The HIV envelope (Env) protein gpl20 is protected from antibody recognition by a dense glycan shield. However, several of the recently identified PGT broadly neutralizing antibodies appear to ...interact directly with the HIV glycan coat. Crystal structures of antigen-binding fragments (Fabs) PGT 127 and 128 with Man 9 at 1.65 and 1.29 angstrom resolution, respectively, and glycan binding data delineate a specific high mannose-binding site. Fab PGT 128 complexed with a fully g ly cosy la ted gpl20 outer domain at 3.25 angstroms reveals that the antibody penetrates the glycan shield and recognizes two conserved glycans as well as a short ß-strand segment of the gpl20 V3 loop, accounting for its high binding affinity and broad specificify. Furthermore, our data suggest that the high neutralization potency of PGT 127 and 128 immunoglobulin Gs may be mediated by cross-linking Env trimers on the viral surface.
Illicit drug use causes over half a million deaths worldwide every year. Drugs of abuse are commonly smuggled through customs and border checkpoints and, increasingly, through parcel delivery ...services. Improved methods for detection of trace drug residues from surfaces are needed. Such methods should be robust, fieldable, sensitive, and capable of detecting a wide range of drugs. In this work, commercially produced paper with a pressure-sensitive adhesive coating was utilized for the collection and analysis of trace drug residues by paper spray mass spectrometry (MS). This modified substrate was used to combine sample collection of drug residues from surfaces with rapid detection using a single paper spray ticket. The all-in-one ticket was used to probe different surfaces commonly encountered in forensic work including clothing, cardboard, glass, concrete, asphalt, and aluminum. A total of 10 drugs (acetyl fentanyl, fentanyl, clonazolam, cocaine, heroin, ketamine, methamphetamine, methylone, U-47700, and XLR-11) were evaluated and found to be detectable in the picogram range using a benchtop mass spectrometer and in the low nanogram range using a portable ion trap MS. The novel approach demonstrates a simple yet effective sampling strategy, allowing for rapid identification from difficult surfaces via paper spray mass spectrometry.
Abstract
Efforts with extreme-precision radial velocity (EPRV) instruments to detect small-amplitude planets are largely limited, on many timescales, by the effects of stellar variability and ...instrumental systematics. One avenue for investigating these effects is the use of small solar telescopes which direct disk-integrated sunlight to these EPRV instruments, observing the Sun at high cadence over months or years. We have designed and built a solar feed system to carry out “Sun-as-a-star” observations with NEID, a very high precision Doppler spectrometer recently commissioned at the WIYN 3.5 m Telescope at Kitt Peak National Observatory. The NEID solar feed has been taking observations nearly every day since 2020 December; data is publicly available at the NASA Exoplanet Science Institute NEID Solar Archive:
https://neid.ipac.caltech.edu/search_solar.php
. In this paper, we present the design of the NEID solar feed and explanations behind our design intent. We also present early radial velocity (RV) results which demonstrate NEID’s RV stability on the Sun over 4 months of commissioning: 0.66 m s
−1
rms under good sky conditions and improving to 0.41 m s
−1
rms under best conditions.
Misincorporation of uracil or spontaneous cytidine deamination is a common mutagenic insult to DNA. Herpesviruses encode a viral uracil-DNA glycosylase (vUNG) and a viral dUTPase (vDUT), each with ...enzymatic and nonenzymatic functions. However, the coordinated roles of these enzymatic activities in gammaherpesvirus pathogenesis and viral genomic stability have not been defined. In addition, potential compensation by the host UNG has not been examined
The genetic tractability of the murine gammaherpesvirus 68 (MHV68) system enabled us to delineate the contribution of host and viral factors that prevent uracilated DNA. Recombinant MHV68 lacking vUNG (ORF46.stop) was not further impaired for acute replication in the lungs of UNG
mice compared to wild-type (WT) mice, indicating host UNG does not compensate for the absence of vUNG. Next, we investigated the separate and combinatorial consequences of mutating the catalytic residues of the vUNG (ORF46.CM) and vDUT (ORF54.CM). ORF46.CM was not impaired for replication, while ORF54.CM had a slight transient defect in replication in the lungs. However, disabling both vUNG and vDUT led to a significant defect in acute expansion in the lungs, followed by impaired establishment of latency in the splenic reservoir. Upon serial passage of the ORF46.CM/ORF54.CM mutant in either fibroblasts or the lungs of mice, we noted rapid loss of the nonessential yellow fluorescent protein (YFP) reporter gene from the viral genome, due to recombination at repetitive elements. Taken together, our data indicate that the vUNG and vDUT coordinate to promote viral genomic stability and enable viral expansion prior to colonization of latent reservoirs.
