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Abstract Physical activity (PA) and fruit and vegetable consumption (FVC) are crucial factors jointly affecting young adults’ physical and mental health. However, the psychosocial interactive mechanisms of these behaviors remain understudied. Using a two-wave prospective design over two months, this study investigated the psychological mechanisms underlying multiple health behavior change (MHBC) through a novel two-layer social-cognitive framework, the Compensatory Carry-Over Action Model (CCAM), among 322 Chinese college students (19.47 ± 0.99 years; 55.6% female). Structural equation modeling with path analysis was conducted using Mplus 8.8 for data analysis. Results indicated an acceptable model fit for the hypothesized model, with χ 2 = 120.845, df = 41, χ 2/df = 2.947, CFI = 0.940, TLI = 0.901, RMSEA = 0.078 [90% CI = 0.062 to 0.094], and SRMR = 0.079. The model explained 54.9% and 50.0% of the variance in PA and FVC, respectively. In the first layer, focusing on the individual behavior change process, both volitional self-efficacy and planning were identified as significant mediators in the intention-behavior relationship for PA and FVC (indirect effects = 0.03 to 0.14, all p .05). However, volitional self-efficacy and planning played a significant mediating role in the interaction between PA/FVC intention and FVC/PA behavior (indirect effects = 0.01 to 0.04, all p

Abstract In this study, peripheral whole blood samples from 22 hospitalized patients and 10 healthy individuals were analyzed using a combination of Data Independent Acquisition (DIA) and Enzyme-Linked Immunosorbent Assay (ELISA) techniques to identify differentially expressed proteins (DEPs) in sepsis patients’ plasma. The aim was to provide accurate and detailed biomarkers, such as SPP1, for determining the pathological stages of sepsis. SPP1, known as osteopontin1 is a pleiotropic protein with a wide distribution and multifunctional effects. Its protein expression is associated with inflammatory changes, including variations in expression levels in infectious diseases, allergic diseases, and situations involving tissue damage. The registration number was ChiCTR1900021261.The full date of first registration year is 2018. In the affiliated hospital of southwest medical university, 22 sepsis patients were hospitalized from January 2019 to September 2020 and 10 normal healthy individuals were selected for DIA-based quantitative proteomics analysis. In addition to gene ontology analysis and Kyoto Encyclopedia of genes and genomes analysis, enrichment analysis of data was performed and target protein network was screened through joint protein–protein interaction and visualization techniques. The selected protein targets were then validated by Elisa kit. The software was used to analyze the differences comparing the control group to the sepsis group and the sepsis group, as well as between sepsis survivals and non-survivals, and a ROC curve was drawn to evaluate the diagnostic value and prognostic effect of the method of the corresponding target proteins. A total of 174 DEPs were screened by bioinformatics analysis. An analysis of go pathway enrichment revealed the following: These proteins were mainly involved in biological processes among them are the inflammation response, the metabolism of extracellular matrix, the secretion of cell secretions, the activation of cells, and the immune response. According to the Kegg pathway analysis, they were mainly involved in complement cascade polymerization, extracellular protease and glycosylase activation, protein synthesis process, biotin metabolism, leukocyte transmembrane migration, bacterial infection and phagosome formation. SPP1 was identified as a possible plasma biomarker and was therefore further validated using Elisa. As a result of experiments, it has been demonstrated that level in sepsis patients is significantly compared to the normal control group and the level is also higher in non-survivals of sepsis. The ROC curve can be used to see that it can diagnose sepsis more accurately and improve prognostic ability prediction. Cell experiments confirm that SPP1 is highly expressed in sepsis. There is a significant difference in the levels of SPP1 protein between the normal group and the sepsis group; it not only has good diagnostic significance for sepsis, but also provides corresponding reference value for patient prognosis; Therefore, it is more likely to become a biological marker of sepsis over time.

