Mechanical Properties of the Sarcolemma and Myoplasm in Frog Muscle as a Function of Sarcomere Length

The elastimeter method was applied to the single muscle fiber of the frog semitendinosus to obtain the elastic moduli of the sarcolemma and myoplasm, as well as their relative contributions to resting fiber tension at different extensions. A bleb which was sucked into a flat-mouthed pipette at the fiber surface separated into an external sarcolemmal membrane and a thick inner myoplasmic region. Measurements showed that the sarcolemma does not contribute to intact fiber tension at sarcomere lengths below 3 µ. It was estimated that the sarcolemma contributed on the order of 10% to intact fiber tension at sarcomere lengths between 3 and 3.75 µ, and more so with further extension. Between these sarcomere lengths, the sarcolemma can be linearly extended and has a longitudinal elastic modulus of 5 x 10⁶ dyne/cm² (assuming a thickness of 0.1 µ). Resistance to deformation of the inner bleb region is due to myoplasmic elasticity. The myoplasmic elastic modulus was estimated by use of a model and was used to predict a fiber length-tension curve which agreed approximately with observations.     

Elastic Energy Storage and Radial Forces in the Myofilament Lattice Depend on Sarcomere Length

We most often consider muscle as a motor generating force in the direction of shortening, but less often consider its roles as a spring or a brake. Here we develop a fully three-dimensional spatially explicit model of muscle to isolate the locations of forces and energies that are difficult to separate experimentally. We show the strain energy in the thick and thin filaments is less than one third the strain energy in attached cross-bridges. This result suggests the cross-bridges act as springs, storing energy within muscle in addition to generating the force which powers muscle. Comparing model estimates of energy consumed to elastic energy stored, we show that the ratio of these two properties changes with sarcomere length. The model predicts storage of a greater fraction of energy at short sarcomere lengths, suggesting a mechanism by which muscle function shifts as force production declines, from motor to spring. Additionally, we investigate the force that muscle produces in the radial or transverse direction, orthogonal to the direction of shortening. We confirm prior experimental estimates that place radial forces on the same order of magnitude as axial forces, although we find that radial forces and axial forces vary differently with changes in sarcomere length.     

CONTRACTILITY AND ULTRASTRUCTURE IN GLYCEROL-EXTRACTED MUSCLE FIBERS : I. The Relationship of Contractility to Sarcomere Length

This study was undertaken to determine whether glycerol-extracted rabbit psoas muscle fibers can develop tension and shorten after being stretched to such a length that the primary and secondary filaments no longer overlap. A method was devised to measure the initial sarcomere length and the ATP-induced isotonic shortening in prestretched isolated fibers subjected to a small preload (0.02 to 0.15 P₀). At all degrees of stretch, the fiber was able to shorten (60 to 75 per cent): to a sarcomere length of 0.7 µ when the initial length was 3.7 µ or less, and to an increasing length of 0.9 to 1.8 µ with increasing initial sarcomere length (3.8 to 4.4 µ). At sarcomere lengths of 3.8 to 4.5 µ, overlap of filaments was lost, as verified by electron microscopy. The variation in sarcomere length within individual fibers has been assessed by both light and electron microscopic measurements. In fibers up to 10 mm in length the stretch was evenly distributed along the fiber, and with sarcomere spacings greater than 4 µ there was only a slight chance of finding sarcomeres with filament overlap. These observations are in apparent contradiction to the assumption that an overlap of A and I filaments is necessary for tension generation and shortening.     

Biochemical Activities of the Wiskott-Aldrich Syndrome Homology Region 2 Domains of Sarcomere Length Short (SALS) Protein

