Resveratrol Mitigates Cognitive Impairments and Cholinergic Cell Loss in the Medial Septum in a Mouse Model of Gradual Cerebral Hypoperfusion.

Vascular cognitive impairment and dementia (VCID) is the second leading cause of dementia. There is currently no effective treatment for VCID. Resveratrol (RSV) is considered an antioxidant; however, our group has observed pleiotropic effects in stroke paradigms, suggesting more effects may contribute to mechanistic changes beyond antioxidative properties.

Resveratrol Preconditioning Protects Against Ischemia-Induced Synaptic Dysfunction and Cofilin Hyperactivation in the Mouse Hippocampal Slice.

Perturbations in synaptic function are major determinants of several neurological diseases and have been associated with cognitive impairments after cerebral ischemia (CI). Although the mechanisms underlying CI-induced synaptic dysfunction have not been well defined, evidence suggests that early hyperactivation of the actin-binding protein, cofilin, plays a role. Given that synaptic impairments manifest shortly after CI, prophylactic strategies may offer a better approach to prevent/mitigate synaptic damage following an ischemic event.

Resveratrol Preconditioning Mitigates Ischemia-Induced Septal Cholinergic Cell Loss and Memory Impairments.

Background: Cholinergic cells originating from the nuclei of the basal forebrain (BF) are critical for supporting various memory processes, yet BF cholinergic cell viability has not been explored in the context of focal cerebral ischemia. In the present study, we examined cell survival within several BF nuclei in rodents following transient middle cerebral artery occlusion. We tested the hypothesis that a previously established neuroprotective therapy-resveratrol preconditioning-would rescue BF cell loss, deficits in cholinergic-related memory performance, and hippocampal synaptic dysfunction after focal cerebral ischemia.

Resveratrol Preconditioning Downregulates PARP1 Protein to Alleviate PARP1-Mediated Cell Death Following Cerebral Ischemia.

Stroke remains a leading cause of mortality; however, available therapeutics are limited. The study of ischemic tolerance, in paradigms such as resveratrol preconditioning (RPC), provides promise for the development of novel prophylactic therapies. The heavily oxidative environment following stroke promotes poly-ADP-ribose polymerase 1 (PARP1)-overactivation and parthanatos, both of which are major contributors to neuronal injury.

Sirtuins and cognition: implications for learning and memory in neurological disorders.

Sirtuins are an evolutionarily conserved family of regulatory proteins that function in an NAD -dependent manner. The mammalian family of sirtuins is composed of seven histone deacetylase and ADP-ribosyltransferase proteins (SIRT1-SIRT7) that are found throughout the different cellular compartments of the cell. Sirtuins in the brain have received considerable attention in cognition due to their role in a plethora of metabolic and age-related diseases and their ability to induce neuroprotection.

Ischemic Neuroprotectant PKCε Restores Mitochondrial Glutamate Oxaloacetate Transaminase in the Neuronal NADH Shuttle after Ischemic Injury.

The preservation of mitochondrial function is a major protective strategy for cerebral ischemic injuries. Previously, our laboratory demonstrated that protein kinase C epsilon (PKCε) promotes the synthesis of mitochondrial nicotinamide adenine dinucleotide (NAD). NAD along with its reducing equivalent, NADH, is an essential co-factor needed for energy production from glycolysis and oxidative phosphorylation.

The FATZO mouse, a next generation model of type 2 diabetes, develops NAFLD and NASH when fed a Western diet supplemented with fructose.

Background: Metabolic disorders such as insulin resistance, obesity, and hyperglycemia are prominent risk factors for the development of non-alcoholic fatty liver disease (NAFLD)/steatohepatitis (NASH). Dietary rodent models employ high fat, high cholesterol, high fructose, methionine/choline deficient diets or combinations of these to induce NAFLD/NASH. The FATZO mice spontaneously develop the above metabolic disorders and type 2 diabetes (T2D) when fed with a normal chow diet.

