HIV-1 Vpr induces the K48-linked polyubiquitination and proteasomal degradation of target cellular proteins to activate ATR and promote G2 arrest

HIV-1 viral protein R (Vpr) induces a cell cycle arrest at the G2/M phase by a mechanism involving the activation of the DNA damage sensor ATR. We and others recently showed that Vpr performs this function by subverting the activity of the DDB1-CUL4A (VPRBP) E3 ubiquitin ligase. Vpr could thus act as a connector between the E3 ligase and an unknown cellular factor whose ubiquitination would induce G2 arrest. While attractive, this model is solely based on the indirect observation that some mutants of Vpr retain their interaction with the E3 ligase but fail to induce G2 arrest. Using a tandem affinity purification approach, we observed that Vpr interacts with ubiquitinated cellular proteins and that this association requires the recruitment of an active E3 ligase given that depletion of VPRBP by RNA interference or overexpression of a dominant-negative mutant of CUL4A decreased this association. Importantly, G2-arrest-defective mutants of Vpr in the C-terminal putative substrate-interacting domain displayed decreased association with ubiquitinated proteins. We also found that inhibition of proteasomal activity increased this association and that the ubiquitin chains were at least in part constituted of classical K48 linkages. Interestingly, inhibition of K48 polyubiquitination specifically impaired Vpr-induced phosphorylation of H2AX, an early target of ATR, but did not affect UV-induced H2AX phosphorylation. Overall, our results provide direct evidence that association of Vpr with the DDB1-CUL4A (VPRBP) E3 ubiquitin ligase induces the K48-linked polyubiquitination of yet-unknown cellular proteins resulting in their proteasomal degradation and ultimately leading to activation of ATR and G2 arrest.

Exploration of implicit theories in the formation of expert opinion in portuguese criminal law

This dissertation examines different aspects involved in the formation of psychologists’ expert opinion in the Portuguese criminal justice system, more precisely, as this opinion is reflected in assessment reports. The present dissertation is comprised of three qualitative studies, the first sought to provide a general portrait of a sample of 106 forensic psychological reports as to their overall quality as measured in terms of relevance and coherence. Results show that the formal markers of quality are present in the sample analysed, a certain number of weaknesses have been observed, notably concerning the internal coherence of the reports as well as the relevance of the information reported on. The second study explored the opinions of 17 Portuguese judges and state prosecutors concerning the use they make of this type of forensic report. It appears that they consider these reports to be useful and very credible, specially so when they have been produced under the auspices of the National Institute of Legal Medicine and Forensic Sciences, which is the state forensic institution. Furthermore, it appears that judges and prosecutors were particularly interested in data that allowed for a personalised portrait of the assessee. The third study sought to better comprehend the conceptual bases on which psychologists construct their reports. To this end, an exploratory study was undertaken with a sample of key-actors; the analysis of their interviews shows that they define their judicial mandate as well as the basic concepts that are associated to this mandate in different ways. A theoretical framework provided by an implicit theories model was used to help understand these results.

Recruitment And Training Of Managers In The Public Sector Concerns In Kerala

Public undertakings have been assigned a significant role to play in the systematic socio-economic development of India. My interest in the subject was kindled while I was doing my Masters Diploma in Public Administration at the Indian Institute of Public Administration, New Delhi during 1960-61. It was further strengthened by my teaching of the subject in different courses offered by me at the School of Management Studies and in several programmes organised by various voluntary and training organisations like the Institute of Management in Government, Trivandrum, Centre for Management Development, Trivandrum, etc. The several years in which I served as a member of the faculty in the School of Management Studies, University of Cochin,gave me the opportunity to come into close contact with different public sector concerns and their managers at various levels. This rich opportunity gave me a better insight into the problems faced by these concerns. The present study is a result of the interest so developed.

