Microtubule-associated protein tau in development, degeneration and protection of neurons

As a principal neuronal microtubule-associated protein, tau has been recognized to play major roles in promoting microtubule assembly and stabilizing the microtubules and to maintain the normal morphology of the neurons. Recent studies suggest that tau, upon alternative mRNA splicing and multiple posttranslational modifications, may participate in the regulations of intracellular signal transduction, development and viability of the neurons. Furthermore, tau gene mutations, aberrant mRNA splicing and abnormal posttranslational modifications, such as hyperphosphorylation, have also been found in a number of neurodegenerative disorders, collectively known as tauopathies. Therefore, changes in expression of the tau gene, alternative splicing of its mRNA and its posttranslational modification can modulate the normal architecture and functions of neurons as well as in a situation of tauopathies, such as Alzheimer's disease. The primary aim of this review is to summarize the latest developments and perspectives in our understanding about the roles of tau, especially hyperphosphorylation, in the development, degeneration and protection of neurons.     

Using functional data analysis to summarise and interpret lactate curves

John Tukey used the term exploratory data analysis (EDA) to describe a philosophy for analyzing data where graphical and numerical summaries are used to uncover interesting structures. The applied statistician today has a much more sophisticated set of methods to use when applying the EDA philosophy. One such collection of methods is functional data analysis (FDA), which was used to explore the structure of lactate curves. A principal components analysis and plots of the second derivatives provide new intuitive endurance markers which correlates highly with other numerical summaries of lactate curves that have been suggested in the literature.     

A computer program for the simulation of fiber deposition in the human respiratory tract

As inhaled fibers may lead to a variety of lung diseases, detailed information on their deposition in the human respiratory tract is an indispensable requirement in medical science. In the work presented here, a Visual Basic((R)) computer program, termed FIBROS, is described which enables the simulation of fibrous particle deposition in both the extrathoracic region and different parts of the lung itself, including the results of published numerical studies on inertial/interceptional as well as diffusional and gravitational deposition. The input window of FIBROS includes the selection of specific breathing conditions by variation of the tidal volume and breathing cycle. Furthermore, the user is able to determine fiber properties such as diameter, aspect ratio, specific weight, and fiber orientation with respect to the air stream in the upper and lower airways of the lungs. Besides the offer of various deposition formulae for each region of the respiratory tract, thereby also allowing a distinction between mouth and nose breathing, the user may select between different morphometric datasets of the lung and respective airway scaling procedures. Analysis routines of FIBROS include the estimation of regional deposition fractions, thereby distinguishing between extrathoracic, bronchial, and acinar compartments, and a calculation of generation-by-generation deposition probabilities within tubular and alveolar structures. Preliminary results presented here should demonstrate the effects on fiber deposition due to variations of the breathing behaviour and the particle properties.     

Tolerance of aged Fischer 344 rats against chlordecone-amplified carbon tetrachloride toxicity

