Structure and function of the Rad9-binding region of the DNA-damage checkpoint adaptor TopBP1

TopBP1 is a scaffold protein that coordinates activation of the DNA-damage-checkpoint response by coupling binding of the 9-1-1 checkpoint clamp at sites of ssDNA, to activation of the ATR-ATRIP checkpoint kinase complex. We have now determined the crystal structure of the N-terminal region of human TopBP1, revealing an unexpected triple-BRCT domain structure. The arrangement of the BRCT domains differs significantly from previously described tandem BRCT domain structures, and presents two distinct sites for binding phosphopeptides in the second and third BRCT domains. We show that the site in the second but not third BRCT domain in the N-terminus of TopBP1, provides specific interaction with a phosphorylated motif at pSer387 in Rad9, which can be generated by CK2

Diabetic Neuropathy and Axon Reflex-Mediated Neurogenic Vasodilatation in Type 1 Diabetes

Objective: Axon reflex-mediated neurogenic vasodilatation in response to cutaneous heating may reflect early, pre-clinical small fibre dysfunction. We aimed to evaluate the distribution of the vascular flare area measured by laser doppler imaging (‘‘LDI FLARE area’’) in type 1 diabetes and in healthy volunteers. Research and Methods: Concurrent with clinical and electrophysiological examination to classify diabetic sensorimotor polyneuropathy (DSP), LDIFLARE area (cm 2) was determined in 89 type 1 diabetes subjects matched to 64 healthy volunteers. We examined the association and diagnostic performance of LDI with clinical and subclinical measures of DSP and its severity. Results: Compared to the 64 healthy volunteers, the 56 diabetes controls without DSP had significantly lower LDIFLARE area (p = 0.006). The 33 diabetes cases with DSP had substantially lower LDIFLARE area as compared to controls without DSP (p = 0.002). There was considerable overlap in LDIFLARE area between all groups such that the ROC curve had an AUC of 0.72 and optimal sensitivity of 70 % for the detection of clinical DSP. Use of a subclinical definition for DSP, according to subclinical sural nerve impairment, was associated with improved AUC of 0.75 and sensitivity of 79%. In multivariate analysis higher HbA1c and body mass index had independent associations with smaller LDIFLARE area. Conclusions: Axon reflex-mediated neurogenic vasodilatation in response to cutaneous heating is a biomarker of earl

Modelling the cost-effectiveness of combination therapy for early, rapidly progressing rheumatoid arthritis by simulating the reversible and irreversible effects of the disease

Objective. To estimate the cost-effectiveness of adalimumab plus methotrexate (MTX) versus MTX monotherapy in early, aggressive rheumatoid arthritis (RA) when explicitly modelling short-term (reversible) and long-term (irreversible, ie, joint damage) disease activity and physical function. Methods. A microsimulation model was developed to unify, in a single cost-effectiveness model, measures of reversible and irreversible disease activity and physical function based on data from the PREMIER trial. Short term, reversible disease activity was modelled using DAS28 variables, including swollen joint counts, tender joint counts, C reactive protein concentration and pain. The DAS28 variables were then used in a logistic regression to predict short-term American College of Rheumatology (ACR) responses, which informed treatment continuation and switches. Long term, irreversible, radiographically documented joint damage was modelled using modified Total Sharp Score (mTSS). The model then linked both short-term disease activity and mTSS to the Health Assessment Questionnaire score, which was used to calculate direct and indirect costs, and quality adjusted life-years (QALYs). Results. When both reversible and irreversible effects of therapy were included, combination therapy was estimated to produce 6-month 50% ACR responses in 75% of patients versus 54% in MTX monotherapy. Compared to MTX monotherapy, combination therapy resulted in 2.68 and 3.04 discounted life years and QALYs gained, respectively. Combination therapy also resulted in a net increase in direct costs of £106 207 for a resulting incremental cost/QALY gain of £32 425. When indirect costs were included in the analysis, the ICER (incremental cost-effectiveness ratio) decreased to £27 238. Disregarding irreversible effects increased the incremental cost-effectiveness ratio to £78 809 (when only direct costs were included). Conclusions. Starting with adalimumab plus MTX combination therapy in early, aggressive RA is cost-effective when irreversible damage is adequately considered

