Missileborne Artificial Vision System (MAVIS)

Several years ago when INTEL and China Lake designed the ETANN chip, analog VLSI appeared to be the only way to do high density neural computing. In the last five years, however, digital parallel processing chips capable of performing neural computation functions have evolved to the point of rough equality with analog chips in system level computational density. The Naval Air Warfare Center, China Lake, has developed a real time, hardware and software system designed to implement and evaluate biologically inspired retinal and cortical models. The hardware is based on the Adaptive Solutions Inc. massively parallel CNAPS system COHO boards. Each COHO board is a standard size 6U VME card featuring 256 fixed point, RISC processors running at 20 MHz in a SIMD configuration. Each COHO board has a companion board built to support a real time VSB interface to an imaging seeker, a NTSC camera, and to other COHO boards. The system is designed to have multiple SIMD machines each performing different corticomorphic functions. The system level software has been developed which allows a high level description of corticomorphic structures to be translated into the native microcode of the CNAPS chips. Corticomorphic structures are those neural structures with a form similar to that of the retina, the lateral geniculate nucleus, or the visual cortex. This real time hardware system is designed to be shrunk into a volume compatible with air launched tactical missiles. Initial versions of the software and hardware have been completed and are in the early stages of integration with a missile seeker

Public health training in internal medicine residency programs: a national survey

BACKGROUND: The IOM recommends public health training for all physicians. Data characterizing such training of internal medicine (IM) residents are lacking. PURPOSE: To describe the current state of public health education at IM residency programs, characterize programs offering public health education, and quantify interest in expanding training opportunities. METHODS: IM residency program directors from the 380 Accreditation Council for Graduate Medical Education-accredited residency programs in the U.S were invited to participate in a cross-sectional survey. Responses were received from 127 programs (33%). Data were collected July-December 2012 and analyzed in January 2013. Participants were queried on domestic public health training offered, perceived resident interest in and satisfaction with this training, and interest in expanding training. RESULTS: Eighty-four respondents (66%) provide some form of public health training, but structure and content vary widely. In many programs offering public health training, few residents (\u3c10%) receive it. Although 93 programs (73%) integrate public health into core curricula, only three topics were common to a majority of these programs. Sixty-six respondents (52%) offer clinical training at community-based health centers. Most residency program directors (90%) are very or somewhat interested in expanding their public health training. CONCLUSIONS: This study characterizes the structures and content of public health training across IM residency programs. The wide range highlights the diverse definition of public health training used by IM residency program directors and lack of universal public health competencies required for IM physicians. Opportunities exist for collaboration among residency programs and between IM and public health educators to share best practices

Mechanistic Heterogeneity in Site Recognition by the Structurally Homologous DNA-Binding Domains of the ETS-Family Transcription Factors Ets-1 and PU.1

ETS-family transcription factors regulate diverse genes through binding at cognate DNA sites that overlap substantially in sequence. The DNA-binding domains of ETS proteins (ETS domains) are highly conserved structurally, yet share limited amino acid homology. To define the mechanistic implications of sequence diversity within the ETS family, we characterized the thermodynamics and kinetics of DNA site recognition by the ETS domains of Ets-1 and PU.1, which represent the extremes in amino acid divergence among ETS proteins. Even though the two ETS domains bind their optimal sites with similar affinities under physiologic conditions, their nature of site recognition differs strikingly in terms of the role of hydration and counter-ion release. The data suggest two distinct mechanisms wherein Ets-1 follows a “dry” mechanism that rapidly parses sites through electrostatic interactions and direct protein-DNA contacts, while PU.1 utilizes hydration to interrogate sequence-specific sites and form a long-lived complex relative to the Ets-1 counterpart. The kinetic persistence of the high-affinity PU.1/DNA complex may be relevant to an emerging role of PU.1, but not Ets-1, as a pioneer transcription factor in vivo. In addition, PU.1 activity is critical to the development and function of macrophages and lymphocytes, which present osmotically variable environments, and hydrationdependent specificity may represent an important regulatory mechanism in vivo, a hypothesis that finds support in gene expression profiles of primary murine macrophages

