A Small-Molecule Inhibitor of Mps1 Blocks the Spindle-Checkpoint Response to a Lack of Tension on Mitotic Chromosomes

SummaryThe spindle checkpoint prevents chromosome loss by preventing chromosome segregation in cells with improperly attached chromosomes [1–3]. The checkpoint senses defects in the attachment of chromosomes to the mitotic spindle [4] and the tension exerted on chromosomes by spindle forces in mitosis [5–7]. Because many cancers have defects in chromosome segregation, this checkpoint may be required for survival of tumor cells and may be a target for chemotherapy. We performed a phenotype-based chemical-genetic screen in budding yeast and identified an inhibitor of the spindle checkpoint, called cincreasin. We used a genome-wide collection of yeast gene-deletion strains and traditional genetic and biochemical analysis to show that the target of cincreasin is Mps1, a protein kinase required for checkpoint function [8]. Despite the requirement for Mps1 for sensing both the lack of microtubule attachment and tension at kinetochores, we find concentrations of cincreasin that selectively inhibit the tension-sensitive branch of the spindle checkpoint. At these concentrations, cincreasin causes lethal chromosome missegregation in mutants that display chromosomal instability. Our results demonstrate that Mps1 can be exploited as a target and that inhibiting the tension-sensitive branch of the spindle checkpoint may be a way of selectively killing cancer cells that display chromosomal instability

To Splint or Not to Splint Short Dental Implants Under the Same Partial Fixed Prosthesis? One-year Post-loading Data From a Multicentre Randomised Controlled Trial

PURPOSE. To compare the clinical outcomes of two adjacent 6-mm-long dental implants splinted under the same prosthesis (control group) versus two identical implants sup-porting single crowns (test group). MATERIALS AND METHODS. Forty-seven patients with edentulous posterior (premolars and/or molars) jaws received two adjacent 6-mm-long dental implants, which were sub-merged. Four months later, at impression taking, patients were randomised to receive splinted or unsplinted definitive cemented metal-composite prostheses. Unfortunately, four patients died before randomisation and three patients lost five implants, so only 40 patients were randomised, according to a parallel-group design, to have both implants splinted under the same partial fixed prosthesis (19 patients) or with two single crowns (21 patients). Outcome measures were: prosthesis and implant failures, any complica-tions, peri-implant marginal bone level changes and patient satisfaction. Patients were followed-up to 1 year after loading. RESULTS. One patient from the splinted group dropped out. No implant failures occurred after randomisation. One complication occurred in the unsplinted group versus no complications at splinted implants, the difference not being statistically different (Fisher’s exact test P = 1.000; difference in proportions =-0.04; 95% CI-0.16 to 0.09). Both groups presented significant peri-implant marginal bone loss at 1 year after loading (P<0.05), respectively-0.36 (0.45) mm at splinted implants and-0.17 (0.31) mm at unsplinted implan-ts, but there were no statistically significant differences between the two groups (mean difference 0.19 mm; 95% CI-0.10 to 0.48; P = 0.194). All patients were fully or reasonably satisfied with the treatment, with the exception of two patients, both from the splinted group: one patient was not sure about the aesthetics, and another would not undergo the same treatment again. CONCLUSIONS. The present data seems to suggest that up to 1 year after loading the prognosis of short implants, mostly placed in mandibles characterised by dense bone quality, may not be influenced by splinting or not under the same fixed prostheses. Howe-ver, these preliminary results need to be confirmed by larger trials with follow-ups of at least 5 years

Comparison Between Single Early-loaded Implants With Sandblasted Acidetched (Sa) Surface Versus Sa Surface Modified With Ph Buffering Agent (Soi): Four-month Data From a Split-mouth, Multicentre Randomized Controlled Trial

PURPOSE. To compare implant survival and success rates and implant stability quotient (ISQ) values of early-loaded single implants with sandblasted acid-etched (SA, control group) surface versus implants with SA surface modified with pH buffering agent (SOI, test group). MATERIALS AND METHODS. This study was designed as multicentre, split-mouth, randomized controlled trial to evaluate implant and prosthesis survival rates, complications, and implant stability quotient (ISQ) in any partially edentulous subject requiring at least two single implant-supported crowns. A one-stage implant placement procedure was used, and implants were randomized after implant site preparation. ISQ values were eva-luated for each implant, at baseline and then every week up to 8 weeks after surgery, and finally at definitive crown delivery (12 weeks after implant placement). RESULTS. Overall, 62 patients from 9 centres were enrolled in this study. One patient dropped out from the study at 8 weeks. In the first 12 weeks of observation, 2 implants failed, both in the SA group, the difference not being statistically significant (P = 0.5). No prosthesis failure occurred up to 4 months after fitting. Five complications were expe-rienced, 3 in the SA group and 2 in the SOI group. The difference between groups was not statistically significant (OR = 0.66, 95% CI: 0.11 to 4.07; P = 0.650). Of these complications, loss of stability without rotation was observed in 2 implants from the SOI group and 2 implants from the SA group, all in the third and fourth weeks of measurements. All the implants were submerged and successfully osseointegrated at the twelfth week. The last complication was an SA implant screw loosening, which was resolved chair-side. The baseline mean ISQ values were 76.57 ± 7.54 (95% CI 74.69 to 78.44) in the SA group and 75.92 ± 7.69 (95% CI 73.89 to 77.73) in the SOI group. The mean ISQ values at 12 weeks were 79.17 ± 7.83 (95% CI 77.03 to 81.29) and 78.82 ± 8.80 (95% CI 76.42 to 81.21) in the SA and SOI groups, respectively. Mixed-effects modelling revealed a statistically significant difference between groups over time, with slightly lower ISQ values for the SOI group (-0.65; 95% CI-1.14 to-0.15). Statistically significant differences were also estimated among centres (P <0.001). CONCLUSIONS. Within the limitations of the present preliminary report, it is possible to conclude that both implants can be successfully loaded early

