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The data assimilation scheme used in the Met Office's Operational Sea Surface Temperature and Ice Analysis (OSTIA) system has been updated from an Optimal Interpolation (OI)‐type scheme to a variational assimilation scheme. The updated system includes a dual length‐scale background error correlation operator, and a flow‐dependent component to adjust the length‐scale combination in favour of the short scale in regions of high sea surface temperature (SST) variability. The variational assimilation scheme improves both the analysis performance and the representation of SST features in the OSTIA analysis compared to the OI scheme of the original system. The results of spectral analysis, assessment of horizontal SST gradients and the response of an atmospheric model to the OSTIA SST analysis as a boundary condition indicate that the flow‐dependent formulation successfully contributes to improvements in the feature resolution capability of the analysis. Overall, using a short length‐scale of 15 km and including a flow‐dependent adjustment component produces the best results compared to using either 40 km or the first Rossby radius of deformation as the short length‐scale. The new system successfully captures realistic ocean variability without introducing noise into the analysis, allowing the feature resolution capability of the new system to out‐perform that of other comparable SST analysis products. [ABSTRACT FROM AUTHOR]

Although sphingomyelins known to be are lipid constituents of the plasma membrane in vertebrates, much remains obscure about the metabolism of sphingomyelins in insects. With ultra performance liquid chromatography‐time‐of‐flight‐tandem mass spectrometry analysis, we revealed for the first time that sphingomyelins are abundant in Nilaparvata lugens (Stål), the brown planthopper (BPH), and their biosynthesis is carried out by sphingomyelin synthase‐like protein 2 (SMSL2), which is homologous to sphingomyelin synthase‐related protein (SMSr). Unlike other insect species, high concentrations of sphingomyelins rather than ceramide phosphoethanolamines exist in the BPH. Two putative genes, which are homologous to SMSr, are named Nilaparvata lugensSMS‐like 1 (NlSMSL1) and 2 (NlSMSL2). Knockdowns of both NlSMSL2 and NlSMSL1 were conducted but only the first decreased concentrations of sphingomyelins in the BPH, indicating that NlSMSL2 plays a role in the biosynthesis of sphingomyelins. Real‐time quantitative PCR analysis revealed both NlSMSL1 and NlSMSL2 are highly expressed in BPH adults, with NlSMSL1 specifically highly expressed in reproductive organs (ovaries and testes) whereas NlSMSL2 was highly expressed in the malpighian tubules. The knockdown of NlSMSL1 or NlSMSL2 increased BPH female body weight but not that of males, suggesting sex‐specific roles for SMSLs in influencing BPH body weight. The results suggest that NlSMSL2 catalyses the synthesis of sphingomyelins and maintains female BPH body weight through alteration of sphingolipid content. [ABSTRACT FROM AUTHOR]

The neutral sphingomyelinase (nSMase) 1 homologue gene LsSMase was cloned from Laodelphax striatellus, a direct sap-sucker and virus vector of gramineous plants, and expressed via a Bac to Bac baculovirus expression system. The LsSMase-enhanced green fluorescent protein fusion protein was located in the endoplasmic reticulum in a similar manner to mammalian nSMase 1. The biochemical properties of LsSMase were determined in detail. The optimal pH and temperature for recombinant LsSMase were 8 and 37 °C, respectively. LsSMase was an Mg2+ or Mn2+ dependent enzyme, but different concentration of each were needed. The activity of LsSMase was significantly stimulated by Ethylene glycol bis(2-aminoethyl ether)tetraacetic acid (EGTA), whereas it was inhibited by ethylenediaminetetraacetic acid. Millimolar concentrations of Zn2+ completely inhibited LsSMase. The reducing agents dithiothreitol and β-mercaptoethanol varied in their effects on activity. Phospholipids were not found to stimulate LsSMase. [ABSTRACT FROM AUTHOR]

An operational system for producing a global diurnally varying analysis of skin sea-surface temperature (SST) has been developed at the Met Office. Skin SST is formulated as the sum of a foundation temperature, a warm-layer temperature difference, and a thermal skin temperature difference. Foundation temperature is taken from the Operational Sea surface Temperature and sea Ice Analysis (OSTIA) system, while numerical models are used for the warm layer and thermal skin layer. Both the thermal skin layer and warm-layer models are forced using outputs from the Met Office's numerical weather prediction system. Data assimilation is used to improve estimates of the warm layer, with observations coming from the geostationary SEVIRI and GOES-W instruments, as well as the polar orbiting NOAA-AVHRR sensors. The SST observations of these instruments are converted to observations of the warm-layer temperature difference by subtracting an instrument-specific foundation SST calculated using just night-time data from that sensor. A quality control procedure removes warm-layer observations where the satellite-specific foundation estimates are less robust due to lack of data. Validation of the analysis system has been performed by comparing the model to the assimilated satellite data, and to independent near-surface observations from Argo floats. The mean state of the system was assessed via a comparison to a climatology generated from drifting buoys. Results from the validation show that the system does a good job of replicating the climatology and that assimilation improves the analysis when assessed against Argo. However, the system has been found to underestimate the diurnal range of skin SST by approximately 0.1-0.3 °C on average. Data from the system are available free of charge from the Copernicus Marine Environment Monitoring Service. [ABSTRACT FROM AUTHOR]

Background It is uncertain whether concurrent use of low-dose aspirin removes the gastrointestinal benefit displayed by COX-2 selective inhibitors (coxibs) when compared to traditional nonsteroidal anti-inflammatory drugs ( NSAIDs). Aim To evaluate the gastrointestinal risks associated with coxibs and traditional NSAIDs and the interaction with concurrent use of low-dose aspirin. Methods We searched MEDLINE, EMBASE and the Cochrane Library through April 2016 to identify randomised trials comparing the gastrointestinal risk between coxibs and traditional NSAIDs in patients taking or not taking low-dose aspirin. Results were combined using random effects meta-analysis. Subgroup analyses by concurrent use of aspirin were undertaken. Results Eleven trials (84 150 participants) were included. The overall relative risk ( RR) of coxibs vs. traditional NSAIDs for complicated gastrointestinal events was 0.54 (95% CI, confidence interval 0.32-0.92), with a significant subgroup difference ( P = 0.04) according to concurrent use of aspirin (used: RR = 0.96, 95% CI 0.66-1.24; not used: RR = 0.33, 95% CI 0.14-0.83). The overall RR for clinical gastrointestinal events was 0.59 (95% CI 0.47-0.75), with a significant subgroup difference according to aspirin usage ( P = 0.008; used: RR = 0.77, 95% CI 0.62-0.95; not used: RR = 0.50, 95% CI 0.39-0.64). Overall coxibs were associated with significantly lower risk of symptomatic ulcers ( RR = 0.60, 95% CI 0.50-0.72) and endoscopic ulcers ( RR = 0.29, 95% CI 0.16-0.53) than traditional NSAIDs; a significant subgroup difference was shown for endoscopic ulcers ( P = 0.05) but not for symptomatic ulcers ( P = 0.27). Conclusion Concomitant use of low-dose aspirin reduces but does not completely eliminate the gastrointestinal benefit of coxibs over traditional NSAIDs. [ABSTRACT FROM AUTHOR]

