Cyclin dependent kinase 4 and 6 inhibitors as novel therapeutic agents for targeted treatment of malignant mesothelioma

Malignant Mesothelioma (MM) is a rare and aggressive form of tumour that affects the lining of the internal organs for which current treatments have not been proven to be very effective. P16(INK4A) tumour suppressor encoding CDKN2A gene is often downregulated in MM. This protein is a cyclin dependent kinase 4 and 6 inhibitor, that normally phosphorylates RB1, which has to be un-phosphorylated in order to block cell-cycle at G1 in normal cells. Adding CDK inhibitor molecules to MM in pre-clinical studies has been proven to restore the normal function of p16(INK4A), blocking thereby MM cell cycle at G1. Future randomised phase III studies with CDK4/6 inhibitors in MM carrying relevant CDK4/6, cyclin D1/3 or p16 aberrations will be warranted

A Clustered Overflow Configuration of Inpatient Beds in Hospitals

Problem Definition: The shortage of inpatient beds is a major cause of delays and cancellations in many hospitals. It may also lead to patients being admitted to inappropriate wards, whereby resulting in a lower quality of care and a longer length of stay. Academic/Practical Relevance: Investment in additional beds is not always feasible. Instead, new and creative solutions for a more efficient use of existing resources must be sought. Methodology: We propose a new configuration of inpatient beds which we call the clustered overflow configuration. In this configuration, patients who are denied admission to their primary wards as a result of beds being fully occupied are admitted to overflow wards, with each designated to serve overflows from a certain subset of specialties and providing the same quality of care as in primary wards. We propose two different formulations for partitioning and bed allocation in the proposed configuration: one minimizing the sum of average daily costs of turning patients away and nursing teams, and another minimizing the numbers turned away subject to nursing cost falling below a given threshold. We heuristically solve instances from both formulations. Results: Applying the models to real data shows that the configurations obtained from our models compare very well with the other configurations proposed in the literature, provided that patients' willingness to wait is relatively short. Managerial Implications: The proposed configuration provides the combined advantages of the dedicated configuration, wherein patients are only admitted to their primary wards, and the exible configuration, in which all specialties share a single ward. On the other hand, it restricts the adverse impacts of pooling and minimizes cross-training costs through appropriate partitioning and bed allocation. As such, it serves as a viable alternative to existing inpatient configurations

The role of MscL amphipathic N terminus indicates a blueprint for bilayer-mediated gating of mechanosensitive channels

The bacterial mechanosensitive channel MscL gates in response to membrane tension as a result of mechanical force transmitted directly to the channel from the lipid bilayer. MscL represents an excellent model system to study the basic biophysical principles of mechanosensory transduction. However, understanding of the essential structural components that transduce bilayer tension into channel gating remains incomplete. Here using multiple experimental and computational approaches, we demonstrate that the amphipathic N-terminal helix of MscL acts as a crucial structural element during tension-induced gating, both stabilizing the closed state and coupling the channel to the membrane. We propose that this may also represent a common principle in the gating cycle of unrelated mechanosensitive ion channels, allowing the coupling of channel conformation to membrane dynamics

The Energy Loss of a Heavy Quark Moving in a Viscous Fluid

To study the rate of energy and momentum loss of a heavy quark in QGP, specifically in the hydrodynamic regime, we use fluid/gravity duality and construct a perturbative procedure to find the string solution in gravity side. We show that by this construction the drag force exerted on the quark can be computed perturbatively, order by order in a boundary derivative expansion. At ideal order, our result is just the drag force exerted on a moving quark in thermal plasma with thermodynamics variables promoted to become local functions of space and time. Furthermore, we apply this procedure to a transverse quark in Bjorken flow and compute the first-derivative corrections, namely the viscous corrections, to the drag force.Comment: 33 pages, 6 figures, references added v5: Some correction

A Novel Wideband and Wide Beam High Gain Unidirectional Dipole Antenna for Next Generation WLAN Applications

In this paper, a novel wideband and widebeam unidirectional magneto-electric (ME) dipole antenna for Wi-Fi-7 (5.18-7.125GHz) applications is presented. The element is printed on low-cost substrate and is showing wide-band characteristics with impedance matching over 50% of fractional bandwidth. A tilted ME antenna with a tilted parasitic scatterer is radiating across wide frequency, while meeting over 100{\deg} angular width in both E-plane and H-plane across the wide bandwidth from 5GHz to >8GHz. Adding one parasitic scatterer on each side of dipole, broaden bandwidth of the antenna as well

Simulation of gait asymmetry and energy transfer efficiency between unilateral and bilateral amputees

Efficient walking or running requires symmetrical gait. Gait symmetry is one of the key factors in efficient human dynamics, kinematics and kinetics. The desire of individuals with a lower-limb amputation to participate in sports has resulted in the development of energy-storing and-returning (ESR) feet. This paper analyses a case study to show the effect of symmetry and asymmetry as well as energy transfer efficiency during periodic jumping between simulated bilateral and unilateral runners. A custom gait analysis system is developed as part of this project to track the motion of the body of a physically active subject during a set of predefined motions. Stance and aerial times are accurately measured using a high speed camera. Gait frequency, the level of symmetry and the non-uniform displacement between left and right foot and their effects on the position of the Centre of Mass (CM) were used as criteria to calculate both peak energies and transformation efficiency. Gait asymmetry and discrepancy of energy transfer efficiency between the intact foot and the ESR are observed. It is concluded that unilateral runners require excessive effort to compensate for lack of symmetry as well as asymmetry in energy transfer, causing fatigue which could be a reason why bilateral amputee runners using ESR feet have a superior advantage over unilateral amputees

