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

Postcard: Come to Topeka

This black and white printed postcard features a black background with white printed text and illustrations. Horses and carts are lined up and floats are being pulled along in a row suggesting a parade is illustrated. There is print at the top and bottom of the card. There is handwriting on the back of the card.https://scholars.fhsu.edu/tj_postcards/1467/thumbnail.jp

Effectiveness of Harm Reduction on Substance Abuse in Homeless Adults

In addressing the high-risk substance misuse and addictive disorders that have emerged as a public health crisis over the last 40 years, we looked into the following evidence based PICOT question: In homeless adults are harm reduction therapies compared to preventative therapies effective in reducing the rate of substance abuse in one year? Harm reduction therapy is an alternative approach that aims to decrease direct and indirect harm associated with drug use without necessarily preventing drug consumption. This form of therapy is guided by clinical ethics to institute policies and services, such as naloxone availability and clean needle exchanges for those with substance use disorders. In contrast, preventative policies that focus on interventions to prevent the use of drugs, such as reducing the prescription drug supply, may ultimately lead to increased illicit drug use and reduced quality of life. A literature search was conducted using the databases CINHAL, OneSearch, and Google Scholar, using the phrases “harm reduction”, “benefits of harm reduction,” “shelters,\u27\u27 “reducing substance use,” “homeless adults,\u27\u27 and “substance abuse.” Inclusion criteria involved homeless adults between the ages of 21-65 years, and articles limited to adolescents and children were excluded from the search. Eleven articles were chosen that fell within the search criteria. Research suggests that continued use of harm reduction therapies along with the integration of preventative substance use policies will help decrease substance abuse within the homeless population

Effect of Hindlimb Unweighting on Tissue Blood Flow in the Rat

The purpose of this study was to characterize the distribution of blood flow in the rat during hindlimb unweighting (HU) and post-HU standing and exercise and examine whether the previously reported elevation in anaerobic metabolism observed with contractile activity in the atrophied soleus muscle was caused by a reduced hindlimb blood flow. After either 15 days of HU or cage control, blood flow was measured with radioactive microspheres during unweighting, normal standing, and running on a treadmill (15 m/min). In another group of control and experimental animals, blood flow was measured during preexercise (PE) treadmill standing and treadmill running (15 m/min). Soleus muscle blood flow was not different between groups during unweighting, PE standing, and running at 15 m/min. Chronic unweighting resulted in the tendency for greater blood flow to muscles composed of predominantly fast-twitch glycolytic fibers. With exercise, blood flow to visceral organs was reduced compared with PE values in the control rats, whereas flow to visceral organs in 15-day HU animals was unaltered by exercise. These higher flows to the viscera and to muscles composed of predominantly fast-twitch glycolytic fibers suggest an apparent reduction in the ability of the sympathetic nervous system to distribute cardiac output after chronic HU. In conclusion, because 15 days of HU did not affect blood flow to the soleus during exercise, the increased dependence of the atrophied soleus on anerobic energy production during contractile activity cannot be explained by a reduced muscle blood flow

Skeletal Muscle PGC-1β Signaling is Sufficient to Drive an Endurance Exercise Phenotype and to Counteract Components of Detraining in Mice

Peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α and -1β serve as master transcriptional regulators of muscle mitochondrial functional capacity and are capable of enhancing muscle endurance when overexpressed in mice. We sought to determine whether muscle-specific transgenic overexpression of PGC-1β affects the detraining response following endurance training. First, we established and validated a mouse exercise-training-detraining protocol. Second, using multiple physiological and gene expression end points, we found that PGC-1β overexpression in skeletal muscle of sedentary mice fully recapitulated the training response. Lastly, PGC-1β overexpression during the detraining period resulted in partial prevention of the detraining response. Specifically, an increase in the plateau at which O2 uptake (V̇o2) did not change from baseline with increasing treadmill speed [peak V̇o2 (ΔV̇o2max)] was maintained in trained mice with PGC-1β overexpression in muscle 6 wk after cessation of training. However, other detraining responses, including changes in running performance and in situ half relaxation time (a measure of contractility), were not affected by PGC-1β overexpression. We conclude that while activation of muscle PGC-1β is sufficient to drive the complete endurance phenotype in sedentary mice, it only partially prevents the detraining response following exercise training, suggesting that the process of endurance detraining involves mechanisms beyond the reversal of muscle autonomous mechanisms involved in endurance fitness. In addition, the protocol described here should be useful for assessing early-stage proof-of-concept interventions in preclinical models of muscle disuse atrophy

Immunolocalization of a PIGR-like Protein in Tetrahymena thermophila

Netrins are pleiotropic signaling molecules which guide axonal development and help regulate processes such as angiogenesis. Netrins can act as chemorepellents for developing axons, and our previous work has shown that several netrins, including netrin-1, netrin-3, and netrin-4, are chemorepellents in Tetrahymena thermophila. In vertebrates, netrin-1 signals through several receptors, including those in the UNC-5 family. UNC-5 family proteins often signal through the src family of tyrosine kinases. We have previously characterized UNC-5 and src-like proteins in Tetrahymena, by immunolocalization and Western blotting. Sequencing of our src-like proteins gave a number of homologous sequences, including the sequence for polymeric immunoglobulin-like receptor (PIGR). With all of these findings in mind, we hypothesized that Tetrahymena might possess a receptor similar to PIGR, which would localize either to the plasma membrane or cilia of Tetrahymena

