Assessment of penetration of Ascorbyl Tetraisopalmitate into biological membranes by molecular dynamics

The present work, involves the simulation of the transport of a vitamin C derivative, Ascorbyl Tetraisopalmitate (ATI), through human skin by molecular dynamics. Percutaneous absorption of the ATI molecule through the infundibulum, an important route of absorption into the hair follicle of the human skin, has been modeled and compared with the stratum corneum membrane. The comparative study was done, using molecular dynamics with Martini force field. In infundibulum, a single ATI molecule require more time to penetrate, and the data obtained suggested that a high concentration of ATI molecule accelerated the process of penetration. In conclusion, the ATI molecule was found to have more affinity towards the stratum corneum as compared towards the infundibulum and it followed a straight pathway to penetrate (until 600 ns of simulation). In infundibulum, it showed less affinity, more mobility and followed a lateral pathway. Thus, this work contributes to a better understanding of the different molecular interactions during percutaneous absorption of active molecules in these two different types of biological membranes.The authors acknowledge financial support from the Brazilian agencies CAPES, Finep and Fapesp (Project FINEP 01.10.0661-00, FAPESP 2011/13250-0, FAPESP 2013/17247-9, FAPESP 2014/05975-2, CAPES 88887068264/2014-00), of Institute of Research and Development, University of Vale Paraíba

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Non-AIDS defining cancers in the D:A:D Study-time trends and predictors of survival : a cohort study

BACKGROUND:Non-AIDS defining cancers (NADC) are an important cause of morbidity and mortality in HIV-positive individuals. Using data from a large international cohort of HIV-positive individuals, we described the incidence of NADC from 2004-2010, and described subsequent mortality and predictors of these.METHODS:Individuals were followed from 1st January 2004/enrolment in study, until the earliest of a new NADC, 1st February 2010, death or six months after the patient's last visit. Incidence rates were estimated for each year of follow-up, overall and stratified by gender, age and mode of HIV acquisition. Cumulative risk of mortality following NADC diagnosis was summarised using Kaplan-Meier methods, with follow-up for these analyses from the date of NADC diagnosis until the patient's death, 1st February 2010 or 6 months after the patient's last visit. Factors associated with mortality following NADC diagnosis were identified using multivariable Cox proportional hazards regression.RESULTS:Over 176,775 person-years (PY), 880 (2.1%) patients developed a new NADC (incidence: 4.98/1000PY [95% confidence interval 4.65, 5.31]). Over a third of these patients (327, 37.2%) had died by 1st February 2010. Time trends for lung cancer, anal cancer and Hodgkin's lymphoma were broadly consistent. Kaplan-Meier cumulative mortality estimates at 1, 3 and 5 years after NADC diagnosis were 28.2% [95% CI 25.1-31.2], 42.0% [38.2-45.8] and 47.3% [42.4-52.2], respectively. Significant predictors of poorer survival after diagnosis of NADC were lung cancer (compared to other cancer types), male gender, non-white ethnicity, and smoking status. Later year of diagnosis and higher CD4 count at NADC diagnosis were associated with improved survival. The incidence of NADC remained stable over the period 2004-2010 in this large observational cohort.CONCLUSIONS:The prognosis after diagnosis of NADC, in particular lung cancer and disseminated cancer, is poor but has improved somewhat over time. Modifiable risk factors, such as smoking and low CD4 counts, were associated with mortality following a diagnosis of NADC

Skin symptoms in bakery and auto body shop workers: associations with exposure and respiratory symptoms

