Despite antiretroviral therapy, proviral latency of human immunodeficiency virus type 1 (HIV-1) remains a principal obstacle to curing the infection. Inducing the expression of latent genomes within ...resting CD4(+) T cells is the primary strategy to clear this reservoir. Although histone deacetylase inhibitors such as suberoylanilide hydroxamic acid (also known as vorinostat, VOR) can disrupt HIV-1 latency in vitro, the utility of this approach has never been directly proven in a translational clinical study of HIV-infected patients. Here we isolated the circulating resting CD4(+) T cells of patients in whom viraemia was fully suppressed by antiretroviral therapy, and directly studied the effect of VOR on this latent reservoir. In each of eight patients, a single dose of VOR increased both biomarkers of cellular acetylation, and simultaneously induced an increase in HIV RNA expression in resting CD4(+) cells (mean increase, 4.8-fold). This demonstrates that a molecular mechanism known to enforce HIV latency can be therapeutically targeted in humans, provides proof-of-concept for histone deacetylase inhibitors as a therapeutic class, and defines a precise approach to test novel strategies to attack and eradicate latent HIV infection directly.
Context:
Inadequate vitamin D status is common within elderly populations and may be implicated in the etiology of autoimmune disease and inflammation. Few studies have investigated the relationship ...between vitamin D status and age-related immune dysfunction in humans.
Objective:
The aim of this study was to investigate the association between vitamin D status and immune markers of inflammation in a large sample of older adults.
Design, Setting, and Participants:
An observational investigation of 957 Irish adults (>60 years of age) recruited in Northern Ireland (55°N latitude) as part of the Trinity Ulster Department of Agriculture aging cohort study.
Main Outcome Measure:
We measured serum 25-hydroxyvitamin D (25(OH)D) by liquid chromatography tandem mass spectrometry and serum cytokines IL-6, TNF-α, IL-10, and C-reactive protein (CRP) by ELISA.
Results:
Concentrations of IL-6, CRP, and the ratios of IL-6 to IL-10 and CRP to IL-10 were significantly higher in individuals with deficient (<25 nmol/L) serum 25(OH)D compared with those with sufficient (>75 nmol/L) status after adjustment for age, sex, and body mass index (P < .05). Vitamin D status was a significant predictor of the IL-6 to IL-10 cytokine ratio, and those participants defined as deficient were significantly more likely to have an IL-6 to IL-10 ratio >2:1 compared with those defined as sufficient.
Conclusions:
This study demonstrated significant associations between low vitamin D status and markers of inflammation (including the ratio of IL-6 to IL-10) within elderly adults. These findings suggest that an adequate vitamin D status may be required for optimal immune function, particularly within the older adult population.
Entanglement is a fundamental property of quantum mechanics, and is a primary resource in quantum information systems. Its manipulation remains a central challenge in the development of quantum ...technology. In this work, we demonstrate a device which can generate, manipulate, and analyse two-qubit entangled states, using miniature and mass-manufacturable silicon photonics. By combining four photon-pair sources with a reconfigurable six-mode interferometer, embedding a switchable entangling gate, we generate two-qubit entangled states, manipulate their entanglement, and analyse them, all in the same silicon chip. Using quantum state tomography, we show how our source can produce a range of entangled and separable states, and how our switchable controlled-Z gate operates on them, entangling them or making them separable depending on its configuration.
Summary
In this cohort of community dwelling older adults (>60 years), we observed significant positive associations between the frequencies of yogurt intake with measures of bone density, bone ...biomarkers, and indicators of physical function. Improving yogurt intakes could be a valuable health strategy for maintaining bone health in older adults.
Introduction
The associations of yogurt intakes with bone health and frailty in older adults are not well documented. The aim was to investigate the association of yogurt intakes with bone mineral density (BMD), bone biomarkers, and physical function in 4310 Irish adults from the Trinity, Ulster, Department of Agriculture aging cohort study (TUDA).
Methods
Bone measures included total hip, femoral neck, and vertebral BMD with bone biochemical markers. Physical function measures included Timed Up and Go (TUG), Instrumental Activities of Daily Living Scale, and Physical Self-Maintenance Scale.
Results
Total hip and femoral neck BMD in females were 3.1–3.9% higher among those with the highest yogurt intakes (
n
= 970) compared to the lowest (
n
= 1109;
P
< 0.05) as were the TUG scores (−6.7%;
P
= 0.013). In males, tartrate-resistant acid phosphatase (TRAP 5b) concentrations were significantly lower in those with the highest yogurt intakes (−9.5%;
P
< 0.0001). In females, yogurt intake was a significant positive predictor of BMD at all regions. Each unit increase in yogurt intake in females was associated with a 31% lower risk of osteopenia (OR 0.69; 95% CI 0.49–0.96;
P
= 0.032) and a 39% lower risk of osteoporosis (OR 0.61; 95% CI 0.42–0.89;
P
= 0.012) and in males, a 52% lower risk of osteoporosis (OR 0.48; 95% CI 0.24–0.96;
P
= 0.038).
Conclusion
In this cohort, higher yogurt intake was associated with increased BMD and physical function scores. These results suggest that improving yogurt intakes could be a valuable public health strategy for maintaining bone health in older adults.