We have investigated the effects of chlordecone 1(CD)+CCl4 combination in adult (3 months), middle aged (14 months), and old aged (24 months) male Fischer 344 (F344) rats. After a non-toxic dietary regimen of CD (10 ppm) or normal powdered diet for 15 days, rats received a single non-toxic dose of CCl4 (100 microl/kg, i.p., 1:4 in corn oil) or corn oil (500 microl/kg, i.p.) alone on day 16. Liver injury was assessed by plasma ALT, AST, and histopathology during a time course of 0-96 h. Liver tissue repair was measured by [3H-CH3]-thymidine (3H-T) incorporation into hepatic nuclear DNA and proliferating cell nuclear antigen (PCNA) immunohistochemistry. Hepatomicrosomal CYP2E1 protein, enzyme activity, and covalent binding of 14CCl4-derived radiolabel were measured in normal and CD fed rats. Exposure to CCl4 alone caused modest liver injury only in 14- and 24-month-old rats but neither progression of injury nor mortality. The CD+CCl4 combination led to 100% mortality in 3-month-old rats by 72 h, whereas none of the 14- and 24-month-old rats died. Both 3- and 14-month-old rats exposed to CD+Cl4 had identical liver injury up to 36 h indicating that bioactivation-mediated CCl4 injury was the same in the two age groups. Thereafter, liver injury escalated only in 3-month-old while it declined in 14-month-old rats. In 24-month-old rats initial liver injury at 6 h was similar to the 3- and 14-month-old rats and thereafter did not develop to the level of the other two age groups, recovering from injury by 96 h as in the 14-month-old rats. Neither hepatomicrosomal CYP2E1 protein nor the associated p-nitrophenol hydroxylase activity or covalent binding of 14CCl4-derived radiolabel to liver tissue differed between the age groups or diet regimens 2 h after the administration of 14CCl4. Compensatory liver tissue repair (3H-T, PCNA) was prompt and robust soon after CCl4 liver injury in the 14- and 24-month-old rats. In stark contrast, in the 3-month-old rats it failed allowing unabated progression of liver injury. These findings suggest that stimulation of early onset and robust liver tissue repair rescue the 14- and 24-month-old F344 rats from the lethal effect of the CD+CCl4 combination.     

Is mycobacterial heat shock protein 16 kDa,a marker of the dormant stage of Mycobacterium tuberculosis, a sarcoid antigen?

We demonstrated opposite presence of mycobacterial heat shock proteins (Mtb-hsp) 70 kDa, 65 kDa, 16 kDa in sera and lymph nodes in sarcoidosis (SA). Higher occurrence of serum Mtb-hsp70 than Mtb-hsp65 and Mtb-hsp16 could be caused by sequestration of Mtb-hsp65 and Mtb-hsp16 in circulating immune complexes (CIs). It is possible that in genetically different predisposed hosts, Mtb-hsp16 induced by dose-dependent nitrate/nitrite (NOx) may be involved in latent tuberculosis (TB), active TB, or SA development. We evaluated Mtb-hsp70, Mtb-hsp65, Mtb-hsp16 presence in precipitated CIs and serum NOx level in 20 SA patients, 19 TB patients, and 21 healthy volunteers using PEG precipitation, Western Blot, and Griess methods. We revealed higher NOx concentrations in SA and TB than in controls, but lower in SA than TB. Mtb-hsp16, Mtb-hsp65, and Mtb-hsp70 concentrations in precipitated CIs were higher in SA than in TB and controls. In all tested groups, Mtb-hsp16 concentration was higher than Mtb-hsp70 and Mtb-hsp65. We suggest that lower levels of NOx may induce a M. tuberculosis genetic dormancy program via higher Mtb-hsp16 expression in SA. It seems that Mtb-hsp16 may be more important than Mtb-hsp70 and Mtb-hsp65 in CIs formation and initiate an autoimmune response in SA related to mycobacteria’s stationary-phase.     

Patient-recognition data-mining model for BCG-plus interferon immunotherapy bladder cancer treatment

Bladder cancer is the fifth most common malignant disease in the United States with an annual incidence of around 63,210 new cases and 13,180 deaths. The cost for providing care for patients with bladder cancer disease is high. Bladder cancer treatment options such as immunotherapy, chemotherapy, radiation therapy, transurethral resection, and cystectomy, are used with varying success rates. In this research, data from a nationwide bacillus Calmette-Gue rin (BCG) plus interferon-alpha (IFN-alpha) immunotherapy clinical trial was considered. Data mining algorithms were used to analyze the effectiveness of immunotherapy treatment and to understand the prominent parameters and their interactions. The extracted knowledge was used to build a patient recognition model for prediction of treatment outcomes. The data was analyzed to understand the impact of various parameters on the treatment outcome. A list of significant parameters such as cumulative tumor size, presence of residual disease, stages of prior bladder cancer, current state of bladder cancer, and the presence of current bladder cancer (T1) is provided. The decision-making approach outlined in the paper supplemented with additional knowledge bases will lead to a comprehensive analytical road map of the BCG/IFN-alpha immunotherapy treatment. It will provide individualized guidelines for each stage of the treatment as well as measure the success of the treatment.     

