Restoration of HMGCS2-mediated ketogenesis alleviates tacrolimus-induced hepatic lipid metabolism disorder.

Tacrolimus, one of the macrolide calcineurin inhibitors, is the most frequently used immunosuppressant after transplantation. Long-term administration of tacrolimus leads to dyslipidemia and affects liver lipid metabolism. In this study, we investigated the mode of action and underlying mechanisms of this adverse reaction. Mice were administered tacrolimus (2.5 mg·kg-1·d-1, i.g.) for 10 weeks, then euthanized; the blood samples and liver tissues were collected for analyses. We showed that tacrolimus administration induced significant dyslipidemia and lipid deposition in mouse liver. Dyslipidemia was also observed in heart or kidney transplantation patients treated with tacrolimus. We demonstrated that tacrolimus did not directly induce de novo synthesis of fatty acids, but markedly decreased fatty acid oxidation (FAO) in AML12 cells. Furthermore, we showed that tacrolimus dramatically decreased the expression of HMGCS2, the rate-limiting enzyme of ketogenesis, with decreased ketogenesis in AML12 cells, which was responsible for lipid deposition in normal hepatocytes. Moreover, we revealed that tacrolimus inhibited forkhead box protein O1 (FoxO1) nuclear translocation by promoting FKBP51-FoxO1 complex formation, thus reducing FoxO1 binding to the HMGCS2 promoter and its transcription ability in AML12 cells. The loss of HMGCS2 induced by tacrolimus caused decreased ketogenesis and increased acetyl-CoA accumulation, which promoted mitochondrial protein acetylation, thereby resulting in FAO function inhibition. Liver-specific HMGCS2 overexpression via tail intravenous injection of AAV8-TBG-HMGCS2 construct reversed tacrolimus-induced mitochondrial protein acetylation and FAO inhibition, thus removing the lipid deposition in hepatocytes. Collectively, this study demonstrates a novel mechanism of liver lipid deposition and hyperlipidemia induced by long-term administration of tacrolimus, resulted from the loss of HMGCS2-mediated ketogenesis and subsequent FAO inhibition, providing an alternative target for reversing tacrolimus-induced adverse reaction.

Epidemiology and outcomes of multidrug-resistant bacterial infection in non-cystic fibrosis bronchiectasis.

PURPOSE: Multidrug-resistant (MDR) bacteria impose a considerable health-care burden and are associated with bronchiectasis exacerbation. This study investigated the clinical outcomes of adult patients with bronchiectasis following MDR bacterial infection. METHODS: From the Chang Gung Research Database, we identified patients with bronchiectasis and MDR bacterial infection from 2008 to 2017. The control group comprised patients with bronchiectasis who did not have MDR bacterial infection and were propensity-score matched at a 1:2 ratio. The main outcomes were in-hospital and 3-year mortality. RESULTS: In total, 554 patients with both bronchiectasis and MDR bacterial infection were identified. The types of MDR bacteria that most commonly affected the patients were MDR- Acinetobacter baumannii (38.6%) and methicillin-resistant Staphylococcus aureus (18.4%), Extended-spectrum-beta-lactamases (ESBL)- Klebsiella pneumoniae (17.8%), MDR-Pseudomonas (14.8%), and ESBL-E. coli (7.5%). Compared with the control group, the MDR group exhibited lower body mass index scores, higher rate of chronic bacterial colonization, a higher rate of previous exacerbations, and an increased use of antibiotics. Furthermore, the MDR group exhibited a higher rate of respiratory failure during hospitalization (MDR vs. control, 41.3% vs. 12.4%; p < 0.001). The MDR and control groups exhibited in-hospital mortality rates of 26.7% and 7.6%, respectively (p < 0.001); 3-year respiratory failure rates of 33.5% and 13.5%, respectively (p < 0.001); and 3-year mortality rates of 73.3% and 41.5%, respectively (p < 0.001). After adjustments were made for confounding factors, the infection with MDR and MDR bacteria species were determined to be independent risk factors affecting in-hospital and 3-year mortality. CONCLUSIONS: MDR bacteria were discovered in patients with more severe bronchiectasis and were independently associated with an increased risk of in-hospital and 3-year mortality. Given our findings, we recommend that clinicians identify patients at risk of MDR bacterial infection and follow the principle of antimicrobial stewardship to prevent the emergence of resistant bacteria among patients with bronchiectasis.