Mechanistic Heterogeneity in Site Recognition by the Structurally Homologous DNA-Binding Domains of the ETS-Family Transcription Factors Ets-1 and PU.1

ETS-family transcription factors regulate diverse genes through binding at cognate DNA sites that overlap substantially in sequence. The DNA-binding domains of ETS proteins (ETS domains) are highly conserved structurally, yet share limited amino acid homology. To define the mechanistic implications of sequence diversity within the ETS family, we characterized the thermodynamics and kinetics of DNA site recognition by the ETS domains of Ets-1 and PU.1, which represent the extremes in amino acid divergence among ETS proteins. Even though the two ETS domains bind their optimal sites with similar affinities under physiologic conditions, their nature of site recognition differs strikingly in terms of the role of hydration and counter-ion release. The data suggest two distinct mechanisms wherein Ets-1 follows a “dry” mechanism that rapidly parses sites through electrostatic interactions and direct protein-DNA contacts, while PU.1 utilizes hydration to interrogate sequence-specific sites and form a long-lived complex relative to the Ets-1 counterpart. The kinetic persistence of the high-affinity PU.1/DNA complex may be relevant to an emerging role of PU.1, but not Ets-1, as a pioneer transcription factor in vivo. In addition, PU.1 activity is critical to the development and function of macrophages and lymphocytes, which present osmotically variable environments, and hydrationdependent specificity may represent an important regulatory mechanism in vivo, a hypothesis that finds support in gene expression profiles of primary murine macrophages

Dual molecular mechanisms govern escape at immunodominant HLA A2-restricted HIV epitope

Serial accumulation of mutations to fixation in the SLYNTVATL (SL9) immunodominant, HIV p17 Gag-derived, HLA A2-restricted CTL epitope produce the SLFNTIAVL triple mutant ‘ultimate’ escape variant. These mutations in solvent-exposed residues are believed to interfere with TCR recognition, although confirmation has awaited structural verification. Here, we solved a TCR co-complex structure with SL9 and the triple escape mutant to determine the mechanism of immune escape in this eminent system. We show that, in contrast to prevailing hypotheses, the main TCR contact residue is 4N and the dominant mechanism of escape is not via lack of TCR engagement. Instead, mutation of solvent exposed residues in the peptide destabilize the peptide-HLA and reduce peptide density at the cell surface. These results highlight the extraordinary lengths that HIV employs to evade detection by high-affinity TCRs with a broad peptide-binding footprint and necessitate reevaluation of this exemplar model of HIV TCR escape

Transcranial magnetic stimulation input–output curve slope differences suggest variation in recruitment across muscle representations in primary motor cortex

Measurement of the input–output (IO) curves of motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) can be used to assess corticospinal excitability and motor recruitment. While IO curves have been used to study disease and pharmacology, few studies have compared the IO curves across the body. This study sought to characterize IO curve parameters across the dominant and non-dominant sides of upper and lower limbs in healthy participants. Laterality preferences were assessed in eight healthy participants and IO curves were measured bilaterally for the first dorsal interosseous (FDI), biceps brachii (BB), and tibialis anterior (TA) muscles. Results show that FDI has lower motor threshold than BB which is, in turn, lower than TA. In addition, both BB and TA have markedly shallower logarithmic IO curve slopes from small to large MEP responses than FDI. After normalizing these slopes by their midpoints to account for differences in motor thresholds, which could result from geometric factors such as the target depth, large differences in logarithmic slopes remain present between all three muscles. The differences in slopes between the muscles could not be explained by differences in normalized IO curve spreads, which relate to the extent of the cortical representation and were comparable across the muscles. The IO curve differences therefore suggest muscle-dependent variations in TMS-evoked recruitment across the primary motor cortex, which should be considered when utilizing TMS-evoked MEPs to study disease states and treatment effects

Preparing for Climatic Change: The Water, Salmon, and Forests of the Pacific Northwest

