Telomeres are the physical ends of linear chromosomes in eukaryotes. Telomeres not only protect chromosome ends from being recognized as double-strand breaks but also maintain the chromosome terminal sequences. These processes involve a number of telomere-related proteins. A major challenge in the field is to elucidate the full constitution of telomere-associated proteins and to understand how different protein complexes are regulated at chromosome termini. Here, I report the identification and characterization of STN1 (Suppressor of cdc thirteen, 1), CTC1 (Conserved Telomere maintenance Component 1) and TEN1 (Telomeric pathways in association with Stn1, 1) in Arabidopsis. CTC1/STN1/TEN1 (CST) forms a trimeric complex that specifically associates with telomeres. Loss of any component of the CST induces catastrophic telomere loss, disrupted telomere end architecture, and massive chromosome end-to-end fusions. Thus, CST plays an essential role in chromosome end protection. I also show that CST function at telomeres is independent of a previously characterized capping complex KU70/KU80, and that ATR is responsible for a checkpoint response in plants lacking CTC1/STN1. Additionally, I present data showing that Arabidopsis POT1a (Protection Of Telomere 1, a) has evolved as a telomerase recruitment factor. Unlike POT1 in other eukaryotes which binds and protects ss telomeric DNA, AtPOT1a interacts with telomerase RNA (TER). Based on an evolutionary analysis, we found that the POT1a lineage is under positive selection in the Brassicaceae family in which Arabidopsis belongs. Mutations of two positive selection sites significantly reduce POT1a?s activity in vivo. These data suggest POT1a is under pressure to evolve from a telomeric DNA binding protein to a TER binding protein. I also discovered that POT1a interacts with the novel telomere capping protein CTC1 in vitro and in vivo. Thus, I hypothesize that POT1a acts as a telomerase recruitment factor linking this enzyme to the chromosome termini via interacting with TER and CTC1. Finally, I dissected the functional domains of POT1a and demonstrated that both the N-terminus and the C-terminus of POT1a are required for its function in vivo. In summary, my work has uncovered several new and essential telomereassociated proteins that provide new insight into mechanisms of chromosome end protection and maintenance.

Thesis (Ph.D.) -- University of Texas Southwestern Medical Center at Dallas, 2006. / Partial embargo. Vita. Bibliography: 131-152.

Transtornos mentais graves são doenças crônicas altamente incapacitantes que geram um alto custo para a sociedade. Indivíduos acometidos por essas doenças apresentam maior morbidade e mortalidade. Dentre elas, a esquizofrenia parece possuir os piores desfechos. Portanto, estudar a esquizofrenia pode trazer contribuições importantes para o entendimento e manejo de transtornos mentais graves como a depressão maior e o transtorno bipolar. Esse trabalho buscou compreender mecanismos fisiopatológicos da esquizofrenia ao longo de quatro artigos que exploram aspectos de funcionamento cognitivo, funcionamento intelectual, de biomarcadores e de estrutura cerebral. O primeiro artigo investigou as alterações de performance de memória em indivíduos com esquizofrenia em estágios iniciais e tardios da doença comparadas ao transtorno bipolar e a sujeitos saudáveis. Os resultados mostraram que indivíduos com esquizofrenia apresentaram precoces prejuízos cognitivos de memória, diferentemente de indivíduos com transtorno bipolar quando comparados a controles. O segundo artigo investigou as influências das performances cognitiva e intelectual em estruturas cerebrais de indivíduos com esquizofrenia comparados a controles saudáveis. Os resultados indicaram que o funcionamento intelectual pré-morbido estava relacionado ao volume de estruturas globais, enquanto o funcionamento cognitivo estava relacionado ao volume e espessura de massa cinzenta cortical, sugerindo influências diferentes e complementares relacionadas a neurodesenvolvimento e neurodegeneração. O terceiro artigo investigou um biomarcador de envelhecimento precoce, um possível mecanismo para a neuroprogressão