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Alzheimer’s disease (AD) is the most common form of dementia and without readily available clinical biomarkers. Blood-derived proteins are routinely used for diagnostics; however, comprehensive plasma profiling is challenging due to the dynamic range in protein concentrations. Extracellular vesicles (EVs) can cross the blood–brain barrier and may provide a source for AD biomarkers. We investigated plasma-derived EV proteins for AD biomarkers from 10 AD patients, 10 Mild Cognitive Impairment (MCI) patients, and 9 healthy controls (Con) using liquid chromatography-tandem mass spectrometry (LC–MS/MS). The ultracentrifuged EVs were washed and confirmed according to the MISEV2018 guidelines. Some AD patients presented with highly elevated FXIIIA1 (log2 FC: 4.6, p-value: 0.005) and FXIIIB (log2 FC: 4.9, p-value: 0.018). A panel of proteins was identified discriminating Con from AD (AUC: 0.91, CI: 0.67–1.00) with ORM2 (AUC: 1.00, CI: 1.00–1.00), RBP4 (AUC: 0.99, CI: 0.95–1.00), and HYDIN (AUC: 0.89, CI: 0.72–1.00) were found especially relevant for AD. This indicates that EVs provide an easily accessible matrix for possible AD biomarkers. Some of the MCI patients, with similar protein profiles as the AD group, progressed to AD within a 2-year timespan.

Lutein, a type of carotenoids, is found to delay the onset and progression of age-related macular degeneration (AMD). Several lutein supplementation studies showed that after an initial increase, lutein serum levels demonstrated a subsequent decrease despite continuous supplementation. In this systematic literature review, this obscure phenomenon was tried to be explained. The subsequent drop in lutein levels was postulated due to down-regulation of lutein receptors scavenger receptor class B type I (SR-BI) in the gastrointestinal tract, upregulation of lutein degrading enzyme β-carotene dioxygenase (BCDO2), or perhaps a combination of both. Some single nucleotides polymorphisms (SNPs) that could have influence on the occurrence of this phenomenon. To date, an exact scientific explanation for this phenomenon has not been established. Further research is needed to investigate this phenomenon in depth to reach an irrefutable explanation, giving that lutein is proven to be effective in delaying the onset and progression of AMD and its metabolism in the human body becomes of equal importance.

Lutein, a type of carotenoids, is found to delay the onset and progression of age-related macular degeneration (AMD). Several lutein supplementation studies showed that after an initial increase, lutein serum levels demonstrated a subsequent decrease despite continuous supplementation. In this systematic literature review, this obscure phenomenon was tried to be explained. The subsequent drop in lutein levels was postulated due to down-regulation of lutein receptors scavenger receptor class B type I (SR-BI) in the gastrointestinal tract, upregulation of lutein degrading enzyme β-carotene dioxygenase (BCDO2), or perhaps a combination of both. Some single nucleotides polymorphisms (SNPs) that could have influence on the occurrence of this phenomenon. To date, an exact scientific explanation for this phenomenon has not been established. Further research is needed to investigate this phenomenon in depth to reach an irrefutable explanation, giving that lutein is proven to be effective in delaying the onset and progression of AMD and its metabolism in the human body becomes of equal importance.

Partial substitution of wheat flour with orange-fleshed sweet potato (OFSP) purée in bread can increase vitamin A intake among consumers. The study investigated the influence of wheat flour substitution with 20–50% of OFSP purée on proximate composition, color, β-carotene, water activity, and microbial keeping quality. The moisture content, crude protein, crude fat, total ash, crude fiber, and carbohydrate in bread ranged from 28.6–32.7%, 9.9–10.6%, 5.0–5.5%, 1.9–3.2%, 1.4–1.8%, and 79.1–80.9%, respectively. β-carotene, total ash, and crude fiber contents in bread, and Hunter color values a*, b*, chroma, and ∆E significantly increased with the addition of OFSP purée. Total viable counts (TVC), yeast, and molds in bread ranged from 2.82–3.64 log10 cfu/g and 1.48–2.16 log10 cfu/g, respectively, on the last day of storage. Water activity, TVC, and fungal counts were low in sweet potato composite bread as compared to white bread. Total β-carotene in OFSP bread ranged from 1.9–5.4 mg/100 g (on dry weight). One hundred grams of bread portion enriched with 40% and 50% OFSP purée provides more than 50% of vitamin A dietary requirements to children aged 4–8 years. Incorporation of up to 50% OFSP purée in wheat flour produces a relatively shelf-stable, nutritious, and health-promoting functional bread.