Drosophila melanogaster sarcomere length short (SALS) is a recently identified Wiskott-Aldrich syndrome protein homology 2 (WH2) domain protein involved in skeletal muscle thin filament regulation. SALS was shown to be important for the establishment of the proper length and organization of sarcomeric actin filaments. Here, we present the first detailed characterization of the biochemical activities of the tandem WH2 domains of SALS (SALS-WH2). Our results revealed that SALS-WH2 binds both monomeric and filamentous actin and shifts the monomer-filament equilibrium toward the monomeric actin. In addition, SALS-WH2 can bind to but fails to depolymerize phalloidin- or jasplakinolide-bound actin filaments. These interactions endow SALS-WH2 with the following two major activities in the regulation of actin dynamics: SALS-WH2 sequesters actin monomers into non-polymerizable complexes and enhances actin filament disassembly by severing, which is modulated by tropomyosin. We also show that profilin does not influence the activities of the WH2 domains of SALS in actin dynamics. In conclusion, the tandem WH2 domains of SALS are multifunctional regulators of actin dynamics. Our findings suggest that the activities of the WH2 domains do not reconstitute the presumed biological function of the full-length protein. Consequently, the interactions of the WH2 domains of SALS with actin must be tuned in the cellular context by other modules of the protein and/or sarcomeric components for its proper functioning.     

Application of the Asthma Phenotype Algorithm from the Severe Asthma Research Program to an Urban Population

Rationale

Identification and characterization of asthma phenotypes are challenging due to disease complexity and heterogeneity. The Severe Asthma Research Program (SARP) used unsupervised cluster analysis to define 5 phenotypically distinct asthma clusters that they replicated using 3 variables in a simplified algorithm. We evaluated whether this simplified SARP algorithm could be used in a separate and diverse urban asthma population to recreate these 5 phenotypic clusters.

Methods

The SARP simplified algorithm was applied to adults with asthma recruited to the New York University/Bellevue Asthma Registry (NYUBAR) to classify patients into five groups. The clinical phenotypes were summarized and compared.

Results

Asthma subjects in NYUBAR (n = 471) were predominantly women (70%) and Hispanic (57%), which were demographically different from the SARP population. The clinical phenotypes of the five groups generated by the simplified SARP algorithm were distinct across groups and distributed similarly to those described for the SARP population. Groups 1 and 2 (6 and 63%, respectively) had predominantly childhood onset atopic asthma. Groups 4 and 5 (20%) were older, with the longest duration of asthma, increased symptoms and exacerbations. Group 4 subjects were the most atopic and had the highest peripheral eosinophils. Group 3 (10%) had the least atopy, but included older obese women with adult-onset asthma, and increased exacerbations.

Conclusions

Application of the simplified SARP algorithm to the NYUBAR yielded groups that were phenotypically distinct and useful to characterize disease heterogeneity. Differences across NYUBAR groups support phenotypic variation and support the use of the simplified SARP algorithm for classification of asthma phenotypes in future prospective studies to investigate treatment and outcome differences between these distinct groups.

Trial Registration

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00212537","term_id":"NCT00212537"}}NCT00212537     

心肌特异表达的肌小节相关激酶基因p93的克隆与鉴定

心肌收缩受到由蛋白质因子构成的信号转导通路的调控 ,但确切机制尚未完全明了。从人心脏cDNA文库中克隆到心肌特异表达的可能参与信号转导调控的新基因 ,命名为p93基因。该基因定位于 1p31.1,属于MAP KKKs家族的相近亚家族。Northern印迹及含 76种组织的点杂交显示了p93仅在心肌组织中表达 ;免疫组化表明它主要定位于成人与胎儿的心肌细胞核 ,胞液次之 ;体外激酶活性实验证明野生型p93是一个可以进行自我磷酸化的功能性激酶分子 ;以该基因C端为诱饵质粒的酵母双杂交筛选表明 ,p93主要与心肌肌钙蛋白I(cTnI)等与收缩有关的肌小节蛋白发生相互作用 ,并以免疫共沉淀实验得到了验证。推测p93可能通过激酶信号转导通路的方式参与对肌小节收缩蛋白的调节。     

No Association between Mean Telomere Length and Life Stress Observed in a 30 Year Birth Cohort

Telomeres are specialised structures that cap the ends of chromosomes. They shorten with each cell division and have been proposed as a marker of cellular aging. Previous studies suggest that early life stressors increase the rate of telomere shortening with potential impact on disease states and mortality later in life. This study examined the associations between telomere length and exposure to a number of stressors that arise during development from the antenatal/perinatal period through to young adulthood. Participants were from the Christchurch Health and Development Study (CHDS), a New Zealand longitudinal birth cohort which has followed participants from birth until age 30. Telomere length was obtained on DNA from peripheral blood samples collected from consenting participants (n = 677) at age 28–30, using a quantitative PCR assay. These data were assessed for associations with 26 measures of life course adversity or stress which occurred prior to 25 years of age. No associations were found between telomere length measured at age 28–30 years and life course adversity or stress for specific measures and for the summary risk scores for each developmental domain. The correlations were very small ranging from −0.06 to 0.06 with a median of 0.01, and none were statistically significant. Our results in this well-studied birth cohort do not support prior reports of such associations, and underscore the need for more extensive replication of proposed links between stress and telomere biology in larger cohorts with appropriate phenotypic data.     

