Decreased Pyruvate but Not Fatty Acid Driven Mitochondrial Respiration in Skeletal Muscle of Growth Restricted Fetal Sheep.

Fetuses with intrauterine growth restriction (FGR) have impaired oxidative and energy metabolism, with persistent consequences on their postnatal development. In this study, we test the hypothesis that FGR skeletal muscle has lower mitochondrial respiration rate and alters the transcriptomic profiles associated with energy metabolism in an ovine model. At late gestation, mitochondrial oxygen consumption rates (OCRs) and transcriptome profiles were evaluated in the skeletal muscle collected from FGR and control fetuses. The ex vivo mitochondrial OCRs were reduced (p < 0.01) in permeabilized FGR soleus muscle compared to the control muscle but only with pyruvate as the metabolic substrate. Mitochondrial OCRs were similar between the FGR and control groups for palmitoyl-carnitine (fatty acid-driven) or pyruvate plus palmitoyl-carnitine metabolic substrates. A total of 2284 genes were differentially expressed in the semitendinosus muscle from growth restricted fetuses (false discovery rate (FDR) ≤ 0.05). A pathway analysis showed that the upregulated genes (FGR compared to control) were overrepresented for autophagy, HIF-1, AMPK, and FOXO signaling pathways (all with an FDR < 0.05). In addition, the expression of genes modulating pyruvate's entry into the TCA cycle was downregulated, whereas the genes encoding key fatty acid oxidation enzymes were upregulated in the FGR muscle. These findings show that FGR skeletal muscle had attenuated mitochondrial pyruvate oxidation, possibly associated with the inability of pyruvate to enter into the TCA cycle, and that fatty acid oxidation might compensate for the attenuated energy metabolism. The current study provided phenotypic and molecular evidence for adaptive deficiencies in FGR skeletal muscle.

Elevated Norepinephrine Stimulates Adipocyte Hyperplasia in Ovine Fetuses With Placental Insufficiency and IUGR.

Prevailing hypoxemia and hypoglycemia in near-term fetuses with placental insufficiency-induced intrauterine growth restriction (IUGR) chronically increases norepinephrine concentrations, which lower adrenergic sensitivity and lipid mobilization postnatally, indicating a predisposition for adiposity. To determine adrenergic-induced responses, we examined the perirenal adipose tissue transcriptome from IUGR fetuses with or without hypercatecholaminemia. IUGR was induced in sheep with maternal hyperthermia, and hypercatecholaminemia in IUGR was prevented with bilateral adrenal demedullation. Adipose tissue was collected from sham-operated control (CON) and IUGR fetuses and adrenal-demedullated control (CAD) and IUGR (IAD) fetuses. Norepinephrine concentrations were lower in IAD fetuses than in IUGR fetuses despite both being hypoxemic and hypoglycemic. In IUGR fetuses, perirenal adipose tissue mass relative to body mass was greater compared with the CON, adrenal-demedullated control, and IAD groups. Transcriptomic analysis identified 581 differentially expressed genes (DEGs) in CON vs IUGR adipose tissue and 193 DEGs in IUGR vs IAD adipose tissue. Integrated functional analysis of these 2 comparisons showed enrichment for proliferator-activated receptor signaling and metabolic pathways and identified adrenergic responsive genes. Within the adrenergic-regulated DEGs, we identified transcripts that regulate adipocyte proliferation and differentiation: adipogenesis regulatory factor, C/CCAAT/enhancer binding protein α, and sterol carrier protein 2. DEGs associated with the metabolic pathway included pyruvate dehydrogenase kinase 4, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4, IGF-binding proteins (IGFBP-5 and IGFBP-7). Sex-specific expression differences were also found for adipogenesis regulatory factor, pyruvate dehydrogenase kinase 4, IGFBP5, and IGFBP7. These findings indicate that sustained adrenergic stimulation during IUGR leads to adipocyte hyperplasia with alterations in metabolism, proliferation, and preadipocyte differentiation pathways.

Prenatal Oxygen and Glucose Therapy Normalizes Insulin Secretion and Action in Growth-Restricted Fetal Sheep.

