Disk-covering, a fast-converging method for phylogenetic tree reconstruction.

The evolutionary history of a set of species is represented by a phylogenetic tree, which is a rooted, leaf-labeled tree, where internal nodes represent ancestral species and the leaves represent modern day species. Accurate (or even boundedly inaccurate) topology reconstructions of large and divergent trees from realistic length sequences have long been considered one of the major challenges in systematic biology. In this paper, we present a simple method, the Disk-Covering Method (DCM), which boosts the performance of base phylogenetic methods under various Markov models of evolution. We analyze the performance of DCM-boosted distance methods under the Jukes-Cantor Markov model of biomolecular sequence evolution, and prove that for almost all trees, polylogarithmic length sequences suffice for complete accuracy with high probability, while polynomial length sequences always suffice. We also provide an experimental study based upon simulating sequence evolution on model trees. This study confirms substantial reductions in error rates at realistic sequence lengths.     

Rituximab treatment in rheumatoid arthritis: how does it work?

Treatment with the chimerical monoclonal antibody rituximab results in CD20-directed B cell depletion. Although this depletion is almost complete in the peripheral blood of nearly all patients with rheumatoid arthritis, a proportion of patients does not exhibit a clinical response. The paper by Nakou and colleagues suggests that a decrease in CD19+CD27+ memory B cells in both peripheral blood and bone marrow precedes the clinical response to rituximab. This finding adds to the emerging evidence that lack of response to rituximab is associated with persistence of B lineage cells in specific body compartments.     

Epidemiologic features of an intracranial abscessation/suppurative meningoencephalitis complex in white-tailed deer

Case records of 683 white-tailed deer (Odocoileus virginianus) submitted to the Southeastern Cooperative Wildlife Disease Study (Georgia, USA) for diagnostic purposes from 1971 to 1989 were reviewed for the occurrence of pyogenic infections of the central nervous system, specifically intracranial abscessation or suppurative meningoencephalitis. These conditions, either alone or in combination, were diagnosed in 24 of 683 (4%) deer. Thirteen genera of bacteria were isolated; the most frequent species was Actinomyces pyogenes. The disease was strongly sex biased (P less than 0.01); 88% of the cases occurred in males. Cases were more prevalent (P less than 0.05) in older bucks; the median age of infected bucks was 3.2 yr, and 71% of these were greater than or equal to 2.5-yr-old. Intracranial abscessation/suppurative meningoencephalitis cases accounted for 20% of the diagnoses among 56 bucks greater than or equal to 3-yr-old. Cases were seasonal, occurring only from October to April. Characteristic necrosis, erosion, and pitting of skull bones were common, and this bone damage may be useful in determining cause of death when only skeletal remains are found. Males, especially older bucks, apparently are predisposed to intracranial abscessation/suppurative meningoencephalitis because of the cycle of antler development and behavioral traits associated with reproduction. The strong bias toward prime age bucks suggests that these infections could specifically hinder management strategies designed to produce populations with older buck age structures.     

Molecular docking of alkaloid compounds with the matrix metalloproteinase 2

Matrix metalloproteinase protein-2 (MMP-2) is linked to the human oral squamous cell carcinoma. Therefore, it is of interest to design new inhibitors for MMP-2 to combat the disease. Thus, we document the molecular docking features of Aristolochic acid, Cryptopleurine, Epipodophyllotoxin, and Fagaronine with MMP-2 for further consideration.     

MARCH6 and TRC8 facilitate the quality control of cytosolic and tail‐anchored proteins

Misfolded or damaged proteins are typically targeted for destruction by proteasome‐mediated degradation, but the mammalian ubiquitin machinery involved is incompletely understood. Here, using forward genetic screens in human cells, we find that the proteasome‐mediated degradation of the soluble misfolded reporter, mCherry‐CL1, involves two ER‐resident E3 ligases, MARCH6 and TRC8. mCherry‐CL1 degradation is routed via the ER membrane and dependent on the hydrophobicity of the substrate, with complete stabilisation only observed in double knockout MARCH6/TRC8 cells. To identify a more physiological correlate, we used quantitative mass spectrometry and found that TRC8 and MARCH6 depletion altered the turnover of the tail‐anchored protein heme oxygenase‐1 (HO‐1). These E3 ligases associate with the intramembrane cleaving signal peptide peptidase (SPP) and facilitate the degradation of HO‐1 following intramembrane proteolysis. Our results highlight how ER‐resident ligases may target the same substrates, but work independently of each other, to optimise the protein quality control of selected soluble and tail‐anchored proteins.     

Improved Crystallographic Structures Using Extensive Combinatorial Refinement

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Repeated low-level infection of white-tailed deer with Parelaphostrongylus andersoni

Two white-tailed deer (Odocoileus virginianus) were given 5 infective larvae of Parelaphostrongylus andersoni each weekday for 13 weeks. At 23 weeks one of these deer and a control were challenged with single doses of 200 third-stage larvae. Repeated low-level infection of P. andersoni resulted in a sustained leukocytosis with an absolute eosinophilia which declined only after administration of larvae ceased, partial failure of worms to become established in the musculature, reduced numbers and reduced viability of eggs in the lungs, and an apparent active immunity which enabled the deer to resist challenge. The results of this study suggest that wild deer become infected with P. andersoni by isolated chance encounters with infected gastropods.     

In situ cross-linking of elastin-like polypeptide block copolymers for tissue repair

Rapid cross-linking of elastin-like polypeptides (ELPs) with hydroxymethylphosphines (HMPs) in aqueous solution is attractive for minimally invasive in vivo implantation of biomaterials and tissue engineering scaffolds. In order to examine the independent effect of the location and number of reactive sites on the chemical cross-linking kinetics of ELPs and the mechanical properties of the resulting hydrogels, we have designed ELP block copolymers comprised of cross-linkable, hydrophobic ELP blocks with periodic Lys residues (A block) and aliphatic, hydrophilic ELP blocks with no cross-linking sites (B block); three different block architectures, A, ABA, and BABA were synthesized in this study. All ELP block copolymers were rapidly cross-linked with HMPs within several minutes under physiological conditions. The inclusion of the un-cross-linked hydrophilic block, its length relative to the cross-linkable hydrophobic block, and the block copolymer architecture all had a significant effect on swelling ratios of the cross-linked hydrogels, their microstructure, and mechanical properties. Fibroblasts embedded in the ELP hydrogels survived the cross-linking process and remained viable for at least 3 days in vitro when the gels were formed from an equimolar ratio of HMPs and Lys residues of ELPs. DNA quantification of the embedded cells indicated that the cell viability within triblock ELP hydrogels was statistically greater than that in the monoblock gels at day 3. These results suggest that the mechanical properties of ELP hydrogels and the microenvironment that they present to cells can be tuned by the design of the block copolymer architecture.