Sequence-Specific Recognition and Cooperative Dimerization of N-Terminal Aromatic Peptides in Aqueous Solution by a Synthetic Host

This article describes the selective recognition and noncovalent dimerization of N-terminal aromatic peptides in aqueous solution by the synthetic host compound, cucurbit[8]uril (Q8). Q8 is known to bind two aromatic guests simultaneously and, in the presence of methyl viologen, to recognize N-terminal tryptophan over internal and C-terminal sequence isomers. Here, the binding of Q8 to aromatic peptides in the absence of methyl viologen was studied by isothermal titration calorimetry (ITC), 1H NMR spectroscopy, and X-ray crystallography. The peptides studied were of sequence X-Gly-Gly, Gly-X-Gly, and Gly-Gly-X (X = Trp, Phe, Tyr, and His). Q8 selectively binds and dimerizes Trp-Gly-Gly (1) and Phe-Gly-Gly (4) with high affinity (ternary K = 109−1011 M-2); binding constants for the other 10 peptides were too small to be measured by ITC. Both peptides bound in a stepwise manner, and peptide 4 bound with positive cooperativity. Crystal structures of Q8·1 and Q8·42 reveal the basis for selective recognition as simultaneous inclusion of the hydrophobic aromatic side chain into the cavity of Q8 and chelation of the proximal N-terminal ammonium group by carbonyl groups of Q8. The peptide sequence selectivity and positively cooperative dimerization reported here are, to the best of our knowledge, unprecedented for synthetic hosts in aqueous solution. Specific peptide recognition and dimerization by synthetic hosts such as Q8 should be important in the study of dimer-mediated biochemical processes and for the separation of peptides and proteins

Risk of atrial fibrillation and stroke among older men exposed to prolonged endurance sport practice: a 10-year follow-up. The Birkebeiner Ageing Study and the Tromsø Study

Aims Endurance sport practice is associated with a high prevalence of atrial fibrillation (AF), which increases the risk of stroke in the general population. However, stroke risk in endurance athletes with AF is sparsely investigated. Most studies have been limited by design and are largely restricted to younger and middle-aged populations. Thus, we aimed to investigate AF and stroke risk in older athletes exposed to prolonged endurance training. Method During a 10-year period, 505 male athletes aged ≥65 years frequently participating in a long-distance ski race were compared with 1867 men of the same age from the general population. The main exposure was endurance sport practice with self-reported AF and stroke as outcomes. Stroke risk was further examined by joint modelling of AF and endurance practice. Statistical analysis was conducted with a modified Poisson model. Results Athletes (median age: 68, range: 65–90) participated in a long-distance ski race over a median of 14 years (range: 1–53). Prevalence (28.5% vs 17.8%) and adjusted risk of AF (risk ratio (RR): 1.88, 95% CI: 1.49 to 2.37) were higher in athletes compared with non-athletes, whereas the prevalence (5.4% vs 9.7%) and risk of stroke were lower (RR: 0.60, 95% CI: 0.37 to 0.95). Compared with athletes without AF, risk of stroke was twofold in athletes (RR: 2.38, 95% CI: 1.08 to 5.24) and nearly fourfold in non-athletes (RR: 3.87, 95% CI: 1.98 to 7.57) with AF. Conclusion Although older male endurance athletes experienced an increased risk of AF, the long-term risk of stroke was substantially reduced compared with non-athletes

A rapid antibody screening haemagglutination test for predicting immunity to SARS-CoV-2 variants of concern

