H umanized Monoclonal Antibody DREG-200 Di rected Against L-Selectin Protects in Feline Myocardial Reperfusion Injury1

ABSTRAC

Critical mutation rate has an exponential dependence on population size for eukaryotic-length genomes with crossover

The critical mutation rate (CMR) determines the shift between survival-of-the-fittest and survival of individuals with greater mutational robustness (“flattest”). We identify an inverse relationship between CMR and sequence length in an in silico system with a two-peak fitness landscape; CMR decreases to no more than five orders of magnitude above estimates of eukaryotic per base mutation rate. We confirm the CMR reduces exponentially at low population sizes, irrespective of peak radius and distance, and increases with the number of genetic crossovers. We also identify an inverse relationship between CMR and the number of genes, confirming that, for a similar number of genes to that for the plant Arabidopsis thaliana (25,000), the CMR is close to its known wild-type mutation rate; mutation rates for additional organisms were also found to be within one order of magnitude of the CMR. This is the first time such a simulation model has been assigned input and produced output within range for a given biological organism. The decrease in CMR with population size previously observed is maintained; there is potential for the model to influence understanding of populations undergoing bottleneck, stress, and conservation strategy for populations near extinction

Hearing effects from intermittent and continuous noise exposure in a study of Korean factory workers and firefighters

<p>Abstract</p> <p>Background</p> <p>South Korea and surrounding countries in East Asia are believed to have the highest proportion in the world of high frequency hearing loss due to occupational noise exposure, yet there has been limited information published in international journals, and limited information for control of noise in local workplaces beyond strategies from western countries. We exploit medical surveillance information from two worker groups to enhance local knowledge about noise-induced hearing loss and explore the possible importance of shift work to risk.</p> <p>Methods</p> <p>Four-years of hearing data were evaluated for 81 male farm machine factory workers and 371 male firefighters who had successfully completed a health examination and questionnaires for the duration of the study period. The averages of hearing thresholds at 2, 3, and 4 kHz were used as the primary end-point for comparison. Repeat measure analysis adjusted for age, exposure duration and smoking status was used to measure the difference in hearing threshold between the two groups.</p> <p>Results</p> <p>Noise levels were measured in the factory at a mean of 82 dBA, with a range of 66-97. No concurrent measurements were taken for the firefighters, but historic comparison values showed a wider range but a similar mean of 76-79 dBA. Although losses during follow-up were negligible, the factory workers had significantly (<it>P </it>< 0.0001) more hearing loss at the baseline of the study than the firefighters in both ears at 2, 3, and 4 kHz, adjusted for age, duration of employment and smoking status. Among those with 10 years of employment, mean losses at these frequencies among the factory workers fell into the impairment range (> 25 dB loss). Firefighters also showed increased losses associated with longer exposure duration, but these were significantly less marked. Losses at lower frequencies (< or = 1 kHz) were negligible in both groups.</p> <p>Conclusions</p> <p>Korean work environments with continuous noise exposure in the measured range should consider implementation of a hearing conservation program. Further evaluation of hearing loss in workers exposed to irregular or intermittent high noise levels, such as firefighters, is also warranted.</p

Measurement of the Z/gamma* + b-jet cross section in pp collisions at 7 TeV

The production of b jets in association with a Z/gamma* boson is studied using proton-proton collisions delivered by the LHC at a centre-of-mass energy of 7 TeV and recorded by the CMS detector. The inclusive cross section for Z/gamma* + b-jet production is measured in a sample corresponding to an integrated luminosity of 2.2 inverse femtobarns. The Z/gamma* + b-jet cross section with Z/gamma* to ll (where ll = ee or mu mu) for events with the invariant mass 60 < M(ll) < 120 GeV, at least one b jet at the hadron level with pT > 25 GeV and abs(eta) < 2.1, and a separation between the leptons and the jets of Delta R > 0.5 is found to be 5.84 +/- 0.08 (stat.) +/- 0.72 (syst.) +(0.25)/-(0.55) (theory) pb. The kinematic properties of the events are also studied and found to be in agreement with the predictions made by the MadGraph event generator with the parton shower and the hadronisation performed by PYTHIA.Comment: Submitted to the Journal of High Energy Physic

A Selective HDAC 1/2 Inhibitor Modulates Chromatin and Gene Expression in Brain and Alters Mouse Behavior in Two Mood-Related Tests