Age differences in the functional organization of the prefrontal cortex: analyses of competing hypotheses.

We employed a mixed design task for block and event-related functional magnetic resonance imaging with manipulations of levels of abstraction and duration in task-relevant cues and probes. Age-related differences between younger and older adults in task-related functional brain activity patterns of the prefrontal cortex (PFC) were reported. The results showed that (1) the low episodic condition evoked more activity in the more anterior PFC than the high episodic control condition for both age groups; (2) the low abstraction condition evoked more activity in the more anterior PFC than the high abstraction condition for both age groups; and (3) the signal change did not vary as a function of activity dynamics (transient and sustained responses) and maintenance duration (single-trial and multiple-trial). The findings showed that baseline conditions evoked more activity in the more anterior PFC for the older group than the younger group across most task contrasts and conditions, where these additional activities in the brain regions overlapped within the default mode network (DMN). We tentatively concluded that deficiency in the anterior DMN deactivation during externally driven tasks might be attributed to less efficiency in modulating local connectivity propagate to surrounding tissue, which may paradoxically increase brain activity.

Targeting autophagy with SAR405 alleviates doxorubicin-induced cardiotoxicity.

Anthracycline antitumor agents, such as doxorubicin (DOX), are effective in the treatment of solid tumors and hematological malignancies, but anthracycline-induced cardiotoxicity (AIC) limits their application as chemotherapeutics. Dexrazoxane (DEX) has been adopted to prevent AIC. Using a chronic AIC mouse model, we demonstrated that DEX is insufficient to reverse DOX-induced cardiotoxicity. Although therapies targeting autophagy have been explored to prevent AIC, but whether novel autophagy inhibitors could alleviate or prevent AIC in clinically relevant models needs further investigation. Here, we show that genetic ablation of Atg7, a key regulator in the early phase of autophagy, protected mice against AIC. We further demonstrated that SAR405, a novel autophagy inhibitor, attenuated DOX-induced cytotoxicity. Intriguingly, the combination of DEX and SAR405 protected cells against DOX-induced cardiotoxicity in vivo. Using the cardiomyocyte cell lines AC16 and H9c2, we determined that autophagy was initiated during AIC. Our results suggest that inhibition of autophagy at its early phase with SAR405 combined with DEX represents an effective therapeutic strategy to prevent AIC.

Multimodal magnetic resonance imaging in the diagnosis of cervical cancer and its correlation with the differentiation process of cervical cancer.

