Interaction between HTR2A rs3125 and negative life events in suicide attempts among patients with major depressive disorder: a cross-sectional study.

BACKGROUND: Both genetic and environmental factors play crucial roles in the development of major depressive disorder (MDD) and suicide attempts (SA). However, the interaction between both items remains unknown. This study aims to explore the interactions between the genetic variants of the serotonin 2 A receptor (HTR2A) and the nitric oxide synthase 1 (NOS1) and environmental factors in patients who experience MDD and SA. METHODS: A total of 334 patients with MDD and a history of SA (MDD-SA) were recruited alongside 518 patients with MDD with no history of SA (MDD-NSA), and 716 healthy controls (HC). The demographic data and clinical characteristics were collected. Sequenom mass spectrometry was used to detect eight tag-single nucleotide polymorphisms (tagSNPs) in HTR2A (rs1328683, rs17068986, and rs3125) and NOS1 (rs1123425, rs2682826, rs3741476, rs527590, and rs7959232). Generalized multifactor dimensionality reduction (GMDR) was used to analyze the gene-environment interactions. RESULTS: Four tagSNPs (rs17068986, rs3125, rs527590, and rs7959232) exhibited significant differences between the three groups. However, these differences were not significant between the MDD-SA and MDD-NSA groups after Bonferroni correction. A logistic regression analysis revealed that negative life events (OR = 1.495, 95%CI: 1.071-2.087, P = 0.018), self-guilt (OR = 2.263, 95%CI: 1.515-3.379, P < 0.001), and negative cognition (OR = 2.252, 95%CI: 1.264-4.013, P = 0.006) were all independently associated with SA in patients with MDD. Furthermore, GMDR analysis indicated a significant interaction between HTR2A rs3125 and negative life events. Negative life events in conjunction with the HTR2A rs3125 CG + GG genotype were associated with a higher SA risk in patients with MDD when compared to the absence of negative life events in conjunction with the CC genotype (OR = 2.547, 95% CI: 1.264-5.131, P = 0.009). CONCLUSION: Several risk factors and a potential interaction between HTR2A rs3125 and negative life events were identified in patients with SA and MDD. The observed interaction likely modulates the risk of MDD and SA, shedding light on the pathogenesis of SA in patients with MDD.

Multi-average high-acceleration modified volumetric interpolated breath-hold examination (VIBE) for free-breathing multiphase contrast-enhanced liver MRI: a comparative study with breath-hold VIBE.

BACKGROUND: Breath-hold volumetric interpolated breath-hold examination (BH-VIBE) of multiphase contrast-enhanced liver magnetic resonance imaging (MPCE-LMRI) requires good cooperative individuals to comply with multiple breath-holds. PURPOSE: To develop a free-breathing modified VIBE (FB-mVIBE) as a substitute of BH-VIBE in MPCE-LMRI. MATERIAL AND METHODS: We modified VIBE with a high acceleration factor (2 × 2) and four averages to produce the mVIBE scan. A total of 90 individuals (40 men; mean age = 54.6 ± 10.0 years) who had received MPCE-LMRI as part of a voluntary health check-up for oncology survey were enrolled. Each participant was scanned in four phases (pre-contrast, arterial phase, venous phase, and delay phase), and each phase had two sequential scans. To encounter the timing effect of contrast enhancement, three scan orders were designed: BH-VIBE and FB-mVIBE (group A, n = 30); BH-VIBE and FB-VIBE (group B, n = 30); and FB-mVIBE and BH-VIBE (group C, n = 30). The comparisons included the objective measurements and 25 visual-score by two abdominal radiologists independently. RESULTS: Consistency between raters was observed for all three sequences (intraclass correlation coefficient [ICC] = 0.741-0.829). For rater 1, the mean scores of FB-mVIBE (23.67 ± 1.32) were equal to those of BH-VIBE (23.83 ± 1.98) in groups C and B (P = 0.852). The mean scores of FB-mVIBE (22.07 ± 3.02), but significantly higher than those of FB-VIBE (14.7 ± 3.41) in groups A and B (P <0.001). Similar scores were found for rater 2. The objective measurement of FB-mVIBE were equal to or higher than BH-VIBE and markedly superior to FB-VIBE. CONCLUSION: FB-mVIBE is a practical alternative to BH-VIBE for individuals who cannot cooperate with multiple breath-holds for MPCE-LMRI.

