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Contemporary CO2 laser systems are capable to delivering picosecond pulses of the multi-terawatt peak power. Further pulse compression to a few cycles is possible using a post-compression in bulk materials with negative group velocity dispersion (GVD). We have experimentally demonstrated the post-compression of a long-wave infrared (9.2 μm) 150-GW peak power pulse from 1.85 ps to less than 500 fs using a combination of two optical materials with significantly different ratios of the nonlinear refractive index to the GVD coefficient. Such combination allows for optimization of the compression mechanism and promises a viable path to scaling peak powers to multi-terawatt levels.

Background and Methods: Schistosomiasis is debilitating and reported to impair immune responsiveness of infected hosts. In Cameroon, mass drug administration (MDA) is used in schoolchildren to reduce transmission of S. haematobium and S. mansoni. The effects of MDA and the impact of schistosomiasis on the titers of antibodies in vaccinated children have been poorly studied. We therefore assessed the prevalence of schistosomiasis in schoolchildren, eight months after MDA, in two locations: Barombi Koto (BK), endemic for S. haematobium (N = 169) and Yoro (Y), endemic for S. mansoni (N = 356). Age, gender, residence time and frequency of contact with river water were assessed as risk factors for infection and morbidity in both localities. In 70 schoolchildren from BK and 83 from Y, ultrasound was used to assess morbidity according to the WHO guidelines. Evaluation of measles antibodies was performed in previously vaccinated schoolchildren (14 with S. haematobium and 12 egg-negative controls from BK and 47 with S. mansoni and12 egg-negative controls from Y).Principal Findings and conclusions: The prevalence of S. haematobium was 25. 4% in BK (43/169) and 34.8% for S. mansoni in Y (124/356), indicating the persistent transmission of schistosomiasis despite MDA. Older age (AOR 1.31; 95%CI 1.12–1.54) and higher frequencies of exposure to river water (AOR 1.99; 95%CI 1.03–3.86) were identified as risks for infection in BK whereas only older age (OR 1.15; 95%CI 1.04–1.27) was a risk for infection in Y. Bladder pathology (score 2 to 5) was observed in 29.2% (7/24) of egg-positive children in BK and liver pathology (pattern C) in 31.1% (19/61) of egg-positive children in Y. There was a positive correlation between S. haematobium egg burden and bladder pathology (AOR 1.01; 95% CI 0.99–1.02) and positive correlation between S. mansoni-driven liver pathology and female gender (AOR 3.01; 95% CI 0.88–10.26). Anti-measles antibodies in vaccinated children were significantly lower in S. mansoni-infected when compared to egg-negative controls (p = 0.001), which was not observed in the S. haematobium-infected group from BK. Our results demonstrate a questionable efficacy of MDA alone in halting schistosomiasis transmission and confirm a possible immunomodulatory effect of S. mansoni on response to vaccines.

Matthew B Palmer,1 Alfred A Vichot,2 Lloyd G Cantley,2 Gilbert W Moeckel1 1Department of Pathology, Yale University School of Medicine, New Haven, CT, USA; 2Department of Medicine, Yale University School of Medicine, New Haven, CT, USA Abstract: This study addresses for the first time the question whether there is significant macrophage population in human kidney sections from patients with acute tubular injury (ATI). We examined therefore the interstitial macrophage population in human kidney tissue with biopsy-proven diagnosis of ATI, minimal change disease (MCD), and MCD with ATI. Kidney biopsies from patients with the above diagnoses were stained with antibodies directed against CD68 (general macrophage marker), CD163 (M2 marker), and HLA-DR (M1 marker) and their respective electron microscopy samples were evaluated for the presence of interstitial macrophages. Our study shows that patients with ATI have significantly increased numbers of interstitial CD68+ macrophages, with an increase in both HLA-DR+ M1 macrophages and CD163+ M2 macrophages as compared to patients with MCD alone. Approximately 75% of macrophages were M2 (CD163+) whereas only 25% were M1 (HLA-DR+). M2 macrophages, which are believed to be critical for wound healing, were found to localize close to the tubular basement membrane of injured proximal tubule cells. Ultra structural examination showed close adherence of macrophages to the basement membrane of injured tubular epithelial cells. We conclude that macrophages accumulate around injured tubules following ATI and exhibit predominantly an M2 phenotype. We further speculate that macrophage-mediated repair may involve physical contact between the M2 macrophage and the injured tubular epithelial cell. Keywords: macrophages, acute kidney injury, CD163, HLA-DR, CD68, electron microscopy