Abstract Unconjugated bilirubin (UB) levels during the first week after birth are related to outcomes in neonatal hypoxic-ischemic encephalopathy (HIE). Clinical Sarnat staging of HIE, brain magnetic resonance imaging (MRI), hearing outcomes, and neurodevelopmental outcomes ≥ 1 year were used to correlate UB in 82 HIE patients. The initial UB level was significantly correlated with lactic acid levels. The peak UB was higher (p

Abstract The effective treatment of breast cancer remains a profound clinical challenge, especially due to drug resistance and metastasis which unfortunately arise in many patients. The transcription inhibitor 5,6-dichloro-1-beta-D-ribofuranosyl-benzimidazole (DRB), as a selective inhibitor of cyclin-dependent kinase 9, was shown to be effective in inducing apoptosis in various hematopoietic malignancies. However, the anticancer efficacy of DRB against breast cancer is still unclear. Herein, we demonstrated that administration of DRB to the breast cancer cell line led to the inhibition of cellular proliferation and induction of the typical signs of apoptotic cells, including the increases in Annexin V-positive cells, DNA fragmentation, and activation of caspase-7, caspase-9, and poly (ADP ribose) polymerase (PARP). Treatment of DRB resulted in a rapid decline in the myeloid cell leukemia 1 (Mcl-1) protein, whereas levels of other antiapoptotic proteins did not change. Overexpression of Mcl-1 decreased the DRB-induced PARP cleavage, whereas knockdown of Mcl-1 enhanced the effects of DRB on PARP activation, indicating that loss of Mcl-1 accounts for the DRB-mediated apoptosis in MCF-7 cells, but not in T-47D. Furthermore, we found that co-treatment of MCF-7 cells with an inhibitor of AKT (LY294002) or an inhibitor of the proteasome (MG-132) significantly augmented the DRB-induced apoptosis. These data suggested that DRB in combination with LY294002 or MG-132 may have a greater therapeutic potency against breast cancer cells.

Abstract Background Intracerebral hemorrhage (ICH) is a condition associated with high morbidity and mortality, and glia-mediated inflammation is a major contributor to neurological deficits. However, there is currently no proven effective treatment for clinical ICH. Recently, low-intensity pulsed ultrasound (LIPUS), a non-invasive method, has shown potential for neuroprotection in neurodegenerative diseases. This study aimed to investigate the neuroprotective effects and potential mechanisms of LIPUS on glia-mediated inflammation in ICH. Methods This study used 289 mice to investigate the effects of LIPUS on ICH. ICH was induced by injecting bacterial collagenase (type VII-S; 0.0375 U) into the striatum of the mice. LIPUS was applied noninvasively for 3 days, including a 2-h-delayed intervention to mimic clinical usage. The study evaluated neurological function, histology, brain water content, hemoglobin content, MRI, and protein expression of neurotrophic factors, inflammatory molecules, and apoptosis. In vitro studies investigated glia-mediated inflammation by adding thrombin (10 U/mL) or conditioned media to primary and cell line cultures. The PI3K inhibitor LY294002 was used to confirm the effects of PI3K/Akt signaling after LIPUS treatment. Results LIPUS treatment improved neurological deficits and reduced tissue loss, edema, and neurodegeneration after ICH. The protective effects of LIPUS resulted from decreased glia-mediated inflammation by inhibiting PI3K/Akt-NF-κB signaling, which reduced cytokine expression and attenuated microglial activation-induced neuronal damage in vitro. Conclusions LIPUS treatment improved neurological outcomes and reduced glia-mediated inflammation by inhibiting PI3K/Akt-NF-κB signaling after ICH. LIPUS may provide a non-invasive potential management strategy for ICH.

Proper differentiation of sperm from germline stem cells, essential for production of the next generation, requires dramatic changes in gene expression that drive remodeling of almost all cellular components, from chromatin to organelles to cell shape itself. Here, we provide a single nucleus and single cell RNA-seq resource covering all of spermatogenesis in Drosophila starting from in-depth analysis of adult testis single nucleus RNA-seq (snRNA-seq) data from the Fly Cell Atlas (FCA) study. With over 44,000 nuclei and 6000 cells analyzed, the data provide identification of rare cell types, mapping of intermediate steps in differentiation, and the potential to identify new factors impacting fertility or controlling differentiation of germline and supporting somatic cells. We justify assignment of key germline and somatic cell types using combinations of known markers, in situ hybridization, and analysis of extant protein traps. Comparison of single cell and single nucleus datasets proved particularly revealing of dynamic developmental transitions in germline differentiation. To complement the web-based portals for data analysis hosted by the FCA, we provide datasets compatible with commonly used software such as Seurat and Monocle. The foundation provided here will enable communities studying spermatogenesis to interrogate the datasets to identify candidate genes to test for function in vivo.