na esquizofrenia. Os resultados monstraram que indivíduos com esquizofrenia apresentaram encurtamento de telômero quando comparados a controles, mas não houveram diferenças entre o tamanho de telômero de pacientes e seus irmãos não afetados pela doença. Por fim, o quarto artigo buscou investigar a teoria do envelhecimentoa patológico acelerado na esquizofrenia, integrando os achados dos artigos anteriores. Os resultados demonstraram correlações entre comprimento de telômero, níveis de CCL11, performance de memória, volume de massa cinzenta e tempo de doença em indivíduos com esquizofrenia. Esses achados sugerem que a esquizofrenia seria uma doença do neurodesenvolvimento associada a uma carga adicional ao longo do curso da doença que levaria a um envelhecimento patológico precoce. A partir dos achados em esquizofrenia, pode-se ampliar a compreensão de alterações percebidas nas trajetórias de outras psicopatologias. Com adequado entendimento desses mecanismos, será possível o desenvolvimento de novos tratamentos e intervenções mais efetivas e eficazes. / Severe mental disorders are debilitating chronic diseases that have a high cost to society. Individuals affected by these diseases have increased morbidity and mortality. Among them, schizophrenia seems to have the worst outcomes. Therefore, studying schizophrenia may provide important contributions to the understanding and management of severe mental disorders such as major depression and bipolar disorder. The present study aimed to understand the pathophysiological mechanisms of schizophrenia over four articles that explore aspects of cognitive functioning, intellectual functioning, biomarkers and brain structure. The first article investigated changes in memory performance in individuals with schizophrenia in early and late stages of disease compared to bipolar disorder and healthy subjects. The results showed that subjects with schizophrenia had early cognitive deficits of memory, unlike individuals with bipolar disorder compared to controls. The second article investigated influences of cognitive and intellectual performances on brain structures of individuals with schizophrenia compared to healthy controls. The results indicated that premorbid intellectual functioning was related to volume of global structures, while cognitive functioning was related to volume and thickness of cortical gray matter, suggesting different and complementary influences related to neurodevelopment and neurodegeneration. The third article investigated an early aging biomarker, a possible mechanism of neuroprogression in schizophrenia. The results showed that individuals with schizophrenia had shortened telomeres when compared to controls, but there were no differences between the telometer length of patients and their siblings not affected by the disease. Finally, the fourth article sought to investigate the theory of pathological accelerated aging in schizophrenia, integrating the findings of the previous articles. The results demonstrated correlations between telometer length, CCL11 levels, memory performance, gray matter volume and illness duration in individuals with schizophrenia. These findings suggest that schizophrenia is a neurodevelopmental disorder associated with an additional burden over the course of the disease that leads to a pathological accelerated agig.

Transtornos mentais graves são doenças crônicas altamente incapacitantes que geram um alto custo para a sociedade. Indivíduos acometidos por essas doenças apresentam maior morbidade e mortalidade. Dentre elas, a esquizofrenia parece possuir os piores desfechos. Portanto, estudar a esquizofrenia pode trazer contribuições importantes para o entendimento e manejo de transtornos mentais graves como a depressão maior e o transtorno bipolar. Esse trabalho buscou compreender mecanismos fisiopatológicos da esquizofrenia ao longo de quatro artigos que exploram aspectos de funcionamento cognitivo, funcionamento intelectual, de biomarcadores e de estrutura cerebral. O primeiro artigo investigou as alterações de performance de memória em indivíduos com esquizofrenia em estágios iniciais e tardios da doença comparadas ao transtorno bipolar