Caves of the Guadalupe Mountains have experienced many modifications since their final phase of sulfuric acid speleogenesis several million years ago. Petrographic and geochemical data reveal details of the change from H2SO4 to CO2-dominated reactions. The H2SO4 dissolution front acquired a coating of replacement gypsum with local pockets of anhydrite and by-products of altered clay, including Fe-Mn oxides. Alteration of bedrock beneath the gypsum produced a white micritized rind with small negative shifts in δ13C and δ18O. Solution basins contain records of the earliest post-speleogenetic processes: corroded bedrock, residual anhydrite, Fe-Mn oxides from fluctuating pH and Eh, mammillary calcite, and dolomitization. Later meteoric water removed or recrystallized much of the gypsum and early micrite, and replaced some gypsum with calcite. Mammillary crusts demonstrate fluctuating groundwater, with calcite layers interrupted by films of Fe-Mn oxides precipitated during periodic inflow of anoxic water. Condensation moisture (from local evaporation) absorbs CO2 from cave air, corroding earlier features and lowering their δ13C and δ18O. Drips of condensation water deposit minerals mainly by evaporation, which increases δ18O in the speleothems while δ13C remains nearly constant. By forcing calcite precipitation, evaporation raises the Mg content of remaining water and subsequent precipitates. Dolomite (both primary and replacive) is abundant. In areas of low air circulation, water on and within carbonate speleothems equilibrates with cave-air CO2, causing minerals to recrystallize with glassy textures. Fluorite on young evaporative speleothems suggests a recent release of deep-source HF gas and absorption by droplets of condensation water.

Gaia Data Release 1 contains parallaxes for more than 700 Galactic Cepheids and RR Lyrae stars, computed as part of the Tycho-Gaia Astrometric Solution (TGAS). We have used TGAS parallaxes, along with literature (V, I, J, Ks, W1) photometry and spectroscopy, to calibrate the zero point of the period-luminosity and period-Wesenheit relations of classical and type II Cepheids, and the near-infrared period-luminosity, period-luminosity-metallicity and optical luminosity-metallicity relations of RR Lyrae stars. In this contribution we briefly summarise results obtained by fitting these basic relations adopting different techniques that operate either in parallax or distance (absolute magnitude) space.

Abstract Background Plant endophytic bacteria play an important role benefiting plant growth or being pathogenic to plants or organisms that consume those plants. Multiple species of bacteria have been found co-inhabiting plants, both cultivated and wild, with viruses and fungi. For these reasons, a general understanding of plant endophytic microbial communities and their diversity is necessary. A key issue is how the distributions of these bacteria vary with location, with plant species, with individual plants and with plant growing season. Results Five common plant species were collected monthly for four months in the summer of 2010, with replicates from four different sampling sites in the Tallgrass Prairie Preserve in Osage County, Oklahoma, USA. Metagenomic DNA was extracted from ground, washed plant leaf samples, and fragments of the bacterial 16S rDNA genes were amplified for analysis of terminal restriction fragment length polymorphism (T-RFLP). We performed mono-digestion T-RFLP with restriction endonuclease DdeI, to reveal the structures of leaf endophytic bacterial communities, to identify the differences between plant-associated bacterial communities in different plant species or environments, and to explore factors affecting the bacterial distribution. We tested the impacts of three major factors on the leaf endophytic bacterial communities, including host plant species, sampling dates and sampling locations. Conclusions Results indicated that all of the three factors were significantly related (α = 0.05) to the distribution of leaf endophytic bacteria, with host species being the most important, followed by sampling dates and sampling locations.