Isoelectric point determination of proteins and other macromolecules: oscillating method

A program written in Visual Basic has been developed to calculate the isoelectric point of proteins and other macromolecules bearing acid-basic residues. The pI value can be theoretically calculated with the precision required. The computer automatically supplies a representation of the charge of the protein versus pH values. The corresponding values can also be obtained, on command, in the form of table.     

Image-type dependent eigen-regions-of-interest define conspicuity operators for predicting human scanpath fixation

Top-down informativeness elaboration and bottom-up conspicuity processing are intimately interconnected in visual perception. An internal cognitive model of the external world must necessarily control not only our recognition but also the scanpath sequence of eye movement/shift of attention jumps. A self-organizing process based on principal component analysis and scanpath experimental data are used in this paper to define spatial visual conspicuity from the eigen-features of the scanpath sequence image loci. Eight different classes of images are used as both training and testing set. We first demonstrate that cognitive-driven scanpath loci can be discriminated in terms of these bottom-up eigen conspicuity features. We can finally define a conspicuity processing algorithm and measure its ability to predict human scanpaths as evidenced by the positional similarity measure Sp. Some computer vision applications will also be discussed.     

A computer model for the clearance of insoluble particles from the tracheobronchial tree of the human lung

A multi-compartment model for the clearance of insoluble particles from the tracheobronchial tree of the human lung was created. As a significant innovation, the model considers specific mass transfer paths that may play an important role for slow bronchial clearance. These include the accumulation of particulate mass in the periciliary sol layer, an uptake of stored particles by airway macrophages, and the endocytosis of deposited mass by epithelial cells. Besides the gel layer representing fast mucociliary clearance, all cellular and extracellular units involved into the slow clearance process are described by respective compartments which are connected by specific transfer paths. The gastrointestinal tract (GIT), lymph nodes (LN), and blood capillaries are included into the model as final accumulation compartments, to which mass is transferred via the airway route and the transepithelial path. Besides a basic version of the model describing the whole tracheobronchial region by one set of compartments, also an advanced approach is introduced which, in accordance with the International Commission on Radiation Protection (ICRP), subdivides the conducting airways into a bronchial (BB) and bronchiolar (bb) part. Preliminary results were generated with MS-Excel from deposition data of 1-mummass median aerodynamic diameter (MMAD) particles, calculating local slow clearance fractions according to mathematical procedures introduced in previous publications. While mucociliary clearance is completely finished within 24h after exposure, slow clearance takes place in distinct phases and needs several days to weeks. This multi-stage event is also reflected in the respective retention curves which correspond well to previously published graphs.     

Handling outliers in brain tumour MRS data analysis through robust topographic mapping

Uncertainty is inherent in medical decision making and poses a challenge for intelligent technologies. This paper focuses on magnetic resonance spectra (MRS) for discrimination of brain tumour types and grades. Modelling of this type of high-dimensional data is commonly affected by uncertainty caused by the presence of outliers. Multivariate data clustering and visualization of MRS data is proposed using the GTM framework with basis functions comprising Student t-distributions in order to minimize the negative impact on the model from outliers. The effectiveness of this model on the MRS data is demonstrated empirically.     

