Uncoupling of p97 ATPase activity has a dominant negative effect on protein extraction

p97 is a highly abundant, homohexameric AAA+ ATPase that performs a variety of essential cellular functions. Characterized as a ubiquitin-selective chaperone, p97 recognizes proteins conjugated to K48-linked polyubiquitin chains and promotes their removal from chromatin and other molecular complexes. Changes in p97 expression or activity are associated with the development of cancer and several related neurodegenerative disorders. Although pathogenic p97 mutations cluster in and around p97's ATPase domains, mutant proteins display normal or elevated ATPase activity. Here, we show that one of the most common p97 mutations (R155C) retains ATPase activity, but is functionally defective. p97-R155C can be recruited to ubiquitinated substrates on chromatin, but is unable to promote substrate removal. As a result, p97-R155C acts as a dominant negative, blocking protein extraction by a similar mechanism to that observed when p97's ATPase activity is inhibited or inactivated. However, unlike ATPase-deficient proteins, p97-R155C consumes excess ATP, which can hinder high-energy processes. Together, our results shed new insight into how pathogenic mutations in p97 alter its cellular function, with implications for understanding the etiology and treatment of p97-associated diseases

Archaeal phylogenomics provides evidence in support of a methanogenic origin of the Archaea and a thaumarchaeal origin for the eukaryotes

We have developed a machine-learning approach to identify 3537 discrete orthologue protein sequence groups distributed across all available archaeal genomes. We show that treating these orthologue groups as binary detection/non-detection data is sufficient to capture the majority of archaeal phylogeny. We subsequently use the sequence data from these groups to infer a method and substitution-model-independent phylogeny. By holding this phylogeny constrained and interrogating the intersection of this large dataset with both the Eukarya and the Bacteria using Bayesian and maximum-likelihood approaches, we propose and provide evidence for a methanogenic origin of the Archaea. By the same criteria, we also provide evidence in support of an origin for Eukarya either within or as sisters to the Thaumarchaea

A colimit decomposition for homotopy algebras in Cat

Badzioch showed that in the category of simplicial sets each homotopy algebra of a Lawvere theory is weakly equivalent to a strict algebra. In seeking to extend this result to other contexts Rosicky observed a key point to be that each homotopy colimit in simplicial sets admits a decomposition into a homotopy sifted colimit of finite coproducts, and asked the author whether a similar decomposition holds in the 2-category of categories Cat. Our purpose in the present paper is to show that this is the case.Comment: Some notation changed; small amount of exposition added in intr

Physiotherapy students\u27 perceptions and experiences of clinical prediction rules

Objectives: Clinical reasoning can be difficult to teach to pre-professional physiotherapy students due to their lack of clinical experience. It may be that tools such as clinical prediction rules (CPRs) could aid the process, but there has been little investigation into their use in physiotherapy clinical education. This study aimed to determine the perceptions and experiences of physiotherapy students regarding CPRs, and whether they are learning about CPRs on clinical placement. Design: Cross-sectional survey using a paper-based questionnaire. Participants: Final year pre-professional physiotherapy students (n=371, response rate 77%) from five universities across five states of Australia. Results: Sixty percent of respondents had not heard of CPRs, and a further 19% had not clinically used CPRs. Only 21% reported using CPRs, and of these nearly three-quarters were rarely, if ever, learning about CPRs in the clinical setting. However most of those who used CPRs (78%) believed CPRs assisted in the development of clinical reasoning skills and none (0%) was opposed to the teaching of CPRs to students. The CPRs most commonly recognised and used by students were those for determining the need for an X-ray following injuries to the ankle and foot (67%), and for identifying deep venous thrombosis (63%). Conclusions: The large majority of students in this sample knew little, if anything, about CPRs and few had learned about, experienced or practiced them on clinical placement. However, students who were aware of CPRs found them helpful for their clinical reasoning and were in favour of learning more about them

Transduodenal Sphincteroplasty and Transampullary Septectomy for Papillary Stenosis

Twenty patients received transduodenal sphincteroplasty and transampullary septectomy between 1987 and 1993. Seven patients had post-cholecystectomy pain which was much improved or abolished in 5 of 7 patients at a mean follow-up of 4 years and 5 months. Four of five patients with chronic pancreatitis were improved at 3 years and 2 months. Three of five patients with recurrent acute pancreatitis were improved at 4 years and 5 months. One of three patients with chronic abdominal pain of hepatobiliary origin was improved at 3 years. Transduodenal sphincteroplasty and transampullary septectomy can relieve pain in patients with post-cholecystectomy pain, recurrent acute pancreatitis, chronic pancreatitis, and chronic abdominal pain of hepatobiliary origin, presumably by improving drainage of the obstructed ducts

