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This would ensure the appropriate inhibitory-excitatory balance critical for the correct functioning of neuronal networks.

Integrated medical programmes are coming under increasing scrutiny to ensure that students are learning science in the context of medicine and in a way that prepares them for their future career as doctors.

This scrutiny has led to questions and concerns about 1 the ways that learning outcomes for the sciences underpinning medical practice are determined and 2 the ways that science is taught to medical students.

This talk will give an overview of how decisions are made about what science should be included within integrated curricula, with an emphasis on medical curricula.

At the end of the talk, I will offer some views on the potential role of portfolio or video taping in the teaching, learning and assessment of the sciences within integrated medical curricula.

This will form the necessary platform for a similar approach to the patient and his state of health or disease. Medical education benefits from a global approach of normal and abnormal processes at the cellular, organ and body level.

In the medical curriculum at the Brussels Free University-VUB, the courses of physiology and physiopathology are conceived as individual entities that are not subdivided in independent organ-based modules.

Lectures in an auditorium are considered as a crucial instrument in this form of teaching as long as it stimulates interactions with the students.

It is therefore important to limit the number of students per lecture session. It is the task, and challenge, of the lecturer to clarify and illustrate the basic mechanisms and insights with relevant examples from the life and medical sciences.

This will not only force the teacher to seek the most attractive and convincing tools and illustrations but will also stimulate students into further reading and thinking.

Professionalism of the teachers will be the key in this mode of education. The teacher can propose the framework of a topic, followed by the context application to stimulate clinical understanding.

Also, case studies can be used to gain understanding of the physiopathological processes involved. The portfolio is a tool to actively involve students and learners, with regular reciprocal evaluations.

On the contrary it allows articulating these concepts with the influence of a wide range of internal and external factors influencing health and disease.

In order to achieve these goals, schools of medicine will have to ensure the scientific and medical significance of their biomedical departments.

In medical education, portfolios can be used to accommodate effective learning of medical knowledge and skills, as well as generic competencies, such as effective communication, organization, team-work and professionalism.

At the Maastricht University, we have implemented a assessment system, partly based on a portfolio, for medical and generic competencies in a 4-year physician-clinical investigator master program MD-Msc.

In this program, the medical degree is combined with a clinical investigator degree, focusing on translational medicine to bridge the gap between research and care delivery by translating questions from patient care into research, and applying research results to care.

In the assessment program, the portfolio is used to integrate a wide range of module assessments, progress tests, medical skills assessment and professional behaviour to assess development and progress in 4 competency domains medical experts, scientist, health care worker and person.

Students reflect regularly on strengths and weaknesses in each of the competency domains and formulate learning objectives formative portfolios which are discussed with a personal counselor mentor.

Throughout the program, 4 summative portfolios are assembled, which are assessed by an independent assessment committee.

A drawback of our current approach is that competency-assessment is still mixed, thus regular assessments exams are combined with portfolio-assessment, which still skews student priority towards the regular exams.

Currently, we are in the process of reevaluating the assessment program and examining the possibility of a program-wide assessment program that is based on the portfolio alone.

Learning amounts to encoding information in long-term memory and being able to appropriately retrieve and apply the information stored.

Traditionally, learning is usually tested immediately after a study period or a course. It is wellknow that retention and transfer of basic science is a problem and a variety of instructional strategies such as integrated curricula and problem-based learning aims at ameliorating this problem.

Yet, until now curriculum level comparisons show no dramatic advantages of these strategies and there is a concern that basic science learning will be too shallow.

In this presentation I will give some perspectives of the importance of basic science knowledge to clinical practice with examples from Anaesthesiology.

Biomedical Sciences and CNR Neuroscience Institute, Padova, Italy Cell-to-cell communication evolved as a fundamental process to coordinate the physiological behavior in multicellular organisms.

How cell behavior is regulated by the diverse signalling pathways, what mechanisms the cells use to distinguish the input from different receptors activating the same signals, are key questions in modern biomedical research that need to be addressed for a better understanding of physiology and physiopathology.

To gain insights into the complexity of the spatio-temporal patterns of the signals that govern cell communication, we need tools that permit the visualization and quantitative measurement of such signals by fluorescent microscopic imaging in living cells.

The spatial complexity of the cell and the spatiotemporal heterogeneity of signals require not only the quantitative determination of such signals in the cytoplasm of living cells, but also within subcellular compartments and organelles.

Finally, I will concentrate on the mechanisms regulating second messenger homeostasis in mitochondria, an organelle that in the last few years has been at the centre of biomedical research for its participation not only in cell energy production, but also for its role as master regulator of programmed cell death.

Increasing evidence suggests an important role for astrocytes in the neurogenic niche. Previously we showed that ablating the intermediate filament proteins glial fibrillary acidic protein GFAP and vimentin facilitates regeneration and increases plasticity after injury and neural grafting.

Here, we investigated the role of GFAP and vimentin in the regulation of endogenous neurogenesis. Ablation of GFAP and vimentin reduced Notch signaling from astrocytes and increased the number of newly born neurons.

These findings correlated with enhanced learning and memory and greater plasticity in the adult hippocampus in response to injury and running.

We conclude that intermediate filament proteins in astrocytes are important for astrocyte-mediated control of neurogenesis and that this control is at least partially mediated by Notch signaling.

Thus, changing the intrinsic properties of astrocytes by modulating intermediate filament proteins affects the efficiency and plasticity of the neurogenic niche.

Yu1,2, U. Wilhelmsson3, M. Pekny3, Y. Though new opportunities to treat brain and spinal cord trauma have been provided by marked advance made in the field of stem cell research, the progress is hindered by the complex post lesion pathology which diminishes effective donor engraftment.

These findings are consistent with our earlier reports that scaffolded hNSC engraftment improves locomotion in rats.

Our data indicate that recovery of locomotion in the treated GV mice largely results from reactivation of the propriospinal neuronal participation in locomotor pattern generation, which is markedly enhanced by genetic ablation of GFAP and vimentin plus the engraftment of hNSCs.

The results suggest that reactive gliosis negatively affects neuroplasticity following neurotrauma, and that attenuation of reactive gliosis enhances NSC-based neuroanatomic and functional repair of traumatically injured central nervous system.

Hol Dept. Recently, important novel IF network functions have emerged: it transduces biomechanical and molecular signals and it controls many associated proteins.

Over the last years, we identified novel GFAP splice isoforms, which are expressed in different subtypes of astrocytes in the developing and the adult human brain [1, 2].

These specific isoforms are not expressed during brain development or in brains of young healthy adults. The exact function of the specialized IF network in the neurogenic SVZ astrocytes and the astrocytes near amyloid plaques is still elusive.

The research in my group is currently aimed at understanding the functional changes in these cells induced by the specific composition of the IF-network.

We have set up astrocyte and neurosphere cultures isolated from post-mortem human brains to enable to study the different astrocyte subtypes and the function of the different GFAP isoforms.

We ultimately aim to develop novel therapeutic approaches by targeting reactive astrocytes and the astrocytic neural stem cells.

Psychiatry, 8 Glia 52 Glutamate stimulation of astrocytes was followed by an increase in the incidence of small transient inward currents in sniffers, reminiscent of postsynaptic quantal events observed at synapses.

This indicates that glutamate-stimulated ATP release from astrocytes was most likely exocytotic. Prior fusing with the plasma membrane in the process of exocytosis, membrane-bound vesicles are transported through the cytoplasm.

Their trafficking and consequently release of their content may be changed in altered physiological conditions, therefore affecting the physiological status of neurons.

We studied the prefusion mobility of fluorescently labeled peptidergic ANP vesicles atrial natriuretic peptide; ANP in the cytoplasm of single rat and mouse astrocytes in culture.

We found out that delivery of vesicles to the plasma membrane for exocytosis involves an interaction with the cytoskeleton, in particular microtubules and actin filaments, which is similar to neurons and excitable secretory cells.

Some of the membrane-bound vesicles are retrieved from the plasma membrane to be recycled back into the cytosol.

Postfusion transport of glutamatergic and peptidergic vesicles was studied by labeling vesicles with antibodies against specific membrane or luminal vesicle proteins.

Trafficking velocity of prefusion and postfusion recycling vesicles differ in velocity for one order of magnitude and the traffic of diverse vesicles appears to be differently regulated by calcium ions.

Prinzen Dept. We investigated whether pacing at alternative sites can maintain a better cardiac pump function as well as mechano-energetic efficiency of the heart.

LVs paced animal received a modification of the Medtronic pacing lead, with extended helix which was introduced transvenously and, after positioning against the RV septum using a pre-shaped guiding catheter, driven into the interventricular septum by rotation of the screw-in lead until the LV endocardium ; a trans-ventricular septal approach.

At these times also myocardial oxygen consumption MVO2 was measured. At 16 weeks, MRI tagging was performed to measure mechanical dyssynchrony and discoordination from myocardial strains.