Dexamethasone Liposomes Alleviate Osteoarthritis in miR-204/-211-Deficient Mice by Repolarizing Synovial Macrophages to M2 Phenotypes.

We undertook this study to investigate the effects and mechanisms of dexamethasone liposome (Dex-Lips) on alleviating destabilization of the medial meniscus (DMM)-induced osteoarthritis (OA) in miR-204/-211-deficient mice. Dex-Lips was prepared by the thin-film hydration method. The characterization of Dex-Lips was identified by the mean size, zeta potential, drug loading, and encapsulation efficiencies. Experimental OA was established by DMM surgery in miR-204/-211-deficient mice, and then Dex-Lips was treated once a week for 3 months. Von Frey filaments was used to perform the pain test. The inflammation level was evaluated with quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Polarization of macrophages was evaluated by immunofluorescent staining. X-ray, micro-CT scanning, and histological observations were conducted in vivo on DMM mice to describe the OA phenotype. We found that miR-204/-211-deficient mice displayed more severe OA symptoms than WT mice after DMM surgery. Dex-Lips ameliorated DMM-induced OA phenotype and suppressed pain and inflammatory cytokine expressions. Dex-Lips could attenuate pain by regulating PGE2. Dex-Lips treatments reduced the expression of TNF-α, IL-1ß, and IL-6 in DRG. Moreover, Dex-Lips could reduce inflammation in the cartilage and serum. Additionally, Dex-Lips repolarize synovial macrophages to M2 phenotypes in miR-204/-211-deficient mice. In conclusion, Dex-Lips inhibited the inflammatory response and alleviated the pain symptoms of OA by affecting the polarization of macrophages.

Maternal RNA binding protein with multiple splicing 2 (RBPMS2) is involved in mouse blastocyst formation through the bone morphogenetic protein pathway.

RESEARCH QUESTION: Is early embryo development in mice influenced by RNA binding protein with multiple splicing 2 (RBPMS2), a maternal factor that accumulates and is stored in the cytoplasm of mature oocytes? DESIGN: The expression patterns of RBPMS2 in mouse were analysed using quantitative real-time PCR (qRT PCR) and immunofluorescence staining. The effect of knockdown of RBPMS2 on embryo development was evaluated through a microinjection of specific morpholino or small interfering RNA. RNA sequencing was performed for mechanistic analysis. The interaction between RBPMS2 and the bone morphogenetic protein (BMP) pathway was studied using BMP inhibitor and activator. The effect on the localization of E-cadherin was determined by immunofluorescence staining. RESULTS: Maternal protein RBPMS2 is highly expressed in mouse oocytes, and knockdown of RBPMS2 inhibits embryo development from the morula to the blastocyst stage. Mechanistically, RNA sequencing showed that the differentially expressed genes were enriched in the transforming growth factor-ß (TGF-ß) signalling pathway. BMPs are members of the TGF-ß superfamily of growth factors. It was found that the addition of BMP inhibitor to the culture medium led to a morula-stage arrest, similar to that seen in RBPMS2 knockdown embryos. This morula-stage arrest defect caused by RBPMS2 knockdown was partially rescued by BMP activator. Furthermore, the localization of E-cadherin to the membrane was impaired in response to a knockdown of RBPMS2 or inhibition of the BMP pathway. CONCLUSION: This study suggests that RBPMS2 activates the BMP pathway and thus influences the localization of E-cadherin, which is important for early mouse embryo development during blastocyst formation.

Enhancement of bioavailability and bioactivity of diet-derived flavonoids by application of nanotechnology: a review.