Abstract Background We introduce the linguistic annotation of a corpus of 97 full-text biomedical publications, known as the Colorado Richly Annotated Full Text (CRAFT) corpus. We further assess the performance of existing tools for performing sentence splitting, tokenization, syntactic parsing, and named entity recognition on this corpus. Results Many biomedical natural language processing systems demonstrated large differences between their previously published results and their performance on the CRAFT corpus when tested with the publicly available models or rule sets. Trainable systems differed widely with respect to their ability to build high-performing models based on this data. Conclusions The finding that some systems were able to train high-performing models based on this corpus is additional evidence, beyond high inter-annotator agreement, that the quality of the CRAFT corpus is high. The overall poor performance of various systems indicates that considerable work needs to be done to enable natural language processing systems to work well when the input is full-text journal articles. The CRAFT corpus provides a valuable resource to the biomedical natural language processing community for evaluation and training of new models for biomedical full text publications.

Abstract Background Amyotrophic lateral sclerosis (ALS) is a fatal disorder involving the degeneration and loss of motor neurons. The mechanisms of motor neuron loss in ALS are unknown and there are no effective treatments. Defects in the distal axon and at the neuromuscular junction are early events in the disease course, and zebrafish provide a promising in vivo system to examine cellular mechanisms and treatments for these events in ALS pathogenesis. Results We demonstrate that transient genetic manipulation of zebrafish to express G93A-SOD1, a mutation associated with familial ALS, results in early defects in motor neuron outgrowth and axonal branching. This is consistent with previous reports on motor neuron axonal defects associated with familial ALS genes following knockdown or mutant protein overexpression. We also demonstrate that upregulation of growth factor signaling is capable of rescuing these early defects, validating the potential of the model for therapeutic discovery. We generated stable transgenic zebrafish lines expressing G93A-SOD1 to further characterize the consequences of G93A-SOD1 expression on neuromuscular pathology and disease progression. Behavioral monitoring reveals evidence of motor dysfunction and decreased activity in transgenic ALS zebrafish. Examination of neuromuscular and neuronal pathology throughout the disease course reveals a loss of neuromuscular junctions and alterations in motor neuron innervations patterns with disease progression. Finally, motor neuron cell loss is evident later in the disease. Conclusions This sequence of events reflects the stepwise mechanisms of degeneration in ALS, and provides a novel model for mechanistic discovery and therapeutic development for neuromuscular degeneration in ALS.

Abstract Background Culture of M. bovis from diagnostic specimens is the gold standard for bovine tuberculosis diagnostics in the USA. Detection of M. bovis by PCR in tissue homogenates may provide a simple rapid method to complement bacterial culture. A significant impediment to PCR based assays on tissue homogenates is specificity since mycobacteria other than M. bovis may be associated with the tissues. Results Previously published IS6110 based PCR diagnostic assays, along with one developed in house, were tested against environmental mycobacteria commonly isolated from diagnostic tissues submitted to the National Veterinary Services Laboratory. A real-time PCR assay was developed (IS6110_T) that had increased specificity over other IS6110 based assays. Of the 13 non-tuberculous mycobacteria tested with IS6110_T only M. wolinskyi was positive. Thirty M. bovis infected tissue homogenates and 18 control tissues were used to evaluate the potential for the assay as a diagnostic test. In this small sample, IS6110_T detected 20/30 samples from M. bovis infected animals and 0/18 control tissues. Conclusions The IS6110_T assay provides a PCR based assay system that is compatible with current diagnostic protocols for the detection of M. bovis in the USA and compliments current testing strategies.