Placental insufficiency (PI) lowers fetal oxygen and glucose concentrations, which disrupts glucose-insulin homeostasis and promotes fetal growth restriction (FGR). To date, prenatal treatments for FGR have not attempted to correct the oxygen and glucose supply simultaneously. Therefore, we investigated whether a 5-day correction of oxygen and glucose concentrations in PI-FGR fetuses would normalize insulin secretion and glucose metabolism. Experiments were performed in near-term FGR fetal sheep with maternal hyperthermia-induced PI. Fetal arterial oxygen tension was increased to normal levels by increasing the maternal inspired oxygen fraction and glucose was infused into FGR fetuses (FGR-OG). FGR-OG fetuses were compared with maternal air insufflated, saline-infused fetuses (FGR-AS) and control fetuses. Prior to treatment, FGR fetuses were hypoxemic and hypoglycemic and had reduced glucose-stimulated insulin secretion (GSIS). During treatment, oxygen, glucose, and insulin concentrations increased, and norepinephrine concentrations decreased in FGR-OG fetuses, whereas FGR-AS fetuses were unaffected. On treatment day 4, glucose fluxes were measured with euglycemic and hyperinsulinemic-euglycemic clamps. During both clamps, rates of glucose utilization and production were greater in FGR-AS than FGR-OG fetuses, while glucose fluxes in FGR-OG fetuses were not different than control rates. After 5 days of treatment, GSIS increased in FGR-OG fetuses to control levels and their ex vivo islet GSIS was greater than FGR-AS islets. Despite normalization in fetal characteristics, GSIS, and glucose fluxes, FGR-OG and FGR-AS fetuses weighed less than controls. These findings show that sustained, simultaneous correction of oxygen and glucose normalized GSIS and whole-body glucose fluxes in PI-FGR fetuses after the onset of FGR.

Applying the RISE Model of Resilience in Partners Post-Stroke: A Qualitative Analysis.

BACKGROUND: Resilience is dynamic and influenced by internal and external factors. In persons with chronic illness and/or disability, resilience is viewed as the ability to adapt to new life circumstances. Existing models of resilience typically focus on the absence of deficit and pathology in the individual, overlooking resources, well-being, and broader social impacts. Our proposed novel Relational, Intrapersonal, Social and Environmental (RISE) Model of resilience incorporates and describes the interconnection and influence of constructs that impact resilience and affect the quality of life. PURPOSE: The purpose of this study is to examine the fit of the RISE Model against original interview data obtained from persons with stroke and their partners. METHODS: This study is a secondary analysis of qualitative data collected from post-intervention interviews that were part of an intervention pilot study designed to promote resilience in couples coping with stroke. Interviews were coded to examine relationships between RISE Model constructs. RESULTS: The study included 36 interviews from 18 cohabitating couples; mean participant age was 53.33 years (SD ±14.70). Examples of each construct within the RISE Model appeared in transcribed interviews and common patterns of co-occurring constructs were identified. CONCLUSION: The constructs within the RISE Model were supported by the interviews. The impact of disability does not remain confined to a single individual and instead branches out into the broader social context, including close interpersonal relationships. A deeper understanding of resilience and its relationship with intrapersonal, interpersonal and socio-ecological constructs would add value to our understanding and fostering of resilience in persons with disabilities and/or chronic illness. CLINICAL TRIAL INFORMATION: NCT03335358.

Corn substitution by mesquite bean flour (Prosopis juliflora) maintains growth and improves protein metabolism of Nile tilapia juveniles (Oreochromis niloticus).

The objective of this study was to evaluate the potential of mesquite bean flour (Prosopis juliflora) as an energy ingredient in extruded diets for juvenile Nile tilapia (Oreochromis niloticus). Two experiments were carried out: the first consisted of a study to evaluate the chemical composition and digestibility of the energy and nutrients of MBF; the second consisted of a growth test, in which juveniles consumed diets containing different proportions of corn substitution by MBF, in which zootechnical, hematological, physiological, and metabolic variables were evaluated. It was observed that MBF has a chemical composition similar to corn, as well as the apparent digestibility of energy and nutrients. The higher sucrose/starch ratio of the ingredient stands out, as well as the difference in digestibility (p < 0.05) between the predominant carbohydrates 87.63 and 99.25% for starch and sucrose, respectively. In the growth assay, no difference was observed between zootechnical variables (p > 0.05), and sucrase and alkaline phosphatase activities were increased (p < 0.05), which was not observed for amylase and lipase (p > 0.05). The hematological variables did not change (p > 0.05). Metabolic variables indicate a reduction in gluconeogenesis from amino acids, as can be seen by the reduction in liver transaminase levels (ALT and AST) and glutamate dehydrogenase (GDH), as well as the greater availability of free amino acids in plasmas (p < 0.05). Thus, it can be said that MBF has a high nutritional value and can totally replace corn in diets for juvenile tilapia and the metabolic findings indicate a potential protein-sparing effect.

