Increased gene expression of a facilitated diffusion urea transporter in the skin of the African lungfish (Protopterus annectens) during massively elevated post-terrestrialization urea excretion

The full-length cDNA sequence of a putative urea transporter (IfUl) of the facilitated diffusion UT-A type has been cloned from the African lungfish Protopterus annectens. The IFUTcDNA is 1990bp in length and its open reading frame encodes a 409 amino acid long protein, with a calculated molecular mass of 44,723 Da. The sequence is closest to those of amphibians (∼65% amino acid homology), followed by mammals and elasmobranchs (∼60%), and then teleosts (∼50%). IfUT was clearly expressed in gill, kidney, liver, skeletal muscle and skin. Upon re-immersion in water after 33days of air exposure (\u27terrestrialization\u27), lungfish exhibited a massive rise in urea-N excretion which peaked at 12-30h with rates of 2000-5000μmol-N kg-1 h -1 (versus normal aquatic rates of \u3c130μmol-Nkg -1h-1) and persisted until 70h. This appears to occur mainly through the skin. Total \u27excess\u27 urea-N excretion amounted to ∼81,000-91,000 μmol-N kg-1 over 3 days. By real-time PCR, there was no difference in IfUT expression in the ventral abdominal skin between aquatic ammoniotelic controls and terrestrialized lungfish immediately after return to water (0h), and no elevation of urea-N excretion at this time. However, skin biopsies revealed a significant 2.55-fold elevation of IfUT expression at 14h, coincident with peak urea-N excretion. At 48h, there was no longer any significant difference in IFUT mRNA levels from those at 0 and 14h, or from aquatic fed controls. In accordance with earlier studies, which identified elevated urea-N excretion w\u27athe skin of P. dolloi with pharmacology typical of UT-A carriers, these results argue that transcriptional activation of a facilitated diffusion type urea transporter (IfUT) occurs in the skin during re-immersion. This serves to clear the body burden of urea-N accumulated during terrestrialization

Germline Met Mutations in Mice Reveal Mutation- and Background-Associated Differences in Tumor Profiles

BACKGROUND: The receptor tyrosine kinase Met is involved in the progression and metastasis of numerous human cancers. Although overexpression and autocrine activation of the Met signaling pathway are commonly found in human cancers, mutational activation of Met has been observed in small cell and non-small cell lung cancers, lung adenocarcinomas, renal carcinomas, and mesotheliomas. METHODOLOGY/PRINCIPAL FINDINGS: To investigate the influence of mutationally activated Met in tumorigenesis, we utilized a novel mouse model. Previously, we observed that various Met mutations developed unique mutation-specific tumor spectra on a C57BL/6 background. Here, we assessed the effect of genetic background on the tumorigenic potential of mutationally activated Met. For this purpose, we created congenic knock-in lines of the Met mutations D1226N, M1248T, and Y1228C on the FVB/N background. Consistent with the mutation-specific tumor spectra, several of the mutations were associated with the same tumor types as observed on C57BL/6 background. However, on the FVB/N background most developed a high incidence of mammary carcinomas with diverse histopathologies. CONCLUSIONS/SIGNIFICANCE: This study demonstrates that on two distinct mouse backgrounds, Met is able to initiate tumorigenesis in multiple cell types, including epithelial, hematopoietic, and endothelial. Furthermore, these observations emphasize that even a modest increase in Met activation can initiate tumorigenesis with both the Met mutational spectra and host background having profound influence on the type of tumor generated. Greater insight into the interaction of genetic modifiers and Met signaling will significantly enhance our ability to tailor combination therapies for Met-driven cancers

Can metal-tolerant endophytic biocontrol agents promote plant-growth under metal stress?