A Proposal for Enterprise Value Phase of the Lean Aerospace Initiative

The Massachusetts Institute of Technology (MIT) submits this proposal for the Enterprise Value Phase of the Lean Aerospace Initiative (LAI) in response to the October 9, 2002 Request for Proposal (RFP) F33615-02-2-5501 from the Air Force Research Laboratory (AFRL/MLKT), Wright-Patterson Air Force Base, Ohio. This proposal addresses the conduct of the LAI as set forth in the Enterprise Value Phase Concept of Operations (final draft dated 5 June 2002. The creation of this Enterprise Value Phase Concept of Operations (ConOps) was the result of extensive interaction among all stakeholders in the LAI consortium. The proposed products and research topics have been developed by the MIT LAI team based on this extended interaction with the Lean Aerospace Initiative consortium members during the concept of operations development. This proposal is in consonance with the Enterprise Value Phase vision, and mission as set forth in the concept of operations so as to meet stakeholder needs to achieve the goals and deliverables desired, prioritized to fit available funding.

The Pursuit of Acquisition Intrapreneurs

This report represents research conducted at the Massachusetts Institute of Technology under the Lean Aerospace Initiative (LAI) program. The research focused on identifying Acquisition Intrapreneurs, viewed and defined for the purpose of this research as, individuals within the acquisition profession who take direct responsibility for turning ideas into products through assertive risk taking. The basis for this research stems from the agile acquisition push for “breeding innovators” to achieve a leaner and more responsive approach to the design, build, test and fielding of warfighting systems.

Modeling the Transport Sector: The Role of Existing Fuel Taxes in Climate Policy

Existing fuel taxes play a major role in determining the welfare effects of exempting the transportation sector from measures to control greenhouse gases. To study this phenomenon we modify the MIT Emissions Prediction and Policy Analysis (EPPA) model to disaggregate the household transportation sector. This improvement requires an extension of the GTAP data set that underlies the model. The revised and extended facility is then used to compare economic costs of cap-and-trade systems differentiated by sector, focusing on two regions: the USA where the fuel taxes are low, and Europe where the fuel taxes are high. We find that the interplay between carbon policies and pre-existing taxes leads to different results in these regions: in the USA exemption of transport from such a system would increase the welfare cost of achieving a national emissions target, while in Europe such exemptions will correct pre-existing distortions and reduce the cost.

Applying the Lessons of “Lean Now” to Transform the US Aerospace Enterprise

Lean is common sense and good business sense. As organizations grow and become more successful, they begin to lose insight into the basic truths of what made them successful. Organizations have to deal with more and more issues that may not have anything to do with directly providing products or services to their customers. Lean is a holistic management approach that brings the focus of the organization back to providing value to the customer. In August 2002, Mrs. Darleen Druyun, the Principal Deputy to the Assistant Secretary of the Air Force for Acquisition and government co-chairperson of the Lean Aerospace Initiative (LAI), decided it was time for Air Force acquisitions to embrace the concepts of lean. At her request, the LAI Executive Board developed a concept and methodology to employ lean into the Air Force’s acquisition culture and processes. This was the birth of the “Lean Now” initiative. An enterprise-wide approach was used, involving Air Force System Program Offices (SPOs), aerospace industry, and several Department of Defense agencies. The aim of Lean Now was to focus on the process interfaces between these “enterprise” stakeholders to eliminate barriers that impede progress. Any best practices developed would be institutionalized throughout the Air Force and the Department of Defense (DoD). The industry members of LAI agreed to help accelerate the government-industry transformation by donating lean Subject Matter Experts (SMEs) to mentor, train, and facilitate the lean events of each enterprise. Currently, the industry SMEs and the Massachusetts Institute of Technology are working together to help the Air Force develop its own lean infrastructure of training courses and Air Force lean SMEs. The first Lean Now programs were the F/A-22, Global Hawk, and F-16. Each program focused on specific acquisition processes. The F/A-22 focused on the Test and Evaluation process; the Global Hawk focused on Evolutionary Acquisitions; and the F-16 focused on improving the Contract Closeout process. Through lean, each enterprise made many significant improvements. The F/A-22 was able to reduce its Operational Flight Plan (OFP) Preparation and Load process time of 2 to 3 months down to 7 hours. The Global Hawk developed a new production plan that increases the annual production of its Integrated Sensor Suite from 3 per year to 6 per year. The F-16 enterprise generated and is working 12 initiatives that could result in a contract closeout cycle time reduction of 3 to 7 years. Each enterprise continues to generate more lean initiatives that focus on other areas and processes within their respective enterprises.

