A truncated lipoglycan from mycobacteria with altered immunological properties

Maintenance of cell-wall integrity in Mycobacterium tuberculosis is essential and is the target of several antitubercular drugs. For example, ethambutol targets arabinogalactan and lipoarabinomannan (LAM) biosynthesis through the inhibition of several arabinofuranosyltransferases. Apart from their role in cell-wall integrity, mycobacterial LAMs also exhibit important immunomodulatory activities. Here we report the isolation and detailed structural characterization of a unique LAM molecule derived from Mycobacterium smegmatis deficient in the arabinofuranosyltransferase AftC (AftC-LAM). This mutant LAM expresses a severely truncated arabinan domain completely devoid of 3,5-Araf–branching residues, revealing an intrinsic involvement of AftC in the biosynthesis of LAM. Furthermore, we found that ethambutol efficiently inhibits biosynthesis of the AftC-LAM arabinan core, unambiguously demonstrating the involvement of the arabinofuranosyltransferase EmbC in early stages of LAM-arabinan biosynthesis. Finally, we demonstrate that AftC-LAM exhibits an enhanced proinflammatory activity, which is due to its ability to activate Toll-like receptor 2 (TLR2). Overall, our efforts further describe the mechanism of action of an important antitubercular drug, ethambutol, and demonstrate a role for specific arabinofuranosyltransferases in LAM biosynthesis. In addition, the availability of sufficient amounts of chemically defined wild-type and isogenic truncated LAMs paves the way for further investigations of the structure–function relationship of TLR2 activation by mycobacterial lipoglycans

Risk factors and cardio-metabolic outcomes associated with metabolic-associated fatty liver disease in childhood

Background Non-Alcoholic Fatty Liver Disease (NAFLD) is defined as increased liver fat percentage, and is the most common chronic liver disease in children. Rather than NAFLD, Metabolic-Associated Fatty Liver Disease (MAFLD), defined as increased liver fat with presence of adverse cardio-metabolic measures, might have more clinical relevance in children. We assessed the prevalence, risk-factors and cardio-metabolic outcomes of MAFLD at school-age. Methods This cross-sectional analysis was embedded in an ongoing population-based prospective cohort study started in 2001, in the Netherlands. In 1910 children of 10 years, we measured liver fat fraction by magnetic resonance imaging (MRI), body mass index (BMI), blood pressure, and lipids, insulin, and glucose concentrations. Childhood lifestyle factors were obtained through questionnaires. MAFLD was defined as ≥2% liver fat in addition to excess adiposity (BMI or visceral adiposity), presence of metabolic risk (blood pressure, triglycerides and HDL-concentrations) or prediabetes (glucose). Findings Of all children, 49.6% had ≥2% liver fat, and 25.2% fulfilled the criteria of MAFLD. Only non-European descent was associated with increased odds of MAFLD at nominal significance (Odds Ratio 1.38, 95% Confidence Interval 1.04, 1.82). Compared to children with <2% liver fat, those with MAFLD had increased odds of cardio-metabolic-risk-factor clustering (Odds Ratio 7.65, 95% Confidence Interval 5.04, 11.62). Interpretation In this study, no NAFLD-associated childhood risk factors were associated with increased odds of childhood MAFLD, yet the findings suggest that ethnicity could be, despite mostly explained by socio-economic factors. Use of MAFLD criteria, rather than NAFLD, may identify children at risk for impaired cardio-metabolic health. Funding Erasmus University MC, the Netherlands Organisation for Health Research and Development, the Ministry of Health, Welfare, and Sport, and the European Research Council.The general design of the Generation R Study was made possible by financial support from the Erasmus University Medical Center, the Netherlands Organisation for Health Research and Development, and the Ministry of Health, Welfare, and Sport. The study was supported by the European Research Council (Consolidator Grant ERC-2014-CoG-648916), and the European Union’s Horizon 2020 research and innovation program (Grant Agreement No. 733206 LifeCycle). We gratefully acknowledge the contribution of the participating children, their mothers, general practitioners, hospitals, midwives, and pharmacies in Rotterdam. We additionally would like to thank the staff of the data collection team and data-management team of Generation R for their work that resulted in the population data

Maternal Early-Pregnancy Glucose Concentrations and Liver Fat Among School-Age Children

