ABCG5 and ABCG8: More Than a Defense Against Xenosterols

The elucidation of the molecular basis of the rare disease, sitosterolemia, has revolutionized our mechanistic understanding of how dietary sterols are excreted and how cholesterol is eliminated from the body. Two proteins, ABCG5 and ABCG8, encoded by the sitosterolemia locus, work as obligate dimers to pump sterols out of hepatocytes and enterocytes. ABCG5/ABCG8 are key in regulating whole-body sterol trafficking, by eliminating sterols via the biliary tree as well as the intestinal tract. Importantly, these transporters keep xenosterols from accumulating in the body. The sitosterolemia locus has been genetically associated with lipid levels and downstream atherosclerotic disease, as well as formation of gallstones and the risk of gallbladder cancer. While polymorphic variants raise or lower the risks of these phenotypes, loss of function of this locus leads to more dramatic phenotypes, such as premature atherosclerosis, platelet dysfunction, and thrombocytopenia, and, perhaps, increased endocrine disruption and liver dysfunction. Whether small amounts of xenosterol exposure over a lifetime cause pathology in normal humans with polymorphic variants at the sitosterolemia locus remains largely unexplored. The purpose of this review will be to summarize the current state of knowledge, but also highlight key conceptual and mechanistic issues that remain to be explored

Methodological considerations for neuroimaging in deep brain stimulation of the subthalamic nucleus in Parkinson’s disease patients

Deep brain stimulation (DBS) of the subthalamic nucleus is a neurosurgical intervention for Parkinson’s disease patients who no longer appropriately respond to drug treatments. A small fraction of patients will fail to respond to DBS, develop psychiatric and cognitive side-effects, or incur surgery-related complications such as infections and hemorrhagic events. In these cases, DBS may require recalibration, reimplantation, or removal. These negative responses to treatment can partly be attributed to suboptimal pre-operative planning procedures via direct targeting through low-field and low-resolution magnetic resonance imaging (MRI). One solution for increasing the success and efficacy of DBS is to optimize preoperative planning procedures via sophisticated neuroimaging techniques such as high-resolution MRI and higher field strengths to improve visualization of DBS targets and vasculature. We discuss targeting approaches, MRI acquisition, parameters, and post-acquisition analyses. Additionally, we highlight a number of approaches including the use of ultra-high field (UHF) MRI to overcome limitations of standard settings. There is a trade-off between spatial resolution, motion artifacts, and acquisition time, which could potentially be dissolved through the use of UHF-MRI. Image registration, correction, and post-processing techniques may require combined expertise of traditional radiologists, clinicians, and fundamental researchers. The optimization of pre-operative planning with MRI can therefore be best achieved through direct collaboration between researchers and clinicians

An examination of five theoretical foundations associated with localized thermosensory testing

Purpose: To assess five theoretical foundations underlying thermosensory testing using local thermal stimuli. Methods: Thermal sensation, discomfort and the confidence of thermal sensation scores were measured in 9 female and 8 male volunteers in response to 17 physical contact temperature stimuli, ranging between 18–42 °C. These were applied to their dorsal forearm and lateral torso, across two sessions. Results: Thermal sensation to physical temperature relationships followed a positive linear and sigmoidal fit at both forearm (r2 = 0.91/r2 = 0.91, respectively) and lateral torso (r2 = 0.90/ r2 = 0.91, respectively). Thermal discomfort to physical temperature relationships followed second and third-order fits at both forearm (r2 = 0.33/r2 = 0.34, respectively) and lateral torso (r2 = 0.38/r2 = 0.39, respectively) test sites. There were no sex-related or regional site differences in thermal sensation and discomfort across a wide range of physical contact temperatures. The median confidence of an individual’s thermal sensation rating was measured at 86%. Conclusion: The relation between thermal sensation and physical contact temperature was well described by both linear and sigmoidal models, i.e., the distance between the thermal sensation anchors is close to equal in terms of physical temperatures changes for the range studied. Participants rated similar thermal discomfort level in both cold and hot thermal stimuli for a given increase or decrease in physical contact temperature or thermal sensation. The confidence of thermal sensation rating did not depend on physical contact temperature

Reaction mechanism of dimethyl ether carbonylation to methyl acetate over mordenite: a combined DFT/experimental study

Dimethyl ether carbonylation to methyl acetate over mordenite was studied theoretically with density functional theory calculations and experimentally in a fixed bed flow reactor. A new reaction path to methyl acetate entirely in the 8 membered ring was discovered.</p

Muscle Loss Is Associated with Overall Survival in Patients with Metastatic Colorectal Cancer Independent of Tumor Mutational Status and Weight Loss

