Role of heme regulated eIF2α kinase in pancreatic beta cell function and viability

The eukaryotic translation initiation factor 2 alpha (eIF2α) is part of the initiation complex that drives the initiator amino acid methionine to the ribosome, a crucial step in protein translation. In stress conditions such as virus infection, endoplasmic reticulum (ER) stress, amino acid or heme deficiency eIF2α can be phosphorylated and thereby inhibit global protein synthesis. This adaptive mechanism prevents protein accumulation and consequent cytotoxic effects. Heme-regulated eIF2α kinase (HRI) is a member of the eIF2α kinase family that regulates protein translation in heme deficiency conditions. Although present in all tissues, HRI is predominantly expressed in erythroid cells where it remains inactive in the presence of normal heme concentrations. In response to heme deficiency, HRI is activated and phosphorylates eIF2α decreasing globin synthesis. This mechanism is important to prevent accumulation of heme-free globin chains which cause ER stress and apoptosis. RNA sequencing data from our group showed that in human islets and in primary rat beta cells HRI is the most expressed eIF2α kinase compared to the other family members. Despite its high expression levels, little is known about HRI function in beta cells. The aim of this project is to identify the role of HRI in pancreatic beta cells. This was investigated taking a loss-of-function approach. HRI knock down (KD) by RNA interference induced beta cell apoptosis in basal condition. HRI KD potentiated the apoptotic effects of palmitate or proinflammatory cytokines, two in vitro models for type 2 and type 1 diabetes, respectively. Increased cytokine-induced apoptosis was also observed in HRI-deficient primary rat beta cells. Unexpectedly, we observed a mild increase in eIF2α phosphorylation in HRI-deficient cells. The levels of mRNA or protein expression of C/EBP homologous protein (CHOP) and activating transcription factor 4 (ATF4) were not modified. HRI KD cells have decreased spliced X-box binding protein 1 (XBP1s), an important branch of the ER stress response. However, overexpression of XBP1s by adenovirus in HRI KD cells did not protect from HRI siRNA-induced apoptosis. HRI deficiency decreased phosphorylation of Akt and its downstream targets glycogen synthase kinase 3 (GSK3), forkhead box protein O1 (FOXO1) and Bcl-2-associated death promoter (BAD). Overexpression of a constitutively active form of Akt by adenovirus in HRI-deficient beta cells partially decreased HRI KD-mediated apoptosis. Interestingly, BAD silencing protected from apoptosis caused by HRI deficiency. HRI silencing in beta cells also induced JNK activation. These results suggest an important role of HRI in beta cell survival through modulation of the Akt/BAD pathway. Thus, HRI may be an interesting target to modulate beta cell fate in diabetic conditions.

Feedbacks between vegetation pattern and resource loss dramatically decrease ecosystem resilience and restoration potential in a simple dryland model

Conceptual frameworks of dryland degradation commonly include ecohydrological feedbacks between landscape spatial organization and resource loss, so that decreasing cover and size of vegetation patches result in higher water and soil losses, which lead to further vegetation loss. However, the impacts of these feedbacks on dryland dynamics in response to external stress have barely been tested. Using a spatially-explicit model, we represented feedbacks between vegetation pattern and landscape resource loss by establishing a negative dependence of plant establishment on the connectivity of runoff-source areas (e.g., bare soils). We assessed the impact of various feedback strengths on the response of dryland ecosystems to changing external conditions. In general, for a given external pressure, these connectivity-mediated feedbacks decrease vegetation cover at equilibrium, which indicates a decrease in ecosystem resistance. Along a gradient of gradual increase of environmental pressure (e.g., aridity), the connectivity-mediated feedbacks decrease the amount of pressure required to cause a critical shift to a degraded state (ecosystem resilience). If environmental conditions improve, these feedbacks increase the pressure release needed to achieve the ecosystem recovery (restoration potential). The impact of these feedbacks on dryland response to external stress is markedly non-linear, which relies on the non-linear negative relationship between bare-soil connectivity and vegetation cover. Modelling studies on dryland vegetation dynamics not accounting for the connectivity-mediated feedbacks studied here may overestimate the resistance, resilience and restoration potential of drylands in response to environmental and human pressures. Our results also suggest that changes in vegetation pattern and associated hydrological connectivity may be more informative early-warning indicators of dryland degradation than changes in vegetation cover.