Effects of CPAP on clinical variables and autonomic modulation in children during an asthma attack

Continuous positive airway pressure (CPAP) causes changes in alveolar and intrathoracic pressure and the activation of pulmonary stretch receptors affects the balance of the autonomic nervous system. The acute effects of CPAP on autonomic modulation have been demonstrated in different diseases, but no studies have been carried out addressing CPAP in patients with asthma. The hypothesis tested in the present study is that CPAP can produce an autonomic effect beyond a mechanical effect of bronchial dilatation in children with asthma. The results demonstrated improvements in clinical variables and an increase in vagal tone with the administration of CPAP during an asthma attack, as demonstrated by a diminished respiratory rate and a reduction in signs of respiratory distress. Regarding autonomic modulation, an increase in parasympathetic variables was found, indicating non-cholinergic activation stemming from the persistent increase in peak flow.     

Insulin-independent glycogen supercompensation in isolated mouse skeletal muscle: role of phosphorylase inactivation

Glycogen supercompensation (increase in muscle glycogen content above basal) is an established phenomenon induced by unknown mechanisms. It consists of both insulin-dependent and -independent components. Here, we investigate insulin-independent glycogen supercompensation in isolated, intact extensor digitorum longus muscles from mice. Muscles were stimulated electrically, incubated in vitro with 5.5 mM glucose for up to 16 h and then analysed for glycogen, glucose uptake and enzyme activities. Basal glycogen was 84±6 µmol glucosyl units/g dry muscle and was depleted by 80% after 10 min contraction. Glycogen increased after contraction, reaching a peak value of 113±9 µmol glucosyl units/g dry muscle (P<0.05 vs. basal) by 6 h, and returned to basal values by 16 h (84±8). Maximal activities of glycogen synthase, phosphorylase and -glucosidase were not significantly altered by contraction or during the 6-h recovery period. Glycogen synthase fractional activity (0.17/7.2 mM glucose-6-P; inversely related to phosphorylation state of the enzyme) was increased about twofold early after contraction but then decreased and was slightly lower than baseline during the period of supercompensation (4–6 h). Phosphorylase fractional activity (±adenosine monophosphate; directly related to phosphorylation state of the enzyme) decreased to 60% of basal after contraction and decreased further during the initial 4 h of recovery to 40% of basal (P<0.01 vs. basal). After 4 h recovery, glucose uptake was slightly (50%) higher in the stimulated than in the non-stimulated muscle (P<0.01). Thus, insulin-independent glycogen supercompensation involves inactivation of phosphorylase and hence an inhibition of glycogen breakdown.     

Stress hormonal response to exercise after sleep loss

Summary While prolonged loss of sleep is unpleasant and demanding, it remains unclear if it blunts or enhances the physiological stress imposed by subsequent exercise. To investigate this, we deprived eight subjects of sleep prior to exercise to see if this altered the stress hormonal response to that exercise. In a first series of experiments, two fragmented nights of sleep preceded 30 min of heavy treadmill walking exercise. While sleep loss disturbed mood before and during exercise (p<0.05), it left stress hormonal levels (cortisol and -endorphin) in blood identical to control. In a second series, subjects performed light treadmill walking exercise for 3 h after 36 sleepless hours. As before, sleep deprivation disturbed mood before and throughout exercise (p<0.05), but failed to change blood levels of stress hormones. In both series, sleeplessness left heart rate, oxygen uptake, minute ventilation, and body core temperature unchanged in exercise. We conclude that sleep loss provokes psychological changes during subsequent exercise without measurably altering the stress hormonal response to that exercise.     

Blood flow and O2 extraction as a function of O2 uptake in muscles composed of different fiber types