A Fast Algorithm to Estimate the Deepest Points of Lakes for Regional Lake Registration

When conducting image registration in the U.S. state of Alaska, it is very difficult to locate satisfactory ground control points because ice, snow, and lakes cover much of the ground. However, GCPs can be located by seeking stable points from the extracted lake data. This paper defines a process to estimate the deepest points of lakes as the most stable ground control points for registration. We estimate the deepest point of a lake by computing the center point of the largest inner circle (LIC) of the polygon representing the lake. An LIC-seeking method based on Voronoi diagrams is proposed, and an algorithm based on medial axis simplification (MAS) is introduced. The proposed design also incorporates parallel data computing. A key issue of selecting a policy for partitioning vector data is carefully studied, the selected policy that equalize the algorithm complexity is proved the most optimized policy for vector parallel processing. Using several experimental applications, we conclude that the presented approach accurately estimates the deepest points in Alaskan lakes; furthermore, we gain perfect efficiency using MAS and a policy of algorithm complexity equalization.     

鱼类肌节的组成及装配

肌节作为横纹肌上最小的收缩单位,是一个高度有序的结构,主要由粗丝和细丝构成。其装配过程十分复杂,涉及到一系列结构蛋白和相关蛋白质的组装。其中,Z带和M带的正确装配是维持肌节结构的关键。该文结合近期的研究进展,对肌节中的主要组分进行综述,并探讨了鱼类肌节的装配机制。     

Development of an Agent-Based Model (ABM) to Simulate the Immune System and Integration of a Regression Method to Estimate the Key ABM Parameters by Fitting the Experimental Data

Agent-based models (ABM) and differential equations (DE) are two commonly used methods for immune system simulation. However, it is difficult for ABM to estimate key parameters of the model by incorporating experimental data, whereas the differential equation model is incapable of describing the complicated immune system in detail. To overcome these problems, we developed an integrated ABM regression model (IABMR). It can combine the advantages of ABM and DE by employing ABM to mimic the multi-scale immune system with various phenotypes and types of cells as well as using the input and output of ABM to build up the Loess regression for key parameter estimation. Next, we employed the greedy algorithm to estimate the key parameters of the ABM with respect to the same experimental data set and used ABM to describe a 3D immune system similar to previous studies that employed the DE model. These results indicate that IABMR not only has the potential to simulate the immune system at various scales, phenotypes and cell types, but can also accurately infer the key parameters like DE model. Therefore, this study innovatively developed a complex system development mechanism that could simulate the complicated immune system in detail like ABM and validate the reliability and efficiency of model like DE by fitting the experimental data.     

Prolonged Exercise in Type 1 Diabetes: Performance of a Customizable Algorithm to Estimate the Carbohydrate Supplements to Minimize Glycemic Imbalances

Physical activity in patients with type 1 diabetes (T1DM) is hindered because of the high risk of glycemic imbalances. A recently proposed algorithm (named Ecres) estimates well enough the supplemental carbohydrates for exercises lasting one hour, but its performance for prolonged exercise requires validation. Nine T1DM patients (5M/4F; 35–65 years; HbA1c 54±13 mmol·mol^-1) performed, under free-life conditions, a 3-h walk at 30% heart rate reserve while insulin concentrations, whole-body carbohydrate oxidation rates (determined by indirect calorimetry) and supplemental carbohydrates (93% sucrose), together with glycemia, were measured every 30 min. Data were subsequently compared with the corresponding values estimated by the algorithm. No significant difference was found between the estimated insulin concentrations and the laboratory-measured values (p = NS). Carbohydrates oxidation rate decreased significantly with time (from 0.84±0.31 to 0.53±0.24 g·min^-1, respectively; p<0.001), being estimated well enough by the algorithm (p = NS). Estimated carbohydrates requirements were practically equal to the corresponding measured values (p = NS), the difference between the two quantities amounting to –1.0±6.1 g, independent of the elapsed exercise time (time effect, p = NS). Results confirm that Ecres provides a satisfactory estimate of the carbohydrates required to avoid glycemic imbalances during moderate intensity aerobic physical activity, opening the prospect of an intriguing method that could liberate patients from the fear of exercise-induced hypoglycemia.     