Recent acquisition of Helicobacter pylori by Baka Pygmies

Both anatomically modern humans and the gastric pathogen Helicobacter pylori originated in Africa, and both species have been associated for at least 100,000 years. Seven geographically distinct H. pylori populations exist, three of which are indigenous to Africa: hpAfrica1, hpAfrica2, and hpNEAfrica. The oldest and most divergent population, hpAfrica2, evolved within San hunter-gatherers, who represent one of the deepest branches of the human population tree. Anticipating the presence of ancient H. pylori lineages within all hunter-gatherer populations, we investigated the prevalence and population structure of H. pylori within Baka Pygmies in Cameroon. Gastric biopsies were obtained by esophagogastroduodenoscopy from 77 Baka from two geographically separated populations, and from 101 non-Baka individuals from neighboring agriculturalist populations, and subsequently cultured for H. pylori. Unexpectedly, Baka Pygmies showed a significantly lower H. pylori infection rate (20.8%) than non-Baka (80.2%). We generated multilocus haplotypes for each H. pylori isolate by DNA sequencing, but were not able to identify Baka-specific lineages, and most isolates in our sample were assigned to hpNEAfrica or hpAfrica1. The population hpNEAfrica, a marker for the expansion of the Nilo-Saharan language family, was divided into East African and Central West African subpopulations. Similarly, a new hpAfrica1 subpopulation, identified mainly among Cameroonians, supports eastern and western expansions of Bantu languages. An age-structured transmission model shows that the low H. pylori prevalence among Baka Pygmies is achievable within the timeframe of a few hundred years and suggests that demographic factors such as small population size and unusually low life expectancy can lead to the eradication of H. pylori from individual human populations. The Baka were thus either H. pylori-free or lost their ancient lineages during past demographic fluctuations. Using coalescent simulations and phylogenetic inference, we show that Baka almost certainly acquired their extant H. pylori through secondary contact with their agriculturalist neighbors

Demonstration of a positron beam-driven hollow channel plasma wakefield accelerator

International audiencePlasma wakefield accelerators have been used to accelerate electron and positron particle beams with gradients that are orders of magnitude larger than those achieved in conventional accelerators. In addition to being accelerated by the plasma wakefield, the beam particles also experience strong transverse forces that may disrupt the beam quality. Hollow plasma channels have been proposed as a technique for generating accelerating fields without transverse forces. Here we demonstrate a method for creating an extended hollow plasma channel and measure the wakefields created by an ultrarelativistic positron beam as it propagates through the channel. The plasma channel is created by directing a high-intensity laser pulse with a spatially modulated profile into lithium vapour, which results in an annular region of ionization. A peak decelerating field of 230 MeV/m is inferred from changes in the beam energy spectrum, in good agreement with theory and particle-in-cell simulations

SIRENIA FOSSILS FROM QOM FORMATION (BURDIGALIAN) OF THE KABUDAR AHANG AREA, NORTHWEST IRAN

Fossil remains of sirenians (Mammalia; Dugongidae) are reported from the late early Miocene (Burdigalian) Qom Formation near the town of Shirin Su, northwest Kabudar Ahang region, west of Tehran, Iran. The fossils consist of partial postcranial skeletons preserved mostly as natural molds in limestone. In the absence of skulls or other diagnostic elements, it is not evident which dugongid subfamily these specimens represent: Halitheriinae or Dugonginae. Both subfamilies were present in contemporaneous Western Tethys (Mediterranean) deposits, but so far only dugongines have been found in Neogene rocks of Eastern Tethys. Since the Iranian deposits are located between these two parts of the former Tethys Seaway, it will be interesting to see which group(s) the Iranian sirenians prove to represent, once their taxonomic identity has been determined through future discoveries

Adaptive Optimal Control of Faulty Nonlinear DC Microgrids with Constant Power Loads: Dual-Extended Kalman Filter Approach

This article investigates the problem of estimating actuator fault and states and controlling the bus voltage in direct current microgrids (DC MGs) with linear and nonlinear constant power loads (CPLs). It is considered that the DC MG states are not fully measurable and the utilized sensors are not ideal and noisy. Additionally, the actuator fault occurs and it is modeled as an additive term in the power system dynamics. These issues, including nonlinearities, un-measurable states, noisy measures, and actuator fault indispensably degrade the operation of the DC MG. To solve this issue, initially, a dual-extended Kalman filter (dual-EKF) is suggested for the fault and state estimation. It decomposes the process of estimating the state and actuator fault to reduce the online computational burden. For the control purpose, a linear parameter varying (LPV) model predictive control (MPC) is suggested to regulate the current and voltage of the DC MG. It benefits the nonlinear system modeling of LPV representation and constrained-based design procedure of the MPC to result in an accurate and low online computational burden dealing with system constraints. By deploying the overall robust adaptive dual-EKF estimation-based LPV-MPC, there is no need to have any prior knowledge of all system states and actuator faults in prior. The theoretical analysis and controller design are validated by numerical simulations on a typical islanded DC MG and comparisons are done with state-of-the-art estimation and control strategies.©2022 IEEE. Personal use of this material is permitted. Permission from IEEE must be obtained for all other uses, in any current or future media, including reprinting/republishing this material for advertising or promotional purposes, creating new collective works, for resale or redistribution to servers or lists, or reuse of any copyrighted component of this work in other works.fi=vertaisarvioitu|en=peerReviewed