Peptides and biologics provide unique opportunities to modulate intracellular targets not druggable by conventional small molecules. Most peptides and biologics are fused with cationic uptake ...moieties or formulated into nanoparticles to facilitate delivery, but these systems typically lack potency due to low uptake and/or entrapment and degradation in endolysosomal compartments. Because most delivery reagents comprise cationic lipids or polymers, there is a lack of reagents specifically optimized to deliver cationic cargo. Herein, we demonstrate the utility of the cytocompatible polymer poly(propylacrylic acid) (PPAA) to potentiate intracellular delivery of cationic biomacromolecules and nano-formulations. This approach demonstrates superior efficacy over all marketed peptide delivery reagents and enhances delivery of nucleic acids and gene editing ribonucleoproteins (RNPs) formulated with both commercially-available and our own custom-synthesized cationic polymer delivery reagents. These results demonstrate the broad potential of PPAA to serve as a platform reagent for the intracellular delivery of cationic cargo.
The epidemiology and prognostic impact of increased pulmonary pressure among HIV-infected individuals in the antiretroviral therapy era is not well described.
To examine the prevalence, clinical ...features, and outcomes of increased echocardiographic pulmonary pressure in HIV-infected and -uninfected individuals.
This study evaluated 8,296 veterans referred for echocardiography with reported pulmonary artery systolic pressure (PASP) estimates from the Veterans Aging Cohort study, an observational cohort of HIV-infected and -uninfected veterans matched by age, sex, race/ethnicity, and clinical site. The primary outcome was adjusted mortality by HIV status.
PASP was reported in 2,831 HIV-infected and 5,465 HIV-uninfected veterans (follow-up mean ± SD, 3.8 ± 2.6 yr). As compared with uninfected veterans, HIV-infected veterans with HIV viral load greater than 500 copies/ml (odds ratio, 1.27; 95% confidence interval CI, 1.05-1.54) and those with CD4 cell count less than 200 cells/μl (odds ratio, 1.28; 95% CI, 1.02-1.60) had a higher prevalence of PASP greater than or equal to 40 mm Hg. As compared with uninfected veterans with a PASP less than 40 mm Hg, HIV-infected veterans with a PASP greater than or equal to 40 mm Hg had an increased risk of death (adjusted hazard ratio, 1.78; 95% CI, 1.57-2.01). This risk persisted even among participants without prevalent comorbidities (adjusted hazard ratio, 3.61; 95% CI, 2.17-6.01). The adjusted risk of mortality in HIV-infected veterans was higher at all PASP values than in uninfected veterans, including at values currently considered to be normal.
HIV-infected people with high HIV viral loads or low CD4 cell counts have a higher prevalence of increased PASP than uninfected people. Mortality risk in HIV-infected veterans increases at lower values of PASP than previously recognized and is present even among those without prevalent comorbidities. These findings may inform clinical decision-making regarding screening and surveillance of pulmonary hypertension in HIV-infected individuals.
Intervention: Critical physical geography Lave, Rebecca; Wilson, Matthew W.; Barron, Elizabeth S. ...
The Canadian geographer,
03/2014, Letnik:
58, Številka:
1
Journal Article
Recenzirano
A recent opinion piece rekindled debate as to whether geography's current interdisciplinary make‐up is a historical relic or an actual and potential source of intellectual vitality. Taking the latter ...position, we argue here for the benefits of sustained integration of physical and critical human geography. For reasons both political and pragmatic, we term this area of intermingled research and practice critical physical geography (CPG). CPG combines critical attention to power relations with deep knowledge of biophysical science or technology in the service of social and environmental transformation. We argue that whether practiced by individuals or teams, CPG research can improve the intellectual quality and expand the political relevance of both physical and critical human geography because it is increasingly impractical to separate analysis of natural and social systems: socio‐biophysical landscapes are as much the product of unequal power relations, histories of colonialism, and racial and gender disparities as they are of hydrology, ecology, and climate change. Here, we review existing CPG work; discuss the primary benefits of critically engaged integrative research, teaching, and practice; and offer our collective thoughts on how to make CPG work.
