Bispecific antibodies promote natural killer cell-mediated elimination of HIV-1 reservoir cells.

The persistence of CD4+ T cells carrying latent human immunodeficiency virus-1 (HIV-1) proviruses is the main barrier to a cure. New therapeutics to enhance HIV-1-specific immune responses and clear infected cells will probably be necessary to achieve reduction of the latent reservoir. In the present study, we report two single-chain diabodies (scDbs) that target the HIV-1 envelope protein (Env) and the human type III Fcγ receptor (CD16). We show that the scDbs promoted robust and HIV-1-specific natural killer (NK) cell activation and NK cell-mediated lysis of infected cells. Cocultures of CD4+ T cells from people with HIV-1 on antiretroviral therapy (ART) with autologous NK cells and the scDbs resulted in marked elimination of reservoir cells that was dependent on latency reversal. Treatment of human interleukin-15 transgenic NSG mice with one of the scDbs after ART initiation enhanced NK cell activity and reduced reservoir size. Thus, HIV-1-specific scDbs merit further evaluation as potential therapeutics for clearance of the latent reservoir.

Replication-competent noninduced proviruses in the latent reservoir increase barrier to HIV-1 cure.

Antiretroviral therapy fails to cure HIV-1 infection because latent proviruses persist in resting CD4(+) T cells. T cell activation reverses latency, but <1% of proviruses are induced to release infectious virus after maximum in vitro activation. The noninduced proviruses are generally considered defective but have not been characterized. Analysis of 213 noninduced proviral clones from treated patients showed 88.3% with identifiable defects but 11.7% with intact genomes and normal long terminal repeat (LTR) function. Using direct sequencing and genome synthesis, we reconstructed full-length intact noninduced proviral clones and demonstrated growth kinetics comparable to reconstructed induced proviruses from the same patients. Noninduced proviruses have unmethylated promoters and are integrated into active transcription units. Thus, it cannot be excluded that they may become activated in vivo. The identification of replication-competent noninduced proviruses indicates that the size of the latent reservoir-and, hence, the barrier to cure-may be up to 60-fold greater than previously estimated.

Complex decay dynamics of HIV virions, intact and defective proviruses, and 2LTR circles following initiation of antiretroviral therapy.

In persons living with HIV-1 (PLWH) who start antiretroviral therapy (ART), plasma virus decays in a biphasic fashion to below the detection limit. The first phase reflects the short half-life (<1 d) of cells that produce most of the plasma virus. The second phase represents the slower turnover (t1/2 = 14 d) of another infected cell population, whose identity is unclear. Using the intact proviral DNA assay (IPDA) to distinguish intact and defective proviruses, we analyzed viral decay in 17 PLWH initiating ART. Circulating CD4+ T cells with intact proviruses include few of the rapidly decaying first-phase cells. Instead, this population initially decays more slowly (t1/2 = 12.9 d) in a process that largely represents death or exit from the circulation rather than transition to latency. This more protracted decay potentially allows for immune selection. After ∼3 mo, the decay slope changes, and CD4+ T cells with intact proviruses decay with a half-life of 19 mo, which is still shorter than that of the latently infected cells that persist on long-term ART. Two-long-terminal repeat (2LTR) circles decay with fast and slow phases paralleling intact proviruses, a finding that precludes their use as a simple marker of ongoing viral replication. Proviruses with defects at the 5' or 3' end of the genome show equivalent monophasic decay at rates that vary among individuals. Understanding these complex early decay processes is important for correct use of reservoir assays and may provide insights into properties of surviving cells that can constitute the stable latent reservoir.

Measuring the latent reservoir for HIV-1: Quantification bias in near full-length genome sequencing methods.

