though with no statistically significant difference between the 5.6 and 10 mmol/L groups (P = 0.302). After pretreatment with rapamycin, the expression of the LC3 protein and those of the Beclin-1 protein and mRNA were markedly up-regulated (P < 0.05), while those of the P62 protein and mRNA remarkably down-regulated (P < 0.05), indicating the enhancement of autophagy, and the apoptosis rate of the CCSMCs dramatically decreased (P < 0.01). CONCLUSIONS: In vitro culture of CCSMCs with glucose within a certain range of concentration can promote autophagy, inhibit the apoptosis and thus have a protective effect on the cells, but when the proper concentration exceeded, it may also reduce autophagy, promote the apoptosis and consequently affect the vitality and function of CCSMCs.

The convenient Michael addition of imidazoles to acrylates catalyzed by Lipozyme TL IM from Thermomyces lanuginosus in a continuous flow microreactor.

A fast and green protocol for the Michael addition of imidazoles to acrylates catalyzed by Lipozyme TL IM from Thermomyces lanuginosus in a continuous flow microreactor was developed. In contrast with existing methods, this method is simple (35 min), uses mild reaction conditions (45 °C) and is environmentally friendly. This enzymatic Michael addition performed in continuous flow microreactors is an innovation that may open up the use of enzymatic microreactors in imidazole analogue biotransformations.

Augmenter of liver regeneration promotes mitochondrial biogenesis in renal ischemia-reperfusion injury.

Mitochondria are the center of energy metabolism in the cell and the preferential target of various toxicants and ischemic injury. Renal ischemia-reperfusion (I/R) injury triggers proximal tubule injury and the mitochondria are believed to be the primary subcellular target of I/R injury. The promotion of mitochondrial biogenesis (MB) is critical for the prevention I/R injury. The results of our previous study showed that augmenter of liver regeneration (ALR) has anti-apoptotic and anti-oxidant functions. However, the modulatory mechanism of ALR remains unclear and warrants further investigation. To gain further insight into the role of ALR in MB, human kidney (HK)-2 cells were treated with lentiviruses carrying ALR short interfering RNA (siRNA) and a model of hypoxia reoxygenation (H/R) injury in vitro was created. We observed that knockdown of ALR promoted apoptosis of renal tubular cells and aggravated mitochondrial injury, as evidenced by the decrease in the mitochondrial respiratory proteins adenosine triphosphate (ATP) synthase subunit ß, cytochrome c oxidase subunit 1, and nicotinamide adenine dinucleotide dehydrogenase (ubiquinone) beta subcomplex 8. Meanwhile, the production of reactive oxygen species was increased and ATP levels were decreased significantly in HK-2 cells, as compared with the siRNA/control group (p < 0.05). In addition, the mitochondrial DNA copy number and membrane potential were markedly decreased. Furthermore, critical transcriptional regulators of MB (i.e., peroxisome proliferator-activated receptor-gamma coactivator 1 alpha, mitochondrial transcription factor A, sirtuin-1, and nuclear respiratory factor-1) were depleted in the siRNA/ALR group. Taken together, these findings unveil essential roles of ALR in the inhibition of renal tubular cell apoptosis and attenuation of mitochondrial dysfunction by promoting MB in AKI.

A novel PADRE-Kv1.3 vaccine effectively induces therapeutic antibodies and ameliorates experimental autoimmune encephalomyelitis in rats.

Previous studies have confirmed that selective blockade of Kv1.3 channels could modulate the activities of pathogenic T cells and microglia/macrophages, which play key roles in experimental autoimmune encephalomyelitis (EAE). In this study, we designed an anti-Kv1.3 vaccine (PADRE-Kv1.3) to explore its protective role in EAE rat models. When the vaccine was applied in EAE rats, clinical scores and several staining techniques were used to evaluate the severity of the disease. T cell subtypes and related cytokines, as well as microglia/macrophage activation were assayed through flow cytometry, qRT-PCR or immunofluorescence staining, respectively. We herein showed that rats and mice developed high titers of anti-Kv1.3 antibodies and appeared no abnormal manifestations after the PADRE-Kv1.3 vaccine treatment. In EAE models, the vaccine treatment effectively alleviated the clinical severity and lessened pathological damages in the central nervous system (CNS). In addition, we found the vaccine significantly decreased the number of pathogenic T cells (Th17 and IFN-γ-producing T cells) and the production of related pro-inflammatory cytokines (IL-17A, IFN-γ and IL-1ß), but increased the number of protective T subsets (CD4+IL-10+ T cells and Treg cells) in the spleen or CNS. Moreover, the infiltration of microglia/macrophages significantly reduced and these cells shifted toward anti-inflammatory M2 subtype in the CNS after the vaccine treatment. Thus, we demonstrated that the PADRE-Kv1.3 vaccine could induce therapeutic anti-Kv1.3 antibodies and ameliorate EAE in rats effectively and safely, which provides a new field of vision for the protection and therapy of multiple sclerosis.

Transition-Metal-Free Oxidative Aminooxyarylation of Alkenes: Annulations toward Aminooxylated Oxindoles.

An efficient oxidative aminooxyarylation of alkenes under a transition-metal-free condition was described. Under the reaction conditions, N-hydroxyphthalimide (NHPI) reacted readily with N-arylacrylamides to produce cyclic products via a radical C-H functionalization process, achieving both C-O and C-C bonds formation in one pot. This reaction provided a facile access to the valuable aminooxylated oxindoles. The benzylic and α-methylene C(sp3)-H bonds were also aminooxylated under the reaction conditions.

Reverse electrodialysis in bilayer nanochannels: salinity gradient-driven power generation.

To evaluate the possibility of nano-fluidic reverse electrodialysis (RED) for salinity gradient energy harvesting, we consider the behavior of ion transportation in a bilayer cylindrical nanochannel consisting of different sized nanopores connecting two large reservoirs at different NaCl concentrations. Numerical simulations to illustrate the electrokinetic behavior at asymmetric sub-pore length and surface charge density are conducted, the impacts of which on transference number, osmotic current, diffusive voltage, maximum power and maximum power efficiency are systematically investigated. The results reveal that the transference number in Config. I (where high NaCl concentration is applied at the larger nanopore) is always larger than that in the opposite configuration (Config. II). At low concentration ratios, the osmotic current and maximum power have maximum values, while the maximum power efficiency decreases consistently. For Config. II, the ion transportation is impacted by the surface charge density at both sub-nanopores, while for Config. I, it is determined by the surface charge density at the downstream small nanopore. When large surface charge density is applied at the downstream small nanopore in contact with a very low concentration reservoir, there exists an interesting phenomenon: the larger surface charge density at the large nanopore induces a slight performance drop due to the impact of upstream EDL overlap.