HIV-1 protease function and structure studies with the simplicial neighborhood analysis of protein packing method

The Simplicial Neighborhood Analysis of Protein Packing (SNAPP) method was used to predict the effect of mutagenesis on the enzymatic activity of the HIV-1 protease (HIVP). SNAPP relies on a four-body statistical scoring function derived from the analysis of spatially nearest neighbor residue compositional preferences in a diverse and representative subset of protein structures from the Protein Data Bank. The method was applied to the analysis of HIVP mutants with residue substitutions in the hydrophobic core as well as at the interface between the two protease monomers. Both wild type and tethered structures were employed in the calculations. We obtained a strong correlation, with R2 as high as 0.96, between ΔSNAPP score (i.e., the difference in SNAPP scores between wild type and mutant proteins) and the protease catalytic activity for tethered structures. A weaker but significant correlation was also obtained for non-tethered structures as well. Our analysis identified residues both in the hydrophobic core and at the dimeric interface (DI) that are very important for the protease function. This study demonstrates a potential utility of the SNAPP method for rational design of mutagenesis studies and protein engineering

STAT3 activation impairs the stability of Th9 cells

Th9 cells regulate multiple immune responses including immunity to pathogens and tumors, allergic inflammation, and autoimmunity. Despite ongoing research into Th9 development and function, little is known about the stability of the Th9 phenotype. In this report we demonstrate that IL-9 production is progressively lost in Th9 cultures over several rounds of differentiation. The loss of IL-9 is not due to an outgrowth of cells that do not secrete IL-9, as purified IL-9 secretors demonstrate the same loss of IL-9 in subsequent rounds of differentiation. The loss of IL-9 production correlates with increases in phospho-STAT3 levels within the cell, and the production of IL-10. STAT3-deficient Th9 cells have increased IL-9 production that is maintained for longer in culture than IL-9 in control cultures. IL-10 is responsible for STAT3 activation during the first round of differentiation, and contributes to instability in subsequent rounds of culture. Together, our results indicate that environmental cues dictate the instability of the Th9 phenotype, and suggest approaches to enhance Th9 activity in beneficial immune responses

Recovery of resistant enterococci during vancomycin prophylaxis.

We report a case of a patient undergoing hemodialysis who developed a wound infection and subsequently bacteremia with a strain of vancomycin-resistantent erococcus identified as Enterococcus gallinarum. He had been receiving vancomycin prophylaxis before developing these infections. Both isolates were susceptible to ampicillin, rifampin, teicoplanin, and daptomycin (LY146032)

Processing sites in the human immunodeficiency virus type 1 (HIV-1) Gag-Pro-Pol precursor are cleaved by the viral protease at different rates

Abstract We have examined the kinetics of processing of the HIV-1 Gag-Pro-Pol precursor in an in vitro assay with mature protease added in trans. The processing sites were cleaved at different rates to produce distinct intermediates. The initial cleavage occurred at the p2/NC site. Intermediate cleavages occurred at similar rates at the MA/CA and RT/IN sites, and to a lesser extent at sites upstream of RT. Late cleavages occurred at the sites flanking the protease (PR) domain, suggesting sequestering of these sites. We observed paired intermediates indicative of half- cleavage of RT/RH site, suggesting that the RT domain in Gag-Pro-Pol was in a dimeric form under these assay conditions. These results clarify our understanding of the processing kinetics of the Gag-Pro-Pol precursor and suggest regulated cleavage. Our results further suggest that early dimerization of the PR and RT domains may serve as a regulatory element to influence the kinetics of processing within the Pol domain

Brief Amici Curiae of Electronic Frontier Foundation, 1851 Center for Constitutional Law, and Profs. Jonathan Entin, David F. Forte, Andrew Geronimo, Raymond Ku, Stephen Lazarus, Kevin Francis O’Neill, Margaret Tarkington, Aaron H. Caplan, and Eugene Volokh in Support of Respondent-Appellant, Joni Bey and Rebecca Rasawehr v. Jeffrey Rasawehr, Supreme Court of Ohio (Case No. 2019-0295)

The brief argues that the Third District Court of Appeals, in violation of the First Amendment, erred in upholding an injunction that barred defendant from any online postings regarding plaintiff, whether or not those postings were to plaintiff or to third parties

Effective Field Theory, Black Holes, and the Cosmological Constant

Bekenstein has proposed the bound S < pi M_P^2 L^2 on the total entropy S in a volume L^3. This non-extensive scaling suggests that quantum field theory breaks down in large volume. To reconcile this breakdown with the success of local quantum field theory in describing observed particle phenomenology, we propose a relationship between UV and IR cutoffs such that an effective field theory should be a good description of Nature. We discuss implications for the cosmological constant problem. We find a limitation on the accuracy which can be achieved by conventional effective field theory: for example, the minimal correction to (g-2) for the electron from the constrained IR and UV cutoffs is larger than the contribution from the top quark.Comment: 5 pages, no figures minor clarifications, refs adde

PPAR-γ in Macrophages Limits Pulmonary Inflammation and Promotes Host Recovery Following Respiratory Viral Infection

