Negative regulation of gene expression by the tumor suppressor p53

The tumor suppressor p53 inhibits the expression of a substantial number of genes whose protein products serve to promote cell survival or cell cycle progression, thereby ensuring efficient execution of p53-dependent apoptosis, cell-cycle arrest or senescence. Furthermore, p53-mediated repression has also been shown to participate in pathways that regulate diverse cellular processes, including angiogenesis, maintenance of pluripotency, and metabolic flux. p53 inhibits gene expression by both direct and indirect means. Briefly, p53 can block transcription through direct DNA binding, association with transcription factors, and through the induction of genes whose functional products facilitate downstream repression. Indirect regulation of gene repression by p53 often involves induction of intermediary factors that fall into several categories: proteins (e.g. p21), microRNAs (e.g. miR-34a), and lincRNAs (lincRNA-p21). This dissertation discusses multiple aspects of p53-dependent gene repression and presents novel targets of p53-mediated regulation. Specifically, we have found that p53 down-regulates the transcription of the oncogenic transcription factor FoxM1. Mechanistically, this repression is largely dependent upon the p53-inducible gene p21, and consequently involves the Rb-family of tumor suppressors. Functionally, p53-dependent repression of FoxM1 contributes to the maintenance of a stable G2 cell cycle arrest in response to DNA-damage. In addition, we have identified PVT1 as a novel target of p53-transactivation. PVT1 encodes both spliced non-coding RNAs (ncRNA), as well as a series of microRNAs (miR-1204, miR-1205, miR-1206, miR-1207-5p, miR-1207-3p and miR-1208). p53 upregulates PVT1 ncRNA, primary microRNAs, and mature miR-1204. Ectopic expression of miR-1204 induces changes in cell fate that are consistent with the role of p53 (cell death, cell cycle arrest), thus miR-1204 is likely to represent a functional target of p53 at the PVT1 locus

A General Approach to Optomechanical Parametric Instabilities

We present a simple feedback description of parametric instabilities which can be applied to a variety of optical systems. Parametric instabilities are of particular interest to the field of gravitational-wave interferometry where high mechanical quality factors and a large amount of stored optical power have the potential for instability. In our use of Advanced LIGO as an example application, we find that parametric instabilities, if left unaddressed, present a potential threat to the stability of high-power operation

Uncertainty quantification and sensitivity analysis of volcanic columns models: results from the integral model PLUME-MoM

The behavior of plumes associated with explosive volcanic eruptions is complex and dependent on eruptive source parameters (e.g. exit velocity, gas fraction, temperature and grain-size distribution). It is also well known that the atmospheric environment interacts with volcanic plumes produced by explosive eruptions in a number of ways. The wind field can bend the plume but also affect atmospheric air entrainment into the column, enhancing its buoyancy and in some cases, preventing column collapse. In recent years, several numerical simulation tools and observational systems have investigated the action of eruption parameters and wind field on volcanic column height and column trajectory, revealing an important influence of these variables on plume behavior. In this study, we assess these dependencies using the integral model PLUME-MoM, whereby the continuous polydispersity of pyroclastic particles is described using a quadrature-based moment method, an innovative approach in volcanology well-suited for the description of the multiphase nature of magmatic mixtures. Application of formalized uncertainty quantification and sensitivity analysis techniques enables statistical exploration of the model, providing information on the extent to which uncertainty in the input or model parameters propagates to model output uncertainty. In particular, in the framework of the IAVCEI Commission on tephra hazard modeling inter-comparison study, PLUME-MoM is used to investigate the parameters exerting a major control on plume height, applying it to a weak plume scenario based on 26 January 2011 Shinmoe-dake eruptive conditions and a strong plume scenario based on the climatic phase of the 15 June 1991 Pinatubo eruption

A soft, synergy-based robotic glove for grasping assistance

This paper presents a soft, tendon-driven, robotic glove designed to augment grasp capability and provide rehabilitation assistance for postspinal cord injury patients. The basis of the design is an underactuation approach utilizing postural synergies of the hand to support a large variety of grasps with a single actuator. The glove is lightweight, easy to don, and generates sufficient hand closing force to assist with activities of daily living. Device efficiency was examined through a characterization of the power transmission elements, and output force production was observed to be linear in both cylindrical and pinch grasp configurations. We further show that, as a result of the synergy-inspired actuation strategy, the glove only slightly alters the distribution of forces across the fingers, compared to a natural, unassisted grasping pattern. Finally, a preliminary case study was conducted using a participant suffering from an incomplete spinal cord injury (C7). It was found that through the use of the glove, the participant was able to achieve a 50% performance improvement (from four to six blocks) in a standard Box and Block test

Histopathology of the muscle in rheumatic diseases.

The presence of muscular symptoms is common in rheumatological clinical practice, but often the differential diagnosis between muscular involvement in connective tissue diseases, vasculitis and drug-induced myopathy may be difficult. In addition to clinical assessment, laboratory analysis and instrumental examinations, muscle biopsy may help to clarify the diagnosis in patients with muscular involvement. The purpose of this review is to provide a critical analysis of the current medical literature on muscular histopathology, to help clinicians to identify when to perform muscular biopsy and to provide a practical guide to a better understanding of the pathology report. Moreover, we provide an overview of the muscular involvement and the most common histopathological findings in rheumatic diseases

Frequency-Dependent Squeezing for Advanced LIGO

The first detection of gravitational waves by the Laser Interferometer Gravitational-wave Observatory (LIGO) in 2015 launched the era of gravitational wave astronomy. The quest for gravitational wave signals from objects that are fainter or farther away impels technological advances to realize ever more sensitive detectors. Since 2019, one advanced technique, the injection of squeezed states of light is being used to improve the shot noise limit to the sensitivity of the Advanced LIGO detectors, at frequencies above $\sim 50$ Hz. Below this frequency, quantum back action, in the form of radiation pressure induced motion of the mirrors, degrades the sensitivity. To simultaneously reduce shot noise at high frequencies and quantum radiation pressure noise at low frequencies requires a quantum noise filter cavity with low optical losses to rotate the squeezed quadrature as a function of frequency. We report on the observation of frequency-dependent squeezed quadrature rotation with rotation frequency of 30Hz, using a 16m long filter cavity. A novel control scheme is developed for this frequency-dependent squeezed vacuum source, and the results presented here demonstrate that a low-loss filter cavity can achieve the squeezed quadrature rotation necessary for the next planned upgrade to Advanced LIGO, known as "A+."Comment: 6 pages, 2 figures, to be published in Phys. Rev. Let