Depletion of circulating progenitor cells precedes overt diabetes: A substudy from the VA enhanced fitness trial

BackgroundOne theory of aging and disease development is that chronic injury (pathology) results in activation of regenerative processes and initial repair, with overt disease arising only after exhaustion of reparative capability leads to inadequate repair. While depletion of circulating progenitor cells (CPCs) has been noted in diabetes, the degree to which CPC depletion predates and is associated with propensity to develop overt disease is unclear.MethodsThe Enhanced Fitness trial enrolled overweight/obese (body mass index > 25) sedentary patients with glucose intolerance but without overt diabetes. Baseline CPCs were measured in 129 patients based on the cell surface markers CD34, CD133, and aldehyde dehydrogenase (ALDH) activity. HgbA_1C, fasting insulin and glucose levels, and HOMA calculations were ascertained.ResultsLower counts of early angiogenic CPCs identified as CD34⁺, CD34⁺CD133⁺, and ALDH-bright (ALDH^br) cells were associated with impairments in glucose homeostasis as reflected by HgbA_1C, but not fasting insulin, glucose, or HOMA-IR. These associations remained when corrected for age and cardiovascular risk factors.Conclusions/InterpretationThe numbers of CD34⁺ and ALDH^br CPCs were significantly lower in patients with impaired glucose tolerance. Depletion of reparative capacity as reflected by loss of CPCs may presage overt disease as exemplified in this pre-diabetes model.     

PirB regulates a structural substrate for cortical plasticity

Experience-driven circuit changes underlie learning and memory. Monocular deprivation (MD) engages synaptic mechanisms of ocular dominance (OD) plasticity and generates robust increases in dendritic spine density on L5 pyramidal neurons. Here we show that the paired immunoglobulin-like receptor B (PirB) negatively regulates spine density, as well as the threshold for adult OD plasticity. In PirB^−/− mice, spine density and stability are significantly greater than WT, associated with higher-frequency miniature synaptic currents, larger long-term potentiation, and deficient long-term depression. Although MD generates the expected increase in spine density in WT, in PirB^−/− this increase is occluded. In adult PirB^−/−, OD plasticity is larger and more rapid than in WT, consistent with the maintenance of elevated spine density. Thus, PirB normally regulates spine and excitatory synapse density and consequently the threshold for new learning throughout life.Experience generates both functional and structural changes in neural circuits. The learning process is robust at younger ages during developmental critical periods and continues, albeit at a lower level, into adulthood and old age (1–3). For example, young barn owls exposed to horizontally shifting prismatic spectacles can adapt readily to altered visual input, but adult owls cannot. The experience in the young owls results in a rearranged audiovisual map in tectum that is accompanied by ectopic axonal projections (1). Experience-dependent structural changes have also been observed in the mammalian cerebral cortex. Enriched sensory experience or motor learning are both associated with an increase in dendritic spine density, and a morphological shift from immature thin spines to mushroom spines which harbor larger postsynaptic densities (PSDs) and stronger synapses (4–7). On the flip side, bilateral sensory deprivation induces spine loss (8, 9). Abnormal sensory experience also results in structural modification of inhibitory synapses and circuitry that is temporally and spatially coordinated with changes in excitatory synapses on dendritic spines (10–13).These experience-driven spine changes are thought to involve synaptic mechanisms of long-term potentiation (LTP) and long-term depression (LTD). In hippocampal slices, induction of LTP causes new spines to emerge, as well as spine head enlargement on existing spines (14–16); induction of LTD results in rapid spine regression (14, 17). Importantly, the emergence or regression of spines starts soon after the induction of LTP or LTD, suggesting that these structural changes underlie the persistent expression of long-term plasticity (14, 17).Little is known about molecular mechanisms that restrict experience-dependent plasticity at circuit and synaptic levels and connect it to spine stability. Paired Ig-like receptor B (PirB), a receptor expressed in cortical pyramidal neurons, is known to limit ocular dominance (OD) plasticity both during the critical period and in adulthood (18). PirB binds major histocompatibility class I (MHCI) ligands, whose expression is regulated by visual experience and neural activity (19–21) and thus could act as a key link connecting functional to structural plasticity. If so, mice lacking PirB might be expected to have altered synaptic plasticity rules on the one hand and changes in the density and stability of dendritic spines on the other.     