Psychiatric diseases, including schizophrenia, bipolar disorder and major depression, are projected to lead global disease burden within the next decade. Pharmacotherapy, the primary – albeit often ineffective – treatment method, has remained largely unchanged over the past 50 years, highlighting the need for novel target discovery and improved mechanism-based treatments. Here, we examined in wild type mice the impact of chronic, systemic treatment with Compound 60 (Cpd-60), a slow-binding, benzamide-based inhibitor of the class I histone deacetylase (HDAC) family members, HDAC1 and HDAC2, in mood-related behavioral assays responsive to clinically effective drugs. Cpd-60 treatment for one week was associated with attenuated locomotor activity following acute amphetamine challenge. Further, treated mice demonstrated decreased immobility in the forced swim test. These changes are consistent with established effects of clinical mood stabilizers and antidepressants, respectively. Whole-genome expression profiling of specific brain regions (prefrontal cortex, nucleus accumbens, hippocampus) from mice treated with Cpd-60 identified gene expression changes, including a small subset of transcripts that significantly overlapped those previously reported in lithium-treated mice. HDAC inhibition in brain was confirmed by increased histone acetylation both globally and, using chromatin immunoprecipitation, at the promoter regions of upregulated transcripts, a finding consistent with in vivo engagement of HDAC targets. In contrast, treatment with suberoylanilide hydroxamic acid (SAHA), a non-selective fast-binding, hydroxamic acid HDAC 1/2/3/6 inhibitor, was sufficient to increase histone acetylation in brain, but did not alter mood-related behaviors and had dissimilar transcriptional regulatory effects compared to Cpd-60. These results provide evidence that selective inhibition of HDAC1 and HDAC2 in brain may provide an epigenetic-based target for developing improved treatments for mood disorders and other brain disorders with altered chromatin-mediated neuroplasticity.Stanley Medical Research InstituteNational Institutes of Health (U.S.) (R01DA028301)National Institutes of Health (U.S.) (R01DA030321

The Pochonia chlamydosporia Serine Protease Gene vcp1 Is Subject to Regulation by Carbon, Nitrogen and pH: Implications for Nematode Biocontrol

The alkaline serine protease VCP1 of the fungus Pochonia chlamydosporia belongs to a family of subtilisin-like enzymes that are involved in infection of nematode and insect hosts. It is involved early in the infection process, removing the outer proteinaceous vitelline membrane of nematode eggs. Little is known about the regulation of this gene, even though an understanding of how nutrients and other factors affect its expression is critical for ensuring its efficacy as a biocontrol agent. This paper provides new information on the regulation of vcp1 expression. Sequence analysis of the upstream regulatory region of this gene in 30 isolates revealed that it was highly conserved and contained sequence motifs characteristic of genes that are subject to carbon, nitrogen and pH-regulation. Expression studies, monitoring enzyme activity and mRNA, confirmed that these factors affect VCP1 production. As expected, glucose reduced VCP1 expression and for a few hours so did ammonium chloride. Surprisingly, however, by 24 h VCP1 levels were increased in the presence of ammonium chloride for most isolates. Ambient pH also regulated VCP1 expression, with most isolates producing more VCP1 under alkaline conditions. There were some differences in the response of one isolate with a distinctive upstream sequence including a variant regulatory-motif profile. Cryo-scanning electron microscopy studies indicated that the presence of nematode eggs stimulates VCP1 production by P. chlamydosporia, but only where the two are in close contact. Overall, the results indicate that readily-metabolisable carbon sources and unfavourable pH in the rhizosphere/egg-mass environment may compromise nematode parasitism by P. chlamydosporia. However, contrary to previous indications using other nematophagous and entomopathogenic fungi, ammonium nitrate (e.g. from fertilizers) may enhance biocontrol potential in some circumstances

Recapitulation of tumor heterogeneity and molecular signatures in a 3D brain cancer model with decreased sensitivity to histone deacetylase inhibition