Flavonoids, which are a class of polyphenols widely existing in food and medicine, have enormous pharmacological effects. The functional properties of flavonoids are mainly distributed to their anti-oxidative, anticancer, and anti-inflammatoryeffects, etc. However, flavonoids' low bioavailability limits their clinical application, which is closely related to their intestinal absorption and metabolism. In addition, because of the short residence time of oral bioactive molecules in the stomach, low permeability and low solubility in the gastrointestinal tract, flavonoids are easy to be decomposed by the external environment and gastrointestinal tract after digestion. To tackle these obstacles, technological approaches like microencapsulation have been developed and applied for the formulation of flavonoid-enriched food products. In the light of these scientific advances, the objective of this review is to establish the structural requirements of flavonoids for appreciable anticancer, anti-inflammatory, and antioxidant effects, and elucidate a comprehensive mechanism that can explain their activity. Furthermore, the novelty in application of nanotechnology for the safe delivery of flavonoids in food matrices is discussed. After a literature on the flavonoids and their health attributes, the encapsulation methods and the coating materials are presented.

Food matrix-flavonoid interactions and their effect on bioavailability.

Flavonoid compounds exhibit a wide range of health benefits as plant-derived dietary components. Typically, co-consumed with the food matrix,they must be released from the matrix and converted into an absorbable form (bioaccessibility) before reaching the small intestine, where they are eventually absorbed and transferred into the bloodstream (bioavailability) to exert their biological activity. However, a large number of studies have revealed the biological functions of individual flavonoid compounds in different experimental models, ignoring the more complex but common relationships established in the diet. Besides, it has been appreciated that the gut microbiome plays a crucial role in the metabolism of flavonoids and food substrates, thereby having a significant impact on their interactions, but much progress still needs to be made in this area. Therefore, this review intends to comprehensively investigate the interactions between flavonoids and food matrices, including lipids, proteins, carbohydrates and minerals, and their effects on the nutritional properties of food matrices and the bioaccessibility and bioavailability of flavonoid compounds. Furthermore, the health effects of the interaction of flavonoid compounds with the gut microbiome have also been discussed. HIGHLIGHTSFlavonoids are able to bind to nutrients in the food matrix through covalent or non-covalent bonds.Flavonoids affect the digestion and absorption of lipids, proteins, carbohydrates and minerals in the food matrix (bioaccessibility).Lipids, proteins and carbohydrates may favorably affect the bioavailability of flavonoids.Improved intestinal flora may improve flavonoid bioavailability.

Flavonoids and gastrointestinal health: single molecule for multiple roles.

Diet can be considered as one of the pivotal factors in regulating gastrointestinal health, and polyphenols widely distributed in human daily diet. The polyphenols and their metabolites playing a series of beneficial effects in human gastrointestinal tract that can regulate of the gut microbiota, increase intestinal barrier function, repair gastrointestinal mucosa, reduce oxidative stress, inhibit the secretion of inflammatory factors and regulating immune function, and their absorption and biotransformation mainly depend on the activity of intestinal microflora. However, little is known about the two-way interaction between polyphenols and intestinal microbiota. The objective of this review is to highlight the structure optimization and effect of flavonoids on intestinal flora, and discusses the mechanisms of dietary flavonoids regulating intestinal flora. The multiple effects of single molecule of flavonoids, and inter-dependence between the gut microbiota and polyphenol metabolites. Moreover, the protective effects of polyphenols on intestinal barrier function, and effects of interaction between plant polyphenols and macromolecules on gastrointestinal health. This review provided valuable insight that may be useful for better understanding the mechanism of the gastrointestinal health effects of polyphenols, and provide a scientific basis for their application as functional food.

Possible mechanism of flavonoids regulating intestinal flora.Flavonoids optimize the structure and composition of gut microbiota.Polyphenol improve intestinal barrier function.Interaction between polyphenols and macromolecules improves gastrointestinal healthThe two-way interaction between flavonoids and intestinal microflora to improve bioavailability.

Deep learning-based identification of spine growth potential on EOS radiographs.

