Explore the vast range of titles available.

Heme is a cofactor in proteins that function in almost all sub-cellular compartments and in many diverse biological processes. Heme is produced by a conserved biosynthetic pathway that is highly regulated to prevent the accumulation of heme--a cytotoxic, hydrophobic tetrapyrrole. Caenorhabditis elegans and related parasitic nematodes do not synthesize heme, but instead require environmental heme to grow and develop. Heme homeostasis in these auxotrophs is, therefore, regulated in accordance with available dietary heme. We have capitalized on this auxotrophy in C. elegans to study gene expression changes associated with precisely controlled dietary heme concentrations. RNA was isolated from cultures containing 4, 20, or 500 microM heme; derived cDNA probes were hybridized to Affymetrix C. elegans expression arrays. We identified 288 heme-responsive genes (hrgs) that were differentially expressed under these conditions. Of these genes, 42% had putative homologs in humans, while genomes of medically relevant heme auxotrophs revealed homologs for 12% in both Trypanosoma and Leishmania and 24% in parasitic nematodes. Depletion of each of the 288 hrgs by RNA-mediated interference (RNAi) in a transgenic heme-sensor worm strain identified six genes that regulated heme homeostasis. In addition, seven membrane-spanning transporters involved in heme uptake were identified by RNAi knockdown studies using a toxic heme analog. Comparison of genes that were positive in both of the RNAi screens resulted in the identification of three genes in common that were vital for organismal heme homeostasis in C. elegans. Collectively, our results provide a catalog of genes that are essential for metazoan heme homeostasis and demonstrate the power of C. elegans as a genetic animal model to dissect the regulatory circuits which mediate heme trafficking in both vertebrate hosts and their parasites, which depend on environmental heme for survival.

Declining serum concentrations of 25-hydroxyvitamin D seen in the fall and winter as distance increases from the equator may be a factor in the seasonal increased prevalence of influenza and other viral infections. This study was done to determine if serum 25-hydroxyvitamin D concentrations correlated with the incidence of acute viral respiratory tract infections. In this prospective cohort study serial monthly concentrations of 25-hydroxyvitamin D were measured over the fall and winter 2009-2010 in 198 healthy adults, blinded to the nature of the substance being measured. The participants were evaluated for the development of any acute respiratory tract infections by investigators blinded to the 25-hydroxyvitamin D concentrations. The incidence of infection in participants with different concentrations of vitamin D was determined. One hundred ninety-five (98.5%) of the enrolled participants completed the study. Light skin pigmentation, lean body mass, and supplementation with vitamin D were found to correlate with higher concentrations of 25-hydroxyvitamin D. Concentrations of 38 ng/ml or more were associated with a significant (p<0.0001) two-fold reduction in the risk of developing acute respiratory tract infections and with a marked reduction in the percentages of days ill. Maintenance of a 25-hydroxyvitamin D serum concentration of 38 ng/ml or higher should significantly reduce the incidence of acute viral respiratory tract infections and the burden of illness caused thereby, at least during the fall and winter in temperate zones. The findings of the present study provide direction for and call for future interventional studies examining the efficacy of vitamin D supplementation in reducing the incidence and severity of specific viral infections, including influenza, in the general population and in subpopulations with lower 25-hydroxyvitamin D concentrations, such as pregnant women, dark skinned individuals, and the obese.

Obesity is associated with multiple metabolic disturbances and nutritional risks. Minimally invasive small-intestine interventions are being developed as alternatives to bariatric surgery, aiming to induce weight reduction with a lower risk of malabsorption. This 3-year pilot study evaluated the safety, metabolic effects, and nutritional outcomes of a novel incisionless magnetic anastomosis system (IMAS) creating an endoscopic dual-path intestinal diversion in obese subjects. Ten obese adults (mean BMI 41 kg/m2) underwent endoscopic creation of a jejuno-ileal diversion using the IMAS device. The cohort included subjects with normal glycemia, prediabetes, and type 2 diabetes. Clinical and biochemical parameters were monitored at baseline and at 6-, 12-, 18-, 24-, and 36-month visits. Anthropometry and a full micronutrient profile (vitamins A, E, B1-B12, D, folate, ferritin, albumin, total protein) were assessed. Mean body weight decreased from 120.9±17.8 kg to 101.9±22.2 kg after 36 months (p<0.05), with an excess weight loss of 43.2 %. Serum concentrations of most micronutrients remained within physiological limits; only vitamin B12 and 25(OH)D showed significant declines during long-term follow-up. The procedure was generally well tolerated, with mild gastrointestinal symptoms resolving over time. Endoscopically created dual-path intestinal diversion achieved durable weight reduction over 3 years with a favorable nutritional risk profile. The incidence of micronutrient deficiencies was substantially lower than that reported after malabsorptive bariatric surgery. These results support the potential of this incisionless technique as a less invasive option for obesity management and warrant larger controlled trials.