The impacts of year-to-year and decade-to-decade climatic variations on some of the Pacific Northwest’s key natural resources can be quantified to estimate sensitivity to regional climatic changes expected as part of anthropogenic global climatic change. Warmer, drier years, often associated with El Niño events and/or the warm phase of the Pacific Decadal Oscillation, tend to be associated with below-average snowpack, streamflow, and flood risk, below-average salmon survival, below-average forest growth, and above-average risk of forest fire. During the 20th century, the region experienced a warming of 0.8 ◦C. Using output from eight climate models, we project a further warming of 0.5–2.5 ◦C (central estimate 1.5 ◦C) by the 2020s, 1.5–3.2 ◦C (2.3◦C) by the 2040s, and an increase in precipitation except in summer. The foremost impact of a warming climate will be the reduction of regional snowpack, which presently supplies water for ecosystems and human uses during the dry summers. Our understanding of past climate also illustrates the responses of human management systems to climatic stresses, and suggests that a warming of the rate projected would pose significant challenges to the management of natural resources. Resource managers and planners currently have few plans for adapting to or mitigating the ecological and economic effects of climatic change

Preparing for Climatic Change: The Water, Salmon, and Forests of the Pacific Northwest

The impacts of year-to-year and decade-to-decade climatic variations on some of the Pacific Northwest’s key natural resources can be quantified to estimate sensitivity to regional climatic changes expected as part of anthropogenic global climatic change. Warmer, drier years, often associated with El Niño events and/or the warm phase of the Pacific Decadal Oscillation, tend to be associated with below-average snowpack, streamflow, and flood risk, below-average salmon survival, below-average forest growth, and above-average risk of forest fire. During the 20th century, the region experienced a warming of 0.8 ◦C. Using output from eight climate models, we project a further warming of 0.5–2.5 ◦C (central estimate 1.5 ◦C) by the 2020s, 1.5–3.2 ◦C (2.3◦C) by the 2040s, and an increase in precipitation except in summer. The foremost impact of a warming climate will be the reduction of regional snowpack, which presently supplies water for ecosystems and human uses during the dry summers. Our understanding of past climate also illustrates the responses of human management systems to climatic stresses, and suggests that a warming of the rate projected would pose significant challenges to the management of natural resources. Resource managers and planners currently have few plans for adapting to or mitigating the ecological and economic effects of climatic change

Multi-omic analysis of two common p53 mutations: Proteins regulated by mutated p53 as potential targets for immunotherapy

The p53 protein is mutated in more than 50% of human cancers. Mutated p53 proteins not only lose their normal function but often acquire novel oncogenic functions, a phenomenon termed mutant p53 gain-of-function. Mutant p53 has been shown to affect the transcription of a range of genes, as well as protein–protein interactions with transcription factors and other effectors; however, no one has intensively investigated and identified these proteins, or their MHC presented epitopes, from the viewpoint of their ability to act as targets for immunotherapeutic interventions. We investigated the molecular changes that occurred after the TP53 null osteosarcoma cells, SaOS-2, were transfected with one of two conformational p53-mutants, either R175H or R273H. We then examined the phenotypic and functional changes using macroscopic observations, proliferation, gene expression and proteomics alongside immunopeptidome profiling of peptide antigen presentation in the context of major histocompatibility complex (MHC) class I molecules. We identified several candidate proteins in both TP53 mutant cell lines with differential expression when compared to the TP53 null vector control, SaOS-V. Quantitative SWATH proteomics combined with immune-peptidome analysis of the class-I eluted peptides identified several epitopes presented on pMHC and in silico analysis shortlisted which antigens were expressed in a range of cancerous but not adjacent healthy tissues. Out of all the candidates, KLC1 and TOP2A showed high levels of expression in every tumor type examined. From these proteins, three A2 and four pan HLA-A epitopes were identified in both R175H and R273H from TOP2A. We have now provided a short list of future immunotherapy targets for the treatment of cancers harboring mutated TP53