Five metal-tolerant endophytic isolates (Bipolaris sp. LF7, Diaporthe miriciae LF9, Trichoderma asperellum LF11, Phomopsis asparagi LF15, Saccharicola bicolor LF22), with known metal-tolerance attributes and biocontrol activities against Ganoderma boninense, were tested for growth-promoting activities independent of (in vitro) and associated with plants (height, weight, root mass and stem circumference) (in vivo). Results revealed that metal-tolerant endophytes did not significantly render benefit to host plants as plant growth was compromised by the presence of metals. Lower production of indole-acetic acid (0.74-21.77 μg mL-1), siderophores (8.82-90.26%), and deaminase activities of 1-aminocyclopropane carboxylic acid (3.00-69.2 μmol mg protein-1 hr-1) were observed

Cost-effectiveness of non-invasive methods for assessment and monitoring of liver fibrosis and cirrhosis in patients with chronic liver disease: systematic review and economic evaluation

BACKGROUND: Liver biopsy is the reference standard for diagnosing the extent of fibrosis in chronic liver disease; however, it is invasive, with the potential for serious complications. Alternatives to biopsy include non-invasive liver tests (NILTs); however, the cost-effectiveness of these needs to be established. OBJECTIVE: To assess the diagnostic accuracy and cost-effectiveness of NILTs in patients with chronic liver disease. DATA SOURCES: We searched various databases from 1998 to April 2012, recent conference proceedings and reference lists. METHODS: We included studies that assessed the diagnostic accuracy of NILTs using liver biopsy as the reference standard. Diagnostic studies were assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Meta-analysis was conducted using the bivariate random-effects model with correlation between sensitivity and specificity (whenever possible). Decision models were used to evaluate the cost-effectiveness of the NILTs. Expected costs were estimated using a NHS perspective and health outcomes were measured as quality-adjusted life-years (QALYs). Markov models were developed to estimate long-term costs and QALYs following testing, and antiviral treatment where indicated, for chronic hepatitis B (HBV) and chronic hepatitis C (HCV). NILTs were compared with each other, sequential testing strategies, biopsy and strategies including no testing. For alcoholic liver disease (ALD), we assessed the cost-effectiveness of NILTs in the context of potentially increasing abstinence from alcohol. Owing to a lack of data and treatments specifically for fibrosis in patients with non-alcoholic fatty liver disease (NAFLD), the analysis was limited to an incremental cost per correct diagnosis. An analysis of NILTs to identify patients with cirrhosis for increased monitoring was also conducted. RESULTS: Given a cost-effectiveness threshold of £20,000 per QALY, treating everyone with HCV without prior testing was cost-effective with an incremental cost-effectiveness ratio (ICER) of £9204. This was robust in most sensitivity analyses but sensitive to the extent of treatment benefit for patients with mild fibrosis. For HBV [hepatitis B e antigen (HBeAg)-negative)] this strategy had an ICER of £28,137, which was cost-effective only if the upper bound of the standard UK cost-effectiveness threshold range (£30,000) is acceptable. For HBeAg-positive disease, two NILTs applied sequentially (hyaluronic acid and magnetic resonance elastography) were cost-effective at a £20,000 threshold (ICER: £19,612); however, the results were highly uncertain, with several test strategies having similar expected outcomes and costs. For patients with ALD, liver biopsy was the cost-effective strategy, with an ICER of £822. LIMITATIONS: A substantial number of tests had only one study from which diagnostic accuracy was derived; therefore, there is a high risk of bias. Most NILTs did not have validated cut-offs for diagnosis of specific fibrosis stages. The findings of the ALD model were dependent on assuptions about abstinence rates assumptions and the modelling approach for NAFLD was hindered by the lack of evidence on clinically effective treatments. CONCLUSIONS: Treating everyone without NILTs is cost-effective for patients with HCV, but only for HBeAg-negative if the higher cost-effectiveness threshold is appropriate. For HBeAg-positive, two NILTs applied sequentially were cost-effective but highly uncertain. Further evidence for treatment effectiveness is required for ALD and NAFLD. STUDY REGISTRATION: This study is registered as PROSPERO CRD42011001561. FUNDING: The National Institute for Health Research Health Technology Assessment programme

Enhanced Maternal Origin of the 22q11.2 Deletion in Velocardiofacial and DiGeorge Syndromes

