Loss of JAK2 regulation via a heterodimeric VHL-SOCS1 E3 ubiquitin ligase underlies Chuvash polycythemia

Chuvash polycythemia is a rare congenital form of polycythemia caused by homozygous R200W and H191D mutations in the VHL (von Hippel-Lindau) gene, whose gene product is the principal negative regulator of hypoxia-inducible factor. However, the molecular mechanisms underlying some of the hallmark abnormalities of Chuvash polycythemia, such as hypersensitivity to erythropoietin, are unclear. Here we show that VHL directly binds suppressor of cytokine signaling 1 (SOCS1) to form a heterodimeric E3 ligase that targets phosphorylated JAK2 (pJAK2) for ubiquitin-mediated destruction. In contrast, Chuvash polycythemia-associated VHL mutants have altered affinity for SOCS1 and do not engage with and degrade pJAK2. Systemic administration of a highly selective JAK2 inhibitor, TG101209, reversed the disease phenotype in Vhl(R200W/R200W) knock-in mice, an experimental model that recapitulates human Chuvash polycythemia. These results show that VHL is a SOCS1-cooperative negative regulator of JAK2 and provide biochemical and preclinical support for JAK2-targeted therapy in individuals with Chuvash polycythemia.     

Further studies on short-term adaptations in the expression of lipogenic genes in broilers

This experiment was conducted to determine possible relationships between certain indices of lipid metabolism and specific gene expression in chickens fed graded levels of dietary crude protein. Male, broiler chickens (Gallus gallus) growing from 7 to 28days of age were fed diets containing 12 or 30% protein ad libitum. Both groups were then switched to the diets containing the opposite level of protein. Birds were sampled at 0, 6, 9, 12, 18 and 24h following the switch in protein levels. Measurements taken included in vitro lipogenesis (IVL), malic enzyme (ME), aspartate aminotransferase (AAT) and isocitrate dehydrogenase (NADP) (ICD) activities. In addition, ME, AAT, ICD, fatty acid synthase (FAS), and acetyl coenzyme carboxylase (ACC) gene expression rates were determined. IVL and ME activities were inversely related to dietary protein levels (12 to 30%) and to acute changes from 12 to 30%. In contrast, expression of ME, FAS and ACC genes was decreased by feeding a 30% protein diet (acute or chronic feeding). Results of the present study demonstrate a continued role for protein in the regulation of broiler metabolism. It should be pointed out; however, that metabolic regulation at the gene level only occurs when feeding very high or very low levels of dietary protein.     

An optimization-based sampling scheme for phylogenetic trees

Much modern work in phylogenetics depends on statistical sampling approaches to phylogeny construction to estimate probability distributions of possible trees for any given input data set. Our theoretical understanding of sampling approaches to phylogenetics remains far less developed than that for optimization approaches, however, particularly with regard to the number of sampling steps needed to produce accurate samples of tree partition functions. Despite the many advantages in principle of being able to sample trees from sophisticated probabilistic models, we have little theoretical basis for concluding that the prevailing sampling approaches do in fact yield accurate samples from those models within realistic numbers of steps. We propose a novel approach to phylogenetic sampling intended to be both efficient in practice and more amenable to theoretical analysis than the prevailing methods. The method depends on replacing the standard tree rearrangement moves with an alternative Markov model in which one solves a theoretically hard but practically tractable optimization problem on each step of sampling. The resulting method can be applied to a broad range of standard probability models, yielding practical algorithms for efficient sampling and rigorous proofs of accurate sampling for heated versions of some important special cases. We demonstrate the efficiency and versatility of the method by an analysis of uncertainty in tree inference over varying input sizes. In addition to providing a new practical method for phylogenetic sampling, the technique is likely to prove applicable to many similar problems involving sampling over combinatorial objects weighted by a likelihood model.     

Effects of dynein on microtubule mechanics and centrosome positioning

To determine forces on intracellular microtubules, we measured shape changes of individual microtubules following laser severing in bovine capillary endothelial cells. Surprisingly, regions near newly created minus ends increased in curvature following severing, whereas regions near new microtubule plus ends depolymerized without any observable change in shape. With dynein inhibited, regions near severed minus ends straightened rapidly following severing. These observations suggest that dynein exerts a pulling force on the microtubule that buckles the newly created minus end. Moreover, the lack of any observable straightening suggests that dynein prevents lateral motion of microtubules. To explain these results, we developed a model for intracellular microtubule mechanics that predicts the enhanced buckling at the minus end of a severed microtubule. Our results show that microtubule shapes reflect a dynamic force balance in which dynein motor and friction forces dominate elastic forces arising from bending moments. A centrosomal array of microtubules subjected to dynein pulling forces and resisted by dynein friction is predicted to center on the experimentally observed time scale, with or without the pushing forces derived from microtubule buckling at the cell periphery.     

