HDAC inhibitors potentiate the apoptotic effect of enzastaurin in lymphoma cells

Enzastaurin is an investigational PKCβ inhibitor that has growth inhibitory and pro-apoptotic effects in both B and T-cell lymphomas. We investigated the cytotoxicity and mechanisms of cell death of the combination of enzastaurin and low concentrations of histone deacetylase (HDAC) inhibitors in B-cell and T-cell lymphoma cell lines and primary lymphoma/leukemia cells. Combined enzastaurin/suberoylanilide hydroxamic acid treatment synergistically induced apoptosis in diffuse large B-cell lymphoma and T-cell lymphoma cell lines, and primary lymphoma/leukemia samples. Similarly, combined treatment of B-cell-like lymphoma cells with enzastaurin and two different HDAC inhibitors, valproic acid and (2E,4E)-6-(4-chlorophenylsulfanyl)-2,4-hexadienoic acid hydroxyamide synergistically induced apoptosis, suggesting the synergy is generalizable to other HDAC inhibitors. Our data indicate that enzastaurin/HDAC inhibitors therapy can synergistically inhibit growth and induce apoptosis in lymphoid malignancies and may be an effective therapeutic strategy. Potential mechanisms including enzastaurin mediated inhibition of HDAC inhibitor-induced compensatory survival pathways are discussed.     

Secondary Structure,a Missing Component of Sequence-Based Minimotif Definitions

Minimotifs are short contiguous segments of proteins that have a known biological function. The hundreds of thousands of minimotifs discovered thus far are an important part of the theoretical understanding of the specificity of protein-protein interactions, posttranslational modifications, and signal transduction that occur in cells. However, a longstanding problem is that the different abstractions of the sequence definitions do not accurately capture the specificity, despite decades of effort by many labs. We present evidence that structure is an essential component of minimotif specificity, yet is not used in minimotif definitions. Our analysis of several known minimotifs as case studies, analysis of occurrences of minimotifs in structured and disordered regions of proteins, and review of the literature support a new model for minimotif definitions that includes sequence, structure, and function.     

A simple parallel gas chromatography column screening system

A simple approach to the automated screening of four different columns on a single gas chromatography (GC) instrument is used for rapid chiral GC method development. Configuration of a conventional GC instrument with a second autosampler and several inexpensive Y-splitters enables simultaneous evaluation of two different columns, allowing a total of four different columns to be evaluated in two automated back to back runs. The resulting system affords a simple and effective approach to chiral GC method development that speeds analysis while eliminating the need for slow and tedious manual interchange of columns. An example of developing a rapid isothermal GC method from the screening results obtained by the instrument is also shown.     

An inclusive fitness analysis of synergistic interactions in structured populations

We study the evolution of a pair of competing behavioural alleles in a structured population when there are non-additive or ‘synergistic’ fitness effects. Under a form of weak selection and with a simple symmetry condition between a pair of competing alleles, Tarnita et al. provide a surprisingly simple condition for one allele to dominate the other. Their condition can be obtained from an analysis of a corresponding simpler model in which fitness effects are additive. Their result uses an average measure of selective advantage where the average is taken over the long-term—that is, over all possible allele frequencies—and this precludes consideration of any frequency dependence the allelic fitness might exhibit. However, in a considerable body of work with non-additive fitness effects—for example, hawk–dove and prisoner''s dilemma games—frequency dependence plays an essential role in the establishment of conditions for a stable allele-frequency equilibrium. Here, we present a frequency-dependent generalization of their result that provides an expression for allelic fitness at any given allele frequency p. We use an inclusive fitness approach and provide two examples for an infinite structured population. We illustrate our results with an analysis of the hawk–dove game.     

Modeling the role of environmental variables on the population dynamics of the malaria vector Anopheles gambiae sensu stricto

ABSTRACT: BACKGROUND: The impact of weather and climate on malaria transmission has attracted considerable attention in recent years, yet uncertainties around future disease trends under climate change remain. Mathematical models provide powerful tools for addressing such questions and understanding the implications for interventions and eradication strategies, but these require realistic modeling of the vector population dynamics and its response to environmental variables. METHODS: Published and unpublished field and experimental data are used to develop new formulations for modeling the relationships between key aspects of vector ecology and environmental variables. These relationships are integrated within a validated deterministic model of Anopheles gambiae s.s. population dynamics to provide a valuable tool for understanding vector response to biotic and abiotic variables. RESULTS: A novel, parsimonious framework for assessing the effects of rainfall, cloudiness, wind speed, desiccation, temperature, relative humidity and density-dependence on vector abundance is developed, allowing ease of construction, analysis, and integration into malaria transmission models. Model validation shows good agreement with longitudinal vector abundance data from Tanzania, suggesting that recent malaria reductions in certain areas of Africa could be due to changing environmental conditions affecting vector populations. CONCLUSIONS: Mathematical models provide a powerful, explanatory means of understanding the role of environmental variables on mosquito populations and hence for predicting future malaria transmission under global change. The framework developed provides a valuable advance in this respect, but also highlights key research gaps that need to be resolved if we are to better understand future malaria risk in vulnerable communities.     

Branches of the right pulmonary artery supplying the basal segments of the lung.

The studies were carried out on 100 right lungs taken from dead human bodies of both sexes whose age varied from 16 to 81 years. The pulmonary artery and the bronchus were injected with a 65% solution of duracryl and then digested in sulfuric acid. The specimens obtained were then examined to determine the number and dimensions of the branches of the basal portion of the right pulmonary artery (RPA) penetrating into the basal segments of the right lower pulmonary lobe. Their length was 52 mm at the most, and their diameter 14 mm. Three types of ramification of the basal portion of the RPA were distinguished on the basis of the trunks, segmental and subsegmental branches present. In 72% of the cases the branches penetrating into the basal segments showed a tree-like type, in 2% of the cases a bushy-like type and in 26% of the cases a middle type.     

SPY Imaging Assessment Correlates With Transesophageal Echocardiogram Assessment of Ventricular Function During Off-Pump Coronary Artery Bypass Grafting

Intraoperative assessment of graft anastomoses is commonly performed after off-pump coronary artery bypass grafting (OPCAB). The SPY imaging system allows intraoperative graft assessment. We document correlation between intraoperative SPY images and wall motion abnormality by transesophageal echocardiogram (TEE) during OPCAB. A 79-year-old female underwent OPCAB. Intraoperative graft patency assessment was performed with the SPY and left ventricular wall motion was assessed by TEE. SPY imaging demonstrated poor flow trough the distal vein graft anastomosis to the posterior descending artery, which correlated with a new posterior wall motion hypokinesis. After graft revision, SPY imaging demonstrated good distal flow and the TEE demonstrated normalization of the left ventricular posterior wall motion. SPY technology allows the surgeon to accurately assess graft patency intraoperatively and allows immediate correction of a technical problem.