Background: Food insecurity is emerging as an important barrier to antiretroviral (ARV) adherence in sub-Saharan Africa and elsewhere, but little is known about the mechanisms through which food insecurity leads to ARV non-adherence and treatment interruptions. Methodology: We conducted in-depth, open-ended interviews with 47 individuals (30 women, 17 men) living with HIV/AIDS recruited from AIDS treatment programs in Mbarara and Kampala, Uganda to understand how food insecurity interferes with ARV therapy regimens. Interviews were transcribed, coded for key themes, and analyzed using grounded theory. Findings: Food insecurity was common and an important barrier to accessing medical care and ARV adherence. Five mechanisms emerged for how food insecurity can contribute to ARV non-adherence and treatment interruptions or to postponing ARV initiation: 1) ARVs increased appetite and led to intolerable hunger in the absence of food; 2) Side effects of ARVs were exacerbated in the absence of food; 3) Participants believed they should skip doses or not start on ARVs at all if they could not afford the added nutritional burden; 4) Competing demands between costs of food and medical expenses led people either to default from treatment, or to give up food and wages to get medications; 5) While working for food for long days in the fields, participants sometimes forgot medication doses. Despite these obstacles, many participants still reported high ARV adherence and exceptional motivation to continue therapy. Conclusions: While reports from sub-Saharan Africa show excellent adherence to ARVs, concerns remain that these successes are not sustainable in the presence of widespread poverty and food insecurity. We provide further evidence on how food insecurity can compromise sustained ARV therapy in a resource-limited setting. Addressing food insecurity as part of emerging ARV treatment programs is critical for their long-term success.

Background: In several autoimmune diseases, including multiple sclerosis (MS), a compromised regulatory T cell (Treg) function is believed to be critically involved in the disease process. In vitro, the biologically active metabolite of vitamin D has been shown to promote Treg development. A poor vitamin D status has been linked with MS incidence and MS disease activity. In the present study, we assess a potential in vivo correlation between vitamin D status and Treg function in relapsing remitting MS (RRMS) patients. Methodology/Principal Findings: Serum levels of 25-hydroxyvitamin D (25(OH)D) were measured in 29 RRMS patients. The number of circulating Tregs was assessed by flow-cytometry, and their functionality was tested in vitro in a CFSE-based proliferation suppression assay. Additionally, the intracellular cytokine profile of T helper cells was determined directly ex-vivo by flow-cytometry. Serum levels of 25(OH)D correlated positively with the ability of Tregs to suppress T cell proliferation (R = 0.590, P = 0.002). No correlation between 25(OH)D levels and the number of Tregs was found. The IFN-γ/IL-4 ratio (Th1/Th2-balance) was more directed towards IL-4 in patients with favourable 25(OH)D levels (R = −0.435, P = 0.023). Conclusions/Significance: These results show an association of high 25(OH)D levels with an improved Treg function, and with skewing of the Th1/Th2 balance towards Th2. These findings suggest that vitamin D is an important promoter of T cell regulation in vivo in MS patients. It is tempting to speculate that our results may not only hold for MS, but also for other autoimmune diseases. Future intervention studies will show whether modulation of vitamin D status results in modulation of the T cell response and subsequent amelioration of disease activity.

Since the creation of \"Golden Rice\", biofortification of plant-derived foods is a promising strategy for the alleviation of nutritional deficiencies. Potato is the most important staple food for mankind after the cereals rice, wheat and maize, and is extremely poor in provitamin A carotenoids. We transformed potato with a mini-pathway of bacterial origin, driving the synthesis of beta-carotene (Provitamin A) from geranylgeranyl diphosphate. Three genes, encoding phytoene synthase (CrtB), phytoene desaturase (CrtI) and lycopene beta-cyclase (CrtY) from Erwinia, under tuber-specific or constitutive promoter control, were used. 86 independent transgenic lines, containing six different promoter/gene combinations, were produced and analyzed. Extensive regulatory effects on the expression of endogenous genes for carotenoid biosynthesis are observed in transgenic lines. Constitutive expression of the CrtY and/or CrtI genes interferes with the establishment of transgenosis and with the accumulation of leaf carotenoids. Expression of all three genes, under tuber-specific promoter control, results in tubers with a deep yellow (\"golden\") phenotype without any adverse leaf phenotypes. In these tubers, carotenoids increase approx. 20-fold, to 114 mcg/g dry weight and beta-carotene 3600-fold, to 47 mcg/g dry weight. This is the highest carotenoid and beta-carotene content reported for biofortified potato as well as for any of the four major staple foods (the next best event being \"Golden Rice 2\", with 31 mcg/g dry weight beta-carotene). Assuming a beta-carotene to retinol conversion of 6ratio1, this is sufficient to provide 50% of the Recommended Daily Allowance of Vitamin A with 250 gms (fresh weight) of \"golden\" potatoes.

