Modelling optimal vaccination strategy for SARS-CoV-2 in the UK

The COVID-19 outbreak has highlighted our vulnerability to novel infections.Faced with this threat and no effective treatment, in line with many other countries, the UK adopted enforced social distancing (lockdown) to reduce transmission—successfully reducing the reproductive number R below one. However, given the large pool of susceptible individuals that remain, complete relaxation of controls is likely to generate a substantial further outbreak. Vaccination remains the only foreseeable means of both containing the infection and returning to normal interactions and behaviour. Here, we consider the optimal targeting of vaccination within the UK, with the aim of minimising future deaths or quality adjusted life year (QALY) losses. We show that, for a range of assumptions on the action and efficacy of the vaccine, targeting older age groups first is optimal and may be sufficient to stem the epidemic if the vaccine prevents transmission as well as disease.     

The association between the total antioxidant potential of plasma and the presence of coronary heart disease and renal dysfunction in patients with NIDDM

Oxidative stress may be an important pathogenetic factor in the development of diabetic vascular complications. The total antioxidative potential of plasma reflects the ability of an individual to resist oxidative stress. We measured the plasma total peroxyl radical-trapping potential (TRAP) and the concentrations of four plasma chain-breaking antioxidants in 81 patients with non-insulin-dependent diabetes mellitus (NIDDM) nine years after diagnosis and in 102 well-matched non-diabetic control subjects. The association between the total antioxidative potential and the presence of coronary heart disease (CHD) and diabetic kidney disease were also studied. There were no significant differences in plasma TRAP between NIDDM patients and control subjects (1250 ± 199 vs. 1224 ± 198 μM). Nor were there any significant differences in the concentrations of plasma uric acid, ascorbic acid, α-tocopherol, and protein thiols between NIDDM patients and control subjects. Patients with a low glomerular filtration rate and/or high urinary albumin excretion had elevated plasma uric acid. Plasma TRAP was not, however, associated with renal dysfunction. The plasma of NIDDM patients with CHD had a significantly higher value of unidentified antioxidative potential than that of patients without CHD. This relation was strongly dependent upon smoking. In conclusion, these data demonstrate that there are no major defects in the antioxidative potential of plasma caused by NIDDM per se. CHD and diabetic renal dysfunction were not associated with changes in plasma TRAP.     

PGC-1 Coactivators Regulate MITF and the Tanning Response

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Highlights? PGC-1 induces pigment formation in melanocytes ? PGC-1s activate expression of MITF ? α-MSH induces PGC-1s, which are required for induction of melanogenic genes ? eQTLs in human PGC-1β are associated with tanning ability and melanoma protection     

WormFarm: a quantitative control and measurement device toward automated Caenorhabditis elegans aging analysis

Caenorhabditis elegans is a leading model organism for studying the basic mechanisms of aging. Progress has been limited, however, by the lack of an automated system for quantitative analysis of longevity and mean lifespan. To address this barrier, we developed ‘WormFarm’, an integrated microfluidic device for culturing nematodes. Cohorts of 30–50 animals are maintained throughout their lifespan in each of eight separate chambers on a single WormFarm polydimethylsiloxane chip. Design features allow for automated removal of progeny and efficient control of environmental conditions. In addition, we have developed computational algorithms for automated analysis of video footage to quantitate survival and other phenotypes, such as body size and motility. As proof‐of‐principle, we show here that WormFarm successfully recapitulates survival data obtained from a standard plate‐based assay for both RNAi‐mediated and dietary‐induced changes in lifespan. Further, using a fluorescent reporter in conjunction with WormFarm, we report an age‐associated decrease in fluorescent intensity of GFP in transgenic worms expressing GFP tagged with a mitochondrial import signal under the control of the myo‐3 promoter. This marker may therefore serve as a useful biomarker of biological age and aging rate.     

C/EBP homologous protein drives pro-catabolic responses in chondrocytes

Introduction

Excess C/EBP homologous protein (CHOP) expression is one feature of the unfolded protein response (UPR) to endoplasmic reticulum (ER) stress. Here, we focused on CHOP expression and function in chondrocytes.

Methods

We studied human knee osteoarthritis (OA) cartilage, bovine chondrocytes cultured in alginate and subjected to sub-lethal biomechanical injury, and knee chondrocytes of human autopsy donors. We performed siRNA knockdown and transfection.