Augmented glucose production is not contingent on high catecholamines in fetal sheep with IUGR.

Fetuses with intrauterine growth restriction (IUGR) have high concentrations of catecholamines, which lowers the insulin secretion and glucose uptake. Here, we studied the effect of hypercatecholaminemia on glucose metabolism in sheep fetuses with placental insufficiency-induced IUGR. Norepinephrine concentrations are elevated throughout late gestation in IUGR fetuses but not in IUGR fetuses with a bilateral adrenal demedullation (IAD) at 0.65 of gestation. Euglycemic (EC) and hyperinsulinemic-euglycemic (HEC) clamps were performed in control, intact-IUGR, and IAD fetuses at 0.87 of gestation. Compared to controls, basal oxygen, glucose, and insulin concentrations were lower in IUGR groups. Norepinephrine concentrations were five-fold higher in IUGR fetuses than in IAD fetuses. During the EC, rates of glucose entry (GER, umbilical + exogenous), glucose utilization (GUR), and glucose oxidation (GOR) were greater in IUGR groups than in controls. In IUGR and IAD fetuses with euglycemia and euinsulinemia, glucose production rates (GPR) remained elevated. During the HEC, GER and GOR were not different among groups. In IUGR and IAD fetuses, GURs were 40% greater than in controls, which paralleled the sustained GPR despite hyperinsulinemia. Glucose-stimulated insulin concentrations were augmented in IAD fetuses compared to IUGR fetuses. Fetal weights were not different between IUGR groups but were less than controls. Regardless of norepinephrine concentrations, IUGR fetuses not only develop greater peripheral insulin sensitivity for glucose utilization but also develop hepatic insulin resistance because GPR was maintained and unaffected by euglycemia or hyperinsulinemia. These findings show that adaptation in glucose metabolism of IUGR fetuses are independent of catecholamines, which implicate that hypoxemia and hypoglycemia cause the metabolic responses.

Terapias aplicadas no tratamento das lesões por queimaduras de terceiro grau e extensão variável: revisão integrativa / Therapies applied in the treatment of injuries by burns of third degreeand variable extension: an integrative review

RESUMO: Lesões por queimaduras se apresentam como simples ou graves de acordo com sua profundidade, extensão e localização. Diversas terapias são lançadas no mercado, devendo prover um ambiente úmido, amplo aspecto antimicrobiano e serem efetivas, mesmo na presença de grande quantidade de exsudato, visando os benefícios que trarão para o processo de cicatrização. Neste sentido, este estudo objetivou revisar a literatura acerca da caracterização clínica e terapias aplicadas no tratamento das queimaduras de terceiro grau e de extensão variável. Para alcançar o objetivo proposto, foi realizada uma revisão integrativa da literatura nas bases de dados LILACS, BDENF e SciELO. Foram selecionados 17 artigos e os resultados apontaram que os curativos a base de prata são os mais utilizados, dentre eles, sulfadiazina de prata, prata nanocristalina e espuma absorvente. Para casos particulares mais complexos, a matriz de regeneração dérmica assume-se como uma alternativa eficaz e segura. A utilização da terapia por pressão negativa no tratamento da contratura cicatricial, muito presente nas lesões de terceiro grau, agrega como vantagem o fato de o paciente não precisar ficar imobilizado e imóvel após as cirurgias. Dentre as terapias inovadoras no tratamento de queimaduras, evidenciou-se o uso de enxerto da pele de tilápia, que foi citado por um estudo como um possível subproduto com alta aplicabilidade clínica. Ao longo do estudo foi possível concluir que os pacientes necessitam de uma assistência adequada desde os cuidados imediatos até o fim da reabilitação. Com o passar dos anos, inovações terapêuticas vêm sendo estudadas para serem implantadas no tratamento ao paciente queimado, entre elas a substituição de pele vem ganhando espaço pelos resultados positivos. (AU)

