The conformational coupling and translocation mechanism of vitamin B12 ATP-binding cassette transporter BtuCD

ATP-binding cassette transporter BtuCD mediating vitamin B₁₂ uptake in Escherichia coli couples the energy of ATP hydrolysis to the translocation of vitamin B₁₂ across the membrane into the cell. Elastic normal mode analysis of BtuCD demonstrates that the simultaneous substrate trapping at periplasmic cavity and ATP binding at the ATP-binding cassette (BtuD) dimer proceeds readily along the lowest energy pathway. The transport power stroke is attributed to ATP-hydrolysis-induced opening of the nucleotide-binding domain dimer, which is coupled to conformational rearrangement of transmembrane domain (BtuC) helices leading to the closing at the periplasmic side and opening at the cytoplasmic gate. Simultaneous hydrolysis of two ATP is supported by the fact that antisymmetric movement of BtuD dimer implying alternating hydrolysis cannot induce effective conformational change of the translocation pathway. A plausible mechanism of translocation cycle is proposed in which the possible effect of the association of periplasmic binding protein BtuF to the transporter is also considered.     

Early Detection for Cases of Enterovirus- and Influenza-Like Illness through a Newly Established School-Based Syndromic Surveillance System in Taipei,January 2010 ~ August 2011

School children may transmit pathogens with cluster cases occurring on campuses and in families. In response to the 2009 influenza A (H1N1) pandemic, Taipei City Government officials developed a School-based Infectious Disease Syndromic Surveillance System (SID-SSS). Teachers and nurses from preschools to universities in all 12 districts within Taipei are required to daily report cases of symptomatic children or sick leave requests through the SID-SSS. The pre-diagnosis at schools is submitted firstly as common pediatric disease syndrome-groups and re-submitted after confirmation by physicians. We retrieved these data from January 2010 to August 2011 for spatio-temporal analysis and evaluated the temporal trends with cases obtained from both the Emergency Department-based Syndromic Surveillance System (ED-SSS) and the Longitudinal Health Insurance Database 2005 (LHID2005). Through the SID-SSS, enterovirus-like illness (EVI) and influenza-like illness (ILI) were the two most reported syndrome groups (77.6% and 15.8% among a total of 19,334 cases, respectively). The pre-diagnosis judgments made by school teachers and nurses showed high consistency with physicians’ clinical diagnoses for EVI (97.8%) and ILI (98.9%). Most importantly, the SID-SSS had better timeliness with earlier peaks of EVI and ILI than those in the ED-SSS. Furthermore, both of the syndrome groups in these two surveillance systems had the best correlation reaching 0.98 and 0.95, respectively (p<0.01). Spatio-temporal analysis observed the patterns of EVI and ILI both diffuse from the northern suburban districts to central Taipei, with ILI spreading faster. This novel system can identify early suspected cases of two important pediatric infections occurring at schools, and clusters from schools/families. It was also cost-effective (95.5% of the operation cost reduced and 59.7% processing time saved). The timely surveillance of mild EVI and ILI cases integrated with spatial analysis may help public health decision-makers with where to target for enhancing surveillance and prevention measures to minimize severe cases.     

Abacus Training Affects Math and Task Switching Abilities and Modulates Their Relationships in Chinese Children

Our previous work demonstrated that abacus-based mental calculation (AMC), a traditional Chinese calculation method, could help children improve their math abilities (e.g. basic arithmetical ability) and executive function (e.g. working memory). This study further examined the effects of long-term AMC training on math ability in visual-spatial domain and the task switching component of executive function. More importantly, this study investigated whether AMC training modulated the relationship between math abilities and task switching. The participants were seventy 7-year-old children who were randomly assigned into AMC and control groups at primary school entry. Children in AMC group received 2-hour AMC training every week since primary school entry. On the contrary, children in the control group had never received any AMC training. Math and task switching abilities were measured one year and three years respectively after AMC training began. The results showed that AMC children performed better than their peers on math abilities in arithmetical and visual-spatial domains. In addition, AMC group responded faster than control group in the switching task, while no group difference was found in switch cost. Most interestingly, group difference was present in the relationships between math abilities and switch cost. These results implied the effect of AMC training on math abilities as well as its relationship with executive function.     

Racial differences in genome-wide methylation profiling and gene expression in breast tissues from healthy women

Breast cancer is more common in European Americans (EAs) than in African Americans (AAs) but mortality from breast cancer is higher among AAs. While there are racial differences in DNA methylation and gene expression in breast tumors, little is known whether such racial differences exist in breast tissues of healthy women. Genome-wide DNA methylation and gene expression profiling was performed in histologically normal breast tissues of healthy women. Linear regression models were used to identify differentially-methylated CpG sites (CpGs) between EAs (n = 61) and AAs (n = 22). Correlations for methylation and expression were assessed. Biological functions of the differentially-methylated genes were assigned using the Ingenuity Pathway Analysis. Among 485 differentially-methylated CpGs by race, 203 were hypermethylated in EAs, and 282 were hypermethylated in AAs. Promoter-related differentially-methylated CpGs were more frequently hypermethylated in EAs (52%) than AAs (27%) while gene body and intergenic CpGs were more frequently hypermethylated in AAs. The differentially-methylated CpGs were enriched for cancer-associated genes with roles in cell death and survival, cellular development, and cell-to-cell signaling. In a separate analysis for correlation in EAs and AAs, different patterns of correlation were found between EAs and AAs. The correlated genes showed different biological networks between EAs and AAs; networks were connected by Ubiquitin C. To our knowledge, this is the first comprehensive genome-wide study to identify differences in methylation and gene expression between EAs and AAs in breast tissues from healthy women. These findings may provide further insights regarding the contribution of epigenetic differences to racial disparities in breast cancer.     

