CD4 mimetics sensitize HIV-1-infected cells to ADCC Richard, Jonathan; Veillette, Maxime; Brassard, Nathalie ...
Proceedings of the National Academy of Sciences - PNAS,
05/2015, Letnik:
112, Številka:
20
Journal Article
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Odprti dostop
Significance The prevention of HIV-1 transmission and progression likely requires approaches that can specifically eliminate HIV-1-infected cells. Rationally designed CD4-mimetic compounds (CD4mc) ...have been shown to efficiently inhibit viral entry and sensitize HIV-1 particles to neutralization by otherwise nonneutralizing CD4-induced antibodies. Here we found that CD4mc can also sensitize HIV-1-infected cells to antibody-dependent cell-mediated cytotoxicity (ADCC). Indeed, CD4mc induced the CD4-bound conformation of HIV-1 envelope glycoproteins, exposing CD4-induced epitopes recognized by easy-to-elicit antibodies present in sera, cervicovaginal lavages, and breast milk from HIV-1-infected individuals. Importantly, we provide evidence that CD4mc can efficiently sensitize primary CD4 T cells from HIV-1-infected individuals to ADCC mediated by autologous sera and effector cells. Therefore, CD4mc might represent an attractive approach to prevent and control HIV-1 infection.
HIV-1-infected cells presenting envelope glycoproteins (Env) in the CD4-bound conformation on their surface are preferentially targeted by antibody-dependent cell-mediated cytotoxicity (ADCC). HIV-1 has evolved a sophisticated mechanism to avoid exposure of ADCC-mediating Env epitopes by down-regulating CD4 and by limiting the overall amount of Env at the cell surface. Here we report that small-molecule CD4-mimetic compounds induce the CD4-bound conformation of Env, and thereby sensitize cells infected with primary HIV-1 isolates to ADCC mediated by antibodies present in sera, cervicovaginal lavages, and breast milk from HIV-1-infected individuals. Importantly, we identified one CD4 mimetic with the capacity to sensitize endogenously infected ex vivo-amplified primary CD4 T cells to ADCC killing mediated by autologous sera and effector cells. Thus, CD4 mimetics hold the promise of therapeutic utility in preventing and controlling HIV-1 infection.
•What is the primary question addressed by this study?Mental healthcare disparities are routinely documented, yet they remain wider than in most other areas of healthcare services and common mental ...disorders (depression and anxiety) remain as one of the highest health burdens for older people of color.•What is the main finding of this study?Although mental health disorders do not discriminate based on race, ethnicity, or age, older people of color face a disproportionate number of challenges across the care mental healthcare continuum due to internalized, interpersonal, systemic, and medical racism.•What is the meaning of the finding?To better support older African American, Asian American, and Latino individuals living with or at increased susceptibility for mental health concerns, it is imperative that researchers, clinicians, and policymakers acknowledge the realities of racism and discrimination as leading causes of mental healthcare disparities and work collaboratively across disciplines to create, implement, and evaluate culturally-tailored interventions that acknowledge the diverse needs of these often-overlooked populations.
Mental healthcare disparities are routinely documented, yet they remain wider than in most other areas of healthcare services and common mental disorders (depression and anxiety) continue to be one of the highest health burdens for older people of color. To address disparities in mental health services for older people of color, the narrative must move beyond simply documenting these inequities and attain a better understanding of the internalized, interpersonal, systemic, and medical racism that have harmed these communities and excluded them from its services in the first place. It is imperative that researchers, clinicians, and policymakers acknowledge the realities of racism and discrimination as leading causes of mental healthcare disparities. Therefore, this review is a call-to-action. Authors adopt an antiracist and health equity lens in evaluating the differing needs of Blacks/African-Americans, Asian Americans, and Latinos by exploring psychiatric comorbidity, experiences with seeking, accessing, and engaging in treatment, and the unique cultural and psychosocial factors that affect treatment outcomes for these diverse groups. Further, authors offer researchers and practitioners tangible tools for developing and implementing culturally-sensitive, mental health focused interventions for older people of color with special attention placed on cultural adaptations, models of care, prevention, and practical strategies that can be implemented to reduce disparities and increase equity in mental healthcare.