Therefore, using a good site of pacing the heart can pump better at a higher efficiency. Any stress generated in one part of the wall reflects in all other parts of the wall therefore, the earlier activated region causes stretch in later activated regions.

Most informative are mid-wall circumferential strains, which are determined for given location in the LV wall. CP are studied to obtain maps of the LV activation time and parameters of global ventricular function.

The maps and the parameters are used to improve selection of patients for cardiac resynchronisation therapy CRT.

Maps are obtained from the prominent events in the CP like the onset of shortening time, peak shortening time and magnitude of shortening.

The parameters of global ventricular function consider interplay of CP in different regions to evaluate the coherence and the reserve capacity of the LV contraction.

One of them is internal stretch fraction ISF , which is defined as the amount of stretch relative to the amount of shortening during ventricular ejection.

ISF is better predictor of reverse remodeling after CRT than differences in time to onset and time to peak shortening.

An alternative to mapping prominent events in CP is decomposition of patterns with respect to activation time.

For this purpose, a lumped parameter model CircAdapt is used to simulate CP in dyssynchronous hearts. The activation time map is determined with reverse modelling by using measured CP.

In the cardiac muscle, on top of altered activation times also the contractility may differ in regions. This adds a new dimension in the complexity of CP and imposes challenges in mapping both simultaneously.

We have previously shown in the embryonic chick heart model that chronic ventricular pacing leads to structural, hemodynamic, and metabolic remodeling.

Methods and results. Sham operated and paced hearts were then submitted in vitro to anoxia 30 minutes and reoxygenation 60 minutes.

ECG disturbances and alterations of atrial and ventricular electromechanical delay EMD reflecting excitation-contraction E-C coupling were systematically investigated.

Baseline functional parameters were stable during at least 2 hours. Anoxia induced tachycardia, followed by bradycardia, atrial ectopy, first-, second-, and third-degree atrio-ventricular blocks and, finally, transient electromechanical arrest.

Reoxygenation triggered also Wenckebach phenomenon and ventricular escape beats. Under normoxia, heart rate, QT duration, conduction, EMD, and ventricular shortening were similar in sham and paced hearts.

During reoxygenation, arrhythmias ceased earlier and ventricular EMD recovered faster in paced hearts than in sham hearts.

In contrast, none of these agents further ameliorated recovery of the paced hearts. Stams, Stephan K. Winckels, Morten B. Thomsen, Jet D.

Beekman, Roel van der Nagel, and Marc A. Creation of AV block will lead abruptly to a bradycardia decrease in heart rate from towards 50 bpm , b AV-dyssynchrony and c altered variable ventricular activation.

In most animals, the idioventricular rhythm IVR will originate from the left ventricular LV low septum.

To control ventricular remodeling and arrhythmogenesis, we have set out a number of experiments to investigate the relevance of ventricular activation.

In the first group 9 dogs , a pacemaker lead was implanted in the high septal region 4 weeks CAVB and dofetilide was used as the arrhythmogenic challenge.

After dofetilide, the decreased repolarization reserve was unmasked. Altered ventricular activation results in more proarrhythmia after dofetilide, whereas the origin of ventricular activation is less important.

Sufficient cell-to-cell electrical coupling seems to ensure coordinated depolarization pattern and insulin release that can be further modulated by rich innervation.

The complex structure and coordinated action develop after birth during fast proliferation of the endocrine tissue.

These emergent properties can be lost due to various reasons later in life and can lead to glucose intolerance and diabetes mellitus.

Pancreas slice is a novel method of choice to study the physiology of beta-cells still embedded in their normal cellulo-social context.

These channels close in response to glucose stimulation and this results in membrane depolarization. The KATP-channels are the target of hypoglycaemic sulphonylureas and they stimulate insulin secretion by direct interaction with the channel protein.

Glucose- or tolbutamide-induced inhibition of the KATP-channels via acceleration of glucose metabolism and increased ATP production leads to the initiation of action potential firing in the beta-cell.

The ion channels involved in beta-cell action potential firing have been characterized in some detail. Increased availability of human islet cells as a by-product of islet transplantation programmes has challenged this view.

It is unlikely that the differences are limited to those already described and confined to ion channels. Our work so far has demonstrated the potential pitfalls of extrapolating rodent data to the situation in man.

More work is required to understand the molecular and cellular causes of human diabetes rodent diabetes is a very rare clinical condition!

Detailed knowledge about the genes expressed in human beta-cells is also essential for the interpretation of the genetic data that are now emerging.

Clearly, understanding the 42 functional consequences of a given gene polymorphism linked to diabetes depends critically on whether the gene is expressed in the beta-cell or not.

Walther1 1 Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany 2 Institute of Physiology of the Medical Faculty, University of Maribor, Maribor, Slovenia Diabetes mellitus is one of the most important metabolic disorders and is characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism, resulting from defects in insulin secretion, insulin action, or both.

It is known for more than three decades that 5-HT co-localizes with insulin in the secretory granules of these cells and it is co-released when pancreatic islets are stimulated with glucose.

Nevertheless, the function of 5-HT in this context was not identified so far. The serotonergic system is unique amongst monoaminergic neuro- hormonal systems for its biosynthesis via two distinct rate-limiting tryptophan hydroxylases in the brain TPH2 and peripheral tissues TPH1.

Mice lacking peripheral 5-HT biosynthesis have a wide spectrum of physiological phenotypes, such as impaired primary haemostasis and liver regeneration, and diabetes.

However, reduced 5-HT levels also exert protective effects within the cardiovascular system, e. Together with its early onset and the inheritable pattern, this phenotype can be classified as maturity-onset diabetes of the young.

Thus, monoaminylation serotonylation of small GTPases seems to be a crucial mechanism in the fine tuning of insulin secretion.

This is the third microserotonergic system that has so far been described to depend on this posttranslational protein modification, adding strong evidence to our view, that monoaminylation plays a decisive modulatory role in signalling within a broad variety of tissues under physiological conditions.

In various secretory cells cytoplasmic swelling is a potent stimulus for hormone secretion. In native and clonal beta cells glucose uptake induces cell swelling and activation of swelling-dependent Cl- currents termed IClswell, IClglucose or IClislet.

In clonal INS-1E cells this process is paralleled by cytosol to membrane translocation of ICln, a protein which is crucially involved in generating IClswell.

IClswell activation contributes to membrane depolarization and insulin release and therefore provides a synergistic, under certain circumstances independent, alternative pathway of SSC.

Since IClswell activation requires intracellular ATP, this current seems to be of critical importance for insulin secretion under conditions where the classical SSC pathway is silenced.

The phytostilbene resveratrol reversibly inhibits Cav and IClswell and counteracts secretagogue- and hypotonicity-induced depolarization, and electrical activity.

Likewise, reduction of the medium glucose concentration results in growth arrest. These events are accompanied by decreased phosphorylation of Akt PKB , a downstream target in insulin receptor signaling which is crucial for beta cell survival.

The inhibition mechanism of serpins involves the initial recognition of the protease followed by the protease cleaving the RCL, concomitant with the conformational change in serpin to form the covalently-linked final serpin-protease complex, where the protease is destroyed due to active site deformation.

The native serpin is metastable and contains a 5-stranded beta sheet A, and upon cleavage, RCL inserts into the beta sheet A, resulting in a much more stable 6stranded form.

Work in our lab focus on the serpins in the blood coagulation system, namely antithrombin, heparin cofactor II and protein C inhibitor.

Over the past few years, we have solved a number of crystal structures of native serpins and serpinprotease complexes which provide us the molecular insight into how these serpins are activated and how specificity is achieved.

In blood, serpins are generally circulating in a state with low activity, with high activity conferred by binding to cofactors at the appropriate time and place.

The inhibition specificity can be regulated by interactions in the RCL or exosite through either allostery or bridging.

Target proteases of PCI include proteases of the blood coagulation and fibrinolytic systems e. PCI is present in blood, urine, and most other body fluids.

The highest PCI concentrations are found in seminal plasma. These data together with our finding that male homozygous PCI-deficient knockout mice are infertile Uhrin et al.

However, studies in mice are limited by the fact that in adult mice PCI is exclusively expressed in the reproductive tract.

In the human system PCI may therefore have additional, different functions. PCI is a heparin-binding serpin, and in vitro glycosaminoglycans modulate not only its activity but also its target enzyme specificity.

Internalized PCI can translocate to the nucleus, and this nuclear targeting requires basic amino acids of the H-helix.

JFC1 is a phospholipid-binding protein and an effector molecule of the small GTPase Rab27a, which is involved in vesicular transport processes in the cell.

In order to determine the biological role of PCI we therefore have to consider its interaction not only with glycosaminoglycans, but also with phospholipids, which may act as locally inducible regulators of PCI activity and specificity e.

