Fusion of Sendai virus with the target cell membrane is required for T cell cytotoxicity

INFECTION of mice with viruses can generate cytotoxic T lymphocytes (CTL) which show restricted specificity for target cell lysis. Specific lysis requires that the virus used to prime the target cells must be of the same type as that used to sensitise the CTL, and that both target and CTL cells must express the same major histocompatability complex (MHC) gene product(s). The nature of the viral gene product(s) and their interaction with the MHC gene product(s) have been the subject of recent stud1−5. Previously we used Sendai virus to show that lysable target cells can be obtained using membrane vesicles which contain only the viral glycoproteins, indicating that these may be the specific viral gene products involved in target formation5. Sendai virus contains two glycoproteins—the haemagglutinin-neuraminidase (HANA) which promotes attachment of virus to cells and the fusion protein (F) which is involved in subsequent virus cell fusion7−9. Both activities are necessary for insertion of these viral glycoproteins into the plasma membrane of the cell10. In this letter we suggest that the insertion of the viral glycoproteins into the cell membrane is an essential step in target cell formation since we can show that virus containing an inactive fusion protein precursor (F0) cannot elicit T cell cytotoxicity unless the fusion activity is generated by proteolytic cleavage of the precursor. Sugamura et al. 6 have suggested that it is primarily the F glycoprotein of the Sendai virus envelope which is essential for the formation of the target antigen, as virus lacking the functional activities of F following trypsin digestion was inactive in priming target cells for T cell killing. However, we show that proteolytic inactivation of either of the two glycoproteins (F or HANA) of virus used to prime target cells will abolish the cytotoxic response

Modular and predictable assembly of porous organic molecular crystals

Nanoporous molecular frameworks are important in applications such as separation, storage and catalysis. Empirical rules exist for their assembly but it is still challenging to place and segregate functionality in three-dimensional porous solids in a predictable way. Indeed, recent studies of mixed crystalline frameworks suggest a preference for the statistical distribution of functionalities throughout the pores rather than, for example, the functional group localization found in the reactive sites of enzymes. This is a potential limitation for 'one-pot' chemical syntheses of porous frameworks from simple starting materials. An alternative strategy is to prepare porous solids from synthetically preorganized molecular pores. In principle, functional organic pore modules could be covalently prefabricated and then assembled to produce materials with specific properties. However, this vision of mix-and-match assembly is far from being realized, not least because of the challenge in reliably predicting three-dimensional structures for molecular crystals, which lack the strong directional bonding found in networks. Here we show that highly porous crystalline solids can be produced by mixing different organic cage modules that self-assemble by means of chiral recognition. The structures of the resulting materials can be predicted computationally, allowing in silico materials design strategies. The constituent pore modules are synthesized in high yields on gram scales in a one-step reaction. Assembly of the porous co-crystals is as simple as combining the modules in solution and removing the solvent. In some cases, the chiral recognition between modules can be exploited to produce porous organic nanoparticles. We show that the method is valid for four different cage modules and can in principle be generalized in a computationally predictable manner based on a lock-and-key assembly between modules

Blood pressure variability and cardiovascular risk in the PROspective study of pravastatin in the elderly at risk (PROSPER)

