Mutations in genes encoding condensin complex proteins cause microcephaly through decatenation failure at mitosis

Correction to Martin et al. available at: Genes & Development 30 (19): 2158 (http://genesdev.cshlp.org/content/31/9/953.full.pdf+html).Compaction of chromosomes is essential for accurate segregation of the genome duringmitosis. In vertebrates, two condensin complexes ensure timely chromosome condensation, sister chromatid disentanglement, and maintenance of mitotic chromosome structure. Here,we report that biallelic mutations inNCAPD2,NCAPH, orNCAPD3, encoding subunits of these complexes, cause microcephaly. In addition, hypomorphic Ncaph2 mice have significantly reduced brain size, with frequent anaphase chromatin bridge formation observed in apical neural progenitors during neurogenesis. Such DNA bridges also arise in condensin-deficient patient cells, where they are the consequence of failed sister chromatid disentanglement during chromosome compaction. This results in chromosome segregation errors, leading to micronucleus formation and increased aneuploidy in daughter cells. These findings establish “condensinopathies” as microcephalic disorders, with decatenation failure as an additional disease mechanism for microcephaly, implicating mitotic chromosome condensation as a key process ensuring mammalian cerebral cortex size.This work was supported by funding from the Medical Research Council, the Lister Institute for Preventative Medicine, and the European Research Council (ERC; 281847 to A.P.J.); a Biotechnology and Biological Sciences Research Council grant (BB/ K017632/1 to P.V); a Sir Henry Dale Fellowship (grant 102560/ Z/13/Z to A.J.W.); Medical Research Scotland (to L.S.B.); the Potentials Foundation (to C.A.W.); and the Indian Council of Medical Research (BMS 54/2/2013 to S.R.P). The Deciphering Developmental Disorders Study presents independent research commissioned by the Health Innovation Challenge Fund (grant no. HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant no. WT098051). The views expressed here are those of the authors and not necessarily those of the Wellcome Trust or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83) granted by the Cambridge South Research Ethics Committee, and GEN/ 284/12 granted by the Republic of Ireland. We acknowledge the support of the National Institute for Health Research through the Comprehensive Clinical Research Network

Satisfaction is not all – patients' perceptions of outcome of general practice consultations, a qualitative study

BACKGROUND: Evaluation of outcome in general practice can be seen from different viewpoints. In this study we focus on the concepts patients use to describe the outcome of a consultation with a GP. METHOD: Patients were interviewed within a week after a consultation with a GP. The interviews were made with 20 patients in 5 focus groups and 8 individually. They were analysed with a phenomenographic research approach. RESULTS: From the patient's perspective, the outcome of a consultation is about cure or symptom relief, understanding, confirmation, reassurance, change in self-perception and satisfaction. CONCLUSION: General practice consultations are often more important for patients than generally supposed. Understanding is the most basic concept

Use of mitogenic cascade blockers for treatment of C-Raf induced lung adenoma in vivo: CI-1040 strongly reduces growth and improves lung structure

BACKGROUND: Signaling networks promoting cell growth and proliferation are frequently deregulated in cancer. Tumors often are highly dependent on such signaling pathways and may become hypersensitive to downregulation of key components within these signaling cascades. The classical mitogenic cascade transmits stimuli from growth factor receptors via Ras, Raf, MEK and ERK to the cell nucleus and provides attractive molecular targets for cancer treatment. For example, Ras and Raf kinase inhibitors are already in a number of ongoing phase II and phase III clinical trials. In this study the effect of the Raf kinase inhibitor BAY 43-9006 and of the MEK inhibitor CI-1040 (PD184352) on a Raf dependent lung tumor mouse model was analyzed in detail. METHODS: We have generated a lung cancer mouse model by targeting constitutively active C-Raf kinase to the lung. These mice develop adenomas within 4 months of life. At this time-point they received daily intraperitoneal injections of either 100 mg/kg BAY 43-9006 or CI-1040 for additional 21 days. Thereafter, lungs were isolated and the following parameters were analyzed using histology and immunohistochemistry: overall lung structure, frequency of adenoma foci, proliferation rate, ERK activity, caspase-3 activation, and lung differentiation. RESULTS: Both inhibitors were equally effective in vitro using a sensitive Raf/MEK/ERK ELISA. In vivo, the systemic administration of the MEK inhibitor CI-1040 reduced adenoma formation to a third and significantly restored lung structure. The proliferation rate of lung cells of mice treated with CL-1040 was decreased without any obvious effects on differentiation of pneumocytes. In contrast, the Raf inhibitor BAY 43-9006 did not influence adenoma formation in vivo. CONCLUSION: The MEK inhibitor CI-1040 may be used for the treatment of Ras and/or Raf-dependent human malignancies