Additionally phospholipids may regulate the inhibition of transmembrane serine proteases by PCI, and may also present a link to so far unrecognized intracellular actions of PCI.

Initially identified from human normal mammary epithelial cells, maspin expression is either reduced or completely silenced in breast cancers.

Numerous studies have implicated maspin function in cancer progression and angiogenesis. Maspin has also been targeted for breast cancer gene therapy.

Recently, transgenic and gene knockout mouse models have been used by our laboratory to identify the biological functions of maspin in vivo.

In this report, I will summarize the multiple functions of maspin in tumor progression and mouse development. Maspin knockout mice have been generated to address its function.

Beginning with embryo development, maspin is required for the appropriate cell-matrix interactions to occur so that a healthy and viable embryo develops.

In adult mouse, maspin is present in the epithelial cells of most tissues. Our laboratory has begun to unveil the role of maspin in the development of mammary gland and several other organs.

These data demonstrate that maspin not only plays a role in tumor progression and metastasis but also is a key regulatory molecule for normal mammary gland and embryonic development.

Both, Cavalpha1. The Cav1. Depolarizing K influx into sensory hair cells through apical mechanosensitive channels requires a high K concentration mM in the scala media.

It is generated by the epithelium of the stria vascularis which needs basolateral Cl channels for the recycling of Cl taken up by NaK2Cl cotransport.

Mutations in barttin lead to Bartter syndrome IV, which combines severe renal salt loss with congenital deafness.

We have generated a mouse model in which barttin is selectively inactivated in the inner ear, avoiding early lethality due to salt and fluid loss.

These mice display congenital deafness. This sufficed to suppress otoacoustic emissions from outer hair cells.

Outer hair cells also degenerated progressively. We have discivered that KCNQ4 mutations lead to slowly progressive hearing loss in humans and have generated appropriate mouse models.

Knock-out of either cotransporter leads to deafness in mice, with KCC3 disruption resulting in a slowly progressing hearing loss that is associated with hair cell degeneration.

References Kubisch C. KCNQ4, a potassium channel expressed in sensory outer hair cells, is mutated in dominant deafness.

Cell Boettger T. Nature , EMBO J. Rickheit G. Endocochlear potential depends on chloride channels: mechanism underlying deafness in Bartter syndrome IV.

Currently there are two putative candidates for the cochlear amplifier. These are voltage-dependent, somatic, motility mediated by the unique outer hair cell motor protein prestin and calcium-mediated, hair-bundle, motility, which is a ubiquitous feature of hair cells.

We have attempted to distinguish between these possibilities by measuring basilar membrane displacements from Tecta mice in response to acoustic and electrical stimulation.

At low stimulus levels basilar membrane displacements at and around the peak of the travelling wave are dominated by electromechanical amplification from the outer hair cells.

In response to acoustic stimulation this amplification is mediated through sensory transduction caused by displacements of the outer hair cell hair-bundles through their interaction with the tectorial membrane, to which they are attached.

Electrical stimulation of the cochlea bypasses sensory transduction and drives directly both outer hair cell somatic and hair-bundle motility.

If time permits, evidence will be presented for a role for prestin in the frequency tuning of cochlear mechanical responses and their transmission to neural excitation.

In recent years, significant progress in our understanding of the molecular mechanisms of presynaptic active zone function has been achieved by creating and analyzing k.

However, molecular perturbation of this large brainstem synapse has been difficult, since many k. In a second study, we have established a tissue-specific k.

Neuroscience and RIM2, crossed with an auditory-brainstem specific Cre mouse line. Besides for teaching purposes it can be also used for integration of multiple clinical and laboratory measurements.

Thus, the model enables to to predict the arterial oxygen saturation and blood CO2 levels by interactively changing different parameters that are accessible from clinical and laboratory measurements or alternatively replaced by the corresponding demographic data.

In the model it is possible to vary the gas composition and the barometric pressure, alveolar ventilation, diffusion capacity of the lungs, blood hemoglobin concentration, plasma protein concentration both affect pH , blood perfusion of different tissues so far we use 6 different tissues , specific tissue metabolism and the tissue capillary density.

It is possible to change the acid-base status by adding bicarbonate and nonvolatile acids, and thus to change base excess.

The model is based on known kinetic principles to describe transport of blood gases in human body from the outer atmosphere to different tissues.

It is composed of four compartments for transport of blood gases O2 and CO2 : airways, alveolo - capillary interface, the blood and the blood vessels, and the Krogh cylinder for blood gas exchange in tissues, including chemical regulation of breathing.

It is a steady state model, and does not provide transients. The components of the model were validated using published data from different experiments, such as those of Siggaard Anderson for the acid-base status of the blood.

Introduction: Our interactive personal computer based mathematical model for the oxygen transport uses clinical and laboratory data for the purpose of simulation of physiological and pathophysiological states, and is based on the known kinetic principles to describe transport of blood gases in human body from the outer atmosphere to different tissues1.

Recently, the model was upgraded to include the influence of acid-base balance in the chemoreflex control of breathing2, as well as the influence of hypoxia on the peripheral blood flow3.

With such model we simulated adaptation of breathing to the prolonged hypoxia to find which of the known compensatory mechanism is most effective.

Material and methods: The model is composed of four compartments for transport of blood gases O2 and CO2 : airways, alveolo - capillary interface, the blood and the blood vessels, and the Krogh cylinder for blood gas exchange in tissues.

With the model, it is possible to change interactively in real-time different parameters that are accessible from clinical and laboratory measurements to monitor the arterial oxygen saturation and blood CO2 levels.

Thus, it is possible to vary the gas composition and the barometric pressure, alveolar ventilation, diffusion capacity of the lungs, blood hemoglobin concentration, plasma protein concentration both affect pH , blood perfusion of different tissues so far we use 6 different tissues , specific tissue metabolism and the tissue capillary density.

In addition, it is possible to vary strong ion difference SID in the blood plasma and cerebrospinal liquor, or to change the concentration of 2,3DPG in the erythrocytes.

Results: The most effective adaptation measure to reduce effects of hypoxia were found to be changes of brain SID and acidification of blood due to bicarbonate excretion by kidneys, whereas substantial changes in 2,3 DPG in the blood inexpectedly reduced the efficincy oxygen transport to tissues, particularly after acid-base adaptation has already reached Conclusions: The model enables understanding of integrative function of respiratory adaptation and suggests direction of the experimental studies connected with hypoxia.

References: 1. Starc V. Zbornik prispevkov Ljubljana: Medicinska fakulteta, Katedra za interno medicino, ; Effects of myogenic and metabolic mechanisms on the autoregulation of blood flow through muscle tissue: a mathematical model study.

Cardiovasc Eng ; 4 1 Duffin J. Role of acid-base balance in the chemoreflex control of breathing. Scienze e Tecnologie Biomediche, Univ.

This is a measure of the amount of energy which has to be covered by other sources, mainly: 1 utilization of O2 already stored in the body and 2 phosphocreatine PCr breakdown.

The present work was carried out to quantify the changes in the body oxygen stores from transient or steady state measurements. Alveolar VO2, cardiac output Q; obtained from the signals of a photoplethysmographic system , and PCr signal, by means of 31P-MR spectroscopy, were measured noninvasively on 8 healthy volunteers 1.

Present results support the view that difference in the arterio-to-mixed-venous blood oxygen content between rest and steady state provide a good estimate of the changes in the venous blood O2 stores at exercise onset, thus showing that it is possible to obtain information on variables characterizing the metabolic transient from data obtained at steady state, which can be considered the "memory" of the events having occurred at exercise onset.

Sixty-four adult male SpragueDawley rats, weighing g at the beginning of the experiment were used. Chronic exercise consisted of treadmill running at 25 m.

Rats in the acute exercise groups were run on the treadmill at 30 m. Rats were sacrificed by cardiac puncture immediately after the exercise in acute exercise groups and 24 h after the last exercise in chronic exercise groups.

Control rats were sacrificed under similar conditions. Plasma MDA levels were higher in acute exercise groups and lower in chronic exercise groups compared to the controls.

Although NO level increased with chronic exercise and with GSE supplementation, it was not different in acute exercise groups compared to the controls.

SOD and GPx activities were lower in acute exercise group and higher in chronic exercise group compared to their controls. Antioxidant enzyme activities were higher in GSE-supplemented groups compared to the controls.

We concluded that oxidative stress increases with acute exercise and decreases with chronic exercise and antioxidant enzyme activities decrease with acute exercise and increase with chronic exercise.

Oral grape seed extract supplementation prevents exercise-induced oxidative stress by preventing lipid peroxidation and increasing the antioxidant enzyme activities in rats.

