Control of cell cycle progression by phosphorylation of cyclin-dependent kinase (CDK) substrates

The eukaryotic cell cycle is a fundamental evolutionarily conserved process that regulates cell division from simple unicellular organisms, such as yeast, through to higher multicellular organisms, such as humans. The cell cycle comprises several phases, including the S-phase (DNA synthesis phase) and M-phase (mitotic phase). During S-phase, the genetic material is replicated, and is then segregated into two identical daughter cells following mitotic M-phase and cytokinesis. The S- and M-phases are separated by two gap phases (G1 and G2) that govern the readiness of cells to enter S- or M-phase. Genetic and biochemical studies demonstrate that cell division in eukaryotes is mediated by CDKs (cyclin-dependent kinases). Active CDKs comprise a protein kinase subunit whose catalytic activity is dependent on association with a regulatory cyclin subunit. Cell-cycle-stage-dependent accumulation and proteolytic degradation of different cyclin subunits regulates their association with CDKs to control different stages of cell division. CDKs promote cell cycle progression by phosphorylating critical downstream substrates to alter their activity. Here, we will review some of the well-characterized CDK substrates to provide mechanistic insights into how these kinases control different stages of cell division.

Evidence of a conserved role for Chlamydia HtrA in the replication phase of the chlamydial developmental cycle

Identification of the HtrA inhibitor JO146 previously enabled us to demonstrate an essential function for HtrA during the mid-replicative phase of the Chlamydia trachomatis developmental cycle. Here we extend our investigations to other members of the Chlamydia genus. C. trachomatis isolates with distinct replicative phase growth kinetics showed significant loss of viable infectious progeny after HtrA was inhibited during the replicative phase. Mid-replicative phase addition of JO146 was also significantly detrimental to Chlamydia pecorum, Chlamydia suis and Chlamydia cavie. These data combined indicate that HtrA has a conserved critical role during the replicative phase of the chlamydial developmental cycle.

Optimal HMM processing of differentially phase modulated communication systems

This paper investigates demodulation of differentially phase modulated signals DPMS using optimal HMM filters. The optimal HMM filter presented in the paper is computationally of order N3 per time instant, where N is the number of message symbols. Previously, optimal HMM filters have been of computational order N4 per time instant. Also, suboptimal HMM filters have be proposed of computation order N2 per time instant. The approach presented in this paper uses two coupled HMM filters and exploits knowledge of ...

Modeling and control of a CLC resonant dual active bridge

This paper proposes a linear large signal state-space model for a phase controlled CLC (Capacitor Inductor Capacitor) Resonant Dual Active Bridge (RDAB). The proposed model is useful for fast simulation and for the estimation of state variables under large signal variation. The model is also useful for control design because the slow changing dynamics of the dq variables are relatively easy to control. Simulation results of the proposed model are presented and compared to the simulated circuit model to demonstrate the proposed model's accuracy. This proposed model was used for the design of a Proportional-Integral (PI) controller and it has been implemented in the circuit simulation to show the proposed models usefulness in control design.

Double star chopper cell converter for battery electric vehicles with inter-module SoC balancing and fault tolerant control

A modularized battery system with Double Star Chopper Cell (DSCC) based modular multilevel converter is proposed for a battery operated electric vehicle (EV). A design concept for the modularized battery micro-packs for DSCC is described. Multidimensional pulse width modulation (MD-PWM) with integrated inter-module SoC balancing and fault tolerant control is proposed and explained. The DSCC can be operated either as an inverter to drive the EV motor or as a synchronous rectifier connected to external three phase power supply equipment for charging the battery micro-packs. The methods of operation as inverter and synchronous rectifier with integrated inter-module SoC balancing and fault tolerant control are discussed. The proposed system operation as inverter and synchronous rectifier are verified through simulations and the results are presented.