Background Many strategies are used to prevent nonsteroidal anti-inflammatory drug ( NSAID)-associated gastrointestinal toxicity, but the comparative effectiveness remains unclear. Aim To evaluate the comparative effectiveness of clinical strategies for preventing gastrointestinal toxicity induced by NSAIDs. Methods MEDLINE, EMBASE and the Cochrane Library (from their inception to May 2015) were searched for randomised controlled trials comparing the risk of gastrointestinal adverse events in patients taking nonselective NSAIDs, selective cyclooxygenase( COX)-2 inhibitors or nonselective NSAIDs/ COX-2 inhibitors plus gastroprotective agents [proton pump inhibitors ( PPIs), histamine-2 receptor antagonists, misoprostol]. Both pairwise meta-analysis and Bayesian network meta-analysis were performed. Results Analyses were based on 82 trials including 125 053 participants. Network meta-analysis demonstrated that selective COX-2 inhibitors + PPIs [Risk ratio ( RR), 95% Credible Interval (CrI): ulcer complications 0.07, 0.02-0.18], selective COX-2 inhibitors ( RR, 95% CrI: ulcer complications 0.25, 0.15- 0.38; symptomatic ulcer 0.12, 0.04-0.30), nonselective NSAIDs + PPIs ( RR, 95% CrI: ulcer complications 0.28, 0.18-0.41; symptomatic ulcer 0.11, 0.04-0.23), nonselective NSAIDs + misoprostol ( RR, 95% CrI: ulcer complications 0.47, 0.24-0.81; symptomatic ulcer 0.41, 0.13-1.00) were associated with significantly lower risk of clinical gastrointestinal events compared with nonselective NSAIDs. For all effectiveness endpoints, selective COX-2 inhibitors + PPIs was associated with the lowest absolute event probability and the highest rank, followed by selective COX-2 inhibitors and thirdly by nonselective NSAIDs + PPIs. Conclusion The combination of selective COX-2 inhibitors plus PPIs provides the best gastrointestinal protection, followed by selective COX-2 inhibitors, and thirdly by nonselective NSAIDs plus PPIs. [ABSTRACT FROM AUTHOR]

Objective: The umbilical cord provides nutrition and oxygen to the fetus. The aim of this study was to determine the effects of acetylcholine (ACh) on umbilical cords from humans and other mammals, and the mechanisms of ACh-mediated vasoconstriction in the human umbilical cord.Design: Human and animal umbilical cords used in vascular and cellular experiments.Setting: Institute for Fetology, First Hospital of Soochow University, Suzhou, China.Population: A total of 85 pregnant women, 16 Sprague Dawley rats and seven pregnant sheep.Methods: Umbilical cord veins and arteries from humans, rats and sheep, aortas and mesenteric arteries from rats, and mesenteric, carotid and femoral arteries from ovine fetuses were used to compare vascular functions in response to ACh and to determine the mechanisms of ACh-mediated umbilical vasoconstriction. Vascular tension and ion channel currents were measured on isolated vessels and smooth muscle cells from human umbilical cords.Main Outcome Measures: Provision of new evidence to conclude that ACh-stimulated vasoconstriction is common to all umbilical cords, and cellular mechanisms are linked to potassium channels.Results: ACh caused reliable vasoconstriction in umbilical veins/arteries in humans, rats and sheep, but not in any other vessels, including fetal vessels. Atropine inhibited the effects of ACh. The mRNA of ACh-muscarinic receptor subtypes M1 -M5 was expressed in human umbilical vessels. The protein kinase C antagonist GF109203X and the calcium inhibitor nifedipine decreased ACh-induced vasoconstriction in human umbilical vessels. ACh also caused a reduction in whole-cell potassium channel currents and the single-channel current of large-conductance calcium-activated potassium (BKca) channels.Conclusion: Umbilical vessels are significantly different from other vessels in their response to ACh. BKca channels in smooth muscle cells may play important roles in ACh-mediated vasoconstriction in human umbilical cords. This information may be important for fetal medicine and practice with regard to the effect on fetal development of umbilical vascular functions. [ABSTRACT FROM AUTHOR]

Background There is limited information involving population data about the role of maternal health, fetal growth and neonatal health on children's developmental status at ages 4-7 years. Our aim was to determine the contribution of maternal, fetal and neonatal health to developmental status at ages 4-7 years. Methods In this 7-year follow-up prospective cohort study, a sample of 26 803 mothers participated in the beginning. Among their children, 19 187 voluntarily completed the development screening test or the social life ability survey, which were designed for two different age groups (<6 or ≥6 years old, respectively). Logistic regression analysis was used to link the data with the prenatal outcome card and interview questionnaire applied to pregnant women in previous study, to the analysis of various related factors such as demographic, socio-economic, disease and menstrual history, marriage and pregnancy care. Result Univariate and multivariate logistic regression analysis were used separately in two age groups [4-6 ( n = 8439) and 6-7 ( n = 10 748) years old] to analyse relative factors. Maternal age of 25-30 years, maternal education of high school and greater, family income and not drinking during pregnancy were associated with higher scores in development. Conclusion Both preconception and pregnancy health education and health care are the important maternal factors closely associated with children's cognitive and social competence. Public health policies for preconception care and public welfare for high-quality childcare are essential for improving children's life. [ABSTRACT FROM AUTHOR]

Objective Studies investigating the association between interleukin (IL)-4 gene promoter -590C/T (rs2243250) polymorphism and autoimmune diseases report conflicting results. To derive a more precise estimation of the relationship, a meta-analysis was performed. Methods A systematic literature search was conducted to identify relevant studies. Pooled odds ratio (OR) with 95% confidence interval (CI) was used to estimate the strength of association. Results A total of 6001 cases and 6788 controls from 24 studies were analysed. Significant association of the C allele of IL-4 rs2243250 polymorphism with rheumatoid arthritis (RA) was detected (odds ratio (OR) = 0.696, 95% confidence interval (CI) = 0.601-0.807). Stratification by ethnicity indicated an association between the IL-4 rs2243250 polymorphism and RA in Caucasians. Furthermore, the overall ORs of the associations between the C allele and multiple scleorosis (MS) were 1.340 (95% CI = 1.102-1.630). However, we failed to reveal any association between IL-4 rs2243250 polymorphism and systemic lupus erythematosus (SLE), type 1 diabetes (T1D) or Graves' disease (GD). Conclusions The present study suggests that the IL-4 rs2243250 polymorphism might be associated with genetic susceptibility to autoimmune diseases, including RA and MS. [ABSTRACT FROM AUTHOR]

Ceramidases are a group of enzymes that catalyse hydrolysis of ceramides to generate fatty acid and sphingosine. In this study, we report the cloning and characterization of the rice small brown planthopper Laodelphax striatellus neutral ceramidase ( nCDase), LsnCer. LsnCer was identified by sequencing the transcriptome of L. striatellus and is a protein of 717 amino acids with a predicted molecular weight of 79.3 kDa. Similarly to other known nCDases, the optimum pH for LsnCer is 8.0 and the optimum temperature is 37 ° C for its in vitro activity. LsnCer activity is inhibited by Zn2+ significantly and Fe2+ slightly. LsnCer has broad substrate specificity with a preference for ceramides with a medium acyl-chain or a monounsaturated long acyl-chain. Infection with rice strip virus ( RSV) or treatment with insecticides significantly increased LsnCer mRNA expression and its enzymatic activity in L. striatellus. These results suggest that LsnCer is a bona fide nCDase that may have a role in adaption of L. striatellus to environmental stresses. [ABSTRACT FROM AUTHOR]