Abstract Background A strong dose-volume relationship exists between the amount of small bowel receiving low- to intermediate-doses of radiation and the rates of acute, severe gastrointestinal toxicity, principally diarrhea. There is considerable interest in the application of highly conformal treatment approaches, such as intensity-modulated radiation therapy (IMRT), to reduce dose to adjacent organs-at-risk in the treatment of carcinoma of the rectum. Therefore, we performed a comprehensive dosimetric evaluation of IMRT compared to 3-dimensional conformal radiation therapy (3DCRT) in standard, preoperative treatment for rectal cancer. Methods Using RTOG consensus anorectal contouring guidelines, treatment volumes were generated for ten patients treated preoperatively at our institution for rectal carcinoma, with IMRT plans compared to plans derived from classic anatomic landmarks, as well as 3DCRT plans treating the RTOG consensus volume. The patients were all T3, were node-negative (N = 1) or node-positive (N = 9), and were planned to a total dose of 45-Gy. Pairwise comparisons were made between IMRT and 3DCRT plans with respect to dose-volume histogram parameters. Results IMRT plans had superior PTV coverage, dose homogeneity, and conformality in treatment of the gross disease and at-risk nodal volume, in comparison to 3DCRT. Additionally, in comparison to the 3DCRT plans, IMRT achieved a concomitant reduction in doses to the bowel (small bowel mean dose: 18.6-Gy IMRT versus 25.2-Gy 3DCRT; p = 0.005), bladder (V40Gy: 56.8% IMRT versus 75.4% 3DCRT; p = 0.005), pelvic bones (V40Gy: 47.0% IMRT versus 56.9% 3DCRT; p = 0.005), and femoral heads (V40Gy: 3.4% IMRT versus 9.1% 3DCRT; p = 0.005), with an improvement in absolute volumes of small bowel receiving dose levels known to induce clinically-relevant acute toxicity (small bowel V15Gy: 138-cc IMRT versus 157-cc 3DCRT; p = 0.005). We found that the IMRT treatment volumes were typically larger than that covered by classic bony landmark-derived fields, without incurring penalty with respect to adjacent organs-at-risk. Conclusions For rectal carcinoma, IMRT, compared to 3DCRT, yielded plans superior with respect to target coverage, homogeneity, and conformality, while lowering dose to adjacent organs-at-risk. This is achieved despite treating larger volumes, raising the possibility of a clinically-relevant improvement in the therapeutic ratio through the use of IMRT with a belly-board apparatus.

Abstract Background Rearrangement of the mixed-lineage leukemia gene (MLL) is found in 80% of infant acute lymphoblastic leukemia (ALL) and is associated with poor prognosis and resistance to glucocorticoids (GCs). We have recently observed that GC resistance in T-ALL cell lines is associated with a proliferative metabolism and reduced expression of MLL. In this study we have further explored the relationship between MLL status and GC sensitivity. Results Negative correlation of MLL expression with GC resistance in 15 T-ALL cell lines was confirmed by quantitative RT-PCR. The absence of MLL-rearrangements suggested that this relationship represented expression of wild-type MLL. Analysis of MLL expression patterns revealed a negative relationship with cellular metabolism, proliferation and anti-apoptotic transcriptional networks. In silico analysis of published data demonstrated that reduced levels of MLL mRNA are associated with relapse and prednisolone resistance in T-ALL patients and adverse clinical outcome in children with MLL-rearranged ALL. RNAi knockdown of MLL expression in T-ALL cell lines significantly increased resistance to dexamethasone and gamma irradiation indicating an important role for wild-type MLL in the control of cellular apoptosis. Conclusions The data suggests that reduced expression of wild-type MLL can contribute to GC resistance in ALL patients both with and without MLL-translocations.

Abstract Alzheimer's disease (AD) is characterized by protein aggregates, i.e. senile plaques and neurofibrillary tangles. The ubiquitin-proteasome system has been proposed a role in proteolytic removal of these protein aggregates. Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) is a de-ubiquitinating enzyme with important functions in recycling of ubiquitin. The S18Y polymorphism of the UCHL1 gene confers protection against Parkinson's disease. In this study, the genotype and allele frequencies of the UCHL1 S18Y polymorphism were investigated in 452 AD patients and 234 control subjects, recruited from four memory clinics in Sweden. Using a binary logistic regression model including UCHL1 allele A and APOE ε4 allele positivity, age and sex as covariates with AD diagnosis as dependent variable, an adjusted OR of 0.82 ([95% CI 0.55-1.24], P = 0.35) was obtained for a positive UCHL1 allele A carrier status. The present study thus do not support a protective effect of the UCHL1 S18Y polymorphism against AD.