Keramidas1,2, Stylianos N. Kounalakis1,2, Nickos D. Geladas2 1 Department of Automation, Biocybernetics and Robotics, Jozef Stefan Institute, Ljubljana, Slovenia 2 Department of Sport Medicine and Biology of Exercise, Faculty of Physical Education and Sport Science, National and Kapodistrian University of Athens, Greece It is well known that a moderate reduction of muscle blood flow low body positive pressure of 50 mmHg during endurance continuous exercise training enhances the local aerobic muscle adaptations.

Methods: This study was performed on 60 Sprague-Dawley male rats at 6 weeks. As a result, it can be suggested that exercise application with dietary restriction might more efficient in weight control.

When this cell task force fails we can face a serious health problem. An appropriate example is insulin-secreting tissue organized into groups or islets of beta-cells scattered within pancreas.

Electrical activity in beta-cells exhibits a characteristic bursting pattern, which consists of slow oscillations in membrane potential between a depolarized plateau, on which calcium action potentials are superimposed, and a hyperpolarized electrically silent interval.

The gap junctional coupling between pancreatic beta-cells is critical for synchronous glucose-dependent insuling secretion and bursting electrical activity.

While the heterogeneity of beta-cells was shown to be important in modelling of electrical response of coupled beta-cell clusters most models consider only nearest neighbors coupling between the cells in specified geometries thus excluding any paracrine effects.

Here we take a different route and propose to introduce coupling between beta-cells based on the spatially embedded complex network cytoarchitecture model of an intact living islet.

We used a fitness network model approach to construct complex networks connecting the beta-cells based on their electrophysiological state representing the ability to communicate with other beta-cells in the islet.

The physiology of beta-cells was studied in cytoarchitectural intact islets using pancreas slice method. Under fixed electrophysiological conditions bursting oscillations of the membrane potential of betacells were computed in islets modeled as regular lattices with nearest neighbor interactions and as networks with complex topologies.

We show that long range communication between beta-cells emerging from the scale-free topology of the islet cytoarchitecture can have important consequences for the beta-cells bursting patterns.

Zeydanli, Erkan Tuncay, Aytac A. This makes RyR2 an important therapeutic target. Similar recoveries are also obtained by treating the diabetic rats with another beta-adrenergic receptor blocker, propranolol.

It is concluded that a detailed understanding of the basic structure and function of RyR2 will provide us their involvement in heart diseases, and the development of drugs to prevent RyR2 malfunction.

In the last few years it was shown in a number of different cell types that the stromal interacting molecule 1 Stim1 and the Orai proteins represent the key-proteins responsible for SOCE.

Down-regulation of Stim1 supports the data mentioned above. Thirty-seven adult male SpragueDawley rats weighing g were used.

Diabetes was induced by a single intraperitoneal injection of streptozotocin STZ, 50 mg. On the 7th day after administration of STZ, diabetes was confirmed by measuring blood glucose levels using a glucometer.

Rats with blood glucose level mg. At the end of the 6th week, rats were sacrificed by cardiac puncture. GSE supplementation did not affect blood glucose levels in diabetic rats.

XO and ADA activities were higher in diabetic rats compared to other groups. GSE supplementation increased antioxidant enzyme activities both diabetic and healthy rats.

In conclusion, 6 weeks of oral grape seed extract supplementation prevents oxidative stress and improves antioxidant status in diabetic rats.

Aim of this study was to reveal whether muscle nonshivering thermogenesis could be stimulated by HF diet. At 4 weeks of age, mice were randomly weaned onto a low-fat LF or HF diet.

At the age of 6 weeks, indirect calorimetry and cold tolerance test were performed and tissues for in-vitro experiments, biochemical and gene expression analysis were collected.

Underweight, overweight and obesity was assessed by anthropometric and weight measurements, body mass index BMI , skin folds measurement, and bioelectrical impedance analysis.

Analyses were performed separately in men and women adjusted for age. BMI characterizing underweight under 18,5 was obtained in 1. BMI characterizing overweight and obesity over 25 was obtained in Such difference in results using several measurement methods is acceptable.

The leading somatotype estimated by anthropometric method for men as well for women is ectomorphic-mesomorph. Such results suggest either an increased health risk to more than half of those tested or it is necessary to specify the individual somatotypic feature in the evaluation of increased health risk factors.

To specify the amount of health risk additional studies are required. Our aim was to evaluate the autonomic cardiovascular function in healthy offspring of individuals with vascular pathology related to essential hypertension, metabolic disorders or to its outcome myocardial infarction, cerebral stroke.

The assessment of the autonomic cardiovascular function was based on the measurement of heart rate variability HRV , blood pressure variability BPV and baroreflex sensitivity BRS.

In addition pulse wave velocity PWV was measured as a marker of arterial rigidity. Two cardiovascular function tests were applied: orthostatic test OT as a sympathetic challenge and Valsalva maneuver for BRS evaluation.

Continuous recording of electrocardiogram, noninvasive blood pressure Finapress, Ohmeda and photoplethysmogram was performed using Biopac MP digitizer.

Data were analyzed using Acknowledge and MIS software. Our data revealed the existence of discreet alterations of the autonomic cardiovascular function in young healthy individuals with family history for vascular pathology.

Hence, these noninvasive tests are suitable for screening individuals at risk and for primary prevention of cardiovascular pathology.

Keywords: Heart rate variability; Baroreflex sensitivity; Blood pressure variability; Pulse wave velocity; Cardiovascular autonomic function.

Anatomy and Physiology, sect. A cannula was inserted into the second tracheal ring, and positive pressure ventilation tidal volume 0.

The thorax was open, and the lungs exposed to athmospheric pressure. The tracheal cannula was connected to a constant flow pump set to deliver an inflation volume of 0.

The time for the rise and the fall of flow was about 30 msec. Lateral tracheal pressure was monitored and recorded. The pressure tracings allowed the measurements of lung mechanics according to the end-inflation occlusion method.

The mean value of static lung compliance Cst,l resulted 0. Equipment resistance Req was separately measured and subtracted from results, which hence represent intrinsic values.

Confirming what observed in rats and humans, the component of visco-elastic pressure dissipation in mice lung is higher than the newtonian component.

Mice lung mechanics measurements by the end-inflation occlusion method are scanty in the literature.

Present results are generally comprised in the range of previously reported values for normal mice. Thus, present data validate our measurement technique.

We conclude that the end-inflation occlusion method is suitable for mechanics measurements in the small mice lungs.

However, the model of fusion through hemifusion has not yet been directly demonstrated for exocytosis in living cells. Correlation of SLID with the diffusional behaviour of various fluorescence markers for either content or membrane mixing revealed that the onset of the fast, second, phase of SLID corresponded to the formation of a fusion pore, followed by lamellar body swelling.

In contrast, the slow, first, phase of SLID preceded pore formation but could still be accompanied by diffusion of farnesylated DsRed, a marker for the inner plasma membrane leaflet, or nile red.

We conclude that the first phase of SLID reflects the hemifusion state of exocytotic lamellar body fusion, while the second phase reflects fusion pore opening, fluid entry and lamellar body swelling.

These data indicate that exocytotic fusion proceeds through hemifusion intermediates. Furthermore, hemifusion may last up to 8 s.

SLID is a highly sensitive and non-invasive approach by which hemifusion can be detected independently of membrane markers, thereby providing a new tool to investigate the regulation of hemifusion in living cells.

These changes allow organization of proteins and organelles to adapt to conditions that are best for the efficient function of the growing heart.

The age-related functional changes of the cardiac pump are known. Contractile changes were studied in freshly isolated cardiomyocytes from 14, 21, 28 day old and adult male rats.

An edge detecting device was used to measure changes in myocyte length upon contraction. Cardiomyocyte size varied significantly between all age groups in length, width and surface area.

Contractility results showed a significant difference between all age groups, with the maximal percentage cell shortening seen in adult, minimal at 14 days.

This agrees with changes in intact heart. The opposite is supposed to occur for Na-Ca exchanger. Therefore entry on the exchanger will likely be slower than when the channels open in adult.

Indeed, the sarcoplasmic reticulum of the immature rat myocytes, although present and functional is not fully developed. In fact is has been shown that ryanodine receptor inhibitors have very little effect upon neonatal cell contraction.

The role of this process in the control of behavior is unknown. Since one outcome of SNARE-dependent gliotransmission is the regulation of extracellular adenosine and because adenosine promotes sleep, we genetically inhibited the release of gliotransmitters and asked if astrocytes play an unsuspected role in sleep regulation.

Inhibiting gliotransmission attenuated the accumulation of sleep pressure, assessed by measuring the slow wave activity of the EEG during NREM sleep, and prevented cognitive deficits associated with sleep loss.

Since the sleep-suppressing effects of the A1 receptor antagonist CPT were prevented following inhibition of gliotransmission and because intracerebroventricular delivery of CPT to wild-type mice mimicked the transgenic phenotype, we conclude that astrocytes modulate the accumulation of sleep pressure and its cognitive consequences through a pathway involving A1 receptors.

