Functional Inactivation of Drosophila GCK Orthologs Causes Genomic Instability and Oxidative Stress in a Fly Model of MODY-2

Maturity-onset diabetes of the young (MODY) type 2 is caused by heterozygous inactivating mutations in the gene encoding glucokinase (GCK), a pivotal enzyme for glucose homeostasis. In the pancreas GCK regulates insulin secretion, while in the liver it promotes glucose utilization and storage. We showed that silencing the Drosophila GCK orthologs Hex-A and Hex-C results in a MODY-2-like hyperglycemia. Targeted knock-down revealed that Hex-A is expressed in insulin producing cells (IPCs) whereas Hex-C is specifically expressed in the fat body. We showed that Hex-A is essential for insulin secretion and it is required for Hex-C expression. Reduced levels of either Hex-A or Hex-C resulted in chromosome aberrations (CABs), together with an increased production of advanced glycation end-products (AGEs) and reactive oxygen species (ROS). This result suggests that CABs, in GCK depleted cells, are likely due to hyperglycemia, which produces oxidative stress through AGE metabolism. In agreement with this hypothesis, treating GCK-depleted larvae with the antioxidant vitamin B6 rescued CABs, whereas the treatment with a B6 inhibitor enhanced genomic instability. Although MODY-2 rarely produces complications, our data revealed the possibility that MODY-2 impacts genome integrity.     

The Age-Sensitive Efficacy of Calorie Restriction on Mitochondrial Biogenesis and mtDNA Damage in Rat Liver

Calorie restriction (CR) is the most efficacious treatment to delay the onset of age-related changes such as mitochondrial dysfunction. However, the sensitivity of mitochondrial markers to CR and the age-related boundaries of CR efficacy are not fully elucidated. We used liver samples from ad libitum-fed (AL) rats divided in: 18-month-old (AL-18), 28-month-old (AL-28), and 32-month-old (AL-32) groups, and from CR-treated (CR) 28-month-old (CR-28) and 32-month-old (CR-32) counterparts to assay the effect of CR on several mitochondrial markers. The age-related decreases in citrate synthase activity, in TFAM, MFN2, and DRP1 protein amounts and in the mtDNA content in the AL-28 group were prevented in CR-28 counterparts. Accordingly, CR reduced oxidative mtDNA damage assessed through the incidence of oxidized purines at specific mtDNA regions in CR-28 animals. These findings support the anti-aging effect of CR up to 28 months. Conversely, the protein amounts of LonP1, Cyt c, OGG1, and APE1 and the 4.8 Kb mtDNA deletion content were not affected in CR-28 rats. The absence of significant differences between the AL-32 values and the CR-32 counterparts suggests an age-related boundary of CR efficacy at this age. However, this only partially curtails the CR benefits in counteracting the generalized aging decline and the related mitochondrial involvement.     

Using a multicultural lens to understand illnesses among Haitians living in America.

Currently, ethnic and racial minority individuals represent a large proportion of the U.S. population, and researchers expect that they will represent the majority of the population by 2050. This shift in U.S. demographics calls for a greater awareness and integration of cultural issues into the assessment and treatment of ethnically and linguistically diverse clients. This article examines the unique beliefs and manifestations of illnesses among Haitians in connection with the American Psychological Association's (APA, 2002) Multicultural Guidelines. The authors use a common culture-bound syndrome, Séizisman, to illustrate the cultural beliefs, assessment, and treatment of illnesses among Haitians. In so doing, they demonstrate how to incorporate the APA Multicultural Guidelines into treatment with clients of diverse cultural and racial backgrounds. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

A concept for the generation of out-of-plane distortion from tailored FRP laminates

The phenomenon of thermally induced distortions in unsymmetrical laminates is well understood, and it may be shown that a square, unsymmetrical 0.90 laminate will tend to form two stable geometries with a snap-through phenomenon between them. This paper discusses laminates in which at each point the lay-up is symmetrical across the laminate mid-plane, but which still exhibit multiple stable geometries. The number of stable geometries can be controlled by the details of the lay-up from the minimum of two to, in principle, an unlimited number. In addition it will be shown how a similar process can be used to generate multiple stable stress states and geometries in unidirectional laminates. This paper represents a very preliminary experimental investigation of the design space available for such composite laminates. Possible applications of composites with multiple stable geometries are noted.     