Hepatic stellate cells (HSC) store vitamin A as retinyl esters and control circulating retinol levels. Upon liver injury, quiescent (q)HSC lose their vitamin A and transdifferentiate to myofibroblasts, e.g. activated (a)HSC, which promote fibrosis by producing excessive extracellular matrix. Adipose triglyceride lipase/patatin-like phospholipase domain-containing protein 2 (ATGL/PNPLA2) and adiponutrin (ADPN/PNPLA3) have so far been shown to mobilize retinol from retinyl esters in HSC. Here, we studied the putative role of hormone-sensitive lipase (HSL/LIPE) in HSC, as it is the major retinyl ester hydrolase (REH) in adipose tissue.Lipe/HSL expression was analyzed in rat liver and primary human and rat qHSC and culture-activated aHSC. Retinyl hydrolysis was analyzed after Isoproterenol-mediated phosphorylation/activation of HSL.Primary human HSC contain 2.5-fold higher LIPE mRNA levels compared to hepatocytes. Healthy rat liver contains significant mRNA and protein levels of HSL/Lipe, which predominates in qHSC and cells of the portal tree. Q-PCR comparison indicates that Lipe mRNA levels in qHSC are dominant over Pnpla2 and Pnpla3. HSL is mostly phosphorylated/activated in qHSC and partly colocalizes with vitamin A-containing lipid droplets. Lipe/HSL and Pnpla3 expression is rapidly lost during HSC culture-activation, while Pnpla2 expression is maintained. HSL super-activation by isoproterenol accelerates loss of lipid droplets and retinyl palmitate from HSC, which coincided with a small, but significant reduction in HSC proliferation and suppression of Collagen1A1 mRNA and protein levels.In conclusion, HSL participates in vitamin A metabolism in qHSC. Equivalent activities of ATGL and ADPN provide the healthy liver with multiple routes to control circulating retinol levels.

Mechanisms controlling ureter lenght and the position of the kidney are poorly understood. Glial cell-line derived neurotrophic factor (GDNF) induced RET signaling is critical for ureteric bud outgrowth, but the function of endogenous GDNF in further renal differentiation and urogenital system development remains discursive. Here we analyzed mice where 3′ untranslated region (UTR) of GDNF is replaced with sequence less responsive to microRNA-mediated regulation, leading to increased GDNF expression specifically in cells naturally transcribing Gdnf. We demonstrate that increased Gdnf leads to short ureters in kidneys located in an abnormally caudal position thus resembling human pelvic kidneys. High GDNF levels expand collecting ductal progenitors at the expense of ureteric trunk elongation and result in expanded tip and short trunk phenotype due to changes in cell cycle length and progenitor motility. MEK-inhibition rescues these defects suggesting that MAPK-activity mediates GDNF’s effects on progenitors. Moreover, Gdnf hyper mice are infertile likely due to effects of excess GDNF on distal ureter remodeling. Our findings suggest that dysregulation of GDNF levels, for example via alterations in 3′UTR, may account for a subset of congenital anomalies of the kidney and urinary tract (CAKUT) and/or congenital infertility cases in humans and pave way to future studies.

From the mid-19th century until the 1980's, frogs and toads provided important research models for many fundamental questions in visual neuroscience. In the present century, they have been largely neglected. Yet they are animals with highly developed vision, a complex retina built on the basic vertebrate plan, an accessible brain, and an experimentally useful behavioural repertoire. They also offer a rich diversity of species and life histories on a reasonably restricted physiological and evolutionary background. We suggest that important insights may be gained from revisiting classical questions in anurans with state-of-the-art methods. At the input to the system, this especially concerns the molecular evolution of visual pigments and photoreceptors, at the output, the relation between retinal signals, brain processing and behavioural decision-making.

The interaction between host and external environment mainly occurs in the gastrointestinal tract, where the mucosal barrier has a critical role in many physiologic functions ranging from digestion, absorption, and metabolism. This barrier allows the passage and absorption of nutrients, but at the same time, it must regulate the contact between luminal antigens and the immune system, confining undesirable products to the lumen. Diet is an important regulator of the mucosal barrier, and the cross-talk among dietary factors, the immune system, and microbiota is crucial for the modulation of intestinal permeability and for the maintenance of gastrointestinal tract (GI) homeostasis. In the present review, we will discuss the role of a number of dietary nutrients that have been proposed as regulators of inflammation and epithelial barrier function. We will also consider the metabolic function of the microbiota, which is capable of elaborating the diverse nutrients and synthesizing products of great interest. Better knowledge of the influence of dietary nutrients on inflammation and barrier function can be important for the future development of new therapeutic approaches for patients with mucosal barrier dysfunction, a critical factor in the pathogenesis of many GI and non-GI diseases. ispartof: NUTRIENTS vol:12 issue:4 ispartof: location:Switzerland status: published

