E2F-1 is essential for normal epidermal wound repair.

E2F factors are involved in proliferation and apoptosis. To understand the role of E2F-1 in the epidermis, we screened wild type and E2F-1(-/-) keratinocyte mRNA for genes differentially expressed in the two cell populations. We demonstrate the reduced expression of integrins alpha(5), alpha(6), beta(1), and beta(4) in E2F-1(-/-) keratinocytes associated with reduced activation of Jun terminal kinase and Erk upon integrin stimulation. As a consequence of altered integrin expression and function, E2F-1(-/-) keratinocytes also show impaired migration, adhesion to extracellular matrix proteins, and a blunted chemotactic response to transforming growth factor-gamma1. E2F-1(-/-) keratinocytes, but not dermal fibroblasts, exhibit altered patterns of proliferation, including significant delays in transit through both G(1) and S phases of the cell cycle. Recognizing that proliferation and migration are key for proper wound healing in vivo, we postulated that E2F-1(-/-) mice may exhibit abnormal epidermal repair upon injury. Consistent with our hypothesis, E2F-1(-/-) mice exhibited impaired cutaneous wound healing. This defect is associated with substantially reduced local inflammatory responses and rates of re-epithelialization. Thus, we demonstrate that E2F-1 is indispensable for a hitherto unidentified cell type-specific and unique role in keratinocyte proliferation, adhesion, and migration as well as in proper wound repair and epidermal regeneration in vivo.     

Neogene paleobiogeography and East African paleoenvironments: contributions from the Tugen Hills rodents and lagomorphs.

A minimum of 28 genera of rodents and one genus of lagomorph were recovered from the Tugen Hills, Baringo District, Kenya, from localities dating from over 15.5 to about 4.4 Ma. The middle Miocene (sites dated between 15.8 and 15.3 Ma) rodent fauna recovered primarily from the Kipsaramon site complex, Muruyur Formation, includes a mixture of characteristically early Miocene taxa, and more derived forms. Composition of the African rodent fauna changes dramatically with the introduction of myocricetodontines, democricetodontines, and dendromurines, immigrants primarily from southern Asia. In the Tugen Hills, these taxa are first found in the Kabasero localities, Ngorora Formation, at sites dating from 12.5-12.33 Ma. A second major change in the African rodent fauna reflects the introduction of murines, immigrants from southern Asia. In the Tugen Hills murines are first encountered at Kapcheberek, Lukeino Formation, dated to 5.9-5.7 Ma. One rodent genus from the Lukeino Formation (Arvicanthis), and two from the Tabarin locality, Chemeron Formation (Heliosciurus, Paraxerus; 4.5-4.4 Ma), represent the earliest records of these extant African genera. A cricetomyine from the Ngorora Formation (12.5 Ma) is likely the earliest report of this exclusively African group. One of the earliest African records of porcupines (Hystricide) is from the Lukeino Formation. Lagomorphs are poorly represented, but include one of the earliest African occurrences of the family Leporidae from the Mpesida Beds (bracketed by dates of 7-6.2 Ma), and possibly a new genus of leporid from the Kapcheberek locality. Analysis of the Tugen Hills small mammals in association with other African records suggests several episodes of dispersal between Africa and Eurasia during the middle and late Miocene. Rodents from Kipsaramon are indicative of forests in conjunction with more open habitats. Those from the Kapcheberek locality are suggestive of a savanna habitat. The rodents from the Tabarin locality suggest a woodland environment.     

