Muscle Fatigue from the Perspective of a Single Crossbridge

The repeated intense stimulation of skeletal muscle rapidly decreases its force- and motion-generating capacity. This type of fatigue can be temporally correlated with the accumulation of metabolic by-products, including phosphate (Pi) and protons (H+). Experiments on skinned single muscle fibers demonstrate that elevated concentrations of these ions can reduce maximal isometric force, unloaded shortening velocity, and peak power, providing strong evidence for a causative role in the fatigue process. This seems to be due, in part, to their direct effect on muscle’s molecular motor, myosin, because in assays using isolated proteins, these ions directly inhibit myosin’s ability to move actin. Indeed, recent work using a single molecule laser trap assay has revealed the specific steps in the crossbridge cycle affected by these ions. In addition to their direct effects, these ions also indirectly affect myosin by decreasing the sensitivity of the myofilaments to calcium, primarily by altering the ability of the muscle regulatory proteins, troponin and tropomyosin, to govern myosin binding to actin. This effect seems to be partially due to fatigue-dependent alterations in the structure and function of specific subunits of troponin. Parallel efforts to understand the molecular basis of muscle contraction are providing new technological approaches that will allow us to gain unprecedented molecular detail of the fatigue process. This will be crucial to fully understand this ubiquitous phenomenon and develop appropriately targeted therapies to attenuate the debilitating effects of fatigue in clinical populations

Status of SHAFT 78 with respect to modeling radioactive waste burial in Eleana argillite, including calculations to date

The SHAFT 78 Code (multidimensional, two fluid phases, porous medium) has been used to begin assessment of the consequences of nuclear waste burial in a 1000-acre repository emplaced in argillite. The methodology used can well be applied to other argillaceous rocks as well as to hard rocks in general so long as their in-situ rock permeability can reasonably be assumed to be temperature- and stress-independent. The repository is assumed to contain spent fuel (SF) UO{sub 2} at an initial power loading of 150 kW/acre and located at a depth of 600 m. It was found that with perfect backfill (permeabilty = 1 x 10{sup 7} darcy), a maximum fluid pressure of 770 bars existed in the repository at a time of 55 y after burial. Holding all other input variables constant, the maximum fluid pressure in the repository never exceeded the local lithostatic pressure when the permeability of the backfill material was increased to 1 x 10{sup -1} darcy. The calculated temperature histories are essentially independent of backfill permeability and porosity, indicating that heat transfer is conduction-dominated

Structural diversity in the type IV pili of multidrug-resistant Acinetobacter

Acinetobacter baumannii is a Gram-negative coccobacillus found primarily in hospital settings that has recently emerged as a source of hospital-acquired infections. A. baumannii expresses a variety of virulence factors, including type IV pili, bacterial extracellular appendages often essential for attachment to host cells. Here, we report the high resolution structures of the major pilin subunit, PilA, from three Acinetobacter strains, demonstrating thatA. baumannii subsets produce morphologically distinct type IV pilin glycoproteins. We examine the consequences of this heterogeneity for protein folding and assembly as well as host-cell adhesion by Acinetobacter. Comparisons of genomic and structural data with pilin proteins from other species of soil gammaproteobacteria suggest that these structural differences stem from evolutionary pressure that has resulted in three distinct classes of type IVa pilins, each found in multiple species

Integrating Teaching and Research in Undergraduate Biology Laboratory Education

A course recently designed and implemented at Stanford University applies practical suggestions for creating research-based undergraduate courses that benefit both teaching and research

Spring School on Language, Music, and Cognition: Organizing Events in Time

The interdisciplinary spring school “Language, music, and cognition: Organizing events in time” was held from February 26 to March 2, 2018 at the Institute of Musicology of the University of Cologne. Language, speech, and music as events in time were explored from different perspectives including evolutionary biology, social cognition, developmental psychology, cognitive neuroscience of speech, language, and communication, as well as computational and biological approaches to language and music. There were 10 lectures, 4 workshops, and 1 student poster session. Overall, the spring school investigated language and music as neurocognitive systems and focused on a mechanistic approach exploring the neural substrates underlying musical, linguistic, social, and emotional processes and behaviors. In particular, researchers approached questions concerning cognitive processes, computational procedures, and neural mechanisms underlying the temporal organization of language and music, mainly from two perspectives: one was concerned with syntax or structural representations of language and music as neurocognitive systems (i.e., an intrapersonal perspective), while the other emphasized social interaction and emotions in their communicative function (i.e., an interpersonal perspective). The spring school not only acted as a platform for knowledge transfer and exchange but also generated a number of important research questions as challenges for future investigations

Small-Molecule Hydrophobic Tagging Induced Degradation of HaloTag Fusion Proteins

The ability to regulate any protein of interest in living systems with small molecules remains a challenge. We hypothesized that appending a hydrophobic moiety to the surface of a protein would mimic the partially denatured state of the protein, thus engaging the cellular quality control machinery to induce its proteasomal degradation. We designed and synthesized bifunctional small molecules to bind a bacterial dehalogenase (the HaloTag protein) and present a hydrophobic group on its surface. Hydrophobic tagging of the HaloTag protein with an adamantyl moiety induced the degradation of cytosolic, isoprenylated and transmembrane HaloTag fusion proteins in cell culture. We demonstrated the in vivo utility of hydrophobic tagging by degrading proteins expressed in zebrafish embryos and by inhibiting Hras1G12V-driven tumor progression in mice. Therefore, hydrophobic tagging of HaloTag fusion proteins affords small-molecule control over any protein of interest, making it an ideal system for validating potential drug targets in disease models

The Physicist's Guide to the Orchestra

An experimental study of strings, woodwinds (organ pipe, flute, clarinet, saxophone and recorder), and the voice was undertaken to illustrate the basic principles of sound production in music instruments. The setup used is simple and consists of common laboratory equipment. Although the canonical examples (standing wave on a string, in an open and closed pipe) are easily reproduced, they fail to explain the majority of the measurements. The reasons for these deviations are outlined and discussed.Comment: 11 pages, 10 figures (jpg files). Submitted to European Journal of Physic

Tailoring Adjuvant Endocrine Therapy for Postmenopausal Breast Cancer: A CYP2D6 Multiple-Genotype-Based Modeling Analysis and Validation

Purpose: Previous studies have suggested that postmenopausal women with breast cancer who present with wild-type CYP2D6 may actually have similar or superior recurrence-free survival outcomes when given tamoxifen in place of aromatase inhibitors (AIs). The present study established a CYP2D6 multiple-genotype-based model to determine the optimal endocrine therapy for patients harboring wild-type CYP2D6. Methods: We created a Markov model to determine whether tamoxifen or AIs maximized 5-year disease-free survival (DFS) for extensive metabolizer (EM) patients using annual hazard ratio (HR) data from the BIG 1-98 trial. We then replicated the model by evaluating 9-year event-free survival (EFS) using HR data from the ATAC trial. In addition, we employed two-way sensitivity analyses to explore the impact of HR of decreased-metabolizer (DM) and its frequency on survival by studying a range of estimates. Results: The 5-year DFS of tamoxifen-treated EM patients was 83.3%, which is similar to that of genotypically unselected patients who received an AI (83.7%). In the validation study, we further demonstrated that the 9-year EFS of tamoxifentreated EM patients was 81.4%, which is higher than that of genotypically unselected patients receiving tamoxifen (78.4%) and similar to that of patients receiving an AI (83.2%). Two-way sensitivity analyses demonstrated the robustness of the results