Abstract Background Our laboratories have previously reported on the experimental infection of cattle with Mycobacterium avium subsp paratuberculosis (M. paratuberculosis) using an intratonsillar infection model. In addition, we have recently developed a partial protein array representing 92 M. paratuberculosis coding sequences. These combined tools have enabled a unique look at the temporal analysis of M. paratuberculosis antigens within the native host. The primary objective of this study was to identify M. paratuberculosis antigens detected by cattle early during infection. A secondary objective was to evaluate the humoral immune response in cattle during the initial year of infection. Results Sera from two experimentally infected cattle, taken pre-inoculation and at day 70, 194 and 321 post infection, identified dynamic antibody reactivity among antigens with some showing an increased response over time and others showing declining levels of reactivity over the same time period. A M. paratuberculosis specific protein, encoded by MAP0862, was strongly detected initially, but the antibody response became weaker with time. The most reactive protein was a putative surface antigen encoded by MAP1087. A second protein, MAP1204, implicated in virulence, was also strongly detected by day 70 in both cattle. Subsequent experiments showed that these two proteins were detected with sera from 5 of 9 naturally infected cattle in the subclinical stage of Johne's disease. Conclusion Collectively these results demonstrate that M. paratuberculosis proteins are detected by sera from experimentally infected cattle as early as 70 days after exposure. These data further suggest at least two antigens may be useful in the early diagnosis of M. paratuberculosis infections. Finally, the construction and use of a protein array in this pilot study has led to a novel approach for discovery of M. paratuberculosis antigens.

Abstract Background Many patients at high risk of cardiovascular disease do not achieve recommended low-density lipoprotein cholesterol (LDL-C) goals. This study compared the efficacy and safety of low doses of rosuvastatin (10 mg) and atorvastatin (20 mg) in high-risk patients with hypercholesterolemia. Methods A total of 996 patients with hypercholesterolemia (LDL-C ≥ 3.4 and < 5.7 mmol/L [130 and 220 mg/dL]) and coronary heart disease (CHD), atherosclerosis, or a CHD-risk equivalent were randomized to once-daily rosuvastatin 10 mg or atorvastatin 20 mg. The primary endpoint was the percentage change from baseline in LDL-C levels at 6 weeks. Secondary endpoints included LDL-C goal achievement (National Cholesterol Education Program Adult Treatment Panel III [NCEP ATP III] goal < 100 mg/dL; 2003 European goal < 2.5 mmol/L for patients with atherosclerotic disease, type 2 diabetes, or at high risk of cardiovascular events, as assessed by a Systematic COronary Risk Evaluation (SCORE) risk ≥ 5% or 3.0 mmol/L for all other patients), changes in other lipids and lipoproteins, cost-effectiveness, and safety. Results Rosuvastatin 10 mg reduced LDL-C levels significantly more than atorvastatin 20 mg at week 6 (44.6% vs. 42.7%, p < 0.05). Significantly more patients achieved NCEP ATP III and 2003 European LDL-C goals with rosuvastatin 10 mg compared with atorvastatin 20 mg (68.8% vs. 62.5%, p < 0.05; 68.0% vs. 63.3%, p < 0.05, respectively). High-density lipoprotein cholesterol was increased significantly with rosuvastatin 10 mg versus atorvastatin 20 mg (6.4% vs. 3.1%, p < 0.001). Lipid ratios and levels of apolipoprotein A-I also improved more with rosuvastatin 10 mg than with atorvastatin 20 mg. The use of rosuvastatin 10 mg was also cost-effective compared with atorvastatin 20 mg in both a US and a UK setting. Both treatments were well tolerated, with a similar incidence of adverse events (rosuvastatin 10 mg, 27.5%; atorvastatin 20 mg, 26.1%). No cases of rhabdomyolysis, liver, or renal insufficiency were recorded. Conclusion In high-risk patients with hypercholesterolemia, rosuvastatin 10 mg was more efficacious than atorvastatin 20 mg at reducing LDL-C, enabling LDL-C goal achievement and improving other lipid parameters. Both treatments were well tolerated.