Cardiovascular disease (CVD) is common and overall graft survival is suboptimal among kidney transplant recipients. Although albuminuria is a known risk factor for adverse outcomes among persons with ...native chronic kidney disease, the relationship of albuminuria with cardiovascular and kidney outcomes in transplant recipients is uncertain.
Post hoc longitudinal cohort analysis of the Folic Acid for Vascular Outcomes Reduction in Transplantation (FAVORIT) Trial.
Stable kidney transplant recipients with elevated homocysteine levels from 30 sites in the United States, Canada, and Brazil.
Urine albumin-creatinine ratio (ACR) at randomization.
Allograft failure, CVD, and all-cause death.
Multivariable Cox models adjusted for age; sex; race; randomized treatment allocation; country; systolic and diastolic blood pressure; history of CVD, diabetes, and hypertension; smoking; cholesterol; body mass index; estimated glomerular filtration rate (eGFR); donor type; transplant vintage; medications; and immunosuppression.
Among 3,511 participants with complete data, median ACR was 24 (Q1-Q3, 9-98) mg/g, mean eGFR was 49±18 (standard deviation) mL/min/1.73m2, mean age was 52±9 years, and median graft vintage was 4.1 (Q1-Q3, 1.7-7.4) years. There were 1,017 (29%) with ACR < 10mg/g, 912 (26%) with ACR of 10 to 29mg/g, 1,134 (32%) with ACR of 30 to 299mg/g, and 448 (13%) with ACR ≥ 300mg/g. During approximately 4 years, 282 allograft failure events, 497 CVD events, and 407 deaths occurred. Event rates were higher at both lower eGFRs and higher ACR. ACR of 30 to 299 and ≥300mg/g relative to ACR < 10mg/g were independently associated with graft failure (HRs of 3.40 95% CI, 2.19-5.30 and 9.96 95% CI, 6.35-15.62, respectively), CVD events (HRs of 1.25 95% CI, 0.96-1.61 and 1.55 95% CI, 1.13-2.11, respectively), and all-cause death (HRs of 1.65 95% CI, 1.23-2.21 and 2.07 95% CI, 1.46-2.94, respectively).
No data for rejection; single ACR assessment.
In a large population of stable kidney transplant recipients, elevated baseline ACR is independently associated with allograft failure, CVD, and death. Future studies are needed to evaluate whether reducing albuminuria improves these outcomes.
Abstract
SN 2018aoz is a Type Ia SN with a
B
-band plateau and excess emission in infant-phase light curves ≲1 day after the first light, evidencing an over-density of surface iron-peak elements as ...shown in our previous study. Here, we advance the constraints on the nature and origin of SN 2018aoz based on its evolution until the nebular phase. Near-peak spectroscopic features show that the SN is intermediate between two subtypes of normal Type Ia: core normal and broad line. The excess emission may be attributable to the radioactive decay of surface iron-peak elements as well as the interaction of ejecta with either the binary companion or a small torus of circumstellar material. Nebular-phase limits on H
α
and He
i
favor a white dwarf companion, consistent with the small companion size constrained by the low early SN luminosity, while the absence of O
i
and He
i
disfavors a violent merger of the progenitor. Of the two main explosion mechanisms proposed to explain the distribution of surface iron-peak elements in SN 2018aoz, the asymmetric Chandrasekhar-mass explosion is less consistent with the progenitor constraints and the observed blueshifts of nebular-phase Fe
ii
and Ni
ii
. The helium-shell double-detonation explosion is compatible with the observed lack of C spectral features, but current 1D models are incompatible with the infant-phase excess emission,
B
max
–
V
max
color, and weak strength of nebular-phase Ca
ii
. Although the explosion processes of SN 2018aoz still need to be more precisely understood, the same processes could produce a significant fraction of Type Ia SNe that appear to be normal after ∼1 day.
Single nucleotide polymorphism (SNP) genotyping provides the means to develop a practical, rapid, inexpensive assay that will uniquely identify any Plasmodium falciparum parasite using a small amount ...of DNA. Such an assay could be used to distinguish recrudescence from re-infection in drug trials, to monitor the frequency and distribution of specific parasites in a patient population undergoing drug treatment or vaccine challenge, or for tracking samples and determining purity of isolates in the laboratory during culture adaptation and sub-cloning, as well as routine passage.