Background: The authors conducted a systematic review and meta-analysis to examine whether patients who had metastatic colorectal cancer (mCRC) with the v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) p.G13D mutation (an amino acid substitution at position 13 in KRAS from a glycine to an aspartic acid) and received cetuximab treatment had better clinical outcomes than patients who had mCRC tumors with KRAS codon 12 mutations.Methods: Relevant studies were identified by a search of MEDLINE, EMBASE, the Chinese Biomedical Database, and Wan Fang Digital Journals from inception to October 2011. The primary clinical outcomes included the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). The pooled relative risk (RR) or hazard ratio (HR) was estimated by using fixed-effects or random-effects models according to heterogeneity between studies.Results: Ten studies were considered eligible that included 1487 patients with mCRC. Patients who had tumors with the KRAS p.G13D mutation had a significantly higher ORR (10 studies; RR, 1.642; 95% confidence interval [CI], 1.131-2.384), longer PFS (1 study; HR, 0.54; 95% CI, 0.36-0.81), and longer OS (1 study; HR, 0.52; 95% CI, 0.33-0.80) than patients who had tumors with KRAS codon 12 mutations. Compared with patients who had KRAS wild-type tumors, patients with the p.G13D mutation had a significantly lower ORR (9 studies; RR, 0.540; 95% CI, 0.381-0.765) and nonsignificantly shorter PFS (1 study; HR, 0.99; 95% CI, 0.68-1.45) and OS (1 study; HR, 1.01; 95% CI, 0.66-1.54).Conclusions: Patients who had mCRC with the KRAS p.G13D mutation appeared to benefit more from cetuximab than patients who had tumors with KRAS codon 12 mutations. However, because of the limited sample sizes in the current meta-analysis, these results should be interpreted with caution. [ABSTRACT FROM AUTHOR]

A full-length cDNA encoding a general odorant binding protein 2 (GOBP2) was cloned from the antennae of the rice striped stem borer, Chilo suppressalis (Lepidoptera: Pyralidae), by the combination of reverse transcription PCR (RT-PCR) and rapid amplification of cDNA ends PCR (RACE-PCR). The cDNA contains a 489 bp open reading frame, which encodes a 162 amino acid protein, termed as Ch. suppressalis GOBP2 (CsupGOBP2). CsupGOBP2 is similar in the number of amino acids and protein sequence to GOBP2s in other species of Lepidoptera. RT-PCR results showed that CsupGOBP2 mRNA was highly expressed in the adult antennae of both females and males, as was CsupGOBP2 protein as revealed by Western blot analysis. CsupGOBP2 expressed in Escherichia coli was purified by affinity chromatography, refolding and gel filtration from the inclusion body. Fluorescence emission spectra and competitive binding assays by using N-phenyl-1-naphthylamine as first binding ligand and odorants as potential competitors revealed that the CsupGOBP2 protein has significant affinity to cis-11-hexadecenal (Z11–16:Ald), the main component of Ch. suppressalis pheromone and to laurinaldehyd and benzaldehyde, two general plant volatile aldehydes. [ABSTRACT FROM AUTHOR]

Among vertebrates, fish and mammals show intriguing differences in their growth control properties with age. The potential for unlimited or indeterminate growth in a variety of fish species has prompted many questions regarding the senescent phenomena that appear during the aging process in these animals. Using zebrafish as our model system, we have attempted in our current study to examine the growth phenomena in fish in relation to the onset of senescence-associated symptoms, and to evaluate the effects of genotoxic stress on these processes. We observed in the course of these analyses that the zebrafish undergoes continuous growth, irrespective of age, past the point of sexual maturation with gradually decreasing growth rates at later stages. Animal population density, current body size and chronological age also play predominant roles in regulating zebrafish growth and all inversely influence the growth rate. Interestingly, the induction of genotoxic stress by exposure to ionizing radiation (IR) did not adversely affect this body growth ability in zebrafish. However, IR was found to chronically debilitate the regeneration of amputated caudal fins and thereby induce high levels of abnormal fin regeneration in the adult zebrafish. In addition, by resembling and mimicking the natural course of aging, IR treatments likewise enhanced several other symptoms of senescence, such as a decline in reproductive abilities, increased senescence-associated β-galactosidase activity and a reduction in melatonin secretion. Our current data thus suggest that during the lifespan of zebrafish, the onset of senescence-associated symptoms occurs in parallel with continuous growth throughout mid-adulthood. Moreover, our present findings indicate that genotoxic DNA damage may play a role as a rate-limiting factor during the induction of senescence, but not in the inhibition of continuous, density-dependent growth in adult zebrafish. [ABSTRACT FROM AUTHOR]

The association of Fcγ receptor (FcγR) polymorphisms with systemic lupus erythematosus (SLE) has been demonstrated in various populations; however, the results have been inconsistent. We recently identified a single-nucleotide polymorphism encoding a non-synonymous substitution, Ile232Thr (I232T), of FCGR2B and its association with SLE in Japanese and in Thais. Multiple functional FcγR genes with polymorphisms ( FCGR2A, FCGR2B, FCGR3A, and FCGR3B) cluster in 1q23, and some of them are in linkage disequilibrium (LD). To differentiate contributions from multiple-linked loci, comparison of different populations may provide useful information. In this study, we analyzed the above four FCGR polymorphisms of the Chinese patients and controls for the association with SLE. FCGR2A-H131R, FCGR2B-I232T, FCGR3A-F176V, and FCGR3B genotypes were determined in 167 Chinese patients with SLE and 129 healthy controls. Association was examined using case-control analysis. Allele frequencies of FCGR2B-232T and FCGR3A-176F were significantly increased in SLE [odds ratio (OR) = 1.67 and OR = 1.41, respectively]. Interestingly, while these alleles had a tendency of positive LD in the controls, FCGR2B-232T was in positive association with FCGR3A-176V in SLE, suggesting that these two alleles were associated with SLE in an independent manner. Comparison between SLE with and without nephritis indicated significant association of FCGR2B-232T with nephritis (OR = 2.65). When the present results were combined with our previous data on the Japanese and the Thais using meta-analytic methods, highly significant and independent association was observed for FCGR2B and FCGR3A genotypes. These results strongly suggested that FCGR2B is a common susceptibility factor to SLE in the Asians. [ABSTRACT FROM AUTHOR]

Summary Nervous disorders were found in two horses and verified as aseptic encephalitis by necropsy in the summer of 2000. To investigate agents that affected the horses, diagnostic procedures involving virus isolation, neutralization test and reverse transcription–polymerase chain reaction (RT-PCR) were performed. We intracranially inoculated litters of suckling mice with tissues suspected of containing aseptic encephalitis, including cerebrum, cerebellum, brain stem, thalamus, and cerebrospinal fluids; the mice were then observed for 14 days. Neutralizing antibodies against Japanese encephalitis (JE) viruses were present in the cerebrospinal fluid of the horses in titers of 10. Sequences of 500 nucleotides of the premembrane gene of JE virus, synthesized by RT-PCR, from both the cerebrum and cerebellum were determined. The phylogenetic analysis based on sequences of the premembrane gene revealed a relationship with the JE virus. The divergences at the nucleotide level of 1.2–5.7% and at the amino acid level of 0–4.3% were conserved with other JE strains. The results demonstrated that the pathogens causing equine encephalitis were JE viruses. The strains were closely related to Taiwanese isolates. [ABSTRACT FROM AUTHOR]