Following a request from the European Commission, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver an opinion on the safety of an extension of use of the novel food `plant sterol esters' when added to vegetable fat spreads and to liquid vegetable fat-based emulsions for cooking and baking purposes pursuant to Regulation (EU) 2015/2283. Member States expressed concerns in relation to plant sterol oxidation products (POP) and consumption by non-target population groups. The median (0.5%) and P90 (2.28%) value of the oxidation rates of plant sterols determined by a wide range of cooking experiments were used together with exposure estimates for plant sterol when added and cooked with vegetable fat spreads and liquids. The no-observed adverse effect level (NOAEL) of a subchronic rat study and an applied default uncertainty factor of 200 served to derive levels (i.e. 0.64 mg POP/kg body weight (bw) per day) considered safe for humans. This safe level of exposure would be exceeded at the P95 by all age groups when considering the P90 oxidation rate and using EFSA's comprehensive food consumption database for assessing the potential exposure. When considering the median oxidation rate, the safe level of 0.64 mg POP/kg bw per day would be exceeded at the highest P95 intake estimates in children below 9 years of age. When considering an intake of the maximum authorised use level of 3 g plant sterols/person per day and oxidation rates of 0.5% and 2.28%, the resulting daily POP intakes per kg bw by an adult weighing 70 kg would be 0.21 and 0.98 mg/kg bw per day, respectively, the latter value exceeding 0.64 mg/kg bw per day. The Panel concludes that the safety of the intended extension of use of plant sterol esters under the proposed conditions of use has not been established. (C) 2020 European Food Safety Authority. EFSA Journal published by John Wiley and Sons Ltd on behalf of European Food Safety Authority.

Ending all forms of hunger by 2030, as set forward in the UN-Sustainable Development Goal 2 (UN-SDG2), is a daunting but essential task, given the limited timeline ahead and the negative global health and socio-economic impact of hunger. Malnutrition or hidden hunger due to micronutrient deficiencies affects about one third of the world population and severely jeopardizes economic development. Staple crop biofortification through gene stacking, using a rational combination of conventional breeding and metabolic engineering strategies, should enable a leap forward within the coming decade. A number of specific actions and policy interventions are proposed to reach this goal., Nature Communications, 11 (1), ISSN:2041-1723

β-Carotene, the precursor of vitamin-A, is found in fruits and vegetables and routinely ingested as a vital nutritional supplement. Despite its beneficial effects in treating various diseases, the antifibrotic potential of β-carotene has not been reported so far. We report here the effect of β-carotene in ameliorating N′-Nitrosodiethylamine-induced liver injury in rats. The experimental rats were divided into four groups: Control, β-carotene-treated, NDEA-treated and NDEA + β-carotene supplemented group. Hepatic enzymes, malondialdehyde, antioxidant levels, vitamin-A content, histopathology and ultrastructure were examined following sacrifice after two weeks. Activation of HSCs and hepatic inflammation were assessed by immunohistochemistry of α-SMA and COX-2, respectively. NDEA provoked significant increase in liver enzymes, peroxides and depletion of antioxidant enzymes, ATPases and vitamin-A contents. Histopathological and ultrastructural observations revealed alterations in hepatic architecture. Elevated levels of α-SMA and COX-2 signify the activation of HSCs and liver inflammation in NDEA-treated group. Our results show that β-Carotene refurbished antioxidant status and inhibits HSC activation by restoring their shape and vitamin-A contents in rats. It is suggested that β-carotene may be a potential curative bioagent to combat experimental hepatic fibrogenesis.