Abstract. Background:. Hyperbaric oxygen treatment (HBOT) has been demonstrated to influence the keloid recurrence rate after surgery and to relieve keloid symptoms and other pathological processes in keloids. To explore the mechanism of the effect of HBOT on keloids, tumor immune gene expression and immune cell infiltration were studied in this work. Methods:. From February 2021 to April 2021, HBOT was carried out on keloid patients four times before surgery. Keloid tissue samples were collected and divided into an HBOT group (keloid with HBOT before surgery [HK] group, n = 6) and a non-HBOT group (K group, n = 6). Tumor gene expression was analyzed with an Oncomine Immune Response Research Assay kit. Data were mined with R package. The differentially expressed genes between the groups were compared. Hub genes between the groups were determined and verified with Quantitative Real-time PCR. Immune cell infiltration was analyzed based on CIBERSORT deconvolution algorithm analysis of gene expression and verified with immunohistochemistry (IHC). Results:. Inflammatory cell infiltration was reduced in the HK group. There were 178 upregulated genes and 217 downregulated genes. Ten hub genes were identified, including Integrin Subunit Alpha M (ITGAM), interleukin (IL)-4, IL-6, IL-2, Protein Tyrosine Phosphatase Receptor Type C (PTPRC), CD86, transforming growth factor (TGF), CD80, CTLA4, and IL-10. CD80, ITGAM, IL-4, and PTPRC with significantly downregulated expression were identified. IL-10 and IL-2 were upregulated in the HK group but without a significant difference. Infiltration differences of CD8 lymphocyte T cells, CD4 lymphocyte T-activated memory cells, and dendritic resting cells were identified with gene CIBERSORT deconvolution algorithm analysis. Infiltration levels of CD4 lymphocyte T cell in the HK group were significantly higher than those of the K group in IHC verification. Conclusion:. HBOT affected tumor gene expression and immune cell infiltration in keloids. CD4 lymphocyte T cell, especially activated memory CD4+T, might be the key regulatory immune cell, and its related gene expression needs further study.

In recent years, China's industrial economy has grown rapidly and steadily. Concurrently, carbon emissions have gradually increased, among which agricultural production is an important source of greenhouse gas emissions. It is necessary to reduce agricultural carbon emissions by improving their efficiency to achieve the global goal of peak carbon dioxide emissions in 2030. From a dynamic and static point of view, this study puts agricultural carbon emissions into the evaluation index system of agricultural carbon emission efficiency and analyzes the agricultural carbon emission efficiency and its influencing factors in Hubei Province. First, the unexpected output Slacks-based measure (SBM) model in data envelopment analysis was used to evaluate the agricultural carbon emission efficiency of Hubei Province in 2018 and compared it with other provinces horizontally. Second, the Malmquist-Luenberger index was used to analyze the comprehensive efficiency of agricultural carbon emissions in Hubei Province from 2004 to 2018. The role of technological progress and technical efficiency change in the development of low-carbon agriculture in Hubei Province was analyzed. The results showed that agricultural production efficiency in Hubei Province improved from 2004 to 2018, and the overall level was slightly higher than the average level in China. However, agriculture has not eliminated the extensive development modes of high input, low efficiency, high emission, and high pollution. The efficiency of technological progress in agricultural resource utilization in Hubei Province was close to the optimal level. The improvement space was small. Hence, the low efficiency of agricultural technology is a key factor restricting the improvement of agricultural production efficiency. The results provide a reference for low-carbon agricultural policy formulation and expand the policy choice path. This has practical significance.