Viral replication and latently infected cellular reservoirs persist in HIV-infected patients achieving undetectable plasma virus levels with potent antiretroviral therapy. We exploited a predictable ...drug resistance mutation in the HIV reverse transcriptase to label and track cells infected during defined intervals of treatment and to identify cells replenished by ongoing replication. Decay rates of subsets of latently HIV-infected cells paradoxically decreased with time since establishment, reflecting heterogeneous lymphocyte activation and clearance. Residual low-level replication can replenish cellular reservoirs; however, it does not account for prolonged clearance rates in patients without detectable viremia. In patients receiving potent antiretroviral therapy, the latent pool has a heterogeneous and dynamic composition that comprises a progressively increasing proportion of stable lymphocytes. Eradication will not be achieved with complete inhibition of viral replication alone.
Background. A single dose of the histone deacetylase inhibitor vorinostat (VOR) up-regulates HIV RNA expression within resting CD4⁺ T cells of treated, aviremic human immunodeficiency virus ...(HIV)-positive participants. The ability of multiple exposures to VOR to repeatedly disrupt latency has not been directly measured, to our knowledge. Methods. Five participants in whom resting CD4⁺ T-cell-associated HIV RNA (rc-RNA) increased after a single dose of VOR agreed to receive daily VOR Monday through Wednesday for 8 weekly cycles. VOR serum levels, peripheral blood mononudear cell histone acetylation, plasma HIV RNA single-copy assays, rc-RNA, total cellular HIV DNA, and quantitative viral outgrowth assays from resting CD4⁺ T cells were assayed. Results. VOR was well tolerated, with exposures within expected parameters. However, rc-RNA measured after dose 11 (second dose of cycle 4) or dose 22 (second dose of cycle 8) increased significantly in only 3 of the 5 participants, and the magnitude of the rc-RNA increase was much reduced compared with that after a single dose. Changes in histone acetylation were blunted. Results of quantitative viral outgrowth and other assays were unchanged. Conclusions. Although HIV latency is disrupted by an initial VOR dose, the effect of subsequent doses in this protocol was much reduced. We hypothesize that the global effect of VOR results in a refractory period of ≥24 hours. The optimal schedule for VOR administration is still to be defined.
High precision measurements in various applications rely on active seismic isolation to decouple the experiment from seismic motion; therefore, closed feed-back control techniques such as sensor ...blending and sensor correction are commonly implemented. This paper reviews the active isolation techniques of the Albert Einstein Institute seismic attenuation system (AEI-SAS). Two approaches to improve the well known techniques are presented. First, the influence of the sensor basis for the signal-to-noise ratio in the chosen coordinate system is calculated and second, a procedural optimization of blending filters to minimize the optical table velocity is performed. Active isolation techniques are adapted to the mechanical properties and the available sensors and actuators of the AEI-SAS. The performance of the final isolation is presented and limitations to the isolation are analyzed in comparison to a noise model. The optical table motion reaches approximately 8 × 1 0 − 10 m / H z at 1 Hz, reducing the ground motion by a factor of approximately 100.
Background
Consumption of dairy products has been associated with positive health outcomes including a lower risk of hypertension, improved bone health and a reduction in the risk of type 2 diabetes. ...The suggested dairy intake for health in older adults is three servings per day but recent analysis of the NHANES data for older adults reported 98% were not meeting these recommendations. No studies have investigated the consequences of such declines in the dairy intakes of Irish older adults and the subsequent effects on vitamin micronutrient status.
Objectives
To study the daily dairy intakes of older Irish adults and to examine how the frequency of dairy food consumption affects vitamin micronutrient status.
Methods
Participants (n 4,317) were from the Trinity Ulster Department of Agriculture (TUDA) Study, a large study of older Irish adults (aged >60 yrs) designed to investigate gene-nutrient interactions in the development of chronic diseases of aging. The daily intake portion for milk, cheese and yoghurt was calculated from food frequency questionnaire (FFQ) responses. Blood samples were analysed for vitamin biomarkers as follows: vitamin B12 (total serum cobalamin and holotranscobalamin (holoTC)), folate (red cell folate (RCF) and serum folate), vitamin B2 (erythrocyte glutathione reductase activation coefficient (EGRac)), vitamin B6 (serum pyridoxal phosphate) and vitamin D (serum 25(OH)D).
Results
The mean total reported dairy intake was 1.16 (SD 0.79) portions per day with males consuming significantly fewer total dairy portions compared to females (1.07 vs 1.21 respectively) (P<0.05). There was no significant difference in total daily dairy serving intakes by age decade (60-69, 70-79, >80 yrs). Overall, only 3.5% of the total population (n 151) achieved the recommended daily dairy intake of three or more servings per day. A significantly higher proportion of females (4%) compared to males (2.4%) met these dairy requirements (P=0.011). Blood concentrations of vitamin B12 biomarkers, RCF, vitamin B2 and vitamin B6 were significantly worse in those with the lowest tertile of dairy intake (0-0.71 servings) compared to those in the highest tertile (1.50-4.50 servings) (P<0.05).
Conclusion
This study found that more than 96% of the older adults sampled did not meet current daily dairy intake recommendations. The study is the largest to-date examining dairy intakes in older Irish adults, and provides evidence that daily dairy intakes (in particular yogurt) contribute significantly to the B-vitamin and vitamin D biomarker status of older adults. These results suggest that older adults who are already vulnerable to micronutrient inadequacies, are forgoing the nutritional advantages of vitamin-rich dairy products.
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