PURPOSE: This study seeks to evaluate the value of MRI (Magnetic resonance imaging) diffusion weighted images (DWI), diffusion kurtosis imaging (DKI) and intravoxel incoherent motion (IVIM) in the diagnosis of cervical carcinoma. METHODS: Seventy-nine cases of cervical cancer (CC group) (39 cases of squamous carcinoma (SCC group) and 40 cases of adenocarcinoma (ACC group)) and 30 cases of healthy controls (HC group) were included in this study. All the subjects were informed of the purpose of this study. The study was approved by the Ethics Committee of Beihua University Hospital, Jinlin, China. In this study, images were acquired based on a 3T MR scanner (Ingenia; Philips, Best, the Netherlands) and measured the imaging parameters by DWI, IVIM and DKI techniques. The parameters were obtained by Philips post-processing workstation, DKE and IVIM. These ROIs (region of interest) were manually drawn on each parameter mapping image by MRI physicians. Finally, SPSS 23.0 statistical software was used for data analysis. RESULTS: The ADC (apparent diffusion coefficient) value of M group was lower than that of N group, and the difference was statistically significant (P < 0.05). The D (true diffusion coefficient) value, D*(pseudo diffusion coefficient) value, f (perfusion fraction) value, MD (mean diffusivity) value, and ADC value in the SCC group were lower than those in the ACC group with statistically significant differences (P < 0.05). The MK (mean kurtosis) value was higher than that of the ACC group, and the difference was statistically significant (P < 0.05). Compared with the HC group, the ADC values, D values, MD values of group CC group were lower, and the D* values, f values, MK values were higher; all the parameters were statistically significant (P < 0.05). The higher the differentiation degree of cervical cancer, the higher ADC values, D values, MD values, and the smaller D* values, f values, MK values. The difference of ADC values, D values and MK values was statistically significant (P < 0.05). MK value had the best diagnostic efficiency in the differential diagnosis of cervical cancer with low and medium differentiation, high and low differentiation (P < 0.05). There was no significant difference in the f value between high and low differentiation cervical cancer (P > 0.05). There was no significant difference in the MD value between low and high differentiation cervical cancer (P > 0.05). The strongest correlation between MK values (r = 0.796) and the degree of pathological differentiation of cervical cancer is positively correlated. The D values, MD values, and ADC values are negatively correlated with the degree of pathological differentiation of cervical cancer. CONCLUSION: The ADC value of DWI parameters has important diagnostic value for different menstrual states of cervical cancer. The parameter values of DWI, IVIM, and DKI can be used to differentiate cervical cancer from normal cervical tissue, and thus have important diagnostic value for differentiating pathological types of cervical cancer. This means that these parameter values may have great significance in the differential diagnosis of cervical cancer with different degrees of pathological differentiation. The pathological differentiation degree of cervical cancer is significantly positively correlated with the MK value in the parameter values of DWI, IVIM, and DKI, while negatively correlated with the D value, MD value, and ADC value.

Associations between posttraumatic stress symptoms and abuse experiences in child and adolescent girls from a Central African country.

Posttraumatic stress disorder (PTSD) is frequently reported among survivors of abuse. However, there is a paucity of research examining the association between PTSD and abuse, including polyvictimization, in nonconflict areas of the Democratic Republic of Congo (DRC). We aimed to investigate the prevalence and correlates of PTSD among girls in nonconflict zones who experienced at least one type of abuse. Participants in this cross-sectional study were 3,011 middle-school girls, aged 11-18 years, who attended randomly selected schools and completed questionnaires. The probable PTSD prevalence was 67.5%. The rate of probable PTSD increased with the number of experienced abuse types over a 12-month period. The findings demonstrated associations between probable PTSD and exposure to five (86.9%), four (63.9%), and three types of abuse (60.1%). The strongest association was observed between probable PTSD and experiencing five types of abuse, OR = 26.806, 95% CI [19.303, 37.225]; associations were also found between PTSD and abuse with a weapon, OR = 4.341, 95% CI [3.519, 5.354]; rape with penetration, OR = 4.728, 95% CI [3.447, 6.484]; and experiencing three, OR = 6.625, 95% CI [4.325, 10.148], or four types of abuse, OR = 7.114, 95% CI [5.025,10.070]. The findings of this study underscore the importance of the need for psychological and physical health care for girls who have been exposed to abuse, regardless of the number of abuse experiences or abuse types she has experienced.

Mesorhizobium xinjiangense sp. nov., isolated from rhizosphere soil of Alhagi sparsifolia.