PURPOSE: Despite the importance of skin exposure, studies of skin symptoms in relation to exposure and respiratory symptoms are rare. The goals of this study were to describe exposure-response relationships for skin symptoms, and to investigate associations between skin and respiratory symptoms in bakery and auto body shop workers. METHODS: Data from previous studies of bakery and auto body shop workers were analyzed. Average exposure estimates for wheat allergen and isocyanates were used. Generalized linear models were constructed to describe the relationships between exposure and skin symptoms, as well as between skin and respiratory symptoms. RESULTS: Data from 723 bakery and 473 auto body shop workers were analyzed. In total, 5.3% of bakery and 6.1% of auto body shop workers were female; subjects' mean age was 39 and 38 years, respectively. Exposure-response relationships were observed in auto body shop workers for itchy or dry skin (PR 1.55, 95% CI 1.2-2.0) and work-related itchy skin (PR 1.97, 95% CI 1.2-3.3). A possible exposure-response relationship for work-related itchy skin in bakery workers did not reach statistical significance. In both groups, reporting skin symptoms was strongly and significantly associated with reporting respiratory symptoms, both work-related and non-work-related. CONCLUSIONS: Exposure-response relationships were observed for skin symptoms in auto body shop workers. The lack of significant exposure-response associations in bakery workers should be interpreted cautiously. Workers who reported skin symptoms were up to four times more likely to report respiratory symptoms. Improved awareness of both skin and respiratory outcomes in exposed workers is needed

Optimizing the balance between heterologous acetate- and CO2-reduction pathways in anaerobic cultures of Saccharomyces cerevisiae strains engineered for low-glycerol production

In anaerobic Saccharomyces cerevisiae cultures, NADH (reduced form of nicotinamide adenine dinucleotide)-cofactor balancing by glycerol formation constrains ethanol yields. Introduction of an acetate-to-ethanol reduction pathway based on heterologous acetylating acetaldehyde dehydrogenase (A-ALD) can replace glycerol formation as 'redox-sink' and improve ethanol yields in acetate-containing media. Acetate concentrations in feedstock for first-generation bioethanol production are, however, insufficient to completely replace glycerol formation. An alternative glycerol-reduction strategy bypasses the oxidative reaction in glycolysis by introducing phosphoribulokinase (PRK) and ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO). For optimal performance in industrial settings, yeast strains should ideally first fully convert acetate and, subsequently, continue low-glycerol fermentation via the PRK-RuBisCO pathway. However, anaerobic batch cultures of a strain carrying both pathways showed inferior acetate reduction relative to a strain expressing only the A-ALD pathway. Complete A-ALD-mediated acetate reduction by a dual-pathway strain, grown anaerobically on 50 g L-1 glucose and 5 mmol L-1 acetate, was achieved upon reducing PRK abundance by a C-terminal extension of its amino acid sequence. Yields of glycerol and ethanol on glucose were 55% lower and 6% higher, respectively, than those of a nonengineered reference strain. The negative impact of the PRK-RuBisCO pathway on acetate reduction was attributed to sensitivity of the reversible A-ALD reaction to intracellular acetaldehyde concentrations.BT/Industriele MicrobiologieBT/Biotechnologi

RhoA, RhoB and RhoC differentially regulate endothelial barrier function

RhoGTPases are known regulators of intracellular actin dynamics that are important for maintaining endothelial barrier function. RhoA is most extensively studied as a key regulator of endothelial barrier function, however the function of the 2 highly homologous family-members (> 88%) RhoB and RhoC in endothelial barrier function is still poorly understood. This study aimed to determine whether RhoA, RhoB and RhoC have overlapping or distinct roles in barrier function and permeability in resting and activated endothelium. By using primary endothelial cells in combination with siRNA transfection to establish individual, double or triple knockdown of the RhoA/B/C RhoGTPases, we found that RhoB, but not RhoA or RhoC, is in resting endothelium a negative regulator of permeability. Loss of RhoB accounted for an accumulation of VE-cadherin at cell-cell contacts. Thrombin-induced loss of endothelial integrity is mediated primarily by RhoA and RhoB. Combined loss of RhoA/B showed decreased phosphorylation of Myosin Light Chain and increased expression of VE-cadherin at cell-cell contacts after thrombin stimulation. RhoC contributes to the Rac1-dependent restoration of endothelial barrier function. In summary, this study shows that these highly homologous RhoGTPases differentially control the dynamics of endothelial barrier function

Back to the drawing board-The relationship between self-report and neuropsychological tests of cognitive flexibility in clinical cohorts: A systematic review and meta-analysis

