A Missense Mutation in CRYBB2 Leads to Progressive Congenital Membranous Cataract by Impacting the Solubility and Function of βB2-Crystallin

Congenital cataract is a major cause of visual impairment and childhood blindness. The solubility and stability of crystallin proteins play critical roles in maintaining the optical transparency of the lens during the life span. Previous studies have shown that approximately 8.3%∼25% of congenital cataracts are inherited, and mutations in crystallins are the most common. In this study, we attempted to identify the genetic defect in a four-generation family affected with congenital cataracts. The congenital cataract phenotype of this four-generation family was identified as membranous cataract by slit-lamp photography. Mutation screening of the candidate genes detected a heterozygous c.465G→C change in the exon6 of the βB2-crystallin gene (CRYBB2) in all family members affected with cataracts, resulting in the substitution of a highly conserved Tryptophan to Cystine (p.W151C). The mutation was confirmed by restriction fragment length polymorphism (RFLP) analysis and found that the transition resulted in the absence of a BslI restriction site in the affected members of the pedigree. The outcome of PolyPhen-2 and SIFT analysis predicted that this W151C mutation would probably damage to the structure and function of βB2-crystallin. Wild type (wt) and W151C mutant βB2-crystallin were expressed in human lens epithelial cells (HLECs), and the fluorescence results showed that Wt-βB2-crystallin was evenly distributed throughout the cells, whereas approximately 34.7% of cells transfected with the W151C mutant βB2-crystallin formed intracellular aggregates. Taken together, these data suggest that the missense mutation in CRYBB2 gene leads to progressive congenital membranous cataract by impacting the solubility and function of βB2-crystallin.     

A Phenotypic Structure and Neural Correlates of Compulsive Behaviors in Adolescents

Background

A compulsivity spectrum has been hypothesized to exist across Obsessive-Compulsive disorder (OCD), Eating Disorders (ED), substance abuse (SA) and binge-drinking (BD). The objective was to examine the validity of this compulsivity spectrum, and differentiate it from an externalizing behaviors dimension, but also to look at hypothesized personality and neural correlates.

Method

A community-sample of adolescents (N=1938; mean age 14.5 years), and their parents were recruited via high-schools in 8 European study sites. Data on adolescents’ psychiatric symptoms, DSM diagnoses (DAWBA) and substance use behaviors (AUDIT and ESPAD) were collected through adolescent- and parent-reported questionnaires and interviews. The phenotypic structure of compulsive behaviors was then tested using structural equation modeling. The model was validated using personality variables (NEO-FFI and TCI), and Voxel-Based Morphometry (VBM) analysis.

Results

Compulsivity symptoms best fit a higher-order two factor model, with ED and OCD loading onto a compulsivity factor, and BD and SA loading onto an externalizing factor, composed also of ADHD and conduct disorder symptoms. The compulsivity construct correlated with neuroticism (r=0.638; p≤0.001), conscientiousness (r=0.171; p≤0.001), and brain gray matter volume in left and right orbitofrontal cortex, right ventral striatum and right dorsolateral prefrontal cortex. The externalizing factor correlated with extraversion (r=0.201; p≤0.001), novelty-seeking (r=0.451; p≤0.001), and negatively with gray matter volume in the left inferior and middle frontal gyri.

Conclusions

Results suggest that a compulsivity spectrum exists in an adolescent, preclinical sample and accounts for variance in both OCD and ED, but not substance-related behaviors, and can be differentiated from an externalizing spectrum.     

Alzheimer's Disease Risk Assessment Using Large-Scale Machine Learning Methods

The goal of this work is to introduce new metrics to assess risk of Alzheimer''s disease (AD) which we call AD Pattern Similarity (AD-PS) scores. These metrics are the conditional probabilities modeled by large-scale regularized logistic regression. The AD-PS scores derived from structural MRI and cognitive test data were tested across different situations using data from the Alzheimer''s Disease Neuroimaging Initiative (ADNI) study. The scores were computed across groups of participants stratified by cognitive status, age and functional status. Cox proportional hazards regression was used to evaluate associations with the distribution of conversion times from mild cognitive impairment to AD. The performances of classifiers developed using data from different types of brain tissue were systematically characterized across cognitive status groups. We also explored the performance of anatomical and cognitive-anatomical composite scores generated by combining the outputs of classifiers developed using different types of data. In addition, we provide the AD-PS scores performance relative to other metrics used in the field including the Spatial Pattern of Abnormalities for Recognition of Early AD (SPARE-AD) index and total hippocampal volume for the variables examined.     

Identification of broadly neutralizing antibody epitopes in the HIV-1 envelope glycoprotein using evolutionary models

Background

Identification of the epitopes targeted by antibodies that can neutralize diverse HIV-1 strains can provide important clues for the design of a preventative vaccine.