We examined how the greater vasodilatory capacity of slow--(ST) versus fast-twitch (FT) muscles impacts the relationship between blood flow (Q ) and O2 uptake (VO2) and, consequently, the O2 extraction (a-vO2 diff.)-to-VO2 relationship. Q was measured with radiolabelled microspheres, while VO2 was calculated by the Fick principle using measurements of microvascular O2 pressure (phosphorescence quenching) at rest, low--(2.5 V) and high-intensity contractions (4.5 V) for soleus (Sol; ST, n=5), mixed-gastrocnemius (MG; FT, n=7) and white-gastrocnemius (WG; FT, n=7). The slope of the Q-to-VO2 relationship (delta Q/delta VO2] ) was not different among muscles (Sol = 5.5 +/- 0.2, MG = 6.0 +/- 0.11 and WG = 5.8 +/- 0.06; P > 0.05). In contrast, the intercept was greater (P < 0.05) for Sol (16.3 +/- 2.7 ml min(-1) 100 g(-1)) versus MG and WG (in ml min(-1) 100 g(-1): 1.39 +/- 0.26 and 1.45 +/- 0.23, respectively; MG and WG, P > 0.05). In addition, the a-vO2 diff.-to-VO2] relationship for Sol was shifted rightward compared to MG and WG. These data suggest that the increase in Q for a given change in VO2 is similar for slow- and fast-twitch muscles, at least for the range of metabolic rates and muscles studied herein and that a-vO2 diff. differences result from the lower resting Q in FT muscles.     

β-endorphin and adrenocorticotropic hormone production during marathon and incremental exercise

Summary To evaluate the increases in concentration of -endorphin and adrenocorticotropic hormone (ACTH) 16 healthy athletes, well-trained for endurance exercise, volunteered for an exhausting incremental graded treadmill exercise and a marathon run. Maximum oxygen uptake was determined during the treadmill exercise. Venous blood samples were drawn before and after exercise, and at 30, 60 and 120 min during the recovery phase. For the marathon race venous blood was collected before, after 1 and 2 h of running and at the end, as well as at 0.5, 1, 2 and 24 h during the recovery phase. Lactate concentration, heart rate and perceived exertion were also determined at all points of blood collection. Both types of exercise led to significant increases in concentration of -endorphin and ACTH of similar magnitude, with -endorphin tending to be higher after the marathon run. The decrease of both was slower during the recovery from the marathon than after the incremental test. Concentrations of both hormones increased exponentially during the marathon run. Positive correlations between -endorphin and ACTH concentrations were determined at the end of both runs. It was found that incremental exhausting and prolonged exhausting endurance exercise such as marathon running induced an increase of similar magnitude in both -endorphin and ACTH concentration.     

Effect of exercise training on muscle glucose transporter 4 protein and intramuscular lipid content in elderly men with impaired glucose tolerance

This study determined the effects of exercise training on adaptations of skeletal muscle including fibre composition, capillarity, intra-muscular triglyceride concentration (IMTG), as well as glucose transporter 4 protein (GLUT4) and metabolic enzyme activities. Percutaneous muscle biopsies from the vastus lateralis muscle were obtained from non-obese elderly Korean men (n=10; age range 58–67 years) with impaired glucose tolerance. Subjects performed 12 weeks of endurance exercise training (60–70% of the heart rate reserve). The training program improved the total GLUT4 protein expression (P<0.01), decreased the IMTG, increased the fatty acid oxidation capacity, and the number of capillaries around type 1 fibres (P<0.05), whereas no significant alteration was observed around type II fibres. All data are presented as the means together with the standard deviation. The results suggest that endurance training evokes morphological and biochemical changes in the skeletal muscle of elderly men with impaired glucose tolerance that may be considered to limit the development of type 2 diabetes.     

Plasma lactate accumulation is reduced during incremental exercise in untrained women compared with untrained men