Background: Evaluation of susceptibility to emerging SARS-CoV-2 variants of concern (VOC) requires rapid screening tests for neutralising antibodies which provide protection. Methods: Firstly, we developed a receptor-binding domain-specific haemagglutination test (HAT) to Wuhan and VOC (alpha, beta, gamma and delta) and compared to pseudotype, microneutralisation and virus neutralisation assays in 835 convalescent sera. Secondly, we investigated the antibody response using the HAT after two doses of mRNA (BNT162b2) vaccination. Sera were collected at baseline, three weeks after the first and second vaccinations from older (80–99 years, n = 89) and younger adults (23–77 years, n = 310) and compared to convalescent sera from naturally infected individuals (1–89 years, n = 307). Results: Here we show that HAT antibodies highly correlated with neutralising antibodies (R = 0.72–0.88) in convalescent sera. Home-dwelling older individuals have significantly lower antibodies to the Wuhan strain after one and two doses of BNT162b2 vaccine than younger adult vaccinees and naturally infected individuals. Moverover, a second vaccine dose boosts and broadens the antibody repertoire to VOC in naïve, not previously infected older and younger adults. Most (72–76%) older adults respond after two vaccinations to alpha and delta, but only 58–62% to beta and gamma, compared to 96–97% of younger vaccinees and 68–76% of infected individuals. Previously infected older individuals have, similarly to younger adults, high antibody titres after one vaccination. Conclusions: Overall, HAT provides a surrogate marker for neutralising antibodies, which can be used as a simple inexpensive, rapid test. HAT can be rapidly adaptable to emerging VOC for large-scale evaluation of potentially decreasing vaccine effectiveness.publishedVersio

Intakes of calcium, vitamin D, and dairy servings and dental plaque in older Danish adults

BACKGROUND: To investigate whether intakes of calcium and dairy-servings within-recommendations were associated with plaque score when allowing for vitamin D intakes. METHODS: In this cross-sectional study, including 606 older Danish adults, total dietary calcium intake (mg/day) was classified as below vs. within-recommendations and dairy intake as <3 vs. ≥3 servings/ d. Dental plaque, defined as the percentage of tooth surfaces exhibiting plaque, was classified as < median vs. ≥median value (9.5%). Analyses were stratified by lower and higher (≥6.8 μg/d) vitamin D intake. FINDINGS: Intakes of calcium (OR = 0.53; 95% CI = 0.31-0.92) and dairy servings (OR = 0.54; 95% CI = 0.33-0.89) within-recommendations were significantly associated with lower plaque score after adjustments for age, gender, education, intakes of alcohol, sucrose and mineral supplements, smoking, diseases, number of teeth, visits to the dentist, use of dental floss/tooth pick and salivary flow, among those with higher, but not lower, vitamin D intake. CONCLUSION: Intakes of calcium dairy-servings within-recommendations were inversely associated with plaque, among those with higher, but not lower, vitamin D intakes. Due to the cross-sectional nature of the study, it is not possible to infer that this association is causal

Progressive skin fibrosis is associated with a decline in lung function and worse survival in patients with diffuse cutaneous systemic sclerosis in the European Scleroderma Trials and Research (EUSTAR) cohort.

Objectives To determine whether progressive skin fibrosis is associated with visceral organ progression and mortality during follow-up in patients with diffuse cutaneous systemic sclerosis (dcSSc). Methods We evaluated patients from the European Scleroderma Trials and Research database with dcSSc, baseline modified Rodnan skin score (mRSS) ≥7, valid mRSS at 12±3 months after baseline and ≥1 annual follow-up visit. Progressive skin fibrosis was defined as an increase in mRSS &gt;5 and ≥25% from baseline to 12±3 months. Outcomes were pulmonary, cardiovascular and renal progression, and all-cause death. Associations between skin progression and outcomes were evaluated by Kaplan-Meier survival analysis and multivariable Cox regression. Results Of 1021 included patients, 78 (7.6%) had progressive skin fibrosis (skin progressors). Median follow-up was 3.4 years. Survival analyses indicated that skin progressors had a significantly higher probability of FVC decline ≥10% (53.6% vs 34.4%; p&lt;0.001) and all-cause death (15.4% vs 7.3%; p=0.003) than non-progressors. These significant associations were also found in subgroup analyses of patients with either low baseline mRSS (≤22/51) or short disease duration (≤15 months). In multivariable analyses, skin progression within 1 year was independently associated with FVC decline ≥10% (HR 1.79, 95% CI 1.20 to 2.65) and all-cause death (HR 2.58, 95% CI 1.31 to 5.09). Conclusions Progressive skin fibrosis within 1 year is associated with decline in lung function and worse survival in dcSSc during follow-up. These results confirm mRSS as a surrogate marker in dcSSc, which will be helpful for cohort enrichment in future trials and risk stratification in clinical practice