A beige-pigmented, Gram-strain-negative, aerobic, rod-shaped, non-flagellated and non-gliding bacterium, designated strain lm94T, was isolated from rhizosphere soil of Alhagi sparsifolia obtained from Alar city, located in Xinjiang province, China. Growth occurred at 20-45 °C (optimum, 37 °C), in the presence of 0-6% (w/v) NaCl (optimum, 0-1%) and at pH 6.0-9.5 (optimum, pH 7.0-7.5). Phylogenetic analysis based on 16S rRNA gene sequence showed that strain lm94T belonged to the genus Mesorhizobium, with highest sequence similarity to Mesorhizobium wenxiniae WYCCWR 10195T (96.6%). Genome sequencing revealed a genome size of 5 256 375 bp and a G + C content of 63.6 mol%. The average nucleotide identity value and the digital DNA-DNA hybridization value between strain lm94T and M. wenxiniae LMG 30254T were 75.0% and 20.0%, respectively. The major respiratory quinone was Q-10. The major fatty acids were C19:0 cyclo ω8c and Summed Feature 8 (C18:1 ω6c and/or C18:1 ω7c) and its polar lipids consisted of phosphatidylethanolamine (PE), phosphatidylglycerol (PG), unidentified phospholipid (PL), phosphatidylcholine (PC), diphosphatidylglycerol (DPG), unidentified aminolipid (AL), unknown glycolipid (GL), unidentified aminophospholipid (APL2) and unidentified polar lipid (L1 and L2). On the basis of these data, strain lm94T is considered to represent a novel species of the genus Mesorhizobium, for which the name Mesorhizobium xinjiangense sp. nov. is proposed. The type strain is lm94T (=KCTC 72863T=CCTCC AB2019377T).

Cardiorespiratory coupling is associated with exercise capacity in patients with chronic obstructive pulmonary disease.

BACKGROUND: The interaction between the pulmonary function and cardiovascular mechanics is a crucial issue, particularly when treating patients with chronic obstructive pulmonary disease (COPD). Synchrogram index is a new parameter that can quantify this interaction and has the potential to apply in COPD patients. Our objective in this study was to characterize cardiorespiratory interactions in terms of cardiorespiratory coupling (CRC) using the synchrogram index of the heart rate and respiratory flow signals in patients with chronic obstructive pulmonary disease. METHODS: This is a cross-sectional and preliminary data from a prospective study, which examines 55 COPD patients. K-means clustering analysis was applied to cluster COPD patients based on the synchrogram index. Linear regression and multivariable regression analysis were used to determine the correlation between the synchrogram index and the exercise capacity assessed by a six-minute walking test (6MWT). RESULTS: The 55 COPD patients were separated into a synchronized group (median 0.89 (0.64-0.97), n = 43) and a desynchronized group (median 0.23 (0.02-0.51), n = 12) based on K-means clustering analysis. Synchrogram index was correlated significantly with six minutes walking distance (r = 0.42, p = 0.001) and distance saturation product (r = 0.41, p = 0.001) assessed by 6MWT, and still was an independent variable by multivariable regression analysis. CONCLUSION: This is the first result studying the heart-lung interaction in terms of cardiorespiratory coupling in COPD patients by the synchrogram index, and COPD patients are clustered into synchronized and desynchronized groups. Cardiorespiratory coupling is associated with exercise capacity in patients with COPD.

Prognostic Factors in Lung Adenocarcinoma with Bone Metastasis Treated with EGFR-TKIs.

Background and Objectives: Patients who have advanced lung cancer and bone metastasis (BM) often suffer from skeletal-related events (SREs) that lead to poor quality of life and poor prognosis. Our study aimed to investigate the prognostic factors in patients with BM from epidermal growth factor receptor (EGFR) mutation-positive lung adenocarcinoma. Materials and Methods: This retrospective study included 77 lung adenocarcinoma patients with synchronous BM. These patients had first-line EGFR tyrosine kinase inhibitors (EGFR-TKIs) between January 2017 and December 2019. Among them, 42 patients were treated with 120 mg of subcutaneous denosumab monthly. We investigated their baseline characteristics, cancer management, SREs, progression-free survival (PFS), and overall survival (OS). Results: The PFS in the patients treated with or without denosumab were 10.1 vs. 12.5 months (p = 0.971). The median OS was 26.9 vs. 29.5 months (p = 0.967) in no denosumab and denosumab groups, respectively. Univariate analyses showed benefit of afatinib in PFS and good performance status in OS. Conclusion: Those patients that took afatinib as first-line EGFR-TKIs had significantly longer PFS than those treated with other TKIs. Denosumab had no prognostic effect on PFS or OS.