Overexpression of BIRC6 Is a Predictor of Prognosis for Colorectal Cancer

MethodsWe used Western blotting and immunohistochemistry to examine BIRC6 expression in 7 CRC cell lines and 126 CRC clinical samples. We determined the biological significance of BIRC6 in CRC cell lines by a lentivirus-mediated silencing method.ResultsWe reported that BIRC6 was overexpressed in CRC cell lines and clinical CRC tissues. BIRC6 overexpression was correlated with tumor size and invasion depth of CRC. BIRC6 overexpression is associated with worse overall survival (OS) (P = 0.001) and shorter disease-free survival (DFS) (P = 0.010). BIRC6 knockdown inhibited cell proliferation, arrested cell cycle at S phase, downregulated cyclin A2, B1, D1 and E1 levels, and sensitized CRC cells to chemotherapy in vitro and in vivo.ConclusionsTaken together, these data suggests that BIRC6 overexpression is a predictor of poor prognosis in colorectal cancer and BIRC6 could be a potential target of CRC therapy.     

Risk of Shingles in Adults with Primary Sjogren’s Syndrome and Treatments: A Nationwide Population-Based Cohort Study

Background

Primary Sjögren''s syndrome (pSS) is associated with immunological dysfunctions—a well-known risk factor of shingles. This study aimed to examine the incidence and risk of shingles in adults with pSS and pharmacological treatments.

Methods

This retrospective population-based cohort study was conducted using National Health Insurance claims data. Using propensity scores, 4,287 pSS adult patients and 25,722-matched cohorts by age, gender, selected comorbidities and Charlson comorbidity index scores were identified. Kaplan-Meier analysis and Cox regression were conducted to compare the differences in developing shingles. In pSS, oral and eye dryness are treated with substitute agents. Extraglandular features are often treated with pharmacological drugs including steroids and immunosuppressants. pSS patients were grouped as follows: no pharmacological drugs, steroids alone; immunosuppressants alone; combined therapies.

Results

During the follow-up, 463 adults with pSS (10.80%) and 1,345 control cohorts (5.23%) developed shingles. The cumulative incidence of shingles in pSS patients (18.74/1,000 patient-years) was significantly higher than controls (8.55/1,000 patient-years). The adjusted hazard ratio (HR) of shingles was 1.69 (95% confidence interval (CI) 1.50–1.90). In age-subgroup analyses, incidences of shingles in pSS increased with age and peaked in pSS patients aged ≧60; however, adjusted HRs decreased with age. Compared to control cohorts with no drugs, adjusted HRs for shingles in pSS patients were ranked from high to low as: combined therapies (4.14; 95% CI 3.14–5.45) > immunosuppressants alone (3.24; 95% CI 2.36–4.45) > steroids alone (2.54; 95% CI 2.16–2.97) > no pharmacological drugs (2.06; 95% CI 1.76–2.41). Rates of shingles-associated hospitalization and postherpetic neuralgia were 5.62% and 24.41%, both of which were significantly higher than those (2.60%; 13.01%) in the control cohorts.

Conclusions

Adults with pSS were at greater risk for shingles than control cohorts. Drug exposures significantly increased the risk of shingles in pSS.     

Individual Variability and Test-Retest Reliability Revealed by Ten Repeated Resting-State Brain Scans over One Month

Individual differences in mind and behavior are believed to reflect the functional variability of the human brain. Due to the lack of a large-scale longitudinal dataset, the full landscape of variability within and between individual functional connectomes is largely unknown. We collected 300 resting-state functional magnetic resonance imaging (rfMRI) datasets from 30 healthy participants who were scanned every three days for one month. With these data, both intra- and inter-individual variability of six common rfMRI metrics, as well as their test-retest reliability, were estimated across multiple spatial scales. Global metrics were more dynamic than local regional metrics. Cognitive components involving working memory, inhibition, attention, language and related neural networks exhibited high intra-individual variability. In contrast, inter-individual variability demonstrated a more complex picture across the multiple scales of metrics. Limbic, default, frontoparietal and visual networks and their related cognitive components were more differentiable than somatomotor and attention networks across the participants. Analyzing both intra- and inter-individual variability revealed a set of high-resolution maps on test-retest reliability of the multi-scale connectomic metrics. These findings represent the first collection of individual differences in multi-scale and multi-metric characterization of the human functional connectomes in-vivo, serving as normal references for the field to guide the use of common functional metrics in rfMRI-based applications.