Results

UPR activation was increased in human knee OA cartilage in situ, and in biomechanically injured cultured chondrocytes in vitro. In normal human chondrocytes, CHOP “gain of function” sensitized chondrocytes to IL-1β induced nitric oxide (NO) and matrix metalloproteinase (MMP)-3 release without inducing these responses by itself. Excess CHOP expression, by itself, induced superoxide production and apoptosis. Conversely, siRNA knockdown of CHOP and the UPR-specific mediator X-box binding protein (XBP1) inhibited NO release by >80% (P <0.0005) in response to IL-1β, and blunted MMP-3 release, whereas there were only minimal effects of the UPR mediator GRP78 on these responses. The anti-inflammatory metabolic “super-regulator” AMP kinase (AMPK) is known to limit UPR activation in vascular muscle cells. Here, CHOP supported the capacity of IL-1β to suppress AMPK activity in chondrocytes. We also observed that inhibition of AMPK activity promoted an increase in chondrocyte CHOP expression. Conversely, pharmacologic activation of AMPK by 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR) blunted chondrocyte CHOP expression in response to biomechanical injury.

Conclusions

Biomechanical injury and IL-1 signaling stimulate UPR activation in chondrocytes. CHOP mediates chondrocyte catabolic and apoptotic responses to IL-1β, and does so partly by inhibiting AMPK activity. Conversely, development of excess CHOP activity is limited by AMPK activity in chondrocytes. Our findings suggest a mechanism for potential chondroprotection by AICAR and other AMPK activators. The work is of translational relevance for OA, since several drugs that activate AMPK are already in the clinic for arthritis (for example, allosteric AMPK activators sodium salicylate and high dose aspirin, and methotrexate, which activates AMPK by generating AICAR).     

The Synthesis,Fluorescence and Antiviral Studies of 3′-Amino-2′,3′-Dideoxythymidine/substituted 10-Cyano-9-isothiocyanatoanthracene Adducts

Abstract

Adducts of 3′-amino-2′,3′-dideoxythymidine and various methoxy-substituted 10-cyano-9-isothiocyanatoanthracenes were prepared for use as fluorescent-tagged molecular probes. The thymidine/anthracene adducts were subjected to antiviral assays to determine if the adducts possessed antiviral activity.     

Evaluation of urinary trans-3′-hydroxycotinine as a biomarker of children's environmental tobacco smoke exposure

Abstract

The utility of urinary trans-3′-hydroxy cotinine (3HC) as a biomarker of environmental tobacco smoke (ETS) exposure was investigated in comparison with urinary cotinine (COT), the sum (3HC?+?COT), and ratio of the two nicotine metabolites (3HC/COT). Participants were 150 ETS exposed children (aged 1–44 months) and their parents. Child urine samples were collected during 3weekly baseline assessments and at interviews administered 3, 6, 12, and 18 months after baseline. Findings indicate that 3HC and COT can be measured reliably (rho?=?0.96, 0.88) and show equivalent levels of repeated measures stability (rho?=?0.71, 0.75). COT, 3HC, and 3HC?+?COT showed equally strong associations with air nicotine levels, reported ETS contamination, and reported ETS exposure (r=0.60–0.70). The intraclass correlations of 3HC/COT were lower than those for COT or 3HC. Older children had a higher 3HC/COT ratio than younger children (3.5 versus 2.2), and non-Hispanic White children had a higher ratio than African-American children (3.2 versus 1.9). These findings suggest that COT, 3HC, and 3HC?+?COT are approximately equivalent and equally strong biomarkers of ETS exposure in children. Moreover, 3HC/COT may provide a useful indicator to investigate age- and race-related differences in the metabolism of COT and 3HC.     

Role of forefinger and thumb loops in production of Ψ54 and Ψ55 in tRNAs by archaeal Pus10

Pseudouridines (Ψ) are found in structurally and functionally important regions of RNAs. Six families of Ψ synthases, TruA, TruB, TruD, RsuA, RluA, and Pus10 have been identified. Pus10 is present in Archaea and Eukarya. While most archaeal Pus10 produce both tRNA Ψ54 and Ψ55, some produce only Ψ55. Interestingly, human PUS10 has been implicated in apoptosis and Crohn’s and Celiac diseases. Homology models of archaeal Pus10 proteins based on the crystal structure of human PUS10 reveal that there are subtle structural differences in all of these Pus10 proteins. These observations suggest that structural changes in homologous proteins may lead to loss, gain, or change of their functions, warranting the need to study the structure-function relationship of these proteins. Using comparison of structural models and a series of mutations, we identified forefinger loop (reminiscent of that of RluA) and an Arg and a Tyr residue of archaeal Pus10 as critical determinants for its Ψ54, but not for its Ψ55 activity. We also found that a Leu residue, in addition to the catalytic Asp, is essential for both activities. Since forefinger loop is needed for both rRNA and tRNA Ψ synthase activities of RluA, but only for tRNA Ψ54 activity of Pus10, archaeal Pus10 proteins must use a different mechanism of recognition for Ψ55 activity. We propose that archaeal Pus10 uses two distinct mechanisms for substrate uridine recognition and binding. However, since we did not observe any mutation that affected only Ψ55 activity, both mechanisms for archaeal Pus10 activities must share some common features.