Chronic Obstructive Pulmonary Disease as a Phenotype of Bronchiectasis for Long-Term Clinical Presentation and Treatment.

Background and Objectives: Bronchiectasis and chronic obstructive pulmonary disease (COPD) often coexist, although the causality is not currently clear. Currently, the clinical influence of COPD on patients with major bronchiectasis over time has not yet been investigated. Material and Methods: This retrospective study recruited consecutive patients with bronchiectasis from outpatient clinic between January 2006 and December 2007. Under the setting of quantification with HRCT, patients who should undergo multiple pulmonary function and exercise tests with regularclinic follow-up were included. The final analysis consisted of 66 eligible patients who were evaluated for clinical status, treatment, and sputum culture from up to 10-year electronic medical records. Results: Of these 66 patients, 45 (68%) had bronchiectasis without COPD and 21 (32%) had COPD. Patients with COPD group had a higher bronchiectasis extent score (32.21 ± 13.09 points vs. 21.89 ± 10.08 points, p = 0.001). Sputum production was reported more frequently by patients with COPD; however, no significant difference was observed after 3 years of follow-up (82.4% vs. 81.6%, p = 0.945). Bronchiectasis extent score correlated with positive sputum culture with Pseudomonas without a synergistic effect from COPD (odds ratio: 1.06, confidence interval: 1.00-1.12, p = 0.031). Regardless of COPD, after 10 years, the proportion of patients using inhaled corticosteroids and/or long-acting ß2-agonist between the two groups was not significantly different. Conclusion: COPD aggravated bronchiectasis extension, which was correlated with chronic Pseudomonas aeruginosa colonisation. Moreover, COPD would affect the medium-term (in 3-5 years) bronchiectasis treatment. Therefore, the COPD phenotype of bronchiectasis could be a clinical predictor of the course of treatment.

Knowledge, attitudes, and practices towards COVID-19 among primary school students in Hubei Province, China.

This study was aimed to investigate the knowledge, attitudes, and practices (KAP) towards coronavirus disease 2019 (COVID-19) among school-aged children in the Hubei province when children were being confined to their homes. The questionnaire included questions of KAP about COVID-19, depressive and anxiety symptoms scales. Multivariable generalized linear regressions models were applied to estimate the unstandardized regression coefficients (ß) of KAP. The awareness rates about COVID-19 were 70.1%-99.5% for all 1650 valid questionnaires. 37.2% of the participants quite worried about being infected with COVID-19. Approximately 96% of them washed hands in certain situations, while 85.6% of them washed hands after coughing or sneezing. Compared to the students without depressive symptoms, those who had depressive symptoms scored lower of total KAP, knowledge, attitudes, and practice. The findings suggest that primary students had a relatively good awareness of COVID-19 during the epidemic, as well as optimistic attitudes and appropriate practices. However, some items of appropriate practices still needed to be enhanced.

Association of health-risk behaviors and depressive symptoms and anxiety symptoms: a school-based sample of Chinese adolescents.

Background Depressive symptoms and anxiety symptoms of adolescents not only affect youth but also have wide-ranging impacts on the health of adults. The study was carried out to determine the epidemiological characteristics of depressive symptoms and anxiety symptoms and the associations between the two and health-risk behaviors in Chinese adolescents. Methods Participants were recruited from the junior and senior high schools in China. Data were collected by self-designed questionnaires. The questionnaires included questions about demographic characteristics, depressive symptom scales, anxiety symptom scales and nine categories of health-risk behaviors. Descriptive analysis and binary logistic regression were performed by SPSS 21.0 software. Results There were 4.4% of the participants with depressive symptoms. Approximately 32.0% of the participants had anxiety symptoms. Girls and general senior school students were risk factors for depressive symptoms and anxiety symptoms. Multiple health-risk behaviors were associated with depressive symptoms and anxiety symptoms in Chinese adolescents. Conclusion Depressive symptoms and anxiety symptoms were prevalent in Chinese adolescents. Their distribution was affected by certain health-risk behaviors. Multiple health-risk behaviors were associated with depressive symptoms and anxiety symptoms in Chinese adolescents.