Birth weight is an important indicator of maternal and fetal health and a predictor of health in later life. However, the determinants of variance in birth weight are still poorly understood. We aimed to identify the biological pathways, which may be perturbed by environmental exposures, that are important in determining birth weight. We applied untargeted mass-spectrometry-based metabolomics to 481 cord blood samples collected at delivery in four birth cohorts from across Europe: ENVIRONAGE (Belgium), INMA (Spain), Piccolipiu (Italy), and Rhea (Greece). We performed a metabolome-wide association scan for birth weight on over 4000 metabolic features, controlling the false discovery rate at 5%. Annotation of compounds was conducted through reference to authentic standards. We identified 68 metabolites significantly associated with birth weight, including vitamin A, progesterone, docosahexaenoic acid, indolelactic acid, and multiple acylcarnitines and phosphatidylcholines. We observed enrichment (p < 0.05) of the tryptophan metabolism, prostaglandin formation, C21-steroid hormone signaling, carnitine shuttle, and glycerophospholipid metabolism pathways. Vitamin A was associated with both maternal smoking and birth weight, suggesting a mediation pathway. Our findings shed new light on the pathways central to fetal growth and will have implications for antenatal and perinatal care and potentially for health in later life. This work has been supported by the Exposomics EC FP7 grant (grant agreement no: 308610). Data collection in the INMA Sabadell cohort was funded by grants from Instituto de Salud Carlos III (Red INMA G03/176) and the Generalitat de Catalunya (CIRIT 1999SGR 00241). O.R. was supported by an MRC Early Career Fellowship. ISGlobal is a member of the CERCA Programme, Generalitat de Catalunya. Piccolipiii was partially funded by the Italian National Centre for Disease Prevention and Control and by the Italian Ministry of Health.

With the arrival of atomic force microscopy (AFM) about thirty years ago, this new imaging tool opened up a new area for the exploration of biological samples, ranging from the tissue and cellular level down to the supramolecular scale. Commercial instruments of this new imaging technique began to appear in the five years following its discovery in 1986 by Binnig, Quate & Gerber. From that point onwards the AFM has attracted many liver biologists, and the number of publications describing structure-function relationships on the diverse set of liver cells has grown steadily ever since. It is therefore timely to reflect on the achievements of AFM in disclosing the cellular architecture of hepatocytes, liver sinusoidal endothelial cells, Kupffer cells, stellate cells and liver-associated natural killer cells. In this thematic paper, we present new data and provide an in-depth overview of the current AFM literature on liver cell biology. We furthermore include a future outlook on how this scanning probe imaging tool and its latest developments can contribute to clarify various structural and functional aspects of cells in liver health and disease. (c) 2017 Elsevier Ltd. All rights reserved.

With the arrival of atomic force microscopy (AFM) about thirty years ago, this new imaging tool opened up a new area for the exploration of biological samples, ranging from the tissue and cellular level down to the supramolecular scale. Commercial instruments of this new imaging technique began to appear in the five years following its discovery in 1986 by Binnig, Quate & Gerber. From that point onwards the AFM has attracted many liver biologists, and the number of publications describing structure-function relationships on the diverse set of liver cells has grown steadily ever since. It is therefore timely to reflect on the achievements of AFM in disclosing the cellular architecture of hepatocytes, liver sinusoidal endothelial cells, Kupffer cells, stellate cells and liver-associated natural killer cells. In this thematic paper, we present new data and provide an in-depth overview of the current AFM literature on liver cell biology. We furthermore include a future outlook on how this scanning probe imaging tool and its latest developments can contribute to clarify various structural and functional aspects of cells in liver health and disease. (c) 2017 Elsevier Ltd. All rights reserved.

Unhealthy conditions of eye/sight in poor communities in South-Saharan African countries are many and becoming a global concern. The aim of the study is to determine the lifestyle variables and their associations with unhealthy ophthalmic conditions of men in a peri-urban community in Ghana. The study was a cross-sectional; involving men aged ≥18 years of age. Data were gathered using WHO Stepwise questionnaires. Analyses included frequencies, Chi-squares, correlations and regressions. The participants were made up of 1449 men. The dietary intakes of vitamin A rich food were so low that they could not be represented quantitatively. About 71.0% of the men were habitual users of alcoholic beverages and 22.0% smoked tobacco. About 21.7% of men had Bitot’s spot while 4.3% had keratomalacia . The logistic regression analysis predicted that alcohol users were about twice more likely to suffer Bitot’s spot (p=0.20) while tobacco smokers were about 3 times and 13 times more likely to suffer from Bitot’s spot (p

The skull bones are formed by osteoblasts by intramembranous ossification. WNT signaling is a regulator of bone formation. Retinoic Acid (RA) act as a teratogen affecting craniofacial development. We evaluated the effects of RA on the differentiation and mineralization of MC-3T3 cells, and on the expression of WNT components. MC-3T3 were cultured with or without 0.5 μM RA in osteogenic medium and mineralization was assessed by alizarin red staining. The expression of osteogenic marker genes and WNT genes was evaluated at several time points up to 28 days. RA significantly inhibited MC-3T3 mineralization (p