Key normative, legal, and policy considerations for supporting pregnant and postpartum adolescents in high HIV-burden settings: a critical analysis

Rates of adolescent pregnancy within sub-Saharan Africa are increasing. Adolescent mothers ages 10-19 years face a distinct set of risks to their own and their children's health, compounded by many economic, social, and epidemiological challenges, such as living with HIV. In navigating this complex developmental period, many adolescent mothers face structural barriers impeding safe transitions to adulthood and motherhood. Drawing on existing literature and emerging data, we outline three normative, legal, and policy issues - violence and gender inequity, access to sexual and reproductive health services, and access to social and structural supports - which affect the health, wellbeing and development of adolescent mothers and their children. We also highlight emergent evidence about programming and policy changes that can better support adolescent mothers and their children. These key proposed responses include removing barriers to SRH and HIV service integration; ensuring implementation of return-to-school policies; and extending social protection systems to cater for adolescent mothers. Despite ongoing global crises and shifts in funding priorities, these normative, legal, and policy considerations remain critical to safeguard the health and wellbeing of adolescent mothers and their children

Elastic Chiral Waveguides with Gyro-Hinges

This article presents a novel chiral structure, consisting of Euler–Bernoulli beams connected to gyroscopic spinners.Anew type of boundary condition is introduced, which is referred to as a gyrohinge. In this system, flexural waves are coupled with rotational motion.Time-harmonic conditions are derived by assuming small nutation angles of the spinners. It is shown that the eigenfrequencies of a finite beam with gyro-hinges at one or both ends change dramatically with the moments of inertia and the spin and precession rates of the spinners. The formulation is then extended to elastic beams with periodically-spaced gyro-hinges, whose dispersion properties are investigated in detail. In particular, it is shown how stop-bands and standing modes are affected by the introduction of gyroscopic spinners at the junctions. It is also demonstrated that a periodic system composed of beams connected by gyro-hinges represents a good approximation of a gyrobeam, a theoretical structural element consisting of an elastic beam possessing a continuous distribution of stored angular momentum. The gyricity coefficient of a gyrobeam is then interpreted in terms of the physical parameters of the system of beams with gyroscopic spinners. This article opens a new perspective on the design and practical implementation of chiral mechanical systems

Decatransin, a novel natural product inhibiting protein translocation at the Sec61/SecY translocon

A new cyclic decadepsipeptide was isolated from Chaetosphaeria tulasneorum with potent bioactivity on mammalian and yeast cells. Chemogenomic profiling in S. cerevisiae indicated that the Sec61 translocon, the machinery for protein translocation and membrane insertion at the endoplasmic reticulum, is the target. The profiles were similar to those of cyclic heptadepsipeptides of a distinct chemotype (HUN-7293/cotransin) that had previously been shown to inhibit cotranslational translocation at the mammalian Sec61 translocon. Unbiased, genome-wide mutagenesis followed by full-genome sequencing in both fungal and mammalian cells identified dominant mutations in Sec61p/Sec61α1 to confer resistance. Most, but not all, of these mutations affected inhibition by both chemotypes, despite an absence of structural similarity. Biochemical analysis confirmed inhibition of protein translocation into the endoplasmic reticulum of both co- and posttranslationally translocated substrates by both chemotypes, demonstrating a mechanism independent of a translating ribosome. Most interestingly, both chemotypes were found to also inhibit SecYEG, the bacterial Sec61 homolog. We suggest "decatransin" as the name for this novel decadepsipeptide translocation inhibitor

The nuclear receptors of Biomphalaria glabrata and Lottia gigantea: Implications for developing new model organisms

© 2015 Kaur et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are creditedNuclear receptors (NRs) are transcription regulators involved in an array of diverse physiological functions including key roles in endocrine and metabolic function. The aim of this study was to identify nuclear receptors in the fully sequenced genome of the gastropod snail, Biomphalaria glabrata, intermediate host for Schistosoma mansoni and compare these to known vertebrate NRs, with a view to assessing the snail's potential as a invertebrate model organism for endocrine function, both as a prospective new test organism and to elucidate the fundamental genetic and mechanistic causes of disease. For comparative purposes, the genome of a second gastropod, the owl limpet, Lottia gigantea was also investigated for nuclear receptors. Thirty-nine and thirty-three putative NRs were identified from the B. glabrata and L. gigantea genomes respectively, based on the presence of a conserved DNA-binding domain and/or ligand-binding domain. Nuclear receptor transcript expression was confirmed and sequences were subjected to a comparative phylogenetic analysis, which demonstrated that these molluscs have representatives of all the major NR subfamilies (1-6). Many of the identified NRs are conserved between vertebrates and invertebrates, however differences exist, most notably, the absence of receptors of Group 3C, which includes some of the vertebrate endocrine hormone targets. The mollusc genomes also contain NR homologues that are present in insects and nematodes but not in vertebrates, such as Group 1J (HR48/DAF12/HR96). The identification of many shared receptors between humans and molluscs indicates the potential for molluscs as model organisms; however the absence of several steroid hormone receptors indicates snail endocrine systems are fundamentally different.The National Centre for the Replacement, Refinement and Reduction of Animals in Research, Grant Ref:G0900802 to CSJ, LRN, SJ & EJR [www.nc3rs.org.uk]