Abstract Background Intracerebral hemorrhage (ICH) induces a complex sequence of apoptotic cascades that contribute to secondary neuronal damage. Tropomyosin-related kinase receptor B (TrkB) signaling plays a crucial role in promoting neuronal survival following brain damage. Methods The present study investigated the protective effects and underlying mechanisms of TrkB activation by the specific TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF), in a model of collagenase-induced ICH and in neuronal cultures. Mice subjected to collagenase-induced ICH were intraperitoneally injected with either 7,8-DHF or vehicle 10 min after ICH and, subsequently, daily for 3 days. Behavioral studies, brain edema measurement, and histological analysis were conducted. Levels of TrkB signaling-related molecules and apoptosis-related proteins were analyzed by western blots. Results Treatment with 20 mg/kg 7,8-DHF significantly improved functional recovery and reduced brain damage up to 28 days post-ICH. Reduction in neuronal death, apoptosis, and brain edema were also observed in response to 7,8-DHF treatment at 3 days post-ICH. These changes were accompanied by a significant increase in the phosphorylation of TrkB and Akt (Ser473/Thr308) at 1 and 3 days, but had no effect on Erk 44/42 phosphorylation. 7,8-DHF also enhanced the phosphorylation of Ask-1 Ser967 and FOXO-1, downstream targets of Akt at 1 and 3 days. Moreover, 7,8-DHF increased brain-derived neurotrophic factor levels at 1 day. In primary cultured neurons stimulated with hemin, 7,8-DHF promoted survival and reduced apoptosis. Furthermore, delaying the administration of 7,8-DHF to 3 h post-ICH reduced brain tissue damage and neuronal death. Conclusions Our findings demonstrate that the activation of TrkB signaling by 7,8-DHF protects against ICH via the Akt, but not the Erk, pathway. These data provide new insights into the role of TrkB signaling deficit in the pathophysiology of ICH and highlight TrkB/Akt as possible therapeutic targets in this disease.

Background: Acute lung injury (ALI) is a severe life-threatening inflammatory disease. Neutrophil activation is a major pathogenic factor in ALI. Protein kinase B (PKB)/AKT regulates diverse cellular responses, but the significance in neutrophilic inflammation and ALI remains unknown. Methods: Human neutrophils and neutrophil-like differentiated HL-60 (dHL-60) cells were used to examine the anti-inflammatory effects of 5,7-dimethoxy-1,4-phenanthrenequinone (CLLV-1). The therapeutic potential of CLLV-1 was determined in a mouse model of lipopolysaccharide (LPS)-induced ALI. Findings: CLLV-1 inhibited respiratory burst, degranulation, adhesion, and chemotaxis in human neutrophils and dHL-60 cells. CLLV-1 inhibited the phosphorylation of AKT (Thr308 and Ser473), but not of ERK, JNK, or p38. Furthermore, CLLV-1 blocked AKT activity and covalently reacted with AKT Cys310 in vitro. The AKT309–313 peptide-CLLV-1 adducts were determined by NMR or mass spectrometry assay. The alkylation agent-conjugated AKT (reduced form) level was also inhibited by CLLV-1. Significantly, CLLV-1 ameliorated LPS-induced ALI, neutrophil infiltration, and AKT activation in mice. Interpretation: Our results identify CLLV-1 as a covalent allosteric AKT inhibitor by targeting AKT Cys310. CLLV-1 shows potent anti-inflammatory activity in human neutrophils and LPS-induced mouse ALI. Our findings provide a mechanistic framework for redox modification of AKT that may serve as a novel pharmacological target to alleviate neutrophilic inflammation. Keywords: Acute lung injury, AKT, 5,7-dimethoxy-1,4-phenanthrenequinone, Inflammation, Neutrophil

Study objectiveThe purpose of this feasibility study is to develop and validate a new assessment tool and scoring system for multitasking competency for physicians in-training in a timed simulated setting. The multitasking competency includes ability to appropriately prioritize and implement tasks for different patients who present simultaneously.MethodsWe designed three single task stations with different levels of difficulty and priority. These skill stations were then combined to create a multitasking simulation scenario. Skill checklists and the global rating scale were utilized to assess the participants' performance. A multitasking score, multitasking index, and priority score were developed to measure the multitasking ability of participants.ResultsThirty-three first-year postgraduate physicians were recruited for this prospective study. The total performance scores were significantly higher for the single-tasking stations than for the multitasking scenario. In terms of the time needed to complete the tasks, the participants spent more time on the multitasking scenario than on the single-tasking scenario. There were significant correlations between the global rating scale and the multitasking score (rho = 0.693, p < 0.001) and between the global rating scale and the multitasking index (rho = 0.515, p < 0.001). The multitasking score, multitasking index, and priority score did not have any significant correlations with the total single-tasking score.ConclusionWe demonstrated that the use of a simulated multitasking scenario could be an effective method of assessing multitasking ability and allow assessors to offer better quality feedback.