A phase II trial of brivanib in recurrent or persistent endometrial cancer: An NRG oncology/gynecologic oncology group study

PURPOSE Brivanib, an oral, multi-targeted tyrosine kinase inhibitor with activity against vascular endothelial growth factor (VEGF) and fibroblast growth factor receptor (FGFR) was investigated as a single agent in a phase II trial to assess the activity and tolerability in recurrent or persistent endometrial cancer (EMC). PATIENTS AND METHODS Eligible patients had persistent or recurrent EMC after receiving one to two prior cytotoxic regimens, measurable disease, and performance status of ≤2. Treatment consisted of brivanib 800 mg orally every day until disease progression or prohibitive toxicity. Primary endpoints were progression-free survival (PFS) at six months and objective tumor response. Expression of multiple angiogenic proteins and FGFR2 mutation status was assessed. RESULTS Forty-five patients were enrolled. Forty-three patients were eligible and evaluable. Median age was 64 years. Twenty-four patients (55.8%) received prior radiation. Median number of cycles was two (range 1-24). No GI perforations but one rectal fistula were seen. Nine patients had grade 3 hypertension, with one experiencing grade 4 confusion. Eight patients (18.6%; 90% CI 9.6%-31.7%) had responses (one CR and seven PRs), and 13 patients (30.2%; 90% CI 18.9%-43.9%) were PFS at six months. Median PFS and overall survival (OS) were 3.3 and 10.7 months, respectively. When modeled jointly, VEGF and angiopoietin-2 expression may diametrically predict PFS. Estrogen receptor-α (ER) expression was positively correlated with OS. CONCLUSION Brivanib is reasonably well tolerated and worthy of further investigation based on PFS at six months in recurrent or persistent EMC.

Job uncertainty and personal control during downsizing: A comparison of survivors and victims

This study developed and tested a model of job uncertainty for survivors and victims of downsizing. Data were collected from three samples of employees in a public hospital, each representing three phases of the downsizing process: immediately before the announcement of the redeployment of staff, during the implementation of the downsizing, and towards the end of the official change programme. As predicted, levels of job uncertainty and personal control had a direct relationship with emotional exhaustion and job satisfaction. In addition, there was evidence to suggest that personal control mediated the relationship between job uncertainty and employee adjustment, a pattern of results that varied across each of the three phases of the change event. From the perspective of the organization’s overall climate, it was found that levels of job uncertainty, personal control and job satisfaction improved and/or stabilized over the downsizing process. During the implementation phase, survivors experienced higher levels of personal control than victims, but both groups of employees reported similar levels of job uncertainty. We discuss the implications of our results for strategically managing uncertainty during and after organizational change.

Predicting a new phase (T′′) of two-dimensional transition metal di-chalcogenides and strain-controlled topological phase transition

Single layered transition metal dichalcogenides have attracted tremendous research interest due to their structural phase diversities. By using a global optimization approach, we have discovered a new phase of transition metal dichalcogenides (labelled as T′′), which is confirmed to be energetically, dynamically and kinetically stable by our first-principles calculations. The new T′′ MoS2 phase exhibits an intrinsic quantum spin Hall (QSH) effect with a nontrivial gap as large as 0.42 eV, suggesting that a two-dimensional (2D) topological insulator can be achieved at room temperature. Most interestingly, there is a topological phase transition simply driven by a small tensile strain of up to 2%. Furthermore, all the known MX2 (M = Mo or W; X = S, Se or Te) monolayers in the new T′′ phase unambiguously display similar band topologies and strain controlled topological phase transitions. Our findings greatly enrich the 2D families of transition metal dichalcogenides and offer a feasible way to control the electronic states of 2D topological insulators for the fabrication of high-speed spintronics devices.

