Charged residues on the side of the nucleosome contribute to normal Spt16-gene interactions in budding yeast

Previous work in Saccharomyces cerevisiae identified three residues located in close proximity to each other on the side of the nucleosome whose integrity is required for proper association of the Spt16 component of the FACT complex across transcribed genes. In an effort to gain further insights into the parameters that control Spt16 interactions with genes in vivo, we tested the effects of additional histone mutants on Spt16 occupancy across two constitutively transcribed genes. These studies revealed that mutations in several charged residues in the vicinity of the three residues originally identified as important for Spt16-gene interactions also significantly perturb normal association of Spt16 across genes. Based on these and our previous findings, we propose that the charge landscape across the region encompassed by these residues, which we refer to as the Influences Spt16-Gene Interactions or ISGI region, is an important contributor to proper Spt16-gene interactions in vivo.     

Mice with endogenous TDP‐43 mutations exhibit gain of splicing function and characteristics of amyotrophic lateral sclerosis

TDP‐43 (encoded by the gene TARDBP) is an RNA binding protein central to the pathogenesis of amyotrophic lateral sclerosis (ALS). However, how TARDBP mutations trigger pathogenesis remains unknown. Here, we use novel mouse mutants carrying point mutations in endogenous Tardbp to dissect TDP‐43 function at physiological levels both in vitro and in vivo. Interestingly, we find that mutations within the C‐terminal domain of TDP‐43 lead to a gain of splicing function. Using two different strains, we are able to separate TDP‐43 loss‐ and gain‐of‐function effects. TDP‐43 gain‐of‐function effects in these mice reveal a novel category of splicing events controlled by TDP‐43, referred to as “skiptic” exons, in which skipping of constitutive exons causes changes in gene expression. In vivo, this gain‐of‐function mutation in endogenous Tardbp causes an adult‐onset neuromuscular phenotype accompanied by motor neuron loss and neurodegenerative changes. Furthermore, we have validated the splicing gain‐of‐function and skiptic exons in ALS patient‐derived cells. Our findings provide a novel pathogenic mechanism and highlight how TDP‐43 gain of function and loss of function affect RNA processing differently, suggesting they may act at different disease stages.     

Design and synthesis of potent RSK inhibitors

Utilizing the already described 3,4-bi-aryl pyridine series as a starting point, incorporation of a second ring system with a hydrogen bond donor and additional hydrophobic contacts yielded the azaindole series which exhibited potent, picomolar RSK2 inhibition and the most potent in vitro target modulation seen thus far for a RSK inhibitor. In the context of the more potent core, several changes at the phenol moiety were assessed to potentially find a tool molecule appropriate for in vivo evaluation.     

Seasonal dynamics of agonistic behavior and hormones in an ex situ all‐male colony of large flying foxes

Large flying foxes (Pteropus vampyrus) are a socially complex species. In situ colonies typically comprise thousands of individuals in small harems of one male to many females. In ex situ environments, all‐male colonies are becoming more common due to a surplus of males in the population. There is limited information describing the hormonal and behavioral patterns of all‐male colonies during the breeding season. We assessed seasonal changes in hormones and behavior in an all‐male colony of 12 large flying foxes at Disney's Animal Kingdom^®. We validated hormone assays using morning urine and fecal samples to assess seasonal changes in excreted immunoreactive testosterone and glucocorticoid metabolites. We collected behavior data using an all‐occurrence method, recording agonistic behaviors related to territorial defense (hooking, biting, wing flexing, vocalizing, and wrestling), and sexual behavior (mounting and frontal grabbing). Results indicated that (i) we could reliably measure testosterone and glucocorticoid metabolites concentrations from fecal and urine samples collected from individual bats; (ii) there were distinct relationships between changes in levels of agonism and hormone concentrations throughout the year; and (iii) three agonistic behaviors (chasing, wrestling, and open‐mouth threat) peaked prior to the increase in testosterone and glucocorticoid hormones measured during the breeding season. These three behaviors could potentially be used as early indicators to signal the onset of the breeding season and allow time to implement ex situ management changes to reduce the incidence of agonism between individuals.     

Lipid levels,insulin resistance and cardiovascular risk over 96 weeks of antiretroviral therapy: a randomised controlled trial comparing low-dose stavudine and tenofovir

Background

HIV infection and antiretroviral treatment are associated with changes in lipid levels, insulin resistance and risk of cardiovascular disease (CVD). We investigated these changes in the first 96 weeks of treatment with low-dose stavudine or tenofovir regimens.

Methods

This is a secondary analysis of a double blind, randomised controlled trial performed in South-Africa, Uganda and India comparing low-dose stavudine (20 mg twice daily) with tenofovir in combination with efavirenz and lamivudine in antiretroviral-naïve adults (n?=?1067) (Clinicaltrials.gov, NCT02670772). Over 96 weeks, data were collected on fasting lipids, glucose and insulin. Insulin resistance was assessed with the HOMA-IR index and 10-year CVD risk with the Framingham risk score (FRS). A generalized linear mixed model was used to estimate trends over time.

Results

Participants were on average 35.3 years old, 57.6% female and 91.8% Black African. All lipid levels increased following treatment initiation, with the sharpest increase in the first 24 weeks of treatment. The increase in all lipid subcomponents over 96 weeks was higher among those in the stavudine than the tenofovir group. Insulin resistance increased steadily with no difference detected between study groups. FRS rose from 1.90% (1.84–1.98%) at baseline to 2.06 (1.98–2.15%) at week 96 for the total group, with no difference between treatment arms (p?=?0.144). Lipid changes were more marked in Indian than African participants.