SummaryobjectivesThe autoimmune thyroid diseases (AITDs) comprising Graves’ disease (GD) and Hashimoto’s thyroiditis (HT) are complex genetic diseases, which result from an interaction between predisposing genes and environmental triggers. The aim of our study was to dissect the genetic predisposition to GD and HT in one large Chinese family with multiple members affected with AITD. patientsWe completed a whole genome screen of a large multiplex Chinese–American family. We enrolled 27 family members from three generations. Eight members were affected with AITD, six had GD and two had HT. designWe determined the information limits of the family. Power calculations indicated that the maximum attainable LOD scores were 5·1 assuming dominant inheritance, and 3·4 assuming recessive inheritance. These estimates both assumed 100% penetrance and one gene. Whole genome screening was performed using 400 highly polymorphic and densely spaced microsatellite markers spanning the entire human genome (intermarker distance < 10 cM). Linkage analysis was performed using two-point and multipoint parametric and nonparametric methods. resultsInitial whole genome screening performed with 400 microsatellite markers identified two markers that showed evidence for linkage to AITD in this family, D11S4191 and D9S175, with two-point LOD scores of 2·31 and 2·05, respectively. Multipoint linkage analysis focusing on the regions containing these markers revealed a maximum multipoint LOD score (MLS) of 2·13 and a nonparametric linkage score (NPL) of 6·1 for D11S4191 and an MLS of 2·01 and NPL of 7·5 for D9S175. conclusionsThese results showed that this Chinese family harboured susceptibility loci for AITD which were distinct from those previously found in the Caucasian population. This suggests that different susceptibility loci exist between different ethnic groups. Furthermore, even within a single family from a genetically... [ABSTRACT FROM AUTHOR]

Previous mitochondrial DNA (mtDNA) D-loop and microsatellite studies have shown that Chinese horses have multiple maternal origins and high genetic diversity. To better characterize maternal genetic origins and diversity of Chinese domestic horses, we conducted a comprehensive analysis of 407 complete 1140 bp sequences of the horse mitochondrially encoded cytochrome b (CYTB) gene, including 323 horses from 13 Chinese indigenous breeds and 84 reference sequences from GenBank. A total of 114 haplotypes were identified, of which 73 appeared among the 13 Chinese horse breeds. The high mitochondrially encoded cytochrome b haplotypic diversity suggests multiple maternal origins in Chinese horses. [ABSTRACT FROM AUTHOR]

The article describes the use of a low-cost 3-D printer to create a circular polarized (CP) antenna. The authors discuss the aim of this Letter, the design and performance of the CP antenna, and topics including CP patch antenna geometry, and the antenna's reflection coefficient and measured and simulated axial ratio and radiation patterns.

Aim: To establish a reproducible experimental animal model for systemic lupus erythematosus (SLE)-associated periodontitis (PD), investigate the effects of SLE on PD and assess the therapeutic potential of alpha-ketoglutarate (αKG) for SLE-PD treatment., Materials and Methods: An SLE-PD murine model was established via ligature-induced PD in MRL-lpr strain, with MRL/MpJ strain as a non-SLE control. The periodontal state was assessed using micro-CT, real-time PCR, histology, immunofluorescence and flow cytometry assays. αKG levels were analysed, and a thermoresponsive gel was designed as a periodontal dimethyl (DM)-αKG delivery system. αKG levels were analysed in gingival crevicular fluid (GCF) of PD patients with or without SLE., Results: SLE significantly increased the periodontal inflammation and bone resorption in the SLE-PD model. αKG levels in GCF were lower in PD patients with SLE than in PD patients without SLE. Decreased αKG levels in the gingiva and macrophage M1/M2 imbalance were observed in SLE-PD mice. However, DM-αKG thermoresponsive gel effectively alleviated the periodontal inflammation, bone resorption and macrophage M1/M2 imbalance in SLE-PD mice., Conclusions: Our study established, for the first time, a novel SLE-PD murine model and revealed that SLE increases the severity of PD in vivo. Our findings highlight the therapeutic potential of αKG for SLE-associated PD., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Previous studies have suggested that the morphology and function of the thalamus and cortex are abnormal in patients with knee osteoarthritis (KOA). However, whether the thalamocortical network is differentially affected in this disorder is unknown. In this study, we examined functional and effective connectivity between the thalamus and major divisions of the cortex in 27 healthy controls and 27 KOA patients using functional magnetic resonance imaging. We also explored the topological features of the brain via graph theory analysis. The results suggested that patients with KOA had significantly reduced resting-state functional connectivity (rsFC) of the thalamo-sensorimotor pathway; enhanced rsFC of the thalamo-medial/lateral frontal cortex (mFC/LFC), parietal, temporal and occipital pathways; reduced effective connectivity of the left sensorimotor-to-thalamus pathway; and enhanced effective connectivity of the right thalamus-to-sensorimotor pathway compared with healthy controls. The functional connectivity of the thalamo-sensorimotor and thalamo-mFC pathways was enhanced when patients performed the multisource interference task. Moreover, patients with KOA presented altered nodal properties associated with thalamocortical circuits, including the thalamus, amygdala, and regions in default mode networks, compared with healthy controls. The correlation analysis suggested a significant negative correlation between thalamo-mFC rsFC and pain intensity, between thalamo-sensorimotor task-related connectivity and disease duration/depression scores, and a positive correlation between right frontal nodal properties and pain intensity in KOA patients. Taken together, these findings establish abnormal and differential alterations in the thalamocortical network associated with pain characteristics in KOA patients, which extends our understanding of their role in the pathophysiology of KOA., (© 2024 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Aims: To investigate the associations of conicity index (C-index) and relative fat mass (RFM) with incident type 2 diabetes mellitus (T2DM) among adults in China., Materials and Methods: A total of 10 813 participants aged over 18 years in Shenzhen Longhua district were enrolled in a follow-up study conducted from 2018 to 2022. The participants were categorized based on quartiles (Q) of C-index and RFM. The Cox proportional hazards model was performed to examine the relationships between C-index, RFM and the risk of T2DM., Results: After adjusting for potential confounding factors, including age, sex, occupation, marital status, education level, smoking status, alcohol consumption, physical exercise, hypertension status, fasting blood glucose (FBG) and total cholesterol (TC), both C-index and RFM showed positive and independent associations with risk of T2DM. The multivariable-adjusted hazard ratios (95% confidence intervals) for T2DM risk in participants in C-index Q3 and Q4 compared with those in C-index Q1 were 1.50 (1.12, 2.02) and 1.73 (1.29, 2.30), and 1.94 (1.44, 2.63), 3.18 (1.79, 5.64), 4.91 (2.68, 9.00) for participants in RFM Q2, Q3 and Q4 compared with RFM Q1. These differences were statistically significant (all p < 0.05)., Conclusion: C-index and RFM are strongly associated with new-onset T2DM and could be used to identify the risk of diabetes in large-scale epidemiological studies., (© 2024 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: Although white matter hyperintensity (WMH) is closely associated with cognitive decline, the precise neurobiological mechanisms underlying this relationship are not fully elucidated. Connectome studies have identified a primary-to-transmodal gradient in functional brain networks that support the spectrum from sensation to cognition. However, whether connectome gradient structure is altered as WMH progresses and how this alteration is associated with WMH-related cognitive decline remain unknown., Methods: A total of 758 WMH individuals completed cognitive assessment and resting-state functional MRI (rs-fMRI). The functional connectome gradient was reconstructed based on rs-fMRI by using a gradient decomposition framework. Interrelations among the spatial distribution of WMH, functional gradient measures, and specific cognitive domains were explored., Results: As the WMH volume increased, the executive function (r = -0.135, p = 0.001) and information-processing speed (r = -0.224, p = 0.001) became poorer, the gradient range (r = -0.099, p = 0.006), and variance (r = -0.121, p < 0.001) of the primary-to-transmodal gradient reduced. A narrower gradient range (r = 0.131, p = 0.001) and a smaller gradient variance (r = 0.136, p = 0.001) corresponded to a poorer executive function. In particular, the relationship between the frontal/occipital WMH and executive function was partly mediated by gradient range/variance of the primary-to-transmodal gradient., Conclusions: These findings indicated that WMH volume, the primary-to-transmodal gradient, and cognition were interrelated. The detrimental effect of the frontal/occipital WMH on executive function was partly mediated by the decreased differentiation of the connectivity pattern between the primary and transmodal areas., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Objectives: Gait disorder (GD) is a common problem in cerebral small vessel disease (CSVD). This study aimed to determine (1) the early characteristics of GD in CSVD, (2) cerebellar neuroimaging features related to GD in CSVD, and (3) the association of cognitive impairment with GD., Methods: In total, 183 subjects were enrolled in this study: patients with CSVD with normal cognitive function (CSVD-NC) group (64 subjects), patients with CSVD with mild cognitive impairment (CSVD-MCI) group (66 subjects), and a healthy control (HC) group (53 subjects). The GD patterns were evaluated using the ReadyGo three-dimensional motion balance testing system. Meanwhile, we analyzed the cerebrum and cerebellum structurally and functionally. Correlation analyses were conducted among gait indicators, neuroimaging features, and neuropsychological tests., Results: Both the CSVD-NC and CSVD-MCI groups had a reduced stride length, cortical atrophy in the left cerebellum VIIIb, and decreased functional connectivity between the left cerebellum VIIIb and left SFGmed compared with the HC group. In the correlation analysis, the gray matter probability of the left cerebellum VIIIb was closely related to stride length in the HC group. In the CSVD-MCI group, linguistic function, memory, and attention were significantly correlated with gait performance., Conclusion: Decreased stride length was the earliest characteristic of GD in CSVD. Structural and functional regulation of the left cerebellum VIIIb could play a particularly important role in early GD in CSVD., (© 2024 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