Altered Neural Networks in the Papez Circuit: Implications for Cognitive Dysfunction after Cerebral Ischemia.

Cerebral ischemia remains a leading cause of mortality worldwide. Although the incidence of death has decreased over the years, surviving patients may suffer from long-term cognitive impairments and have an increased risk for dementia. Unfortunately, research aimed toward developing therapies that can improve cognitive outcomes following cerebral ischemia has proved difficult given the fact that little is known about the underlying processes involved.

Resveratrol Preconditioning Induces Genomic and Metabolic Adaptations within the Long-Term Window of Cerebral Ischemic Tolerance Leading to Bioenergetic Efficiency.

Neuroprotective agents administered post-cerebral ischemia have failed so far in the clinic to promote significant recovery. Thus, numerous efforts were redirected toward prophylactic approaches such as preconditioning as an alternative therapeutic strategy. Our laboratory has revealed a novel long-term window of cerebral ischemic tolerance mediated by resveratrol preconditioning (RPC) that lasts for 2 weeks in mice.

Effects of ischemic preconditioning on mitochondrial and metabolic neruoprotection: 5' adenosine monophosphate-activated protein kinase and sirtuins.

Stroke and cardiac arrest result in cerebral ischemia, a highly prevalent medical issue around the world, which is characterized by a reduction or loss of blood flow to the brain. The loss of adequate nutrient supply in the brain during ischemia results in neuronal cell death contributing to cognitive and motor deficits that are usually permanent. Current effective therapies for cerebral ischemia are only applicable after the fact.

Model evidence for a seasonal bias in Antarctic ice cores.

Much of the global annual mean temperature change over Quaternary glacial cycles can be attributed to slow ice sheet and greenhouse gas feedbacks, but analysis of the short-term response to orbital forcings has the potential to reveal key relationships in the climate system. In particular, obliquity and precession both produce highly seasonal temperature responses at high latitudes. Here, idealized single-forcing model experiments are used to quantify Earth's response to obliquity, precession, CO, and ice sheets, and a linear reconstruction methodology is used to compare these responses to long proxy records around the globe.

The ZDSD rat: a novel model of diabetic nephropathy.

The ZDSD rat is a new obese-diabetic rat model that expresses type 2 diabetes in the presence of an intact leptin pathway. During a long pre-diabetic state, the animals exhibit most of the features of metabolic syndrome including obesity, hyperlipidemia, hypertension, insulin resistance and decreased glucose disposal. The animals used in these studies were either allowed to become spontaneously diabetic at 16-30 weeks of age, or diabetes was induced with a diabetogenic diet.

Correlation of disease severity with body weight and high fat diet in the FATZO/Pco mouse.

Obesity in many current pre-clinical animal models of obesity and diabetes is mediated by monogenic mutations; these are rarely associated with the development of human obesity. A new mouse model, the FATZO mouse, has been developed to provide polygenic obesity and a metabolic pattern of hyperglycemia and hyperinsulinemia, that support the presence of insulin resistance similar to metabolic disease in patients with insulin resistance/type 2 diabetes. The FATZO mouse resulted from a cross of C57BL/6J and AKR/J mice followed by selective inbreeding for obesity, increased insulin and hyperglycemia.

Glucose dysregulation and response to common anti-diabetic agents in the FATZO/Pco mouse.

Unlabelled: The FATZO/Pco mouse is the result of a cross of the C57BL/6J and AKR/J strains. The crossing of these two strains and the selective inbreeding for obesity, insulin resistance and hyperglycemia has resulted in an inbred strain exhibiting obesity in the presumed presence of an intact leptin pathway. Routinely used rodent models for obesity and diabetes research have a monogenic defect in leptin signaling that initiates obesity.

Effects of Inhibiting VPS4 Support a General Role for ESCRTs in Extracellular Vesicle Biogenesis.

