The reproductive cycle of the thorny skate (Amblyraja radiata) in the western Gulf of Maine

The thorny skate (Amblyraja radiata) is a large species of skate that is endemic to the waters of the western north Atlantic in the Gulf of Maine. Because the biomass of thorny skates has recently declined below threshold levels mandated by the Sustainable Fisheries Act, commercial harvests from this region are prohibited. We have undertaken a comprehensive study to gain insight into the life history of this skate. The present study describes and characterizes the reproductive cycle of female and male thorny skates, based on monthly samples taken off the coast of New Hampshire, from May 2001 to May 2003. Gonadosomatic index (GSI), shell gland weight, follicle size, and egg case formation, were assessed for 48 female skates. In general, these reproductive parameters remained relatively constant throughout most of the year. However, transient but significant increases in shell gland weight and GSI were obser ved during certain months. Within the cohort of specimens sampled monthly throughout the year, a subset of females always had large preovulatory follicles present in their ovaries. With the exception of June and September specimens, egg cases undergoing various stages of development were observed in the uteri of specimens captured during all other months of the year. For males (n=48), histological stages III through VI (SIII−SVI) of spermatogenesis, GSI, and hepatosomatic index (HSI) were examined. Although there appeared to be monthly fluctuations in spermatogenesis, GSI, and HSI, no significant differences were found. The production and maintenance of mature spermatocysts (SVI) within the testes was observed throughout the year. These findings collectively indicate that the thorny skate is reproductively active year round

MEPicides: Potent antimalarial prodrugs targeting isoprenoid biosynthesis

AbstractThe emergence of Plasmodium falciparum resistant to frontline therapeutics has prompted efforts to identify and validate agents with novel mechanisms of action. MEPicides represent a new class of antimalarials that inhibit enzymes of the methylerythritol phosphate (MEP) pathway of isoprenoid biosynthesis, including the clinically validated target, deoxyxylulose phosphate reductoisomerase (Dxr). Here we describe RCB-185, a lipophilic prodrug with nanomolar activity against asexual parasites. Growth of P. falciparum treated with RCB-185 was rescued by isoprenoid precursor supplementation, and treatment substantially reduced metabolite levels downstream of the Dxr enzyme. In addition, parasites that produced higher levels of the Dxr substrate were resistant to RCB-185. Notably, environmental isolates resistant to current therapies remained sensitive to RCB-185, the compound effectively treated sexually-committed parasites, and was both safe and efficacious in malaria-infected mice. Collectively, our data demonstrate that RCB-185 potently and selectively inhibits Dxr in P. falciparum, and represents a promising lead compound for further drug development.</jats:p

Regulation of neutrophil senescence by microRNAs

Neutrophils are rapidly recruited to sites of tissue injury or infection, where they protect against invading pathogens. Neutrophil functions are limited by a process of neutrophil senescence, which renders the cells unable to respond to chemoattractants, carry out respiratory burst, or degranulate. In parallel, aged neutrophils also undergo spontaneous apoptosis, which can be delayed by factors such as GMCSF. This is then followed by their subsequent removal by phagocytic cells such as macrophages, thereby preventing unwanted inflammation and tissue damage. Neutrophils translate mRNA to make new proteins that are important in maintaining functional longevity. We therefore hypothesised that neutrophil functions and lifespan might be regulated by microRNAs expressed within human neutrophils. Total RNA from highly purified neutrophils was prepared and subjected to microarray analysis using the Agilent human miRNA microarray V3. We found human neutrophils expressed a selected repertoire of 148 microRNAs and that 6 of these were significantly upregulated after a period of 4 hours in culture, at a time when the contribution of apoptosis is negligible. A list of predicted targets for these 6 microRNAs was generated from http://mirecords.biolead.org and compared to mRNA species downregulated over time, revealing 83 genes targeted by at least 2 out of the 6 regulated microRNAs. Pathway analysis of genes containing binding sites for these microRNAs identified the following pathways: chemokine and cytokine signalling, Ras pathway, and regulation of the actin cytoskeleton. Our data suggest that microRNAs may play a role in the regulation of neutrophil senescence and further suggest that manipulation of microRNAs might represent an area of future therapeutic interest for the treatment of inflammatory disease

Cytoplasmic p53 couples oncogene-driven glucose metabolism to apoptosis and is a therapeutic target in glioblastoma.