In this study, the synergistic effect of glutaraldehyde-cross-linking and remineralization on the strength and durability of resin-dentin bonds was investigated. Dentin surfaces were etched with 35% phosphoric acid. The control specimens were bonded with Adper Single Bond 2 using wet bonding without pretreatment. The experimental specimens were pretreated with 5% (v/v) glutaraldehyde solution for 3 min and placed in a remineralizing solution for 0, 12, and 24 h, followed by dry bonding. After performing composite build-ups on the specimens, they were longitudinally sectioned, immediately, and after aging for 3 h with sodium hypochlorite (NaOCl), to evaluate microtensile bond strength (µTBS). The cross-linked specimens exhibited µTBS values comparable with those of the control group, but the µTBS decreased significantly after NaOCl aging. The cross-linked dentin remineralized for 24 h exhibited an increase in µTBS. After aging in NaOCl, the µTBS of the specimens remineralized for 24 h did not decrease and was significantly higher than for the other experimental groups. Cross-linking with dry bonding maintained µTBS in specimens before aging in NaOCl, but the bonding durability was compromised. Remineralization of cross-linked dentin for 24 h followed by dry bonding increased the immediate µTBS and improved bond durability. Therefore, combining cross-linking with remineralization of collagen fibrils progressively increased resistance to degradation, improving bond durability., (© 2023 Scandinavian Division of the International Association for Dental Research. Published by John Wiley & Sons Ltd.)

The maintenance of diminished acid ceramidase (ASAH1) gene expression leading to the accumulation of antiproliferative intracellular ceramides in oral squamous cell carcinoma (OSCC) has emerged as a prospective oral cancer therapeutic regimen. Our published study demonstrated that the key periodontal pathogen Porphyromonas gingivalis downregulates the expression patterns of ASAH1 mRNA in normal epithelial cells in vitro. Therefore, P. gingivalis may also beneficially diminish the expression of ASAH1 in OSCC. Because a uniquely structured P. gingivalis-derived phosphoethanolamine dihydroceramide (PEDHC) inhibits the proliferation of normal human fibroblasts, this study aimed to test the effect of PEDHC on the survival of human oral squamous OECM-1 cells in vitro. We demonstrated that the P. gingivalis dihydroceramide-null (ΔPG1780) strain upregulates the expression of ASAH1 mRNA and promotes aggressive proliferation and migration of OECM-1 cells compared to the parent P. gingivalis-W83 strain. In addition, the intracellular concentration of ceramides was dramatically elevated in OECM-1 cells exposed to PEDHC in vitro. Furthermore, PEDHC inhibited expression patterns of ASAH1 mRNA as well as some genes associated with degradation of the basement membranes and extracellular matrix, for example, MMP-2, ADAM-17 and IL-6, in OECM-1 cells. Altogether, these data indicated that PEDHC produced by P. gingivalis inhibits acid ceramidase expression, promotes intracellular ceramide accumulation and suppresses the survival and migration of OSCC cells in vitro. Further studies are needed to determine molecular mechanisms of PEDHC-mediated inhibitory effect(s) on OSCC using in vivo models of oral cancer., (© 2023 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Objective: The aim of this study was to determine the clinical outcomes and long-term stability of individualized titanium mesh combined with free flap for orbital floor reconstruction after maxillectomy and to identify the risk factors for titanium mesh exposure., Material and Methods: The data of 66 patients who underwent maxillectomy and orbital floor defect reconstruction by individualized titanium mesh in Peking University School and Hospital of Stomatology between 2011 and 2019 were retrospectively reviewed. Postoperative ophthalmic function and success of aesthetic restoration were assessed. Titanium mesh exposure was recorded and the risk factors were identified., Results: Mean follow-up was for 24.8 months (range, 6-92 months). Ophthalmic function was successfully restored in 63/66 patients. Aesthetic restoration was not considered satisfactory by 10 patients. Titanium mesh exposure occurred in six patients (exposure rate, 9.1%). Preoperative radiotherapy was identified as an independent risk factor for mesh exposure (OR = 28.8, P = 0.006). Previous surgery, postoperative radiotherapy, pathological type of the primary lesion, the type of tissue flap applied, and the use of intraoperative navigation were not significant risk factors. Six patients with titanium mesh exposure underwent second surgery, but mesh exposure recurred in two patients due to insufficient soft tissue coverage., Conclusion: Individualized titanium mesh with free flap can effectively restore maxilla-orbital defects. Preoperative radiotherapy is an independent predictor of postoperative titanium mesh exposure. Adequate soft tissue coverage of the mesh may reduce the risk of mesh exposure., Level of Evidence: 4 (case-control study) Laryngoscope, 131:2231-2237, 2021., (© 2021 The American Laryngological, Rhinological and Otological Society, Inc.)