The lactate threshold (LT) is commonly reported as not different between sexes, yet lower blood lactate concentrations have been reported in women during submaximal exercise. The purpose of the present study was to measure the changes in plasma lactate concentration [La(-1)] in men and women during incremental cycle ergometer exercise using the same protocol and compare the data using several different methods of analysis. A group of untrained men (n = 21) and women (n = 22) were studied and venous blood drawn at regular intervals during and after exercise for assay of plasma [La(-1)]. Plasma [La(-1)] increased during exercise in both sexes, reaching higher values in men, both at exhaustion (men 8.6 +/- 2.3 mmol l(-1); women 6.2 +/- 2.3 mmol l(-1); P = 0.01) and post-exercise (men 11.8 +/- 2.1 mmol l(-1); women 10.2 +/- 2.4 mmol l(-1); P = 0.03). Logarithmic transformation of the data yielded LT values that were not different between sexes (men 44.2 +/- 12.9; women 50.2 +/- 12.6; %VO2peak; P = 0.45), yet both the 2 and 4 mmol l(-1) fixed concentration LT occurred at lower relative intensities in men (2 mmol l(-1): men 50.9 +/- 12.9; women 66.9 +/- 11.1; %VO2peak; P = 0.01). 4 mmol l(-1): men 75.7 +/- 11.0; women 90.6 +/- 9.2; VO2peak; P = 0.01). However, when the plasma [La(-1)] was examined in both sexes throughout exercise, using a single exponential function, plasma [La(-1)] was significantly lower in women (P < 0.05) at all relative intensities between 30 and 100%VO2peak. While the basis of this sex difference is unknown, reduced plasma [La(-1)] during submaximal exercise in women may offset to some degree the endurance performance disadvantage of their lower VO2peak.     

Prediction of maximal oxygen uptake from the ratings of perceived exertion and heart rate during a perceptually-regulated sub-maximal exercise test in active and sedentary participants

This study assessed whether the accuracy of predicting maximal oxygen uptake (VO2max) from sub-maximal heart rate (HR) and ratings of perceived exertion (RPE) values was moderated by gender and habitual activity. In total, 27 men and 18 women completed two GXTs to determine VO2max and three perceptually-regulated GXTs, incremented by RPE 9, 11, 13, 15 and 17. The RPE and HR were individually regressed against VO2max (approximately 0.96) to enable predictions of VO2max. The VO2max was predicted from three RPE ranges (9-17, 9-15, 9-13). The RPE ranges were extrapolated to RPE(19), RPE(20) and age-predicted maximal HR (HRmax(pred)). ANOVA revealed no differences between measured and predicted VO2max (P > 0.05) when the RPE range 9-17 was extrapolated to RPE(19) and HRmax(pred). Extrapolation of RPE 9-17 to RPE(20) overestimated VO2max (P < 0.05), but no differences were observed when predicted from the RPE ranges 9-15 and 9-13. The prediction of VO2max was not moderated by gender or activity status. Hierarchical regression analysis revealed that HR explained additional variance in VO2max when added to the RPE (2%). Hierarchical multiple regression analysis also indicated that VO2max was significantly correlated with power output at sub-maximal RPE values of 13 and 15 (P < 0.01) in men and women. The addition of HRmax(pred) improved the accuracy of the prediction equation for men (P = 0.05) but not for women. The study confirmed the validity of estimating VO2max from perceptually-regulated, sub-maximal GXT and indicated the potential utility of regression analysis to gauge appropriate sub-maximal exercise intensities.     

Exhaled nitric oxide is associated with acute mountain sickness susceptibility during exposure to normobaric hypoxia

Nitric oxide is a gaseous signaling molecule that participates in a large variety of physiological functions and may have a role in the pathology of altitude illnesses, such as acute mountain sickness (AMS). The effect of normobaric hypoxia on the fraction of exhaled NO (FENO) is a controversial area of high altitude physiology, with the effect varying widely across studies. We exposed 19 male subjects to normobaric hypoxia for 6 h and measured FENO and AMS (via Lake Louise Score) each hour. For data analysis, subjects were divided into AMS-positive and AMS-negative groups based on their Lake Louise Scores during exposure. Eighteen subjects completed the study, and the incidence of AMS was 50%. Mean FENO was unchanged at hour 1 but was significantly elevated above baseline for the remainder of the normobaric hypoxia exposure (p < 0.001). Subjects who developed AMS had a significantly lower mean FENO at baseline compared to resistant subjects (p = 0.013). Further investigations are warranted to confirm our results and to understand the physiological basis of this association.