Background and Aims: Gestational diabetes seems to be associated with offspring NAFLD. We hypothesized that maternal glucose concentrations across the full range may have persistent effects on offspring liver fat accumulation. Approach and Results: In a multiethnic, population-based, prospective cohort study among 2,168 women and their offspring, maternal early-pregnancy glucose concentrations were measured at a median of 13.1 weeks’ gestation (95% CI, 9.6-17.2). Liver fat fraction was measured at 10 years by MRI. NAFLD was defined as liver fat fraction ≥5.0%. We performed analyses among all mothers with different ethnic backgrounds and those of European ancestry only. The multiethnic group had a median maternal early-pregnancy glucose concentration of 4.3 mmol/L (interquartile range, 3.9-4.9) and a 2.8% (n = 60) prevalence of NAFLD. The models adjusted for child age and sex only showed that in the multiethnic group, higher maternal early-pregnancy glucose concentrations were associated with higher liver fat accumulation and higher odds of NAFLD, but these associations attenuated into nonsignificance after adjustment for potential confounders. Among mothers of European ancestry only, maternal early-pregnancy glucose concentrations were associated with increased odds of NAFLD (OR, 1.95; 95% CI, 1.32; 2.88, after adjustment for confounders) per 1-mmol/L increase in maternal early-pregnancy glucose concentration. These associations were not explained by maternal prepregnancy and childhood body mass index, visceral fat, and metabolic markers. Conclusions: In this study, maternal early-pregnancy glucose concentrations were only among mothers of European ancestry associated with offspring NAFLD. The associations of higher maternal early-pregnancy glucose concentrations with offspring NAFLD may differ between ethnic groups.</p

Effectiveness of cognitive remediation in depression:a meta-analysis

Background Preliminary evidence suggests beneficial effects of cognitive remediation in depression. An update of the current evidence is needed. The aim was to systematically assess the effectiveness of cognitive remediation in depression on three outcomes. Methods The meta-analysis was pre-registered on PROSPERO (CRD42019124316). PubMed, PsycINFO, Embase and Cochrane Library were searched on 2 February 2019 and 8 November 2020 for peer-reviewed published articles. We included randomized and non-randomized clinical trials comparing cognitive remediation to control conditions in adults with primary depression. Random-effects models were used to calculate Hedges' g, and moderators were assessed using mixed-effects subgroup analyses and meta-regression. Main outcome categories were post-treatment depressive symptomatology (DS), cognitive functioning (CF) and daily functioning (DF). Results We identified 5221 records and included 21 studies reporting on 24 comparisons, with 438 depressed patients receiving cognitive remediation and 540 patients in a control condition. We found a small effect on DS (g = 0.28, 95% CI 0.09-0.46, I2 40%), a medium effect on CF (g = 0.60, 95% CI 0.37-0.83, I2 44%) and a small effect on DF (g = 0.22, 95% CI 0.06-0.39, I2 3%). There were no significant effects at follow-up. Confounding bias analyses indicated possible overestimation of the DS and DF effects in the original studies. Conclusions Cognitive remediation in depression improves CF in the short term. The effects on DS and DF may have been overestimated. Baseline depressive symptom severity should be considered when administering cognitive remediation

Augmenting neurocognitive remediation therapy to Preventive Cognitive Therapy for partially remitted depressed patients:protocol of a pragmatic multicentre randomised controlled trial

Introduction Major depressive disorder (MDD) affects 163 million people globally every year. Individuals who experience subsyndromal depressive symptoms during remission (ie, partial remission of MDD) are especially at risk for a return to a depressive episode within an average of 4 months. Simultaneously, partial remission of MDD is associated with work and (psycho)social impairment and a lower quality of life. Brief psychological interventions such as preventive cognitive therapy (PCT) can reduce depressive symptoms or relapse for patients in partial remission, although achieving full remission with treatment is still a clinical challenge. Treatment might be more effective if cognitive functioning of patients is targeted as well since cognitive problems are the most persisting symptom in partial remission and predict poor treatment response and worse functioning. Studies show that cognitive functioning of patients with (remitted) MDD can be improved by online neurocognitive remediation therapy (oNCRT). Augmenting oNCRT to PCT might improve treatment effects for these patients by strengthening their cognitive functioning alongside a psychological intervention. Methods and analysis This study will examine the effectiveness of augmenting oNCRT to PCT in a pragmatic national multicentre superiority randomised controlled trial. We will include 115 adults partially remitted from MDD with subsyndromal depressive symptoms defined as a Hamilton Depression Rating Scale score between 8 and 15. Participants will be randomly allocated to PCT with oNCRT, or PCT only. Primary outcome measure is the effect on depressive symptomatology over 1 year. Secondary outcomes include time to relapse, cognitive functioning, quality of life and healthcare costs. This first dual approach study of augmenting oNCRT to PCT might facilitate full remission in partially remitted individuals as well as prevent relapse over time. Ethics and dissemination Ethical approval was obtained by Academic Medical Center, Amsterdam. Outcomes will be made publicly available

Biomimetic Sniffing Improves the Detection Performance of a 3D Printed Nose of a Dog and a Commercial Trace Vapor Detector