Adhesion-type GPCRs (aGPCRs) participate in a vast range of physiological processes. Their frequent association with mechanosensitive functions suggests that processing of mechanical stimuli may be a common feature of this receptor family. Previously, we reported that the Drosophila aGPCR CIRL sensitizes sensory responses to gentle touch and sound by amplifying signal transduction in low-threshold mechanoreceptors (Scholz et al., 2017). Here, we show that Cirl is also expressed in high-threshold mechanical nociceptors where it adjusts nocifensive behaviour under physiological and pathological conditions. Optogenetic in vivo experiments indicate that CIRL lowers cAMP levels in both mechanosensory submodalities. However, contrasting its role in touch-sensitive neurons, CIRL dampens the response of nociceptors to mechanical stimulation. Consistent with this finding, rat nociceptors display decreased Cirl1 expression during allodynia. Thus, cAMP-downregulation by CIRL exerts opposing effects on low-threshold mechanosensors and high-threshold nociceptors. This intriguing bipolar action facilitates the separation of mechanosensory signals carrying different physiological information.

Rapid development and deployment of vaccines is crucial to control the continuously evolving COVID-19 pandemic. The placebo-controlled phase 3 efficacy trial is still the standard for authorizing vaccines in the majority of the world. However, due to a lack of eligible participants in parts of the world, this has not always been feasible. Recently, the Taiwan Food and Drug Administration, following the consensus of the International Coalition of Medicines Regulatory Authorities (ICMRA), adopted the use of immunobridging studies as acceptable for authorizing COVID-19 vaccines in lieu of efficacy data. Here, we describe a study in which our candidate vaccine, MVC-COV1901, an adjuvanted protein subunit vaccine, has been granted emergency use authorization (EUA) in Taiwan based on a noninferiority immunobridging study. Immunogenicity results from the per protocol immunogenicity (PPI) subset (n = 903) from the MVC-COV1901 phase 2 trial were compared with results from 200 subjects who had received an adenovirus vector vaccine, AstraZeneca ChAdOx nCOV-19 (AZD1222), in a separate study. The lower bound of the 95% confidence interval (CI) of the geometric mean titer (GMT) ratio comparing MVC-COV1901 to AZD1222 was 3.4. The lower bound of the 95% CI of the sero-response rate was 95.5%. Both the GMT ratio and sero-response rate exceeded the criteria established by the Taiwan regulatory authority, leading to EUA approval of MVC-COV1901 in Taiwan.

Abstract Whether red cell distribution width (RDW) can be a potential indicator for diabetic nephropathy (DN) is unknown. A total of 809 type 2 diabetes mellitus (T2D) patients were divided into 4 groups according to the quartiles (Q) of the RDW (%): Q1 ≤ 12.4 (n = 229), 12.4

Abstract The enzyme 3β-hydroxysteroid dehydrogenase/isomerase (3β-HSD) is involved in the synthesis of active steroid hormones. Two human 3β-HSD isoforms are expressed in a tissue-specific pattern. HSD3B1 (type I) expression is essential to produce progesterone for pregnancy maintenance. To understand the mechanisms of human HSD3B1 activation in the placenta, 2.2 kb of 5′-flanking sequence and 5′-deletions were fused to the luciferase reporter gene and transfected into human JEG-3 cells. The proximal −238/+337 sequence had the highest promoter activity. Two GATA elements were identified at −106/−99 and −52/−45. Mutations of either sites greatly reduced promoter activity in JEG-3 cells, demonstrating the importance of GATA sites. EMSA revealed the specific binding of GATA2 and GATA3 to the GATA sequences at −106/−99 and −52/−45. ChIP assays demonstrated the association of GATA2 but not GATA3 with the GATA-binding regions of the HSD3B1 promoter in JEG-3 cells. GATA2 knockdown significantly reduced HSD3B1 expression in JEG-3 cells; however, GATA3 knockdown increased HSD3B1 expression. Western blot analysis revealed high levels of GATA2 but not GATA3 in human placental tissues. This study identified GATA motifs as essential control elements for HSD3B1 transcription and GATA2 as a novel transcriptional regulator of HSD3B1 expression in the human placenta.