ABSTRACT: Burn injuries are classified as simple or severe according to their depth, extent, and location. Several therapies are commercially available, which should provide a humid skin, broad antimicrobial aspect and be effective, even if a large amount of exudate is present, aiming at benefiting the healing process. Therefore, this study aimed to review the literature on the clinical characterization and therapies applied in the treatment of third-degree burns and of variable extension. To reach the proposed objective, an integrative literature review was carried out in the LILACS, BDENF, and SciELO databases. Seventeen papers were selected, and the results showed that silver-based dressings are the most used, and among these, stand out: silver sulfadiazine, nanocrystalline silver, and an absorbent foam. For more complex cases, the dermal regeneration matrix is an effective and safe alternative. The use of negative pressure therapy in the treatment of scar contracture, present in third-degree injuries, has some advantage since the patient does not need to be immobilized and still after the surgeries. Among the innovative therapies in the treatment of burns, the use of tilapia skin graft was evidenced, which was mentioned by a study as a possible by-product with high clinical applicability. Throughout the study, it was possible to conclude that patients need adequate assistance, from immediate care, until the end of the rehabilitation. Over the years, therapeutic innovations have been studied to be implemented in the treatment of burned patients, including the replacement of skin, which has been highlighted due to the positive results. (AU)

Neuroprotective Effects of Chronic Resveratrol Treatment and Exercise Training in the 3xTg-AD Mouse Model of Alzheimer's Disease.

To date, there is no cure or effective treatment for Alzheimer's disease (AD), a chronic neurodegenerative condition that affects memory, language, and behavior. AD is characterized by neuroinflammation, accumulation of brain amyloid-beta (Aß) oligomers and neurofibrillary tangles, increased neuronal apoptosis, and loss of synaptic function. Promoting regular exercise and a diet containing polyphenols are effective non-pharmacological approaches that prevent the progression of neurodegenerative diseases. In this study, we measured various conformational toxic species of Aß and markers of inflammation, apoptosis, endolysosomal degradation, and neuroprotection after 5 months of exercise training (ET), resveratrol (Resv) treatment, or combination treatment in the 3xTg-AD mouse model of AD. Our main results indicate that Resv decreased neuroinflammation and accumulation of Aß oligomers, increased levels of neurotrophins, synaptic markers, silent information regulator, and decreased markers of apoptosis, autophagy, endolysosomal degradation and ubiquitination in the brains of 3xTg-AD mice. ET improved some markers related to neuroprotection, but when combined with Resv treatment, the benefits achieved were as effective as Resv treatment alone. Our results show that the neuroprotective effects of Resv, ET or Resv and ET are associated with reduced toxicity of Aß oligomers, suppression of neuronal autophagy, decreased apoptosis, and upregulation of key growth-related proteins.

Publisher Correction: Non-cuttable material created through local resonance and strain rate effects.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Developmental programming: Prenatal testosterone excess disrupts pancreatic islet developmental trajectory in female sheep.

Prenatal testosterone (T)- treated female sheep manifest juvenile insulin resistance, post-pubertal increase in insulin sensitivity and return to insulin resistance during adulthood. Since compensatory hyperinsulinemia is associated with insulin resistance, altered pancreatic islet ontogeny may contribute towards metabolic defects. To test this, pregnant sheep were treated with or without T propionate from days 30-90 of gestation and pancreas collected from female fetuses at gestational day 90 and female offspring at 21 months-of-age. Uterine (maternal) and umbilical (fetal) arterial blood insulin/glucose ratios were determined at gestational day 90. The morphological and functional changes in pancreatic islet were assessed through detection of 1) islet hormones (insulin, glucagon) and apoptotic beta cells at fetal day 90 and 2) islet hormones (insulin, glucagon and somatostatin), and pancreatic lipid and collagen accumulation in adults. At gestational day 90, T-treatment led to maternal but not fetal hyperinsulinemia, decrease in pancreatic/fetal weight ratio and alpha cells, and a trend for increase in beta cell apoptosis in fetal pancreas. Adult prenatal T-treated female sheep manifested 1) significant increase in beta cell size and a tendency for increase in insulin and somatostatin stained area and proportion of beta cells in the islet; and 2) significant increase in pancreatic islet collagen and a tendency towards increased lipid accumulation. Gestational T-treatment induced changes in pancreatic islet endocrine cells during both fetal and adult ages track the trajectory of hyperinsulinemic status with the increase in adult pancreatic collagen accumulation indicative of impending beta cell failure with chronic insulin resistance.

Chronically elevated norepinephrine concentrations lower glucose uptake in fetal sheep.