A panel of twenty-four SNP markers has been identified that exhibit a high minor allele frequency (average MAF > 35%), for which robust TaqMan genotyping assays were constructed. All SNPs were identified through whole genome sequencing and MAF was estimated through Affymetrix array-based genotyping of a worldwide collection of parasites. These assays create a "molecular barcode" to uniquely identify a parasite genome.
Using 24 such markers no two parasites known to be of independent origin have yet been found to have the same allele signature. The TaqMan genotyping assays can be performed on a variety of samples including cultured parasites, frozen whole blood, or whole blood spotted onto filter paper with a success rate > 99%. Less than 5 ng of parasite DNA is needed to complete a panel of 24 markers. The ability of this SNP panel to detect and identify parasites was compared to the standard molecular methods, MSP-1 and MSP-2 typing.
This work provides a facile field-deployable genotyping tool that can be used without special skills with standard lab equipment, and at reasonable cost that will unambiguously identify and track P. falciparum parasites both from patient samples and in the laboratory.
This paper is concerned with using multivariate binary observations to estimate the probabilities of unobserved classes with scientific meanings. We focus on the setting where additional information ...about sample similarities is available and represented by a rooted weighted tree. Every leaf in the given tree contains multiple samples. Shorter distances over the tree between the leaves indicate a priori higher similarity in class probability vectors. We propose a novel data integrative extension to classical latent class models with tree‐structured shrinkage. The proposed approach enables (1) borrowing of information across leaves, (2) estimating data‐driven leaf groups with distinct vectors of class probabilities, and (3) individual‐level probabilistic class assignment given the observed multivariate binary measurements. We derive and implement a scalable posterior inference algorithm in a variational Bayes framework. Extensive simulations show more accurate estimation of class probabilities than alternatives that suboptimally use the additional sample similarity information. A zoonotic infectious disease application is used to illustrate the proposed approach. The paper concludes by a brief discussion on model limitations and extensions.
Health care systems need effective models to manage chronic diseases like tobacco dependence across transitions in care. Hospitalizations provide opportunities for smokers to quit, but research ...suggests that hospital-delivered interventions are effective only if treatment continues after discharge.
To determine whether an intervention to sustain tobacco treatment after hospital discharge increases smoking cessation rates compared with standard care.
A randomized clinical trial compared sustained care (a postdischarge tobacco cessation intervention) with standard care among 397 hospitalized daily smokers (mean age, 53 years; 48% were males; 81% were non-Hispanic whites) who wanted to quit smoking after discharge and received a tobacco dependence intervention in the hospital; 92% of eligible patients and 44% of screened patients enrolled. The study was conducted from August 2010 through November 2012 at Massachusetts General Hospital.
Sustained care participants received automated interactive voice response telephone calls and their choice of free smoking cessation medication (any type approved by the US Food and Drug Administration) for up to 90 days. The automated telephone calls promoted cessation, provided medication management, and triaged smokers for additional counseling. Standard care participants received recommendations for postdischarge pharmacotherapy and counseling.
The primary outcome was biochemically confirmed past 7-day tobacco abstinence at 6-month follow-up after discharge from the hospital; secondary outcomes included self-reported tobacco abstinence.
Smokers randomly assigned to sustained care (n = 198) used more counseling and more pharmacotherapy at each follow-up assessment than those assigned to standard care (n = 199). Biochemically validated 7-day tobacco abstinence at 6 months was higher with sustained care (26%) than with standard care (15%) (relative risk RR, 1.71 95% CI, 1.14-2.56, P = .009; number needed to treat, 9.4 95% CI, 5.4-35.5). Using multiple imputation for missing outcomes, the RR for 7-day tobacco abstinence was 1.55 (95% CI, 1.03-2.21; P = .04). Sustained care also resulted in higher self-reported continuous abstinence rates for 6 months after discharge (27% vs 16% for standard care; RR, 1.70 95% CI, 1.15-2.51; P = .007).
Among hospitalized adult smokers who wanted to quit smoking, a postdischarge intervention providing automated telephone calls and free medication resulted in higher rates of smoking cessation at 6 months compared with a standard recommendation to use counseling and medication after discharge. These findings, if replicated, suggest an approach to help achieve sustained smoking cessation after a hospital stay.
clinicaltrials.gov Identifier: NCT01177176.
