The causes and prevention of cancer.

Epidemiological evidence indicates that avoidance of smoking, increased consumption of fruits and vegetables, and control of infections will have a major effect on reducing rates of cancer. Other factors include avoidance of intense sun exposure, increases in physical activity, and reduction of alcohol consumption and possibly red meat. A substantial reduction in breast cancer is likely to require modification of sex hormone levels, and development of practical methods for doing so is a high research priority. Resolution of the potential protective roles of specific antioxidants and other constituents of fruits and vegetables deserves major attention. Mechanistic studies of carcinogenesis indicate an important role of endogenous oxidative damage to DNA that is balanced by elaborate defense and repair processes. Also key is the rate of cell division, which is influenced by hormones, growth, cytotoxicity, and inflammation, as this determines the probability of converting DNA lesions to mutations. These mechanisms may underlie many epidemiologic observations.

Ectopic expression of the agouti gene in transgenic mice causes obesity, features of type II diabetes, and yellow fur.

Mice that carry the lethal yellow (Ay) or viable yellow (Avy) mutation, two dominant mutations of the agouti (a) gene in mouse chromosome 2, exhibit a phenotype that includes yellow fur, marked obesity, a form of type II diabetes associated with insulin resistance, and an increased susceptibility to tumor development. Molecular analyses of these and several other dominant "obese yellow" a-locus mutations suggested that ectopic expression of the normal agouti protein gives rise to this complex pleiotropic phenotype. We have now tested this hypothesis directly by generating transgenic mice that ectopically express an agouti cDNA clone encoding the normal agouti protein in all tissues examined. Transgenic mice of both sexes have yellow fur, become obese, and develop hyperinsulinemia. In addition, male transgenic mice develop hyperglycemia by 12-20 weeks of age. These results demonstrate conclusively that the ectopic agouti expression is responsible for most, if not all, of the phenotypic traits of the dominant, obese yellow mutants.

Continuous activation of gp130, a signal-transducing receptor component for interleukin 6-related cytokines, causes myocardial hypertrophy in mice.

To investigate the physiological roles of gp130 in detail and to determine the pathological consequence of abnormal activation of gp130, transgenic mice having continuously activated gp130 were created. This was carried out by mating mice from interleukin 6 (IL-6) and IL-6 receptor (IL-6R) transgenic lines. Offspring overexpressing both IL-6 and IL-6R showed constitutive tyrosine phosphorylation of gp130 and a downstream signaling molecule, acute phase response factor/signal transducer and activator of transcription 3. Surprisingly, the distinguishing feature of such offspring was hypertrophy of ventricular myocardium and consequent thickened ventricular walls of the heart, where gp130 is also expressed, in adulthood. Transgenic mice overexpressing either IL-6 or IL-6R alone did not show detectable myocardial abnormalities. Neonatal heart muscle cells from normal mice, when cultured in vitro, enlarged in response to a combination of IL-6 and a soluble form of IL-6R. The results suggest that activation of the gp130 signaling pathways leads to cardiac hypertrophy and that these signals might be involved in physiological regulation of myocardium.

Disruption of the gene for hsp30, an alpha-crystallin-related heat shock protein of Neurospora crassa, causes defects in thermotolerance.

The alpha-crystallin-related heat shock proteins are produced by all eukaryotes, but the role of these proteins in thermoprotection remains unclear. To investigate the function of one of these proteins, we disrupted expression of the single-copy hsp30 gene of Neurospora crassa, using repeat-induced point mutagenesis, and we generated and characterized mutant strains that were deficient in hsp30 synthesis. These strains could grow at high temperature and they acquired thermotolerance from a heat shock. However, the hsp30-defective strains proved to be extremely sensitive to the combined stresses of high temperature and carbohydrate limitation, enforced by the addition of a nonmetabolizable glucose analogue. Under these conditions, their survival was reduced by 90% compared with wild-type cells. This sensitive phenotype was reversed by reintroduction of a functional hsp30 gene into the mutant strains. The mutant cells contained mitochondria from which a 22-kDa protein was readily extracted with detergents, in contrast to its retention by the mitochondria of wild-type cells. Antibodies against hsp30 coimmunoprecipitated a protein also of approximately 22 kDa from wild-type cells. Results of this study suggest that hsp30 may be important for efficient carbohydrate utilization during high temperature stress and that it may interact with other mitochondrial membrane proteins and function as a protein chaperone.

Disruption of the adenosine deaminase gene causes hepatocellular impairment and perinatal lethality in mice.