e a sujeitos saudáveis. Os resultados mostraram que indivíduos com esquizofrenia apresentaram precoces prejuízos cognitivos de memória, diferentemente de indivíduos com transtorno bipolar quando comparados a controles. O segundo artigo investigou as influências das performances cognitiva e intelectual em estruturas cerebrais de indivíduos com esquizofrenia comparados a controles saudáveis. Os resultados indicaram que o funcionamento intelectual pré-morbido estava relacionado ao volume de estruturas globais, enquanto o funcionamento cognitivo estava relacionado ao volume e espessura de massa cinzenta cortical, sugerindo influências diferentes e complementares relacionadas a neurodesenvolvimento e neurodegeneração. O terceiro artigo investigou um biomarcador de envelhecimento precoce, um possível mecanismo para a neuroprogressão na esquizofrenia. Os resultados monstraram que indivíduos com esquizofrenia apresentaram encurtamento de telômero quando comparados a controles, mas não houveram diferenças entre o tamanho de telômero de pacientes e seus irmãos não afetados pela doença. Por fim, o quarto artigo buscou investigar a teoria do envelhecimentoa patológico acelerado na esquizofrenia, integrando os achados dos artigos anteriores. Os resultados demonstraram correlações entre comprimento de telômero, níveis de CCL11, performance de memória, volume de massa cinzenta e tempo de doença em indivíduos com esquizofrenia. Esses achados sugerem que a esquizofrenia seria uma doença do neurodesenvolvimento associada a uma carga adicional ao longo do curso da doença que levaria a um envelhecimento patológico precoce. A partir dos achados em esquizofrenia, pode-se ampliar a compreensão de alterações percebidas nas trajetórias de outras psicopatologias. Com adequado entendimento desses mecanismos, será possível o desenvolvimento de novos tratamentos e intervenções mais efetivas e eficazes. / Severe mental disorders are debilitating chronic diseases that have a high cost to society. Individuals affected by these diseases have increased morbidity and mortality. Among them, schizophrenia seems to have the worst outcomes. Therefore, studying schizophrenia may provide important contributions to the understanding and management of severe mental disorders such as major depression and bipolar disorder. The present study aimed to understand the pathophysiological mechanisms of schizophrenia over four articles that explore aspects of cognitive functioning, intellectual functioning, biomarkers and brain structure. The first article investigated changes in memory performance in individuals with schizophrenia in early and late stages of disease compared to bipolar disorder and healthy subjects. The results showed that subjects with schizophrenia had early cognitive deficits of memory, unlike individuals with bipolar disorder compared to controls. The second article investigated influences of cognitive and intellectual performances on brain structures of individuals with schizophrenia compared to healthy controls. The results indicated that premorbid intellectual functioning was related to volume of global structures, while cognitive functioning was related to volume and thickness of cortical gray matter, suggesting different and complementary influences related to neurodevelopment and neurodegeneration. The third article investigated an early aging biomarker, a possible mechanism of neuroprogression in schizophrenia. The results showed that individuals with schizophrenia had shortened telomeres when compared to controls, but there were no differences between the telometer length of patients and their siblings not affected by the disease. Finally, the fourth article sought to investigate the theory of pathological accelerated aging in schizophrenia, integrating the findings of the previous articles. The results demonstrated correlations between telometer length, CCL11 levels, memory performance, gray matter volume and illness duration in individuals with schizophrenia. These findings suggest that schizophrenia is a neurodevelopmental disorder associated with an additional burden over the course of the disease that leads to a pathological accelerated agig.