Abstract Demand for rapid and massive-scale exfoliation of bulky graphite remains high in graphene commercialization and property manipulation. We report a procedure utilizing “preformed acidic oxidizing medium (PAOM)” as a modified version of the Hummers’ method for fast and reliable synthesis of graphene oxide. Pre-mixing of KMnO4 and concentrated H2SO4 prior to the addition of graphite flakes enables the formation of effectively and efficiently oxidized graphene oxide (EEGO) featured by its high yields and suspension homogeneity. PAOM expedites diffusion of the Mn-oxidants into the graphite galleries, resulting in the rapid graphite oxidation, capable of oxidizing bulky graphite flakes (~0.8 mm in diameter) that can not be realized by the Hummers’ method. In the scale-up tests, ten-time amount of graphite can be completely exfoliated by PAOM without need of extended reaction time. The remarkable suspension homogeneity of EEGO can be exploited to deposit ultra-flat coating for wafer-scale nanopatterning. We successfully fabricated GO optical gratings with well-defined periodicity (300 nm) and uniform thickness (variation

Background and aimsCost-effective serology tests may increase the predictive accuracy of colonoscopy for colorectal cancer screening. Reportedly, gamma-glutamyl transferase (GGT) is associated with oxidative stress and carcinogenesis and has been found to be elevated in the serum of cancer patients and colorectal adenoma tissue. We aimed to investigate the association between serum GGT levels and colorectal adenoma.MethodsThis single-center, health examination-based cohort enrolled 2475 subjects from 2006 to 2015. Baseline characteristics, laboratory data, bidirectional gastrointestinal endoscopy, and transabdominal ultrasonography were used to evaluate the severity of fatty liver.ResultsWe found an elevated median GGT level in subjects with tubular adenoma compared with those without (23 IU/L and 20 IU/L, pConclusionsThe results suggested a positive correlation of GGT with colon adenoma incidence and a predictive value with a cutoff point of >20 IU/L, which is within the normal range. The effect may be most prominent for those without steatohepatitis.

PurposeThe use of Virtual Reality (VR) in health professions education has increased dramatically in recent years, yet there is limited evidence of its impact on educational outcomes. The purpose of the study was to assess the impact of VR anatomy instruction on the ultrasound competency of novice learners participating in a ultrasonography workshop.MethodWe designed a VR-enhanced ultrasonography training program and utilized a plane transection tool to interact with a three-dimensional (3D) VR model of the human body which facilitated the 3D conceptualization of the spatial relationship of anatomical structures, leading to faster and better development of ultrasonographic competency. This was a randomized control study which enrolled third-year medical students (n = 101) without previous exposure to formal or informal ultrasonography training. The participants were randomly divided into an intervention and control group. We assessed participants' competency through ultrasound performance stations on live subjects, we also measured anatomical and ultrasound image identification ability using multiple choice tests.ResultParticipants in the intervention group (median = 16; interquartile 13 to 19) had significantly higher scores in ultrasonography task performance tests than the control group (median = 10; interquartile 7 to 14; Mann-Whitney U = 595; P < 0.01). In sub-group analysis, the intervention group performed significantly better in the six out of ten ultrasound tasks. Participants in the intervention group also had greater improvement in ultrasonographic image identification MCQ tests than the control group (Mann-Whitney U = 914; P < 0.05).ConclusionThis study suggests that VR-enhanced anatomical training could be of significant benefit in ultrasonography training by promoting a better understanding of the spatial relationships of anatomical structures and the development of early psychomotor skills transferable to the handling of ultrasonographic probes.

OBJECTIVES:Changes in impedance between 24 hours and one month after cochlear implantation have never been explored due to the inability to switch on within one day. This study examined the effect of early activation (within 24 hours) on the evolution of electrode impedance with the aim of providing information on the tissue-to-electrode interface when electrical stimulation was commenced one day post implantation. METHODS:We performed a retrospective review at a single institution. Patients who received a Nucleus 24RECA implant system (Cochlear, Sydney, Australia) and underwent initial switch-on within 24 hours postoperatively were included. Impedance measurements were obtained intraoperatively and postoperatively at 1 day, 1 week, 4 weeks, and 8 weeks. RESULTS:A significant drop in impedance was noted 1 day after an initial activation within 24 hours followed by a significant rise in impedance in all channels until 1 week, after which the impedance behaved differently in different segments. Basal and mid-portion electrodes revealed a slight increase while apical electrodes showed a slight decrease in impedance from 1 week to 8 weeks postoperatively. Impedance was relatively stable 4 weeks after surgery. CONCLUSIONS:This is the first study to report the evolution of impedance in all channels between initial mapping 1 day and 1 month after cochlear implantation. The underlying mechanism for the differences in behavior between different segments of the electrode may be associated with the combined effect of dynamics among the interplay of cell cover formation, electrical stimulation, and fibrotic reaction.