Fetal conditions associated with placental insufficiency and intrauterine growth restriction (IUGR) chronically elevate plasma norepinephrine (NE) concentrations. Our objective was to evaluate the effects of chronically elevated NE on insulin-stimulated glucose metabolism in normally grown, non-IUGR fetal sheep, which are independent of other IUGR-related reductions in nutrients and oxygen availability. After surgical placement of catheters, near-term fetuses received either a saline (control) or NE intravenous infusion with controlled euglycemia. In NE fetuses, plasma NE concentrations were 5.5-fold greater than controls, and fetal euglycemia was maintained with a maternal insulin infusion. Insulin secretion was blunted in NE fetuses during an intravenous glucose tolerance test. Weight-specific fluxes for glucose were measured during a euinsulinemic-euglycemic clamp (EEC) and a hyperinsulinemic-euglycemic clamp (HEC). Plasma glucose and insulin concentrations were not different between groups within each clamp, but insulin concentrations increased 10-fold between the EEC and the HEC. During the EEC, rates of glucose uptake (umbilical uptake + exogenous infusion) and glucose utilization were 47% and 35% lower (P < 0.05) in NE fetuses compared with controls. During the HEC, rates of glucose uptake were 28% lower (P < 0.05) in NE fetuses than controls. Glucose production was undetectable in either group, and glucose oxidation was unaffected by the NE infusion. These findings indicate that chronic exposure to high plasma NE concentrations lowers rates of net glucose uptake in the fetus without affecting glucose oxidation rates or initiating endogenous glucose production. Lower fetal glucose uptake was independent of insulin, which indicates insulin resistance as a consequence of chronically elevated NE.

Non-cuttable material created through local resonance and strain rate effects.

We have created a new architected material, which is both highly deformable and ultra-resistant to dynamic point loads. The bio-inspired metallic cellular structure (with an internal grid of large ceramic segments) is non-cuttable by an angle grinder and a power drill, and it has only 15% steel density. Our architecture derives its extreme hardness from the local resonance between the embedded ceramics in a flexible cellular matrix and the attacking tool, which produces high-frequency vibrations at the interface. The incomplete consolidation of the ceramic grains during the manufacturing also promoted fragmentation of the ceramic spheres into micron-size particulate matter, which provided an abrasive interface with increasing resistance at higher loading rates. The contrast between the ceramic segments and cellular material was also effective against a waterjet cutter because the convex geometry of the ceramic spheres widened the waterjet and reduced its velocity by two orders of magnitude. Shifting the design paradigm from static resistance to dynamic interactions between the material phases and the applied load could inspire novel, metamorphic materials with pre-programmed mechanisms across different length scales.

Lower oxygen consumption and Complex I activity in mitochondria isolated from skeletal muscle of fetal sheep with intrauterine growth restriction.

Fetal sheep with placental insufficiency-induced intrauterine growth restriction (IUGR) have lower hindlimb oxygen consumption rates (OCRs), indicating depressed mitochondrial oxidative phosphorylation capacity in their skeletal muscle. We hypothesized that OCRs are lower in skeletal muscle mitochondria from IUGR fetuses, due to reduced electron transport chain (ETC) activity and lower abundances of tricarboxylic acid (TCA) cycle enzymes. IUGR sheep fetuses (n = 12) were created with mid-gestation maternal hyperthermia and compared with control fetuses (n = 12). At 132 ± 1 days of gestation, biceps femoris muscles were collected, and the mitochondria were isolated. Mitochondria from IUGR muscle have 47% lower State 3 (Complex I-dependent) OCRs than controls, whereas State 4 (proton leak) OCRs were not different between groups. Furthermore, Complex I, but not Complex II or IV, enzymatic activity was lower in IUGR fetuses compared with controls. Proteomic analysis (n = 6/group) identified 160 differentially expressed proteins between groups, with 107 upregulated and 53 downregulated mitochondria proteins in IUGR fetuses compared with controls. Although no differences were identified in ETC subunit protein abundances, abundances of key TCA cycle enzymes [isocitrate dehydrogenase (NAD+) 3 noncatalytic subunit ß (IDH3B), succinate-CoA ligase ADP-forming subunit-ß (SUCLA2), and oxoglutarate dehydrogenase (OGDH)] were lower in IUGR mitochondria. IUGR mitochondria had a greater abundance of a hypoxia-inducible protein, NADH dehydrogenase 1α subcomplex 4-like 2, which is known to incorporate into Complex I and lower Complex I-mediated NADH oxidation. Our findings show that mitochondria from IUGR skeletal muscle adapt to hypoxemia and hypoglycemia by lowering Complex I activity and TCA cycle enzyme concentrations, which together, act to lower OCR and NADH production/oxidation in IUGR skeletal muscle.