Extensive literature points towards a hypertrophic reaction of astrocytes during ageing, neurodegenerative processes and AD. Here, we have studied the astrocytic changes and modifications that appear throughout the progression of AD within the hippocampus.

We studied this in a recently developed triple transgenic mouse model of AD 3xTg-AD that mimics the temporal evolution and progression of AD.

Surprisingly and apposed to what has been described till now we found that from early ages 3 months of age; 1. We observed similar atrophic reaction within the CA1 hippocampal sub-field but later at 18 months of age but accounting for a 3.

This atrophy also appears in the entorhinal cortex but with earlier incidence, being significant from 1 month of age.

However, we found that whilst this is a generalised process, astrocytes surrounding plaques show a cytoskeleton hypertrophy as revealed by an increase of complexity 7.

Despite these changes in cytoskeleton organisation, the numerical density of astrocytes in both areas remain constant.

Therefore, our results suggest that there are differential effects of AD on astrocytic subpopulations depending on their association with amyloid plaques which will account for the progressive glial and neuronal alterations in synaptic connectivity and neurotransmitters imbalance that appear in AD and that are responsible for the observed mnesic and cognitive impairments.

The composition and size of the ECS changes dynamically during neuronal activity as well as during pathological states. Following their release, a number of neuroactive substances, including ions, mediators, metabolites and neurotransmitters, diffuse via the ECS to targets distant from their release sites.

A decrease in ECS volume and an increase in diffusion barriers were found during ageing in the rat and mouse cortex, corpus callosum and hippocampus.

These changes were accompanied by a learning deficit, astrogliosis, the rearrangement of astrocytic processes and a loss of extracellular matrix ECM.

An increase in diffusion barriers, manifested also as a decrease in the apparent diffusion coefficient ADC , due to astrogliosis as well as due to an increase in chondroitin sulphate proteoglycans was also found after cortical injury and in grafts of embryonic tissue.

Glutamate excitotoxicity depends entirely on calcium overload of the cytoplasm and can be initiated by disruption of glutamate homeostasis.

Thus, inhibition of glutamate uptake in isolated oligodendrocytes in vitro and in the optic nerve in vivo, is sufficient to trigger cell death, which is prevented by glutamate receptor antagonists.

On the other hand, non-lethal, brief activation of glutamate receptors in oligodendrocytes rapidly sensitizes these cells to complement attack.

Intriguingly, these effects are exclusively mediated by kainate receptors which induce calcium overload of the cytosol and the generation of reactive oxygen species.

In addition, ATP signaling can trigger oligodendrocyte excitotoxicity via activation of calcium-permeable P2X7 purinergic receptors expressed by these cells.

Sustained activation of P2X7 receptors in vivo causes lesions that are reminiscent of the major features of MSplaques, i.

In addition, treatment with P2X7 antagonists of chronic experimental autoimmune encephalomyelitis EAE , a model of MS, reduces demyelination and ameliorates the associated neurological symptoms.

Importantly, P2X7 expression is elevated in normal-appearing axon tracts in MS patients, suggesting that signaling through this receptor in oligodendrocytes may be enhanced in this disease.

Thus, P2X7 receptor antagonists may be beneficial for the treatment of MS. In conjunction, these observations reveal novel mechanisms by which altered glutamate and ATP homeostasis can trigger oligodendrocyte death.

This knowledge may generate new therapeutic avenues to protect white matter from acute and chronic damage. By investigating acute lesions of spinal cord white matter in anesthetized mice with fluorescently labeled microglia and axons using in vivo twophoton laser-scanning microscopy 2P-LSM , we identified the messenger nitric oxide NO as a modulator of injury-activated microglia.

Local tissue damages evoked by high-power laser pulses provoked an immediate attraction of microglial processes. Spinal superfusion with NO synthase and guanylate cyclase inhibitors blocked these extensions.

High tissue levels of NO, achieved by uniform superfusion with SPNO and mimicking extended tissue damage, resulted in a fast conversion of the microglial shape from ramified to ameboid indicating cellular activation.

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Use our online homework helper around the clock. Get rid of your headache and let us help you improve your grades. Health Promotion in Nursing Practice A BitTorrent file distribution consists of these entities: There are ideally many end users for a single file.

Start running a tracker or, more likely, have one running already. Start running an ordinary web server, such as apache, or have one already.

Associate the extension. Generate a metainfo. Put the metainfo file on the web server. Link to the metainfo. Start a downloader which already has the complete file the 'origin'.

Install BitTorrent or have done so already. Surf the web. Click on a link to a. Select where to save the file locally, or select a partial download to resume.

Wait for download to complete. Tell downloader to exit it keeps uploading until this happens. Metainfo files also known as.

All strings in a. The name key maps to a UTF-8 encoded string which is the suggested name to save the file or directory as. It is purely advisory.

For the purposes of transfer, files are split into fixed-size pieces which are all the same length except for possibly the last one which may be truncated.

It is to be subdivided into strings of length 20, each of which is the SHA1 hash of the piece at the corresponding index.

There is also a key length or a key files , but not both or neither. If length is present then the download represents a single file, otherwise it represents a set of files which go in a directory structure.

In the single file case, length maps to the length of the file in bytes. For the purposes of the other keys, the multi-file case is treated as only having a single file by concatenating the files in the order they appear in the files list.

The files list is the value files maps to, and is a list of dictionaries containing the following keys: length - The length of the file, in bytes.

In the single file case, the name key is the name of a file, in the muliple file case, it's the name of a directory. Tracker GET requests have the following keys: The 20 byte sha1 hash of the bencoded form of the info value from the metainfo file.

This value will almost certainly have to be escaped. Note that this is a substring of the metainfo file.

The info-hash must be the hash of the encoded form as found in the. Conversely that means clients must either reject invalid metainfo files or extract the substring directly.

They must not perform a decode-encode roundtrip on invalid data. Each downloader generates its own id at random at the start of a new download.

This value will also almost certainly have to be escaped. Generally used for the origin if it's on the same machine as the tracker. Common behavior is for a downloader to try to listen on port and if that port is taken try , then , etc.

Note that this can't be computed from downloaded and the file length since it might be a resume, and there's a chance that some of the downloaded data failed an integrity check and had to be re-downloaded.

If not present, this is one of the announcements done at regular intervals. An announcement using started is sent when a download first begins, and one using completed is sent when the download is complete.

No completed is sent if the file was complete when started. Downloaders send an announcement using stopped when they cease downloading.

Tracker responses are bencoded dictionaries. If a tracker response has a key failure reason , then that maps to a human readable string which explains why the query failed, and no other keys are required.

Otherwise, it must have two keys: interval , which maps to the number of seconds the downloader should wait between regular rerequests, and peers.

Note that downloaders may rerequest on nonscheduled times if an event happens or they need more peers. More commonly is that trackers return a compact representation of the peer list, see BEP If you want to make any extensions to metainfo files or tracker queries, please coordinate with Bram Cohen to make sure that all extensions are done compatibly.

It is common to announce over a UDP tracker protocol as well. Peer connections are symmetrical. Messages sent in both directions look the same, and data can flow in either direction.

The peer protocol refers to pieces of the file by index as described in the metainfo file, starting at zero. When a peer finishes downloading a piece and checks that the hash matches, it announces that it has that piece to all of its peers.

Connections contain two bits of state on either end: choked or not, and interested or not.

Choking is a notification that no data will be sent until unchoking happens. The reasoning and common techniques behind choking are explained later in this document.

Data transfer takes place whenever one side is interested and the other side is not choking. Interest state must be kept up to date at all times - whenever a downloader doesn't have something they currently would ask a peer for in unchoked, they must express lack of interest, despite being choked.

Implementing this properly is tricky, but makes it possible for downloaders to know which peers will start downloading immediately if unchoked.

Connections start out choked and not interested. When data is being transferred, downloaders should keep several piece requests queued up at once in order to get good TCP performance this is called 'pipelining'.

On the other side, requests which can't be written out to the TCP buffer immediately should be queued up in memory rather than kept in an application-level network buffer, so they can all be thrown out when a choke happens.

The peer wire protocol consists of a handshake followed by a never-ending stream of length-prefixed messages.

The handshake starts with character ninteen decimal followed by the string 'BitTorrent protocol'.

The leading character is a length prefix, put there in the hope that other new protocols may do the same and thus be trivially distinguishable from each other.

All later integers sent in the protocol are encoded as four bytes big-endian. After the fixed headers come eight reserved bytes, which are all zero in all current implementations.

If you wish to extend the protocol using these bytes, please coordinate with Bram Cohen to make sure all extensions are done compatibly.

Next comes the 20 byte sha1 hash of the bencoded form of the info value from the metainfo file. If both sides don't send the same value, they sever the connection.