Application of diffusion tensor imaging and blood oxygenation level-dependent magnetic resonance imaging to assess bilateral renal function induced by Iohexol in rabbits.

BACKGROUND: Blood oxygenation level-dependent magnetic resonance imaging (BOLD-MRI) and diffusion tensor imaging (DTI) are useful methods for investigating the morphology and function of the kidneys, including revealing unilateral renal damage. Nevertheless, these techniques have not yet been applied for bilateral renal function. The aim of this study was to investigate whether the combination of DTI and BOLD could be used to examine different degrees of contrast-induced acute kidney injury (CI-AKI) in bilateral kidneys compared to standard methods such as serum creatinine (SCr) detection. METHODS: Forty-Two New Zealand white rabbits were divided into two groups: the experimental group and the control group. Physiological saline and iodine contrast agent (iohexol, 1.0 g iodine/kg, 1.0 ml/sec) were injected via the right renal artery. DTI and BOLD-MR data were acquired longitudinally at the baseline and 1, 24, 48, and 72 h after high-pressure syringe injection to measure the apparent diffusion coefficient (ADC), fractional anisotropy (FA) and relative transverse relaxation rate (R2*). After the MR scan at each time point, three rabbits in each group were sacrificed, and changes in SCr and hypoxia-inducible factor-1α (HIF-1α) were analyzed using histopathology and immunochemistry. RESULTS: Twenty-four hours after iohexol administration, the values of ADC and FA decreased significantly (P < 0.05), while R2* values increased (P < 0.05) in the renal cortex (CO), outer medulla (OM) and inner medulla (IM). Besides, significant negative correlations were observed among ADC, FA, and R2* in CO, OM, and IM (all P < 0.001, r = - 0.654-0.828). CONCLUSIONS: DTI and BOLD can simultaneously and non-invasively assess different degrees of CI-AKI in bilateral kidneys.

Mapping publication status and exploring hotspots in a research field: Rheumatoid arthritis with depression.

AIM: To make a bibliometric analysis of the current research status and hot spots in the field of rheumatoid arthritis (RA) -related depression. DESIGN: Systematic review. METHODS: Based on the Web of Science database, studies in the past 5 years from 1 January 2015-5 November 2019 have been included. Data were analysed from annual number of published papers, main research institutions, core authors, core teams and research topics by using bibliometric approaches. RESULTS: Related papers (N = 1,073) were obtained. The field of RA-related depression is in a stable development stage, forming core authors and core teams. The epidemiological characteristics, influencing factors, prediction effect and the intervention of RA-related depression are common research directions and themes. The common role of auto-antibodies and inflammatory factors in the development of RA and depression, the risk of cardiovascular events and disease burden caused by RA-related depression are newly emerging research topics. CONCLUSION: The RA-related depression has been widely concerned by scholars and the research field is gradually mature. However, the research on the prevention and intervention of RA-related depression is still wanting, which needs to be strengthened. WHERE AND ON WHOM WILL THE RESEARCH HAVE AN IMPACT?: The research revealed the most popular institutions, authors, research teams, emerging issues and 'hot topics' in the RA-related depression field, which might suggest avenues for future research in this field.

Multimodal neuroimaging analysis reveals age-associated common and discrete cognitive control constructs.

