Mapping the complete glycoproteome of virion-derived HIV-1 gp120 provides insights into broadly neutralizing antibody binding

The surface envelope glycoprotein (SU) of Human immunodeficiency virus type 1 (HIV-1), gp120SU plays an essential role in virus binding to target CD4+ T-cells and is a major vaccine target. Gp120 has remarkably high levels of N-linked glycosylation and there is considerable evidence that this “glycan shield” can help protect the virus from antibody-mediated neutralization. In recent years, however, it has become clear that gp120 glycosylation can also be included in the targets of recognition by some of the most potent broadly neutralizing antibodies. Knowing the site-specific glycosylation of gp120 can facilitate the rational design of glycopeptide antigens for HIV vaccine development. While most prior studies have focused on glycan analysis of recombinant forms of gp120, here we report the first systematic glycosylation site analysis of gp120 derived from virions produced by infected T lymphoid cells and show that a single site is exclusively substituted with complex glycans. These results should help guide the design of vaccine immunogens

Revealing dendritic pattern formation in Ni, Fe and Co alloys using synchrotron tomography

The microstructural patterns formed during liquid to solid phase transformations control the properties of a wide range of materials. We developed a novel methodology that allows in situ quantification of the microstructures formed during solidification of high temperature advanced alloys. The patterns formed are captured in 4D (3D plus time) using a methodology which exploits three separate advances: a bespoke high temperature environment cell; the development of high X-ray contrast alloys; and a novel environmental encapsulation system. This methodology is demonstrated on Ni, Fe, and Co advanced alloy systems, revealing dendritic pattern formation. We present detailed quantification of microstructural pattern evolution in a novel high attenuation contrast Co-Hf alloy, including microstructural patterning and dendrite tip velocity. The images are quantified to provide 4D experimental data of growth and coarsening mechanisms in Co alloys, which are used for a range of applications from energy to aerospace

Genomic Analysis of Response to Neoadjuvant Chemotherapy in Esophageal Adenocarcinoma

Neoadjuvant therapy followed by surgery is the standard of care for locally advanced esophageal adenocarcinoma (EAC). Unfortunately, response to neoadjuvant chemotherapy (NAC) is poor (20-37%), as is the overall survival benefit at five years (9%). The EAC genome is complex and heterogeneous between patients, and it is not yet understood whether specific mutational patterns may result in chemotherapy sensitivity or resistance. To identify associations between genomic events and response to NAC in EAC, a comparative genomic analysis was performed in 65 patients with extensive clinical and pathological annotation using whole-genome sequencing (WGS). We defined response using Mandard Tumor Regression Grade (TRG), with responders classified as TRG1-2 (n = 27) and non-responders classified as TRG4-5 (n =38). We report a higher non-synonymous mutation burden in responders (median 2.08/Mb vs. 1.70/Mb, p = 0.036) and elevated copy number variation in non-responders (282 vs. 136/patient, p < 0.001). We identified copy number variants unique to each group in our cohort, with cell cycle (CDKN2A, CCND1), c-Myc (MYC), RTK/PIK3 (KRAS, EGFR) and gastrointestinal differentiation (GATA6) pathway genes being specifically altered in non-responders. Of note, NAV3 mutations were exclusively present in the non-responder group with a frequency of 22%. Thus, lower mutation burden, higher chromosomal instability and specific copy number alterations are associated with resistance to NAC

Prevalence and Correlates of Common Mental Disorders among Mothers of Young Children in Kilimanjaro Region of Tanzania.

Although poor maternal mental health is a major public health problem, with detrimental effects on the individual, her children and society, information on its correlates in low-income countries is sparse. This study investigates the prevalence of common mental disorders (CMD) among at-risk mothers, and explores its associations with sociodemographic factors. This population-based survey of mothers of children aged 0-36 months used the 14-item Shona Symptom Questionnaire (SSQ). Mothers whose response was "yes" to 8 or more items on the scale were defined as "at risk of CMD." Of the 1,922 mothers (15-48 years), 28.8% were at risk of CMD. Risk of CMD was associated with verbal abuse, physical abuse, a partner who did not help with the care of the child, being in a polygamous relationship, a partner with low levels of education, and a partner who smoked cigarettes. Cohabiting appeared to be protective. Taken together, our results indicate the significance of the quality of relations with one's partner in shaping maternal mental health. The high proportion of mothers who are at risk of CMD emphasizes the importance of developing evidence-based mental health programmes as part of the care package aimed at improving maternal well-being in Tanzania and other similar settings

Resolving the far-IR line deficit : photoelectric heating and far-IR line cooling in NGC 1097 and NGC 4559

The physical state of interstellar gas and dust is dependent on the processes which heat and cool this medium. To probe heating and cooling of the interstellar medium over a large range of infrared surface brightness, on sub-kiloparsec scales, we employ line maps of [C II] 158 mu m, [O I] 63 mu m, and [N II] 122 mu m in NGC 1097 and NGC 4559, obtained with the Photodetector Array Camera & Spectrometer on board Herschel. We matched new observations to existing Spitzer Infrared Spectrograph data that trace the total emission of polycyclic aromatic hydrocarbons (PAHs). We confirm at small scales in these galaxies that the canonical measure of photoelectric heating efficiency, ([C II] + [O I])/TIR, decreases as the far-infrared (far-IR) color, nu f(nu)(70 mu m) nu f(nu)(100 mu m), increases. In contrast, the ratio of far-IR cooling to total PAH emission, ([C II] + [O I])/PAH, is a near constant similar to 6% over a wide range of far-IR color, 0.5 , derived from models of the IR spectral energy distribution. Emission from regions that exhibit a line deficit is characterized by an intense radiation field, indicating that small grains are susceptible to ionization effects. We note that there is a shift in the 7.7/11.3 mu m PAH ratio in regions that exhibit a deficit in ([C II] + [O I])/PAH, suggesting that small grains are ionized in these environments