Antiretroviral therapy (ART) effectively inhibits HIV-1 replication but is not curative due to the persistence of a latent viral reservoir in resting CD4+ T cells. This reservoir is a major barrier to cure. Sequencing studies have revealed that the population of proviruses persisting in ART-treated individuals is dominated by defective proviruses that cannot give rise to viral rebound due to fatal defects including large deletions and APOBEC3-mediated hypermutation. Near full genome sequencing (nFGS) of individual proviruses is used in reservoir assays to provide an estimate of the fraction of proviruses that are intact. nFGS methods rely on a long-distance outer PCR capturing most (~9 kb) of the genome, followed by nested inner PCRs. The outer PCR is carried out at limit dilution, and interpretation of the results is based on the assumption that all proviruses are quantitatively captured. Here, we evaluate nFGS methods using the intact proviral DNA assay (IPDA), a multiplex digital droplet PCR assay that quantitates intact and defective proviruses with single molecule sensitivity using only short, highly efficient amplicons. We analyzed proviral templates of known sequence to avoid the additional complication of sequence polymorphism. With the IPDA, we quantitated molecular yields at each step of nFGS methods. We demonstrate that nFGS methods are inefficient and miss ~70% of full-length proviruses due to amplification failure at the initial outer PCR step. In contrast, proviruses with large internal deletions encompassing 70% of the genome can be quantitatively amplified under the same conditions. Accurate measurement of the latent reservoir of HIV-1 is essential for evaluating the efficacy of cure strategies, and the bias against full length proviruses in nFGS methods must be considered.

Compact and broadband silicon polarization splitter-rotator using adiabaticity engineering.

We propose and demonstrate a short and broadband silicon mode-conversion polarization splitter-rotator (PSR) consisting of a mode-conversion taper and an adiabatic coupler-based mode sorter both optimized by adiabaticity engineering (AE). AE is used to optimize the distribution of adiabaticity parameter over the length of the PSR, providing shortcut to adiabaticity at a shorter device length. The total length of the PSR is 85 µm. The design is compatible with standard silicon photonics platforms and requires only one patterning step. Fabricated PSR has a polarization cross talk of less than -20 dB over the entire O-band for the TE polarization and a polarization cross talk of less than -15 dB from 1267 to 1348 nm for the TM polarization. Overall, the PSR shows low polarization cross talk (-15 dB) over a bandwidth of 81 nm in the O-band. Cross-wafer measurements show that the PSR has good fabrication tolerance.

Diet quality from mid to late life and its association with physical frailty in late life in a cohort of Chinese adults.

BACKGROUND: It is unclear if improving diet quality after midlife could reduce the risk of physical frailty at late life. We aimed to associate changes in diet quality after midlife with physical frailty at late life. METHODS: Diet quality in 12,580 participants from the Singapore Chinese Health Study was assessed with the Dietary Approaches to Stop Hypertension (DASH) scores at baseline (1993-1998; mean age 53 years) and follow-up 3 (2014-2016; mean age 73 years). Physical frailty was assessed using the modified Cardiovascular Health Study phenotype at follow-up 3. Multivariable logistic regressions examined associations between DASH scores and physical frailty. RESULTS: Comparing participants in extreme quartiles of DASH scores, the odds ratios (OR) [95% confidence interval (CI)] for physical frailty were 0.85 (0.73,0.99) at baseline and 0.49 (0.41, 0.58) at follow-up 3. Compared to participants with consistently low DASH scores, participants with consistently high scores (OR 0.74, 95% CI: 0.59, 0.94) and those with > 10% increase in scores (OR 0.78, 95% CI: 0.64, 0.95) had lower odds of frailty. Compared to those in the lowest DASH tertiles at both time-points, significantly lower odds of physical frailty were observed in those who were in the highest DASH tertiles at both time points [0.59 (0.48, 0.73)], and in those who improved their scores from the lowest [0.68 (0.51, 0.91)] or second tertile at baseline [0.61 (0.48, 0.76)] to the highest tertile at follow-up 3. CONCLUSIONS: Maintaining a high diet quality or a substantial improvement in diet quality after midlife could lower the risk of physical frailty at late life.

Relation of preconception eating behaviours to dietary pattern trajectories and gestational weight gain from preconception to late pregnancy.