Although cancer is highly heterogeneous, all metastatic cancer is considered American Joint Committee on Cancer (AJCC) Stage IV disease. The purpose of this project was to redefine staging of ...metastatic cancer. Internal validation of nationally representative patient data from the National Cancer Database (n = 461 357; 2010-2013), and external validation using the Surveillance, Epidemiology and End Results database (n = 106 595; 2014-2015) were assessed using the concordance index for evaluation of survival prediction. A Cox proportional hazards model was used for overall survival by considering identified phenotypes (latent classes) and other confounding variables. Latent class analysis was performed for phenotype identification, where Bayesian information criterion (BIC) and sample-size-adjusted BIC were used to select the optimal number of distinct clusters. Kappa coefficients assessed external cluster validation. Latent class analysis identified five metastatic phenotypes with differences in overall survival (P < .0001): (Stage IVA) nearly exclusive bone-only metastases (n = 59 049, 12.8%; median survival 12.7 months; common in lung, breast and prostate cancers); (IVB) predominant lung metastases (n = 62 491, 13.5%; 11.4 months; common in breast, stomach, kidney, ovary, uterus, thyroid, cervix and soft tissue cancers); (IVC) predominant liver/lung metastases (n = 130 014, 28.2%; 7.0 months; common in colorectum, pancreatic, lung, esophagus and stomach cancers); (IVD) bone/liver/lung metastases predominant over brain (n = 61 004, 13.2%; 5.9 months; common in lung and breast cancers); and (IVE) brain/lung metastases predominant over bone/liver (n = 148 799, 32.3%; 5.7 months; lung cancer and melanoma). Long-term survivors were identified, particularly in Stages IVA-B. A pan-cancer nomogram model to predict survival (STARS: site, tumor, age, race, sex) was created, validated and provides 13% better prognostication than AJCC: 1-month concordance index of 0.67 (95% confidence interval CI: 0.66-0.67) vs 0.61 (95% CI: 0.60-0.61). STARS is simple, uses easily accessible variables, better prognosticates survival outcomes and provides a platform to develop novel metastasis-directed clinical trials.
We report the scalable growth of aligned graphene and hexagonal boron nitride on commercial copper foils, where each film originates from multiple nucleations yet exhibits a single orientation. ...Thorough characterization of our graphene reveals uniform crystallographic and electronic structures on length scales ranging from nanometers to tens of centimeters. As we demonstrate with artificial twisted graphene bilayers, these inexpensive and versatile films are ideal building blocks for large-scale layered heterostructures with angle-tunable optoelectronic properties.
Bromus tectorum (cheatgrass) has successfully invaded and established throughout the western United States. Bromus tectorum grows early in the season and this early growth allows B. tectorum to ...outcompete native species, which has led to dramatic shifts in ecosystem function and plant community composition after B. tectorum invades. If the phenology of native species is unable to track changing climate as effectively as B. tectorum’s phenology then climate change may facilitate further invasion. To better understand how B. tectorum phenology will respond to future climate, we tracked the timing of B. tectorum germination, flowering, and senescence over a decade in three in situ climate manipulation experiments with treatments that increased temperatures (2°C and 4°C above ambient), altered precipitation regimes, or applied a combination of each. Linear mixed-effects models were used to analyze treatment effects on the timing of germination, flowering, senescence, and on the length of the vegetative growing season (time from germination to flowering) in each experiment. Altered precipitation treatments were only applied in early years of the study and neither precipitation treatments nor the treatments’ legacies significantly affected B. tectorum phenology. The timing of germination did not significantly vary between any warming treatments and their respective ambient plots. However, plots that were warmed had advances in the timing of B. tectorum flowering and senescence, as well as shorter vegetative growing seasons. The phenological advances caused by warming increased with increasing degrees of experimental warming. The greatest differences between warmed and ambient plots were seen in the length of the vegetative growing season, which was shortened by approximately 12 and 7 days in the +4°C and +2°C warming levels, respectively. The effects of experimental warming were small compared to the effects of interannual climate variation, suggesting that interactive controls and the timing of multiple climatic factors are important in determining B. tectorum phenology. Taken together, these results help elucidate how B. tectorum phenology may respond to future climate, increasing our predictive capacity for estimating when to time B. tectorum control efforts and how to more effectively manage this exotic annual grass.
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