Telomeres are repeated sequences at the ends of eukaryotic chromosomes that play prominent role in normal aging and disease development. They are dynamic structures that normally shorten over the lifespan of a cell, but can be elongated in cells with high proliferative capacity. Telomere elongation in stem cells is an advantageous mechanism that allows them to maintain the regenerative capacity of tissues, however, it also allows for survival of cancer cells, thus leading to development of malignancies. Numerous studies have been conducted to explore the role of telomeres in health and disease. However, the majority of these studies have focused on consequences of extreme shortening of telomeres that lead to telomere dysfunction, replicative arrest or chromosomal instability. Very few studies have addressed the regulatory roles of telomeres, and the association of genomic, transcriptomic and epigenomic characteristics of a cell with telomere length dynamics. Scarcity of such studies is partially conditioned by the low-throughput nature of experimental approaches for telomere length measurement and the fact that they do not easily integrate with currently available high-throughput data. In this thesis, we have attempted to build algorithms, in silico pipelines and software packages to utilize high-throughput –omics data for telomere biology research. First, we have developed a software package Computel, to compute telomere length from whole genome next generation sequencing data. We show that it can be used to integrate telomere length dynamics into systems biology research. Using Computel, we have studied the association of telomere length with genomic variations in a healthy human population, as well as with transcriptomic and epigenomic features of lung cancers. Another aim of our study was to develop in silico models to assess the activity of telomere maintenance machanisms (TMM) based on gene expression data. There are two main TMMs: one based on the catalytic activity of ribonucleoprotein complex telomerase, and the other based on recombination events between telomeric sequences. Which type of TMM gets activated in a cancer cell determines the aggressiveness of the tumor and the outcome of the disease. Investigation into TMM mechanisms is valuable not only for basic research, but also for applied medicine, since many anticancer therapies attempt to inhibit the TMM in cancer cells to stop their growth. Therefore, studying the activation mechanisms and regulators of TMMs is of paramount importance for understanding cancer pathomechanisms and for treatment. Many studies have addressed this topic, however many aspects of TMM activation and realization still remain elusive. Additionally, current data-mining pipelines and functional annotation approaches of phenotype-associated genes are not adapted for identification of TMMs. To overcome these limitations, we have constructed pathway networks for the two TMMs based on literature, and have developed a methodology for assessment of TMM pathway activities from gene expression data. We have described the accuracy of our TMM-based approach on a set of cancer samples with experimentally validated TMMs. We have also applied it to explore TMM activity states in lung adenocarcinoma cell lines. In summary, recent developments of high-throughput technologies allow for production of data on multiple levels of cellular organization – from genomic and transcriptiomic to epigenomic. This has allowed for rapid development of various directions in molecular and cellular biology. In contrast, telomere research, although at the heart of stem cell and cancer studies, is still conducted with low-throughput experimental approaches. Here, we have attempted to utilize the huge amount of currently accumulated multi-omics data to foster telomere research and to bring it to systems biology scale.

No description available.

<p> Comprehensive mastery of modern genetics involves a myriad of data processing and analytic techniques; these approaches vary because some genetic conditions are the result of single gene mutations that alter protein function, while other more complex diseases and traits are influenced by many genes. This dissertation will undertake investigation of the heritability and genetic risk of cranial cruciate ligament rupture in Labrador Retrievers, a congenital hypomyelinating polyneuropathy in four Golden Retrievers, and the potential usage of telomere length as a biomarker of welfare in dogs housed in commercial breeding facilities. </p> <p>In the first disease studied, 333 Labrador Retrievers with known torn or healthy cranial cruciate ligament(s) were genotyped via SNP array. Heritability of this polygenic trait was calculated using a variety of programs and including different fixed effects. Overall, heritability was high, ranging from 0.550 to 0.893, with sex and sterilization at a young age (≤12 months) strongly influencing risk of cranial cruciate ligament rupture. Neither genome-wide association analyses using this novel dataset of 333 Labrador Retrievers, nor additional analyses combining this data with publicly-available data, identified any significantly associated SNPs. However, the most associated SNPs were located near biologically relevant genes, such as <em>COL1A2</em> (a collagen gene) and <em>ITGA11</em> (a protein that binds to collagen), as well as genes encoding sex hormone receptors, such as <em>FSHR </em>and <em>LHCCGR</em>. Splitting the data in an attempt to predict phenotypes based on genotype was unsuccessful. Future work focused on parsing out genetic influencers of cranial cruciate ligament rupture risk should continue to collect sex, sterilization status, and age at sterilization data, and larger collaborations and use of publicly-available data will be required to increase the data robustness.