Heterologous expression of the avirulence gene ACE1 from the fungal rice pathogen Magnaporthe oryzae

The ACE1 and RAP1 genes from the avirulence signalling gene cluster of the rice blast fungus Magnaporthe oryzae were expressed in Aspergillus oryzae and M. oryzae itself. Expression of ACE1 alone produced a polyenyl pyrone (magnaporthepyrone), which is regioselectively epoxidised and hydrolysed to give different diols, 6 and 7, in the two host organisms. Analysis of the three introns present in ACE1 determined that A. oryzae does not process intron 2 correctly, while M. oryzae processes all introns correctly in both appressoria and mycelia. Co-expression of ACE1 and RAP1 in A. oryzae produced an amide 8 which is similar to the PKS-NRPS derived backbone of the cytochalasans. Biological testing on rice leaves showed that neither the diols 6 and 7, nor amide 8 was responsible for the observed ACE1 mediated avirulence, however, gene cluster analysis suggests that the true avirulence signalling compound may be a tyrosine-derived cytochalasan compound.Government of Egypt ScholarshipThe School of Chemistry at the University of Bristol and the Mark Evans ScholarshipKano State Government NigeriaMacArthur FoundationBayero UniversityNigerian Petroleum Technology FundMalaysian Govenment ScholarshipEP/F066104/

Multinational survey of osteoporotic fracture management

Abstract Osteoporosis is characterized by a decreased bone mass and an increased bone fragility and susceptibility to fracture

Human metabolic profiles are stably controlled by genetic and environmental variation

A comprehensive variation map of the human metabolome identifies genetic and stable-environmental sources as major drivers of metabolite concentrations. The data suggest that sample sizes of a few thousand are sufficient to detect metabolite biomarkers predictive of disease

Evolutionary conservation of the fidelity of transcription

Accurate transcription is required for the faithful expression of genetic information. However, relatively little is known about the molecular mechanisms that control the fidelity of transcription, or the conservation of these mechanisms across the tree of life. To address these issues, we measured the error rate of transcription in five organisms of increasing complexity and found that the error rate of RNA polymerase II ranges from 2.9 × 10 -6 ± 1.9 × 10 -7/bp in yeast to 4.0 × 10 -6 ± 5.2 × 10 -7/bp in worms, 5.69 × 10 -6 ± 8.2 × 10 -7/bp in flies, 4.9 × 10 -6 ± 3.6 × 10 -7/bp in mouse cells and 4.7 × 10 -6 ± 9.9 × 10 -8/bp in human cells. These error rates were modified by various factors including aging, mutagen treatment and gene modifications. For example, the deletion or modification of several related genes increased the error rate substantially in both yeast and human cells. This research highlights the evolutionary conservation of factors that control the fidelity of transcription. Additionally, these experiments provide a reasonable estimate of the error rate of transcription in human cells and identify disease alleles in a subunit of RNA polymerase II that display error-prone transcription. Finally, we provide evidence suggesting that the error rate and spectrum of transcription co-evolved with our genetic code

Cognitive behaviour therapy (CBT) for anxiety and depression in adults with mild intellectual disabilities (ID): a pilot randomised controlled trial

Background: Several studies have showed that people with intellectual disabilities (ID) have suitable skills to undergo cognitive behavioural therapy (CBT). Case studies have reported successful use of cognitive behavioural therapy techniques (with adaptations) in people with ID. Modified cognitive behavioural therapy may be a feasible and effective approach for the treatment of depression, anxiety, and other mood disorders in ID. To date, two studies have reported group-based manaulised cognitive behavioural treatment programs for depression in people with mild ID. However, there is no individual manualised programme for anxiety or depression in people with intellectual disabilities. The aims of the study are to determine the feasibility of conducting a randomised controlled trial for CBT in people with ID. The data will inform the power calculation and other aspects of carrying out a definitive randomised controlled trial.Methods: Thirty participants with mild ID will be allocated randomly to either CBT or treatment as usual (TAU). The CBT group will receive up to 20 hourly individual CBT over a period of 4 months. TAU is the standard treatment which is available to any adult with an intellectual disability who is referred to the intellectual disability service (including care management, community support, medical, nursing or social support). Beck Youth Inventories (Beck Anxiety Inventory & Beck Depression Inventory) will be administered at baseline; end of treatment (4 months) and at six months to evaluate the changes in depression and anxiety. Client satisfaction, quality of life and the health economics will be secondary outcomes.Discussion: The broad outcome of the study will be to produce clear guidance for therapists to apply an established psychological intervention and identify how and whether it works with people with intellectual disabilities