Osteology, function, and evolution of the Trematopsid (Amphibia: Labyrinthodontia) nasal region / [by] John R. Bolt --.

v.33:no.2(1974)

Description and Prediction of Freezing of Gait in Parkinson's Disease from Wearable Inertial Measurements Units

Parkinson's disease (PD) is a neuro-degenerative disorder, the second most common after Alzheimer's disease. After diagnosis, treatments can help to relieve the symptoms, but there is no known cure for PD. PD is characterized by a combination of motor and no-motor dysfunctions. Among the motor symptoms there is the so called Freezing of Gait (FoG). The FoG is a phenomenon in PD patients in which the feet stock to the floor and is difficult for the patient to initiate movement. FoG is a severe problem, since it is associated with falls, anxiety, loss of mobility, accidents, mortality and it has substantial clinical and social consequences decreasing the quality of life in PD patients. Medicine can be very successful in controlling movements disorders and dealing with some of the PD symptoms. However, the relationship between medication and the development of FoG remains unclear. Several studies have demonstrated that visual or auditory rhythmical cuing allows PD patients to improve their motor abilities. Rhythmic auditory stimulation (RAS) was shown to be particularly effective at improving gait, specially with patients that manifest FoG. While RAS allows to reduce the time and the effects of FoGs occurrence in PD patients after the FoG is detected, it can not avoid the episode due to the latency of detection. An improvement of the system would be the prediction of the FoG. This thesis was developed following two main objectives: (1) the finding of specifics properties during pre FoG periods different from normal walking context and other walking events like turns and stops using the information provided by the inertial measurements units (IMUs) and (2) the formulation of a model for automatically detect the pre FoG patterns in order to completely avoid the upcoming freezing event in PD patients. The first part focuses on the analysis of different methods for feature extraction which might lead in the FoG occurrence.

Interplay between cardiac function and heart development

Mechanotransduction refers to the conversion of mechanical forces into biochemical or electrical signals that initiate structural and functional remodeling in cells and tissues. The heart is a kinetic organ whose form changes considerably during development and disease. This requires cardiomyocytes to be mechanically durable and able to mount coordinated responses to a variety of environmental signals on different time scales, including cardiac pressure loading and electrical and hemodynamic forces. During physiological growth, myocytes, endocardial and epicardial cells have to adaptively remodel to these mechanical forces. Here we review some of the recent advances in the understanding of how mechanical forces influence cardiac development, with a focus on fluid flow forces. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Develomental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel.

The leopard's claw : a thrilling story of love and adventure from a European castle through the West African jungle, disclosing a deep insight into the quality and spiritual influence of African social institutions and conditions, and revealing a profound psyschic [sic] interpretation of African inner life, all clustered about the mysterious function and significance of the leopard's claw /

Mode of access: Internet.

Advanced filtering and prediction software for urban traffic control systems. Final report.

Transportation Department, Office of University Research, Washington, D.C.

Application of Monte Carlo techniques to insolation characterization and prediction : status report, October 1, 1978-June 1, 1979 /

"July 1979."

Shrubland ecosystem genetics and biodiversity : proceedings : Provo, UT, June 13-15, 2000 /

Papers from the 11th Wildland Shrub Symposium, held at the Bringham Young University Conference Center, Provo, Utah, June 13-15, 2000.

Path integral calculation of the three-particle direct and exchange contributions to the pair distribution function and of the third virial coefficient for He4 gas /

Thesis--Illinois.