Audit fees and book-tax differences

We investigate whether book-tax differences are associated with higher audit fees, a proxy for auditor risk assessments and auditor effort. Our evidence suggests that there is a significantly positive relation. Further, this association is larger for firms that appear to have managed earnings (i.e., have high accruals) relative to those that are tax avoiders (i.e., have low cash effective tax rates). Our evidence is consistent with large book-tax differences representing an observable proxy for earnings management that is associated with auditor decisions. Our study contributes to capital market research that examines audit fees, as well as other research that examines the usefulness of book-tax differences for market participants.Ernst & Young (Faculty Fellowship in Accounting

Phytochemicals as antibiotic alternatives to promote growth and enhance host health

There are heightened concerns globally on emerging drug-resistant superbugs and the lack of new antibiotics for treating human and animal diseases. For the agricultural industry, there is an urgent need to develop strategies to replace antibiotics for food-producing animals, especially poultry and livestock. The 2nd International Symposium on Alternatives to Antibiotics was held at the World Organization for Animal Health in Paris, France, December 12-15, 2016 to discuss recent scientific developments on strategic antibiotic-free management plans, to evaluate regional differences in policies regarding the reduction of antibiotics in animal agriculture and to develop antibiotic alternatives to combat the global increase in antibiotic resistance. More than 270 participants from academia, government research institutions, regulatory agencies, and private animal industries from >25 different countries came together to discuss recent research and promising novel technologies that could provide alternatives to antibiotics for use in animal health and production; assess challenges associated with their commercialization; and devise actionable strategies to facilitate the development of alternatives to antibiotic growth promoters (AGPs) without hampering animal production. The 3-day meeting consisted of four scientific sessions including vaccines, microbial products, phytochemicals, immune-related products, and innovative drugs, chemicals and enzymes, followed by the last session on regulation and funding. Each session was followed by an expert panel discussion that included industry representatives and session speakers. The session on phytochemicals included talks describing recent research achievements, with examples of successful agricultural use of various phytochemicals as antibiotic alternatives and their mode of action in major agricultural animals (poultry, swine and ruminants). Scientists from industry and academia and government research institutes shared their experience in developing and applying potential antibiotic-alternative phytochemicals commercially to reduce AGPs and to develop a sustainable animal production system in the absence of antibiotics.Fil: Lillehoj, Hyun. United States Department of Agriculture. Agricultural Research Service; ArgentinaFil: Liu, Yanhong. University of California; Estados UnidosFil: Calsamiglia, Sergio. Universitat Autònoma de Barcelona; EspañaFil: Fernandez Miyakawa, Mariano Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigación en Ciencias Veterinarias y Agronómicas. Instituto de Patobiología; ArgentinaFil: Chi, Fang. Amlan International; Estados UnidosFil: Cravens, Ron L.. Amlan International; Estados UnidosFil: Oh, Sungtaek. United States Department of Agriculture. Agricultural Research Service; ArgentinaFil: Gay, Cyril G.. United States Department of Agriculture. Agricultural Research Service; Argentin

Streptococcal peritonitis in Australian peritoneal dialysis patients: predictors, treatment and outcomes in 287 cases

