A gene with major phenotypic effects as a target for selection vs. homogenizing gene flow

Genes with major phenotypic effects facilitate quantifying the contribution of genetic vs. plastic effects to adaptive divergence. A classical example is Ectodysplasin (Eda), the major gene controlling lateral plate phenotype in three‐spined stickleback. Completely plated marine stickleback populations evolved repeatedly towards low‐plated freshwater populations, representing a prime example of parallel evolution by natural selection. However, many populations remain polymorphic for lateral plate number. Possible explanations for this polymorphism include relaxation of selection, disruptive selection or a balance between divergent selection and gene flow. We investigated 15 polymorphic stickleback populations from brackish and freshwater habitats in coastal North‐western Europe. At each site, we tracked changes in allele frequency at the Eda gene between subadults in fall, adults in spring and juveniles in summer. Eda genotypes were also compared for body size and reproductive investment. We observed a fitness advantage for the Eda allele for the low morph in freshwater and for the allele for the complete morph in brackish water. Despite these results, the differentiation at the Eda gene was poorly correlated with habitat characteristics. Neutral population structure was the best predictor of spatial variation in lateral plate number, suggestive of a substantial effect of gene flow. A meta‐analysis revealed that the signature of selection at Eda was weak compared to similar studies in stickleback. We conclude that a balance between divergent selection and gene flow can maintain stickleback populations polymorphic for lateral plate number and that ecologically relevant genes may not always contribute much to local adaptation, even when targeted by selection.     

μABC: a systematic microsecond molecular dynamics study of tetranucleotide sequence effects in B-DNA

We present the results of microsecond molecular dynamics simulations carried out by the ABC group of laboratories on a set of B-DNA oligomers containing the 136 distinct tetranucleotide base sequences. We demonstrate that the resulting trajectories have extensively sampled the conformational space accessible to B-DNA at room temperature. We confirm that base sequence effects depend strongly not only on the specific base pair step, but also on the specific base pairs that flank each step. Beyond sequence effects on average helical parameters and conformational fluctuations, we also identify tetranucleotide sequences that oscillate between several distinct conformational substates. By analyzing the conformation of the phosphodiester backbones, it is possible to understand for which sequences these substates will arise, and what impact they will have on specific helical parameters.     

Toxicological Profile of Ultrapure 2,2′,3,4,4′,5,5′-Heptachlorbiphenyl (PCB 180) in Adult Rats

PCB 180 is a persistent non-dioxin-like polychlorinated biphenyl (NDL-PCB) abundantly present in food and the environment. Risk characterization of NDL-PCBs is confounded by the presence of highly potent dioxin-like impurities. We used ultrapure PCB 180 to characterize its toxicity profile in a 28-day repeat dose toxicity study in young adult rats extended to cover endocrine and behavioral effects. Using a loading dose/maintenance dose regimen, groups of 5 males and 5 females were given total doses of 0, 3, 10, 30, 100, 300, 1000 or 1700 mg PCB 180/kg body weight by gavage. Dose-responses were analyzed using benchmark dose modeling based on dose and adipose tissue PCB concentrations. Body weight gain was retarded at 1700 mg/kg during loading dosing, but recovered thereafter. The most sensitive endpoint of toxicity that was used for risk characterization was altered open field behavior in females; i.e. increased activity and distance moved in the inner zone of an open field suggesting altered emotional responses to unfamiliar environment and impaired behavioral inhibition. Other dose-dependent changes included decreased serum thyroid hormones with associated histopathological changes, altered tissue retinoid levels, decreased hematocrit and hemoglobin, decreased follicle stimulating hormone and luteinizing hormone levels in males and increased expression of DNA damage markers in liver of females. Dose-dependent hypertrophy of zona fasciculata cells was observed in adrenals suggesting activation of cortex. There were gender differences in sensitivity and toxicity profiles were partly different in males and females. PCB 180 adipose tissue concentrations were clearly above the general human population levels, but close to the levels in highly exposed populations. The results demonstrate a distinct toxicological profile of PCB 180 with lack of dioxin-like properties required for assignment of WHO toxic equivalency factor. However, PCB 180 shares several toxicological targets with dioxin-like compounds emphasizing the potential for interactions.     

Assessment of Activity Limitations with the Health Assessment Questionnaire Predicts the Need for Support Measures in Patients with Rheumatoid Arthritis: A Multicenter Observational Study

Objective

This study investigated whether the Health Assessment Questionnaire (HAQ) can be used as an instrument to assess the need for social support measures that address activity limitations and participation issues in patients with rheumatoid arthritis (RA).