Variability in blood pressure predicts cardiovascular disease in young- and middle-aged subjects, but relevant data for older individuals are sparse. We analysed data from the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) study of 5804 participants aged 70–82 years with a history of, or risk factors for cardiovascular disease. Visit-to-visit variability in blood pressure (standard deviation) was determined using a minimum of five measurements over 1 year; an inception cohort of 4819 subjects had subsequent in-trial 3 years follow-up; longer-term follow-up (mean 7.1 years) was available for 1808 subjects. Higher systolic blood pressure variability independently predicted long-term follow-up vascular and total mortality (hazard ratio per 5 mmHg increase in standard deviation of systolic blood pressure = 1.2, 95% confidence interval 1.1–1.4; hazard ratio 1.1, 95% confidence interval 1.1–1.2, respectively). Variability in diastolic blood pressure associated with increased risk for coronary events (hazard ratio 1.5, 95% confidence interval 1.2–1.8 for each 5 mmHg increase), heart failure hospitalisation (hazard ratio 1.4, 95% confidence interval 1.1–1.8) and vascular (hazard ratio 1.4, 95% confidence interval 1.1–1.7) and total mortality (hazard ratio 1.3, 95% confidence interval 1.1–1.5), all in long-term follow-up. Pulse pressure variability was associated with increased stroke risk (hazard ratio 1.2, 95% confidence interval 1.0–1.4 for each 5 mmHg increase), vascular mortality (hazard ratio 1.2, 95% confidence interval 1.0–1.3) and total mortality (hazard ratio 1.1, 95% confidence interval 1.0–1.2), all in long-term follow-up. All associations were independent of respective mean blood pressure levels, age, gender, in-trial treatment group (pravastatin or placebo) and prior vascular disease and cardiovascular disease risk factors. Our observations suggest variability in diastolic blood pressure is more strongly associated with vascular or total mortality than is systolic pressure variability in older high-risk subjects

Confounders in the assessment of the renal effects associated with low-level urinary cadmium: an analysis in industrial workers

<p>Abstract</p> <p>Background</p> <p>Associations of proteinuria with low-level urinary cadmium (Cd) are currently interpreted as the sign of renal dysfunction induced by Cd. Few studies have considered the possibility that these associations might be non causal and arise from confounding by factors influencing the renal excretion of Cd and proteins.</p> <p>Methods</p> <p>We examined 184 healthy male workers (mean age, 39.5 years) from a zinc smelter (n = 132) or a blanket factory (n = 52). We measured the concentrations of Cd in blood (B-Cd) and the urinary excretion of Cd (U-Cd), retinol-binding protein (RBP), protein HC and albumin. Associations between biomarkers of metal exposure and urinary proteins were assessed by simple and multiple regression analyses.</p> <p>Results</p> <p>The medians (interquartile range) of B-Cd (μg/l) and U-Cd (μg/g creatinine) were 0.80 (0.45-1.16) and 0.70 (0.40-1.3) in smelter workers and 0.66 (0.47-0.87) and 0.55 (0.40-0.90) in blanket factory workers, respectively. Occupation had no influence on these values, which varied mainly with smoking habits. In univariate analysis, concentrations of RBP and protein HC in urine were significantly correlated with both U-Cd and B-Cd but these associations were substantially weakened by the adjustment for current smoking and the residual influence of diuresis after correction for urinary creatinine. Albumin in urine did not correlate with B-Cd but was consistently associated with U-Cd through a relationship, which was unaffected by smoking or diuresis. Further analyses showed that RBP and albumin in urine mutually distort their associations with U-Cd and that the relationship between RBP and Cd in urine was almost the replicate of that linking RBP to albumin</p> <p>Conclusions</p> <p>Associations between proteinuria and low-level urinary Cd should be interpreted with caution as they appear to be largely driven by diuresis, current smoking and probably also the co-excretion of Cd with plasma proteins.</p

Significant nutrient consumption in the dark subsurface layer during a diatom bloom: a case study on Funka Bay, Hokkaido, Japan

We conducted repetitive observations in Funka Bay, Hokkaido, Japan, on 15 February, 4 and 15 March, and 14 April 2019. The diatom spring bloom peaked on 4 March and started declining on 15 March. Funka Bay winter water remained below 30 m depth, which was below the surface mixed-layer and dark-layer depth (0.1 % of the surface photosynthetically active radiation, PAR, depth) on 4 and 15 March. In the subsurface layer at depths of 30–50 m, concentrations of NO3-, PO43-, and Si(OH)4 decreased by half between these dates, even in the dark. Incubation experiments using the diatom Thalassiosira nordenskioeldii showed that this diatom could consume added nutrients in the dark at substantial rates after pre-culturing to deplete nutrients. Incubation experiments using natural seawater collected in the growing phase of the bloom on 8 March 2022 also showed that nutrient-depleted phytoplankton could consume added nutrients in the dark. We excluded three physical process – water mixing, diffusive transport, and subduction – as possible main reasons for the decrease in nutrients in the subsurface layer. We conclude that the nutrient reduction in the subsurface layer (30–50 m) between 4 and 15 March 2019 could be explained by nutrient consumption by diatoms in the dark in that layer.</p