Published online 7 April 2022Cognitive flexibility has been previously described as the ability to adjust cognitive and behavioral strategies in response to changing contextual demands. Cognitive flexibility is typically assessed via self-report questionnaires and performance on neuropsychological tests in research and clinical practice. A common assumption among researchers and clinicians is that self-report and neuropsychological tests of cognitive flexibility assess the same or similar constructs, but the extent of the relationship between these two assessment approaches in clinical cohorts remains unknown. We undertook a systematic review and meta-analysis to determine the relationship between self-report and neuropsychological tests of cognitive flexibility in clinical samples. We searched 10 databases and relevant gray literature (e.g., other databases and pearling) from inception to October 2020 and used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines. Eleven articles including 405 participants satisfied our eligibility criteria. A multilevel random-effects meta-analysis revealed no relationship between self-report and neuropsychological tests of cognitive flexibility (0.01, 95% CI [-0.16 to 0.18]). Individual random-effects meta-analyses between 12 different tests pairs also found no relationship. Based on our results, it is clear that the two assessment approaches of cognitive flexibility provide independent information-they do not assess the same construct. These findings have important ramifications for future research and clinical practice-there is a need to reconsider what constructs self-report and neuropsychological tests of "cognitive flexibility" actually assess, and avoid the interchangeable use of these assessments in clinical samples.Caitlin A. Howlett, Michael A. Wewege, Carolyn Berryman, Annika Oldach, Elizabeth Jennings, Emily Moore, Emma L. Karran, Kimberley Szeto, Leander Pronk, Stephanie Miles, and G. Lorimer Mosele

Same room - different windows? A systematic review and meta-analysis of the relationship between self-report and neuropsychological tests of cognitive flexibility in healthy adults

Cognitive flexibility can be thought of as the ability to effectively adapt one's cognitive and behavioural strategies in response to changing task or environmental demands. To substantiate the common inference that self-report and neuropsychological tests of cognitive flexibility provide ‘different windows into the same room’, we undertook a systematic review and meta-analysis to determine whether self-report and neuropsychological tests of cognitive flexibility are related in healthy adults. Ten databases and relevant grey literature were searched from inception. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were adhered to. Twenty-one articles satisfied our inclusion criteria. A multi-level random-effects meta-analysis revealed no relationship (0.05, 95% CI = −0.00 to 0.10). Random-effects meta-analyses raised the possibility that the Cognitive Flexibility Scale and the Trail Making Test – part B (time) may be related (0.19, 95% CI = 0.06 to 0.31). We conclude that the relationship between self-report and neuropsychological tests of cognitive flexibility is not large enough to be considered convincing evidence for the two assessment approaches sharing construct validity. These results have clear implications for assessing and interpreting cognitive flexibility research and clinical practice.Caitlin A. Howlett, Michael A. Wewege, Carolyn Berryman, Annika Oldach, Elizabeth Jennings, Emily Moore, Emma L. Karran, Kimberley Szeto, Leander Pronk, Stephanie Miles, G. Lorimer Mosele

Skin symptoms in bakery and auto body shop workers: associations with exposure and respiratory symptoms

PURPOSE: Despite the importance of skin exposure, studies of skin symptoms in relation to exposure and respiratory symptoms are rare. The goals of this study were to describe exposure-response relationships for skin symptoms, and to investigate associations between skin and respiratory symptoms in bakery and auto body shop workers. METHODS: Data from previous studies of bakery and auto body shop workers were analyzed. Average exposure estimates for wheat allergen and isocyanates were used. Generalized linear models were constructed to describe the relationships between exposure and skin symptoms, as well as between skin and respiratory symptoms. RESULTS: Data from 723 bakery and 473 auto body shop workers were analyzed. In total, 5.3% of bakery and 6.1% of auto body shop workers were female; subjects' mean age was 39 and 38 years, respectively. Exposure-response relationships were observed in auto body shop workers for itchy or dry skin (PR 1.55, 95% CI 1.2-2.0) and work-related itchy skin (PR 1.97, 95% CI 1.2-3.3). A possible exposure-response relationship for work-related itchy skin in bakery workers did not reach statistical significance. In both groups, reporting skin symptoms was strongly and significantly associated with reporting respiratory symptoms, both work-related and non-work-related. CONCLUSIONS: Exposure-response relationships were observed for skin symptoms in auto body shop workers. The lack of significant exposure-response associations in bakery workers should be interpreted cautiously. Workers who reported skin symptoms were up to four times more likely to report respiratory symptoms. Improved awareness of both skin and respiratory outcomes in exposed workers is needed