New variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue to arise and prolong the coronavirus disease 2019 (COVID-19) pandemic. Here, we used a cell-free expression ...workflow to rapidly screen and optimize constructs containing multiple computationally designed miniprotein inhibitors of SARS-CoV-2. We found the broadest efficacy was achieved with a homotrimeric version of the 75-residue angiotensin-converting enzyme 2 (ACE2) mimic AHB2 (TRI2-2) designed to geometrically match the trimeric spike architecture. Consistent with the design model, in the cryo-electron microscopy structure TRI2-2 forms a tripod at the apex of the spike protein that engaged all three receptor binding domains simultaneously. TRI2-2 neutralized Omicron (B.1.1.529), Delta (B.1.617.2), and all other variants tested with greater potency than the monoclonal antibodies used clinically for the treatment of COVID-19. TRI2-2 also conferred prophylactic and therapeutic protection against SARS-CoV-2 challenge when administered intranasally in mice. Designed miniprotein receptor mimics geometrically arrayed to match pathogen receptor binding sites could be a widely applicable antiviral therapeutic strategy with advantages over antibodies in greater resistance to viral escape and antigenic drift, and advantages over native receptor traps in lower chances of autoimmune responses.
Biospecimens acquired during routine medical practice are the primary sources of molecular information about patients and their diseases that underlies precision medicine and translational research. ...In cancer care, molecular analysis of biospecimens is especially common because it often determines treatment choices and may be used to monitor therapy in real time. However, patient specimens are collected, handled, and processed according to routine clinical procedures during which they are subjected to factors that may alter their molecular quality and composition. Such artefactual alteration may skew data from molecular analyses, render analysis data uninterpretable, or even preclude analysis altogether if the integrity of a specimen is severely compromised. As a result, patient care and safety may be affected, and medical research dependent on patient samples may be compromised. Despite these issues, there is currently no requirement to control or record preanalytical variables in clinical practice with the single exception of breast cancer tissue handled according to the guideline jointly developed by the American Society of Clinical Oncology and College of American Pathologists (CAP) and enforced through the CAP Laboratory Accreditation Program. Recognizing the importance of molecular data derived from patient specimens, the CAP Personalized Healthcare Committee established the Preanalytics for Precision Medicine Project Team to develop a basic set of evidence-based recommendations for key preanalytics for tissue and blood specimens. If used for biospecimens from patients, these preanalytical recommendations would ensure the fitness of those specimens for molecular analysis and help to assure the quality and reliability of the analysis data.
Organ transplantation is an acceptable option for human immunodeficiency virus (HIV)‐infected patients with end‐stage kidney or liver disease. With worse outcomes on the waitlist, HIV‐infected ...patients may actually be disproportionately affected by the organ shortage in the United States. One potential solution is the use of HIV‐infected deceased donors (HIVDD), recently legalized by the HIV Organ Policy Equity (HOPE) Act. This is the first analysis of patient‐specific data from potential HIVDD, retrospectively examining charts of HIV‐infected patients dying in care at six HIV clinics in Philadelphia, Pennsylvania from January 1, 2009 to June 30, 2014. Our data suggest that there are four to five potential HIVDD dying in Philadelphia annually who might yield two to three kidneys and three to five livers for transplant. Extrapolated nationally, this would approximate 356 potential HIVDD yielding 192 kidneys and 247 livers annually. However, several donor risk indices raise concerns about the quality of kidneys that could be recovered from HIVDD as a result of older donor age and comorbidities. On the other hand, livers from these potential HIVDD are of similar quality to HIV‐negative donors dying locally, although there is a high prevalence of positive hepatitis C antibody.
A review of HIV‐positive patients dying in care in Philadelphia demonstrates 4–5 additional potential deceased donors annually, yielding 2–3 kidneys and 3–4 livers, though organ quality may be diminished in renal donors.