Using under-ice hyperspectral transmittance to determine land-fast sea-ice algal biomass in Saroma-ko Lagoon, Hokkaido, Japan

Sea ice, which forms in polar and nonpolar areas, transmits light to ice-associated (sympagic) algal communities. To noninvasively study the distribution of sea-ice algae, empirical relations to estimate its biomass from under-ice hyperspectral irradiance have been developed in the Arctic and Antarctica but lack for nonpolar regions. This study examines relationships between normalised difference indices (NDI) calculated from hyperspectral transmittance and sympagic algal biomass in the nonpolar Saroma-ko Lagoon. We analysed physico-biogeochemical properties of snow and land-fast sea ice supporting 27 paired bio-optical measurements along three transects covering an area of over 250 m × 250 m in February 2019. Snow depth (0.08 ± 0.01 m) and ice-bottom brine volume fraction (0.21 ± 0.02) showed low (0.06) and high (0.58) correlations with sea-ice core bottom section chlorophyll a (Chl. a), respectively. Spatial analyses unveiled the patch size of sea-ice Chl. a to be ~65 m, which is in the same range reported from previous studies. A selected NDI (669, 596 nm) explained 63% of algal biomass variability. This reflects the bio-optical properties and environmental conditions of the lagoon that favour the wavelength pair in the orange/red part of the spectrum and suggests the necessity of a specific bio-optical relationship for Saroma-ko Lagoon

Relationships of Risk Factors for Pre-Eclampsia with Patterns of Occurrence of Isolated Gestational Proteinuria during Normal Term Pregnancy

&lt;p&gt;&lt;b&gt;Background:&lt;/b&gt; Isolated gestational proteinuria may be part of the pre-eclampsia disease spectrum. Confirmation of its association with established pre-eclampsia risk factors and higher blood pressure in uncomplicated pregnancies would support this concept.&lt;/p&gt; &lt;p&gt;&lt;b&gt;Methods:&lt;/b&gt; Data from 11,651 women from the Avon Longitudinal Study of Parents and Children who had a term live birth but did not have pre-existing hypertension or diabetes or develop gestational diabetes or preeclampsia were used. Proteinuria was assessed repeatedly (median 12 measurements per woman) by dipstick and latent class analysis was used to identify subgroups of the population with different patterns of proteinuria in pregnancy.&lt;/p&gt; &lt;p&gt;&lt;b&gt;Results:&lt;/b&gt; Higher maternal pre-pregnancy body mass index (BMI), younger age, nulliparity and twin pregnancy were independently associated with increased odds of any proteinuria in pregnancy. Women who experienced proteinuria showed five patterns: proteinuria in early pregnancy only (&lt;= 20 weeks gestation), and onset at 21-28 weeks, 29-32 weeks, 33-36 weeks and &gt;= 37 weeks gestation. There were higher odds of proteinuria onset after 33 weeks in obese women and after 37 weeks in nulliparous women compared with normal weight and multiparous women respectively. Smoking in pregnancy was weakly negatively associated with odds of proteinuria onset after 37 weeks. Twin pregnancies had higher odds of proteinuria onset from 29 weeks. In women with proteinuria onset after 33 weeks blood pressure was higher in early pregnancy and at the end of pregnancy.&lt;/p&gt; &lt;p&gt;&lt;b&gt;Conclusions:&lt;/b&gt; Established pre-eclampsia risk factors were related to proteinuria occurrence in late gestation in healthy term pregnancies, supporting the hypothesis that isolated gestational proteinuria may represent an early manifestation of preeclampsia.&lt;/p&gt

Equivalence of Deterministic Nested Word to Word Transducers

International audienceWe study the equivalence problem of deterministic nested word to word transducers and show it to be surprisingly robust. Modulo polynomial time reductions, it can be identified with 4 equivalence problems for diverse classes of deterministic non-copying order-preserving transducers. In particular, we present polynomial time back and fourth reductions to the morphism equivalence problem on context free languages, which is known to be solvable in polynomial time