OBJECTIVES: To develop an automatic computer-based method that can help clinicians in assessing spine growth potential based on EOS radiographs. METHODS: We developed a deep learning-based (DL) algorithm that can mimic the human judgment process to automatically determine spine growth potential and the Risser sign based on full-length spine EOS radiographs. A total of 3383 EOS cases were collected and used for the training and test of the algorithm. Subsequently, the completed DL algorithm underwent clinical validation on an additional 440 cases and was compared to the evaluations of four clinicians. RESULTS: Regarding the Risser sign, the weighted kappa value of our DL algorithm was 0.933, while that of the four clinicians ranged from 0.909 to 0.930. In the assessment of spine growth potential, the kappa value of our DL algorithm was 0.944, while the kappa values of the four clinicians were 0.916, 0.934, 0.911, and 0.920, respectively. Furthermore, our DL algorithm obtained a slightly higher accuracy (0.973) and Youden index (0.952) compared to the best values achieved by the four clinicians. In addition, the speed of our DL algorithm was 15.2 ± 0.3 s/40 cases, much faster than the inference speeds of the clinicians, ranging from 177.2 ± 28.0 s/40 cases to 241.2 ± 64.1 s/40 cases. CONCLUSIONS: Our algorithm demonstrated comparable or even better performance compared to clinicians in assessing spine growth potential. This stable, efficient, and convenient algorithm seems to be a promising approach to assist doctors in clinical practice and deserves further study. CLINICAL RELEVANCE STATEMENT: This method has the ability to quickly ascertain the spine growth potential based on EOS radiographs, and it holds promise to provide assistance to busy doctors in certain clinical scenarios. KEY POINTS: • In the clinic, there is no available computer-based method that can automatically assess spine growth potential. • We developed a deep learning-based method that could automatically ascertain spine growth potential. • Compared with the results of the clinicians, our algorithm got comparable results.

Comparison of Rehabilitation Training at Different Timepoints to Restore Shoulder Function in Patients With Breast Cancer After Lymph Node Dissection: A Randomized Controlled Trial.

OBJECTIVE: To investigate whether advancing the initiation of rehabilitation training compared with the time recommended by the guidelines after breast cancer (BC) surgery is beneficial to the recovery of shoulder function and quality of life. DESIGN: Prospective, observational, single center, randomized controlled trial. SETTING: The study was conducted between September 2018 and December 2019, with a 12-week supervised intervention and 6-week home-exercise period concluding in May 2020. PARTICIPANTS: Two hundred BC patients received axillary lymph node dissection (N=200). INTERVENTIONS: Participants were recruited and randomly allocated into 4 groups (A, B, C, and D). Group A started range of motion (ROM) training at 7 days postoperative and progressive resistance training (PRT) at 4 weeks postoperative; group B started ROM training at 7 days postoperative and PRT at 3 weeks postoperative; group C started ROM training at 3 days postoperative and PRT at 4 weeks postoperative; and group D started ROM training at 3 days postoperative and PRT at 3 weeks postoperative. MAIN OUTCOME MEASURES: The primary outcome measure was Constant-Murley Score. Secondary outcome measures included ROM, shoulder strength, grip, European Organization Research and Treatment of Cancer breast cancer-specific quality-of-life questionnaire module (EORTC QLQ-BR23), and SF-36. Incidence of adverse reactions (drainage and pain) and complications (ecchymosis, subcutaneous hematoma, lymphedema) were also assessed. RESULTS: Participants who started ROM training at 3 days postoperative obtained more benefits in mobility, shoulder function, and EORTC QLQ-BR23 score, while patients who started PRT at 3 weeks postoperative saw improvements in shoulder strength and SF-36. Incidence of adverse reactions and complications were low in all 4 groups, with no significant differences among the 4 groups. CONCLUSIONS: Advancing ROM training initiation to 3 days postoperative or PRT to 3 weeks postoperative can better restore shoulder function after BC surgery and lead to faster quality of life improvement.

Absorption, metabolism and bioavailability of flavonoids: a review.

Flavonoids are stored in various plants and widely presented in different kinds of food in variable amounts. Plant roots, stems, leaves, flowers and fruits are known to have high amounts of flavonoids. However, flavonoid aglycones are found less frequently in natural products, as it requires bioconversion through bacteria, which provide ß-glucosidase to convert them. Recently, flavonoids and its metabolites were applied in the prevention and treatment of various diseases such as cancers, obesity, diabetes, hypertension, hyperlipidemia, cardiovascular diseases, neurological disorders and osteoporosis in numerous studies. This review focused on absorption, activity, metabolism, and bioavailability of flavonoids. Also authors organized and collected newly-found reports of flavonoids and their absorption barriers of flavonoids in the gastrointestinal tract, providing the latest findings and evidence from the past decade. Particularly, nanoparticles delivery systems are emphasized regarding fabrication methods and their potential benefits on flavonoids. Moreover, the potential challenges of nanoparticles as delivery system for flavonoids in the gastrointestinal tract are also discussed.