Peripheral nerve injury and regeneration are complex processes and involve multiple molecular and signalling components. However, the involvement of long non-coding RNA (lncRNA) in this process is not fully clarified. In this study, we evaluated the expression of the lncRNA maternally expressed gene 3 (MEG3) in rats after sciatic nerve transection and explored its potential mechanisms. The expression of lncRNA MEG3 was up-regulated following sciatic nerve injury and observed in Schwann cells (SCs). The down-regulation of lncRNA MEG3 in SCs enhanced the proliferation and migration of SCs via the PTEN/PI3K/AKT pathway. The silencing of lncRNA MEG3 promoted the migration of SCs and axon outgrowth in rats after sciatic nerve transection and facilitated rat nerve regeneration and functional recovery. Our findings indicated that lncRNA MEG3 may be involved in nerve injury and injured nerve regeneration in rats with sciatic nerve defects by regulating the proliferation and migration of SCs. This gene may provide a potential therapeutic target for improving peripheral nerve injury., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Background Information is scarce regarding the impact of fragmented health insurance schemes on the management and control of hypertension among migrants in primary care. This study aimed to investigate the relationship between insurance status and management and control of hypertension among migrants in primary care and to examine whether social capital could facilitate migrants' participation in local health insurance schemes. Methods and Results A site-based, cross-sectional, face-to-face patient survey was administered in Shenzhen, China. Hypertensive primary care users who were migrants were selected using a systematic sampling design. The participants covered by local health insurance schemes were more likely than those without coverage to be managed by primary care facilities (82.6% versus 62.0%; odds ratio=2.63, 95% CI 1.41-4.89) and to take antihypertensive medications (87.9% versus 76.4%; odds ratio=2.38, 95% CI 1.34-4.24), and they had higher scores in first contact use (3.49 versus 3.23; β=0.17, 95% CI 0.05-0.29) and continuity of care (3.17 versus 3.02; β=0.11, 95% CI 0.01-0.21). The participants covered by local insurance schemes had higher scores in perceived generalized trust than their counterparts (4.23 versus 3.95; β=0.16, 95% CI 0.09-0.40). The hypertension control rate was also higher among the participants with local health insurance coverage (48.8% versus 42.2%; odds ratio=1.38, 95% CI 1.02-2.12). Conclusions In conclusion, local health insurance schemes are associated with optimal control of hypertension for migrants compared with social health insurance schemes. Our study implies that one form of social capital, namely perceived general trust, contributes to migrant hypertensive patients' participation in local health insurance schemes.

Objectives: The objective of this study was to identify the factors that influence free flap survival after head and neck reconstructive surgery in pediatric patients., Methods: One hundred thirty consecutive cases of head and neck reconstruction with free flaps in pediatric patients at the Department of Oral and Maxillofacial Surgery at Peking University School and Hospital of Stomatology, Beijing, People's Republic of China, between 1999 and 2017 were reviewed. A single head and neck surgical team performed all the included surgeries. Demographic and surgical patient data with possible associations with free flap survival were recorded. Relevant influencing factors were determined using the χ 2 test and logistic regression analysis., Results: There were 135 free flap transfers performed in the patients, with an overall success rate of 95.6%. Free flap failure occurred in six flaps (4.4%). Arterial crisis was the main cause of flap failure. The overall complication rate was 7.0%. Patient age (5-9 years old; odds ratio, 13.397; 95% confidence interval, 1.167-153.838; P = 0.037) was a statistically significant risk factor influencing free flap survival. Donor site, defect region, recipient vessel, and surgery time were not associated with free flap outcome., Conclusion: Free flap transfer for head and neck reconstruction in pediatric patients is safe and reliable. However, special attention should be paid to pediatric patients under 9 years of age when performing head and neck reconstruction., Level of Evidence: 4 Laryngoscope, 129:1915-1921, 2019., (© 2018 The American Laryngological, Rhinological and Otological Society, Inc.)

