Modeling the Effects of Drug Binding on the Dynamic Instability of Microtubules

We propose a stochastic model that accounts for the growth, catastrophe and rescue processes of steady state microtubules assembled from MAP-free tubulin. Both experimentally and theoretically we study the perturbation of microtubule dynamic instability by S-methyl-D-DM1, a synthetic derivative of the microtubule-targeted agent maytansine and a potential anticancer agent. We find that to be an effective suppressor of microtubule dynamics a drug must primarily suppress the loss of GDP tubulin from the microtubule tip.Comment: 17 pages, 11 figures, to appear in Phys. Bio

Reactions of C+ + Cl-, Br-, and I--A comparison of theory and experiment.

Rate constants for the reactions of C+ + Cl-, Br-, and I- were measured at 300 K using the variable electron and neutral density electron attachment mass spectrometry technique in a flowing afterglow Langmuir probe apparatus. Upper bounds of <10-8 cm3 s-1 were found for the reaction of C+ with Br- and I-, and a rate constant of 4.2 ± 1.1 × 10-9 cm3 s-1 was measured for the reaction with Cl-. The C+ + Cl- mutual neutralization reaction was studied theoretically from first principles, and a rate constant of 3.9 × 10-10 cm3 s-1, an order of magnitude smaller than experiment, was obtained with spin-orbit interactions included using a semiempirical model. The discrepancy between the measured and calculated rate constants could be explained by the fact that in the experiment, the total loss of C+ ions was measured, while the theoretical treatment did not include the associative ionization channel. The charge transfer was found to take place at small internuclear distances, and the spin-orbit interaction was found to have a minor effect on the rate constant

A Non-Stop S-Antigen Gene Mutation Is Associated With Late Onset Hereditary Retinal Degeneration in Dogs

Purpose: To identify the causative mutation of canine progressive retinal atrophy (PRA) segregating as an adult onset autosomal recessive disorder in the Basenji breed of dog. Methods: Basenji dogs were ascertained for the PRA phenotype by clinical ophthalmoscopic examination. Blood samples from six affected cases and three nonaffected controls were collected, and DNA extraction was used for a genome-wide association study using the canine HD Illumina single nucleotide polymorphism (SNP) array and PLINK. Positional candidate genes identified within the peak association signal region were evaluated. Results: The highest -Log10(P) value of 4.65 was obtained for 12 single nucleotide polymorphisms on three chromosomes. Homozygosity and linkage disequilibrium analyses favored one chromosome, CFA25, and screening of the S-antigen (SAG) gene identified a non-stop mutation (c.1216T\u3eC), which would result in the addition of 25 amino acids (p.*405Rext*25). Conclusions: Identification of this non-stop SAG mutation in dogs affected with retinal degeneration establishes this canine disease as orthologous to Oguchi disease and SAG-associated retinitis pigmentosa in humans, and offers opportunities for genetic therapeutic intervention

The Time Has Come... To Build, Reflect, and Analyze Connections Between Qualitative and Quantitative Data

This paper will address the development process of a qualitative evaluation tool to aid in the thorough analysis of library resources at the University of Maryland. Specifically, our project looks at the use and added value of this tool for the building, reflecting, and analyzing the connections between qualitative and quantitative data. This will allow for more meaningful justifications of budgetary decisions compared to cost and use metrics alone. Given the necessity for meticulous review of continuing resources, our project addresses a request for enhanced transparency from the university faculty and library oversight bodies and serves as a useful tool for accountability and justification of impactful decisions for stakeholders internally and externally. We will discuss the extant literature and the need for this type of tool, the development process including the output planning and data input format, the initial reception of the project, and future goals and planning for our initial usage. Additionally, we will demonstrate the use of the tool, model output, and discuss options for visualizations, storage, and retrieval of input data

Maternal plasma DHA levels increase prior to 29 days post-LH surge in women undergoing frozen embryo transfer: a prospective, observational study of human pregnancy