An innovative extraction strategy for herbal medicine by adopting p-sulphonatocalix[6]/[8]arenes.

INTRODUCTION: Alkaloids exist in various herbal medicine widely and exhibit diverse biological and pharmacological activities. p-Sulphonatocalix[6]arenes (SC6A) and p-sulphonatocalix[8]arenes (SC8A) are water-soluble supramolecular macrocycles and are applied to the extraction of alkaloids from herbal products. OBJECTIVE: In this study, an innovative method of SC6A/SC8A assisted extraction of the alkaloids from herbs was established. METHODS: SC6A and SC8A were designed to extract 27 alkaloids from seven herbal medicines. Based on the significant solubilisation and extraction effect, Stephaniae Tetrandrae Radix (Fangji, FJ) was selected to obtain the optimal extraction process by adopting single factor test and orthogonal experiment. Then, the alkaloids and SC6A/SC8A were separated by one-step alkalisation and SCnA were reused. The host-guest complexes between alkaloids and SCnA were determined by competitive fluorescence titration, differential scanning calorimetry (DSC), Fourier-transform infrared (FTIR) and proton nuclear magnetic resonance (1 H-NMR) analysis. RESULTS: The optimum condition for SC6A assisted extraction was 5:1:80 (g/g/mL) for herbs/SC6A/solution ratio, 355-250 µm particle size and ultrasonicate 0.5 h, whilst 10:1:40 (g/g/mL) for herbs/SC8A/solution ratio, 355-250 µm particle size and ultrasonicate 0.5 h for SC8A assisted extraction. The total yield of alkaloids (fangchinoline and tetrandrine) from FJ was increased by 4.87 times and 5.97 times with SC6A and SC8A. Moreover, a good reusability of SC6A/SC8A was achieved by alkalisation dissociation. Host-guest complexes were determined by competitive fluorescence titration at a molar ratio of 1:1 between most alkaloids (25/27, except evodiamine and rutaecarpine) and SC6A/SC8A. The complex structure was proved by DSC, FTIR and 1 H-NMR analysis. CONCLUSION: The study provided an effective eco-friendly and energy-saving extraction method of alkaloids from herbal medicine.

Structural Reorganization of Imidazolium Ionic Liquids Induced by Pressure-Enhanced Ionic Liquid-Polyethylene Oxide Interactions.

Mixtures of polyethylene oxide (PEO, M.W.~900,000) and imidazolium ionic liquids (ILs) are studied using high-pressure Fourier-transform infrared spectroscopy. At ambient pressure, the spectral features in the C-H stretching region reveal that PEO can disturb the local structures of the imidazolium rings of [BMIM]+ and [HMIM]+. The pressure-induced phase transition of pure 1-butyl-3-methylimidazolium bromide ([BMIM]Br) is observed at a pressure of 0.4 GPa. Pressure-enhanced [BMIM]Br-PEO interactions may assist PEO in dividing [BMIM]Br clusters to hinder the aggregation of [BMIM]Br under high pressures. The C-H absorptions of pure 1-hexyl-3-methylimidazolium bromide [HMIM]Br do not show band narrowing under high pressures, as observed for pure [BMIM]Br. The band narrowing of C-H peaks is observed at 1.5 GPa for the [HMIM]Br-PEO mixture containing 80 wt% of [HMIM]Br. The presence of PEO may reorganize [HMIM]Br clusters into a semi-crystalline network under high pressures. The differences in aggregation states for ambient-pressure phase and high-pressure phase may suggest the potential of [HMIM]Br-PEO (M.W.~900,000) for serving as optical or electronic switches.

Proteins associated with quality deterioration of prepared chicken breast based on differential proteomics during refrigerated storage.