</p> <p>For the second study, DNA from four unrelated Golden Retrievers diagnosed with congenital hypomyelinating polyneuropathy via neurological examination, electrodiagnostic evaluation, and peripheral nerve pathology were explored for genetic causes. Whole-genome sequencing was performed on all four dogs to identify potential causative variants. When compared to WGS from >1,000 other dogs who were presumably unaffected by this rare disease, likely causative variants were identified in all four dogs. Two cases shared a homozygous <em>MTMR2 </em>splice donor site variant, with a stop codon introduced within six codons following the inclusion of the intron. One case had a heterozygous <em>MPZ</em> missense mutation leading to an isoleucine to threonine substitution. The last case had a homozygous <em>SH3TC2</em> nonsense variant predicted to truncate approximately one-half of the protein. Haplotype analyses using 524 Golden Retrievers indicated that these variants emerged recently. Each of these variants occurred in genes that are associated with the human Charcot-Marie-Tooth group of heterogeneous peripheral nervous system diseases. Testing a population of unrelated Golden Retrievers (n > 200) did not identify any other dogs with these variants, though breeders should be cautious to avoid propagating these alleles.</p> <p>Finally, the last study within this dissertation investigates the relationship between telomere length and metrics such as age, breed, environment, average breed lifespan, parity, and response to a mild social stressor in a population of dogs housed at commercial breeding facilities. FIDO scores (behavioral phenotypes) were collected for all dogs as a measurement of response to a social stressor. This study is not yet complete; many more dogs remain to be recruited in the near future. Telomere lengths were measured using qPCR and compared to a single-copy gene, <em>36B4</em>, for 309 dogs representing 37 breeds or breed crosses. Age was not significantly associated with telomere length after making appropriate corrections (p-value = 0.077). Breed and facility were significantly associated with telomere length after corrections (p-value = 0.010 and <2.2E-16, respectively). Neither parity nor average breed lifespan were associated with telomere length, however, response to a mild social stressor was, with dogs who responded positively having significantly longer telomeres than dogs who responded negatively across all analyses. This preliminary data indicates that, within this population, breed, environment, and response to stress have strong influences on telomere length, while parity and average breed lifespan did not. As this work continues, increased sample sizes will lead to increased power for detecting associations. Future work should examine these identified relationships in other populations of dogs.</p> <p>Taken together, these studies encompass phenotypes of various complexity, and each study encompassed different methodologies utilized in modern canine genetics. The overall goal for this work was to improve canine health, with the potential for translational implications to human health. The identification of genetic markers associated with or causative of disease, or indicative of health and welfare traits, is necessary for reducing the prevalence of disease and increasing the knowledge of welfare metrics in canines, respectively.</p>

<p>TRF1, a shelterin protein, is a negative mediator of telomere length maintenance. Phosphorylation has been shown to play an important role in modulating TRF1 function. T137 and S249 of TRF1 have been indentified to be candidate phosphorylation sites in vivo, and one of my thesis objectives was to examine their role in regulating TRF1 function. Both T137 and S249 have each been changed to either alanine (nonphosphorylatable) or phosphomimic mutation. The TRF1 mutants were introduced into a TRF1-depleted cell line. Southern analysis revealed that neither T137 nor S249 of TRF1 is involved in telomere length maintenance. Immunoprecipitation studies showed that T137 and S249 are not required for TRF1 interaction with TIN2. In vitro gel-shift assays indicated that T137 and S249 are not important for TRF1 binding to telomeric DNA. Taken together, these results suggest that T137 and S249 may not be required for TRF1 function in telomere length maintenance. Human Est1A has been suggested to play a role in telomere length maintenance. To identify the domain of hEst1A involved in telomere length maintenance, a number of deletion constructs were generated and retrovirally introduced into HT1080 cells. Southern analysis revealed that the RID domain may positively regulate telomere length maintenance whereas the first 220 amino acids at the N-terminus may be a negative mediator of telomere length maintenance. In S. cerevisiae, Est1 recruits telomerase to telomeres in a Tel1- (homolog of ATM) and MRX-dependent manner. To assess whether atm-1 and smg-6 may function in the same genetic pathway of regulation of telomere length in C.elegans, the single mutant strain atm-1(gk186) was crossed with three of smg-6 mutant strains (tm1308, ok1794 and r896) to generate double mutants. Southern analysis revealed that deletion of ATM-1 or SMG-6 (tm1308) results in telomere shortening, suggesting that atm-1 and smg-6 may function in the same genetic pathway to regulate telomere length maintenance.</p> / Master of Science (MSc)