Dynamics of proteins predicted by molecular dynamics simulations and analytical approaches: application to alpha-amylase inhibitor

The dynamics of alpha-amylase inhibitors has been investigated using molecular dynamics (MD) simulations and two analytical approaches, the Gaussian network model (GNM) and anisotropic network model (ANM). MD simulations use a full atomic approach with empirical force fields, while the analytical approaches are based on a coarse-grained single-site-per-residue model with a single-parameter harmonic potential between sufficiently close (r 相似文献   

Role of water on unfolding kinetics of helical peptides studied by molecular dynamics simulations

Molecular dynamics simulations have been carried out with four polypeptides, Ala13, Val(13), Ser13, and Ala4Gly5Ala4, in vacuo and with explicit hydration. The unfolding of the polypeptides, which are initially fully alpha-helix in conformation, has been monitored during trajectories of 0.3 ns at 350 K. A rank of Ala < Val < Ser < Gly is found in the order of increasing rate of unwinding. The unfolding of Ala13 and Val(13) is completed in hundreds of picoseconds, while that of Ser13 is about one order of magnitude faster. The helix content of the peptide containing glycine residues falls to zero within a few picoseconds. Ramachandran plots indicate quite distinct equilibrium distributions and time evolution of dihedral angles in water and in vacuum for each residue type. The unfolding of polyalanine and polyvaline helices is accelerated due to solvation. In contrast, polyserine is more stable in water compared to vacuum, because its side chains can form intramolecular hydrogen bonds with the backbone more readily in vacuum, which disrupts the helix. Distribution functions of the spatial and angular position of water molecules in the proximity of the polypeptide backbone polar groups reveal the stabilization of the coiled structures by hydration. The transition from helix to coil is characterized by the appearance of a new peak in the probability distribution at a specific location characteristic of hydrogen bond formation between water and backbone polar groups. No significant insertion of water molecules is observed at the precise onset of unwinding, while (i, i+3) hydrogen bond formation is frequently detected at the initiation of alpha-helix unwinding.     

Efficacy of a Cladosporium sp. fungus against Helicoverpa armigera (Lepidoptera: Noctuidae), other insect pests and beneficial insects of cotton

A strain of the fungus Cladosporium sp. (RM16) from an egg of Helicoverpa armigera Hübner (Lepidoptera: Noctuidae) was assessed as a potential biocontrol agent for this pest. Pathogenicity of the fungus was tested against H. armigera eggs and larvae, cotton aphids (Aphis gossypii Glover; Homoptera: Aphididae), and silverleaf whitefly type B (Bemisia tabaci Gennadius; Hemiptera: Aleyrodidae). The pathogenicity of the fungus to the predatory red and blue beetles (Dicranolaius bellulus Guérin-Méneville; Coleoptera: Melyridae), transverse ladybird beetles (Coccinella transversalis Fabricius; Coleoptera: Coccinellidae), green lacewings (Mallada signatus Schneider; Neuroptera: Chrysopidae) and damsel bugs (Nabis kinbergii Reuter; Hemiptera: Nabidae), was also assessed in the laboratory. Fungus treatment resulted in failure to hatch of up to 64% of H. armigera eggs (compared with 11% in the controls) and mortality of 54% of first instar H. armigera larvae (compared with 5% in the controls). In contrast, it was not pathogenic to later instar H. armigera larvae. Cladosporium RM16 was also efficacious against the sap-sucking insect pests of cotton that were tested. No significant harmful effect of the fungus was found on any of the four beneficial predatory insects assessed in this study. Cladosporium RM16 has the potential as biological control agent to support integrated pest management in cotton farming systems, although this needs intensive study.     

Cost Effectiveness of Different Treatment Strategies in the Treatment of Patients with Moderate to Severe Rheumatoid Arthritis in China

Background

To analyse the cost-effectiveness of traditional disease-modifying anti-rheumatic drugs (tDMARDs) compared to biological therapies from the perspective of Chinese society.

