CDK4 T172 phosphorylation is central in a CDK7-dependent bidirectional CDK4/CDK2 interplay mediated by p21 phosphorylation at the restriction point

Cell cycle progression, including genome duplication, is orchestrated by cyclin-dependent kinases (CDKs). CDK activation depends on phosphorylation of their T-loop by a CDK-activating kinase (CAK). In animals, the only known CAK for CDK2 and CDK1 is cyclin H-CDK7, which is constitutively active. Therefore, the critical activation step is dephosphorylation of inhibitory sites by Cdc25 phosphatases rather than unrestricted T-loop phosphorylation. Homologous CDK4 and CDK6 bound to cyclins D are master integrators of mitogenic/oncogenic signaling cascades by initiating the inactivation of the central oncosuppressor pRb and cell cycle commitment at the restriction point. Unlike the situation in CDK1 and CDK2 cyclin complexes, and in contrast to the weak but constitutive T177 phosphorylation of CDK6, we have identified the T-loop phosphorylation at T172 as the highly regulated step determining CDK4 activity. Whether both CDK4 and CDK6 phosphorylations are catalyzed by CDK7 remains unclear. To answer this question, we took a chemical-genetics approach by using analogue-sensitive CDK7(as/as) mutant HCT116 cells, in which CDK7 can be specifically inhibited by bulky adenine analogs. Intriguingly, CDK7 inhibition prevented activating phosphorylations of CDK4/6, but for CDK4 this was at least partly dependent on its binding to p21(cip1). In response to CDK7 inhibition, p21-binding to CDK4 increased concomitantly with disappearance of the most abundant phosphorylation of p21, which we localized at S130 and found to be catalyzed by both CDK4 and CDK2. The S130A mutation of p21 prevented the activating CDK4 phosphorylation, and inhibition of CDK4/6 and CDK2 impaired phosphorylations of both p21 and p21-bound CDK4. Therefore, specific CDK7 inhibition revealed the following: a crucial but partly indirect CDK7 involvement in phosphorylation/activation of CDK4 and CDK6; existence of CDK4-activating kinase(s) other than CDK7; and novel CDK7-dependent positive feedbacks mediated by p21 phosphorylation by CDK4 and CDK2 to sustain CDK4 activation, pRb inactivation, and restriction point passage

Résection trans urétrale de la prostate : première expérience à Bukavu, RD Congo: Transurethral resection of the prostate: pilot experience in Bukavu, DR Congo

Context and objective. Despite its large use as alternative to open surgical adenomectomy, transurethral resection of the prostate (TURP) is still poorly performed in many African countries. The purpose of this study was to describe a pilotTURP experience in Bukavu. Methods.This retrospective study included 159 patients (average age: 68 ± 8.5 years) with benign prostatic hypertrophy (BPH), treated at three medical centres in Bukavu between February 2014 andFebruary 2017. Socio-demographic, clinical, and ultrasound data were recorded, and comorbidities and complications reported. Each patient was questionned about treatment received before surgery. Results. The average prostatic volume was 53.2 ± 22 grams. All patients were severelysymptomatic (mean International Prostate Symptoms Score (IPSS) 26.8 ± 5.8) and severely bored (mean quality of life score (QOL) 6.2 ± 0.8).Hypertension (42%) and type 2 diabetes (41%) were the most common comorbidities. The most frequent complications of BPH were urinary tractinfection (44%) and urinary retention (40%). Prior to hospital admission, 60% of patients used traditional medicine. Conclusion.This study has revealed a late reference of patients to the hospital, when the illness is already in advanced stage with complications. There is a need of implementing educational measures targeting early detection and reference of patients with BPH in this area. Résumé Contexte et objectif. Bien que la résection trans urétrale de la prostate (RTUP) se soit imposée comme alternative à l’adénomectomie chirurgicale classique à ciel ouvert, sa pratique reste exceptionnelle dans quelques contrées africaines. L’objectif de la présente étude était de décrire la première expérience de la RTUP à Bukavu. Méthodes. La présente étude documentaire a porté sur 159 patients avec hypertrophie bénigne de la prostate (HBP), opérés dans 3 centres médicaux de Bukavu entre février 2014 et février 2017. Les paramètres d’intérêts comprenaient les données sociodémographiques, cliniques, échographiques les comorbidités, les complications et l’attitude thérapeutique avant l’intervention. Résultats. Leur âge moyen était de 68±8,5 ans. Le volume prostatique moyen était de 53,2 ± 22 grammes. Tous les patients étaient sévèrement symptomatiques (score international des symptômes prostatiques (IPSS) moyen de 26,8 ± 5,8) et fortement ennuyés (score de la qualité de vie (QOL) moyen de 6,2 ± 0,8). L’hypertension artérielle (42%) et le diabète sucré de type 2 (41 %) étaient les comorbidités les plus fréquentes. Les complications de l’HBP les plus fréquentes étaient l’infection urinaire (44 %) et la rétention urinaire (40%). Avant l’admission à l’hôpital, 60% des patients ont eu recours à la médecine traditionnelle. Conclusion. L’avènement de la RTUP à Bukavu a permis de déceler que la majorité des patients avec HBP consultent très tardivement au stade de sevérité symptomatique et des complications. Une campagne d’éducation, information et communication de la population sur le dépistage précoce de l’HBP est à envisager