Variability in Biomarkers of Arsenic Exposure and Metabolism in Adults over Time

Background: Urinary arsenic metabolites (UAs) are used as biomarkers of exposure and metabolism. Ojectives: To characterize inter- and intraindividual variability in UAs in healthy individuals. Methods: In a longitudinal study conducted in Bangladesh, we collected water and spot urine samples from 196 participants every 3 months for 2 years. Water arsenic (As) was measured by inductively coupled plasma-mass spectrometry and urinary As [arsenite, arsenate, monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA)] were detected using high-performance liquid chromatography-hydride-generated atomic absorption spectrometry. We used linear mixed-effects models to compute variance components and evaluate the association between UAs and selected factors. Results: The concentrations of UAs were fairly reproducible within individuals, with intraclass correlation coefficients (ICCs) of 0.41, 0.35, 0.47, and 0.49 for inorganic As (InAs), MMA, DMA, and total urinary As (TUA). However, when expressed as a ratio, the percent InAs (%InAs), %MMA, and %DMA were poorly reproducible within individuals, with ICCs of 0.16, 0.16, and 0.17, respectively. Arsenic metabolism was significantly associated with sex, exposure, age, smoking, chewing betel nut, urinary creatinine, and season. Specificity and sensitivity analyses showed that a single urine sample adequately classified a participant's urinary As profile as high or low, but TUA had only moderate specificity for correctly classifying drinking water exposures. Conclusions: Epidemiologic studies should use both urinary As concentrations and the relative proportion of UAs to minimize measurement error and to facilitate interpretation of factors that influence As metabolism

The effect of maternal common mental disorders on infant undernutrition in Butajira, Ethiopia: The P-MaMiE study

BACKGROUND: Although maternal common mental disorder (CMD) appears to be a risk factor for infant undernutrition in South Asian countries, the position in sub-Saharan Africa (SSA) is unclear METHODS: A population-based cohort of 1065 women, in the third trimester of pregnancy, was identified from the demographic surveillance site (DSS) in Butajira, to investigate the effect of maternal CMD on infant undernutrition in a predominantly rural Ethiopian population. Participants were interviewed at recruitment and at two months post-partum. Maternal CMD was measured using the locally validated Self-Reported Questionnaire (score of > or = six indicating high levels of CMD). Infant anthropometry was recorded at six and twelve months of age. RESULT: The prevalence of CMD was 12% during pregnancy and 5% at the two month postnatal time-point. In bivariate analysis antenatal CMD which had resolved after delivery predicted underweight at twelve months (OR = 1.71; 95% CI: 1.05, 2.50). There were no other statistically significant differences in the prevalence of underweight or stunted infants in mothers with high levels of CMD compared to those with low levels. The associations between CMD and infant nutritional status were not significant after adjusting for pre-specified potential confounders. CONCLUSION: Our negative finding adds to the inconsistent picture emerging from SSA. The association between CMD and infant undernutrition might be modified by study methodology as well as degree of shared parenting among family members, making it difficult to extrapolate across low- and middle-income countries

Modulation of glutaredoxin in the lung and sputum of cigarette smokers and chronic obstructive pulmonary disease

BACKGROUND: One typical feature in chronic obstructive pulmonary disease (COPD) is the disturbance of the oxidant/antioxidant balance. Glutaredoxins (Grx) are thiol disulfide oxido-reductases with antioxidant capacity and catalytic functions closely associated with glutathione, the major small molecular weight antioxidant of human lung. However, the role of Grxs in smoking related diseases is unclear. METHODS: Immunohistochemical and Western blot analyses were conducted with lung specimens (n = 45 and n = 32, respectively) and induced sputum (n = 50) of healthy non-smokers and smokers without COPD and at different stages of COPD. RESULTS: Grx1 was expressed mainly in alveolar macrophages. The percentage of Grx1 positive macrophages was significantly lower in GOLD stage IV COPD than in healthy smokers (p = 0.021) and the level of Grx1 in total lung homogenate decreased both in stage I–II (p = 0.045) and stage IV COPD (p = 0.022). The percentage of Grx1 positive macrophages correlated with the lung function parameters (FEV1, r = 0.45, p = 0.008; FEV1%, r = 0.46, p = 0.007, FEV/FVC%, r = 0.55, p = 0.001). Grx1 could also be detected in sputum supernatants, the levels being increased in the supernatants from acute exacerbations of COPD compared to non-smokers (p = 0.013) and smokers (p = 0.051). CONCLUSION: The present cross-sectional study showed that Grx1 was expressed mainly in alveolar macrophages, the levels being decreased in COPD patients. In addition, the results also demonstrated the presence of Grx1 in extracellular fluids including sputum supernatants. Overall, the present study suggests that Grx1 is a potential redox modulatory protein regulating the intracellular as well as extracellular homeostasis of glutathionylated proteins and GSH in human lung