The one possible exception is if a downloader wants to do multiple downloads over a single port, they may wait for incoming connections to give a download hash first, and respond with the same one if it's in their list.

After the download hash comes the byte peer id which is reported in tracker requests and contained in peer lists in tracker responses.

If the receiving side's peer id doesn't match the one the initiating side expects, it severs the connection.

That's it for handshaking, next comes an alternating stream of length prefixes and messages. Messages of length zero are keepalives, and ignored.

Keepalives are generally sent once every two minutes, but note that timeouts can be done much more quickly when data is expected.

All non-keepalive messages start with a single byte which gives their type. The possible values are: 'choke', 'unchoke', 'interested', and 'not interested' have no payload.

Its payload is a bitfield with each index that downloader has sent set to one and the rest set to zero.

Downloaders which don't have anything yet may skip the 'bitfield' message. The first byte of the bitfield corresponds to indices 0 - 7 from high bit to low bit, respectively.

The next one , etc. Spare bits at the end are set to zero. The 'have' message's payload is a single number, the index which that downloader just completed and checked the hash of.

The last two are byte offsets. Length is generally a power of two unless it gets truncated by the end of the file.

They are generally only sent towards the end of a download, during what's called 'endgame mode'. When a download is almost complete, there's a tendency for the last few pieces to all be downloaded off a single hosed modem line, taking a very long time.

To make sure the last few pieces come in quickly, once requests for all pieces a given downloader doesn't have yet are currently pending, it sends requests for everything to everyone it's downloading from.

To keep this from becoming horribly inefficient, it sends cancels to everyone else every time a piece arrives.

Note that they are correlated with request messages implicitly. Downloaders generally download pieces in random order, which does a reasonably good job of keeping them from having a strict subset or superset of the pieces of any of their peers.

Choking is done for several reasons. TCP congestion control behaves very poorly when sending over many connections at once.

Also, choking lets each peer use a tit-for-tat-ish algorithm to ensure that they get a consistent download rate.

The choking algorithm described below is the currently deployed one. It is very important that all new algorithms work well both in a network consisting entirely of themselves and in a network consisting mostly of this one.

There are several criteria a good choking algorithm should meet. It should cap the number of simultaneous uploads for good TCP performance.

It should avoid choking and unchoking quickly, known as 'fibrillation'. It should reciprocate to peers who let it download.

Finally, it should try out unused connections once in a while to find out if they might be better than the currently used ones, known as optimistic unchoking.

The currently deployed choking algorithm avoids fibrillation by only changing who's choked once every ten seconds.

It does reciprocation and number of uploads capping by unchoking the four peers which it has the best download rates from and are interested.

Peers which have a better upload rate but aren't interested get unchoked and if they become interested the worst uploader gets choked.

If a downloader has a complete file, it uses its upload rate rather than its download rate to decide who to unchoke.

For optimistic unchoking, at any one time there is a single peer which is unchoked regardless of its upload rate if interested, it counts as one of the four allowed downloaders.

Which peer is optimistically unchoked rotates every 30 seconds. To give them a decent chance of getting a complete piece to upload, new connections are three times as likely to start as the current optimistic unchoke as anywhere else in the rotation.

The BitTorrent Economics Paper outlines some request and choking algorithms clients should implement for optimal performance When developing a new implementation the Wireshark protocol analyzer and its dissectors for bittorrent can be useful to debug and compare with existing ones.

This document has been placed in the public domain. Singkat, Padat, dan Jelas Ingat bahwa perusahaan membutuhkan resume untuk mempercepat waktu mereka melakukan seleksi sebelum interview.

Oleh karena itu, waktu untuk melihat tiap resume juga sangat singkat menit sehingga resume yang kita buat harus benar benar padat dan jelas.

Untuk orang yang sudah mempunyai pengalaman kerja cukup lama, halaman masih bisa ditoleransi tetapi tetap usahakan dalam 1 halaman kecuali anda benar2 memiliki hal khusus yang perlu ditulis sebanyak itu.

Context Action Result CAR framework Ketika saya melihat resume dari beberapa orang dalam menulis pengalaman kerja, biasanya mereka hanya menulis judul dari pekerjaannya dan waktunya.

Contoh: - Sales Representative PT. Grosir Baju Indonesia - Dengan teknik penulisan seperti itu, apa yang bisa dilihat oleh perusahaan.

Perusahaan hanya tahu bahwa kita punya pengalaman menjadi sales representative selama 4 tahun dan sales supervisor selama 2 tahun di PT.

Grosir Baju Indonesia. Tetapi Perusahaan tidak akan pernah bisa melihat nilai lebih yang anda tawarkan. Ketika mereka melihat resume dari kandidat lain mereka akan melihat hal yang sama.

Bandingkan jika anda menulis seperti ini. Contoh Lain pengalaman sebagai programmer : - Membuat program akuntasi dengan cepat. Telp, E-mail.

Untuk Tempat tanggal lahir, biasanya tidak perlu dimasukkan karena orang akan sudah bisa mengetahui dari waktu anda menempuh pendidikan terakhir.

Tidak perlu mencantumkan daftar pendidikan mulai SD. Orang hanya tertarik untuk mengetahui pendidikan terakhir anda. Untuk mengetahui contoh aplikasi teknik cara membuat resume bisa anda lihat di.

Artikelnya sangat bermanfaat, terima kasih Admin untuk sharingnya. Terima kasih infonya bro, sangat membatu saya.. Terimakasih untuk informasinya.

Setidaknya dapat membantu dalam menambah wawasan kita. Be Careful. Urus Pendirian PT. Urus Pendirian CV. Urus Ijin Prinsip dan perubahan.

Urus Rekomendasi Departemen Perindustrian. Urus Merk Dagang. Urus Ijin ISO Urus Pernikahan di Luar Negeri Beda Agama Dan masih banyak lagi perijinan lainnya untuk informasi lebih lanjut silahkan hubungi kami: atau.

How long did you walk your child to the door for school? Context : Macbeth is talking to the earth, in a soliloquy. Significance : There are several possible meanings to this quote.

If Macbeth is saying that sound will spoil the mood, then that is an example of metatheatre, which in a way, takes away from the gruesome details of the murder, as it somewhat breaks the forth wall and remind the listeners that Macbeth is only a character in a play.

This quote contains apostrophe, as Macbeth is talking to an inanimate object, and personification. Context : This quote is said by Macbeth to Lady Macbeth.

Macbeth had just killed Duncan, and he and Lady Macbeth are discussing what he had done. Macbeth is horrified and imagines voices that speak of his evildoings.

Macbeth will not sleep anymore. Later, Macbeth refers to himself using his three names, which could symbolize the three stages of his prophesy and his development.

Therefore, Glamis could symbolize his past self, which he was before he killed Duncan, Cawdor could symbolize his current self, which is who killed Duncan, and Macbeth could refer to his future self.

This follows the motif of three, as there were three witches and Hecate was commonly portrayed with three faces. He feels very guilty, worried, and paranoid, so much as that he believes he will never be able to sleep again.

His sleep will disappear along with his innocence, as sleep is depicted as innocent and good. The witches punish people with lack of sleep, such as when they punished the sailor whose wife was mean with a lack of sleep.

This quote contains many metaphors. Context : This quote is said by Ross to an old man. They exchanging accounts of recent unnatural happenings.

It is the morning after Macbeth killed Duncan. Meaning : According to the clock, it is day, but darkness blocks the sun.

Is it dark because night has become more powerful than day, or because day is hiding its face in shame?

People at this time believed that social standing was determined by God, so trying to usurp someone to put yourself in their place goes against the natural order of things.

Kings were believed to also have been chosen by divine powers, so killing and usurping Duncan was especially heinous.

The falcon could be representing King Duncan, while the owl, a bird often attributed to death, could represent witchcraft; therefore, this could be saying that witchcraft has killed Duncan.

Also, night, which can represent evil, is taking over day, which is good and supposed to be predominate. This quote contains personification and metaphors.

Context : Macbeth is talking to himself, in a soliloquy. I have ruined my peace for their benefit and given my soul to the devil to make them, the sons on Banquo, kings.

Instead of letting that happen, let fate come to the arena and fight me to the death. Macbeth, who committed evil deeds, will be punished, while Banquo, who has been good and loyal to the king, will be rewarded.

This quote also contains personification and metaphors. Context : Macbeth is speaking to Lady Macbeth.

Meaning : We have hurt the snake, but have not killed it. It is better to be with the dead, whom we have killed and put to rest in order to secure our peace, than to lie with tortured minds in a frenzy of sleeplessness.

He decides that he rather destroy the world than continue to live in fear, which indicates the reign of terror that Scotland will fall under.

Simply choose your favorite and get started. Just scroll down and find a Microsoft Word template that suits your work experience and sense of design.