DNA methylation of ESR-1 and N-33 in colorectal mucosa of patients with Ulcerative Colitis (UC)

Introduction: Epigenetic marking such as DNA methylation influence gene transcription and chromosomal stability and may also be affected by environmental exposures. Few studies exist on alteration in DNA methylation profiles (genomic and gene specific methylation) in patients with Ulcerative Colitis (UC) and none assessing its relationship with lifestyle exposures. Aims & Methods: To assess genomic methylation and promoter methylation of the ESR-1 (oestrogen receptor - 1) and N-33 (tumour suppressor candidate-3) genes in the macroscopically normal mucosa of UC patients as well as to investigate effects of anthropometric and lifestyle exposures on DNA methylation. Sixty eight subjects were recruited (24 UC and 44 age and sex matched controls). Colorectal mucosal biopsies were obtained and DNA was extracted. Genomic DNA methylation was quantified using the tritium-labelled cytosine extension assay (3[H] dCTP) whilst gene specific methylation was quantified using the COBRA method. Results: The methylation level of both ESR-1 and N-33 genes were significantly higher in UC subjects compared with controls (7.9% vs 5.9%; p = 0.015 and 66% vs 9.3%; p < 0.001 respectively). There was no detectable difference in global DNA methylation between patients with UC and age and sex matched controls. No associations between indices of DNA methylation and anthropometric measures or smoking patterns were detected. Conclusions: For the first time, we have shown increased methylation in the promoter regions of the putative tumour suppressor gene N-33 in macroscopically normal mucosa of patients with UC. In addition, we have confirmed that methylation of ESR-1 promoter is higher in UC patients compared with age and sex matched controls. These findings suggests that, inactivation through methylation of the putative tumour suppressor genes N-33 and ESR-1, may not be associated with colorectal carcinogenesis in UC

Sticking to Syntax: The Reflection of Story Grammar in Children\u27s and Adult\u27s Recall of Radio and Television Shows

Two studies were conducted to determine how well story grammar predicted recall of televised stories. In Experiment 1, preschoolers viewed a non-narrated televised story from Sesame Street. In Experiment 2, preschoolers and adults were administered a narrative via television or radio. In both studies, subjects\u27 retention reflected recall of nodal information, regardless of medium of input

Development of Prognosis in Palliative care Study (PiPS) predictor models to improve prognostication in advanced cancer: prospective cohort study

OBJECTIVE: To develop a novel prognostic indicator for use in patients with advanced cancer that is significantly better than clinicians' estimates of survival. DESIGN: Prospective multicentre observational cohort study. SETTING: 18 palliative care services in the UK (including hospices, hospital support teams, and community teams). PARTICIPANTS: 1018 patients with locally advanced or metastatic cancer, no longer being treated for cancer, and recently referred to palliative care services. MAIN OUTCOME MEASURES: Performance of a composite model to predict whether patients were likely to survive for "days" (0-13 days), "weeks" (14-55 days), or "months+" (>55 days), compared with actual survival and clinicians' predictions. RESULTS: On multivariate analysis, 11 core variables (pulse rate, general health status, mental test score, performance status, presence of anorexia, presence of any site of metastatic disease, presence of liver metastases, C reactive protein, white blood count, platelet count, and urea) independently predicted both two week and two month survival. Four variables had prognostic significance only for two week survival (dyspnoea, dysphagia, bone metastases, and alanine transaminase), and eight variables had prognostic significance only for two month survival (primary breast cancer, male genital cancer, tiredness, loss of weight, lymphocyte count, neutrophil count, alkaline phosphatase, and albumin). Separate prognostic models were created for patients without (PiPS-A) or with (PiPS-B) blood results. The area under the curve for all models varied between 0.79 and 0.86. Absolute agreement between actual survival and PiPS predictions was 57.3% (after correction for over-optimism). The median survival across the PiPS-A categories was 5, 33, and 92 days and survival across PiPS-B categories was 7, 32, and 100.5 days. All models performed as well as, or better than, clinicians' estimates of survival. CONCLUSIONS: In patients with advanced cancer no longer being treated, a combination of clinical and laboratory variables can reliably predict two week and two month survival