Malaria burden and costs of intensified control in Bhutan, 2006-2014: A situational analysis

- Introduction Malaria cases have dwindled in Bhutan with aim of malaria elimination by 2016. The aims of this study are to determine the trends and burden of malaria, the costs of intensified control activities, the main donors of the control activities and the costs of different preventive measures in the pre-elimination phase (2006-2014). - Methods A descriptive analysis of malaria surveillance data from 2006-2014 was carried out, using data from the Vector-borne Disease Control Programme (VDCP), Bhutan. Malaria morbidity and mortality among local Bhutanese and foreign nationals were analysed. The cost of different control and preventive measures, and estimation of the average numbers of long-lasting insecticidal nests (LLINs) per person were calculated. - Findings There were 5,491 confirmed malaria cases from 2006 to 2014. By 2013, there was an average of one LLIN for every 1·51 individuals. The Global Fund was the main international donor accounting for > 80% of the total funds. The cost of procuring LLINs accounted for > 90% of the total cost of prevention measures. - Interpretation The malaria burden reduced significantly over the study period with high coverage of LLINs in Bhutan. This foreseeable challenges that require national attention to maintain malaria-free status after elimination are importation of malaria, particularly from India; continued protection of the population in endemic districts through complete coverage with LLINs and IRS; and exploration of local funding modalities post elimination in the event there is a reduction in international funding.

Cilengitide combined with cetuximab and platinum-based chemotherapy as first-line treatment in advanced non-small-cell lung cancer (NSCLC) patients: Results of an open-label, randomized, controlled phase II study (CERTO)

Background: This multicentre, open-label, randomized, controlled phase II study evaluated cilengitide in combination with cetuximab and platinum-based chemotherapy, compared with cetuximab and chemotherapy alone, as first-line treatment of patients with advanced non-small-cell lung cancer (NSCLC). Patients and methods: Patients were randomized 1:1:1 to receive cetuximab plus platinum-based chemotherapy alone (control), or combined with cilengitide 2000 mg 1×/week i.v. (CIL-once) or 2×/week i.v. (CIL-twice). A protocol amendment limited enrolment to patients with epidermal growth factor receptor (EGFR) histoscore ≥200 and closed the CIL-twice arm for practical feasibility issues. Primary end point was progression-free survival (PFS; independent read); secondary end points included overall survival (OS), safety, and biomarker analyses. A comparison between the CIL-once and control arms is reported, both for the total cohorts, as well as for patients with EGFR histoscore ≥200. Results: There were 85 patients in the CIL-once group and 84 in the control group. The PFS (independent read) was 6.2 versus 5.0 months for CIL-once versus control [hazard ratio (HR) 0.72; P = 0.085]; for patients with EGFR histoscore ≥200, PFS was 6.8 versus 5.6 months, respectively (HR 0.57; P = 0.0446). Median OS was 13.6 for CIL-once versus 9.7 months for control (HR 0.81; P = 0.265). In patients with EGFR ≥200, OS was 13.2 versus 11.8 months, respectively (HR 0.95; P = 0.855). No major differences in adverse events between CIL-once and control were reported; nausea (59% versus 56%, respectively) and neutropenia (54% versus 46%, respectively) were the most frequent. There was no increased incidence of thromboembolic events or haemorrhage in cilengitide-treated patients. αvβ3 and αvβ5 expression was neither a predictive nor a prognostic indicator. Conclusions: The addition of cilengitide to cetuximab/chemotherapy indicated potential clinical activity, with a trend for PFS difference in the independent-read analysis. However, the observed inconsistencies across end points suggest additional investigations are required to substantiate a potential role of other integrin inhibitors in NSCLC treatment.

Condensed phase combustion travelling waves with sequential exothermic or endothermic reactions

The one-dimensional propagation of a combustion wave through a premixed solid fuel for two-stage kinetics is studied. We re-examine the analysis of a single reaction travelling-wave and extend it to the case of two-stage reactions. We derive an expression for the travelling wave speed in the limit of large activation energy for both reactions. The analysis shows that when both reactions are exothermic, the wave structure is similar to the single reaction case. However, when the second reaction is endothermic, the wave structure can be significantly different from single reaction case. In particular, as might be expected, a travelling wave does not necessarily exist in this case. We establish conditions in the limiting large activation energy limit for the non-existence, and for monotonicity of the temperature profile in the travelling wave.