We have generated mice with a null mutation at the Ada locus, which encodes the purine catabolic enzyme adenosine deaminase (ADA, EC 3.5.4.4). ADA-deficient fetuses exhibited hepatocellular impairment and died perinatally. Their lymphoid tissues were not largely affected. Accumulation of ADA substrates was detectable in ADA-deficient conceptuses as early as 12.5 days postcoitum, dramatically increasing during late in utero development, and is the likely cause of liver damage and fetal death. The results presented here demonstrate that ADA is important for the homeostatic maintenance of purines in mice.

Strong natural selection causes microscale allozyme variation in a marine snail.

Natural selection is one of the most fundamental processes in biology. However, there is still a controversy over the importance of selection in microevolution of molecular traits. Despite the general lack of data most authors hold the view that selection on molecular characters may be important, but at lower rates than selection on most phenotypic traits. Here we present evidence that natural selection may contribute substantially to molecular variation on a scale of meters only. In populations of the marine snail Littorina saxatilis living on exposed rocky shores, steep microclines in allele frequencies between splash and surf zone groups are present in the enzyme aspartate aminotransferase (allozyme locus Aat; EC. 2.6.1.1). We followed one population over 7 years, including a period of strong natural perturbation. The surf zone part of the population dominated by the allele Aat100 was suddenly eliminated by a bloom of a toxin-producing microflagellate. Downshore migration of splash zone snails with predominantly Aat120 alleles resulted in a drastic increase in surf zone frequency of Aat120, from 0.4 to 0.8 over 2 years. Over the next four to six generations, however, the frequency of Aat120 returned to the original value. We estimated the coefficient of selection of Aat120 in the surf zone to be about 0.4. Earlier studies show similar or even sharper Aat clines in other countries. Thus, we conclude that microclinal selection is an important evolutionary force in this system.

Cystoid Macular Edema: Causes, Diagnosis and Treatment

The purpose of this paper is to conduct a review of studies on cystoid macular edema published in the last seven years. Cystoid macular edema is a major cause of loss of visual acuity. It is the final common pathway of many diseases and can be caused by numerous processes including inflammatory, vascular, adverse drug reactions, retinal dystrophy or intraocular tumors. These processes disrupt the blood-retinal barrier, with fluid extravasation to the macular parenchyma. Imaging tests are essential for both detection and monitoring of this pathology. Fluorescein angiography and autofluorescence show the leakage of liquid from perifoveal vessels into the tissue where it forms cystic spaces. Optical coherence tomography is currently the gold standard technique for diagnosis and monitoring. This allows objective measurement of retinal thickness, which correlates with visual acuity and provides more complete morphological information. Based on the underlying etiology, the therapeutic approach can be either surgical or medical with anti-inflammatory drugs. We found that disruption of the blood-retinal barrier for various reasons is the key point in the pathogenesis of cystoid macular edema, therefore we believe that studies on its treatment should proceed on this path.

Investigating the causes of the response of the thermohaline circulation to past and future climate changes

The Atlantic thermohaline circulation (THC) is an important part of the earth's climate system. Previous research has shown large uncertainties in simulating future changes in this critical system. The simulated THC response to idealized freshwater perturbations and the associated climate changes have been intercompared as an activity of World Climate Research Program (WCRP) Coupled Model Intercomparison Project/Paleo-Modeling Intercomparison Project (CMIP/PMIP) committees. This intercomparison among models ranging from the earth system models of intermediate complexity (EMICs) to the fully coupled atmosphere-ocean general circulation models (AOGCMs) seeks to document and improve understanding of the causes of the wide variations in the modeled THC response. The robustness of particular simulation features has been evaluated across the model results. In response to 0.1-Sv (1 Sv equivalent to 10^6 ms^3 s^-1) freshwater input in the northern North Atlantic, the multimodel ensemble mean THC weakens by 30% after 100 yr. All models simulate sonic weakening of the THC, but no model simulates a complete shutdown of the THC. The multimodel ensemble indicates that the surface air temperature could present a complex anomaly pattern with cooling south of Greenland and warming over the Barents and Nordic Seas. The Atlantic ITCZ tends to shift southward. In response to 1.0-Sv freshwater input, the THC switches off rapidly in all model simulations. A large cooling occurs over the North Atlantic. The annual mean Atlantic ITCZ moves into the Southern Hemisphere. Models disagree in terms of the reversibility of the THC after its shutdown. In general, the EMICs and AOGCMs obtain similar THC responses and climate changes with more pronounced and sharper patterns in the AOGCMs.