Résumé
Un article d'opinion paru récemment est à l'origine de la relance d'un débat qui pose la question à savoir si le fondement interdisciplinaire actuel de la géographie serait une relique historique ou une source réelle et potentielle de vitalité intellectuelle. En prenant la défense de la seconde position, nous militons en faveur des bénéfices découlant de l'intégration soutenue de la géographie physique et de la géographie humaine critique. Pour des raisons à la fois politiques et pragmatiques, nous avons nommé ce domaine de recherche et de pratique enchevêtré la géographie physique critique (GPC). C'est au service de la transformation sociale et environnementale que la GPC intègre un regard critique sur les relations de pouvoir à la connaissance profonde de la science ou de la technologie biophysique. Que se soient des individus ou des équipes qui la pratiquent, les travaux de recherche en GPC peuvent contribuer à l'amélioration de la qualité intellectuelle et à l'élargissement de la pertinence politique de la géographie humaine critique et géographie physique, compte tenu que la séparation de l'analyse des systèmes naturels et des systèmes sociaux pose des difficultés d'ordre pratique. À l'origine des paysages sociobiophysiques se trouvent autant les relations inégales de pouvoir, les histoires de colonialisme et les disparités raciales et entre les sexes que l'hydrologie, l'écologie et les changements climatiques. Dans cette partie de l'article, nous passons en revue les travaux actuels en GPC, nous engageons une discussion sur les principaux avantages des approches intégratives et véritablement critiques en recherche, dans l'enseignement et dans la pratique, et nous proposons nos réflexions collectives sur la façon d'appliquer la GPC.
The persistence of a pool of latently HIV-1-infected cells despite combination anti-retroviral therapy treatment is the major roadblock for a cure. The BAF (mammalian SWI/SNF) chromatin remodeling ...complex is involved in establishing and maintaining viral latency, making it an attractive drug target for HIV-1 latency reversal. Here we report a high-throughput screen for inhibitors of BAF-mediated transcription in cells and the subsequent identification of a 12-membered macrolactam. This compound binds ARID1A-specific BAF complexes, prevents nucleosomal positioning, and relieves transcriptional repression of HIV-1. Through this mechanism, these compounds are able to reverse HIV-1 latency in an in vitro T cell line, an ex vivo primary cell model of HIV-1 latency, and in patient CD4+ T cells without toxicity or T cell activation. These macrolactams represent a class of latency reversal agents with unique mechanism of action, and can be combined with other latency reversal agents to improve reservoir targeting.
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•HTS identifies a macrolactam that inhibits BAF transcriptional repression•The macrolactams are likely targeting specific ARID1A-containing BAF complexes•The macrolactams reverse HIV-1 latency and are non-toxic to T cells•The macrolactams can be combined with other latency reversal agents
The BAF (SWI/SNF) chromatin remodeling complex is involved in repressing HIV-1 transcription in latently infected T cells. Using high-throughput screening, we identified a macrolactam that inhibits ARID1A-containing BAF complexes to reverse HIV-1 latency without T cell activation or toxicity.
In order to investigate the mechanisms of cardiovascular disease in HIV infected and uninfected patients, an analysis of echocardiogram reports is required for a large longitudinal multi-center ...study.
A natural language processing system using a dictionary lookup, rules, and patterns was developed to extract heart function measurements that are typically recorded in echocardiogram reports as measurement-value pairs. Curated semantic bootstrapping was used to create a custom dictionary that extends existing terminologies based on terms that actually appear in the medical record. A novel disambiguation method based on semantic constraints was created to identify and discard erroneous alternative definitions of the measurement terms. The system was built utilizing a scalable framework, making it available for processing large datasets.
The system was developed for and validated on notes from three sources: general clinic notes, echocardiogram reports, and radiology reports. The system achieved F-scores of 0.872, 0.844, and 0.877 with precision of 0.936, 0.982, and 0.969 for each dataset respectively averaged across all extracted values. Left ventricular ejection fraction (LVEF) is the most frequently extracted measurement. The precision of extraction of the LVEF measure ranged from 0.968 to 1.0 across different document types.