The halophilic archaea (haloarchaea) live in hyersaline environments such as salt lakes, salt ponds and marine salterns. To cope with the salt stress conditions, haloarchaea have developed two fundamentally different strategies: the "salt-in" strategy and the "compatible-solute" strategy. Although investigation of the molecular mechanisms underlying the tolerance to high salt concentrations has made outstanding achievements, experimental study from the aspect of transcription is rare. In the present study, we monitored cellular physiology of Natrinema sp. J7-2 cells incubated in different salinity media (15%, 25% and 30% NaCl) from several aspects, such as cellular morphology, growth, global transcriptome and the content of intracellular free amino acids. The results showed that the cells were polymorphic and fragile at a low salt concentration (15% NaCl) but had a long, slender rod shape at high salt concentrations (25% and 30% NaCl). The cells grew best in 25% NaCl, mediocre in 30% NaCl and struggled in 15% NaCl. An RNA-seq analysis revealed differentially expressed genes (DEGs) in various salinity media. A total of 1,148 genes were differentially expressed, consisting of 719 DEGs (348 up-regulated and 371 down-regulated genes) between cells in 15% vs 25% NaCl, and 733 DEGs (521 up-regulated and 212 down-regulated genes) between cells in 25% vs 30% NaCl. Moreover, 304 genes were commonly differentially expressed in both 15% vs 25% and 25% vs30% NaCl. The DEGs were enriched in different KEGG metabolic pathways, such as amino acids, glycerolipid, ribosome, nitrogen, protoporphyrin, porphyrin and porhiniods. The intracellular predominant free amino acids consisted of the glutamate family (Glu, Arg and Pro), aspartate family (Asp) and aromatic amino acids (Phe and Trp), especially Glu and Asp.

Creatine kinase (CK) is a pivotal regulatory enzyme in energy metabolism linked to both blood pressure and cardio-metabolic components. However, data is lacking in a large population of asymptomatic Asians.Cardio-metabolic assessment including anthropometric measures and non-alcoholic fatty liver disease (NAFLD) were evaluated by abdominal echo in 4,562 consecutive subjects who underwent an annual health survey. Serum CK levels were related to blood pressure components [systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP)], anthropometric measures, and excessive adiposity in liver as indicated by NAFLD. Circulating CK levels ranged from 4 to 1842 IU/L (mean [SE]: 108.7 [1.1] IU/L) in the study population which consisted of 2522 males (mean age: 48.7 ± 11.2) and 2040 females (mean age: 49.4±11.5). In general, male subjects presented with higher circulating CK levels than females (mean ± SE: 127.3 ± 1.5 vs. 85.5 ± 1.3 IU/L, respectively, p < .001). Gender-differences in circulating CK levels were also observed with increasing age, which showed a more pronounced positive relationship with age in female subjects (gender interaction: p < .05). Furthermore, an elevated circulating CK level was independently associated with higher blood pressure, waist circumference and fat mass (FM), greater body mass index (BMI), increased lower estimated glomerular filtration rate (eGFR) and presence of NAFLD in multivariate analysis (all p < .05), with CK elevation more pronounced with greater BMI and FM in males compared with females (sex interaction: p < .05).In a large asymptomatic Asian population, circulating CK levels were increased with more advanced age, higher blood pressure, and greater body mass with gender differences. Our findings may be useful in interpreting elevated CK from subjects free of ongoing myocardial damage.

[This corrects the article DOI: 10.1371/journal.pone.0173367.].