BACKGROUND: Prepared chicken breast deterioration is a complex biochemical process, of which protein change is one of the main features. The present research focuses on the analysis of proteins related to the deterioration in quality of prepared chicken breast through differential proteomics analysis. RESULTS: The physicochemical indexes of prepared chicken breast showed that quality gradually decreased at the second week of refrigerated storage, while the deterioration of chicken breast meat was obvious at the third week. Three key time points of quality change were determined to be at 0th, 2th and 5th week, respectively. In addition, 39 differential proteins were successfully identified using two-dimensional gel electrophoresis and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Most of the identified proteins showed significant differences in expression at the three key points of storage, of which actin, myosin, α-1,4-glucan phosphorylase, phosphoglucomutase 1, heat shock protein ß-1, tubulin ß-7 chain and skeletal muscle type tropomodulin (fragment) were closely related to the quality deterioration of prepared chicken breast, and thus potential indicator proteins to evaluate the quality of chicken breast. CONCLUSION: The current study indicated that the physicochemical quality of prepared breast notably changed during refrigerated storage. Three key time points of quality change in the storage process of prepared chicken breast were determined. Furthermore, differential proteomics identified the key proteins related to freshness, which provides a theoretical basis for exploring the mechanism of chicken breast deterioration. © 2020 Society of Chemical Industry.

Marinicella rhabdoformis sp. nov., isolated from coastal sediment.

A Gram-stain-negative, rod-shaped, facultative anaerobic bacterium, designated strain 3539T, was isolated from coastal sediment of Weihai, PR China. Optimal growth occurred at 28 °C, pH 7.5-8.0 and in the presence of 3.0 % (w/v) NaCl. Results of phylogenetic analysis based on 16S rRNA gene sequences revealed that strain 3539T formed a robust clade with members of the genus Marinicella and was closely related to Marinicella litoralis JCM 16154T, Marinicella sediminis F2T and Marinicella pacifica sw153T with 97.7, 96.2 and 95.4 % sequence similarity, respectively. The average amino acid identity, percentage of conserved proteins, average nucleotide identity and digital DNA-DNA hybridization values between strain 3539T and M. litoralis JCM 16154T were 64.9, 68.3, 72.8 and 18.9 %, respectively. The genomic DNA G+C content of strain 3539T was 42.0 mol%. The dominant respiratory quinone was ubiquinone-8, and the major fatty acids were iso-C15 : 0 and summed feature 3 (C16 : 1 ω7c/C16 : 1 ω6c). The polar lipids of strain 3539T consisted of phosphatidyldimethylethanolamine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylcholine, one unidentified aminophospholipid, one unidentified lipid and three unidentified phospholipids. Based on the combination of phylogenetic, phenotypic and chemotaxonomic data, strain 3539T is considered to represent a novel species within the genus Marinicella in he family Alcanivoracaceae, for which the name Marinicella rhabdoformis sp. nov. is proposed. The type strain of the new species is 3539T (=KCTC 72414T=MCCC 1H00388T).

A Comparative Proteome Profile of Female Mouse Gonads Suggests a Tight Link between the Electron Transport Chain and Meiosis Initiation.

Generation of haploid gametes by meiosis is a unique property of germ cells and is critical for sexual reproduction. Leaving mitosis and entering meiosis is a key step in germ cell development. Several inducers or intrinsic genes are known to be important for meiotic initiation, but the regulation of meiotic initiation, especially at the protein level, is still not well understood. We constructed a comparative proteome profile of female mouse fetal gonads at specific time points (11.5, 12.5, and 13.5 days post coitum), spanning a critical window for initiation of meiosis in female germ cells. We identified 3666 proteins, of which 473 were differentially expressed. Further bioinformatics analysis showed that these differentially expressed proteins were enriched in the mitochondria, especially in the electron transport chain and, notably, 9 proteins in electron transport chain Complex I were differentially expressed. We disrupted the mitochondrial electron transport chain function by adding the complex I inhibitor, rotenone to 11.5 days post coitum female gonads cultured in vitro. This treatment resulted in a decreased proportion of meiotic germ cells, as assessed by staining for histone γH2AX. Rotenone treatment also caused decreased ATP levels, increased reactive oxygen species levels and failure of the germ cells to undergo premeiotic DNA replication. These effects were partially rescued by adding Coenzyme Q10. Taken together, our results suggested that a functional electron transport chain is important for meiosis initiation. Our characterization of the quantitative proteome of female gonads provides an inventory of proteins, useful for understanding the mechanisms of meiosis initiation and female fertility.