Peripheral nerve injury results in limited nerve regeneration and severe functional impairment. Mesenchymal stem cells (MSCs) are a remarkable tool for peripheral nerve regeneration. The involvement of human umbilical cord MSC-derived extracellular vesicles (hUCMSC-EVs) in peripheral nerve regeneration, however, remains unknown. In this study, we evaluated functional recovery and nerve regeneration in rats that received hUCMSC-EV treatment after nerve transection. We observed that hUCMSC-EV treatment promoted the recovery of motor function and the regeneration of axons; increased the sciatic functional index; resulted in the generation of numerous axons and of several Schwann cells that surrounded individual axons; and attenuated the atrophy of the gastrocnemius muscle. hUCMSC-EVs aggregated to rat nerve defects, down-regulated interleukin (IL)-6 and IL-1β, up-regulated IL-10 and modulated inflammation in the injured nerve. These effects likely contributed to the promotion of nerve regeneration. Our findings indicate that hUCMSC-EVs can improve functional recovery and nerve regeneration by providing a favourable microenvironment for nerve regeneration. Thus, hUCMSC-EVs have considerable potential for application in the treatment of peripheral nerve injury., (© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Objective: To explore the relationship between motor subtypes and drooling, and other risk factors associated with drooling in a large cohort of Chinese patients with Parkinson's disease (PD)., Methods: A total of 586 PD patients were enrolled in this study. Unified Parkinson's disease rating scale (UPDRS) and Hoehn & Yahr stage (H & Y stage) scale, Epworth Sleepiness Scale (ESS), Pittsburgh Sleep Quality Index (PSQI), Hamilton Rating Scale for Depression-24 item (HRSD), and Mini-Mental State Examination (MMSE) were applied to all subjects. Salivary subscores of UPDRS part II were used to evaluate drooling. Constipation was diagnosed using the Rome III criteria., Results: The prevalence of drooling in this cohort is 54.6% (320/586). Non-TD subtype PD patients tend to have higher daily levodopa-equivalent dose (LED), H & Y stage, UPDRS I, UPDRS II, and UPDRS III scores, HRSD score and ESS score, a higher percentage of levodopa treatment, drooling, dyskinesia, and constipation. After adjusting for confounders, non-TD subtype, male sex, UPDRS III score, ESS and PSQI scores, and constipation were still associated with drooling, with corresponding Odds ratios and 95% confidence intervals (95% CIs) were 1.865 (95% CI, 1.137-3.060), 1. 951 (95% CI, 1.326-2.869), 1.024 (95% CI, 1.002-1.046), 1.064 (95% CI, 1.024-1.105), 1.058 (95% CI, 1.000-1.119), and 1.603 (95% CI, 1.092-2.353), respectively., Conclusion: Drooling is common, even in mild-to-moderate PD patients. PD patients with non-TD subtype are at a higher risk of drooling. Male sex, motor severity, excessive daytime sleepiness, poor nighttime sleep, and constipation are also associated with drooling in patients with PD., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Attenuating oxidative stress-induced damage and promoting endothelial progenitor cell (EPC) differentiation are critical for ischaemic injuries. We suggested monotropein (Mtp), a bioactive constituent used in traditional Chinese medicine, can inhibit oxidative stress-induced mitochondrial dysfunction and stimulate bone marrow-derived EPC (BM-EPC) differentiation. Results showed Mtp significantly elevated migration and tube formation of BM-EPCs and prevented tert-butyl hydroperoxide (TBHP)-induced programmed cell death through apoptosis and autophagy by reducing intracellular reactive oxygen species release and restoring mitochondrial membrane potential, which may be mediated viamTOR/p70S6K/4EBP1 and AMPK phosphorylation. Moreover, Mtp accelerated wound healing in rats, as indicated by reduced healing times, decreased macrophage infiltration and increased blood vessel formation. In summary, Mtp promoted mobilization and differentiation of BM-EPCs and protected against apoptosis and autophagy by suppressing the AMPK/mTOR pathway, improving wound healing in vivo. This study revealed that Mtp is a potential therapeutic for endothelial injury-related wounds., (© 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Helminth-derived products have recently been shown to prevent the development of inflammatory diseases in mouse models. However, most identified immunomodulators from helminthes are mixtures or macromolecules with potentially immunogenic side effects. We previously identified an immunomodulatory peptide called SJMHE1 from the HSP60 protein of Schistosoma japonicum. In this study, we assessed the ability of SJMHE1 to affect murine splenocytes and human peripheral blood mononuclear cells (PBMCs) stimulated by toll-like receptor (TLR) ligands in vitro and its treatment effect on mice with collagen-induced arthritis (CIA). We show that SJMHE1 not only modulates the cytokine production of murine macrophage (MΦ) and dendritic cell but also affects cytokine production upon coculturing with allogeneic CD4 + T cell. SJMHE1 potently inhibits the cytokine response to TLR ligands lipopolysaccharide (LPS), CpG oligodeoxynucleotides (CpG) or resiquimod (R848) from mouse splenocytes, and human PBMCs stimulated by LPS. Furthermore, SJMHE1 suppressed clinical signs of CIA in mice and blocked joint erosion progression. This effect was mediated by downregulation of key cytokines involved in the pathogenesis of CIA, such as interferon-γ (IFN-γ), tumour necrosis factor-α (TNF-α), interleukin (IL)-6, IL-17, and IL-22 and up-regulation of the inhibitory cytokine IL-10, Tgf-β1 mRNA, and CD4 + CD25 + Foxp3 + Tregs. This study provides new evidence that the peptide from S. japonicum, which is the 'safe' selective generation of small molecule peptide that has evolved during host-parasite interactions, is of great value in the search for novel anti-inflammatory agents and therapeutic targets for autoimmune diseases., (© 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Major depressive disorder (MDD) is one of the most common psychiatric disorders with a relatively high heritability (35-40%). Though rs1006737 in the CACNA1C gene showed significant association with MDD in a British large-scale candidate association study, most of the replication analyses with relatively small sample size reported negative association. Moreover, this locus has never been identified in previous genome-wide association studies (GWAS) for MDD. Here, we conducted a comprehensive meta-analysis of the association between CACNA1C variants and MDD risk by combining all published data. Genetic data from one European GWAS and five individual follow-up studies, which include up to 12,629 patients of MDD and 28,653 controls, that is, the largest sample size on CACNA1C to date, were collected. Rs1006737 showed significant association with MDD in the fixed-effect model (Z = 2.56, P = 0.011, OR = 1.08, 95%CI = 1.04-1.12) and the association remained after reanalyzing the data according to ethnicity. We additionally analyzed other 25 SNPs, genotyped in only one replication study, across the CACNA1C locus, and found that two SNPs, rs4765905 (P = 0.041, OR = 1.05, 95%CI 1.00-1.09) and rs4765937 (P = 0.025, OR = 1.05, 95%CI 1.01-1.09) showed nominal association with MDD, while rs2239073 (P = 0.002, OR = 1.07, 95%CI 1.02-1.11) exhibited significant association with MDD, which survived from multiple corrections. Our study provides support for positive association between CACNA1C and MDD; however, the current data suggest the necessity of replication analyses in a larger-scale sample. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Objectives: Toxic epidermal necrolysis (TEN) is a potentially life-threatening dermatological disease involving large areas of skin loss with systemic symptoms. This study evaluated the efficacy of air-fluidised bed therapy for TEN patients., Methods: Of 27 people with TEN, 11 used air-fluidised beds (the air-fluidised group) and 16 used standard beds (the control group). Days to complete re-epithelialisation, re-epithelialisation rate, incidence of complications, mortality, pain measured by visual analogue score and the incidence of cutaneous infection were compared in these groups., Results: The mean body surface area of involvement was 77.0 ± 11.8% and baseline mean severity-of-illness score for TEN (SCORTEN) was 2.81 ± 1.08. The re-epithelialisation rate in the air-fluidised group was 100% but was only 56.3% in the control group (P < 0.05). There was a significant difference in the time taken to complete re-epithelialisation between the air-fluidised group (13 days [95% CI: 9.0-17.0]) and the control group (21 days [16.5-25.5], P < 0.05). Furthermore, the incidence of complications was 18% in the air-fluidised group versus 75% in the control group, including fewer cutaneous infections (P < 0.05). There was a significant reduction in pain among the air-fluidised group compared with the control group (P < 0.05). There were no deaths in the air-fluidised group while 19% of the control group died., Conclusion: Air-fluidised beds can reduce the time to complete re-epithelialisation, relieve pain and increase the re-epithelialisation rate of TEN patients, but there was no significant difference between them in mortality rate in our study., (© 2015 The Australasian College of Dermatologists.)

Objective: The umbilical cord provides nutrition and oxygen to the fetus. The aim of this study was to determine the effects of acetylcholine (ACh) on umbilical cords from humans and other mammals, and the mechanisms of ACh-mediated vasoconstriction in the human umbilical cord., Design: Human and animal umbilical cords used in vascular and cellular experiments., Setting: Institute for Fetology, First Hospital of Soochow University, Suzhou, China., Population: A total of 85 pregnant women, 16 Sprague Dawley rats and seven pregnant sheep., Methods: Umbilical cord veins and arteries from humans, rats and sheep, aortas and mesenteric arteries from rats, and mesenteric, carotid and femoral arteries from ovine fetuses were used to compare vascular functions in response to ACh and to determine the mechanisms of ACh-mediated umbilical vasoconstriction. Vascular tension and ion channel currents were measured on isolated vessels and smooth muscle cells from human umbilical cords., Main Outcome Measures: Provision of new evidence to conclude that ACh-stimulated vasoconstriction is common to all umbilical cords, and cellular mechanisms are linked to potassium channels., Results: ACh caused reliable vasoconstriction in umbilical veins/arteries in humans, rats and sheep, but not in any other vessels, including fetal vessels. Atropine inhibited the effects of ACh. The mRNA of ACh-muscarinic receptor subtypes M1 -M5 was expressed in human umbilical vessels. The protein kinase C antagonist GF109203X and the calcium inhibitor nifedipine decreased ACh-induced vasoconstriction in human umbilical vessels. ACh also caused a reduction in whole-cell potassium channel currents and the single-channel current of large-conductance calcium-activated potassium (BKca) channels., Conclusion: Umbilical vessels are significantly different from other vessels in their response to ACh. BKca channels in smooth muscle cells may play important roles in ACh-mediated vasoconstriction in human umbilical cords. This information may be important for fetal medicine and practice with regard to the effect on fetal development of umbilical vascular functions., (© 2014 Royal College of Obstetricians and Gynaecologists.)