Racial differences in systemic sclerosis disease presentation: a European Scleroderma Trials and Research group study

Objectives. Racial factors play a significant role in SSc. We evaluated differences in SSc presentations between white patients (WP), Asian patients (AP) and black patients (BP) and analysed the effects of geographical locations.Methods. SSc characteristics of patients from the EUSTAR cohort were cross-sectionally compared across racial groups using survival and multiple logistic regression analyses.Results. The study included 9162 WP, 341 AP and 181 BP. AP developed the first non-RP feature faster than WP but slower than BP. AP were less frequently anti-centromere (ACA; odds ratio (OR) = 0.4, P &lt; 0.001) and more frequently anti-topoisomerase-I autoantibodies (ATA) positive (OR = 1.2, P = 0.068), while BP were less likely to be ACA and ATA positive than were WP [OR(ACA) = 0.3, P &lt; 0.001; OR(ATA) = 0.5, P = 0.020]. AP had less often (OR = 0.7, P = 0.06) and BP more often (OR = 2.7, P &lt; 0.001) diffuse skin involvement than had WP.AP and BP were more likely to have pulmonary hypertension [OR(AP) = 2.6, P &lt; 0.001; OR(BP) = 2.7, P = 0.03 vs WP] and a reduced forced vital capacity [OR(AP) = 2.5, P &lt; 0.001; OR(BP) = 2.4, P &lt; 0.004] than were WP. AP more often had an impaired diffusing capacity of the lung than had BP and WP [OR(AP vs BP) = 1.9, P = 0.038; OR(AP vs WP) = 2.4, P &lt; 0.001]. After RP onset, AP and BP had a higher hazard to die than had WP [hazard ratio (HR) (AP) = 1.6, P = 0.011; HR(BP) = 2.1, P &lt; 0.001].Conclusion. Compared with WP, and mostly independent of geographical location, AP have a faster and earlier disease onset with high prevalences of ATA, pulmonary hypertension and forced vital capacity impairment and higher mortality. BP had the fastest disease onset, a high prevalence of diffuse skin involvement and nominally the highest mortality

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Search of the Orion spur for continuous gravitational waves using a loosely coherent algorithm on data from LIGO interferometers

We report results of a wideband search for periodic gravitational waves from isolated neutron stars within the Orion spur towards both the inner and outer regions of our Galaxy. As gravitational waves interact very weakly with matter, the search is unimpeded by dust and concentrations of stars. One search disk (A) is 6.87° in diameter and centered on 20h10m54.71s+33°33′25.29′′, and the other (B) is 7.45° in diameter and centered on 8h35m20.61s-46°49′25.151′′. We explored the frequency range of 50-1500 Hz and frequency derivative from 0 to -5×10-9 Hz/s. A multistage, loosely coherent search program allowed probing more deeply than before in these two regions, while increasing coherence length with every stage. Rigorous follow-up parameters have winnowed the initial coincidence set to only 70 candidates, to be examined manually. None of those 70 candidates proved to be consistent with an isolated gravitational-wave emitter, and 95% confidence level upper limits were placed on continuous-wave strain amplitudes. Near 169 Hz we achieve our lowest 95% C.L. upper limit on the worst-case linearly polarized strain amplitude h0 of 6.3×10-25, while at the high end of our frequency range we achieve a worst-case upper limit of 3.4×10-24 for all polarizations and sky locations. © 2016 American Physical Society