This system illustrates the feasibility and effectiveness of a large-scale information extraction on clinical data. New clinical questions can be addressed in the domain of heart failure using retrospective clinical data analysis because key heart function measurements can be successfully extracted using natural language processing.
Abstract Background This study aims to assess the impact of healthy lifestyle on prostate cancer (PCa) risk in a diverse population. Methods Data for 281,923 men from the Million Veteran Program ...(MVP), a nationwide, health system–based cohort study, were analyzed. Self‐reported information at enrollment included smoking status, exercise, diet, family history of PCa, and race/ethnicity. Body mass index (BMI) was obtained from clinical records. Genetic risk was assessed via a validated polygenic score. Cox proportional hazards models were used to assess associations with PCa outcomes. Results After accounting for ancestry, family history, and genetic risk, smoking was associated with an increased risk of metastatic PCa (hazard ratio HR, 1.83; 95% confidence interval CI, 1.64–2.02; p < 10 −16 ) and fatal PCa (HR, 2.73; 95% CI, 2.36–3.25; p < 10 −16 ). Exercise was associated with a reduced risk of fatal PCa (HR, 0.86; 95% CI, 0.76–0.98; p = .03). Higher BMI was associated with a slightly reduced risk of fatal PCa, and diet score was not independently associated with any end point. Association with exercise was strongest among those who had nonmetastatic PCa at MVP enrollment. Absolute reductions in the risk of fatal PCa via lifestyle factors were greatest among men of African ancestry (1.7% for nonsmokers vs. 6.1% for smokers) or high genetic risk (1.4% for nonsmokers vs. 4.3% for smokers). Conclusions Healthy lifestyle is minimally related to the overall risk of developing PCa but is associated with a substantially reduced risk of dying from PCa. In multivariable analyses, both exercise and not smoking remain independently associated with reduced metastatic and fatal PCa.
In this Million Veteran Program study, exercise and not smoking are shown to be minimally related to the overall risk of developing prostate cancer but are associated with a substantially reduced risk of dying from prostate cancer.
Bone formation during fracture repair inevitably initiates within or around extravascular deposits of a fibrin-rich matrix. In addition to a central role in hemostasis, fibrin is thought to enhance ...bone repair by supporting inflammatory and mesenchymal progenitor egress into the zone of injury. However, given that a failure of efficient fibrin clearance can impede normal wound repair, the precise contribution of fibrin to bone fracture repair, whether supportive or detrimental, is unknown. Here, we employed mice with genetically and pharmacologically imposed deficits in the fibrin precursor fibrinogen and fibrin-degrading plasminogen to explore the hypothesis that fibrin is vital to the initiation of fracture repair, but impaired fibrin clearance results in derangements in bone fracture repair. In contrast to our hypothesis, fibrin was entirely dispensable for long-bone fracture repair, as healing fractures in fibrinogen-deficient mice were indistinguishable from those in control animals. However, failure to clear fibrin from the fracture site in plasminogen-deficient mice severely impaired fracture vascularization, precluded bone union, and resulted in robust heterotopic ossification. Pharmacological fibrinogen depletion in plasminogen-deficient animals restored a normal pattern of fracture repair and substantially limited heterotopic ossification. Fibrin is therefore not essential for fracture repair, but inefficient fibrinolysis decreases endochondral angiogenesis and ossification, thereby inhibiting fracture repair.
Reperfusion after ischemia causes additional cellular damage, known as reperfusion injury, for which there is still no effective remedy. Poloxamer (P)188, a tri-block copolymer-based cell membrane ...stabilizer (CCMS), has been shown to provide protection against hypoxia/reoxygenation (HR) injury in various models by reducing membrane leakage and apoptosis and improving mitochondrial function. Interestingly, substituting one of its hydrophilic poly-ethylene oxide (PEO) blocks with a (
)ert-butyl terminus added to the hydrophobic poly-propylene oxide (PPO) block yields a di-block compound (PEO-PPO
) that interacts better with the cell membrane lipid bi-layer and exhibits greater cellular protection than the gold standard tri-block P188 (PEO
-PPO
-PEO
). For this study, we custom-made three different new di-blocks (PEO
-PPO
, PEO
-PPO
and PEO
-PPO
) to systemically examine the effects of the length of each polymer block on cellular protection in comparison to P188. Cellular protection was assessed by cell viability, lactate dehydrogenase release, and uptake of FM1-43 in mouse artery endothelial cells (ECs) following HR injury. We found that di-block CCMS were able to provide the same or better EC protection than P188. Our study provides the first direct evidence that custom-made di-block CCMS can be superior to P188 in improving EC membrane protection, raising their potential in treating cardiac reperfusion injury.