Cross-talk among oncogenic signaling and metabolic pathways may create opportunities for new therapeutic strategies in cancer. Here we show that although acute inhibition of EGFR-driven glucose metabolism induces only minimal cell death, it lowers the apoptotic threshold in a subset of patient-derived glioblastoma (GBM) cells. Mechanistic studies revealed that after attenuated glucose consumption, Bcl-xL blocks cytoplasmic p53 from triggering intrinsic apoptosis. Consequently, targeting of EGFR-driven glucose metabolism in combination with pharmacological stabilization of p53 with the brain-penetrant small molecule idasanutlin resulted in synthetic lethality in orthotopic glioblastoma xenograft models. Notably, neither the degree of EGFR-signaling inhibition nor genetic analysis of EGFR was sufficient to predict sensitivity to this therapeutic combination. However, detection of rapid inhibitory effects on [18F]fluorodeoxyglucose uptake, assessed through noninvasive positron emission tomography, was an effective predictive biomarker of response in vivo. Together, these studies identify a crucial link among oncogene signaling, glucose metabolism, and cytoplasmic p53, which may potentially be exploited for combination therapy in GBM and possibly other malignancies

Performance of the CMS Cathode Strip Chambers with Cosmic Rays

The Cathode Strip Chambers (CSCs) constitute the primary muon tracking device in the CMS endcaps. Their performance has been evaluated using data taken during a cosmic ray run in fall 2008. Measured noise levels are low, with the number of noisy channels well below 1%. Coordinate resolution was measured for all types of chambers, and fall in the range 47 microns to 243 microns. The efficiencies for local charged track triggers, for hit and for segments reconstruction were measured, and are above 99%. The timing resolution per layer is approximately 5 ns

Performance and Operation of the CMS Electromagnetic Calorimeter

The operation and general performance of the CMS electromagnetic calorimeter using cosmic-ray muons are described. These muons were recorded after the closure of the CMS detector in late 2008. The calorimeter is made of lead tungstate crystals and the overall status of the 75848 channels corresponding to the barrel and endcap detectors is reported. The stability of crucial operational parameters, such as high voltage, temperature and electronic noise, is summarised and the performance of the light monitoring system is presented

Global estimates of mortality associated with long-term exposure to outdoor fine particulate matter.

Exposure to ambient fine particulate matter (PM2.5) is a major global health concern. Quantitative estimates of attributable mortality are based on disease-specific hazard ratio models that incorporate risk information from multiple PM2.5 sources (outdoor and indoor air pollution from use of solid fuels and secondhand and active smoking), requiring assumptions about equivalent exposure and toxicity. We relax these contentious assumptions by constructing a PM2.5-mortality hazard ratio function based only on cohort studies of outdoor air pollution that covers the global exposure range. We modeled the shape of the association between PM2.5 and nonaccidental mortality using data from 41 cohorts from 16 countries-the Global Exposure Mortality Model (GEMM). We then constructed GEMMs for five specific causes of death examined by the global burden of disease (GBD). The GEMM predicts 8.9 million [95% confidence interval (CI): 7.5-10.3] deaths in 2015, a figure 30% larger than that predicted by the sum of deaths among the five specific causes (6.9; 95% CI: 4.9-8.5) and 120% larger than the risk function used in the GBD (4.0; 95% CI: 3.3-4.8). Differences between the GEMM and GBD risk functions are larger for a 20% reduction in concentrations, with the GEMM predicting 220% higher excess deaths. These results suggest that PM2.5 exposure may be related to additional causes of death than the five considered by the GBD and that incorporation of risk information from other, nonoutdoor, particle sources leads to underestimation of disease burden, especially at higher concentrations

Energy scavenging from insect flight

This paper reports the design, fabrication and testing of an energy scavenger that generates power from the wing motion of a Green June Beetle (C otinis nitida ) during its tethered flight. The generator utilizes non-resonant piezoelectric bimorphs operated in the d 31 bending mode to convert mechanical vibrations of a beetle into electrical output. The available deflection, force, and power output from oscillatory movements at different locations on a beetle are measured with a meso-scale piezoelectric beam. This way, the optimum location to scavenge energy is determined, and up to ~115 µW total power is generated from body movements. Two initial generator prototypes were fabricated, mounted on a beetle, and harvested 11.5 and 7.5 µW in device volumes of 11.0 and 5.6 mm 3 , respectively, from 85 to 100 Hz wing strokes during the beetle's tethered flight. A spiral generator was designed to maximize the power output by employing a compliant structure in a limited area. The necessary technology needed to fabricate this prototype was developed, including a process to machine high-aspect ratio devices from bulk piezoelectric substrates with minimum damage to the material using a femto-second laser. The fabricated lightweight spiral generators produced 18.5–22.5 µW on a bench-top test setup mimicking beetles' wing strokes. Placing two generators (one on each wing) can result in more than 45 µW of power per insect. A direct connection between the generator and the flight muscles of the insect is expected to increase the final power output by one order of magnitude.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90804/1/0960-1317_21_9_095016.pd