Alveolar macrophages (AM) play pivotal roles in modulating host defense, pulmonary inflammation, and tissue injury following respiratory viral infections. However, the transcriptional regulation of AM function during respiratory viral infections is still largely undefined. Here we have screened the expression of 84 transcription factors in AM in response to influenza A virus (IAV) infection. We found that the transcription factor PPAR-γ was downregulated following IAV infection in AM through type I interferon (IFN)-dependent signaling. PPAR-γ expression in AM was critical for the suppression of exaggerated antiviral and inflammatory responses of AM following IAV and respiratory syncytial virus (RSV) infections. Myeloid PPAR-γ deficiency resulted in enhanced host morbidity and increased pulmonary inflammation following both IAV and RSV infections, suggesting that macrophage PPAR-γ is vital for restricting severe host disease development. Using approaches to selectively deplete recruiting monocytes, we demonstrate that PPAR-γ expression in resident AM is likely important in regulating host disease development. Furthermore, we show that PPAR-γ was critical for the expression of wound healing genes in AM. As such, myeloid PPAR-γ deficiency resulted in impaired inflammation resolution and defective tissue repair following IAV infection. Our data suggest a critical role of PPAR-γ expression in lung macrophages in the modulation of pulmonary inflammation, the development of acute host diseases, and the proper restoration of tissue homeostasis following respiratory viral infections.IMPORTANCE Respiratory viral infections, like IAV and respiratory syncytial virus (RSV) infections, impose great challenges to public health. Alveolar macrophages (AM) are lung-resident immune cells that play important roles in protecting the host against IAV and RSV infections. However, the underlying molecular mechanisms by which AM modulate host inflammation, disease development, and tissue recovery are not very well understood. Here we identify that PPAR-γ expression in AM is crucial to suppress pulmonary inflammation and diseases and to promote fast host recovery from IAV and RSV infections. Our data suggest that targeting macrophage PPAR-γ may be a promising therapeutic option in the future to suppress acute inflammation and simultaneously promote recovery from severe diseases associated with respiratory viral infections

Evaluation of Lateglacial temperatures in the Southern Alps of New Zealand based on glacier modelling at Irishman Stream, Ben Ohau Range

Climate proxy records from the middle to high latitude Southern Hemisphere indicate that a Lateglacial (15,000-11,500 years ago) climate reversal, approximately coeval with the Antarctic Cold Reversal (ACR), interrupted a warming trend during deglaciation. In New Zealand, some palaeoclimate proxy records indicate a cool episode during the ACR (ca 14,500-12,500 years ago), while others do not express a significant change in climate. Recently published moraine maps and ages present an opportunity to improve the palaeoclimate interpretation through numerical modelling of glaciers. We use a coupled energy-balance and ice-flow model to quantify palaeoclimate from past glacier extent constrained by mapped and dated moraines in the headwaters of Irishman Stream, a high-elevation catchment in the Southern Alps. First, a suite of steady-state model runs is used to identify the temperature and precipitation forcing required to fit the modelled glacier to well-dated Lateglacial moraine crests. Second, time dependent glacier simulations forced by a nearby proxy temperature record derived from chironomids are used to assess the fit with the glacial geomorphic record. Steady-state experiments using an optimal parameter set demonstrate that the conditions under which the 13,000 year old moraine formed were 2.3-3.2 *C colder than present with the range in temperature corresponding to a +/- 20% variance in precipitation relative to the present-day. This reconstructed climate change relative to the present-day corresponds to an equilibrium-line altitude of ca 2000 +/- 40 m above sea level (asl), which is ca 400 m lower than present. Time-dependent simulations of glacier length produce ice advance to within 100 m of the 13,000 year old terminal moraine, indicating that the chironomid-based temperature forcing and moraine record provide consistent information about past climate. Our results, together with other climate proxy reconstructions from pollen records and marine sediment cores, support the notion that temperatures during the ACR in New Zealand were ~2-3 *C cooler than today

Solar Contamination in Extreme-precision Radial-velocity Measurements: Deleterious Effects and Prospects for Mitigation

Solar contamination, due to moonlight and atmospheric scattering of sunlight, can cause systematic errors in stellar radial velocity (RV) measurements that significantly detract from the ~10 cm s−1 sensitivity required for the detection and characterization of terrestrial exoplanets in or near habitable zones of Sun-like stars. The addition of low-level spectral contamination at variable effective velocity offsets introduces systematic noise when measuring velocities using classical mask-based or template-based cross-correlation techniques. Here we present simulations estimating the range of RV measurement error induced by uncorrected scattered sunlight contamination. We explore potential correction techniques, using both simultaneous spectrometer sky fibers and broadband imaging via coherent fiber imaging bundles, that could reliably reduce this source of error to below the photon-noise limit of typical stellar observations. We discuss the limitations of these simulations, the underlying assumptions, and mitigation mechanisms. We also present and discuss the components designed and built into the NEID (NN-EXPLORE Exoplanet Investigations with Doppler spectroscopy) precision RV instrument for the WIYN 3.5 m telescope, to serve as an ongoing resource for the community to explore and evaluate correction techniques. We emphasize that while "bright time" has been traditionally adequate for RV science, the goal of 10 cm s−1 precision on the most interesting exoplanetary systems may necessitate access to darker skies for these next-generation instruments

Hyperbolic quenching problem with damping in the micro-electro mechanical system device

[[abstract]]We study the initial boundary value problem for the damped hyperbolic equation arising in the micro-electro mechanical system device with local or nonlocal singular nonlinearity. For both cases, we provide some criteria for quenching and global existence of the solution. We also derive the existence of the quenching curve for the corresponding Cauchy problem with local source[[notice]]補正完畢[[journaltype]]國外[[incitationindex]]SCI[[ispeerreviewed]]Y[[countrycodes]]US