Save time and effort — it does all of the writing and formatting for you. Click the button below and get started! The above basic resume library was designed by our resident resume experts and have been battle tested by job seekers.

As this set performed the best, we included them in our resume builder software— and now we are offering them to you for free to download in Microsoft Word format.

Each professional template comes in five colors. Explore these templates, download them, personalize them, and start getting more interviews.

Resume Template Library 2: Advanced Layouts. Professional Brick Red. Timeless Dark Blue. Elegant 2. Modern Brick Red.

Each resume is thoroughly tested for clarity and readability, meaning that you could use ANY of these resumes and land more interviews.

So have fun, and pick one that suits your sense of design. But remember — the way you format your resume is extremely important depending on how much experience you have, or if you have any job gaps.

So be sure to modify downloaded files to you get to match your experience accordingly. Template Library 3: Professional Profile Layouts.

Washington Brick Red. Murray Dark Blue. Trump Brick Red. Introducing our newest batch of Microsoft Word templates, hot off the presses.

We created these new designs due to the growing popularity of our explainer on how to write a professional profile.

People interested in a layout featuring a PP introduction skyrocketed, so we toiled to create 8 brand new HR-approved documents for you to download for free.

Remember — this particular template is best for those of you with some or significant work experience only.

Template Library 4: Creative Layouts. Brooklyn Bridge Black. Taj Mahal Dark Blue. White House Brick Red. Empire State Gray.

Mount Rushmore Dark Blue. Are you having trouble separating yourself from your competitors? Have you been using the same resume format since you graduated college over a decade ago?

Then it might be time to add some style to your resume! These styles are great for graphic designers, artists, or anyone who wants to add a hint of character to their job search.

Job Hopper Original. Mid-Level Dark Blue. Career Changer Brick Red. Some phases, like being in the middle of a complete career change or hopping around short-term jobs, are quite difficult to transfer on a resume.

Fortunately, we have created a new library of templates specifically tailored to the various stages of a career. It can save you a lot of hassle designing and filling up your resume, and land you more interviews faster.

Not Sure Which Template to Choose? The answer is yes — if you want to. Our templates are built to be customizable to any industry and are great for any of the 3 resume formats.

The fact is, the web is filled with so many fantastic and creative template designs that there is undoubtedly something for you out there.

Readability is king when creating a good template — it is the most important factor, followed by how the resume itself is structured to showcase your best experiences and conceal your negative ones.

Creating your own is fine, too. Wrong again. Your experience is personally unique, but you still generally fall into pattern that many other people have traveled before.

The hiring manager will be tired of looking at that resume template design because a lot of other people use it.

That hiring manager should be fired. We hope that clears up any misconceptions you may have had. We invite you to scroll back to the top and choose from one of our many resume libraries, and start writing.

Should i include collegiate sports in my resume? And if so where? It depends how much professional experience you have. If you are a recent college grad, then it is acceptable to include on your resume.

Good luck on the job hunt! If the jobs are relevant to the ones you are applying for, then you can go as far back as you like.

Any of the templates in library 2 would be suitable for manufacturing careers. Best of luck!

Multiple employers with jobs lasting two to three years each. The jobs have been similar, so the experience looks a bit repetitive.

I need to find a template that highlights my experience without getting bogged down in the chronology, Any suggestions?

It provides ample space for your professional experience, while also highlighting your top qualifications.

How would I write that on my resume? Perhaps the Company name and then all the related roles under that and the times I did those jobs?

I was always the Executive Admin, but I did other jobs during that period. Yes, your suggestion is correct. Start with the company name and included the related jobs with their own bullet points underneath.

Good luck! Ive never had a job so what should I use? Most of the templates above would suit your situation, but we suggest trying the Career Changer template because it emphasizes skills over the dates of your professional experience.

Good luck with grad school! Hope this helps! Good luck with the internship! Good Day Resume Genius.

The skill I know is more on the medical. What template should I use? Which is good for cabin crew applicant? I have no many work experience in service.

So i want to highlight the other things. Which template would you recommend for a career in education? Best of luck on the promotion!

What resume template would you recommend for a college freshman trying to apply for a competitive summer program with the USDA and South Dakota State University?

Good luck with the summer program. Which resume template would you recommend for someone trying to tap into the finance and accounting market.

Looking for an entry-level position. Good luck with the job hunt. Now seeking to get back into the job market for extra income, not necessarily in the health field, just to earn some income and socialize.

What resume do you suggest? Good luck with your job search! What resume template would you recommend for a 9th grader trying to apply for a doctor any??

Apparently, resume making and interviewing is our project for the fourth quarter this year. Good luck on your project.

Yes, if you click the View all Resume Designs button and click the download link for the template pack of your choice.

Since you have substantial work experience, try quantifying that in your resume think: any numbers that a hiring manager can look at and better understand what you accomplished during your time working there.

Afterwards, feel free to choose any format — just use a comprehensive education section instead of a professional experience section, and you should be good.

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The answer may surprise you. Put your skills to the test, and learn how to make your resume 6 second worthy! There are tons of errors throughout.

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The rich are the big gainers in America's new prosperity. Add this article to your reading list by clicking this button.

The gap between rich and poor is bigger than in any other advanced country, but most people are unconcerned.

Whereas Europeans fret about the way the economic pie is divided, Americans want to join the rich, not soak them.

Eight out of ten, more than anywhere else, believe that though you may start poor, if you work hard, you can make pots of money.

It is a central part of the American Dream. Thanks to a jump in productivity growth after , America's economy has outpaced other rich countries' for a decade.

In the late s everybody shared in this boom. Though incomes were rising fastest at the top, all workers' wages far outpaced inflation.

But after something changed. The pace of productivity growth has been rising again, but now it seems to be lifting fewer boats.

If you take into account the value of employee benefits, such as health care, the contrast is a little less stark. But, whatever the measure, it seems clear that only the most skilled workers have seen their pay packets swell much in the current economic expansion.

The fruits of productivity gains have been skewed towards the highest earners, and towards companies, whose profits have reached record levels as a share of GDP.

Even in a country that tolerates inequality, political consequences follow when the rising tide raises too few boats.

The impact of stagnant wages has been dulled by rising house prices, but still most Americans are unhappy about the economy.

The White House professes to be untroubled. He is right, but his claim is misleading, since the median worker—the one in the middle of the income range—has done less well than the average, whose gains are pulled up by the big increases of those at the top.

Privately, some policymakers admit that the recent trends have them worried, and not just because of the congressional elections in November.

The statistics suggest that the economic boom may fade. Americans still head to the shops with gusto, but it is falling savings rates and rising debts made possible by high house prices , not real income growth, that keep their wallets open.

A bust of some kind could lead to widespread political disaffection. Eventually, the country's social fabric could stretch.

America is nowhere near Brazil yet see chart 1. Despite a quarter century during which incomes have drifted ever farther apart, the distribution of wealth has remained remarkably stable.

The richest Americans now earn as big a share of overall income as they did a century ago see chart 2 , but their share of overall wealth is much lower.

Indeed, it has barely budged in the few past decades. The elites in the early years of the 20th century were living off the income generated by their accumulated fortunes.

Today's rich, by and large, are earning their money. The rise of the working rich reinforces America's self-image as the land of opportunity.

But, by some measures, that image is an illusion. In America about half of the income disparities in one generation are reflected in the next.

In Canada and the Nordic countries that proportion is about a fifth. It is not clear whether this sclerosis is increasing: the evidence is mixed.

Many studies suggest that mobility between generations has stayed roughly the same in recent decades, and some suggest it is decreasing.

Even so, ordinary Americans seem to believe that theirs is still a land of opportunity. The proportion who think you can start poor and end up rich has risen 20 percentage points since That helps explain why voters who grumble about the economy have nonetheless failed to respond to class politics.

Americans tend to blame their woes not on rich compatriots but on poor foreigners. More than six out of ten are sceptical of free trade.

A new poll in Foreign Affairs suggests that almost nine out of ten worry about their jobs going offshore.

Congressmen reflect their concerns. Though the economy grows, many have become vociferous protectionists.

Other rich countries are watching America's experience closely. For many Europeans, America's brand of capitalism is already far too unequal.

Such sceptics will be sure to make much of any sign that the broad middle-class reaps scant benefit from the current productivity boom, setting back the course of European reform even further.

The conventional tale is that the changes of the past few years are simply more steps along paths that began to diverge for rich and poor in the Reagan era.

During the s and s, the halcyon days for America's middle class, productivity boomed and its benefits were broadly shared.

The gap between the lowest and highest earners narrowed. After the oil shocks, productivity growth suddenly slowed.

A few years later, at the start of the s, the gap between rich and poor began to widen. The exact size of that gap depends on how you measure it.

Look at wages, the main source of income for most people, and you understate the importance of health care and other benefits.

Look at household income and you need to take into account that the typical household has fallen in size in recent decades, thanks to the growth in single-parent families.