Background: Survival in patients with metastatic colorectal cancer (mCRC) has been associated with tumor mutational status, muscle loss, and weight loss. We sought to explore the combined effects of these variables on overall survival. Materials and methods: We performed an observational cohort study, prospectively enrolling patients receiving chemotherapy for mCRC. We retrospectively assessed changes in muscle (using computed tomography) and weight, each dichotomized as >5% or ≤5% loss, at 3, 6, and 12 months after diagnosis of mCRC. We used regression models to assess relationships between tumor mutational status, muscle loss, weight loss, and overall survival. Additionally, we evaluated associations between muscle loss, weight loss, and tumor mutational status. Results: We included 226 patients (mean age 59 ± 13 years, 53% male). Tumor mutational status included 44% wild type, 42% RAS-mutant, and 14% BRAF-mutant. Patients with >5% muscle loss at 3 and 12 months experienced worse survival controlling for mutational status and weight (3 months hazard ratio, 2.66; p 5% muscle loss with BRAF-mutational status at 6 and 12 months. Weight loss was not associated with survival nor mutational status. Conclusion: Increased muscle loss at 3 and 12 months may identify patients with mCRC at risk for decreased overall survival, independent of tumor mutational status. Specifically, >5% muscle loss identifies patients within each category of tumor mutational status with decreased overall survival in our sample. Our findings suggest that quantifying muscle loss on serial computed tomography scans may refine survival estimates in patients with mCRC. Implications for practice: In this study of 226 patients with metastatic colorectal cancer, it was found that losing >5% skeletal muscle at 3 and 12 months after the diagnosis of metastatic disease was associated with worse overall survival, independent of tumor mutational status and weight loss. Interestingly, results did not show a significant association between weight loss and overall survival. These findings suggest that muscle quantification on serial computed tomography may refine survival estimates in patients with metastatic colorectal cancer beyond mutational status

Solution structure and DNA-binding properties of the phosphoesterase domain of DNA ligase D

The phosphoesterase (PE) domain of the bacterial DNA repair enzyme LigD possesses distinctive manganese-dependent 3′-phosphomonoesterase and 3′-phosphodiesterase activities. PE exemplifies a new family of DNA end-healing enzymes found in all phylogenetic domains. Here, we determined the structure of the PE domain of Pseudomonas aeruginosa LigD (PaePE) using solution NMR methodology. PaePE has a disordered N-terminus and a well-folded core that differs in instructive ways from the crystal structure of a PaePE•Mn2+• sulfate complex, especially at the active site that is found to be conformationally dynamic. Chemical shift perturbations in the presence of primer-template duplexes with 3′-deoxynucleotide, 3′-deoxynucleotide 3′-phosphate, or 3′ ribonucleotide termini reveal the surface used by PaePE to bind substrate DNA and suggest a more efficient engagement in the presence of a 3′-ribonucleotide. Spectral perturbations measured in the presence of weakly catalytic (Cd2+) and inhibitory (Zn2+) metals provide evidence for significant conformational changes at and near the active site, compared to the relatively modest changes elicited by Mn2+

Lot quality survey: an appealing method for rapid evaluation of vaccine coverage in developing countries – experience in Turkey

<p>Abstract</p> <p>Background</p> <p>Vaccine-preventable diseases cause significant morbidity and mortality worldwide and in developing countries in particular. Information on coverage and reasons for non-vaccination is vital to enhance overall vaccination activities. Of the several survey techniques available for investigating vaccination coverage in a given setting, the Lot Quality Technique (LQT) remains appealing and could be used in developing countries by local health personnel of district or rural health authorities to evaluate their performance in vaccination and many other health-related programs. This study aimed to evaluate vaccination coverage using LQT in a selected semi-urban setting in Turkey.</p> <p>Methods</p> <p>A LQT-based cross-sectional study was conducted in Kecioren District on a representative sample of residents aged 12–23 months in order to evaluate coverage for routine childhood vaccines, to identify health units with coverage below 75%, and to investigate reasons for non-vaccination.</p> <p>Results</p> <p>Based on self-reports, coverage for BCG, diphtheria-pertussis-tetanus (DPT-3), oral polio-3, hepatitis-3, and measles vaccines ranged between 94–99%. Coverage for measles was below 75% in five lots. The relatively high educational and socioeconomic status of parents in the study group alone could not minimize the "considerable" risk of vaccine-preventable diseases in the District and dictates a continuity of efforts for improving vaccination rates, with special emphasis on measles. We believe that administrative methods should be backed up by household surveys to strengthen vaccination monitoring and that families should be trained and motivated to have their children fully vaccinated according to the recommended schedule and in a timely manner.</p> <p>Conclusion</p> <p>This study identified vaccine coverage for seven routine vaccines completed before the age of 24 months as well as the areas requiring special attention in vaccination services. The LQT, years after its introduction to health-related research, remains an appealing technique for rapid evaluation of the extent of a variety of local health concerns in developing countries, in rural areas in particular, and is very efficient in determining performance of individual subunits in a given service area. Training of local health personnel on use of the LQT could expedite response to local health problems and could even motivate them in conducting their own surveys tailored to their professional interests.</p