Assembly and use of new task rules in fronto-parietal cortex

Severe capacity limits, closely associated with fluid intelligence, arise in learning and use of new task rules. We used fMRI to investigate these limits in a series of multirule tasks involving different stimuli, rules, and response keys. Data were analyzed both during presentation of instructions and during later task execution. Between tasks, we manipulated the number of rules specified in task instructions, and within tasks, we manipulated the number of rules operative in each trial block. Replicating previous results, rule failures were strongly predicted by fluid intelligence and increased with the number of operative rules. In fMRI data, analyses of the instruction period showed that the bilateral inferior frontal sulcus, intraparietal sulcus, and presupplementary motor area were phasically active with presentation of each new rule. In a broader range of frontal and parietal regions, baseline activity gradually increased as successive rules were instructed. During task performance, we observed contrasting fronto-parietal patterns of sustained (block-related) and transient (trial-related) activity. Block, but not trial, activity showed effects of task complexity. We suggest that, as a new task is learned, a fronto-parietal representation of relevant rules and facts is assembled for future control of behavior. Capacity limits in learning and executing new rules, and their association with fluid intelligence, may be mediated by this load-sensitive fronto-parietal network

Проблеми побудови відкритої та гнучкої методичної системи навчання математичних методів фізики у педагогічних університетах

(uk) Розглядаються тенденції розвитку фундаментальної фізико-математичної освіти, зближення природничо-наукового та гуманітарного, що уможливлюють розв’язання проблеми побудови відкритої та гнучкої науково-обґрунтованої методичної системи навчання математичних методів фізики у педагогічних університетах.(en) The article examines progressive trends of fundamental physical and mathematical education, rapprochement of naturally scientific and humanitarian, that makes possible to solve the problem of constructing the open and flexible scientifically reasonable methodical systeme of mathematical methods of physics teaching inpedagogical universities

'Sly grog' and 'homebrew': a qualitative examination of illicit alcohol and some of its impacts on Indigenous communities with alcohol restrictions in regional and remote Queensland (Australia)

Background: Indigenous communities in Queensland (Australia) have been subject to Alcohol Management Plans since 2002/03, with significant penalties for breaching restrictions. 'Sly grog' and 'homebrew' provide access to alcohol despite restrictions. This paper describes how this alcohol is made available and the risks and impacts involved. In affected towns and communities across a large area of rural and remote Queensland, interviews and focus groups documented experiences and views of 255 long-standing community members and service providers. Using an inductive framework, transcribed interviews were analysed to identify supply mechanisms, community and service provider responses and impacts experienced. Results: 'Homebrew' was reportedly manufactured in just a few localities, in locally-specific forms bringing locally-specific harms. However, 'sly grog' sourced from licensed premises located long distances from communities, is a widespread concern across the region. 'Sly grog' sellers circumvent retailers' takeaway liquor license conditions, stockpile alcohol outside restricted areas, send hoax messages to divert enforcement and take extraordinary risks to avoid apprehension. Police face significant challenges to enforce restrictions. On-selling of 'sly grog' appears more common in remote communities with total prohibition. Despite different motives for involvement in an illicit trade 'sly grog' consumers and sellers receive similar penalties. Conclusions: There is a need for: (a) a more sophisticated regional approach to managing takeaway alcohol sales from licensed suppliers, (b) targeted penalties for 'sly grog' sellers that reflect its significant community impact, (c) strategies to reduce the demand for alcohol and (d) research to assess the effects of these strategies in reducing harms.Michelle S. Fitts, Jan Robertson, Simon Towle, Chris M. Doran, Robyn McDermott, Adrian Miller, Stephen Margolis, Valmae Ypinazar and Alan R. Cloug

The Integrated Medical Model: Statistical Forecasting of Risks to Crew Health and Mission Success

The Integrated Medical Model (IMM) helps capture and use organizational knowledge across the space medicine, training, operations, engineering, and research domains. The IMM uses this domain knowledge in the context of a mission and crew profile to forecast crew health and mission success risks. The IMM is most helpful in comparing the risk of two or more mission profiles, not as a tool for predicting absolute risk. The process of building the IMM adheres to Probability Risk Assessment (PRA) techniques described in NASA Procedural Requirement (NPR) 8705.5, and uses current evidence-based information to establish a defensible position for making decisions that help ensure crew health and mission success. The IMM quantitatively describes the following input parameters: 1) medical conditions and likelihood, 2) mission duration, 3) vehicle environment, 4) crew attributes (e.g. age, sex), 5) crew activities (e.g. EVA's, Lunar excursions), 6) diagnosis and treatment protocols (e.g. medical equipment, consumables pharmaceuticals), and 7) Crew Medical Officer (CMO) training effectiveness. It is worth reiterating that the IMM uses the data sets above as inputs. Many other risk management efforts stop at determining only likelihood. The IMM is unique in that it models not only likelihood, but risk mitigations, as well as subsequent clinical outcomes based on those mitigations. Once the mathematical relationships among the above parameters are established, the IMM uses a Monte Carlo simulation technique (a random sampling of the inputs as described by their statistical distribution) to determine the probable outcomes. Because the IMM is a stochastic model (i.e. the input parameters are represented by various statistical distributions depending on the data type), when the mission is simulated 10-50,000 times with a given set of medical capabilities (risk mitigations), a prediction of the most probable outcomes can be generated. For each mission, the IMM tracks which conditions occurred and decrements the pharmaceuticals and supplies required to diagnose and treat these medical conditions. If supplies are depleted, then the medical condition goes untreated, and crew and mission risk increase. The IMM currently models approximately 30 medical conditions. By the end of FY2008, the IMM will be modeling over 100 medical conditions, approximately 60 of which have been recorded to have occurred during short and long space missions