Methods

This multicenter observational study included patients with RA and disease duration of at least one year, consulting their rheumatologist for routine evaluation of disease activity. In the single study visit data on demographics, disease history and current treatment were collected. DAS28 values were collected to evaluate current RA disease activity. Patients were asked to fill out the HAQ and SF-36 questionnaires. Receiver Operator Characteristics (ROC) curves were constructed to evaluate the performance of the HAQ, SF-36 and DAS28 in predicting the need for nine supporting measures available for chronically ill patients in the Belgian social security system. The expert opinion of the treating rheumatologist was used as a reference.

Results

The study included 316 patients with a mean age of 59.8±12.6 years, disease duration of 11.4±9.3 years, mean DAS28 values of 2.83±1.17. Mean HAQ score was 0.95±0.73, mean SF-36 score 56.5±21.3. HAQ scores >1 were observed in 39.4% of patients. The area under the HAQ ROC curve was consistently >0.7 and higher for the HAQ than for SF-36 or DAS28 for all support measures. Rheumatologists on average recommended 3.67 support measures.

Conclusion

The HAQ score was found to be a good predictor of the need for social support measures in patients with RA.     

Diatom Cell Size,Coloniality and Motility: Trade-Offs between Temperature,Salinity and Nutrient Supply with Climate Change

Reduction in body size has been proposed as a universal response of organisms, both to warming and to decreased salinity. However, it is still controversial if size reduction is caused by temperature or salinity on their own, or if other factors interfere as well. We used natural benthic diatom communities to explore how “body size” (cells and colonies) and motility change along temperature (2–26°C) and salinity (0.5–7.8) gradients in the brackish Baltic Sea. Fourth-corner analysis confirmed that small cell and colony sizes were associated with high temperature in summer. Average community cell volume decreased linearly with 2.2% per °C. However, cells were larger with artificial warming when nutrient concentrations were high in the cold season. Average community cell volume increased by 5.2% per °C of artificial warming from 0 to 8.5°C and simultaneously there was a selection for motility, which probably helped to optimize growth rates by trade-offs between nutrient supply and irradiation. Along the Baltic Sea salinity gradient cell size decreased with decreasing salinity, apparently mediated by nutrient stoichiometry. Altogether, our results suggest that climate change in this century may polarize seasonality by creating two new niches, with elevated temperature at high nutrient concentrations in the cold season (increasing cell size) and elevated temperature at low nutrient concentrations in the warm season (decreasing cell size). Higher temperature in summer and lower salinity by increased land-runoff are expected to decrease the average cell size of primary producers, which is likely to affect the transfer of energy to higher trophic levels.     

Different dose regimens of a SARS-CoV-2 recombinant spike protein vaccine (NVX-CoV2373) in younger and older adults: A phase 2 randomized placebo-controlled trial

BackgroundNVX-CoV2373 is a recombinant severe acute respiratory coronavirus 2 (rSARS-CoV-2) nanoparticle vaccine composed of trimeric full-length SARS-CoV-2 spike glycoproteins and Matrix-M1 adjuvant.Methods and findingsThe phase 2 component of our randomized, placebo-controlled, phase 1 to 2 trial was designed to identify which dosing regimen of NVX-CoV2373 should move forward into late-phase studies and was based on immunogenicity and safety data through Day 35 (14 days after the second dose). The trial was conducted at 9 sites in Australia and 8 sites in the United States. Participants in 2 age groups (aged 18 to 59 and 60 to 84 years) were randomly assigned to receive either 1 or 2 intramuscular doses of 5-μg or 25-μg NVX-CoV2373 or placebo, 21 days apart. Primary endpoints were immunoglobulin G (IgG) anti-spike protein response, 7-day solicited reactogenicity, and unsolicited adverse events. A key secondary endpoint was wild-type virus neutralizing antibody response. After enrollment, 1,288 participants were randomly assigned to 1 of 4 vaccine groups or placebo, with 1,283 participants administered at least 1 study treatment. Of these, 45% were older participants 60 to 84 years. Reactogenicity was predominantly mild to moderate in severity and of short duration (median <3 days) after first and second vaccination with NVX-CoV2373, with higher frequencies and intensity after second vaccination and with the higher dose. Reactogenicity occurred less frequently and was of lower intensity in older participants. Both 2-dose regimens of 5-μg and 25-μg NVX-CoV2373 induced robust immune responses in younger and older participants. For the 2-dose regimen of 5 μg, geometric mean titers (GMTs) for IgG anti-spike protein were 65,019 (95% confidence interval (CI) 55,485 to 76,192) and 28,137 (95% CI 21,617 to 36,623) EU/mL and for wild-type virus neutralizing antibody (with an inhibitory concentration of 50%—MN_50%) were 2,201 (95% CI 1,343 to 3,608) and 981 (95% CI 560 to 1,717) titers for younger and older participants, respectively, with seroconversion rates of 100% in both age groups. Neutralizing antibody responses exceeded those seen in a panel of convalescent sera for both age groups. Study limitations include the relatively short duration of safety follow-up to date and current lack of immune persistence data beyond the primary vaccination regimen time point assessments, but these data will accumulate over time.ConclusionsThe study confirmed the phase 1 findings that the 2-dose regimen of 5-μg NVX-CoV2373 is highly immunogenic and well tolerated in younger adults. In addition, in older adults, the 2-dose regimen of 5 μg was also well tolerated and showed sufficient immunogenicity to support its use in late-phase efficacy studies.Trial registrationClinicalTrials.gov{"type":"clinical-trial","attrs":{"text":"NCT04368988","term_id":"NCT04368988"}}NCT04368988.