Objective:To evaluate the dietary diversity and the nutrient contribution of traditional foods (locally cultivated and wild) by conducting a food intake study in rural Ecuador.Design:Repeated 24 h recalls over a 14 d interval and frequency of consumption served to simulate the usual diet by the Multiple Source Method. Data on missing visits (n 11) were imputed using multivariate imputation by chained equations. The intakes of three macro- and six micronutrients were reported. Nutrient Adequacy Ratios, Mean Adequacy Ratio (MAR), Dietary Species Richness (DSR) and Minimum Dietary Diversity for Women were used as measures of dietary quality. A linear quantile mixed model was used to investigate the association between DSR, local species, MAR, age, education and occupation.Setting:Guasaganda, Cotopaxi (Ecuador).Participants:Rural, indigenous adult women, non-pregnant and not breast-feeding.Results:The studied diet had MAR of 0·78. Consumption of traditional foods contributed 38·6 % of total energy intake. Daily requirements for protein, carbohydrates, Fe and vitamin C were reached. An extra level of consumption of local species was associated with an increase in median MAR for macronutrients of 0·033 (P < 0·001). On the other hand, an extra level of consumption of local species was associated with an increase in median MAR for micronutrients of 0·052 (P < 0·001).Conclusions:We found statistical evidence that traditional foods contribute to adequate intakes of macro- and micronutrients and dietary diversification in the studied population. Future public health interventions should promote the cultivation and consumption of traditional foods to increase the quality of the local diet.

Congenital anomalies of the kidney and urinary tract (CAKUT) are a major cause of pediatric kidney failure. We performed a genome-wide analysis of copy number variants (CNVs) in 2, 824 cases and 21, 498 controls. Affected individuals carried a significant burden of rare exonic (i.e. affecting coding regions) CNVs and were enriched for known genomic disorders (GD). Kidney anomaly (KA) cases were most enriched for exonic CNVs, encompassing GD- CNVs and novel deletions ; obstructive uropathy (OU) had a lower CNV burden and an intermediate prevalence of GD-CNVs ; vesicoureteral reflux (VUR) had the fewest GD-CNVs but was enriched for novel exonic CNVs, particularly duplications. Six loci (1q21, 4p16.1-p16.3, 16p11.2, 16p13.11, 17q12, and 22q11.2) accounted for 65% of patients with GD-CNVs. Deletions at 17q12, 4p16.1- p16.3, and 22q11.2 were specific for KA ; the 16p11.2 locus showed extensive pleiotropy. Using a multidisciplinary approach, we identified TBX6 as a driver for the CAKUT subphenotypes in the 16p11.2 microdeletion syndrome.

Lipoprotein-related receptor protein 2 (LRP2) is important for development of the embryonic neural crest and brain in both mice and humans. Although a role in cardiovascular development can be expected, the hearts of Lrp2 knockout (KO) mice have not yet been investigated. We studied the cardiovascular development of Lrp2 KO mice between embryonic day 10.5 (E10.5) and E15.5, applying morphometry and immunohistochemistry, using antibodies against Tfap2a (neural crest cells), Nkx2.5 (second heart field), WT1 (epicardium derived cells), tropomyosin (myocardium) and LRP2. The Lrp2 KO mice display a range of severe cardiovascular abnormalities, including aortic arch anomalies, common arterial trunk (persistent truncus arteriosus) with coronary artery anomalies, ventricular septal defects, overriding of the tricuspid valve and marked thinning of the ventricular myocardium. Both the neural crest cells and second heart field, which are essential for the lengthening and growth of the right ventricular outflow tract, are abnormally positioned in the Lrp2 KO. This explains the absence of the aorto-pulmonary septum, which leads to common arterial trunk and ventricular septal defects. Severe blebbing of the epicardial cells covering the ventricles is seen. Epithelialmesenchymal transition does occur; however, there are fewer WT1-positive epicardium-derived cells in the ventricular wall as compared to normal, coinciding with the myocardial thinning and deep intertrabecular spaces. LRP2 plays a crucial role in cardiovascular development in mice. This corroborates findings of cardiac anomalies in humans with LRP2 mutations. Future studies should reveal the underlying signaling mechanisms in which LRP2 is involved during cardiogenesis.