Exchange interaction effects in the thermodynamic properties of quantum dots

We study electron-electron interaction effects in the thermodynamic properties of quantum-dot systems. We obtain the direct and exchange contributions to the specific heat C_v in the self-consistent Hartree-Fock approximation at finite temperatures. An exchange-induced phase transition is observed and the transition temperature is shown to be inversely proportional to the size of the system. The exchange contribution to C_v dominates over the direct and kinetic contributions in the intermediate regime of interaction strength (r_s ~ 1). Furthermore, the electron-electron interaction modifies both the amplitude and the period of magnetic field induced oscillations in C_v.Comment: 4 pages, 4 figures; To appear in Phys. Rev.

Modelling and analysing software in mCRL2

Model checking is an effective way to design correct software.Making behavioural models of software, formulating correctness properties using modal formulas, and verifying these using finite state analysis techniques, is a very efficient way to obtain the required insight in the software. We illustrate this on four common but tricky examples

A Type-Theoretic Account of Neg-Raising Predicates in Tree Adjoining Grammars

International audienceNeg-Raising (NR) verbs form a class of verbs with a clausal complement that show the following behavior: when a negation syntactically attaches to the matrix predicate, it can semantically attach to the embedded predicate. This paper presents an account of NR predicates within Tree Adjoining Grammar (TAG). We propose a lexical semantic interpretation that heavily relies on a Montague-like semantics for TAG and on higher-order types

Concurrent constraint programming with process mobility

We propose an extension of concurrent constraint programming with primitives for process migration within a hierarchical network, and we study its semantics. To this purpose, we first investigate a "pure " paradigm for process migration, namely a paradigm where the only actions are those dealing with transmissions of processes. Our goal is to give a structural definition of the semantics of migration; namely, we want to describe the behaviour of the system, during the transmission of a process, in terms of the behaviour of the components. We achieve this goal by using a labeled transition system where the effects of sending a process, and requesting a process, are modeled by symmetric rules (similar to handshaking-rules for synchronous communication) between the two partner nodes in the network. Next, we extend our paradigm with the primitives of concurrent constraint programming, and we show how to enrich the semantics to cope with the notions of environment and constraint store. Finally, we show how the operational semantics can be used to define an interpreter for the basic calculus.