Cervical determinants of anal HPV infection and high-grade anal lesions in women: a collaborative pooled analysis

Cervical cancer screening might contribute to the prevention of anal cancer in women. We aimed to investigate if routine cervical cancer screening results-namely high-risk human papillomavirus (HPV) infection and cytohistopathology-predict anal HPV16 infection, anal high-grade squamous intraepithelial lesions (HSIL) and, hence, anal cancer.International Agency for Research on Cance

Cervical lymph node metastasis in high-grade transformation of head and neck adenoid cystic carcinoma: a collective international review

Adenoid cystic carcinoma (AdCC) is among the most common malignant tumors of the salivary glands. It is characterized by a prolonged clinical course, with frequent local recurrences, late onset of metastases and fatal outcome. High-grade transformation (HGT) is an uncommon phenomenon among salivary carcinomas and is associated with increased tumor aggressiveness. In AdCC with high-grade transformation (AdCC-HGT), the clinical course deviates from the natural history of AdCC. It tends to be accelerated, with a high propensity for lymph node metastasis. In order to shed light on this rare event and, in particular, on treatment implications, we undertook this review: searching for all published cases of AdCC-HGT. We conclude that it is mandatory to perform elective neck dissection in patients with AdCC-HGT, due to the high risk of lymph node metastases associated with transformation

A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers

Somatic rearrangements contribute to the mutagenized landscape of cancer genomes. Here, we systematically interrogated rearrangements in 560 breast cancers by using a piecewise constant fitting approach. We identified 33 hotspots of large (>100 kb) tandem duplications, a mutational signature associated with homologous-recombination-repair deficiency. Notably, these tandem-duplication hotspots were enriched in breast cancer germline susceptibility loci (odds ratio (OR) = 4.28) and breast-specific 'super-enhancer' regulatory elements (OR = 3.54). These hotspots may be sites of selective susceptibility to double-strand-break damage due to high transcriptional activity or, through incrementally increasing copy number, may be sites of secondary selective pressure. The transcriptomic consequences ranged from strong individual oncogene effects to weak but quantifiable multigene expression effects. We thus present a somatic-rearrangement mutational process affecting coding sequences and noncoding regulatory elements and contributing a continuum of driver consequences, from modest to strong effects, thereby supporting a polygenic model of cancer development.DG is supported by the EU-FP7-SUPPRESSTEM project. SN-Z is funded by a Wellcome Trust Intermediate Fellowship (WT100183MA) and is a Wellcome Beit Fellow. For more information, please visit the publisher's website

HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures.

Approximately 1-5% of breast cancers are attributed to inherited mutations in BRCA1 or BRCA2 and are selectively sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. In other cancer types, germline and/or somatic mutations in BRCA1 and/or BRCA2 (BRCA1/BRCA2) also confer selective sensitivity to PARP inhibitors. Thus, assays to detect BRCA1/BRCA2-deficient tumors have been sought. Recently, somatic substitution, insertion/deletion and rearrangement patterns, or 'mutational signatures', were associated with BRCA1/BRCA2 dysfunction. Herein we used a lasso logistic regression model to identify six distinguishing mutational signatures predictive of BRCA1/BRCA2 deficiency. A weighted model called HRDetect was developed to accurately detect BRCA1/BRCA2-deficient samples. HRDetect identifies BRCA1/BRCA2-deficient tumors with 98.7% sensitivity (area under the curve (AUC) = 0.98). Application of this model in a cohort of 560 individuals with breast cancer, of whom 22 were known to carry a germline BRCA1 or BRCA2 mutation, allowed us to identify an additional 22 tumors with somatic loss of BRCA1 or BRCA2 and 47 tumors with functional BRCA1/BRCA2 deficiency where no mutation was detected. We validated HRDetect on independent cohorts of breast, ovarian and pancreatic cancers and demonstrated its efficacy in alternative sequencing strategies. Integrating all of the classes of mutational signatures thus reveals a larger proportion of individuals with breast cancer harboring BRCA1/BRCA2 deficiency (up to 22%) than hitherto appreciated (∼1-5%) who could have selective therapeutic sensitivity to PARP inhibition