Lipoprotein-related receptor protein 2 (LRP2) is important for development of the embryonic neural crest and brain in both mice and humans. Although a role in cardiovascular development can be expected, the hearts of Lrp2 knockout (KO) mice have not yet been investigated. We studied the cardiovascular development of Lrp2 KO mice between embryonic day 10.5 (E10.5) and E15.5, applying morphometry and immunohistochemistry, using antibodies against Tfap2α (neural crest cells), Nkx2.5 (second heart field), WT1 (epicardium derived cells), tropomyosin (myocardium) and LRP2. The Lrp2 KO mice display a range of severe cardiovascular abnormalities, including aortic arch anomalies, common arterial trunk (persistent truncus arteriosus) with coronary artery anomalies, ventricular septal defects, overriding of the tricuspid valve and marked thinning of the ventricular myocardium. Both the neural crest cells and second heart field, which are essential for the lengthening and growth of the right ventricular outflow tract, are abnormally positioned in the Lrp2 KO. This explains the absence of the aorto-pulmonary septum, which leads to common arterial trunk and ventricular septal defects. Severe blebbing of the epicardial cells covering the ventricles is seen. Epithelial-mesenchymal transition does occur; however, there are fewer WT1-positive epicardium-derived cells in the ventricular wall as compared to normal, coinciding with the myocardial thinning and deep intertrabecular spaces. LRP2 plays a crucial role in cardiovascular development in mice. This corroborates findings of cardiac anomalies in humans with LRP2 mutations. Future studies should reveal the underlying signaling mechanisms in which LRP2 is involved during cardiogenesis., Summary: This paper sheds a new light on the role of the second heart field and neural crest cells in outflow tract formation in the mouse embryo. Depletion of the LPR2 results in a disturbed contribution pattern and subsequent common arterial trunk.

Background: Oral leukoplakia is a white patch or plaque that cannot be characterized clinically or pathologically as any other disease and is not associated with any physical or chemical causative agent except the use of tobacco. The prevalence of leukoplakia in India varies from 0.2% to 4.9% with variable clinical pattern and tendency towards malignant transformation. Current treatment strategies for oral leukoplakia include chemotherapeutic and surgical approaches. Aim and Objective: The study was done to compare the clinical and therapeutic effects of proton pump inhibitor therapy and vitamin-A therapy in oral leukoplakia. Setting and Design: Hospital based in-vivo prospective study. Materials and Method: The study compared two treatment groups; Proton pump inhibitor therapy-(Omeprazole - 20 mg) and vitamin-A therapy (200000 I.U.). The clinical assessment (size and surface texture), salivary pH and fractal dimension values were compared in pre-treatment and post-treatment periods. Statistical Analysis: SPSS® 25.0 (Statistical Package for the Social Sciences) was used for statistical analysis. Mean, standard deviation and independent t test were calculated. Results: The clinical assessment of pre-treatment and post-treatment revealed reduction in size and surface roughness in both the groups. The salivary pH and fractal dimension showed significant alterations in post treatment period of both groups but the P value (0.949) was not significant between the groups. Conclusion: This study demonstrated the efficacy of proton pump inhibitor therapy for oral leukoplakia in comparison with vitamin-A therapy. The study revealed reduction in the size, roughness of oral leukoplakia and alteration of salivary pH with proton pump inhibitor therapy.

Ending the tuberculosis (TB) epidemic by 2030 was recently listed in the United Nations (UN) Sustainable Development Goals alongside HIV/AIDS and malaria as it continues to be a major cause of death worldwide. With a significant proportion of TB cases caused by resistant strains of Mycobacterium tuberculosis (Mtb), there is an urgent need to develop new and innovative approaches to treatment. Since 1989, researchers have been assessing the anti-bacterial effects of the active metabolite of vitamin A, all trans-Retinoic acid (ATRA) solution, in Mtb models. More recently the antibacterial effect of ATRA has been shown to regulate the immune response to infection via critical gene expression, monocyte activation and the induction of autophagy leading to its application as a host-directed therapy (HDT). Inhalation is an attractive route for targeted treatment of TB, and therefore we have developed ATRA-loaded microparticles (ATRA-MP) within the inhalable size range (2.07 ± 0.5 µm) offering targeted delivery of the encapsulated cargo (70.5 ± 2.3%) to the site of action within the alveolar macrophage, which was confirmed by confocal microscopy. Efficient cellular delivery of ATRA was followed by a reduction in Mtb growth (H37Ra) in THP-1 derived macrophages evaluated by both the BACT/ALERT® system and enumeration of colony forming units (CFU). The antibacterial effect of ATRA-MP treatment was further assessed in BALB/c mice infected with the virulent strain of Mtb (H37Rv). ATRA-MP treatments significantly decreased the bacterial burden in the lungs alongside a reduction in pulmonary pathology following just three doses administered intratracheally. The immunomodulatory effects of targeted ATRA treatment in the lungs indicate a distinct yet effective mechanism of action amongst the formulations. This is the first study to-date of a controlled release ATRA treatment for TB suitable for inhalation that offers improved targeting of a HDT, retains antibacterial efficacy and improves pulmonary pathology compared to ATRA solution.