Conventional housing environments for broiler chickens and commercial laying hens are often barren, high-density environments with an emphasis on production efficiency. These housing conditions limit birds' ability to display species-specific behaviors, can negatively impact health, and may contribute to negative cumulative experience. Cumulative experience is the culmination of all positive and negative experienced during an animal's lifetime. However, cumulative experience is difficult to quantify, as no validated measures of cumulative experience exist. Additionally, existing measures of negative animal experience mostly rely on interpretations of animal behavior which can be subjective, time consuming, and difficult to interpret. Therefore, there is scientific need for objective measures that can detect cumulative experience in poultry. Secretory and plasma Immunoglobulin A (IgA), telomere length, feather corticosterone concentrations, and attention bias testing all seem to respond to positive and negative experiences in humans or other non-human animal species, indicating that they may be useful as measures for poultry. Therefore, the objective of this thesis was to determine if these novel measures could be used as indicators of cumulative experience in broiler chickens and laying hens. In chapter 3, secretory and plasma IgA concentrations were measured in broilers raised in either high-complexity or low-complexity environments under either high or low stocking density over three replicated experiments. Birds housed in highly complex environments showed higher concentrations of plasma IgA compared to birds housed in low-complexity environments at day 48 of age, indicating reduced chronic stress in the former. Additionally, day 48 secretory IgA concentrations were decreased in birds housed in high-density environments compared to birds housed in low density environments, indicating birds from high-density environments were more chronically stressed. In chapter 4, gonad and kidney telomere length was measured to determine cumulative experience in broilers raised in the same housing conditions and replicated experiments of chapter 3. Treatment did not impact gonad telomere length, in line with expectations as gonads contain stem cells which produce high concentrations of telomerase. Birds housed in high-complexity pens had longer kidney telomeres compared to birds in low-complexity pens, indicating high-complexity birds had more positive cumulative experience. Stocking density did not impact kidney telomere length. In chapter 5, attention bias, tonic immobility, plasma and secretory IgA concentrations, and feather corticosterone concentrations were determined in laying hens raised in conventional cages or enriched floor pens. Birds in enriched floor pens showed increased attention bias, decreased tonic immobility, increased secretory IgA concentrations at week 22 of age, and decreased feather corticosterone concentrations compared to caged hens. These results indicate that compared to conventional cages, enriched pens in this study improved immune systems, reduced chronic stress, reduced fear, but increased anxiety in hens. In conclusion, secretory and plasma IgA and telomere length show appropriate contrast in response to broiler chicken housing conditions. However, additional work needs to be done before these measures can be widely used as measures of cumulative experience in poultry. Furthermore, attention bias, secretory IgA, and feather corticosterone showed an appropriate contrast between chronic stress responses in laying hens, but confirmation is needed in other contexts. Overall, the results indicate a beneficial relationship between environmental complexity and poultry welfare physiology and affective state, with the exception for anxiety in laying hens. Thus, providing an enriched environment can improve the welfare of commercial poultry and result in positive cumulative experience in most situations. Additionally, these results indicate that stocking density is a negative environment in broilers but potentially less intense than previously thought under experimental conditions. The assessment of behavioral and physiological measures of cumulative and positive animal experience should be included in experiments seeking to determine the impacts of environmental or management conditions to determine the broader impacts on poultry welfare. / Doctor of Philosophy / Conventional housing systems of broiler chickens (raised for meat) and laying hens (raised for egg production) can negatively impact their welfare. Animal welfare, defined as an animal's ability to interact with and cope with their environment, is an individual experience for each animal and fluctuates on a scale from very negative to very positive. Traditionally, measurements