Background There has not been a comprehensive, multi-centre study of streptococcal peritonitis in patients on peritoneal dialysis (PD) to date. Methods The predictors, treatment and clinical outcomes of streptococcal peritonitis were examined by binary logistic regression and multilevel, multivariate poisson regression in all Australian PD patients involving 66 centres between 2003 and 2006. Results Two hundred and eighty-seven episodes of streptococcal peritonitis (4.6% of all peritonitis episodes) occurred in 256 individuals. Its occurrence was independently predicted by Aboriginal or Torres Strait Islander racial origin. Compared with other organisms, streptococcal peritonitis was associated with significantly lower risks of relapse (3% vs 15%), catheter removal (10% vs 23%) and permanent haemodialysis transfer (9% vs 18%), as well as a shorter duration of hospitalisation (5 vs 6 days). Overall, 249 (87%) patients were successfully treated with antibiotics without experiencing relapse, catheter removal or death. The majority of streptococcal peritonitis episodes were treated with either intraperitoneal vancomycin (most common) or first-generation cephalosporins for a median period of 13 days (interquartile range 8–18 days). Initial empiric antibiotic choice did not influence outcomes. Conclusion Streptococcal peritonitis is a not infrequent complication of PD, which is more common in indigenous patients. When treated with either first-generation cephalosporins or vancomycin for a period of 2 weeks, streptococcal peritonitis is associated with lower risks of relapse, catheter removal and permanent haemodialysis transfer than other forms of PD-associated peritonitis.Stacey O'Shea, Carmel M Hawley, Stephen P McDonald, Fiona G Brown, Johan B Rosman, Kathryn J Wiggins, Kym M Bannister and David W Johnso

Identification of deleterious non-synonymous single nucleotide polymorphisms using sequence-derived information

<p>Abstract</p> <p>Background</p> <p>As the number of non-synonymous single nucleotide polymorphisms (nsSNPs), also known as single amino acid polymorphisms (SAPs), increases rapidly, computational methods that can distinguish disease-causing SAPs from neutral SAPs are needed. Many methods have been developed to distinguish disease-causing SAPs based on both structural and sequence features of the mutation point. One limitation of these methods is that they are not applicable to the cases where protein structures are not available. In this study, we explore the feasibility of classifying SAPs into disease-causing and neutral mutations using only information derived from protein sequence.</p> <p>Results</p> <p>We compiled a set of 686 features that were derived from protein sequence. For each feature, the distance between the wild-type residue and mutant-type residue was computed. Then a greedy approach was used to select the features that were useful for the classification of SAPs. 10 features were selected. Using the selected features, a decision tree method can achieve 82.6% overall accuracy with 0.607 Matthews Correlation Coefficient (MCC) in cross-validation. When tested on an independent set that was not seen by the method during the training and feature selection, the decision tree method achieves 82.6% overall accuracy with 0.604 MCC. We also evaluated the proposed method on all SAPs obtained from the Swiss-Prot, the method achieves 0.42 MCC with 73.2% overall accuracy. This method allows users to make reliable predictions when protein structures are not available. Different from previous studies, in which only a small set of features were arbitrarily chosen and considered, here we used an automated method to systematically discover useful features from a large set of features well-annotated in public databases.</p> <p>Conclusion</p> <p>The proposed method is a useful tool for the classification of SAPs, especially, when the structure of the protein is not available.</p

Vitamins A & D Inhibit the Growth of Mycobacteria in Radiometric Culture

The role of vitamins in the combat of disease is usually conceptualized as acting by modulating the immune response of an infected, eukaryotic host. We hypothesized that some vitamins may directly influence the growth of prokaryotes, particularly mycobacteria. complex).Vitamins A and D cause dose-dependent inhibition of all three mycobacterial species studied. Vitamin A is consistently more inhibitory than vitamin D. The vitamin A precursor, β-carotene, is not inhibitory, whereas three vitamin A metabolites cause inhibition. Vitamin K has no effect. Vitamin E causes negligible inhibition in a single strain.We show that vitamin A, its metabolites Retinyl acetate, Retinoic acid and 13-cis Retinoic acid and vitamin D directly inhibit mycobacterial growth in culture. These data are compatible with the hypothesis that complementing the immune response of multicellular organisms, vitamins A and D may have heretofore unproven, unrecognized, independent and probable synergistic, direct antimycobacterial inhibitory activity