In the wake of the worldwide increase in type-2 diabetes, a major focus of research is understanding the signaling pathways impacting this disease. Insulin signaling regulates glucose, lipid, and ...energy homeostasis, predominantly via action on liver, skeletal muscle, and adipose tissue. Precise modulation of this pathway is vital for adaption as the individual moves from the fed to the fasted state. The positive and negative modulators acting on different steps of the signaling pathway, as well as the diversity of protein isoform interaction, ensure a proper and coordinated biological response to insulin in different tissues. Whereas genetic mutations are causes of rare and severe insulin resistance, obesity can lead to insulin resistance through a variety of mechanisms. Understanding these pathways is essential for development of new drugs to treat diabetes, metabolic syndrome, and their complications.
Our knowledge of vitamin D has come a long way since the 100 years it took for doctors to accept, between 1860 and 1890, that both sunlight and cod liver oil (a well-known folk remedy) cured and ...prevented rickets. Vitamins D2/D3 were discovered exactly a hundred years ago, and over the last 50 years vitamin D has been found to have many effects on virtually all human tissues and not just on bone health, while mechanisms affecting the actions of vitamin D at the cellular level are increasingly understood, but deficiency persists globally. Observational studies in humans have shown that better provision of vitamin D is strongly associated, dose-wise, with reductions in current and future health risks in line with the known actions of vitamin D. Randomised controlled trials, commonly accepted as providing a ‘gold standard’ for assessing the efficacy of new forms of treatment, have frequently failed to provide supportive evidence for the expected health benefits of supplementation. Such RCTs, however, have used designs evolved for testing drugs while vitamin D is a nutrient; the appreciation of this difference is critical to identifying health benefits from existing RCT data and for improving future RCT design. This report aims, therefore, to provide a brief overview of the evidence for a range of non-bony health benefits of vitamin D repletion; to discuss specific aspects of vitamin D biology that can confound RCT design and how to allow for them.
Malaria parasites (Plasmodium spp.) and related apicomplexan pathogens contain a nonphotosynthetic plastid called the apicoplast. Derived from an unusual secondary eukaryote-eukaryote endosymbiosis, ...the apicoplast is a fascinating organelle whose function and biogenesis rely on a complex amalgamation of bacterial and algal pathways. Because these pathways are distinct from the human host, the apicoplast is an excellent source of novel antimalarial targets. Despite its biomedical importance and evolutionary significance, the absence of a reliable apicoplast proteome has limited most studies to the handful of pathways identified by homology to bacteria or primary chloroplasts, precluding our ability to study the most novel apicoplast pathways. Here, we combine proximity biotinylation-based proteomics (BioID) and a new machine learning algorithm to generate a high-confidence apicoplast proteome consisting of 346 proteins. Critically, the high accuracy of this proteome significantly outperforms previous prediction-based methods and extends beyond other BioID studies of unique parasite compartments. Half of identified proteins have unknown function, and 77% are predicted to be important for normal blood-stage growth. We validate the apicoplast localization of a subset of novel proteins and show that an ATP-binding cassette protein ABCF1 is essential for blood-stage survival and plays a previously unknown role in apicoplast biogenesis. These findings indicate critical organellar functions for newly discovered apicoplast proteins. The apicoplast proteome will be an important resource for elucidating unique pathways derived from secondary endosymbiosis and prioritizing antimalarial drug targets.
Diabetes is an increasing epidemic; hyperglycemia results from lack of insulin or inadequate insulin secretion following increases in insulin resistance. Huge costs are placed upon sufferers and ...health providers, aggravated as serious and disabling complications develop. Thus, measures to reduce the diabetic burden are public health concerns. Vitamin D, identified ≈100 years ago, promotes calcium absorption and utilization, preventing and curing rickets & osteomalacia. Calcium is necessary for insulin secretion, suggesting vitamin D may contribute to maintaining insulin secretion. Vitamin D, formed in skin in bright sunshine, is scarce in foodstuffs. Data linking hypovitaminosis D to hyperglycemia, type 2 diabetes (T2DM) and metabolic disorders increasing cardiovascular risk metabolic 'syndrome' has accumulated over ≈40 years. Many mechanisms are known whereby hypovitaminosis D could be causal, e.g. by increasing insulin resistance, reducing insulin secretion and increasing autoimmune or inflammatory damage to pancreatic islets. Major questions still to be answered are whether increasing vitamin D status to the maximum seen in healthy people would reduce the risk of diabetes, the severity of the disease or of its complications, including cardiovascular disease. These questions urgently require answers. If on-going/ planned RCTs confirm causality, maintenance of adequate vitamin D status at the population level by food-fortification or supplementation would be cost-effective measures likely to reduce the burden and costs of diabetes to individuals and health services. Additionally, vitamin D(2/3) supplementation is cheap but whether some non-hypercalcemia-inducing analogue may prove safer has not yet been addressed at the population level.
Cytochrome P450 2U1 (CYP2U1) exhibits several distinctive characteristics among the 57 human CYPs, such as its presence in almost all living organisms with a highly conserved sequence, its particular ...gene organization with only five exons, its major location in thymus and brain, and its protein sequence involving an unusually long N-terminal region containing 8 proline residues and an insert of about 20 amino acids containing 5 arginine residues after the transmembrane helix. Few substrates, including fatty acids,
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-arachidonoylserotonin (AS), and some drugs, have been reported so far. However, its biological roles remain largely unknown, even though CYP2U1 mutations have been involved in some pathological situations, such as complicated forms of hereditary spastic paraplegia. These data together with its ability to hydroxylate some fatty acids and AS suggest its possible role in lipid metabolism.