Studies examining preconception eating behaviours with longitudinal dietary patterns from preconception to late pregnancy as well as gestational weight gain (GWG) are limited. We derived dietary pattern trajectories from preconception to late-pregnancy, and related preconception eating behaviours to these trajectories and GWG. Preconception eating behaviours were assessed using the Three-Factor Eating Questionnaire measuring cognitive restraint (CR) - conscious restriction of food intake, emotional eating (EE) - overeating in response to negative emotions, and uncontrolled eating (UE) - overeating with a feeling of lack of control. Dietary intakes were measured at preconception, 20-21 and 34-36 weeks' gestation with food frequency questionnaires. Dietary patterns were determined using factor analysis, and trajectories derived using group-based trajectory modelling. Inadequate and excessive GWG were defined according to Institute of Medicine guidelines based on weights at preconception and the last antenatal visit (median: 38 weeks' gestation). Two dietary patterns were derived: 'Fast Food, Fried Snacks and Desserts (FFD)' and 'Soup, Fish and Vegetables (SFV)'. Adherence trajectories from preconception to late-pregnancy were characterised as consistently high ("stable-high") and low ("stable-low"). Women with higher UE scores had higher odds of being in the "stable-high" trajectory (n = 34) of the FFD pattern [Odds Ratio (OR): 1.25, 95% Confidence Interval (CI): 1.03, 1.51], compared to "stable-low" (n = 260). Percentages of women with inadequate, adequate or excessive GWG were 21.7% (n = 70), 25.8% (n = 83), and 52.5% (n = 169), respectively; women with higher EE scores had a higher likelihood of excessive GWG [Relative Risk Ratio (RRR): 1.35, 95% CI: 1.02, 1.80], but this association was attenuated after adjusting for preconception body mass index. Eating behaviour interventions to improve dietary patterns among pregnant women may need to start as early as preconception, incorporating strategies to manage UE.

Co-expression and interaction network analysis identifies neutrophil-related genes as the core mediator of atrial fibrillation.

Atrial fibrillation (AF) is the most common cardiac arrhythmia and can cause serious complications. Several studies have shown that neutrophils may influence AF progression. However, the key genes related to neutrophils in AF have not been fully elucidated. Here, we downloaded microarray expression data of AF, and screened differentially expressed genes. Key immune cells in AF were identified by immune cell infiltration analysis. Weighted gene co-expression network analysis (WGCNA) and protein-protein interaction (PPI) analysis were used to construct gene co-expression modules and identify hub genes. The association between key genes and neutrophils was then verified. Our results showed that 303 differentially expressed genes (DEGs) were screened in AF and sinus rhythm (SR), of which 194 were up-regulated and 109 were down-regulated. DEGs were mainly enriched in functions and pathways of neutrophil activation and biological functions of neutrophil activation-mediated immune response. Immune infiltration analysis revealed elevated levels of neutrophil infiltration in AF. WGCNA analysis revealed that the modules in dark red were associated with neutrophils. PPI analysis of these modules yielded 10 hub genes. S100A12, FCGR3B and S100A8 are 3 potential key genes related to neutrophils in AF, which are significantly positively correlated with neutrophils. These genes deserve further investigation and may be potential therapeutic targets for AF.

SlERF.H6 mediates the orchestration of ethylene and gibberellin signaling that suppresses bitter-SGA biosynthesis in tomato.

Steroidal glycoalkaloids (SGAs) constitute a characteristic class of antinutritional metabolites that are found in certain Solanum species. Despite the considerable studies on SGA biosynthesis, the mechanisms of crosstalk between hormone signaling pathways that regulate SGA content still remain to be elucidated. Here, we performed a metabolic genome-wide association study (mGWAS) based on the levels of SGA metabolites and identified SlERF.H6 as a negative regulator of bitter-SGA biosynthesis. SlERF.H6 repressed the expression of SGA biosynthetic glycoalkaloid metabolism (GAME) genes and caused a subsequent decrease in the abundance of bitter SGAs. Furthermore, SlERF.H6 were shown to act downstream of GAME9, a regulator of SGA biosynthesis in tomato. We also uncovered the interplay between ethylene and gibberellin (GA) signaling in regulating SGA biosynthesis. SlERF.H6, acting as a downstream component in ethylene signaling, modulated GA content by inhibiting SlGA2ox12 expression. Increasing levels of endogenous GA12 and GA53 in SlERF.H6-OE could inhibit of GA on SGA biosynthesis. Additionally, 1-aminocyclopropane-1-carboxylic acid (ACC) treatment decreased the stability of SlERF.H6, weakening its inhibition on GAME genes and SlGA2ox12, and caused bitter-SGA accumulation. Our findings reveal a key role of SlERF.H6 in the regulation of SGA biosynthesis through the coordinated ethylene-gibberellin signaling.

Parvularcula maris sp. nov., an algicidal bacterium isolated from seawater.

