The titin A-band rod domain is dispensable for initial thick filament assembly in zebrafish

The sarcomeres of skeletal and cardiac muscle are highly structured protein arrays, consisting of thick and thin filaments aligned precisely to one another and to their surrounding matrix. The contractile mechanisms of sarcomeres are generally well understood, but how the patterning of sarcomeres is initiated during early skeletal muscle and cardiac development remains uncertain. Two of the most widely accepted hypotheses for this process include the “molecular ruler” model, in which the massive protein titin defines the length of the sarcomere and provides a scaffold along which the myosin thick filament is assembled, and the “premyofibril” model, which proposes that thick filament formation does not require titin, but that a “premyofibril” consisting of non-muscle myosin, α-actinin and cytoskeletal actin is used as a template. Each model posits a different order of necessity of the various components, but these have been difficult to test in vivo. Zebrafish motility mutants with developmental defects in sarcomere patterning are useful for the elucidation of such mechanisms, and here we report the analysis of the herzschlag mutant, which shows deficits in both cardiac and skeletal muscle. The herzschlag mutant produces a truncated titin protein, lacking the C-terminal rod domain that is proposed to act as a thick filament scaffold, yet muscle patterning is still initiated, with grossly normal thick and thin filament assembly. Only after embryonic muscle contraction begins is breakdown of sarcomeric myosin patterning observed, consistent with the previously noted role of titin in maintaining the contractile integrity of mature sarcomeres. This conflicts with the “molecular ruler” model of early sarcomere patterning and supports a titin-independent model of thick filament organization during sarcomerogenesis. These findings are also consistent with the symptoms of human titin myopathies that exhibit a late onset, such as tibial muscular dystrophy.     

Quantitative prediction of the effect of genetic variation using hidden Markov models

Background

With the development of sequencing technologies, more and more sequence variants are available for investigation. Different classes of variants in the human genome have been identified, including single nucleotide substitutions, insertion and deletion, and large structural variations such as duplications and deletions. Insertion and deletion (indel) variants comprise a major proportion of human genetic variation. However, little is known about their effects on humans. The absence of understanding is largely due to the lack of both biological data and computational resources.

Results

This paper presents a new indel functional prediction method HMMvar based on HMM profiles, which capture the conservation information in sequences. The results demonstrate that a scoring strategy based on HMM profiles can achieve good performance in identifying deleterious or neutral variants for different data sets, and can predict the protein functional effects of both single and multiple mutations.

Conclusions

This paper proposed a quantitative prediction method, HMMvar, to predict the effect of genetic variation using hidden Markov models. The HMM based pipeline program implementing the method HMMvar is freely available at https://bioinformatics.cs.vt.edu/zhanglab/hmm.     

Effects of melanin-concentrating hormone on licking microstructure and brief-access taste responses

The effects of intracerebroventricular application of melanin-concentrating hormone (MCH) on licking for sucrose, quinine hydrochloride (QHCl), and water solutions were evaluated in two experiments. In experiment 1, rats received 90-min access to sucrose and water solutions after MCH or vehicle microinjection to the third ventricle (3V). MCH increased intake largely through increases in the rate of licking early in the meal and in the mean duration of lick bursts, suggesting an effect on gustatory evaluation. Therefore, in experiment 2, brief access tests were used with a series of sucrose and QHCl concentrations to behaviorally isolate the effects of intracerebroventricular MCH on gustatory evaluation. MCH uniformly increased licking for all sucrose solutions, water, and weak concentrations of QHCl; however, it had no effect on licking for the strongest concentrations of QHCl, which were generally avoided under control conditions. Thus MCH did not produce nonspecific increases in oromotor activity, nor did it change the perceived intensity of the tastants. We conclude that MCH enhanced the gain of responses to normally accepted stimuli at a phase of processing after initial gustatory detection and after the decision to accept or reject the taste stimulus. A comparison of 3V NPY and MCH effects on licking microstructure indicated that these two peptides increased intake via dichotomous behavioral processes; although NPY suppressed measures associated with inhibitory feedback from the gut, MCH appeared instead to enhance measures associated with hedonic taste evaluation.     

Population-level resource selection by sympatric brown and American black bears in Alaska

Distribution theory predicts that for two species living in sympatry, the subordinate species would be constrained from using the most suitable resources (e.g., habitat), resulting in its use of less suitable habitat and spatial segregation between species. We used negative binomial generalized linear mixed models with fixed effects to estimate seasonal population-level resource selection at two spatial resolutions for female brown bears (Ursus arctos) and female American black bears (U. americanus) in southcentral Alaska during May–September 2000. Black bears selected areas occupied by brown bears during spring which may be related to spatially restricted (i.e., restricted to low elevations) but dispersed or patchy availability of food. In contrast, black bears avoided areas occupied by brown bears during summer. Brown bears selected areas near salmon streams during summer, presumably to access spawning salmon. Use of areas with high berry production by black bears during summer appeared in response to avoidance of areas containing brown bears. Berries likely provided black bears a less nutritious, but adequate food source. We suggest that during summer, black bears were displaced by brown bears, which supports distribution theory in that black bears appeared to be partially constrained from areas containing salmon, resulting in their use of areas containing less nutritious forage. Spatial segregation of brown and American black bears apparently occurs when high-quality resources are spatially restricted and alternate resources are available to the subordinate species. This and previous work suggest that individual interactions between species can result in seasonal population-level responses.     

Climate-Driven Effects of Fire on Winter Habitat for Caribou in the Alaskan-Yukon Arctic

Climatic warming has direct implications for fire-dominated disturbance patterns in northern ecosystems. A transforming wildfire regime is altering plant composition and successional patterns, thus affecting the distribution and potentially the abundance of large herbivores. Caribou (Rangifer tarandus) are an important subsistence resource for communities throughout the north and a species that depends on terrestrial lichen in late-successional forests and tundra systems. Projected increases in area burned and reductions in stand ages may reduce lichen availability within caribou winter ranges. Sufficient reductions in lichen abundance could alter the capacity of these areas to support caribou populations. To assess the potential role of a changing fire regime on winter habitat for caribou, we used a simulation modeling platform, two global circulation models (GCMs), and a moderate emissions scenario to project annual fire characteristics and the resulting abundance of lichen-producing vegetation types (i.e., spruce forests and tundra >60 years old) across a modeling domain that encompassed the winter ranges of the Central Arctic and Porcupine caribou herds in the Alaskan-Yukon Arctic. Fires were less numerous and smaller in tundra compared to spruce habitats throughout the 90-year projection for both GCMs. Given the more likely climate trajectory, we projected that the Porcupine caribou herd, which winters primarily in the boreal forest, could be expected to experience a greater reduction in lichen-producing winter habitats (−21%) than the Central Arctic herd that wintered primarily in the arctic tundra (−11%). Our results suggest that caribou herds wintering in boreal forest will undergo fire-driven reductions in lichen-producing habitats that will, at a minimum, alter their distribution. Range shifts of caribou resulting from fire-driven changes to winter habitat may diminish access to caribou for rural communities that reside in fire-prone areas.