The Role of Smoking in Cocaine Addiction

The 2010 National Survey on Drug Use and Health reported that almost 37 million Americans,1 2 years of age or older, have tried cocaine in their lifetime, and 5.7 million have used it in the past year – making cocaine the second most commonly used drug of abuse in the United States. The reasons for its popularity are its immediate psychological effects. Snorted or injected cocaine induces self-confidence, euphoria and good feelings, magnifying the intensity of almost all normal pleasures. However, cocaine use also causes medical complications like respiratory failure, cardiovascular and gastrointestinal problems and paranoia. Moreover, after prolonged exposure, individuals become addicted to it, losing control over use of the drug and engaging in destructive behavior related to cocaine procurement. Cocaine addiction is a chronic relapsing condition with high risk of medical complications, cognitive impairment, financial ruin and social issues

The impact of deleterious mutations on the transition to meiotic sex and the structure of the germline

The accumulation of deleterious mutations predicted by Muller’s ratchet – the progressive increase in mutation load caused by genetic drift – can cause the extinction of asexual populations and is considered one of the forces behind the maintenance of sex, the evolution of sex chromosomes, and the loss of genetic information in inversions. Here, I investigate the extent to which this process has influenced, constrained, and shaped the evolution of life. Using theoretical and computational models, I demonstrate that the need for increased purifying selection played a key role in major evolutionary transitions, focussing on the origin of meiotic sex and the evolution of the female germline. Early models of the origin of sex have generally focussed on the transition from asexual to sexual lifestyle. It is now universally accepted that prokaryotes undergo homologous recombination via lateral gene transfer (LGT), which can prevent the mutational meltdown predicted by Muller’s ratchet. Here, I investigate the origin of sex as part of the transition from prokaryotes to eukaryotes. I develop a theoretical model to investigate the impact of the increase in genome size and density of genomic repeats that took place during eukaryogenesis. My results indicate that these conditions led to the failure of LGT, generating a strong selective pressure for the origin of meiotic sex. But while meiotic sex can facilitate purifying selection on nuclear genes, it cannot prevent the accumulation of mutations in mitochondrial DNA (mtDNA). I demonstrate that the need to preserve mtDNA against Muller’s ratchet caused the evolution of tight mechanisms for mitochondrial quality control, shaping the evolution of the female germline in metazoans. This theoretical framework can be applied to a wide range of biological processes, including bacterial evolution, genome streamlining in organelles and endosymbionts, and the evolution of a two-step meiosis

Meier–Gorlin syndrome and Wolf–Hirschhorn syndrome: two developmental disorders highlighting the importance of efficient DNA replication for normal development and neurogenesis

Microcephaly represents one of the most obvious clinical manifestations of impaired neurogenesis. Defects in the DNA damage response, in DNA repair, and structural abnormalities in centrosomes, centrioles and the spindle microtubule network have all been demonstrated to cause microcephaly in humans. Work describing novel functional defects in cell lines from individuals with either Meier–Gorlin syndrome or Wolf–Hirschhorn syndrome highlight the significance of optimal DNA replication and S phase progression for normal human development, including neurogenesis. These findings illustrate how different primary defects in processes impacting upon DNA replication potentially influence similar phenotypic outcomes, including growth retardation and microcephaly. Herein, we will describe the nature of the S phase defects uncovered for each of these conditions and highlight some of the overlapping cellular features

Repeat sequences limit the effectiveness of lateral gene transfer and favored the evolution of meiotic sex in early eukaryotes

The transition from prokaryotic lateral gene transfer to eukaryotic meiotic sex is poorly understood. Phylogenetic evidence suggests that it was tightly linked to eukaryogenesis, which involved an unprecedented rise in both genome size and the density of genetic repeats. Expansion of genome size raised the severity of Muller's ratchet, while limiting the effectiveness of lateral gene transfer (LGT) at purging deleterious mutations. In principle, an increase in recombination length combined with higher rates of LGT could solve this problem. Here, we show using a computational model that this solution fails in the presence of genetic repeats prevalent in early eukaryotes. The model demonstrates that dispersed repeat sequences allow ectopic recombination, which leads to the loss of genetic information and curtails the capacity of LGT to prevent mutation accumulation. Increasing recombination length in the presence of repeat sequences exacerbates the problem. Mutational decay can only be resisted with homology along extended sequences of DNA. We conclude that the transition to homologous pairing along linear chromosomes was a key innovation in meiotic sex, which was instrumental in the expansion of eukaryotic genomes and morphological complexity

The need for high-quality oocyte mitochondria at extreme ploidy dictates mammalian germline development