Velocardiofacial and DiGeorge syndromes, also known as 22q11.2 deletion syndrome (22q11DS), are congenital-anomaly disorders caused by a de novo hemizygous 22q11.2 deletion mediated by meiotic nonallelic homologous recombination events between low-copy repeats, also known as segmental duplications. Although previous studies exist, each was of small size, and it remains to be determined whether there are parent-of-origin biases for the de novo 22q11.2 deletion. To address this question, we genotyped a total of 389 DNA samples from 22q11DS-affected families. A total of 219 (56%) individuals with 22q11DS had maternal origin and 170 (44%) had paternal origin of the de novo deletion, which represents a statistically significant bias for maternal origin (p = 0.0151). Combined with many smaller, previous studies, 465 (57%) individuals had maternal origin and 345 (43%) had paternal origin, amounting to a ratio of 1.35 or a 35% increase in maternal compared to paternal origin (p = 0.000028). Among 1,892 probands with the de novo 22q11.2 deletion, the average maternal age at time of conception was 29.5, and this is similar to data for the general population in individual countries. Of interest, the female recombination rate in the 22q11.2 region was about 1.6–1.7 times greater than that for males, suggesting that for this region in the genome, enhanced meiotic recombination rates, as well as other as-of-yet undefined 22q11.2-specific features, could be responsible for the observed excess in maternal origin

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Examination of Balance and Weightbearing in Post Anterior Cruciate Ligament Reconstruction Utilizing the Weight Bearing and Step Up/Over Tests on the Neurocom Balance Master

Currently in the United States, anterior cruciate ligament reconstruction (ACLR) has become one of the most commonly performed surgeries of the lower extremity. Although sports activities commonly cause injury to the ACL, non-athletic individuals are affected as well. With the increasing prevalence of the ACLR procedure, a need appears for researching the effects an ACLR has on balance and weight bearing. The purpose of this study was to examine the effects an ACLR has on balance and weight bearing using the NeuroCom® Balance Master (NBM), version 8.02, Weight Bearing Squat (WBS) and Step Up/Over (SUO) tests with individuals who were at least 3 months post-op. Thirty-one participants (21 female and 10 males) between the ages of 18-53 (mean age = 24.74 years) with an ACLR took part in a one-time test session. Participants completed the Lysholm Knee Rating Scale functional assessment, a health questionnaire, and then had bilateral knee range of motion measured. The participants performed the WBS test at 0, 30, 60, and 90 degrees of knee flexion for a one second time interval at each position. They then performed 3 trials on each leg of the SUO test. Test results for each participant were collected and data was entered into the SPSS Version 11.0 software system. Comparisons were made between data components using a one-sample t-test for the parametric test, a Mann-Whitney U test for the nonparametric test, and by qualitative analysis. Due to significant differences found in this study, the overall results show that there are some knee deficits following an ACLR. Deficits were found in the involved leg versus the uninvolved leg and patellar grafts versus hamstring grafts in weight bearing, movement time, and impact index in the WBS and SUO tests. Lysholm Knee Rating Scale scores indicated good scores (87.73/100) for participants less than and equal to 18 months and excellent scores (91.00/100) for participants greater than 18 months post ACLR. This study showed variable significant differences throughout test results due to several probable factors. Some limitations that may have hindered this study on balance and weight bearing were individual variability, age, vision, functional status, strength, proprioception, and the presence of other pathologies. This study indicates that there is a need for further investigation to evaluate the effects an ACLR has on function. Recommendations such as a larger sample size, consistent testing times, shorter and variable time frames post-op, and utilizing multiple and repetitive tests may improve results. Hopefully, this will lead to better decision making on rehabilitation for ACLR\u27s and improve the ability to solve increasingly complex problems resulting in efficient cost-effective care. Findings could possibly be used for guidelines on rehabilitation programs in patients with post ACLR\u27

A study of the applicability of the Lewis counselling inventory in Kong Kong

published_or_final_versiontocabstractEducational PsychologyMasterMaster of Social Science