An organelle-specific protein landscape identifies novel diseases and molecular mechanisms

Cellular organelles provide opportunities to relate biological mechanisms to disease. Here we use affinity proteomics, genetics and cell biology to interrogate cilia: poorly understood organelles, where defects cause genetic diseases. Two hundred and seventeen tagged human ciliary proteins create a final landscape of 1,319 proteins, 4,905 interactions and 52 complexes. Reverse tagging, repetition of purifications and statistical analyses, produce a high-resolution network that reveals organelle-specific interactions and complexes not apparent in larger studies, and links vesicle transport, the cytoskeleton, signalling and ubiquitination to ciliary signalling and proteostasis. We observe sub-complexes in exocyst and intraflagellar transport complexes, which we validate biochemically, and by probing structurally predicted, disruptive, genetic variants from ciliary disease patients. The landscape suggests other genetic diseases could be ciliary including 3M syndrome. We show that 3M genes are involved in ciliogenesis, and that patient fibroblasts lack cilia. Overall, this organelle-specific targeting strategy shows considerable promise for Systems Medicine

DNA replication fidelity in Mycobacterium tuberculosis is mediated by an ancestral prokaryotic proofreader

The DNA replication machinery is an important target for antibiotic development for increasingly drug resistant bacteria including Mycobacterium tuberculosis1. While blocking DNA replication leads to cell death, disrupting the processes used to ensure replication fidelity can accelerate mutation and the evolution of drug resistance. In E. coli, the proofreading subunit of the replisome, the ε-exonuclease, is essential for high fidelity DNA replication2; however, we find that it is completely dispensable in M. tuberculosis. Rather, the mycobacterial replicative polymerase, DnaE1, encodes a novel editing function that proofreads DNA replication, mediated by an intrinsic 3′-5′ exonuclease activity within its PHP domain. Inactivation of the DnaE1 PHP domain increases the mutation rate by greater than 3,000 fold. Moreover, phylogenetic analysis of DNA replication proofreading in the bacterial kingdom suggests that E. coli is a phylogenetic outlier and that PHP-domain mediated proofreading is widely conserved and indeed may be the ancestral prokaryotic proofreader

Place of death and health care utilization for people in the last 6 months of life in Switzerland: a retrospective analysis using administrative data

BACKGROUND: There is a growing interest in examining the current state of care and identifying opportunities for improving care and reducing costs at the end of life. The aim of this study is to examine patterns of health care use at the end of life and place of death and to describe the basic characteristics of the decedents in the last six months of their life. METHODS: The empirical analysis is based on data from 58,732 Swiss residents who died between 2007 and 2011. All decedents had mandatory health insurance with Helsana Group, the largest health insurer in Switzerland. Descriptive statistical techniques were used to provide a general profile of the study population and determinants of the outcome for place of death were analyzed with an econometric approach. RESULTS: There were substantial and significant differences in health care utilization in the last six months of life between places of death. The mean numbers of consultations with a general practitioner or a specialist physician as well as the number of different medications and the number of hospital days was consistently highest for the decedents who died in a hospital. We found death occurred in Switzerland most frequently in hospitals (38.4% of all cases) followed by nursing homes (35.1%) and dying at home (26.6%). The econometric analysis indicated that the place of death is significantly associated with age, sex, region and multiple chronic conditions. CONCLUSIONS: The importance of nursing homes and patients' own homes as place of death will continue to grow in the future. Knowing the determinants of place of death and patterns of health care utilization of decedents can help decision makers on the allocation of these needed health care services in Switzerland

Cancer immunotherapy--revisited

Item does not contain fulltextOur insight into antitumour immune responses has increased considerably during the past decades, yet the development of immunotherapy as a treatment modality for cancer has been hampered by several factors. These include difficulties in the selection of the optimal dose and schedule, the methods of evaluation, and financial support. Although durable clinical remissions have been observed with various immunotherapeutic strategies, the percentage of patients who benefited from these interventions has remained too small to justify the general use of such strategies. However, the recent positive results of clinical trials with novel immunoactive drugs as well as the unexpected finding of a positive interaction between immunotherapy and chemotherapy may herald a new era for the immunotherapy of cancer

The association between hope, marital status, depression and persistent pain in men and women following cardiac surgery

Background Cardiac surgery is a major life event, and outcomes after surgery are associated with men’s and women’s ability to self-manage and cope with their cardiac condition in everyday life. Hope is suggested to impact cardiac health by having a positive effect on how adults cope with and adapt to illness and recommended lifestyle changes. Methods We did a secondary analysis of 416 individuals (23% women) undergoing elective coronary artery bypass graft and/or valve surgery between March 2012 and September 2013 enrolled in randomized controlled trial. Hope was assessed using The Herth Hope Index (HHI) at three, six and 12 months following cardiac surgery. Linear mixed model analyses were performed to explore associations after cardiac surgery between hope, marital status, depression, persistent pain, and surgical procedure. Results For the total sample, no statistically significant difference between global hope scores from 3 to 12 months was observed (ranging from 38.3 ± 5.1 at 3 months to 38.7 ± 5.1 at 12 months), and no differences between men and women were observed at any time points. However, 3 out of 12 individual items on the HHI were associated with significantly lower scores in women: #1) I have a positive outlook toward life, #3) I feel all alone, and #6) I feel scared about my future. Over the study period, diminished hope was associated with older age, lower education, depression prior to surgery, and persistent pain at all measurement points. Isolated valve surgery was positively associated with hope. While neither sex nor marital status, as main effects, demonstrated significant associations with hope, women who were divorced/widowed/single were significantly more likely to have lower hope scores over the study period. Conclusion Addressing pain and depression, and promoting hope, particularly for women living alone may be important targets for interventions to improve outcomes following cardiac surgery