Promotion of myofibroblast apoptosis is a potential therapeutic strategy for pulmonary fibrosis. This study investigated the antifibrotic effect of astaxanthin on the promotion of myofibroblast apoptosis based on dynamin-related protein-1 (Drp1)-mediated mitochondrial fission in vivo and in vitro. Results showed that astaxanthin can inhibit lung parenchymal distortion and collagen deposition, as well as promote myofibroblast apoptosis. Astaxanthin demonstrated pro-apoptotic function in myofibroblasts by contributing to mitochondrial fission, thereby leading to apoptosis by increasing the Drp1 expression and enhancing Drp1 translocation into the mitochondria. Two specific siRNAs were used to demonstrate that Drp1 is necessary to promote astaxanthin-induced mitochondrial fission and apoptosis in myofibroblasts. Drp1-associated genes, such as Bcl-2-associated X protein, cytochrome c, tumour suppressor gene p53 and p53-up-regulated modulator of apoptosis, were highly up-regulated in the astaxanthin group compared with those in the sham group. This study revealed that astaxanthin can prevent pulmonary fibrosis by promoting myofibroblast apoptosis through a Drp1-dependent molecular pathway. Furthermore, astaxanthin provides a potential therapeutic value in pulmonary fibrosis treatment., (© 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Apoptosis of type II alveolar epithelial cells (AECs-II) is a key determinant of initiation and progression of lung fibrosis. However, the mechanism of miR-30a participation in the regulation of AECs-II apoptosis is ambiguous. In this study, we investigated whether miR-30a could block AECs-II apoptosis by repressing mitochondrial fission dependent on dynamin-related protein-1 (Drp-1). The levels of miR-30a in vivo and in vitro were determined through quantitative real-time PCR (qRT-PCR). The inhibition of miR-30a in AECs-II apoptosis, mitochondrial fission and its dependence on Drp-1, and Drp-1 expression and translocation were detected using miR-30a mimic, inhibitor-transfection method (gain- and loss-of-function), or Drp-1 siRNA technology. Results showed that miR-30a decreased in lung fibrosis. Gain- and loss-of-function studies revealed that the up-regulation of miR-30a could decrease AECs-II apoptosis, inhibit mitochondrial fission, and reduce Drp-1 expression and translocation. MiR-30a mimic/inhibitor and Drp-1 siRNA co-transfection showed that miR-30a could inhibit the mitochondrial fission dependent on Drp-1. This study demonstrated that miR-30a inhibited AECs-II apoptosis by repressing the mitochondrial fission dependent on Drp-1, and could function as a novel therapeutic target for lung fibrosis., (© 2014 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Oxidative stress is an important molecular mechanism underlying lung fibrosis. The mitochondrion is a major organelle for oxidative stress in cells. Therefore, blocking the mitochondrial signalling pathway may be the best therapeutic manoeuver to ameliorate lung fibrosis. Astaxanthin (AST) is an excellent antioxidant, but no study has addressed the pathway of AST against pulmonary oxidative stress and free radicals by the mitochondrion-mediated signalling pathway. In this study, we investigated the antioxidative effects of AST against H2 O2 - or bleomycin (BLM)-induced mitochondrial dysfunction and reactive oxygen species (ROS) production in alveolar epithelial cells type II (AECs-II) in vivo and in vitro. Our data show that AST blocks H2 O2 - or BLM-induced ROS generation and dose-dependent apoptosis in AECs-II, as characterized by changes in cell and mitochondria morphology, translocation of apoptotic proteins, inhibition of cytochrome c (Cyt c) release, and the activation of caspase-9, caspase-3, Nrf-2 and other cytoprotective genes. These data suggest that AST inhibits apoptosis in AECs-II cells through the ROS-dependent mitochondrial signalling pathway and may be of potential therapeutic value in lung fibrosis treatment., (© 2014 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Objectives/hypothesis: This study aimed to describe the diagnosis and management of congenital dilation of Stensen's duct (CDSD) in seven cases., Study Design: Retrospective study., Methods: We collected data including medical records, radiology, and histopathology findings and follow-up for seven patients (four males) with CDSD. The mean age was 23.9 years (range, 2-72 years)., Results: The clinical features of CDSD were the primary presentation of painless swelling in the cheek without an obvious cause that was unilateral or bilateral and occurred at any age, and a swelling along Stensen's duct. In patients without a history of inflammation, aggressive massage of the swelling could produce abundant intraoral salivary flow. Parotid sialography demonstrated a dilated Stensen's duct with a smooth margin but no obvious obstruction. All seven patients underwent superficial parotidectomy including the intact Stensen's duct. No patient showed recurrent swelling after a follow-up of 6 to 65 months., Conclusions: CDSD is an uncommon congenital disorder of the parotid gland. Management with parotidectomy is effective., (Copyright © 2011 The American Laryngological, Rhinological, and Otological Society, Inc.)

SYK tyrosine kinase has emerged as a master regulator of cellular resistance to oxidative stress (OS) by mediating the activation of the anti-apoptotic nuclear factor kappaB and phosphatidylinositol-3 kinase/AKT pathways after OS exposure. Here, we present unprecedented experimental evidence that polo-like kinase 1 (PLK1) is the upstream regulator of SYK in B-lineage acute lymphoblastic leukaemia (ALL) cells. Selective inhibition of PLK-1 with the leflunomide metabolite analogue alpha-cyano-beta-hydroxy-beta-methyl-N-[4-(trifluoromethoxy) phenyl]-propenamide/LFM-A12 abolished the resistance of B-lineage ALL cells to OS by preventing the activation of the anti-apoptotic SYK signal transduction pathway. Notably, LFM-A12 treatments at non-cytotoxic concentrations resulted in marked augmentation of clonogenic death in resistant human B-lineage ALL cell lines challenged with OS. Further, LFM-A12 augmented OS-induced apoptosis of chemotherapy-resistant primary leukaemic cells from relapsed B-lineage ALL patients in vitro and markedly potentiated the in vivo anti-leukaemic activity of total body irradiation (TBI) against leukaemia-initiating cells in severe combined immunodeficient mouse xenograft models of B-lineage ALL. This study is the first to identify PLK1 as a regulator of SYK tyrosine kinase and a molecular target to overcome SYK-mediated resistance of B-lineage ALL cells to OS.

The hyperthermostable DNA polymerase from a marine Thermococcus archaeon has been crystallized in space group P212121, with unit-cell dimensions a = 94.8, b = 98.2, c = 112.2 A with one molecule per asymmetric unit. Conditions for data collection at 98 K have been identified, and a complete data set was collected to 2.2 A resolution. Strategies employed here may facilitate crystallization of other hyperthermostable proteins. The structure of this enzyme will provide the first structural data on the archaeal and hyperthermostable classes of DNA polymerases. Sequence homology to human polymerase alpha (polymerase B family) may make it a model for studying eukaryotic and viral polymerases and for the development of anti-cancer and anti-viral therapeutics.