Integration of responses within and across Arabidopsis natural accessions uncovers loci controlling root systems architecture

Phenotypic plasticity is presumed to be involved in adaptive change toward species diversification. We thus examined how candidate genes underlying natural variation across populations might also mediate plasticity within an individual. Our implementation of an integrative “plasticity space” approach revealed that the root plasticity of a single Arabidopsis accession exposed to distinct environments broadly recapitulates the natural variation “space.” Genome-wide association mapping identified the known gene PHOSPHATE 1 (PHO1) and other genes such as Root System Architecture 1 (RSA1) associated with differences in root allometry, a highly plastic trait capturing the distribution of lateral roots along the primary axis. The response of mutants in the Columbia-0 background suggests their involvement in signaling key modulators of root development including auxin, abscisic acid, and nitrate. Moreover, genotype-by-environment interactions for the PHO1 and RSA1 genes in Columbia-0 phenocopy the root allometry of other natural variants. This finding supports a role for plasticity responses in phenotypic evolution in natural environments.A long-standing debate in evolutionary biology is the relevance of phenotypic plasticity as a mechanism leading to species diversity (1). It has been argued that selection on plasticity responses to environment pressures could underlie fixed phenotypic changes between natural variants (2), providing a potentially rapid mechanism of evolutionary change (3). Thus, we tested the hypothesis that genes that enable a functional response to the environment within a population also underlie adaptive changes across natural variants. Arabidopsis thaliana offers ample opportunity to study genes involved in phenotypic plasticity in response to experimental laboratory perturbations, whereas its natural variants offer the opportunity to study the genetic basis for developmental variation observed in nature. We took a unique approach to integrating results from these two perspectives to uncover the molecular basis underlying individual plasticity and variation among natural variants. We focused on the root architectural system because it shows a high degree of plasticity under diverse environmental conditions (4–9). We used a quantitative phenotyping model to capture and integrate plastic changes in root system architecture in response to a range of experimental treatments within the laboratory reference accession Columbia-0 (Col-0). We next cross-referenced this plasticity space derived for an individual accession (Col-0) to the range of phenotypic differences in root architecture observed across Arabidopsis accessions that represent the extent of natural variation under one condition. This allowed us to identify candidate genes underlying root systems architecture using genome-wide association mapping and to test their role in individual plasticity using mutants.     

Injectable protease-operated depots of glucagon-like peptide-1 provide extended and tunable glucose control

Peptide drugs are an exciting class of pharmaceuticals increasingly used for the treatment of a variety of diseases; however, their main drawback is a short half-life, which dictates multiple and frequent injections and an undesirable “peak-and-valley” pharmacokinetic profile, which can cause undesirable side-effects. Synthetic prolonged release formulations can provide extended release of biologically active native peptide, but their synthetic nature can be an obstacle to production and utilization. Motivated by these limitations, we have developed a new and entirely genetically encoded peptide delivery system—Protease Operated Depots (PODs)—to provide sustained and tunable release of a peptide drug from an injectable s.c. depot. We demonstrate proof-of-concept of PODs, by fusion of protease cleavable oligomers of glucagon-like peptide-1, a type-2 diabetes drug, and a thermally responsive, depot-forming elastin-like-polypeptide that undergoes a thermally triggered inverse phase transition below body temperature, thereby forming an injectable depot. We constructed synthetic genes for glucagon-like peptide-1 PODs and demonstrated their high-yield expression in Escherichia coli and facile purification by a nonchromatographic scheme we had previously developed. Remarkably, a single injection of glucagon-like peptide-1 PODs was able to reduce blood glucose levels in mice for up to 5 d, 120 times longer than an injection of the native peptide drug. These findings demonstrate that PODs provide the first genetically encoded alternative to synthetic peptide encapsulation schemes for sustained delivery of peptide therapeutics.     

Relationship between Anthropometric Measures and Cardiovascular Risk Factors in Children and Adolescents

Background

Obesity has been identified as an important risk factor in the development of cardiovascular diseases; however, other factors, combined or not with obesity, can influence cardiovascular risk and should be considered in cardiovascular risk stratification in pediatrics.

Objective

To analyze the association between anthropometry measures and cardiovascular risk factors, to investigate the determinants to changes in blood pressure (BP), and to propose a prediction equation to waist circumference (WC) in children and adolescents.

Methods

We evaluated 1,950 children and adolescents, aged 7 to 18 years. Visceral fat was assessed by WC and waist hip relationship, BP and body mass index (BMI). In a randomly selected subsample of these volunteers (n = 578), total cholesterol, glucose and triglycerides levels were evaluated.

Results

WC was positively correlated with BMI (r = 0.85; p < 0.001) and BP (SBP r = 0.45 and DBP = 0.37; p < 0.001). Glycaemia and triglycerides showed a weak correlation with WC (r = 0.110; p = 0.008 e r = 0.201; p < 0.001, respectively). Total cholesterol did not correlate with any of the variables. Age, BMI and WC were significant predictors on the regression models for BP (p < 0.001). We propose a WC prediction equation for children and adolescents: boys: y = 17.243 + 0.316 (height in cm); girls: y = 25.197 + 0.256 (height in cm).

Conclusion

WC is associated with cardiovascular risk factors and presents itself as a risk factor predictor of hypertension in children and adolescents. The WC prediction equation proposed by us should be tested in future studies.