A taxonomic study was carried out on strain BGMRC 0090T, which was isolated from seawater. The isolate was a Gram-negative, aerobic, flagellated, rod-shaped bacterium with algicidal activity. Optimal growth was observed at 30 °C, pH 6.0 and with 2 % (w/v) NaCl. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain BGMRC 0090T belonged to the genus Parvularcula, with highest sequence similarity to Parvularcula lutaonensis CC-MMS-1T (98.4 %). Average nucleotide identity, amino acid identity and digital DNA-DNA hybridization values between strain BGMRC 0090T and five strains of the genus Parvularcula with publicly available genomes were below 84.0, 69.2 and 21.4 %, respectively. The genome of strain BGMRC 0090T was 3.2 Mb with 64.8 mol% DNA G+C content and encoded 2905 predicted proteins, three rRNA, 42 tRNA and four ncRNA genes. Some algicidal biosynthesis-associated genes were detected in the genome. Strain BGMRC 0090T contained Q-10 as the major quinone. The predominant fatty acids were identified as summed feature 8 (C18 : 1ω7c/ω6c) and C16 : 0. Based on the polyphasic evidence presented in this paper, strain BGMRC 0090T is concluded to represent a novel species of the genus Parvularcula, for which the name Parvularcula maris sp. nov. is proposed. The type strain is BGMRC 0090T (= KCTC 92591T=MCCC 1K08100T).

Tellurium-Doped 0D Organic-Inorganic Hybrid Lead-Free Perovskite for X-ray Imaging.

The application of X-ray imaging in military, industrial flaw detection, and medical examination is inseparable from the wide application of scintillator materials. In order to substitute for lead, lower costs, and reduce self-absorption, organic-inorganic hybrid lead-free perovskite scintillators are emerging as a new option. In this work, novel (TEA)2Zr1-xTexCl6 perovskite microcrystals (MCs) were successfully synthesized by a hydrothermal method, with Te4+ doping, which leads to yellow triplet-state self-trapped excitons emission. The emission peak of (TEA)2Zr1-xTexCl6 located at 605 nm under X-ray excitation, which was applied to X-ray imaging, shows a clear wiring structure inside the USB connector. The detection limit (DL) of 820 nGyair/s for (TEA)2Zr0.9Te0.1Cl6 is well below the dose rate corresponding to a standard medical X-ray diagnosis is 5.5 µGyair/s. This work opens up a new path for organic-inorganic hybrid lead-free scintillators.

A Possible Sterilizing Cure of HIV-1 Infection Without Stem Cell Transplantation.

BACKGROUND: A sterilizing cure of HIV-1 infection has been reported in 2 persons living with HIV-1 who underwent allogeneic hematopoietic stem cell transplantations from donors who were homozygous for the CCR5Δ32 gene polymorphism. However, this has been considered elusive during natural infection. OBJECTIVE: To evaluate persistent HIV-1 reservoir cells in an elite controller with undetectable HIV-1 viremia for more than 8 years in the absence of antiretroviral therapy. DESIGN: Detailed investigation of virologic and immunologic characteristics. SETTING: Tertiary care centers in Buenos Aires, Argentina, and Boston, Massachusetts. PATIENT: A patient with HIV-1 infection and durable drug-free suppression of HIV-1 replication. MEASUREMENTS: Analysis of genome-intact and replication-competent HIV-1 using near-full-length individual proviral sequencing and viral outgrowth assays, respectively; analysis of HIV-1 plasma RNA by ultrasensitive HIV-1 viral load testing. RESULTS: No genome-intact HIV-1 proviruses were detected in analysis of a total of 1.188 billion peripheral blood mononuclear cells and 503 million mononuclear cells from placental tissues. Seven defective proviruses, some of them derived from clonally expanded cells, were detected. A viral outgrowth assay failed to retrieve replication-competent HIV-1 from 150 million resting CD4+ T cells. No HIV-1 RNA was detected in 4.5 mL of plasma. LIMITATIONS: Absence of evidence for intact HIV-1 proviruses in large numbers of cells is not evidence of absence of intact HIV-1 proviruses. A sterilizing cure of HIV-1 can never be empirically proved. CONCLUSION: Genome-intact and replication-competent HIV-1 were not detected in an elite controller despite analysis of massive numbers of cells from blood and tissues, suggesting that this patient may have naturally achieved a sterilizing cure of HIV-1 infection. These observations raise the possibility that a sterilizing cure may be an extremely rare but possible outcome of HIV-1 infection. PRIMARY FUNDING SOURCE: National Institutes of Health and Bill & Melinda Gates Foundation.