[Mutations in aminoacyl-tRNA synthetase genes: an analysis of 10 cases].

OBJECTIVE: To study the clinical features of the diseases associated with aminoacyl-tRNA synthetases (ARS) deficiency. METHODS: A retrospective analysis was performed of the clinical and gene mutation data of 10 children who were diagnosed with ARS gene mutations, based on next-generation sequencing from January 2016 to October 2019. RESULTS: The age of onset ranged from 0 to 9 years among the 10 children. Convulsion was the most common initial symptom (7 children). Clinical manifestations included ataxia and normal or mildly retarded intellectual development (with or without epilepsy; n=4) and onset of epilepsy in childhood with developmental regression later (n=2). Some children experienced disease onset in the neonatal period and had severe epileptic encephalopathy, with myoclonus, generalized tonic-clonic seizure, and convulsive seizure (n=4); 3 had severe delayed development, 2 had feeding difficulty, and 1 had hearing impairment. Mutations were found in five genes: 3 had novel mutations in the AARS2 gene (c.331G>C, c.2682+5G>A, c.2164C>T, and c.761G>A), 2 had known mutations in the DARS2 gene (c.228-16C>A and c.536G>A), 1 had novel mutations in the CARS2 gene (c.1036C>T and c.323T>G), 1 had novel mutations in the RARS2 gene (c.1210A>G and c.622C>T), and 3 had novel mutations in the AARS gene (c.1901T>A, c.229C>T, c.244C>T, c.961G>C, c.2248C>T, and Chr16:70298860-70316687del). CONCLUSIONS: A high heterogeneity is observed in the clinical phenotypes of the diseases associated with the ARS deficiency. A total of 14 novel mutations in 5 genes are reported in this study, which enriches the clinical phenotypes and genotypes of the diseases associated with ARS deficiency.

Neurovascular decoupling in type 2 diabetes mellitus without mild cognitive impairment: Potential biomarker for early cognitive impairment.

Type 2 diabetes mellitus (T2DM) is a significant risk factor for mild cognitive impairment (MCI) and the acceleration of MCI to dementia. The high glucose level induce disturbance of neurovascular (NV) coupling is suggested to be one potential mechanism, however, the neuroimaging evidence is still lacking. To assess the NV decoupling pattern in early diabetic status, 33 T2DM without MCI patients and 33 healthy control subjects were prospectively enrolled. Then, they underwent resting state functional MRI and arterial spin labeling imaging to explore the hub-based networks and to estimate the coupling of voxel-wise cerebral blood flow (CBF)-degree centrality (DC), CBF-mean amplitude of low-frequency fluctuation (mALFF) and CBF- mean regional homogeneity (mReHo). We further evaluated the relationship between NV coupling pattern and cognitive performance (false discovery rate corrected). T2DM without MCI patients displayed significant decrease in the absolute CBF-mALFF, CBF-mReHo coupling of CBFnetwork and in the CBF-DC coupling of DCnetwork. Besides, networks which involved CBF and DC hubs mainly located in the default mode network (DMN). Furthermore, less severe disease and better cognitive performance in T2DM patients were significantly correlated with higher coupling of CBF-DC, CBF-mALFF or CBF-mReHo, especially for the cognitive dimensions of general function and executive function. Thus, coupling of CBF-DC, CBF-mALFF and CBF-mReHo may serve as promising indicators to reflect NV coupling state and to explain the T2DM related early cognitive impairment.

Sting is a critical regulator of spinal cord injury by regulating microglial inflammation via interacting with TBK1 in mice.