In a phase 2 randomized placebo-controlled trial, Neil Formica and coauthors investigate the immunogenicity and safety of different dose regimens of a SARS-CoV-2 recombinant spike protein vaccine in younger and older adults in USA and Australia.     

Assessing anthropogenic impact on boreal lakes with historical fish species distribution data and hydrogeochemical modeling

Quantifying the effects of human activity on the natural environment is dependent on credible estimates of reference conditions to define the state of the environment before the onset of adverse human impacts. In Europe, emission controls that aimed at restoring ecological status were based on hindcasts from process‐based models or paleolimnological reconstructions. For instance, 1860 is used in Europe as the target for restoration from acidification concerning biological and chemical parameters. A more practical problem is that the historical states of ecosystems and their function cannot be observed directly. Therefore, we (i) compare estimates of acidification based on long‐term observations of roach (Rutilus rutilus) populations with hindcast pH from the hydrogeochemical model MAGIC; (ii) discuss policy implications and possible scope for use of long‐term archival data for assessing human impacts on the natural environment and (iii) present a novel conceptual model for interpreting the importance of physico‐chemical and ecological deviations from reference conditions. Of the 85 lakes studied, 78 were coherently classified by both methods. In 1980, 28 lakes were classified as acidified with the MAGIC model, however, roach was present in 14 of these. In 2010, MAGIC predicted chemical recovery in 50% of the lakes, however roach only recolonized in five lakes after 1990, showing a lag between chemical and biological recovery. Our study is the first study of its kind to use long‐term archival biological data in concert with hydrogeochemical modeling for regional assessments of anthropogenic acidification. Based on our results, we show how the conceptual model can be used to understand and prioritize management of physico‐chemical and ecological effects of anthropogenic stressors on surface water quality.     

In Vivo Evaluation of Blood Based and Reference Tissue Based PET Quantifications of [11C]DASB in the Canine Brain

This first-in-dog study evaluates the use of the PET-radioligand [¹¹C]DASB to image the density and availability of the serotonin transporter (SERT) in the canine brain. Imaging the serotonergic system could improve diagnosis and therapy of multiple canine behavioural disorders. Furthermore, as many similarities are reported between several human neuropsychiatric conditions and naturally occurring canine behavioural disorders, making this tracer available for use in dogs also provide researchers an interesting non-primate animal model to investigate human disorders. Five adult beagles underwent a 90 minutes dynamic PET scan and arterial whole blood was sampled throughout the scan. For each ROI, the distribution volume (V_T), obtained via the one- and two- tissue compartment model (1-TC, 2-TC) and the Logan Plot, was calculated and the goodness-of-fit was evaluated by the Akaike Information Criterion (AIC). For the preferred compartmental model BP_ND values were estimated and compared with those derived by four reference tissue models: 4-parameter RTM, SRTM2, MRTM2 and the Logan reference tissue model. The 2-TC model indicated in 61% of the ROIs a better fit compared to the 1-TC model. The Logan plot produced almost identical V_T values and can be used as an alternative. Compared with the 2-TC model, all investigated reference tissue models showed high correlations but small underestimations of the BP_ND-parameter. The highest correlation was achieved with the Logan reference tissue model (Y = 0.9266 x + 0.0257; R² = 0.9722). Therefore, this model can be put forward as a non-invasive standard model for future PET-experiments with [¹¹C]DASB in dogs.