Unlike current chemical trace detection technology, dogs actively sniff to acquire an odor sample. Flow visualization experiments with an anatomically-similar 3D printed dog’s nose revealed the external aerodynamics during canine sniffing, where ventral-laterally expired air jets entrain odorant-laden air toward the nose, thereby extending the “aerodynamic reach” for inspiration of otherwise inaccessible odors. Chemical sampling and detection experiments quantified two modes of operation with the artificial nose-active sniffing and continuous inspiration-and demonstrated an increase in odorant detection by a factor of up to 18 for active sniffing. A 16-fold improvement in detection was demonstrated with a commercially-available explosives detector by applying this bio-inspired design principle and making the device “sniff” like a dog. These lessons learned from the dog may benefit the next-generation of vapor samplers for explosives, narcotics, pathogens, or even cancer, and could inform future bio-inspired designs for optimized sampling of odor plumes.United States. Department of Homeland Security. Advanced Research Projects Agency (Interagency Agreement HSHQPM-13-X-00107)United States. Air Force (Contract FA8721-05-C-0002)United States. Air Force (Contract FA8702-15-D-0001

Classical galactosemia: neuropsychological and psychosocial functioning beyond intellectual abilities

BACKGROUND: Despite early diagnosis and treatment, Classical Galactosemia (CG) patients frequently develop long-term complications, such as cognitive impairment. Available literature primarily reports on general intellectual abilities and shows a substantially lower Full Scale Intelligence Quotient (FSIQ) in CG patients than in the general population. Both problems in social functioning as well as internalizing problems are often reported in CG patients. The combination of intelligence, cognitive functioning, beh

Increased brain-predicted aging in treated HIV disease

Objective: To establish whether HIV disease is associated with abnormal levels of age-related brain atrophy, by estimating apparent brain age using neuroimaging and exploring whether these estimates related to HIV status, age, cognitive performance, and HIV-related clinical parameters. Methods: A large sample of virologically suppressed HIV-positive adults (n = 162, age 45-82 years) and highly comparable HIV-negative controls (n = 105) were recruited as part of the Comorbidity in Relation to AIDS (COBRA) collaboration. Using T1-weighted MRI scans, a machinelearning model of healthy brain aging was defined in an independent cohort (n = 2,001, aged 1890 years). Neuroimaging data from HIV-positive and HIV-negative individuals were then used to estimate brain-predicted age; then brain-predicted age difference (brain-PAD 5 brain-predicted brain age 2 chronological age) scores were calculated. Neuropsychological and clinical assessments were also carried out. Results: HIV-positive individuals had greater brain-PAD score (mean +/- SD 2.15 +/- 7.79 years) compared to HIV-negative individuals (20.87 +/- 8.40 years; b = 3.48, p < 0.01). Increased brainPAD score was associated with decreased performance in multiple cognitive domains (information processing speed, executive function, memory) and general cognitive performance across all participants. Brain-PAD score was not associated with age, duration of HIV infection, or other HIV-related measures. Conclusion: Increased apparent brain aging, predicted using neuroimaging, was observed in HIV-positive adults, despite effective viral suppression. Furthermore, the magnitude of increased apparent brain aging related to cognitive deficits. However, predicted brain age difference did not correlate with chronological age or duration of HIV infection, suggesting that HIV disease may accentuate rather than accelerate brain aging

Maternal iron status in early pregnancy and DNA methylation in offspring: an epigenome-wide meta-analysis

This is the final version. Available on open access from BMC via the DOI in this recordAvailability of data and materials: Full meta-analysis results will be made available through an open access database upon acceptance. Cohort-level data are available from the cohort senior authors upon reasonable request and may be subject to local regulations.BACKGROUND: Unbalanced iron homeostasis in pregnancy is associated with an increased risk of adverse birth and childhood health outcomes. DNA methylation has been suggested as a potential underlying mechanism linking environmental exposures such as micronutrient status during pregnancy with offspring health. We performed a meta-analysis on the association of maternal early-pregnancy serum ferritin concentrations, as a marker of body iron stores, and cord blood DNA methylation. We included 1286 mother-newborn pairs from two population-based prospective cohorts. Serum ferritin concentrations were measured in early pregnancy. DNA methylation was measured with the Infinium HumanMethylation450 BeadChip (Illumina). We examined epigenome-wide associations of maternal early-pregnancy serum ferritin and cord blood DNA methylation using robust linear regression analyses, with adjustment for confounders and performed fixed-effects meta-analyses. We additionally examined whether associations of any CpGs identified in cord blood persisted in the peripheral blood of older children and explored associations with other markers of maternal iron status. We also examined whether similar findings were present in the association of cord blood serum ferritin concentrations with cord blood DNA methylation. RESULTS: Maternal early-pregnancy serum ferritin concentrations were inversely associated with DNA methylation at two CpGs (cg02806645 and cg06322988) in PRR23A and one CpG (cg04468817) in PRSS22. Associations at two of these CpG sites persisted at each of the follow-up time points in childhood. Cord blood serum ferritin concentrations were not associated with cord blood DNA methylation levels at the three identified CpGs. CONCLUSION: Maternal early-pregnancy serum ferritin concentrations were associated with lower cord blood DNA methylation levels at three CpGs and these associations partly persisted in older children. Further studies are needed to uncover the role of these CpGs in the underlying mechanisms of the associations of maternal iron status and offspring health outcomes