Spinal cord injury (SCI) is a devastating neurological condition that results in progressive tissue loss, secondary to vascular dysfunction and inflammation. Lack of effective pharmacotherapies for SCI is mainly attributable to an incomplete understanding of its pathogenesis. Stimulator of interferon gene (Sting), also known as Transmembrane protein 173 (TMEM173), activates the type I interferon-regulated innate immune response, playing crucial role in modulating inflammation. However, the mechanism underlying Sting activation in SCI is still unclear. Here, we reported that Sting functioned as a positive regulator of SCI. Sting expression was increased in the injured spinal cord samples of SCI mice, along with significantly up-regulated levels of pro-inflammatory cytokines including tumor necrosis factor α (TNF-α), interleukin (IL)-1ß and IL-6. Suppressing Sting expression in lipopolysaccharide-incubated mouse microglia markedly reduced the activation of nuclear factor-κB (NF-κB) and mitogen activated protein kinases (MAPKs) signaling pathways, as illustrated by the decreased phosphorylation of IKKß, IκBα, NF-κB/p65, p38, ERK1/2 and JNK. Furthermore, LPS-stimulated release of pro-inflammatory cytokines in microglial cells was also reversed by Sting knockdown. In contrast, LPS-induced inflammation was further accelerated in microglial cells with Sting over-expression through potentiating NF-κB and MAPKs signaling. Mechanistically, Sting directly interacted with the TANK-binding kinase 1 (TBK1), thus promoting its phosphorylation and the activation of down-streaming NF-κB and MAPKs signaling pathways. Notably, the effects of Sting on SCI progression were verified in mice. Consistently, Sting knockout alleviated inflammatory response and facilitated recovery after SPI in mice through blocking TBK1 activation and subsequent NF-κB and MAPKs phosphorylation. In summary, our findings may provide a novel strategy for prevention and treatment of SCI by targeting Sting.

Polyphenols and bioavailability: an update.

Based on many cell culture, animal and human studies, it is well known that the most challenge issue for developing polyphenolics as chemoprevention or anti-diabtetic agents is the low oral bioavailability, which may be the major reason relating to its ambiguous therapeutic effects and large inter-individual variations in clinical trials. This review intends to highlight the unscientific evaluation on the basis of the published data regarding in vitro bioactivity of polyphenols, which may sometimes mislead the researchers and to conclude that: first, bio-accessibilities values obtained in the studies for polyphenols should be highly reconsidered in accordance with the abundant newly identified circulating and excreted metabolites, with a particular attention to colonic metabolic products which are obviously contributing much more than expected to their absorptions; second, it is phenolic metabolites, which are formed in the small intestine and hepatic cells,low molecular weight catabolic products of the colonic microflora to travel around the human body in the circulatory system or reach body tissues to elicit bioactive effects. It is concluded that better performed in vivo intervention and in vitro mechanistic studies are needed to fully understand how these molecules interact with human physiological and pathological processes.

Functional characterization of 21 CYP3A4 variants on amiodarone metabolism in vitro.

1. Cytochrome P450 3A4 (CYP3A4) is an important member of the cytochrome P450 enzyme superfamily, with 33 allelic variants reported previously. Genetic polymorphisms of CYP3A4 can produce a significant effect on the efficacy and safety of some drugs, so the purpose of this study was to clarify the catalytic characteristics of 22 CYP3A4 allelic isoforms, including 6 novel variants in Han Chinese population, on the oxidative metabolism of amiodarone in vitro. 2. Wild-type CYP3A4*1 and other variants expressed by insect cells system were incubated respectively with 10-500 µM substrate for 40 min at 37 °C and terminated at -80 °C immediately. Then these samples were treated as required and detected with ultra-performance liquid chromatography-tandem mass spectrometry used to analyze its major metabolite desethylamiodarone. 3. Among the 21 CYP3A4 variants, compared with the wild-type, the intrinsic clearance values (Vmax/Km) of two variants were apparently decreased (11.07 and 2.67% relative clearance) while twelve variants revealed markedly increased values (155.20∼435.96%), and the remaining of seven variants exhibited no significant changes in enzyme activity. 4. This is the first time report describing all these infrequent alleles for amiodarone metabolism, which can provide fundamental data for further clinical studies on CYP3A4 alleles.