Extracellular vesicles (EVs) are proposed to play important roles in intercellular communication. Two classes of EVs can be distinguished based on their intracellular origin. Exosomes are generated within endosomes and released when these fuse with the plasma membrane, whereas ectosomes bud directly from the plasma membrane.

Characterization of the ZDSD Rat: A Translational Model for the Study of Metabolic Syndrome and Type 2 Diabetes.

Metabolic syndrome and T2D produce significant health and economic issues. Many available animal models have monogenic leptin pathway mutations that are absent in the human population. Development of the ZDSD rat model was undertaken to produce a model that expresses polygenic obesity and diabetes with an intact leptin pathway.

Predictors of early and late enrollment in cardiac rehabilitation, among those referred, after acute myocardial infarction.

Background: Cardiac rehabilitation (CR) after acute myocardial infarction (AMI) is a Class I recommendation. Although referral to CR after an AMI has recently become a performance measure, many patients may not participate. To illuminate potential barriers to participation, we examined the prevalence of, and patient-related factors associated with, CR participation within 1 and 6 months after an AMI.

Linkage and association of successful aging to the 6q25 region in large Amish kindreds.

Successful aging (SA) is a multidimensional phenotype involving living to older age with high physical function, preserved cognition, and continued social engagement. Several domains underlying SA are heritable, and identifying health-promoting polymorphisms and their interactions with the environment could provide important information regarding the health of older adults. In the present study, we examined 263 cognitively intact Amish individuals age 80 and older (74 SA and 189 "normally aged") all of whom are part of a single 13-generation pedigree.

Mitochondrial haplogroup X is associated with successful aging in the Amish.

Avoiding disease, maintaining physical and cognitive function, and continued social engagement in long-lived individuals describe successful aging (SA). Mitochondrial lineages described by patterns of common genetic variants ("haplogroups") have been associated with increased longevity in different populations. We investigated the influence of mitochondrial haplogroups on SA in an Amish community sample.

Cardiovascular disease in the elderly.

The aging of the population worldwide will result in increasing numbers of elderly patients, among whom heart disease is the leading cause of death. Changes in cardiovascular physiology with normal aging and prevalent comorbidities result in differences in the effects of common cardiac problems as well as the response to their treatments. Patient-centered goals of care such as maintenance of independence and reduction of symptoms may be preferred over increased longevity.

Successful aging shows linkage to chromosomes 6, 7, and 14 in the Amish.

Successful aging (SA) is a multidimensional phenotype involving preservation of cognitive ability, physical function, and social engagement throughout life. Multiple components of SA are heritable, supporting a genetic component. The Amish are genetically and socially isolated with homogeneous lifestyles, making them a suitable population for studying the genetics of SA.

A genome-wide linkage screen in the Amish with Parkinson disease points to chromosome 6.

Parkinson disease (PD) is a common complex neurodegenerative disorder with an underlying genetic etiology that has been difficult to dissect. Although some PD risk genes have been discovered, most of the underlying genetic etiology remains unknown. To further elucidate the genetic component, we have undertaken a genome-wide linkage screen in an isolated founder population of Amish living in the Midwestern United States.

Distinct roles for CARMIL isoforms in cell migration.

Molecular mechanisms for cell migration, especially how signaling and cytoskeletal systems are integrated, are not understood well. Here, we examined the role of CARMIL (capping protein, Arp2/3, and Myosin-I linker) family proteins in migrating cells. Vertebrates express three conserved genes for CARMIL, and we examined the functions of the two CARMIL genes expressed in migrating human cultured cells.

Intelligent acquisition and learning of fluorescence microscope data models.

We propose a mathematical framework and algorithms both to build accurate models of fluorescence microscope time series, as well as to design intelligent acquisition systems based on these models. Model building allows the information contained in the 2-D and 3-D time series to be presented in a more useful and concise form than the raw image data. This is particularly relevant as the trend in biology tends more and more towards high-throughput applications, and the resulting increase in the amount of acquired image data makes visual inspection impractical.