Influence of diabetes mellitus on heart failure risk and outcome

Our aim is to summarize and discuss the recent literature linking diabetes mellitus with heart failure, and to address the issue of the optimal treatment for diabetic patients with heart failure. THE STUDIES LINKING DIABETES MELLITUS (DM) WITH HEART FAILURE (HF): The prevalence of diabetes mellitus in heart failure populations is close to 20% compared with 4 to 6% in control populations. Epidemiological studies have demonstrated an increased risk of heart failure in diabetics; moreover, in diabetic populations, poor glycemic control has been associated with an increased risk of heart failure. Various mechanisms may link diabetes mellitus to heart failure: firstly, associated comorbidities such as hypertension may play a role; secondly, diabetes accelerates the development of coronary atherosclerosis; thirdly, experimental and clinical studies support the existence of a specific diabetic cardiomyopathy related to microangiopathy, metabolic factors or myocardial fibrosis. Subgroup analyses of randomized trials demonstrate that diabetes is also an important prognostic factor in heart failure. In addition, it has been suggested that the deleterious impact of diabetes may be especially marked in patients with ischemic cardiomyopathy. TREATMENT OF HEART FAILURE IN DIABETIC PATIENTS: The knowledge of the diabetic status may help to define the optimal therapeutic strategy for heart failure patients. Cornerstone treatments such as ACE inhibitors or beta-blockers appear to be uniformly beneficial in diabetic and non diabetic populations. However, in ischemic cardiomyopathy, the choice of the revascularization technique may differ according to diabetic status. Finally, clinical studies are needed to determine whether improved metabolic control might favorably influence the outcome of diabetic heart failure patients

Lowerbounds for Bisimulation by Partition Refinement

We provide time lower bounds for sequential and parallel algorithms deciding bisimulation on labeled transition systems that use partition refinement. For sequential algorithms this is $\Omega((m \mkern1mu {+} \mkern1mu n ) \mkern-1mu \log \mkern-1mu n)$ and for parallel algorithms this is $\Omega(n)$, where $n$ is the number of states and $m$ is the number of transitions. The lowerbounds are obtained by analysing families of deterministic transition systems, ultimately with two actions in the sequential case, and one action for parallel algorithms. For deterministic transition systems with one action, bisimilarity can be decided sequentially with fundamentally different techniques than partition refinement. In particular, Paige, Tarjan, and Bonic give a linear algorithm for this specific situation. We show, exploiting the concept of an oracle, that this approach is not of help to develop a faster generic algorithm for deciding bisimilarity. For parallel algorithms there is a similar situation where these techniques may be applied, too

Objective assessment of intraoperative skills for robot-assisted radical prostatectomy (RARP): results from the ERUS Scientific and Educational Working Groups Metrics Initiative

Objective: To develop and seek consensus from procedure experts on the metrics that best characterise a reference robot-assisted radical prostatectomy (RARP) and determine if the metrics distinguished between the objectively assessed RARP performance of experienced and novice urologists, as identifying objective performance metrics for surgical training in robotic surgery is imperative for patient safety. Materials and methods: In Study 1, the metrics, i.e. 12 phases of the procedure, 81 steps, 245 errors and 110 critical errors for a reference RARP were developed and then presented to an international Delphi panel of 19 experienced urologists. In Study 2, 12 very experienced surgeons (VES) who had performed >500 RARPs and 12 novice urology surgeons performed a RARP, which was video recorded and assessed by two experienced urologists blinded as to subject and group. Percentage agreement between experienced urologists for the Delphi meeting and Mann–Whitney U- and Kruskal–Wallis tests were used for construct validation of the newly identified RARP metrics. Results: At the Delphi panel, consensus was reached on the appropriateness of the metrics for a reference RARP. In Study 2, the results showed that the VES performed ~4% more procedure steps and made 72% fewer procedure errors than the novices (P = 0.027). Phases VIIa and VIIb (i.e. neurovascular bundle dissection) best discriminated between the VES and novices. Limitations: VES whose performance was in the bottom half of their group demonstrated considerable error variability and made five-times as many errors as the other half of the group (P = 0.006). Conclusions: The international Delphi panel reached high-level consensus on the RARP metrics that reliably distinguished between the objectively scored procedure performance of VES and novices. Reliable and valid performance metrics of RARP are imperative for effective and quality assured surgical training