Selection against deleterious mitochondrial mutations is facilitated by germline processes, lowering the risk of genetic diseases. How selection works is disputed: experimental data are conflicting and previous modelling work has not clarified the issues. Here we develop computational and evolutionary models that compare the outcome of selection at the level of individuals, cells and mitochondria. Using realistic de novo mutation rates and germline development parameters from mouse and humans, the evolutionary model predicts the observed prevalence of mitochondrial mutations and diseases in human populations. We show the importance of organelle-level selection, seen in the selective pooling of mitochondria into the Balbiani body, in achieving high-quality mitochondria at extreme ploidy in mature oocytes. Alternative mechanisms debated in the literature, bottlenecks and follicular atresia, are unlikely to account for the clinical data, because neither process effectively eliminates mitochondrial mutations under realistic conditions. Our findings explain the major features of female germline architecture, notably the longstanding paradox of over-proliferation of primordial germ cells followed by massive loss. The near-universality of these processes across animal taxa makes sense in light of the need to maintain mitochondrial quality at extreme ploidy in mature oocytes, in the absence of sex and recombination

The need for high-quality oocyte mitochondria at extreme ploidy dictates germline development

Selection against deleterious mitochondrial mutations is facilitated by germline processes, lowering the risk of genetic diseases. How selection works is disputed: experimental data are conflicting and previous modelling work has not clarified the issues. Here we develop computational and evolutionary models that compare the outcome of selection at the level of individuals, cells and mitochondria. Using realistic de novo mutation rates and germline development parameters, the evolutionary model predicts the observed prevalence of mitochondrial mutations and diseases in human populations. We show the importance of organelle-level selection, seen in the selective pooling of mitochondria into the Balbiani body, in achieving high-quality mitochondria at extreme ploidy in mature oocytes. Alternative mechanisms debated in the literature, bottlenecks and follicular atresia, are unlikely to account for the clinical data, because neither process effectively eliminates mitochondrial mutations under realistic conditions. Our findings explain the major features of female germline architecture, notably the longstanding paradox of over-proliferation of primordial germ cells followed by massive loss. The near-universality of these processes across animal taxa makes sense in light of the need to maintain mitochondrial quality at extreme ploidy in mature oocytes, in the absence of sex and recombination

Immunogenicity and Immunosensitivity of Urethane-induced Murine Lung Adenomata, in Relation to the Immunological Impairment of the Primary Tumour Host

The depression of the immunological status of BALB/c mice treated during infancy with two different doses of urethane, alone or combined with cortisone, was evaluated by counting the number of plaque forming cells at 30 or 50 days of age. The incidence of lung adenomatous nodules was directly related to the degree of immunological impairment at 50 days of age. Twenty-seven lung adenomata were tested in an in vitro system involving spleen cells immune against the same single tumour used as target cell. Eighty-six per cent of tumours in the most immunodepressed group of mice were positive compared with 20-40% in the less immunodepressed groups. Syngeneic cross-reaction tests showed that non-immunogenic tumours were immunosensitive since 66% positive tests were obtained when target cells belonging to the less immunodepressed groups were tested with spleen cells of mice immunized with immunogenic adenomata

Immunodepression During Urethane and N-Nitrosomethylurea Leukaemogenesis in Mice

Five injections of urethane, 1 mg./g. body weight to suckling mice markedly reduced the primary immune response against sheep red blood cells assessed by splenic plaque forming cells (PFC) determination and haemagglutinin (HA) titration. The immunological impairment lasted for about 50 days after the end of the treatment. The secondary response tested by HA titration was not affected. A lower dose of urethane (0.5 mg./g.) produced only a delay of the primary HA response. A single neonatal dose of N-nitrosomethylurea (NMU) caused a profound immunodepression evaluated as HA titre and number of PFC. Both primary and secondary responses were still depressed when tested at 50 and 90 days of age respectively. No clear correlation between the degree of immunodepression and lymphoma development was found

Embryonic Antigens and Growth of Murine Fibrosarcomata

The amount of embryonic antigens (EA) was estimated in 13 BALB/c fibrosarcomata by in vitro cell mediated cytotoxicity of anti-embryo spleen cells and by quantitative absorption of an anti-embryo antiserum. A direct relationship between amount of EA and tumour growing capacity was found. EA were detected also on fast dividing testicular cells. It is suggested that EA expression on tumour cells is related to a cell membrane function controlling mitosis rather than to a function specifically related to the neoplastic status. Tumour take of low doses of 2 EA-bearing sarcomata was found to be enhanced in anti-embryo immune BALB/c mice in comparison with that in normal and anti-fibroblast immune mice

Colonos e poder : a luta pela terra no Sudoeste do Paraná

Orientador: Carlos Roberto Antunes dos SantosDissertaçao (mestrado) -Universidade Federal do Paraná. Curso de Pós-Graduaçao em Históri