HSF1 inhibition attenuates HIV-1 latency reversal mediated by several candidate LRAs In Vitro and Ex Vivo.

HIV-1 latency is a major barrier to cure. Identification of small molecules that destabilize latency and allow immune clearance of infected cells could lead to treatment-free remission. In vitro models of HIV-1 latency involving cell lines or primary cells have been developed for characterization of HIV-1 latency and high-throughput screening for latency-reversing agents (LRAs). We have shown that the majority of LRAs identified to date are relatively ineffective in cells from infected individuals despite activity in model systems. We show here that, for diverse LRAs, latency reversal observed in model systems involves a heat shock factor 1 (HSF1)-mediated stress pathway. Small-molecule inhibition of HSF1 attenuated HIV-1 latency reversal by histone deactylase inhibitors, protein kinase C agonists, and proteasome inhibitors without interfering with the known mechanism of action of these LRAs. However, latency reversal by second mitochondria-derived activator of caspase (SMAC) mimetics was not affected by inhibition of HSF1. In cells from infected individuals, inhibition of HSF1 attenuated latency reversal by phorbol ester+ionomycin but not by anti-CD3+anti-CD28. HSF1 promotes elongation of HIV-1 RNA by recruiting P-TEFb to the HIV-1 long terminal repeat (LTR), and we show that inhibition of HSF1 attenuates the formation of elongated HIV-1 transcripts. We demonstrate that in vitro models of latency have higher levels of the P-TEFb subunit cyclin T1 than primary cells, which may explain why many LRAs are functional in model systems but relatively ineffective in primary cells. Together, these studies provide insights into why particular LRA combinations are effective in reversing latency in cells from infected individuals.

The SlDOG1 Affect Biosynthesis of Steroidal Glycoalkaloids by Regulating GAME Expression in Tomato.

Steroidal alkaloids (SAs) and steroidal glycoalkaloids (SGAs) are common constituents of plant species belonging to the Solanaceae family. However, the molecular mechanism regulating the formation of SAs and SGAs remains unknown. Here, genome-wide association mapping was used to elucidate SA and SGA regulation in tomatoes: a SlGAME5-like glycosyltransferase (Solyc10g085240) and the transcription factor SlDOG1 (Solyc10g085210) were significantly associated with steroidal alkaloid composition. In this study, it was found that rSlGAME5-like can catalyze a variety of substrates for glycosidation and can catalyze SA and flavonol pathways to form O-glucoside and O-galactoside in vitro. The overexpression of SlGAME5-like promoted α-tomatine, hydroxytomatine, and flavonol glycoside accumulation in tomatoes. Furthermore, assessments of natural variation combined with functional analyses identified SlDOG1 as a major determinant of tomato SGA content, which also promoted SA and SGA accumulation via the regulation of GAME gene expression. This study provides new insights into the regulatory mechanisms underlying SGA production in tomatoes.

The Development of Naringin for Use against Bone and Cartilage Disorders.

Bone and cartilage disorders are the leading causes of musculoskeletal disability. There is no absolute cure for all bone and cartilage disorders. The exploration of natural compounds for the potential therapeutic use against bone and cartilage disorders is proving promising. Among these natural chemicals, naringin, a flavanone glycoside, is a potential candidate due to its multifaceted pharmacological activities in bone and cartilage tissues. Emerging studies indicate that naringin may promote osteogenic differentiation, inhibit osteoclast formation, and exhibit protective effects against osteoporosis in vivo and in vitro. Many signaling pathways, such as BMP-2, Wnt/ß-catenin, and VEGF/VEGFR, participate in the biological actions of naringin in mediating the pathological development of osteoporosis. In addition, the anti-inflammatory, anti-oxidative stress, and anti-apoptosis abilities of naringin also demonstrate its beneficial effects against bone and cartilage disorders, including intervertebral disc degeneration, osteoarthritis, rheumatoid arthritis, bone and cartilage tumors, and tibial dyschondroplasia. Naringin exhibits protective effects against bone and cartilage disorders. However, more efforts are still needed due to, at least in part, the uncertainty of drug targets. Further biological and pharmacological evaluations of naringin and its applications in bone tissue engineering, particularly its therapeutic effects against osteoporosis, might result in developing potential drug candidates.