A global experiment suggests climate warming will not accelerate litter decomposition in streams but might reduce carbon sequestration

The decomposition of plant litter is one of the most important ecosystem processes in the biosphere and is particularly sensitive to climate warming. Aquatic ecosystems are well suited to studying warming effects on decomposition because the otherwise confounding influence of moisture is constant. By using a latitudinal temperature gradient in an unprecedented global experiment in streams, we found that climate warming will likely hasten microbial litter decomposition and produce an equivalent decline in detritivore-mediated decomposition rates. As a result, overall decomposition rates should remain unchanged. Nevertheless, the process would be profoundly altered, because the shift in importance from detritivores to microbes in warm climates would likely increase CO(2) production and decrease the generation and sequestration of recalcitrant organic particles. In view of recent estimates showing that inland waters are a significant component of the global carbon cycle, this implies consequences for global biogeochemistry and a possible positive climate feedback.     

Population growth of Mexican free-tailed bats (Tadarida brasiliensis mexicana) predates human agricultural activity

Background  

Human activities, such as agriculture, hunting, and habitat modification, exert a significant effect on native species. Although many species have suffered population declines, increased population fragmentation, or even extinction in connection with these human impacts, others seem to have benefitted from human modification of their habitat. Here we examine whether population growth in an insectivorous bat (Tadarida brasiliensis mexicana) can be attributed to the widespread expansion of agriculture in North America following European settlement. Colonies of T. b. mexicana are extremely large (~10⁶ individuals) and, in the modern era, major agricultural insect pests form an important component of their food resource. It is thus hypothesized that the growth of these insectivorous bat populations was coupled to the expansion of agricultural land use in North America over the last few centuries.     

Morphological Characterization of a Low‐Bandgap Crystalline Polymer:PCBM Bulk Heterojunction Solar Cells

Understanding the morphology of polymer‐based bulk heterojunction (BHJ) solar cells is necessary to improve device efficiencies. Blends of a low‐bandgap silole‐containing conjugated polymer, poly[(4,4′‐bis(2‐ethylhexyl)dithieno[3,2‐b;2′,3′‐d]silole)‐2,6‐diyl‐alt‐(4,7‐bis(2‐thienyl)‐2,1,3‐benzothiadiazole)‐5,5′‐diyl] (PSBTBT) with [6,6]phenyl‐C61‐butyric acid methyl ester (PCBM) were investigated under different processing conditions. The surface morphologies and vertical segregation of the “As‐Spun”, “Pre‐Annealed”, and “Post‐Annealed” films were studied by scanning force microscopy, contact angle measurements, X‐ray photoelectron spectroscopy, near‐edge X‐ray absorption fine structure spectroscopy, dynamic secondary ion mass spectrometry, and neutron reflectivity. The results showed that PSBTBT was enriched at the cathode interface in the “As‐Spun” films and thermal annealing increased the segregation of PSBTBT to the free surface, while thermal annealing after deposition of the cathode increased the PCBM concentration at the cathode interface. Grazing‐incidence X‐ray diffraction and small‐angle neutron scattering showed that the crystallization of PSBTBT and segregation of PCBM occurred during spin coating, and thermal annealing increased the ordering of PSBTBT and enhanced the segregation of the PCBM, forming domains ～10 nm in size, leading to an improvement in photovoltaic performance.     

Cutaneous Mucormycosis in Tornado Survivors

A total of 18 suspected cases of cutaneous mucormycosis were identified in survivors of the May 2011 tornado in Joplin, Missouri. Apophysomyces trapeziformis was identified in 13 of the patients with microbiologically or histologically proven infection by DNA sequencing. Apophysomyces are classically associated with necrotizing skin and soft-tissue infections following traumatic inoculation of the fungal spores. Although cases of Apophysomyces infection were previously reported in survivors of tsunamis and volcanic eruptions, this is believed to be the first reported case series of cutaneous mucormycosis in tornado survivors.     

The impact of a filariasis control program on Lihir Island, Papua New Guinea

Background

Annual mass drug administration (MDA) over five years is the WHO''s recommended strategy to eliminate lymphatic filariasis (LF). Some experts, however, consider that longer periods of treatment might be necessary in certain high prevalence and transmission environments based upon past unsuccessful field experience and modelling.

Methodology/Principal Findings

To evaluate predictors of success in a LF control program we conducted an ecological study during a pre-existing MDA program. We studied 27 villages in Lihir Island, Papua New Guinea, from two areas with different infection rates before MDA. We undertook surveys to collect information on variables potentially having an influence on the outcome of the program, including epidemiological (baseline prevalence of infection, immigration rate), entomological (vector density) and operational (treatment coverage, vector control strategies) variables. The success in a village was defined using variables related to the infection (circulating filarial antigenemia prevalence <1%) and transmission (antigenemia prevalence <1 in 1000 children born since start of MDA). 8709 people were involved in the MDA program and average coverage rates were around 70%. The overall prevalence of filariasis fell from an initial 17.91% to 3.76% at round 5 (p<0.001). Viewed on a village by village basis, 12/27 (44%) villages achieved success. In multivariate analysis, low baseline prevalence was the only factor predicting both success in reducing infection rates (OR 19,26; CI 95% 1,12 to 331,82) and success in preventing new infections (OR 27,44; CI 95% 1,05 to 719,6). Low vector density and the use of an optimal vector control strategy were also associated with success in reducing infection rates, but this did not reach statistical significance.

Conclusions/Significance

Our results provide the data that supports the recommendation that high endemic areas may require longer duration MDA programs, or alternative control strategies.