Implementation of an Intersectoral Program to Eliminate Human and Canine Rabies: The Bohol Rabies Prevention and Elimination Project

Background

The province of Bohol, located in the Visayas islands region in the Philippines has a human population of 1.13 million and was the 4th highest region for human rabies deaths in the country, averaging 10 per year, prior to the initiation of the Bohol Rabies Prevention and Elimination Project (BRPEP).

Aims

The BRPEP was initiated in 2007 with the goal of building a sustainable program that would prevent human rabies by eliminating rabies at its source, in dogs, by 2010. This goal was in line with the Philippine National Rabies Program whose objective is to eliminate rabies by 2020.

Methods

The intersectoral BRPEP was launched in 2007 and integrated the expertise and resources from the sectors of agriculture, public health and safety, education, environment, legal affairs, interior and local government. The program included: increasing local community involvement; implementing dog population control; conducting mass dog vaccination; improving dog bite management; instituting veterinary quarantine; and improving diagnostic capability, surveillance and monitoring. Funding was secured from the national government, provincial, municipal and village units, dog owners, NGOs, the regional office of the WHO, the UBS Optimus Foundation, and the Global Alliance for Rabies Control. The BRPEP was managed by the Bohol Rabies Prevention and Eradication Council (BRPEC) under the jurisdiction of the Governor of Bohol. Parallel organizations were created at the municipal level and village level. Community volunteers facilitated the institution of the program. Dog population surveys were conducted to plan for sufficient resources to vaccinate the required 70% of the dogs living in the province. Two island-wide mass vaccination campaigns were conducted followed by “catch up” vaccination campaigns. Registration of dogs was implemented including a small fee that was rolled back into the program to maintain sustainability. Children were educated by introducing rabies prevention modules into all elementary schools in Bohol. Existing public health legislation at the national, provincial, and municipal level strengthened the enforcement of activities. A Knowledge, Attitude and Practices (KAP) survey was conducted in 2009 to evaluate the educational knowledge of the population. Increased surveillance was instituted to ensure that dogs traveling into and out of the province were vaccinated against rabies. Human and animal cases of rabies were reported to provincial and national authorities.

Key Results

Within the first 18 months of the BRPEP, human rabies deaths had decreased annually from 0.77 to 0.37 to zero per 100,000 population from 2007–2009. Between October 2008 and November 2010 no human and animal cases were detected. Increased surveillance on the island detected one suspected human rabies case in November 2010 and one confirmed case of canine rabies in April 2011. Two mass vaccination campaigns conducted in 2007 and 2008 successfully registered and vaccinated 44% and 70% of the dogs on the island. The additional surveillance activities enabled a mobilization of mop up vaccination activities in the region where the human and canine case was located. Due to the increased effective and continuous surveillance activities, rabies was stopped before it could spread to other areas on the island. The program costs totaled USD 450,000. Registration fees collected to maintain the program amounted to USD 105,740 and were re-allocated back into the community to sustain the program.     

Implementation and Evaluation of an Integrated Program for Rodent Control in a Shantytown of Buenos Aires City, Argentina

The objective of this work was to evaluate the efficiency of an integrated program for the control of rodents in a shantytown of Buenos Aires City, Argentina. This program was developed in one year. During the preparation phase, an environmental survey of public spaces and dwellings was conducted in the test area to identify factors favoring the presence of rodents and to determine strategies and management measures to be implemented in the execution phase. Rodent abundance was monitored in the following four periods: (1) during the preparation phase, (2) during the execution phase, (3) immediately after the execution phase, and (4) 90 days after the end of the execution phase. According to the results of the preparation phase, we combined three different strategies to reduce rodent abundance in both dwellings and public spaces of the experimental area: rodenticide application, environmental sanitation in public spaces, and sanitary education. In this area the proportion of dwellings and public spaces with signs of rodent activity decreased significantly from the beginning of the trial to immediately after the end of the execution phase. There was a significant increase in rodent activity 90 days after the execution phase. This work reveals that although rodent infestation can be reduced in urban shantytowns, a long-term policy for sanitation improvement and sanitary education is required to keep rodent populations at safe levels for the community.     