The sustainability of marshes adjacent to coastal bays is driven by the exchange of sediment across the marsh-bay boundary, where edge erosion commonly leads to lateral marsh loss and enhanced ...vertical accretion. The timing and patterns of sediment deposition on salt marshes adjacent to larger bodies of water such as coastal bays, however, differ from those on better-studied tidal creek marshes primarily owing to the importance of wind-waves. We combined field measurements and modeling to examine controls on suspended sediment concentrations and fluxes on a tidal flat (tidal range of 1.2 m) and rates of sediment deposition on the adjacent marsh at a site on the Eastern Shore of Virginia. Suspended sediment concentrations over tidal flats were strongly controlled by waves. Yet, storm winds sufficient to drive large resuspension events often coincided with peak tidal elevations that were too low to flood the marsh, which was oriented away from the wind directions most favorable for storm surge, thereby restricting storm-driven, episodic sediment delivery to the marsh. Winds also drove wide variability in the direction of surface currents near the marsh edge when water depths were high enough to flood the marsh. Nevertheless, our results show that sediment in the upper water column over the tidal flat was effectively transported across the marsh edge during flooding tides. A sediment deposition model developed to investigate the combined effects of vegetation and wave action on depositional patterns predicted that waves displace maximum deposition inland from the marsh edge, consistent with measured deposition at the study site. Marsh deposition was sensitive to inundation frequency as well as the concentration of sediment in water flooding the marsh, underscoring the importance of nontidal controls on water surface elevation, such as meteorological effects (e.g., storm surge) and sea level rise. Whereas short-term increases in marsh inundation enhance deposition, sea level rise that results in deeper average water depths over the tidal flats decreases deposition if marsh elevation is rising in step with sea level.
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•Study includes 47 newly assembled Pooideae plastomes, 164 total Pooideae plastomes, and 313 Poaceae plastomes.•Estimates divergence date for Pooideae: 84.8 Mya (slightly older than ...recent estimates).•Examines alignment gaps, and how retained gaps can produce differing topologies in large, genome-scale analyses.
In this study, we analyzed 313 plastid genomes (plastomes) of Poaceae with a focus on expanding our current knowledge of relationships among the subfamily Pooideae, which represented over half the dataset (164 representatives). In total, 47 plastomes were sequenced and assembled for this study. This is the largest study of its kind to include plastome-level data, to not only increase sampling at both the taxonomic and molecular levels with the aim of resolving complex and reticulate relationships, but also to analyze the effects of alignment gaps in large-scale analyses, as well as explore divergences in the subfamily with an expanded set of 14 accepted grass fossils for more accurate calibrations and dating. Incorporating broad systematic assessments of Pooideae taxa conducted by authors within the last five years, we produced a robust phylogenomic reconstruction for the subfamily, which included all but two supergeneric taxa (Calothecinae and Duthieeae).
We further explored how including alignment gaps in plastome analyses oftentimes can produce incorrect or misinterpretations of complex or reticulate relationships among taxa of Pooideae. This presented itself as consistently changing relationships at specific nodes for different stripping thresholds (percentage-based removal of gaps per alignment column). Our summary recommendation for large-scale genomic plastome datasets is to strip alignment columns of all gaps to increase pairwise identity and reduce errant signal from poly A/T bias. To do this we used the “mask alignment” tool in Geneious software. Finally, we determined an overall divergence age for Pooideae of roughly 84.8 Mya, which is in line with, but slightly older than most recent estimates.
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