Unrepaired uracils in DNA can lead to mutations and compromise genomic stability. Herpesviruses have hijacked host processes of DNA repair and nucleotide metabolism by encoding a viral UNG that excises uracils and a viral dUTPase that initiates conversion of dUTP to dTTP. To better understand the impact of these processes on gammaherpesvirus pathogenesis, we examined the separate and collaborative roles of vUNG and vDUT upon MHV68 infection of mice. Simultaneous disruption of the enzymatic activities of both vUNG and vDUT led to a severe defect in acute replication and establishment of latency, while also revealing a novel, combinatorial function in promoting viral genomic stability. We propose that herpesviruses require these enzymatic processes to protect the viral genome from damage, possibly triggered by misincorporated uracil. This reveals a novel point of therapeutic intervention to potentially block viral replication and reduce the fitness of multiple herpesviruses.
Traumatic brain injury (TBI) is an increasingly recognized diagnosis with significant, and often costly, associated consequences. Yet, despite their increased recognition, TBIs remain underdiagnosed. ...This issue is especially prominent in the context of mild TBI (mTBI), where there often exists little to no objective evidence of brain injury. In recent years, considerable effort has been made to better define and interpret known objective markers of TBI, as well as identify and explore new ones. An area of particular interest has focused on research related to blood-based biomarkers of TBI. Advancements in our understanding of TBI-related biomarkers can make it possible to characterize the severity of TBI with greater accuracy, improve our understanding of staging within both the injury process and the recovery process, and help us develop quantifiable metrics representative of reversal and recovery from a brain injury following trauma. Proteomic and non-proteomic blood-based biomarkers are being studied extensively and have shown promise for these purposes. Developments in this realm have significant implications not only for clinical care but also for legislation, as well as civil and criminal litigation. Despite their substantial potential, most of these biomarkers are not yet ready for use within the clinical setting, and therefore, are not appropriate for use within the legal or policy-making systems at this time. Given that existing standardization for the accurate and reliable use of TBI biomarkers is currently insufficient for use within either the clinical or legal realms, such data can be vulnerable to misuse and can even result in the abuse of the legal system for unwarranted gain. Courts will need to carefully evaluate the information presented in their role as gatekeepers of the admissibility of scientific evidence within the legal process. Ultimately, the development of biomarkers should lead to improved clinical care following TBI exposure, coherent and informed laws surrounding TBI, and more accurate and just results in litigation surrounding TBI-related sequelae.
In this work, we investigate the effects of grain structure and bromide content on charge transport in methylammonium lead iodide/bromide (MAPb(I1-xBrx)3) perovskites by examining the steady-state ...(ss-PL) and time-resolved (tr-PL) photoluminescence of planar films with varying grain size and bromide content. We controlled the perovskite grain structure via solvent engineering with N,N-dimethylformamide (DMF) or dimethyl sulfoxide : gamma -butyrolactone (DMSO : GBL), and the resultant grain morphology was independent of Br doping between 0-33%. Carrier lifetimes ranged from 29-52 ns with increasing Br content for DMF-produced perovskite films, and from 2-9 ns for films obtained with DMSO : GBL. Analysis of XRD and photoluminescence data suggests this order-of-magnitude difference in lifetimes is attributable to the nature of iodide-rich recombination nuclei within the bulk perovskite. By modulating the precursor solvent and Br composition, the influence of low-bandgap recombination nuclei can be minimized to enhance charge transport and lengthen the carrier lifetime in mixed-halide perovskite films.
Blood Biomarkers in Brain Injury Medicine McBride, William R.; Conlan, Caroline E.; Barylski, Nicole A. ...
Current physical medicine and rehabilitation reports,
06/2022, Volume:
10, Issue:
2
Journal Article
Open access
Purpose of Review
This review seeks to explore blood-based biomarkers with the potential for clinical implementation.
Recent Findings
Emerging non-proteomic biomarkers hold promise for more accurate ...diagnostic and prognostic capabilities, especially in the subacute to chronic phase of TBI recovery. Furthermore, there is a growing understanding of the overlap between TBI-related and dementia-related blood biomarkers.
Summary
Given the significant heterogeneity inherent in the clinical diagnosis of traumatic brain injury (TBI), there has been an exponential increase in TBI-related biomarker research over the past two decades. While TBI-related biomarker assessments include both cerebrospinal fluid analysis and advanced neuroimaging modalities, blood-based biomarkers hold the most promise to be non-invasive biomarkers widely available to Brain Injury Medicine clinicians in diverse practice settings. In this article, we review the most relevant blood biomarkers for the field of Brain Injury Medicine, including both proteomic and non-proteomic blood biomarkers, biomarkers of cerebral microvascular injury, and biomarkers that overlap between TBI and dementia.
In certain forms of severe heart failure there is sufficient improvement in cardiac function during ventricular assist device (VAD) support to allow removal of the device. However, it is critical to ...know whether there is sustained recovery of the heart and long-term patient survival if VAD bridging to recovery is to be considered over the option of transplantation.