Fruit and vegetable intake has been associated with a reduced risk of many chronic diseases. These foods are the main dietary source of carotenoids. The aim of the present study was to evaluate the associations between dietary intake and serum concentrations of &alpha, and &beta, carotene in a sample of young Finnish children from the population-based birth cohort of the Type 1 Diabetes Prediction and Prevention (DIPP) Study. The current analysis comprised 3-day food records and serum samples from 207 children aged 1, 2 and 3 years. Spearman and partial correlations, as well as a cross-classification analyses, were used to assess the relationship between dietary intake and the corresponding biomarkers. Serum concentrations of &alpha, carotene were significantly higher among the 1-year-old compared to the 3-year-old children. Dietary intakes of &alpha, carotene correlated significantly with their respective serum concentrations in all age groups, the association being highest at the age of 1 year (&alpha, carotene r = 0.48, p &lt, 0.001 and &beta, carotene r = 0.47, 0.001), and lowest at the age of 3 years (&alpha, carotene r = 0.44, carotene r = 0.30, 0.001). A cross-classification showed that 72&ndash, 81% of the participants were correctly classified to the same or adjacent quartile, when comparing the reported dietary intakes and the concentrations of the corresponding carotenoid in serum. The 3-day food record seems to be reasonably valid in the assessment of root vegetable consumption among young Finnish children. Root vegetables were the main dietary source of both carotenoids in all age groups. The high consumption of commercial baby foods among the 1-year-old children was reflected in the relatively high dietary intake and serum concentration of both carotenoids.

Summary Background Oral vaccines underperform in low-income and middle-income countries compared with in high-income countries. Whether interventions can improve oral vaccine performance is uncertain. Methods We did a systematic review and meta-analysis of interventions designed to increase oral vaccine efficacy or immunogenicity. We searched Ovid-MEDLINE and Embase for trials published until Oct 23, 2017. Inclusion criteria for meta-analysis were two or more studies per intervention category and available seroconversion data. We did random-effects meta-analyses to produce summary relative risk (RR) estimates. This study is registered with PROSPERO (CRD42017060608). Findings Of 2843 studies identified, 87 were eligible for qualitative synthesis and 66 for meta-analysis. 22 different interventions were assessed for oral poliovirus vaccine (OPV), oral rotavirus vaccine (RVV), oral cholera vaccine (OCV), and oral typhoid vaccines. There was generally high heterogeneity. Seroconversion to RVV was significantly increased by delaying the first RVV dose by 4 weeks (RR 1·37, 95% CI 1·16–1·62) and OPV seroconversion was increased with monovalent or bivalent OPV compared with trivalent OPV (RR 1·51, 95% CI 1·20–1·91). There was some evidence that separating RVV and OPV increased RVV seroconversion (RR 1·21, 95% CI 1·00–1·47) and that higher vaccine inoculum improved OCV seroconversion (RR 1·12, 95% CI 1·00–1·26). There was no evidence of effect for anthelmintics, antibiotics, probiotics, zinc, vitamin A, withholding breastfeeding, extra doses, or vaccine buffering. Interpretation Most strategies did not improve oral vaccine performance. Delaying RVV and reducing OPV valence should be considered within immunisation programmes to reduce global enteric disease. New strategies to address the gap in oral vaccine efficacy are urgently required. Funding Wellcome Trust, Bill & Melinda Gates Foundation, UK Medical Research Council, and WHO Polio Research Committee.