Evaluation of paper-based and web-based food frequency questionnaires for 7-year-old children in Singapore.

Advances in technology enabled the development of a web-based, pictorial FFQ to collect parent-report dietary intakes of 7-year-old children in the Growing Up in Singapore Towards healthy Outcomes study. This study aimed to compare intakes estimated from a paper-FFQ and a web-FFQ and examine the relative validity of both FFQ against 3-d diet records (3DDR). Ninety-two mothers reported food intakes of their 7-year-old child on a paper-FFQ, a web-FFQ and a 3DDR. A usability questionnaire collected participants' feedback on the web-FFQ. Correlations and agreement in energy, nutrients and food groups intakes between the dietary assessments were evaluated using Pearson's correlation, Lin's concordance, Bland-Altman plots, Cohen's κ and tertile classification. The paper- and web-FFQ had good correlations (≥ 0·50) and acceptable-good agreement (Lin's concordance ≥ 0·30; Cohen's κ ≥ 0·41; ≥ 50 % correct and ≤ 10 % misclassification into same or extreme tertiles). Compared with 3DDR, both FFQ showed poor agreement (< 0·30) in assessing absolute intakes except micronutrients (web-FFQ had acceptable-good agreement), but showed acceptable-good ability to classify children into tertiles (κ ≥ 0·21; ≥ 40 % and ≤ 15 % correct or misclassification). Bland-Altman plots suggest good agreement between web-FFQ and 3DDR in assessing micronutrients and several food groups. The web-FFQ was well-received, and majority (81 %) preferred the web-FFQ over the paper-FFQ. The newly developed web-FFQ produced intake estimates comparable to the paper-FFQ, has acceptable-good agreement with 3DDR in assessing absolute micronutrients intakes and has acceptable-good ability to classify children according to categories of intakes. The positive acceptance of the web-FFQ makes it a feasible tool for future dietary data collection.

Tracking of dietary patterns between pregnancy and 6 years post-pregnancy in a multiethnic Asian cohort: the Growing Up in Singapore Towards healthy Outcomes (GUSTO) study.

PURPOSE: Few studies have described adherence to dietary patterns over time in women of childbearing age. This study aims to describe, examine the stability and changes in dietary patterns between pregnancy and 6 years post-pregnancy and the sociodemographic and lifestyle factors influencing the adherence over time. METHODS: During pregnancy and at 6 years post-pregnancy, 24-h recalls and food frequency questionnaires were collected, respectively, from 709 women. Data on sociodemographic and lifestyle factors were collected via questionnaires. Dietary patterns were identified using principal component analysis and stability assessed using Pearson's correlation coefficients (r) and Cohen's weighted kappa (κ). Associations with sociodemographic characteristics were assessed by multiple logistic regression. RESULTS: The 'Fruits, Vegetables and Legumes' (FVL) and 'Seafood, Noodle, Soup' (SNS) patterns were identified at both time points, with low correlation for the dietary pattern z scores (r 0.2 and 0.3, respectively) and modest agreement in tertile assignment, suggesting poor stability. An 'unhealthy' pattern was only observed at 6 years post-pregnancy. Women who showed increased adherence to FVL pattern had higher educational attainment and exhibited healthy lifestyle behaviours. Women who had gestational diabetes during pregnancy were less likely to decrease adherence to FVL pattern over time. Women who adhered more closely to the 'unhealthy' pattern at 6 years post-pregnancy tended to be younger, of Malay ethnicity, had lower socioeconomic status, were less physically active and had additional pregnancies. CONCLUSIONS: Dietary habits of women became less healthy during the transition from pregnancy to 6 years post-pregnancy. However, results should be interpreted with caution due to the different dietary assessment tools used at the two time points.

Association between changes in diet quality from mid-life to late-life and healthy ageing: the Singapore Chinese Health Study.