Methodology/Principal Findings

A mathematical model was developed by incorporating the clinical trial data and Chinese unit costs and treatment sequences from a lifetime perspective. Hypothetical cohorts with moderate to severe RA were simulated. The primary outcome measure–quality-adjusted life years (QALYs)–was derived from disease severity (HAQ scores). Primary analysis included drug costs, monitoring costs, and other costs. Probabilistic and one-way sensitivity analyses were performed. Treatment sequences that included TNF antagonists and rituximab produced a greater number of QALYs than tDMARDs alone or TNF antagonists plus DMARDs. In comparison with tDMARDs, the incremental cost-effectiveness ratios (ICERs) for etanercept, infliximab, and adalimumab without rituximab were $77,357.7, $26,562.4 and $57,838.4 per QALY and $66,422.9, $28,780.6 and $50,937.6 per QALY, for etanercept, infliximab, and adalimumab with rituximab. No biotherapy was cost-effective under the willingness to pay threshold when the threshold was 3 times the per capita GDP of China. When 3 times the per capita GDP of Shanghai used as the threshold, infliximab and rituximab could yield nearly 90% cost-effective simulations in probabilistic sensitivity analysis.

Conclusions/Significance

tDMARD was the most cost-effective option in the Chinese healthcare setting. In some relatively developed regions in China, infliximab and rituximab may be a favorable cost-effective alternative for moderate to severe RA.     

Mapping N-linked glycosylation sites in the secretome and whole cells of Aspergillus niger using hydrazide chemistry and mass spectrometry

Protein glycosylation (e.g., N-linked glycosylation) is known to play an essential role in both cellular functions and secretory pathways; however, our knowledge of in vivo N-glycosylated sites is very limited for the majority of fungal organisms including Aspergillus niger. Herein, we present the first extensive mapping of N-glycosylated sites in A. niger by applying an optimized solid phase glycopeptide enrichment protocol using hydrazide-modified magnetic beads. The enrichment protocol was initially optimized using both mouse blood plasma and A. niger secretome samples, and it was demonstrated that the protein-level enrichment protocol offered superior performance over the peptide-level protocol. The optimized protocol was then applied to profile N-glycosylated sites from both the secretome and whole cell lysates of A. niger. A total of 847 N-glycosylated sites from 330 N-glycoproteins (156 proteins from the secretome and 279 proteins from whole cells) were confidently identified by LC-MS/MS. The identified N-glycoproteins in the whole cell lysate were primarily localized in the plasma membrane, endoplasmic reticulum, Golgi apparatus, lysosome, and storage vacuoles, supporting the important role of N-glycosylation in the secretory pathways. In addition, these glycoproteins are involved in many biological processes including gene regulation, signal transduction, protein folding and assembly, protein modification, and carbohydrate metabolism. The extensive coverage of N-glycosylated sites and the observation of partial glycan occupancy on specific sites in a number of enzymes provide important initial information for functional studies of N-linked glycosylation and their biotechnological applications in A. niger.     

A Simple and Widely Applicable Method for Preparing Homogeneous and Stable Quality Control Samples in Water Microbiology

Test strains suspended in skim milk, quickly frozen in dry ice-ethanol, and stored at - 70°C can be used as quality control samples that are immediately available by quickly thawing at 37°C. The samples remain homogeneous and stable for at least 1 year, except for Aeromonas hydrophila, which decreases 20 to 30% in 1 year.     

Interesting electrophysiological findings in a patient with coincidental right ventricular outflow tract and atrioventricular nodal reentrant tachycardia

Tachycardia induced tachycardias are not common in clinical practice, and it is believed that most cases of double tachycardia are coincidental. The existence of two different tachycardias in the same patient almost always poses problems in the electrophysiology laboratory. However, in rare instances, the emergence of a second tachycardia can actually provide invaluable information about the first one. In this report, we describe a 30-year-old woman who presented with palpitations. Electrophysiological study revealed that atrial programmed stimulation at baseline induced right ventricular outflow tract (RVOT) tachycardia and supraventricular tachycardia. The study also showed that each of the tachycardias was able to induce the other. A short run of RVOT tachycardia during supraventricular tachycardia was able to entrain the latter. This finding provided important information about the nature of the supraventricular tachycardia, which proved to be atrioventricular nodal reentrant tachycardia. Both of these tachycardias were successfully ablated, and the patient's palpitations disappeared.