The aims of this study were to determine which cognitive control functions are most sensitive to cross-sectional age differences and to identify neural features in different neuroimaging modalities that associated cognitive control function across the adult lifespan. We employed a joint independent component analysis (jICA) approach to obtain common networks among three different brain-imaging modalities (i.e., structural MRI, resting-state functional MRI, and diffusion tensor imaging) in relation to the cognitive control function. We differentiated three distinct cognitive constructs: one common (across inhibition, shifting, and updating) and two specific (shifting, updating) factors. These common/specific constructs were transformed from three original performance indexes: (a) stop-signal reaction time, (b) switch-cost, and (c) performance sensitivity collected from 156 individuals aged 20 to 78 years old. The current results show that the cross-sectional age difference is associated with a wide spread of brain degeneration that is not limited to the frontal region. Crucially, these findings suggest there are some common and distinct joined multimodal components that correlate with the psychological constructs of common and discrete cognitive control functions, respectively. To support current findings, other fusion ICA models were also analyzed including, parallel ICA (para-ICA) and multiset canonical correlation analysis with jICA (mCCA + jICA). Dynamic interactions among these brain features across different brain modalities could serve as possible developmental mechanisms associated with these age effects.

Evaluating the pathogenic potential of genes with de novo variants in epileptic encephalopathies.

Epileptic encephalopathies comprise a group of catastrophic epilepsies with heterogeneous genetic etiology. Although next-generation sequencing techniques can reveal a number of de novo variants in epileptic encephalopathies, evaluating the pathogenicity of these variants can be challenging. Determining the pathogenic potential of genes in epileptic encephalopathies is critical before evaluating the pathogenicity of variants identified in an individual. We reviewed de novo variants in epileptic encephalopathies, including their genotypes and functional consequences. We then evaluated the pathogenic potential of genes, with the following additional considerations: (1) recurrence of variants in unrelated cases, (2) information of previously defined phenotypes, and (3) data from genetic experimental studies. Genes related to epileptic encephalopathy revealed pathogenicity with distinct functional alterations, i.e., either a gain of function or loss of function in the majority; however, several genes warranted further study to confirm their pathogenic potential. Whether a gene was associated with distinct phenotype, the genotype (or functional alteration)--phenotype correlation, and quantitative correlation between genetic impairment and phenotype severity were suggested to be specific evidence in determining the pathogenic role of genes. Data from epileptic encephalopathy-related genes would be helpful in outlining guidelines for evaluating the pathogenic potential of genes in other genetic disorders.

Molecular cloning and expression analysis of SRLK1 gene in self-incompatible Asteraceae species Erigeron breviscapus.

Based on the transcriptome data, using RACE techniques, we cloned the full-length EbSRLK1 gene in a medicinal, self-incompatible Asteraceae species, Erigeron breviscapus. Bioinformatics approaches were used to analyze the DNA and protein sequences, physical and chemical properties, and domains of the encoded protein. The full-length EbSRLK1 cDNA is 2891 base pairs (bp) with an open reading frame (ORF) of 2634 bp, which encodes the EbSRLK1 protein with 878 amino acids and an estimated molecular weight of 98.13 kD. The EbSRLK1 protein has the characteristic domain structure of S-locus receptor-like protein kinases, which contains one transmembrane domain but lacks the signal peptide. Quantitative real-time PCR (qRT-PCR) analysis showed that the EbSRLK1 gene is lowly expressed in roots, stems and leaves, but highly expressed in flowers, especially in flowers one day prior to opening. Western blot analysis showed that the EbSRLK1 protein is expressed in stems, leaves, and flowers, but is almost undetectable in roots. The EbSRLK1 protein expression is induced in self-pollinated but not in cross-pollinated E. breviscapus flowers. Cloning and expression analysis of EbSRLK1 lay a solid foundation for elucidating the role of EbSRLK1 in regulating self-incompatibility in E. breviscapus.

ARHGEF9 mutations in epileptic encephalopathy/intellectual disability: toward understanding the mechanism underlying phenotypic variation.