Context: Docosahexaenoic acid (DHA) is an important fatty acid required for neurological development but its importance during early fetal neurological organogenesis is unknown. Objective: To assess plasma fatty acid changes in early pregnancy in women undergoing natural cycle-frozen embryo transfer as a means of achieving accurately-timed periconceptual sampling. Design: Women undergoing frozen embryo transfer were recruited and serial fasting blood samples were taken pre-luteinising hormone (LH) surge, and at days 18, 29 and 45 post-LH surge and fatty acids were analysed using gas chromatography. Setting: Assisted Conception Unit, Glasgow Royal Infirmary, Scotland Main outcome measures: Plasma fatty acid concentrations, influence of twin pregnancies on DHA plasma concentration. Results: In pregnant women, there was a rapid, early increase in the maternal rate of change of plasma DHA concentration observed by 29 days post-LH surge (mean±SD, from 0.1±1.3 to 1.6±2.9 nmol DHA per mL plasma per day). This early pressure to increase plasma DHA concentration was further emphasised in twin pregnancies where the increase in DHA concentration over 45 days was two-fold higher than in singleton pregnancies (mean±SD increase, 74±39 nmol/mL versus 36±40 nmol/mL). An index of delta-6 desaturase activity increased 30% and positively correlated with the rate of change of DHA concentration between day 18 and 29-post LH surge (R-squared adjusted = 41%, P=0.0002). DHA was the only fatty acid with a continual accelerated increase in plasma concentration and a positive incremental area under the curve (mean±SD, 632±911 nmol/mL x day) over the first 45 days of gestation. Conclusions: An increase in maternal plasma DHA concentration is initiated in human pregnancy prior to neural tube closure which occurs at 28 days' gestation

Depressive symptoms are associated with fasting insulin resistance in obese youth

BACKGROUND: In adults, depressive symptoms are positively associated with insulin resistance. OBJECTIVE: To determine whether an association exists between depressive symptoms and markers of insulin resistance in youth. METHODS: This study used a retrospective review of data from an obesity clinic. We evaluated the association between depressive symptoms (Children's Depression Inventory, CDI) and fasting insulin and homeostatic model assessment-insulin resistance (HOMA-IR) in obese youth (n = 207, age 10-18 years). Individuals with lower vs. higher CDI T-scores (<65 vs. ≥65) were compared; this cut-point is accepted as indicating the possibility of clinical depression. Multiple linear regression was used to evaluate relationships between CDI T-scores and insulin resistance. RESULTS: Fasting insulin and HOMA-IR values were 40% higher in patients with higher CDI T-scores (P = 0.04). After accounting for gender, race, age and body mass index, CDI T-score remained associated with HOMA-IR, although the strength of the association was small (b = 0.007, P = 0.049). CONCLUSIONS: Relationships between depressive symptoms and insulin resistance should be considered when evaluating obese youth

MicroRNA and metabolomics signatures for adrenomyeloneuropathy disease severity

Adrenomyeloneuropathy (AMN), the slow progressive phenotype of adrenoleukodystrophy (ALD), has no clinical plasma biomarker for disease progression. This feasibility study aimed to determine whether metabolomics and micro-RNA in blood plasma provide a potential source of biomarkers for AMN disease severity. Metabolomics and RNA-seq were performed on AMN and healthy human blood plasma. Biomarker discovery and pathway analyses were performed using clustering, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and regression against patient\u27s clinical Expanded Disability Status Score (EDSS). Fourteen AMN and six healthy control samples were analyzed. AMN showed strong disease-severity-specific metabolic and miRNA clustering signatures. Strong, significant clinical correlations were shown for 7-alpha-hydroxy-3-oxo-4-cholestenoate (7-HOCA) (r (2) = 0.83, p \u3c 0.00001), dehydroepiandrosterone sulfate (DHEA-S; r (2) = 0.82, p \u3c 0.00001), hypoxanthine (r (2) = 0.82, p \u3c 0.00001), as well as miRNA-432-5p (r (2) = 0.68, p \u3c 0.00001). KEGG pathway comparison of mild versus severe disease identified affected downstream systems: GAREM, IGF-1, CALCRL, SMAD2&3, glutathione peroxidase, LDH, and NOS. This feasibility study demonstrates that miRNA and metabolomics are a source of potential plasma biomarkers for disease severity in AMN, providing both a disease signature and individual markers with strong clinical correlations. Network analyses of affected systems implicate differentially altered vascular, inflammatory, and oxidative stress pathways, suggesting disease-severity-specific mechanisms as a function of disease severity

Transcriptional adaptation in caenorhabditis elegans

Transcriptional adaptation is a recently described phenomenon by which a mutation in one gene leads to the transcriptional modulation of related genes, termed adapting genes. At the molecular level, it has been proposed that the mutant mRNA, rather than the loss of protein function, activates this response. While several examples of transcriptional adaptation have been reported in zebrafish embryos and in mouse cell lines, it is not known whether this phenomenon is observed across metazoans. Here we report transcriptional adaptation in C. elegans, and find that this process requires factors involved in mutant mRNA decay, as in zebrafish and mouse. We further uncover a requirement for Argonaute proteins and Dicer, factors involved in small RNA maturation and transport into the nucleus. Altogether, these results provide evidence for transcriptional adaptation in C. elegans, a powerful model to further investigate underlying molecular mechanisms.publishedVersio