Methods

We have developed a computational approach that can identify key amino acids within the HIV-1 envelope glycoprotein that influence sensitivity to broadly cross-neutralizing antibodies. Given a sequence alignment and neutralization titers for a panel of viruses, the method works by fitting a phylogenetic model that allows the amino acid frequencies at each site to depend on neutralization sensitivities. Sites at which viral evolution influences neutralization sensitivity were identified using Bayes factors (BFs) to compare the fit of this model to that of a null model in which sequences evolved independently of antibody sensitivity. Conformational epitopes were identified with a Metropolis algorithm that searched for a cluster of sites with large Bayes factors on the tertiary structure of the viral envelope.

Results

We applied our method to ID₅₀ neutralization data generated from seven HIV-1 subtype C serum samples with neutralization breadth that had been tested against a multi-clade panel of 225 pseudoviruses for which envelope sequences were also available. For each sample, between two and four sites were identified that were strongly associated with neutralization sensitivity (2ln(BF)?>?6), a subset of which were experimentally confirmed using site-directed mutagenesis.

Conclusions

Our results provide strong support for the use of evolutionary models applied to cross-sectional viral neutralization data to identify the epitopes of serum antibodies that confer neutralization breadth.

     

Genome‐wide association study of genetic factors related to confectionery intake: Potential roles of the ADIPOQ gene

Objective: The excessive consumption of confectionery might have adverse effects on human health. To screen genetic factors associated with confectionery‐intake frequency, a genome‐wide association study (GWAS) in Japan was conducted. Design and Methods: For the discovery phase (stage 1), we conducted a GWAS of 939 noncancer patients in a cancer hospital. Additive models were used to test associations between genotypes of approximately 500,000 single‐nucleotide polymorphisms (SNPs) and the confectionery‐intake score (based on intake frequency). We followed‐up association signals with P < 1 × 10^?5 and minor allele frequency >0.01 in stage 1 by genotyping the SNPs of 4,491 participants in a cross‐sectional study within a cohort (replication phase [stage 2]). Results: We identified 12 SNPs in stage 1 that were potentially related to confectionery intake. In stage 2, this association was replicated for one SNP (rs822396; P = 0.049 for stage 2 and 4.2 × 10^?5 for stage 1+2) in intron 1 of the ADIPOQ gene, which encodes the adipokine adiponectin. Conclusions: Given the biological plausibility and previous relevant findings, the association of an SNP in the ADIPOQ gene with a preference for confectionery is worthy of follow‐up and provides a good working hypothesis for experimental testing.     

Influence of calendar period on the association between BMI and coronary heart disease: A meta‐analysis of 31 cohorts

Objective:

The association between obesity and coronary heart disease (CHD) may have changed over time, for example due to improved pharmacological treatment of CHD risk factors. This meta‐analysis of 31 prospective cohort studies explores the influence of calendar period on CHD risk associated with body mass index (BMI).

Design and Methods:

The relative risks (RRs) of CHD for a five‐BMI‐unit increment and BMI categories were pooled by means of random effects models. Meta‐regression analysis was used to examine the influence of calendar period (>1985 v ≤1985) in univariate and multivariate analyses (including mean population age as a covariate).

Results:

The age, sex, and smoking adjusted RR (95% confidence intervals) of CHD for a five‐BMI‐unit increment was 1.28(1.22:1.34). For underweight, overweight and obesity, the RRs (compared to normal weight) were 1.11(0.91:1.36), 1.31(1.22:1.41), and 1.78(1.55:2.04), respectively. The univariate analysis indicated 31% (95%CI: ?56:0) lower RR of CHD associated with a five‐BMI‐unit increment and a 51% (95%CI: ?78: ?14)) lower RR associated with obesity in studies starting after 1985 (n = 15 and 10, respectively) compared to studies starting in or before 1985 (n = 16 and 10). However, in the multivariate analysis, only mean population age was independently associated with the RRs for a five‐BMI‐unit increment and obesity (?29(95%CI: ?55: ?5)) and ?31(95%CI: ?66:3), respectively) per 10‐year increment in mean age).

Conclusion:

This study provides no consistent evidence for a difference in the association between BMI and CHD by calendar period. The mean population age seems to be the most important factor that modifies the association between the risk of CHD and BMI, in which the RR decreases with increasing age.

     

Glycated Hemoglobin Independently Predicts Stroke Recurrence within One Year after Acute First-Ever Non-Cardioembolic Strokes Onset in A Chinese Cohort Study

Objective

Hyperglycemia is related to stroke. Glycated hemoglobin (HbA1c) can reflect pre-stroke glycaemia status. However, the information on the direct association between HbA1c and recurrence after non-cardioembolic acute ischemic strokes is rare and there is no consistent conclusion.

Methods

The ACROSS-China database comprised of 2186 consecutive first-ever acute ischemic stroke patients with baseline HbA1c values. After excluding patients who died from non-stroke recurrence and patients lost to follow up, 1817 and 1540 were eligible for 3-month and 1-year analyses, respectively. Multivariate Cox regression was performed to evaluate the associations between HbA1c and 3-month and 1-year stroke recurrence.