Conclusion

Lipid levels increased in both groups, with low-dose stavudine resulting in a worse lipid profile compared to tenofovir. Insulin resistance increased, with no difference between regimens. CVD risk increased over time and tended to increase more in the group on stavudine. The low CVD risk across both arms argues against routine lipid and glucose monitoring in the absence of other CVD risk factors. In high risk patients, monitoring may only be appropriate at least a year after treatment initiation.

     

Livestock exclusion alters plant species composition in fen meadows

Questions

Our study evaluated how species composition and plant traits that indicate functioning condition in fens responded to grazing cessation over time in an arid ecosystem of the western US. The specific questions addressed were: (i) how does livestock exclusion influence species composition in fens; (ii) is grazing cessation associated with shifts in species functional traits that indicate fen condition; and (iii) what is the pattern of response to livestock exclusion over time?

Location

Plumas National Forest, California, US.

Methods

We studied paired fenced and unfenced study sites in two fens to examine the effects of livestock exclusion. Parallel transects were established at each site, and plant species and ground cover were repeatedly surveyed, once prior to and multiple times following treatment, using 0.01 m² frequency frames. We used NMDS to analyse species composition, RLQ and fourth‐corner analysis to evaluate species functional traits and environmental variables, and linear mixed effects models to examine differences in responses between fenced and unfenced study sites over time.

Results

After fencing, we observed unexpected shifts in species composition and plant functional traits. Grazed sites were associated with peat‐forming obligate wetland, moss and sedge species, while fenced sites were characterized by non‐peat‐forming facultative upland, and upland forb, grass and early seral species. Species composition also varied between sites and sample years.

Conclusions

We found that livestock exclusion strongly affects plant species composition in fens, including promoting species with functional traits that indicate a loss of functioning condition, such as ruderal and upland species. Possible explanations for these observed shifts include: (1) biomass accumulation in the absence of herbivory, (2) competitive exclusion in fenced sites, (3) succession, (4) the abiotic conditions of our study sites, particularly hydrology and nutrient status, and (5) interactions among these factors. We conclude that degradation of fen wetlands caused by livestock grazing in the arid western US may not be reversed by excluding livestock alone.     

Decomposition of Senesced Leaf Litter is Faster in Tall Compared to Low Birch Shrub Tundra

Many Low Arctic tundra regions are currently undergoing a vegetation shift towards increasing growth and groundcover of tall deciduous shrubs due to recent climate warming. Vegetation change directly affects ecosystem carbon balance, but it can also affect soil biogeochemical cycling through physical and biological feedback mechanisms. Recent studies indicate that enhanced snow accumulation around relatively tall shrubs has negligible physical effect on litter decomposition rates. However, these investigations were no more than 3 years, and therefore may be insufficient to detect differences in inherently slow biogeochemical processes. Here, we report a 5-year study near Daring Lake, Canada, comparing Betula neoalaskana foliar litter decay rates within unmanipulated and snowfenced low-stature birch (height: ~?0.3 m) plots to test the physical effect of experimentally deepened snow, and within tall birch (height: ~?0.8 m) plots to test the combined physical and biological effects, that is, deepened snow plus strong birch dominance. Having corrected for carbon gain by the colonizing decomposers, actual litter carbon loss increased by approximately 25% in the tall birch relative to both low birch sites. Decay of lignin-like acid unhydrolizable litter residues also accelerated in the tall birch site, and a similar but lower magnitude response in the snowfenced low birch site indicated that physical effects of deepened snow were at least partially responsible. In contrast, deepened snow alone did not affect litter carbon loss. Our findings suggest that a combination of greater litter inputs, altered soil microbial community, enhanced soil nutrient pools, and warmer winter soils together promote relatively fast decomposition of recalcitrant litter carbon in tall birch shrub environments.     

Is the Wild Coast in eastern South Africa a distinct marine bioregion?

The South African coastline can be divided into at least four temperature-defined marine bioregions, including the tropical north-east coast, the subtropical east coast, the warm-temperate south coast, and the cool-temperate west coast. There are also two biogeographical transition zones, the south-west coast and the south-east coast (or Wild Coast). The former is sometimes considered a distinct marine bioregion, but no such status has yet been suggested for the Wild Coast. Previous data on the distribution of a recently described but very common coastal crab, Hymenosoma longicrure, indicated that this species could be a Wild Coast endemic. If confirmed, this would be a first indication that this region harbours unique fauna, and that additional research is required to determine whether the Wild Coast constitutes a distinct bioregion that needs to be managed separately from other coastal regions. In the present study, we generated novel genetic data for H. longicrure and compared the species’ range with that of its southern African congeners. We found that H. longicrure occurs north of the Wild Coast, where its range overlaps with that of H. projectum. This finding rejects the idea that the Wild Coast harbours endemic fauna and suggests that the ranges of the two species may be linked to the subtropical and tropical bioregions, respectively, with some southward dispersal facilitated by the southward-flowing Agulhas Current. We conclude that there is as yet no compelling evidence that the Wild Coast is a distinct marine bioregion, and concur with previous biogeographical studies which have suggested that the Wild Coast is an area in which species from the subtropical and warm-temperate bioregions have overlapping ranges. Nonetheless, that fact that no biological information is available for the majority of the region’s estuaries highlights the necessity of comprehensively documenting the biodiversity of this understudied region to fully resolve this issue.