We present optical and near-infrared (NIR) photometry of 28 gamma-ray bursts (GRBs) detected by the Swift satellite and rapidly observed by the Reionization and Transients Infrared/Optical (RATIR) ...camera. We compare the optical flux at fiducial times of 5.5 and 11 h after the high-energy trigger to that in the X-ray regime to quantify optical darkness. 46 ± 9 per cent (13/28) of all bursts in our sample and 55 ± 10 per cent (13/26) of long GRBs are optically dark, which is statistically consistently with previous studies. Fitting RATIR optical and NIR spectral energy distributions of 19 GRBs, most (6/7) optically dark GRBs either occur at high redshift (z > 4.5) or have a high dust content in their host galaxies (A
V > 0.3). Performing Kolmogorov–Smirnov tests, we compare the RATIR sample to those previously presented in the literature, finding our distributions of redshift, optical darkness, host dust extinction and X-ray-derived column density to be consistent. The one reported discrepancy is with host galaxy dust content in the BAT6 sample, which appears inconsistent with our sample and other previous literature. Comparing X-ray-derived host galaxy hydrogen column densities to host galaxy dust extinction, we find that GRBs tend to occur in host galaxies with a higher metal-to-dust ratio than our own Galaxy, more akin to the Large and Small Magellanic Clouds. Finally, to mitigate time evolution of optical darkness, we measure βOX, rest at a fixed rest-frame time, t
rest = 1.5 h and fixed rest-frame energies in the X-ray and optical regimes. Choosing to evaluate optical flux at λrest = 0.25 μm, we remove high redshift as a source of optical darkness, demonstrating that optical darkness must result from either high redshift, dust content in the host galaxy along the GRB sight line, or a combination of the two.
The Large Area Telescope (LAT) on--board the Fermi Gamma ray Space Telescope began its on--orbit operations on June 23, 2008. Calibrations, defined in a generic sense, correspond to synchronization ...of trigger signals, optimization of delays for latching data, determination of detector thresholds, gains and responses, evaluation of the perimeter of the South Atlantic Anomaly (SAA), measurements of live time, of absolute time, and internal and spacecraft boresight alignments. Here we describe on orbit calibration results obtained using known astrophysical sources, galactic cosmic rays, and charge injection into the front-end electronics of each detector. Instrument response functions will be described in a separate publication. This paper demonstrates the stability of calibrations and describes minor changes observed since launch. These results have been used to calibrate the LAT datasets to be publicly released in August 2009.
Selection of the InSight Landing Site Golombek, M.; Kipp, D.; Warner, N. ...
Space science reviews,
10/2017, Letnik:
211, Številka:
1-4
Journal Article
Recenzirano
The selection of the Discovery Program InSight landing site took over four years from initial identification of possible areas that met engineering constraints, to downselection via targeted data ...from orbiters (especially Mars Reconnaissance Orbiter (MRO) Context Camera (CTX) and High-Resolution Imaging Science Experiment (HiRISE) images), to selection and certification via sophisticated entry, descent and landing (EDL) simulations. Constraints on elevation (
≤
−
2.5
km
for sufficient atmosphere to slow the lander), latitude (initially 15°S–5°N and later 3°N–5°N for solar power and thermal management of the spacecraft), ellipse size (130 km by 27 km from ballistic entry and descent), and a load bearing surface without thick deposits of dust, severely limited acceptable areas to western Elysium Planitia. Within this area, 16 prospective ellipses were identified, which lie ∼600 km north of the Mars Science Laboratory (MSL) rover. Mapping of terrains in rapidly acquired CTX images identified especially benign smooth terrain and led to the downselection to four northern ellipses. Acquisition of nearly continuous HiRISE, additional Thermal Emission Imaging System (THEMIS), and High Resolution Stereo Camera (HRSC) images, along with radar data confirmed that ellipse E9 met all landing site constraints: with slopes <15° at 84 m and 2 m length scales for radar tracking and touchdown stability, low rock abundance (<10 %) to avoid impact and spacecraft tip over, instrument deployment constraints, which included identical slope and rock abundance constraints, a radar reflective and load bearing surface, and a fragmented regolith ∼5 m thick for full penetration of the heat flow probe. Unlike other Mars landers, science objectives did not directly influence landing site selection.
The mucosal origins hypothesis of rheumatoid arthritis (RA) proposes a central role for mucosal immune responses in the initiation or perpetuation of the systemic autoimmunity that occurs with ...disease. However, the connection between the mucosa and systemic autoimmunity in RA remains unclear. Using dual immunoglobulin A (IgA) and IgG family plasmablast-derived monoclonal autoantibodies obtained from peripheral blood of individuals at risk for RA, we identified cross-reactivity between RA-relevant autoantigens and bacterial taxa in the closely related families
and
. After generating bacterial isolates within the
genus
from the feces of an individual, we confirmed monoclonal antibody binding and CD4
T cell activation in individuals with RA compared to control individuals. In addition, when
isolate 7 but not isolate 1 colonized germ-free mice, it stimulated T
17 cell expansion, serum RA-relevant IgG autoantibodies, and joint swelling reminiscent of early RA, with histopathology characterized by antibody deposition and complement activation. Systemic immune responses were likely due to mucosal invasion along with the generation of colon-isolated lymphoid follicles driving increased fecal and serum IgA by isolate 7, because B and CD4
T cell depletion not only halted intestinal immune responses but also eliminated detectable clinical disease. In aggregate, these findings demonstrate a mechanism of RA pathogenesis through which a specific intestinal strain of bacteria can drive systemic autoantibody generation and joint-centered antibody deposition and immune activation.