The Development of an Indigenous Knowledge Program in a New Zealand Maori-Language Immersion School

In 1985, Te Wharekura o Rakaumangamanga initiated a Maori-language immersion program for children ages 5 through 18. In recent years, a program based on Waikato-Tainui tribal epistemology has been incorporated into the language immersion program. This article describes the community context and the language immersion and tribal knowledge programs. We consider the relationship of these programs to individual and tribal self-determination and to theories of minority achievement, particularly the work of John Ogbu.     

Sarcomere length changes in a 3D mathematical model of the pig ventricles

Measurements of the geometry and fibrous-sheet structure of the left and right ventricles of the pig heart are fitted with a finite element model. Mechanical changes during the heart cycle are computed by solving the equations of motion under specified ventricular boundary conditions and using experimentally defined constitutive laws for the active and passive material properties of myocardial tissue. The resulting patterns of deformation, such as axial torsion and changes in wall thickness and base-apex length, are consistent with experimental observations. The model can therefore be used to predict sarcomere length changes and other strain patterns throughout the myocardium and throughout the cardiac cycle. Here we present sarcomere length changes at a limited number of material points within the wall. Sarcomere length typically varies by 10% above and below the unloaded length; although under the boundary conditions imposed in the current model the midwall circumferentially oriented sarcomere lengths increased by up to 20% at end diastole. We provide web-access details for a downloadable software program designed to provide more extensive information on mechanical deformation, such as the principal strains and muscle fibre cross-sectional area changes during the cardiac cycle.     

Validation of an Elliptical Anthropometric Model to Estimate Visceral Compartment Area

Objective: The visceral compartment is a surrogate for visceral adipose tissue. Cross‐sectional visceral compartment area (VCA) has been approximated from waist circumference using a circular model. However, the two‐dimensional shape of the abdomen is rarely circular. This study validated an elliptical model of cross‐sectional total abdominal area (TAA), subcutaneous adipose tissue (SAT) area, and VCA at the L₄–L₅ level. Research Methods and Procedures: We analyzed magnetic resonance images (MRIs) at the level of the L₄–L₅ intervertebral space from 35 subjects with a wide range of abdominal adiposity. Waist circumference, abdominal thickness (midline sagittal diameter), abdominal width (coronal diameter at one‐half of abdominal thickness), and abdominal SAT thickness at four sites (front, back, right, and left) were measured from MRI images using an image analysis software. The same anatomical regions were also estimated from anthropometrics purely by geometric formulae of circular and elliptical models. A simple linear regression model was used to interpret the association strength between anthropometric estimates and MRI measures. Results: Estimated TAA by either model was strongly related to MRI TAA (r² = 0.98, p < 0.0001). The SAT and VCA by MRI analysis showed a stronger association with calculation from an elliptical model (r² = 0.95 and 0.88, respectively; p < 0.001) than a circular model (r² = 0.69 and 0.25, respectively; p < 0.001). The absolute prediction residuals and variances were significantly smaller with an elliptical model than a circular model (p < 0.0001). Discussion: An elliptical anthropometric model might be superior to a circular model to estimate abdominal SAT and VCA.     

The Maximization of Mean Vector Length for the Identification of Unknown Periods in Biological Rhythms: An Extension to Continuous Variables

In a recent paper Rocchi and Ghiandoni proposed the maximization of mean vector length as a circular statistics tool for the preliminary identification of unknown and unforeseeable periods in biological rhythms, but its application was limited to unitless data. In this paper an extension of the method to the case of continuous variables collected at equidistant time intervals is proposed. The extended method is proposed as an exploratory tool in the analysis of chronobiological data. Two different examples of the application of this method (to edible white truffle harvesting data and to TSH level data) are also included and compared with the Fourier spectral analysis.