To determine long-term outcome of survivors of VAD bridge-to-recovery procedures, we retrospectively evaluated 22 patients with non-ischemic heart failure successfully weaned from the Thoratec left ventricular assist device (LVAD) or biventricular assist device (BVAD) after recovery of ventricular function at 14 medical centers. All patients were in imminent risk of dying and were selected for VAD support using standard bridge-to-transplant requirements. There were 12 females and 10 males with an average age of 32 (range, 12–49). The etiologies were 12 with myocarditis, 7 with cardiomyopathies (4 post-partum PPCM, 1 viral VCM, and 2 idiopathic IDCM), and 3 with a combination of myocarditis and cardiomyopathy. BVADs were used in 13 patients and isolated LVADs in 9 patients, for an average duration of 57 days (range, 11–190 days), before return of ventricular function and successful weaning from the device. Post-VAD survival was compared with 43 VAD bridge-to-transplant patients with the same etiologies who underwent cardiac transplantation instead of device weaning.
Nineteen of the 22 patients are currently alive. Three patients required heart transplantation, 1 within 1 day, 2 at 12 and 13 months post-weaning, and 2 died at 2.5 and 6 months. The remaining 17 patients are alive with their native hearts after an average of 3.2 years (range, 1.2–10 years). The actuarial survival of native hearts (transplant-free survival) post-VAD support is 86% at 1 year and 77% at 5 years, which was not significantly different (
p = 0.94) from that of post-VAD transplanted patients, also at 86% and 77%, respectively.
Long-term survival for bridge-to-recovery with VADs for acute cardiomyopathies and myocarditis is equivalent to that for cardiac transplantation. Recovery of the native heart, which can take weeks to months of VAD support, is the most desirable clinical outcome and should be actively sought, with transplantation used only after recovery of ventricular function has been ruled out.
Geriatric trauma care (GTC) represents an increasing proportion of injury care, but associated public health research on outcomes and expenditures is limited. The purpose of this study was to ...describe GTC characteristics, location, diagnoses, and expenditures.
Patients at short-term nonfederal hospitals, 65 years or older, with ≥1 injury International Classification of Diseases, Tenth Revision, were selected from 2016 to 2019 Centers for Medicare and Medicaid Services Inpatient Standard Analytical Files. Trauma center levels were linked to Inpatient Standard Analytical Files data via American Hospital Association Hospital ID and fuzzy string matching. Demographics, care location, diagnoses, and expenditures were compared across groups.
A total of 2,688,008 hospitalizations (62% female; 90% White; 71% falls; mean Injury Severity Score, 6.5) from 3,286 hospitals were included, comprising 8.5% of all Medicare inpatient hospitalizations. Level I centers encompassed 7.2% of the institutions (n = 236) but 21.2% of hospitalizations, while nontrauma centers represented 58.5% of institutions (n = 1,923) and 37.7% of hospitalizations. Compared with nontrauma centers, patients at Level I centers had higher Elixhauser scores (9.0 vs. 8.8) and Injury Severity Score (7.4 vs. 6.0; p < 0.0001). The most frequent primary diagnosis at all centers was hip/femur fracture (28.3%), followed by traumatic brain injury (10.1%). Expenditures totaled $32.9 billion for trauma-related hospitalizations, or 9.1% of total Medicare hospitalization expenditures and approximately 1.1% of the annual Medicare budget. The overall mortality rate was 3.5%.
Geriatric trauma care accounts for 8.5% of all inpatient GTC and a similar percentage of expenditures, the most common injury being hip/femur fractures. The largest proportion of GTC occurs at nontrauma centers, emphasizing their vital role in trauma care. Public health prevention programs and GTC guidelines should be implemented by all hospitals, not just trauma centers. Further research is required to determine the optimal role of trauma systems in GTC, establish data-driven triage guidelines, and define the impact of trauma centers and nontrauma centers on GTC mortality.
Therapeutic/care management, Level III.
A molecular epidemiologic investigation in two Brazilian states (Rondônia and São Paulo) was undertaken to determine if
Ehrlichia species responsible for human and animal ehrlichioses in North ...America could be found in Brazilian vectors, potential natural mammalian reservoirs and febrile human patients with a tick bite history. Samples, including 376 ticks comprising 9
Amblyomma species, 29 capybara (
Hydrochaeris hydrochaeris) spleens, 5 canine blood, and 75 human blood samples from febrile patients with history of tick bites were tested by a real-time PCR assay targeting a fragment of the
Ehrlichia dsb gene. Ehrlichia DNA was not detected in any tick, capybara or human samples. In contrast, 4 out of 5 dogs contained
Ehrlichia canis DNA in their blood, which were sequenced, representing the first report of
E. canis infecting dogs in the Amazon region of Brazil. Further studies are needed to evaluate the presence of other agents of human and animal ehrlichioses in Brazil.
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