Arc root mobility on piezoelectrically actuated contacts in miniature circuit breakers

A novel contact opening mechanism has been developed using a piezoelectric actuator to open the contacts in a low contact opening velocity circuit breaker. The arc control on the contacts is critical for successful current interruption (10/sup 3/-10/sup 4/ A) in low voltage (<250V) devices. Previous work has shown how arc root commutation from the contact region into the arc chamber is affected by arc chamber materials, contact materials and the gap behind the moving contact for contact velocities between 1ms/sup -1/ and 10ms/sup -1/. This work is extended using a commercially available piezoelectric actuator to open the contacts. Contact opening speeds are assessed and the arc root mobility is characterized under this operating regime. A flexible test apparatus and solid-state high-speed arc imaging system are used to gather data on the arc root during the opening of the contacts. New experimental results are presented on the anode and cathode root velocity and arc root motion in an arc chamber with piezoelectrically actuated contact opening. These results can be used to improve the design of high current low voltage circuit breakers suitable for piezoelectric actuation.     

Dynamics of photosynthetic pigments in an Andean lake in Colombia

Guatavita Lake is a small, sheltered tropical high mountain lake located in the Colombian Andes, with a closed watershed and a maximum depth of 25 m. It is the freshwater source for human consumption in nearby small towns, as well as being a site of cultural value for the country, as it was a sacred place to indigenous peoples until about five centuries ago. As the structure and function of this aquatic ecosystem is poorly understood, this study provides initial knowledge on its phytoplankton biomass dynamics, which should be useful in designing efficient management plans with environmental baseline information for similar lakes elsewhere. Physical and chemical data, and photosynthetic pigment concentrations, were measured for the period November 1999–November 2000 at the central vertical axis of Guatavita Lake. The vertical profile of the chlorophyll‐a concentration was closely related to the dissolved inorganic nitrogen concentrations and the thermal stratification characteristics. The maximum chlorophyll‐a concentration in the metalimnion was recorded for the thermal stratification period (November 1999–June 2000). Deepening of the maximum chlorophyll‐a concentration began in February, continuing to June, when it reached its lowest value at the 15 m depth. The phytoplankton biomass values showed an increment within the entire water column at the beginning of the mixing period (July). The relation between the metalimnetic peak of chlorophyll‐a and the dissolved inorganic nitrogen concentration suggests the growth of the phytoplankton community is limited mainly by the availability of nitrogen.     

High-dose busulfan, melphalan, thiotepa and peripheral blood stem cell infusion for the treatment of metastatic breast cancer

The purpose of this study was to determine the outcome of patients with metastatic breast cancer treated with high-dose busulfan (Bu), melphalan (Mel) and thiotepa (TT) followed by peripheral blood stem cell (PBSC) infusion. Fifty-one patients with chemotherapy refractory (n = 32) or responsive (n = 19) metastatic breast cancer received Bu (12 mg/kg), Mel (100 mg/m2) and TT (500 mg/m2) followed by PBSC collected after chemotherapy and growth factor (n = 43) or growth factor alone (n = 8). The 100 day treatment-related mortality was 8% including one death from cytomegalovirus pneumonia, one from aspiration pneumonia and two from regimen-related toxicity (RRT). Seven of 28 refractory (25%) and 5/7 (71%) responsive patients with evaluable disease achieved a complete response of all measurable disease or all soft tissue disease with at least improvement in bone lesions (PR*). Fifteen of 51 patients (29%) are alive and progression-free a median of 423 days (range 353-934) after treatment, 5/32 (16%) with refractory disease and 10/19 (53%) with responsive disease. The probabilities of progression-free survival (PFS) at 1.5 years for the patients with refractory (n = 32) and responsive (n = 19) disease were 0.24 and 0.53, respectively. These preliminary data suggest that high-dose Bu/Mel/TT has significant activity in patients with advanced breast cancer and may be superior to some previously published regimens.