Nitroheterocyclic drugs cure experimental <i>Trypanosoma cruzi</i> infections more effectively in the chronic stage than in the acute stage

The insect-transmitted protozoan parasite Trypanosoma cruzi is the causative agent of Chagas disease, and infects 5-8 million people in Latin America. Chagas disease is characterised by an acute phase, which is partially resolved by the immune system, but then develops as a chronic life-long infection. There is a consensus that the front-line drugs benznidazole and nifurtimox are more effective against the acute stage in both clinical and experimental settings. However, confirmative studies have been restricted by difficulties in demonstrating sterile parasitological cure. Here, we describe a systematic study of nitroheterocyclic drug efficacy using highly sensitive bioluminescence imaging of murine infections. Unexpectedly, we find both drugs are more effective at curing chronic infections, judged by treatment duration and therapeutic dose. This was not associated with factors that differentially influence plasma drug concentrations in the two disease stages. We also observed that fexinidazole and fexinidazole sulfone are more effective than benznidazole and nifurtimox as curative treatments, particularly for acute stage infections, most likely as a result of the higher and more prolonged exposure of the sulfone derivative. If these findings are translatable to human patients, they will have important implications for treatment strategies

Biological-effective versus conventional dose volume histograms correlated with late genitourinary and gastrointestinal toxicity after external beam radiotherapy for prostate cancer: a matched pair analysis

BACKGROUND: To determine whether the dose-volume histograms (DVH's) for the rectum and bladder constructed using biological-effective dose (BED-DVH's) better correlate with late gastrointestinal (GI) and genitourinary (GU) toxicity after treatment with external beam radiotherapy for prostate cancer than conventional DVH's (C-DVH's). METHODS: The charts of 190 patients treated with external beam radiotherapy with a minimum follow-up of 2 years were reviewed. Six patients (3.2%) were found to have RTOG grade 3 GI toxicity, and similarly 6 patients (3.2%) were found to have RTOG grade 3 GU toxicity. Average late C-DVH's and BED-DVH's of the bladder and rectum were computed for these patients as well as for matched-pair control patients. For each matched pair the following measures of normalized difference in the DVH's were computed: (a) δ(AUC )= (Area Under Curve [AUC] in grade 3 patient – AUC in grade 0 patient)/(AUC in grade 0 patient) and (b) δ(V60 )= (Percent volume receiving = 60 Gy [V60] in grade 3 patient – V60 in grade 0 patient)/(V60 in grade 0 patient). RESULTS: As expected, the grade 3 curve is to the right of and above the grade 0 curve for all four sets of average DVH's – suggesting that both the C-DVH and the BED-DVH can be used for predicting late toxicity. δ(AUC )was higher for the BED-DVH's than for the C-DVH's – 0.27 vs 0.23 (p = 0.036) for the rectum and 0.24 vs 0.20 (p = 0.065) for the bladder. δ(V60 )was also higher for the BED-DVH's than for the C-DVH's – 2.73 vs 1.49 for the rectum (p = 0.021) and 1.64 vs 0.71 (p = 0.021) for the bladder. CONCLUSIONS: When considering well-established dosimetric endpoints used in evaluating treatment plans, BED-DVH's for the rectum and bladder correlate better with late toxicity than C-DVH's and should be considered when attempting to minimize late GI and GU toxicity after external beam radiotherapy for prostate cancer

A ruthenium polypyridyl intercalator stalls DNA replication forks, radiosensitizes human cancer cells and is enhanced by Chk1 inhibition