...vesicles containing apicoplast outer-membrane proteins have been observed in T. gondii under both apicoplast-intact and -disrupted conditions 29–33. Because apicoplast outer-membrane proteins tend ...to lack TPs 34 and lumenal apicoplast proteins are absent from these outer-membrane protein–containing vesicles 33, these vesicles suggest two distinct trafficking pathways: one TP-dependent for lumenal proteins and one TP-independent for outer-membrane proteins. ...in blood-stage P. falciparum, the only essential role of PfATG8 is its apicoplast function 49, while it is still debated whether canonical macroautophagy occurs at all in this stage 50. ...it is possible that the apicoplast biogenesis functions of ATG8 and PIs are linked, as the autophagy-related protein ATG18 from both T. gondii and P. falciparum binds PIs 53, 54. ...the current data implicate both autophagy machinery and PIs in a critical step of apicoplast biogenesis, whereas further investigation will uncover their exact molecular mechanisms.
Although geographic ecological studies and observational studies find that ultraviolet B exposure and 25-hydroxyvitamin D 25(OH)D concentrations are inversely correlated with 15-20 types of cancer, ...few randomized controlled trials (RCTs) of vitamin D support those findings. The poor design of some RCTs may account for that lack of support. Most vitamin D RCTs to date have considered the vitamin D dose, rather than initial, final, or changes in, serum 25(OH)D concentrations. Here a model is developed for use in designing and analyzing vitamin D RCTs with application to cancer incidence. The input variables of the model are vitamin D dose, baseline and achieved 25(OH)D concentrations, known rates of cancer for the population, and numbers of participants for the treatment and placebo arms is estimated-vitamin D dosage and numbers of participants are varied to achieve desired hazard ratio significance, using information from two vitamin D RCTs on cancer incidence conducted in Nebraska with good agreement between the model estimates and reported hazard ratios. Further improvements to the conduct of vitamin D RCTs would be to start the trial with a moderate bolus dose to achieve the desired 25(OH)D concentrations, and bloodspot 25(OH)D assay use in summer and winter annually to monitor seasonal and long-term changes in 25(OH)D concentration and compliance, and to allow dosage adjustment for achievement of desired vitamin D status.
Although observational studies of health outcomes generally suggest beneficial effects with, or following, higher serum 25-hydroxyvitamin D 25(OH)D concentrations, randomized controlled trials (RCTs) ...have generally not supported those findings. Here we review results from observational studies and RCTs regarding how vitamin D status affects several nonskeletal health outcomes, including Alzheimer’s disease and dementia, autoimmune diseases, cancers, cardiovascular disease, COVID-19, major depressive disorder, type 2 diabetes, arterial hypertension, all-cause mortality, respiratory tract infections, and pregnancy outcomes. We also consider relevant findings from ecological, Mendelian randomization, and mechanistic studies. Although clear discrepancies exist between findings of observational studies and RCTs on vitamin D and human health benefits these findings should be interpreted cautiously. Bias and confounding are seen in observational studies and vitamin D RCTs have several limitations, largely due to being designed like RCTs of therapeutic drugs, thereby neglecting vitamin D’s being a nutrient with a unique metabolism that requires specific consideration in trial design. Thus, RCTs of vitamin D can fail for several reasons: few participants’ having low baseline 25(OH)D concentrations, relatively small vitamin D doses, participants’ having other sources of vitamin D, and results being analyzed without consideration of achieved 25(OH)D concentrations. Vitamin D status and its relevance for health outcomes can usefully be examined using Hill’s criteria for causality in a biological system from results of observational and other types of studies before further RCTs are considered and those findings would be useful in developing medical and public health policy, as they were for nonsmoking policies. A promising approach for future RCT design is adjustable vitamin D supplementation based on interval serum 25(OH)D concentrations to achieve target 25(OH)D levels suggested by findings from observational studies.
Research has repeatedly shown that familiar and unfamiliar voices elicit different neural responses. But it has also been suggested that different neural correlates associate with the feeling of ...having heard a voice and knowing who the voice represents. The terminology used to designate these varying responses remains vague, creating a degree of confusion in the literature. Additionally, terms serving to designate tasks of voice discrimination, voice recognition, and speaker identification are often inconsistent creating further ambiguities. The present study used event-related potentials (ERPs) to clarify the difference between responses to 1) unknown voices, 2) trained-to-familiar voices as speech stimuli are repeatedly presented, and 3) intimately familiar voices. In an experiment, 13 participants listened to repeated utterances recorded from 12 speakers. Only one of the 12 voices was intimately familiar to a participant, whereas the remaining 11 voices were unfamiliar. The frequency of presentation of these 11 unfamiliar voices varied with only one being frequently presented (the trained-to-familiar voice). ERP analyses revealed different responses for intimately familiar and unfamiliar voices in two distinct time windows (P2 between 200-250 ms and a late positive component, LPC, between 450-850 ms post-onset) with late responses occurring only for intimately familiar voices. The LPC present sustained shifts, and short-time ERP components appear to reflect an early recognition stage. The trained voice equally elicited distinct responses, compared to rarely heard voices, but these occurred in a third time window (N250 between 300-350 ms post-onset). Overall, the timing of responses suggests that the processing of intimately familiar voices operates in two distinct steps of voice recognition, marked by a P2 on right centro-frontal sites, and speaker identification marked by an LPC component. The recognition of frequently heard voices entails an independent recognition process marked by a differential N250. Based on the present results and previous observations, it is proposed that there is a need to distinguish between processes of voice "recognition" and "identification". The present study also specifies test conditions serving to reveal this distinction in neural responses, one of which bears on the length of speech stimuli given the late responses associated with voice identification.
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