Postnatal ß2 adrenergic treatment improves insulin sensitivity in lambs with IUGR but not persistent defects in pancreatic islets or skeletal muscle.

KEY POINTS: Previous studies in fetuses with intrauterine growth restriction (IUGR) have shown that adrenergic dysregulation was associated with low insulin concentrations and greater insulin sensitivity. Although whole-body glucose clearance is normal, 1-month-old lambs with IUGR at birth have higher rates of hindlimb glucose uptake, which may compensate for myocyte deficiencies in glucose oxidation. Impaired glucose-stimulated insulin secretion in IUGR lambs is due to lower intra-islet insulin availability and not from glucose sensing. We investigated adrenergic receptor (ADR) ß2 desensitization by administering oral ADRß modifiers for the first month after birth to activate ADRß2 and antagonize ADRß1/3. In IUGR lambs ADRß2 activation increased whole-body glucose utilization rates and insulin sensitivity but had no effect on isolated islet or myocyte deficiencies. IUGR establishes risk for developing diabetes. In IUGR lambs we identified disparities in key aspects of glucose-stimulated insulin secretion and insulin-stimulated glucose oxidation, providing new insights into potential mechanisms for this risk. ABSTRACT: Placental insufficiency causes intrauterine growth restriction (IUGR) and disturbances in glucose homeostasis with associated ß adrenergic receptor (ADRß) desensitization. Our objectives were to measure insulin-sensitive glucose metabolism in neonatal lambs with IUGR and to determine whether daily treatment with ADRß2 agonist and ADRß1/ß3 antagonists for 1 month normalizes their glucose metabolism. Growth, glucose-stimulated insulin secretion (GSIS) and glucose utilization rates (GURs) were measured in control lambs, IUGR lambs and IUGR lambs treated with adrenergic receptor modifiers: clenbuterol atenolol and SR59230A (IUGR-AR). In IUGR lambs, islet insulin content and GSIS were less than in controls; however, insulin sensitivity and whole-body GUR were not different from controls. Of importance, ADRß2 stimulation with ß1/ß3 inhibition increases both insulin sensitivity and whole-body glucose utilization in IUGR lambs. In IUGR and IUGR-AR lambs, hindlimb GURs were greater but fractional glucose oxidation rates and ex vivo skeletal muscle glucose oxidation rates were lower than controls. Glucose transporter 4 (GLUT4) was lower in IUGR and IUGR-AR skeletal muscle than in controls but GLUT1 was greater in IUGR-AR. ADRß2, insulin receptor, glycogen content and citrate synthase activity were similar among groups. In IUGR and IUGR-AR lambs heart rates were greater, which was independent of cardiac ADRß1 activation. We conclude that targeted ADRß2 stimulation improved whole-body insulin sensitivity but minimally affected defects in GSIS and skeletal muscle glucose oxidation. We show that risk factors for developing diabetes are independent of postnatal catch-up growth in IUGR lambs as early as 1 month of age and are inherent to the islets and myocytes.

Increased pyruvate dehydrogenase activity in skeletal muscle of growth-restricted ovine fetuses.

Fetal sheep with placental insufficiency-induced intrauterine growth restriction (IUGR) have lower fractional rates of glucose oxidation and greater gluconeogenesis, indicating lactate shuttling between skeletal muscle and liver. Suppression of pyruvate dehydrogenase (PDH) activity was proposed because of greater pyruvate dehydrogenase kinase (PDK) 4 and PDK1 mRNA concentrations in IUGR muscle. Although PDK1 and PDK4 inhibit PDH activity to reduce pyruvate metabolism, PDH protein concentrations and activity have not been examined in skeletal muscle from IUGR fetuses. Therefore, we evaluated the protein concentrations and activity of PDH and the kinases and phosphatases that regulate PDH phosphorylation status in the semitendinosus muscle from placenta insufficiency-induced IUGR sheep fetuses and control fetuses. Immunoblots were performed for PDH, phosphorylated PDH (E1α), PDK1, PDK4, and pyruvate dehydrogenase phosphatase 1 and 2 (PDP1 and PDP2, respectively). Additionally, the PDH, lactate dehydrogenase (LDH), and citrate synthase (CS) enzymatic activities were measured. Phosphorylated PDH concentrations were 28% lower (P < 0.01) and PDH activity was 67% greater (P < 0.01) in IUGR fetal muscle compared with control. PDK1, PDK4, PDP1, PDP2, and PDH concentrations were not different between groups. CS and LDH activities were also unaffected. Contrary to the previous speculation, PDH activity was greater in skeletal muscle from IUGR fetuses, which parallels lower phosphorylated PDH. Therefore, greater expression of PDK1 and PDK4 mRNA did not translate to greater PDK1 or PDK4 protein concentrations or inhibition of PDH as proposed. Instead, these findings show greater PDH activity in IUGR fetal muscle, which indicates that alternative regulatory mechanisms are responsible for lower pyruvate catabolism.