BACKGROUND: Few studies have evaluated the association between changes in diet quality from mid-life to late-life and healthy ageing. METHODS: We included 12,316 Chinese adults aged 45-74 years at baseline (1993-1998) from the Singapore Chinese Health Study. Diet quality was measured using the Dietary Approaches to Stop Hypertension (DASH) scores at baseline and follow-up 3 interviews (2014-2016). Healthy ageing was assessed at follow-up 3 interviews, and was defined as absence of specific chronic diseases, good mental and overall self-perceived health, good physical functioning and absence of cognitive impairment, limitations in instrumental activities of daily living or function-limiting pain. Multivariable-adjusted logistic regression models were applied to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between changes in DASH scores and healthy ageing. RESULTS: Compared with participants who maintained relatively stable DASH scores, a >10% decrease in DASH score was associated with a 16% (95% CI, 4-26%) lower likelihood of healthy ageing, whereas a >10% increase in DASH score was associated with a 19% (95% CI, 3-37%) higher likelihood of healthy ageing. Compared with participants who were in the low-score group consistently, participants who increased their DASH scores from moderate-score at baseline to high-score at follow-up 3 had a 53% (95% CI, 21-92%) higher likelihood of healthy ageing, whereas those who were in the high-score group consistently had 108% (95% CI, 71-152%) higher likelihood of healthy ageing. CONCLUSIONS: Improving diet quality from mid- to late-life was associated with a higher likelihood of healthy ageing.

Perinatal plasma carotenoid and vitamin E concentrations with maternal blood pressure during and after pregnancy.

BACKGROUND AND AIMS: Few studies examined the influence of carotenoids and vitamin E on blood pressure or hypertension during and after pregnancy. We related perinatal plasma concentrations of carotenoids and vitamin E (in individual forms and in combination) to blood pressure and hypertension at late pregnancy and 4 years post-pregnancy. METHODS AND RESULTS: In 684 women of the Growing Up in Singapore Towards Healthy Outcomes cohort, we quantified plasma carotenoids and vitamin E concentrations at delivery. Systolic blood pressure and diastolic blood pressure (SBP and DBP) around 37-39 weeks' gestation were extracted from obstetric records and measured at 4 years post-pregnancy. Principal component analysis derived patterns of carotenoids (CP) and vitamin E. Associations were examined using linear or logistic regressions adjusting for confounders. Two carotenoids (CP1: α-carotene, ß-carotene, and lutein; CP2: zeaxanthin, lycopene, and ß-cryptoxanthin) and one vitamin E (γ-, δ-, and α-tocopherols) patterns were derived. CP1 (1SD score increment) was associated with lower SBP and DBP [ß (95% CI): -2.36 (-3.47, -1.26) and -1.37 (-2.21, -0.53) mmHg] at late pregnancy> and 4 years post-pregnancy [-1.45 (-2.72, -0.18) and -0.99 (-1.98, -0.01) mmHg]. Higher ß-cryptoxanthin concentrations were associated with lower SBP and DBP [-1.50 (-2.49, -0.51) and -1.20 (-1.95, -0.46) mmHg] at late pregnancy. Individual vitamin E and their pattern were not associated with blood pressure or hypertension. CONCLUSION: Higher perinatal α-carotene, ß-carotene, and lutein concentrations are associated with lower blood pressure in women at late pregnancy and post-pregnancy. Foods rich in these carotenoids, such as red-, orange-, and dark-green-colored vegetables, might be beneficial for blood pressure during and after pregnancy.

Curriculum Reinforcement Learning Based on K-Fold Cross Validation.

With the continuous development of deep reinforcement learning in intelligent control, combining automatic curriculum learning and deep reinforcement learning can improve the training performance and efficiency of algorithms from easy to difficult. Most existing automatic curriculum learning algorithms perform curriculum ranking through expert experience and a single network, which has the problems of difficult curriculum task ranking and slow convergence speed. In this paper, we propose a curriculum reinforcement learning method based on K-Fold Cross Validation that can estimate the relativity score of task curriculum difficulty. Drawing lessons from the human concept of curriculum learning from easy to difficult, this method divides automatic curriculum learning into a curriculum difficulty assessment stage and a curriculum sorting stage. Through parallel training of the teacher model and cross-evaluation of task sample difficulty, the method can better sequence curriculum learning tasks. Finally, simulation comparison experiments were carried out in two types of multi-agent experimental environments. The experimental results show that the automatic curriculum learning method based on K-Fold cross-validation can improve the training speed of the MADDPG algorithm, and at the same time has a certain generality for multi-agent deep reinforcement learning algorithm based on the replay buffer mechanism.