Thiamine (vitamin B1) is an essential molecule for all life forms because thiamine diphosphate (ThDP) is an indispensable cofactor for oxidative energy metabolism. The less abundant thiamine monophosphate (ThMP), thiamine triphosphate (ThTP) and adenosine thiamine triphosphate (AThTP), present in many organisms, may have still unidentified physiological functions. Diseases linked to thiamine deficiency (polyneuritis, Wernicke-Korsakoff syndrome) remain frequent among alcohol abusers and other risk populations. This is the first comprehensive study on the distribution of thiamine derivatives in human biopsies, body fluids and cell lines. Thiamine derivatives were determined by HPLC. In human tissues, the total thiamine content is lower than in other animal species. ThDP is the major thiamine compound and tissue levels decrease at high age. In semen, ThDP content correlates with the concentration of spermatozoa but not with their motility. The proportion of ThTP is higher in humans than in rodents, probably because of a lower 25-kDa ThTPase activity. The expression and activity of this enzyme seems to correlate with the degree of cell differentiation. ThTP was present in nearly all brain and muscle samples and in ∼60% of other tissue samples, in particular fetal tissue and cultured cells. A low ([ThTP]+[ThMP])/([Thiamine]+[ThMP]) ratio was found in cardiovascular tissues of patients with cardiac insufficiency. AThTP was detected only sporadically in adult tissues but was found more consistently in fetal tissues and cell lines. The high sensitivity of humans to thiamine deficiency is probably linked to low circulating thiamine concentrations and low ThDP tissue contents. ThTP levels are relatively high in many human tissues, as a result of low expression of the 25-kDa ThTPase. Another novel finding is the presence of ThTP and AThTP in poorly differentiated fast-growing cells, suggesting a hitherto unsuspected link between these compounds and cell division or differentiation.

Zinc (Zn) is an essential trace element and it is abundant in connective tissues, however biological roles of Zn and its transporters in those tissues and cells remain unknown. Here we report that mice deficient in Zn transporter Slc39a13/Zip13 show changes in bone, teeth and connective tissue reminiscent of the clinical spectrum of human Ehlers-Danlos syndrome (EDS). The Slc39a13 knockout (Slc39a13-KO) mice show defects in the maturation of osteoblasts, chondrocytes, odontoblasts, and fibroblasts. In the corresponding tissues and cells, impairment in bone morphogenic protein (BMP) and TGF-beta signaling were observed. Homozygosity for a SLC39A13 loss of function mutation was detected in sibs affected by a unique variant of EDS that recapitulates the phenotype observed in Slc39a13-KO mice. Hence, our results reveal a crucial role of SLC39A13/ZIP13 in connective tissue development at least in part due to its involvement in the BMP/TGF-beta signaling pathways. The Slc39a13-KO mouse represents a novel animal model linking zinc metabolism, BMP/TGF-beta signaling and connective tissue dysfunction.

Breastfeeding is important for child cognitive development. A study by Caspi et al has suggested that rs174575 within the FADS2 gene moderates this effect so that children homozygous in the minor allele (GG genotype) have similar IQs irrespective of feeding method. In our study of 5934 children aged 8 years, no genetic main effect with IQ was found for rs174575. However, an interaction with this polymorphism was observed such that breastfed GG children performed better than their formula fed counterparts by an additional 5.8 points [1.4, 10.1] (interaction p = 0.0091). Interaction results were attenuated by about 10% after adjustment for 7 factors. This study also investigated rs1535, another FADS2 polymorphism in linkage disequilibrium with rs174575, together with performance and verbal IQ, finding similar results although effect sizes were generally reduced. This study did not replicate the findings of Caspi et al. In contrast to their study, GG children exhibited the greatest difference between feeding methods such that breastfed children performed similarly irrespective of child genotype whereas formula fed GG children performed worse than other children on formula milk. Further studies are required to replicate these findings.

Background: Vitamin D has a potential role in slowing HIV disease progression and preventing mortality based on its extensive involvement in the immune system; however, this relationship has not been examined in large studies or in resource-limited settings. Methodology/Principal Findings: Vitamin D levels were assessed in 884 HIV-infected pregnant women at enrollment in a trial of multivitamin supplementation (not including vitamin D) in Tanzania. Women were followed up for a median of 69.5 months, and information on hemoglobin levels, HIV disease progression, and mortality was recorded. Proportional hazard models and generalized estimating equations were used to assess the relationship of these outcomes with vitamin D status. Conclusions/Significance: Low vitamin D status (serum 25-hydroxyvitamin D<32ng/mL) was significantly associated with progression to WHO HIV disease stage III or greater in multivariate models (incidence rate ratio [RR]: 1.25; 95% confidence intervals [CI]: 1.05, 1.50). No significant relationship was observed between vitamin D status and T-cell counts during follow-up. Women with low vitamin D status had 46% higher risk of developing severe anemia during follow-up, compared to women with adequate vitamin D levels (RR: 1.46; 95% CI: 1.09, 1.96). Women in the highest vitamin D quintile had a 42% lower risk of all-cause mortality, compared to the lowest quintile (RR: 0.58; 95% CI: 0.40, 0.84). Vitamin D status had a protective association with HIV disease progression, all-cause mortality, and development of anemia during follow-up in HIV-infected women. If confirmed in randomized trials, vitamin D supplementation could represent a simple and inexpensive method to prolonging the time to initiation of antiretroviral therapy in HIV-infected patients, particularly in resource-limited settings.