INTRODUCTION Physiologically relevant pre-clinical ex vivo models recapitulating CNS tumor micro-environmental complexity will aid development of biologically-targeted agents. We present comprehensive characterization of tumor aggregates generated using the 3D Rotary Cell Culture System (RCCS). METHODS CNS cancer cell lines were grown in conventional 2D cultures and the RCCS and comparison with a cohort of 53 pediatric high grade gliomas conducted by genome wide gene expression and microRNA arrays, coupled with immunohistochemistry, ex vivo magnetic resonance spectroscopy and drug sensitivity evaluation using the histone deacetylase inhibitor, Vorinostat. RESULTS Macroscopic RCCS aggregates recapitulated the heterogeneous morphology of brain tumors with a distinct proliferating rim, necrotic core and oxygen tension gradient. Gene expression and microRNA analyses revealed significant differences with 3D expression intermediate to 2D cultures and primary brain tumors. Metabolic profiling revealed differential profiles, with an increase in tumor specific metabolites in 3D. To evaluate the potential of the RCCS as a drug testing tool, we determined the efficacy of Vorinostat against aggregates of U87 and KNS42 glioblastoma cells. Both lines demonstrated markedly reduced sensitivity when assaying in 3D culture conditions compared to classical 2D drug screen approaches. CONCLUSIONS Our comprehensive characterization demonstrates that 3D RCCS culture of high grade brain tumor cells has profound effects on the genetic, epigenetic and metabolic profiles of cultured cells, with these cells residing as an intermediate phenotype between that of 2D cultures and primary tumors. There is a discrepancy between 2D culture and tumor molecular profiles, and RCCS partially re-capitulates tissue specific features, allowing drug testing in a more relevant ex vivo system

Microbial Communities in Long-Term, Water-Flooded Petroleum Reservoirs with Different in situ Temperatures in the Huabei Oilfield, China

The distribution of microbial communities in the Menggulin (MGL) and Ba19 blocks in the Huabei Oilfield, China, were studied based on 16S rRNA gene analysis. The dominant microbes showed obvious block-specific characteristics, and the two blocks had substantially different bacterial and archaeal communities. In the moderate-temperature MGL block, the bacteria were mainly Epsilonproteobacteria and Alphaproteobacteria, and the archaea were methanogens belonging to Methanolinea, Methanothermobacter, Methanosaeta, and Methanocella. However, in the high-temperature Ba19 block, the predominant bacteria were Gammaproteobacteria, and the predominant archaea were Methanothermobacter and Methanosaeta. In spite of shared taxa in the blocks, differences among wells in the same block were obvious, especially for bacterial communities in the MGL block. Compared to the bacterial communities, the archaeal communities were much more conserved within blocks and were not affected by the variation in the bacterial communities

Multi-center feasibility study evaluating recruitment, variability in risk factors and biomarkers for a diet and cancer cohort in India

<p>Abstract</p> <p>Background</p> <p>India's population exhibits diverse dietary habits and chronic disease patterns. Nutritional epidemiologic studies in India are primarily of cross-sectional or case-control design and subject to biases, including differential recall of past diet. The aim of this feasibility study was to evaluate whether a diet-focused cohort study of cancer could be established in India, providing insight into potentially unique diet and lifestyle exposures.</p> <p>Methods</p> <p>Field staff contacted 7,064 households within three regions of India (New Delhi, Mumbai, and Trivandrum) and found 4,671 eligible adults aged 35-69 years. Participants completed interviewer-administered questionnaires (demographic, diet history, physical activity, medical/reproductive history, tobacco/alcohol use, and occupational history), and staff collected biological samples (blood, urine, and toenail clippings), anthropometric measurements (weight, standing and sitting height; waist, hip, and thigh circumference; triceps, sub-scapula and supra-patella skin fold), and blood pressure measurements.</p> <p>Results</p> <p>Eighty-eight percent of eligible subjects completed all questionnaires and 67% provided biological samples. Unique protein sources by region were fish in Trivandrum, dairy in New Delhi, and pulses (legumes) in Mumbai. Consumption of meat, alcohol, fast food, and soft drinks was scarce in all three regions. A large percentage of the participants were centrally obese and had elevated blood glucose levels. New Delhi participants were also the least physically active and had elevated lipids levels, suggesting a high prevalence of metabolic syndrome.</p> <p>Conclusions</p> <p>A high percentage of participants complied with study procedures including biological sample collection. Epidemiologic expertise and sufficient infrastructure exists at these three sites in India to successfully carry out a modest sized population-based study; however, we identified some potential problems in conducting a cohort study, such as limited number of facilities to handle biological samples.</p