Picture This: A Review of Research Relating to Narrative Processing by Moving Image Versus Language.

Reading fiction for pleasure is robustly correlated with improved cognitive attainment and other benefits. It is also in decline among young people in developed nations, in part because of competition from moving image fiction. We review existing research on the differences between reading or hearing verbal fiction and watching moving image fiction, as well as looking more broadly at research on image or text interactions and visual versus verbal processing. We conclude that verbal narrative generates more diverse responses than moving image narrative. We note that reading and viewing narrative are different tasks, with different cognitive loads. Viewing moving image narrative mostly involves visual processing with some working memory engagement, whereas reading narrative involves verbal processing, visual imagery, and personal memory (Xu et al., 2005). Attempts to compare the two by creating equivalent stimuli and task demands face a number of challenges. We discuss the difficulties of such comparative approaches. We then investigate the possibility of identifying lower level processing mechanisms that might distinguish cognition of the two media and propose internal scene construction and working memory as foci for future research. Although many of the sources we draw on concentrate on English-speaking participants in European or North American settings, we also cover material relating to speakers of Dutch, German, Hebrew, and Japanese in their respective countries, and studies of a remote Turkish mountain community.

Beneficial effects of resveratrol and exercise training on cardiac and aortic function and structure in the 3xTg mouse model of Alzheimer's disease.

Background: Studies have indicated an association between Alzheimer's disease (AD) and increased risk of developing cardiovascular complications. Lifestyle modifiable factors, such as exercise and diet, are known to prevent cardio-cerebral disease. Recent studies demonstrate that hearts from early onset triple-transgenic AD mice exhibit pathologies, but it is not clear whether cardiovascular function is altered in this model. Methods: In this study, we measured in vivo cardiovascular function in 7-month-old male 3xTg mice and age-matched wild-type (WT) mice using high-frequency high-resolution ultrasound imaging. Results: Our findings indicated that aortic root measurements and interventricular septal dimensions were similar in 3xTg and wild-type mice. Systolic function, expressed as ejection fraction and fractional shortening, were decreased in 3xTg mice. Late (A) ventricular filling velocities, the early/atrial (E/A) ratio, and mitral valve deceleration time, all indices of diastolic function, were increased in 3xTg mice compared to WT mice. Treadmill exercise training and resveratrol supplementation in the diet for 5 months improved ejection fraction, fractional shortening, and restored diastolic deceleration times. Pulse wave velocity was ~33% higher in 3xTg, and accompanied by a significant increase in elastin fiber fragmentation within the aortic wall, which was associated with decrease in elastin content and fiber length. Aortic wall and adventitia thickness were increased in 3xTg mice compared to the WT group. Exercise training and resveratrol supplementation, or both, improved overall aortic morphology with no change in pulse wave velocity. Conclusion: Taken together, the results indicate that the aberrations in cardiac function and aortic elastin morphology observed in the 3xTg mouse model of AD can be prevented with exercise training and treatment with resveratrol. The benefits of regular exercise training and resveratrol supplementation of heart and aortic structure in the 3xTg mouse support the value of healthy lifestyle factors on cardiovascular health.