Ruthenium(II) polypyridyl complexes can intercalate DNA with high affinity and prevent cell proliferation; however, the direct impact of ruthenium-based intercalation on cellular DNA replication remains unknown. Here we show the multi-intercalator [Ru(dppz)2(PIP)]2+ (dppz = dipyridophenazine, PIP = 2-(phenyl)imidazo[4,5-f][1,10]phenanthroline) immediately stalls replication fork progression in HeLa human cervical cancer cells. In response to this replication blockade, the DNA damage response (DDR) cell signalling network is activated, with checkpoint kinase 1 (Chk1) activation indicating prolonged replication-associated DNA damage, and cell proliferation is inhibited by G1-S cell-cycle arrest. Co-incubation with a Chk1 inhibitor achieves synergistic apoptosis in cancer cells, with a significant increase in phospho(Ser139) histone H2AX (γ- H2AX) levels and foci indicating increased conversion of stalled replication forks to double-strand breaks (DSBs). Normal human epithelial cells remain unaffected by this concurrent treatment. Furthermore, pre-treatment of HeLa cells with [Ru(dppz)2(PIP)]2+ before external beam ionising radiation results in a supra-additive decrease in cell survival accompanied by increased γ-H2AX expression, indicating the compound functions as a radiosensitizer. Together, these results indicate ruthenium-based intercalation can block replication fork progression and demonstrate how these DNA-binding agents may be combined with DDR inhibitors or ionising radiation to achieve more efficient cancer cell killing

TRY plant trait database - enhanced coverage and open access

Plant traits-the morphological, anatomical, physiological, biochemical and phenological characteristics of plants-determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait-based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits-almost complete coverage for 'plant growth form'. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait-environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives

Patterns of soil-transmitted helminth infection and impact of four-monthly albendazole treatments in preschool children from semi-urban communities in Nigeria: a double-blind placebo-controlled randomised trial

Background Children aged between one and five years are particularly vulnerable to disease caused by soil-transmitted helminths (STH). Periodic deworming has been shown to improve growth, micronutrient status (iron and vitamin A), and motor and language development in preschool children and justifies the inclusion of this age group in deworming programmes. Our objectives were to describe the prevalence and intensity of STH infection and to investigate the effectiveness of repeated four-monthly albendazole treatments on STH infection in children aged one to four years. Methods The study was carried out in four semi-urban villages situated near Ile-Ife, Osun State, Nigeria. The study was a double-blind placebo-controlled randomised trial. Children aged one to four years were randomly assigned to receive either albendazole or placebo every four months for 12 months with a follow-up at 14 months. Results The results presented here revealed that 50% of the preschool children in these semi-urban communities were infected by one or more helminths, the most prevalent STH being Ascaris lumbricoides (47.6%). Our study demonstrated that repeated four-monthly anthelminthic treatments with albendazole were successful in reducing prevalence and intensity of A. lumbricoides infections. At the end of the follow-up period, 12% and 43% of the children were infected with A. lumbricoides and mean epg was 117 (S.E. 50) and 1740 (S.E. 291) in the treatment and placebo groups respectively compared to 45% and 45% of the children being infected with Ascaris and mean epg being 1095 (S.E. 237) and 1126 (S.E. 182) in the treatment and placebo group respectively at baseline. Conclusion Results from this study show that the moderate prevalence and low intensity of STH infection in these preschool children necessitates systematic treatment of the children in child health programmes

Observation of associated near-side and away-side long-range correlations in √sNN=5.02 TeV proton-lead collisions with the ATLAS detector

Two-particle correlations in relative azimuthal angle (Δϕ) and pseudorapidity (Δη) are measured in √sNN=5.02  TeV p+Pb collisions using the ATLAS detector at the LHC. The measurements are performed using approximately 1  μb-1 of data as a function of transverse momentum (pT) and the transverse energy (ΣETPb) summed over 3.1<η<4.9 in the direction of the Pb beam. The correlation function, constructed from charged particles, exhibits a long-range (2<|Δη|<5) “near-side” (Δϕ∼0) correlation that grows rapidly with increasing ΣETPb. A long-range “away-side” (Δϕ∼π) correlation, obtained by subtracting the expected contributions from recoiling dijets and other sources estimated using events with small ΣETPb, is found to match the near-side correlation in magnitude, shape (in Δη and Δϕ) and ΣETPb dependence. The resultant Δϕ correlation is approximately symmetric about π/2, and is consistent with a dominant cos⁡2Δϕ modulation for all ΣETPb ranges and particle pT