Acute Synaptic Activity Causes Differential miRNA Expression in The Drosophila melanogaster Larval Central Nervous System

The primary goal of this thesis was to determine if spaced synaptic stimulation induced the differential expression of microRNAs (miRNAs) in the Drosophila melanogaster central nervous system (CNS). Prior to attaining this goal, we needed to identify and validate a spaced stimulation paradigm that could induce the formation of new synaptic growth at a model synapse, the larval neuromuscular junction (NMJ). Both Channelrhodopsin- and high potassium-based stimulation paradigms adapted from (Ataman, et al. 2008) were tested. Once validation of these paradigms was complete, we sought to characterize the miRNA expression profile of the larval CNS by miRNA array. Following attainment of these data, we used quantitative real-time PCR (RT-qPCR) to determine if acute synaptic stimulation caused the differential expression of neuronal miRNAs. We found that upon high potassium spaced training in a wild type (Canton S) genotype, 5 miRNAs showed significant differential expression when normalized to a validated reference gene, the U1 snRNA. Moreover, absolute quantification of our RT-qPCR study implicated one miRNA: miR-958 as being significantly regulated by activity. Investigation into potential targets for miR-958 revealed it to be a potential regular of Dlar, a protein tyrosine phosphatase implicated in synapse development. This investigation provides the foundation to directly test our underlying hypothesis that, following spaced training, differential expression of miRNAs alters the translation of proteins required to induce and maintain these structural changes at the synapse.

Coastal Erosion--Causes, Erosion Control Methods, Economic and Environmental Impacts, and Best Management Practices

Coastal erosion is an important and constant issue facing coastal areas all over the world today. The rate of coastal development over the years has increased, in turn requiring that action be taken to protect structures from the threat of erosion. A review of the causes of coastal erosion and the methods implemented to control it was conducted in order to determine the best course of action in response to coastal erosion issues. The potential positive and negative economic and environmental impacts are key concerns in determining whether or not to restore an eroding beach and which erosion control method(s) to implement. Results focus on providing a comparison of these concerns as well as recommendations for addressing coastal erosion issues.

Shoulder pain in overhead athletes : a systematic review of orthopaedic causes

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014

The Pro-Western Turn in Russia's Foreign Policy: Causes, Consequences and Prospects. OSW Point of View, September 2002

From Europe and Poland's point of view, one of the most important recent developments in international politics was the re-orientation of Russia's foreign policy. This paper aims to answer three important questions relating to this issue: 4. When and why did the "pro-Western turn" in the Russian Federation's policy take place? 5. Has it been profitable for Russia? 6. What goals will the Russian policy pursue in the future? An analysis of the last two years in Russia's foreign policy leads to the several conclusions, including those: 5. Clearly, the Russian leaders realise that in the longer term, Russia - in its desire for more influence in the world - will not be able to survive as an independent pole of power in international politics and it will have to join forces with the West (most likely, the European Union). 6. September 11 was not the cause of Russia's pro-Western turn, but rather a catalyst that put the process which started when Vladimir Putin took his office in sharp focus. 7. In the nearest future, this new direction of Russia's foreign policy seems not be challenged by internal opposition in Russia. 8. The "pro-Western turn" proved to be beneficial for Russia, although: d. Russia has not become a strategic ally of the US e. There has been no breakthrough in the relations between Russia and the European Union, and Moscow has not gained any real influence on NATO's important decisions. f. Russia has not become a major decision-maker of international politics. 5. Russia's closing to the West is in Poland's and Europe's interest.

Bosniacki chaos. Zrodla kryzysu politycznego we wspolczesnej Bosni i Hercegowinie. Prace OSW 31/2009. = Bosnia's chaos. Causes of the political crisis in Bosnia and Herzegovina today. OSW Study 31/2009

A new form of 'transformational crisis' has been observed in Bosnia and Herzegovina since at least 2005. Politicians representing the three major ethno-political communities (Bosnians, Croats and Serbs) have successively been raising disputes and have employed various political tools to preserve the conflicts instead of resolving them. As a result, the central state institutions and organisations have been weakened and attempts to replace them with narrower ethnic structures have been made. This is increasingly paralysing the state, thus impeding its everyday operation and preventing its structures and legislation from being modernised; had this been achieved, it would have resulted in a real acceleration of the process of Bosnia's integration with the EU and NATO. The present crisis is also an effect of the disagreement between the key international players - the European Union, the United States and Russia - over the 'plan for Bosnia' and the role and duties of the Office of the High Representative, who acts on behalf of the international community in the country.