Abstract Background The Cotton Microsatellite Database (CMD) http://www.cottonssr.org is a curated and integrated web-based relational database providing centralized access to publicly available cotton microsatellites, an invaluable resource for basic and applied research in cotton breeding. Description At present CMD contains publication, sequence, primer, mapping and homology data for nine major cotton microsatellite projects, collectively representing 5,484 microsatellites. In addition, CMD displays data for three of the microsatellite projects that have been screened against a panel of core germplasm. The standardized panel consists of 12 diverse genotypes including genetic standards, mapping parents, BAC donors, subgenome representatives, unique breeding lines, exotic introgression sources, and contemporary Upland cottons with significant acreage. A suite of online microsatellite data mining tools are accessible at CMD. These include an SSR server which identifies microsatellites, primers, open reading frames, and GC-content of uploaded sequences; BLAST and FASTA servers providing sequence similarity searches against the existing cotton SSR sequences and primers, a CAP3 server to assemble EST sequences into longer transcripts prior to mining for SSRs, and CMap, a viewer for comparing cotton SSR maps. Conclusion The collection of publicly available cotton SSR markers in a centralized, readily accessible and curated web-enabled database provides a more efficient utilization of microsatellite resources and will help accelerate basic and applied research in molecular breeding and genetic mapping in Gossypium spp.

Abstract Background Knowledge of how synapses alter their efficiency of communication is central to the understanding of learning and memory. The most extensively studied forms of synaptic plasticity are long-term potentiation (LTP) and its counterpart long-term depression (LTD) of AMPA receptor-mediated synaptic transmission. In the CA1 region of the hippocampus, it has been shown that LTP often involves a rapid increase in the unitary conductance of AMPA receptor channels. However, LTP can also occur in the absence of any alteration in AMPA receptor unitary conductance. In the present study we have used whole-cell dendritic recording, failures analysis and non-stationary fluctuation analysis to investigate the mechanism of depotentiation of LTP. Results We find that when LTP involves an increase in unitary conductance, subsequent depotentiation invariably involves the return of unitary conductance to pre-LTP values. In contrast, when LTP does not involve a change in unitary conductance then depotentiation also occurs in the absence of any change in unitary conductance, indicating a reduction in the number of activated receptors as the most likely mechanism. Conclusions These data show that unitary conductance can be bi-directionally modified by synaptic activity. Furthermore, there are at least two distinct mechanisms to restore synaptic strength from a potentiated state, which depend upon the mechanism of the previous potentiation.

Abstract Background The response of serum cholesterol to diet may be affected by the apolipoprotein E (APOE) ε2/ε3/ε4 polymorphism, which also is a significant predictor of variation in the risk of coronary heart disease (CHD) and CHD death. Here, we test the hypothesis that the APOE polymorphism may modulate the cholesterol-raising effect of coffee. Objective We determined the effect of a coffee abstention period and a daily intake of 600 mL coffee on serum cholesterol and triglycerides with respect to the APOE polymorphism. Design 121 healthy, non-smoking men (22%) and women (78%) aged 29–65 years, took part in a study with four intervention periods: 1 and 3) a coffee free period of three weeks, 2 and 4) 600 mL coffee/day for four weeks. Results APOE ε2 positive individuals had significantly lower total cholesterol concentration at baseline (4.68 mmol/L and 5.28 mmol/L, respectively, p = 0.01), but the cholesterol-raising effect of coffee was not influenced significantly by APOE allele carrier status. Conclusions The APOE ε 2 allele is associated with lower serum cholesterol concentration. However, the APOE polymorphism does not seem to influence the cholesterol-raising effect of coffee.