Background Nutritional anaemia and vitamin-A deficiency are public health issues confronting Ghanaian children. Their adverse effects are likely pronounced during the dry season when green leafy vegetables, rich-sources of iron and provitamin-A are scarce. This study assessed the effect of dried green leafy vegetables on anaemia and vitamin-A status of Ghanaian school children. Method This was 3 months pretest, posttest nutrition intervention study. Children 4–9 years were randomized to receive or not receive supplement. High Performance Liquid Chromatography and Haemocue hemoglobinometer were used to determine vitamin-A and haemoglobin concentrations respectively. Malaria-parasitaemia and helminthes were examined by Giemsa-staining and Kato-Katz respectively. Nutritional status was assessed by anthropometry. Student’s t-test was used to establish significant differences between groups. Results At baseline, the mean haemoglobin concentrations of control and supplemental were 116.9 ± 9.9 g/l and 117.6 ± 12.7 g/l respectively. At end-line, it was 121.9 ± 13.5 g/l for supplemental and 113.4 ± 8.5 g/l for control, significant at p = 0.001. At baseline prevalence of anaemia was 37.3 and 41.5% in control and supplemental respectively. At end-line it was 33.3% in supplemental against 57.5% in control, significant at p = 0.024. At baseline mean retinol concentrations were 16.79 ± 8.74 μg/dl and 16.97 ± 7.74 μg/dl for control and supplemental respectively. Mean retinol concentrations for control and supplemental were 24.35 ± 5.50 μg/dl and 26.96 ± 6.86 μg/dl respectively at end-line. At end-line 60% of control against 64.0% of supplemental had low vitamin-A status. At end-line, anaemic-control had mean retinol concentration of 23.78 ± 5.23 μg/dl and anaemic-supplemental had 27.46 ± 7.28 μg/dl. Prevalence of low vitamin-A status was 64.3 and 84.2% in anaemic-control and anaemic-supplemental respectively at baseline but it became 23.1 and 21.1% respectively, at end-line. The mean haemoglobin concentrations of anaemic-control and supplemental were 105.7 ± 7.5 g/l and 113.6 ± 13.6 g/l respectively at end-line. The change in prevalence of anaemia between the anaemic groups was 12.2%, significant at p = 0.042. Conclusion Consumption of green leafy vegetables powder increased mean haemoglobin and retinol concentrations of the study participants. It had the potential to minimize prevalence of anaemia and low vitamin-A status of study participants.

One of the major topics in biophysics and physicobiology is to understand and utilize biological functions using various advanced techniques. Taking advantage of the photoreactivity of the seven-transmembrane rhodopsin protein family has been actively investigated by a variety of methods. Rhodopsins serve as models for membrane-embedded proteins, for photoactive proteins and as a fundamental tool for optogenetics, a new technology to control biological activity with light. In this review, we summarize progress of microbial rhodopsin research from the viewpoint of distribution, diversity and potential.

Salamanders are capable of regenerating amputated limbs by generating a mass of lineage-restricted cells called a blastema. Blastemas only generate structures distal to their origin unless treated with retinoic acid (RA), which results in proximodistal (PD) limb duplications. Little is known about the transcriptional network that regulates PD duplication. In this study, we target specific retinoic acid receptors (RARs) to either PD duplicate (RA treatment or RARγ agonist) or truncate (RARβ antagonist) regenerating limbs. RARE-EGFP reporter axolotls showed divergent reporter activity in limbs undergoing PD duplication versus truncation, suggesting differences in patterning and skeletal regeneration. Transcriptomics identified expression patterns that explain PD duplication, including upregulation of proximal homeobox gene expression and silencing of distal-associated genes, whereas limb truncation was associated with disrupted skeletal differentiation. RARβ antagonism in uninjured limbs induced a loss of skeletal integrity leading to long bone regression and loss of skeletal turnover. Overall, mechanisms were identified that regulate the multifaceted roles of RARs in the salamander limb including regulation of skeletal patterning during epimorphic regeneration, skeletal tissue differentiation during regeneration, and homeostatic regeneration of intact limbs. ispartof: DEVELOPMENT vol:144 issue:4 pages:601-611 ispartof: location:England status: published

Carotenoid-dependent sexual coloration is one of the best-studied sexual signals, but how the honesty of such signals is maintained remains uncertain. The main hypotheses focus on acquisition limits and physiological use of carotenoids in immune function and regulating oxidative stress. A hypothesis that has received less attention states that carotenoids can also be detrimental, depending on an animal's state. Hence, carotenoid-dependent signals may be a handicap, signaling the ability to evade or tolerate detrimental effects of carotenoids. To investigate this hypothesis, we examined the effects of carotenoid supplementation on subsequent reproduction in zebra finches in 2 different foraging environments ("easy" and "hard"), thereby generating variation in physiological state. We find support for context-dependent negative effects of carotenoid supplementation on subsequent laying latency and on total number of eggs laid: carotenoids had a detrimental effect in the "easy" conditions and a beneficial effect in the "hard" conditions. Thus, our results support the hypothesis that carotenoids can have context-dependent detrimental effects. Dissecting the relative contribution of the different mutually nonexclusive honesty mechanisms-acquisition, physiological benefits, and context-dependent detrimental effects of carotenoids-maintaining carotenoid-dependent signal honesty will be an exciting challenge.