The effects of the SKILL Program on the language and socialization of hearing impaired children

This study will examine the effects of the SKILL Program on the social and pragmatic skills of the hearing-impaired children in the Pre-K department of the Central Institute for the Deaf. It will assess language and social skills necessary for the children to be successful in the mainstream and how having hearing peers may have contributed to their gaining of those skills.

Speech and the hearing-impaired child: evaluation and revision of the CID Speech Skills Worksheet

The purpose of this study was to evaluate the current use of the Central Institute for the Deaf’s Speech Skills Worksheet by teacher of the deaf and speech-language pathologists, review the current literature on speech development in hearing-impaired children, and apply the findings to develop a more comprehensive Speech Skills Worksheet.

The validation of CID's Grammatical Analysis of Elicited Language with language delayed children

This paper examines the Central Institute for the Deaf’s "Grammatical Analysis of Elicited Language" (GAEL) test of expressive language and whether it identifies children with language disorders. Also examined is the relative difficulty of each of the grammatical categories sampled on the GAEL in relation to the standardization sample.

Evaluation of a feedback equalization algorithm in the CID Wearable Digital Hearing Aid

This paper describes the results of an investigation which examined the efficacy of a feedback equalization algorithm incorporated into the Central Institute for the Deaf Wearable Digital Hearing Aid. The study examined whether the feedback equalization would allow for greater usable gains when subjects listened to soft speech signals, and if so, whether or not this would improve speech intelligibility.

The Convective Storm Initiation Project

The Convective Storm Initiation Project (CSIP) is an international project to understand precisely where, when, and how convective clouds form and develop into showers in the mainly maritime environment of southern England. A major aim of CSIP is to compare the results of the very high resolution Met Office weather forecasting model with detailed observations of the early stages of convective clouds and to use the newly gained understanding to improve the predictions of the model. A large array of ground-based instruments plus two instrumented aircraft, from the U.K. National Centre for Atmospheric Science (NCAS) and the German Institute for Meteorology and Climate Research (IMK), Karlsruhe, were deployed in southern England, over an area centered on the meteorological radars at Chilbolton, during the summers of 2004 and 2005. In addition to a variety of ground-based remote-sensing instruments, numerous rawin-sondes were released at one- to two-hourly intervals from six closely spaced sites. The Met Office weather radar network and Meteosat satellite imagery were used to provide context for the observations made by the instruments deployed during CSIP. This article presents an overview of the CSIP field campaign and examples from CSIP of the types of convective initiation phenomena that are typical in the United Kingdom. It shows the way in which certain kinds of observational data are able to reveal these phenomena and gives an explanation of how the analyses of data from the field campaign will be used in the development of an improved very high resolution NWP model for operational use.

Characteristics and variability of storm tracks in the north Pacific, Bering Sea, and Alaska

The North Pacific and Bering Sea regions represent loci of cyclogenesis and storm track activity. In this paper climatological properties of extratropical storms in the North Pacific/Bering Sea are presented based upon aggregate statistics of individual storm tracks calculated by means of a feature-tracking algorithm run using NCEP–NCAR reanalysis data from 1948/49 to 2008, provided by the NOAA/Earth System Research Laboratory and the Cooperative Institute for Research in Environmental Sciences, Climate Diagnostics Center. Storm identification is based on the 850-hPa relative vorticity field (ζ) instead of the often-used mean sea level pressure; ζ is a prognostic field, a good indicator of synoptic-scale dynamics, and is directly related to the wind speed. Emphasis extends beyond winter to provide detailed consideration of all seasons. Results show that the interseasonal variability is not as large during the spring and autumn seasons. Most of the storm variables—genesis, intensity, track density—exhibited a maxima pattern that was oriented along a zonal axis. From season to season this axis underwent a north–south shift and, in some cases, a rotation to the northeast. This was determined to be a result of zonal heating variations and midtropospheric moisture patterns. Barotropic processes have an influence in shaping the downstream end of storm tracks and, together with the blocking influence of the coastal orography of northwest North America, result in high lysis concentrations, effectively making the Gulf of Alaska the “graveyard” of Pacific storms. Summer storms tended to be longest in duration. Temporal trends tended to be weak over the study area. SST did not emerge as a major cyclogenesis control in the Gulf of Alaska.