Exercise and resveratrol increase fracture resistance in the 3xTg-AD mouse model of Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) and osteoporosis are progressive diseases that affect the elderly population. Both conditions are associated with fracture risk that is greater than twice that of the healthy population. Resveratrol and exercise are two treatments that have been linked with attenuation of age-related diseases, including the risk of bone fractures. In this study, we test the hypothesis that these treatments improve fracture resistance in a mouse model representative of the AD condition. METHODS: Three-month-old male 3xTg-AD mice were treated for 4 months with resveratrol or exercise or both combined, and compared with wild type mice. Exercise training was performed on a treadmill at 15 m/min for 45 min/day, 5 days/week. Resveratrol was given at 4 g/kg diet in the form of pellets. Three-point bending, cross-sectional geometric, and fluorescence analyses were conducted on tibias and compared by treatment group. RESULTS: Tibias of 3xTg mice exhibited signs of diminished bone quality and fracture under less force than age-matched wild type mice (P < 0.05). Treatment with both resveratrol and exercise improved indicators of fracture resistance and bone quality in AD mice to levels comparable to that of wild type mice (P < 0.05). CONCLUSIONS: The 3xTg mouse model of AD is at elevated risk for limb bone fracture compared to wild type controls. Treatment with resveratrol, exercise, or both in combination improves fracture resistance and cross-sectional geometric indicators of bone strength.

Oxygen Perfusion (Persufflation) of Human Pancreata Enhances Insulin Secretion and Attenuates Islet Proinflammatory Signaling.

BACKGROUND: All human islets used in research and for the clinical treatment of diabetes are subject to ischemic damage during pancreas procurement, preservation, and islet isolation. A major factor influencing islet function is exposure of pancreata to cold ischemia during unavoidable windows of preservation by static cold storage (SCS). Improved preservation methods may prevent this functional deterioration. In the present study, we investigated whether pancreas preservation by gaseous oxygen perfusion (persufflation) better preserved islet function versus SCS. METHODS: Human pancreata were preserved by SCS or by persufflation in combination with SCS. Islets were subsequently isolated, and preparations in each group matched for SCS or total preservation time were compared using dynamic glucose-stimulated insulin secretion as a measure of ß-cell function and RNA sequencing to elucidate transcriptomic changes. RESULTS: Persufflated pancreata had reduced SCS time, which resulted in islets with higher glucose-stimulated insulin secretion compared to islets from SCS only pancreata. RNA sequencing of islets from persufflated pancreata identified reduced inflammatory and greater metabolic gene expression, consistent with expectations of reducing cold ischemic exposure. Portions of these transcriptional responses were not associated with time spent in SCS and were attributable to pancreatic reoxygenation. Furthermore, persufflation extended the total preservation time by 50% without any detectable decline in islet function or viability. CONCLUSIONS: These data demonstrate that pancreas preservation by persufflation rather than SCS before islet isolation reduces inflammatory responses and promotes metabolic pathways in human islets, which results in improved ß cell function.

Chronic Adrenergic Signaling Causes Abnormal RNA Expression of Proliferative Genes in Fetal Sheep Islets.

Intrauterine growth restriction (IUGR) increases the risk of developing diabetes in later life, which indicates developmental programming of islets. IUGR fetuses with placental insufficiency develop hypoxemia, elevating epinephrine and norepinephrine (NE) concentrations throughout late gestation. To isolate the programming effects of chronically elevated catecholamines, NE was continuously infused into normally grown sheep fetuses for 7 days. High plasma NE concentrations suppress insulin, but after the NE infusion was terminated, persistent hypersecretion of insulin occurred. Our objective was to identify differential gene expression with RNA sequencing (RNAseq) in fetal islets after chronic adrenergic stimulation. After determining the NE-regulated genes, we identified the subset of differentially expressed genes that were common to both islets from NE fetuses and fetuses with IUGR to delineate the adrenergic-induced transcriptional responses. A portion of these genes were investigated in mouse insulinoma (Min6) cells chronically treated with epinephrine to better approximate the ß-cell response. In islets from NE fetuses, RNAseq identified 321 differentially expressed genes that were overenriched for metabolic and hormone processes, and the subset of 96 differentially expressed genes common to IUGR islets were overenriched for protein digestion, vitamin metabolism, and cell replication pathways. Thirty-eight of the 96 NE-regulated IUGR genes changed similarly between models with functional enrichment for proliferation. In Min6 cells, chronic epinephrine stimulation slowed proliferation and augmented insulin secretion after treatment. These data establish molecular mechanisms underlying persistent adrenergic stimulation in hyperfunctional fetal islets and identify a subset of genes dysregulated by catecholamines in IUGR islets that may represent programming of ß-cell proliferation capacity.