We report the discovery by the Large Area Telescope (LAT) onboard the Fermi Gamma-ray Space Telescope of high-energy gamma-ray emission from the peculiar quasar PMN J0948+0022 (z=0.5846). The optical ...spectrum of this object exhibits rather narrow Hbeta (FWHM(Hbeta) ~ 1500 km s^-1), weak forbidden lines and is therefore classified as a narrow-line type I quasar. This class of objects is thought to have relatively small black hole mass and to accrete at high Eddington ratio. The radio loudness and variability of the compact radio core indicates the presence of a relativistic jet. Quasi simultaneous radio-optical-X-ray and gamma-ray observations are presented. Both radio and gamma-ray emission (observed over 5-months) are strongly variable. The simultaneous optical and X-ray data from Swift show a blue continuum attributed to the accretion disk and a hard X-ray spectrum attributed to the jet. The resulting broad band spectral energy distribution (SED) and, in particular, the gamma-ray spectrum measured by Fermi are similar to those of more powerful FSRQ. A comparison of the radio and gamma-ray characteristics of PMN J0948+0022 with the other blazars detected by LAT shows that this source has a relatively low radio and gamma-ray power, with respect to other FSRQ. The physical parameters obtained from modelling the SED also fall at the low power end of the FSRQ parameter region discussed in Celotti & Ghisellini (2008). We suggest that the similarity of the SED of PMN J0948+0022 to that of more massive and more powerful quasars can be understood in a scenario in which the SED properties depend on the Eddington ratio rather than on the absolute power.
Electrophysiology of Ethanol on Central Neurons SIGGINS, G. R.; BLOOM, F. E.; FRENCH, E. D. ...
Annals of the New York Academy of Sciences,
1987, Letnik:
492, Številka:
1
Journal Article, Conference Proceeding
Recenzirano
With respect to the theme of this volume, the results of our recent studies on three neuronal model systems point to several relevant conclusions: ethanol may interact electrophysiologically with ...certain anesthetics such as urethane; ethanol can selectively enhance responses to certain neurotransmitters; resting membrane properties of individual neurons show a wide range of sensitivities to ethanol and are generally fairly insensitive; the synapse--independent of specific transmitters--seems most sensitive to ethanol. As regards the first point, it has long been known that ethanol and anesthetics have features in common, including the ability to alter the lipid components of biological membranes (see R. A. Harris et al., L. L. M. van Deenen et al., M. J. Hudspith et al., E. Rubin et al., and C. C. Cunningham & P. I. Spach in this volume), so interactions between the two are not unexpected. However, our electrophysiological findings suggest great caution and appropriate controls be used in in-vivo studies of anesthetized animals, as the interactions derived may actually reverse the usual effect of ethanol. The enhancement of responses to ACh and SS (second point) might be assumed to arise postsynaptically in the target cells recorded and are seen with low, intoxicating doses of ethanol. Whether this potentiation involves enhancement of specific agonist binding to the receptor or facilitation of the function of the ionic channel linked to the receptor remains to be determined. It is not hard to imagine that ethanol could perturb membrane properties near receptors, to alter their conformation and ligand binding, or perhaps even uncover hidden receptors. The relative insensitivity of the resting membrane properties (third point) may suggest that membrane channels responsible for these functions (e.g., 'leak' channels for Na+ and K+ ions) do not usually interact with the lipid components affected by ethanol, at least at low, 'intoxicating' ethanol concentrations. Finally, the reduction of synaptic potentials by ethanol may indicate a presynaptic locus of action, as the response to the transmitter for at least one of these synaptic potentials (GABA) was not altered. These data would seem to indicate that synaptic release of the transmitter is reduced by ethanol, at least in the hippocampal slice. The high sensitivity of this presynaptic element for ethanol could indicate that the machinery for synaptic release, such as conductances for calcium entry (see REF. 39) or the action of second messenger systems (e.g., those leading to synapsin phosphorylation) are particularly sensitive to ethanol.
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