ARHGEF9 resides on Xq11.1 and encodes collybistin, which is crucial in gephyrin clustering and GABAA receptor localization. ARHGEF9 mutations have been identified in patients with heterogeneous phenotypes, including epilepsy of variable severity and intellectual disability. However, the mechanism underlying phenotype variation is unknown. Using next-generation sequencing, we identified a novel mutation, c.868C > T/p.R290C, which co-segregated with epileptic encephalopathy, and validated its association with epileptic encephalopathy. Further analysis revealed that all ARHGEF9 mutations were associated with intellectual disability, suggesting its critical role in psychomotor development. Three missense mutations in the PH domain were not associated with epilepsy, suggesting that the co-occurrence of epilepsy depends on the affected functional domains. Missense mutations with severe molecular alteration in the DH domain, or located in the DH-gephyrin binding region, or adjacent to the SH3-NL2 binding site were associated with severe epilepsy, implying that the clinical severity was potentially determined by alteration of molecular structure and location of mutations. Male patients with ARHGEF9 mutations presented more severe phenotypes than female patients, which suggests a gene-dose effect and supports the pathogenic role of ARHGEF9 mutations. This study highlights the role of molecular alteration in phenotype expression and facilitates evaluation of the pathogenicity of ARHGEF9 mutations in clinical practice.

In-Hospital Implementation of Evidence-Based Medications is Associated with Improved Survival in Diabetic Patients with Acute Coronary Syndrome - Data from TSOC ACS-DM Registry.

BACKGROUND: Patients with acute coronary syndrome (ACS) and diabetes mellitus (DM) receive less aggressive treatment and have worse outcomes in Taiwan. We sought to explore whether the current practices of prescribing guideline-directed medical therapy (GDMT) for ACS and clinical outcomes have improved over time. METHODS: A total of 1534 consecutive diabetic patients with ACS were enrolled between 2013 and 2015 from 27 hospitals in the nationwide registry initiated by the Taiwan Society of Cardiology (the TSOC ACS-DM Registry). Baseline and clinical demographics, treatment, and clinical outcomes were compared to those of 1000 ACS patients with DM recruited in the Taiwan ACS-full spectrum (ACS-FS) Registry, which was performed between 2008 and 2010. RESULTS: Compared to the DM patients in the Taiwan ACS-FS Registry, even though reperfusion therapy was carried out in significantly fewer patients, the primary percutaneous coronary intervention (PCI) rate for ST-segment elevation myocardial infarction (STEMI) and the prescription rates of GDMT for ACS including P2Y12 inhibitors, renin-angiotensin blockers, beta-blockers, and statins were significantly higher in those in the TSOC ACS-DM Registry. Moreover, significant reductions in 1-year mortality, recurrent nonfatal MI and stroke were observed compared to those of the DM patients in the Taiwan ACS-FS Registry. Multivariate analysis identified reperfusion therapy in combination with GDMT as a strong predictor of better 1-year outcomes [hazard ratio (95% confidence interval) = 0.54 (0.33-0.89)]. CONCLUSIONS: Marked improvements in performing primary PCI for STEMI and prescribing GDMT for ACS were observed over time in Taiwan. This was associated with improved 1-year event-free survival in the diabetic patients with ACS.

The SCN1A mutation database: updating information and analysis of the relationships among genotype, functional alteration, and phenotype.

Mutations in the SCN1A gene have been identified in epilepsy patients with widely variable phenotypes and modes of inheritance and in asymptomatic carriers. This raises challenges in evaluating the pathogenicity of SCN1A mutations. We systematically reviewed all SCN1A mutations and established a database containing information on functional alterations. In total, 1,257 mutations have been identified, of which 81.8% were not recurrent. There was a negative correlation between phenotype severity and missense mutation frequency. Further analyses suggested close relationships among genotype, functional alteration, and phenotype. Missense mutations located in different sodium channel regions were associated with distinct functional changes. Missense mutations in the pore region were characterized by the complete loss of function, similar to haploinsufficiency. Mutations with severe phenotypes were more frequently located in the pore region, suggesting that functional alterations are critical in evaluating pathogenicity and can be applied to patient management. A negative correlation was found between phenotype severity and familial incidence, and incomplete penetrance was associated with missense and splice site mutations, but not truncations or genomic rearrangements, suggesting clinical genetic counseling applications. Mosaic mutations with a load of 12.5-25.0% were potentially pathogenic with low penetrance, suggesting the need for future studies on less pathogenic genomic variations.