Look at statistics on spending and you find that the gaps between top and bottom have widened less than for income. But every measure shows that, over the past quarter century, those at the top have done better than those in the middle, who in turn have outpaced those at the bottom.

The gains of productivity growth have become increasingly skewed. If all Americans were set on a ladder with ten rungs, the gap between the wages of those on the ninth rung and those on the first has risen by a third since Economists have long debated why America's income disparities suddenly widened after The consensus is that the main cause was technology, which increased the demand for skilled workers relative to their supply, with freer trade reinforcing the effect.

Some evidence suggests that institutional changes, particularly the weakening of unions, made the going harder for people at the bottom.

Whether these shifts were good or bad depends on your political persuasion. Those on the left lament the gaps, often forgetting that the greater income disparities have created bigger incentives to get an education, which has led to a better trained, more productive workforce.

In their haste to applaud or lament this tale, both sides of the debate tend to overlook some nuances. First, America's rising inequality has not, in fact, been continuous.

The gap between the bottom and the middle—whether in terms of skills, age, job experience or income—did widen sharply in the s.

But during the s, particularly towards the end of the decade, that gap stabilised and, by some measures, even narrowed.

Real wages rose faster for the bottom quarter of workers than for those in the middle. After most people lost ground, but, by many measures, those in the middle of the skills and education ladder have been hit relatively harder than those at the bottom.

People who had some college experience, but no degree, fared worse than high-school dropouts. Some statistics suggest that the annual income of Americans with a college degree has fallen relative to that of high-school graduates for the first time in decades.

So, whereas the s were hardest on the lowest skilled, the s and this decade have squeezed people in the middle.

The one truly continuous trend over the past 25 years has been towards greater concentration of income at the very top. The scale of this shift is not visible from most popular measures of income or wages, as they do not break the distribution down finely enough.

But several recent studies have dissected tax records to investigate what goes on at the very top.

The figures are startling. Put these pieces together and you do not have a picture of ever-widening inequality but of what Lawrence Katz of Harvard University, David Autor of the Massachusetts Institute of Technology and Melissa Kearney of the Brookings Institution call a polarisation of the labour market.

The bottom is no longer falling behind, the top is soaring ahead and the middle is under pressure. Can changes in technology explain this revised picture?

Up to a point. Computers and the internet have reduced the demand for routine jobs that demand only moderate skills, such as the work of bank clerks, while increasing the productivity of the highest-skilled.

Studies in Britain and Germany as well as America show that the pace of job growth since the early s has been slower in occupations that are easy to computerise.

For the most talented and skilled, technology has increased the potential market and thus their productivity.

Top entertainers or sportsmen, for instance, now perform for a global audience. Some economists believe that technology also explains the soaring pay of chief executives.

One argument is that information technology has made top managers more mobile, since it no longer takes years to master the intricacies of any one industry.

As a result, the market for chief executives is bigger and their pay is bid up. Global firms plainly do compete globally for talent: Alcoa's boss is a Brazilian, Sony's chief executive is American and Welsh.

But the scale of America's income concentration at the top, and the fact that no other country has seen such extreme shifts, has sent people searching for other causes.

The typical American chief executive now earns times the average wage, up tenfold from the s. Continental Europe's bosses have seen nothing similar.

Whichever explanation you choose for the signs of growing inequality, none of the changes seems transitory. The middle rungs of America's labour market are likely to become ever more squeezed.

And that squeeze feels worse thanks to another change that has hit the middle class most: greater fluctuations in people's incomes.

The overall economy has become more stable over the past quarter century. America has had only two recessions in the past 20 years, in and , both of which were mild by historical standards.

But life has become more turbulent for firms and people's income now fluctuates much more from one year to the next than it did a generation ago.

Some evidence suggests that the trends in short-term income volatility mirror the underlying wage shifts and may now be hitting the middle class most.

What of the future? It is possible that the benign pattern of the late s will return. The disappointing performance of the Bush era may simply reflect a job market that is weaker than it appears.

Although unemployment is low, at 4. More likely, the structural changes in America's job market that began in the s are now being reinforced by big changes in the global economy.

The integration of China's low-skilled millions and the increased offshoring of services to India and other countries has expanded the global supply of workers.

This has reduced the relative price of labour and raised the returns to capital. That reinforces the income concentration at the top, since most stocks and shares are held by richer people.

More important, globalisation may further fracture the traditional link between skills and wages. As Frank Levy of MIT points out, offshoring and technology work in tandem, since both dampen the demand for jobs that can be reduced to a set of rules or scripts, whether those jobs are for book-keepers or call-centre workers.

Alan Blinder of Princeton, by contrast, says that the demand for skills depends on whether they must be used in person: X -rays taken in Boston may be read by Indians in Bangalore, but offices cannot be cleaned at long distance.

So who will be squeezed and who will not is hard to predict. The number of American service jobs that have shifted offshore is small, some 1m at the most.

And most of those demand few skills, such as operating telephones. Mr Levy points out that only 15 radiologists in India are now reading American X -rays.

But nine out of ten Americans worry about offshoring. That fear may be enough to hold down the wages of college graduates in service industries.

All in all, America's income distribution is likely to continue the trends of the recent past. While those at the top will go on drawing huge salaries, those in the broad middle of the middle class will see their incomes churned.

The political consequences will depend on the pace of change and the economy's general health. With luck, the offshoring of services will happen gradually, allowing time for workers to adapt their skills while strong growth will keep employment high.

But if the economy slows, Americans' scepticism of globalisation is sure to rise. And even their famous tolerance of inequality may reach a limit.

Inequality and the American Dream. The world's most impressive economic machine needs a little adjusting. A hidden industry has changed all our lives; but some companies are operating rather close to the.

The battle for Arcelor is about more than steel. It is time to look rationally at the idea of resuming whaling. There is no easy path towards peace, but Hamas cannot yet be wished away.

America's war for hearts and minds. A little politeness goes a long way. Of meat, Mexicans and social mobility. Among the very poor, the American Dream is alive and well.

The public buys its own campaigns, thank you very much. A Democratic candidate in sand-coloured combat boots.

A sudden rush of better news, and not entirely fortuitous. Should the dwellings of the poorest be rebuilt at all?

A story especially for those not watching the football. Violent crime appears to have stopped falling. Democrats have growing worries about the front-runner for the presidential nomination.

But can they. The public sector in Latin America is not spending enough on transport, electricity and water, but.

Fidel Castro declares war on corruption. Roberto Lavagna edges towards a presidential candidacy. The rising sun leaves some Japanese in the shade.

An emotional debate about those untouched by the economic recovery. But the president should survive. Chinese propaganda just isn't what it used to be.

The remarkable but little-discussed story of the world's most durable monarch. A sad case of post-prime-ministerial syndrome.

John Howard blocks Canberra's gay marriages. The Palestinians' Hamas government is increasingly besieged. But it is clinging to power, and to its.

The prime minister's good start. The message from Russia and China. An odd saga with Armenians has mocked the government.

Zambia has managed to avoid the crises plaguing its neighbours. Russian worries about Western encirclement are premature. After the Catalans, Basques and Andalusians want autonomy too.

Locals dream of reopening the frontier between Turkey and Armenia. The ruins of a contested capital are still hostage to geopolitics.

The annual report of the European Union as a club. Labour has focused too much on benefits and not enough on work.

The devil in the details. Not everyone who claims to. How to keep the Tube cool. The world's biggest civil IT project has not yet convinced Britain's doctors.

Company pension funds are being saved from destruction. How changes in the market have revived an ancient Egyptian art.

The limits of compassionate conservatism. Philosophical consistency is not David Cameron's priority. Companies are having to find new ways.

Like information on the internet, goods are moving around the world with ever greater efficiency.

How three large and successful companies are using their supply chains to compete. As distinctions between ownership and control become blurred, supply chains are getting more twisted.

With more and more stuff being moved around the globe, efficiency is at a premium. Winging it to the pot. Delivery companies are consolidating.

A courier company goes online. Being too lean and mean is a dangerous thing. Google dominates the lucrative market for web-search, but its rivals are setting out to change that.

A pioneering blogger moves on to the next big thing. Two historic German drugs firms scrap for control of a third.

Airbus's jumbo-sized problem threatens the firm's future. Mittal Steel's chances of taking over Arcelor are improving.

A turning point in relations between company owners and bosses? Doing business in a lawless part of Italy. Wind power has propelled Tulsi Tanti into the ranks of India's corporate titans.

America's Treasury market is unsettled by inflation, in another jittery week for the world's. The future of the central bank's governor is in doubt.

Why it pays to become America's treasury secretary. A sign that times are good in the overlooked world of accountants.

Securitising intellectual property. Companies are borrowing against their copyrights, trademarks and patents. The World Bank reveals what it thinks of its clients.

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