Results

The HbA1c values at admission were divided into 4 levels by quartiles: Q1 (<5.5%); Q2 (5.5 to <6.1%); Q3 (6.1% to <7.2%); and Q4 (≥7.2%). The cumulative recurrence rates were 8.3% and 11.0% for 3 months and 1 year, respectively. In multivariate analyses, when compared with Q1, the adjusted hazard ratios (AHRs) were 2.83 (95% confidence interval (CI) 1.28-6.26) in Q3 and 3.71(95% CI 1.68-8.21) in Q4 for 3-month stroke recurrence; 3.30 (95% CI 1.31-8.34) in Q3 and 3.35 (95% CI 1.36-8.21) in Q4 for 1-year stroke recurrence. Adding fasting plasma glucose in the multivariate analyses did not modify the association: AHRs were 2.75 (95% CI 1.24-6.11) in Q3 and 3.67 (95% CI 1.59-8.53) in Q4 for 3-month analysis; AHRs were 3.08 (95% CI 1.10-8.64) in Q3 and 3.31(95% CI 1.35-8.14) in Q4 for 1-year analysis.

Conclusions

A higher “normal” HbA1c level reflecting pre-stroke glycaemia status independently predicts stroke recurrence within one year after non-cardioembolic acute ischemic stroke onset. HbA1c is recommended as a routine test in acute ischemic stroke patients.     

Cerebrospinal Fluid Neopterin Analysis in Neuropediatric Patients: Establishment of a New Cut Off-Value for the Identification of Inflammatory-Immune Mediated Processes

Objective

A high level of cerebrospinal fluid (CSF) neopterin is a marker of central nervous system inflammatory-immune mediated processes. We aimed to assess data from 606 neuropediatric patients, describing the clinical and biochemical features of those neurological disorders presenting CSF neopterin values above a new cut-off value that was defined in our laboratory.

Methods

To establish the new CSF neopterin cut-off value, we studied two groups of patients: Group 1 comprised 68 patients with meningoencephalitis, and Group 2 comprised 52 children with a confirmed peripheral infection and no central nervous system involvement. We studied 606 CSF samples from neuropediatric patients who were classified into 3 groups: genetic diagnosis (A), acquired/unknown etiologic neurologic diseases (B) and inflammatory-immune mediated processes (C).

Results

The CSF neopterin cut-off value was 61 nmol/L. Out of 606 cases, 56 presented a CSF neopterin level above this value. Group C had significantly higher CSF neopterin, protein and leukocyte values than the other groups. Sixteen of twenty-three patients in this group had a CSF neopterin level above the cut-off, whereas three and seven patients presented increased leukocyte and protein values, respectively. A significant association was found among CSF neopterin, proteins and leukocytes in the 606 patients. White matter disturbances were associated with high CSF neopterin concentrations.

Conclusions

Although children with inflammatory-immune mediated processes presented higher CSF neopterin values, patients with other neurological disorders also showed increased CSF neopterin concentrations. These results stress the importance of CSF neopterin analysis for the identification of inflammatory-immune mediated processes.     

Periconceptional maternal alcohol consumption and neural tube defects

BACKGROUND: Neural tube defects (NTD)s, which occur when the neural tube fails to close during early gestation, are some of the most common birth defects worldwide. Alcohol is a known teratogen and has been shown to induce NTDs in animal studies, although most human studies have failed to corroborate these results. Using data from the National Birth Defects Prevention Study, associations between maternal reports of periconceptional (1 month prior through 2 months postconception) alcohol consumption and NTDs were examined. METHODS: NTD cases and unaffected live born control infants, delivered from 1997 through 2005, were included. Interview reports of alcohol consumption (quantity, frequency, variability, and type) were obtained from 1223 case mothers and 6807 control mothers. Adjusted odds ratios (aOR)s and 95% confidence intervals were estimated using multivariable logistic regression analysis. RESULTS: For all NTDs combined, most aORs for any alcohol consumption, one or more binge episodes, and different type(s) of alcohol consumed were near unity or modestly reduced (≥0.7<aOR≤1.1) and were not statistically significant. Findings were similar for individual NTD subtypes. CONCLUSIONS: These findings suggest no elevated association between maternal periconceptional alcohol consumption and NTDs. Underreporting of alcohol consumption, due to negative social stigma associated with alcohol consumption during pregnancy, and limited reports for mothers with early pregnancy loss of a fetus with an NTD may have affected the estimated odds ratios. Future studies should aim to increase sample sizes for less prevalent subtypes, reduce exposure misclassification, and improve ascertainment offetal deaths and elective terminations. Birth Defects Research (Part A), 2013. © 2013 Wiley Periodicals, Inc.