OBJECTIVE:N-methyl-D-aspartate receptors (NMDAR) subunit GRIN2A/GluN2A mutations have been identified in patients with various neurological diseases, such as epilepsy and intellectual disability / developmental delay (ID/DD). In this study, we investigated the phenotype and underlying molecular mechanism of a GRIN2A missense mutation identified by next generation sequencing on idiopathic focal epilepsy using in vitro electrophysiology. METHODS:Genomic DNA of patients with epilepsy and ID/DD were sequenced by targeted next-generation sequencing within 300 genes related to epilepsy and ID/DD. The effects of one missense GRIN2A mutation on NMDAR function were evaluated by two-electrode voltage clamp current recordings and whole cell voltage clamp current recordings. RESULTS:We identified one de novo missense GRIN2A mutation (Asp731Asn, GluN2A(D731N)) in a child with unexplained epilepsy and DD. The D731N mutation is located in a portion of the agonist-binding domain (ABD) in the GluN2A subunit, which is the binding pocket for agonist glutamate. This residue in the ABD is conserved among vertebrate species and all other NMDAR subunits, suggesting an important role in receptor function. The proband shows developmental delay as well as EEG-confirmed seizure activity. Functional analyses reveal that the GluN2A(D731N) mutation decreases glutamate potency by over 3,000-fold, reduces amplitude of current response, shortens synaptic-like response time course, and decreases channel open probability, while enhancing sensitivity to negative allosteric modulators, including extracellular proton and zinc inhibition. The combined effects reduce NMDAR function. SIGNIFICANCE:We identified a de novo missense mutation in the GRIN2A gene in a patient with childhood focal epilepsy and acquired epileptic aphasia. The mutant decreases NMDAR activation suggesting NMDAR hypofunction may contribute to the epilepsy pathogenesis.

Gemcitabine-based chemotherapy remains one of the standards in management of metastatic breast cancer. However, intrinsic and acquired resistance to gemcitabine inevitably occurs. The aims of this study were to assess the efficacy of the combination of src inhibition and gemcitabine in gemcitabine-resistant breast cancer cells.By using colony formation, sphere forming, flow cytometry, cell counting kit-8 and transwell assays, 231/GEM-res (gemcitabine-resistant) cell line, which was 10 times more resistant, was shown to have elevated drug tolerance, enhanced proliferative and self-renewal abilities, compared with its parental cells. Inhibition of src by both saracatinib (AZD0530) and siRNA could partially reverse gemcitabine resistance and attenuate resistance-associated anti-apoptosis, migration and stem cell capacities. In addition, the combination of src inhibition and gemcitabine had synergistic antitumor effects. Western blot analysis revealed up-regulation of pro-apoptotic protein BAX, along with the down-regulation of anti-apoptotic proteins (BCL-XL, Survivin), migration associated proteins (p-FAK, MMP-3) and cancer stem cell (CSC) markers (CD44, Oct-4), which was probably mediated by AKT/c-Jun pathway.In highly gemcitabine-resistant 231 cells, src inhibition can synergize with gemcitabine, reverse drug resistance, inhibit tumor growth/metastasis/stemness of cancer stem cells, possibly via the AKT/c-Jun pathway.

Here, we studied the underlying mechanism of aldosterone (Aldo)-induced vascular endothelial cell damages by focusing on ceramide. We confirmed that Aldo (at nmol/L) inhibited human umbilical vein endothelial cells (HUVEC) survival, and induced considerable cell apoptosis. We propose that ceramide (mainly C18) production might be responsible for Aldo-mediated damages in HUVECs. Sphingosine-1-phosphate (S1P), an anti-ceramide lipid, attenuated Aldo-induced ceramide production and following HUVEC damages. On the other hand, the glucosylceramide synthase (GCS) inhibitor PDMP or the ceramide (C6) potentiated Aldo-induced HUVEC apoptosis. Eplerenone, a mineralocorticoid receptor (MR) antagonist, almost completely blocked Aldo-induced C18 ceramide production and HUVEC damages. Molecularly, ceramide synthase 1 (CerS-1) is required for C18 ceramide production by Aldo. Knockdown of CerS-1 by targeted-shRNA inhibited Aldo-induced C18 ceramide production, and protected HUVECs from Aldo. Reversely, CerS-1 overexpression facilitated Aldo-induced C18 ceramide production, and potentiated HUVEC damages. Together, these results suggest that C18 ceramide production mediates Aldo-mediated HUVEC damages. MR and CerS-1 could be the two signaling molecule regulating C18 ceramide production by Aldo.