of animal welfare have focused only on avoiding the negative aspects of animal welfare such as fear, distress (negative stress), hunger, thirst, pain, and suffering. However, it is important that animals are provided opportunities to experience positive animal welfare to provide a life worth living. So, when measuring animal welfare, all positive and negative experiences (termed cumulative experience) should be included to form an accurate picture of an animal's welfare. However, no validated measures of cumulative experience exist in non-human animals. However, recently, several potential measures of cumulative experience have been proposed in human and non-human animals including secretory and plasma IgA, telomere length, feather corticosterone, and attention bias testing. So, the objective of this thesis was to determine if these proposed measures can be used to determine cumulative experience in commercial broilers and laying hens. In chapters 3 and 4, we investigated if secretory and plasma IgA concentrations (measure of chronic stress; chapter 3) and telomere length (measure of cumulative experience; chapter 4) responded to environmental complexity (positive stimulus) and stocking density (negative stimulus) over three replicated experiments. Broilers were housed in a 2 × 2 factorial study of either high or low complexity or high or low density. This resulted in four treatment groups of high-complexity/high-density, low-complexity/low-density, high-complexity/low-density, and low-complexity/high-density. During chapter 3, environmental complexity increased concentrations of plasma IgA, indicating that birds from high-complexity pens were under less chronic stress compared to birds from low-complexity pens. Alternatively, high density decreased secretory IgA, indicating that birds from high-density pens were under a more chronic stress than birds from low density pens. In chapter 4, environmental complexity increased telomere length in broilers compared to low-complexity pens indicating that environmental complexity positively impacted cumulative experience. However, stocking density did not impact telomere length, indicating that high density did not negatively impact cumulative experience. In chapter 5, we investigated if attention bias (measure of anxiety), tonic immobility duration (measure of fear), plasma and secretory IgA (chronic stress), and feather corticosterone (chronic stress) responded to environmentally enriched floor pens (positive housing system) and conventional caging (negative housing system). We found that birds housed in enriched floor pens were more anxious (increased attention bias), less fearful (decreased tonic immobility duration), and less chronically stressed (increased SIgA concentrations at week 22 and increased feather corticosterone concentrations) compared to birds housed in conventional cages. Overall, IgA concentrations and telomere length (broilers) and attention bias, secretory IgA concentration, and feather corticosterone concentrations (layers) seem useable as measures of animal experience in commercial poultry. Additionally, these results indicate that positive experience has a positive impact on cumulative experience in commercial poultry. Stocking density also seems to contribute to chronic stress in broilers, indicated by decreased SIgA concentrations, but only during the last few weeks of life. These findings should be confirmed by additional studies before common use as measures of cumulative experience in animals. However, the inclusion of measures of cumulative and positive animal experience should be included in experiment which wish to determine the broad impacts of housing system on non-human animals.

A instabilidade genômica tem sido implicada como um dos principais fatores relacionados ao processo de envelhecimento. Esta é consequência do acumulo de danos no DNA em células somáticas continuamente expostas a fatores endógenos e exógenos. Um grupo de proteínas que desempenha diversos papéis na manutenção e estabilidade do genoma é formado pelas RecQ helicases, atuando em vários processos do metabolismo celular, tais como replicação do DNA, recombinação, reparo do DNA e manutenção dos telômeros. Algumas evidencias relacionam a expressão aberrante destas proteínas ao envelhecimento precoce. Com o objetivo de determinar os perfis de expressão transcricional de genes da família RecQ helicase e alguns genes envolvidos na via BER (Base excision repair), como PARP1, POL e APEX1 em células mononucleares do sangue periférico (PBMCs, do inglês Peripheral Blood Mononuclear Cells), comparamos grupos de indivíduos jovens (n = 20), idosos (n = 17) e centenários (n = 27). Além disso, foi também foi avaliado o comprimento telomérico em amostras de DNA desses indivíduos, buscando uma comparação entre os mesmos. Foi observada uma diminuição no nível de expressão transcricional do gene BLM nos grupos idoso e centenário quando comparados ao grupo jovem (p<0,05). Também foi observado uma diminuição na expressão do gene RECQL5 no grupo idoso comparado ao grupo jovem. Para os genes da via BER, foi observada uma repressão na expressão transcricional de PARP1 no grupo idoso em relação ao grupo jovem (p<0,05). Em relação ao comprimento telomérico, nossos resultados demonstraram associação entre a diminuição do comprimento telomérico e a idade. Obtivemos diferença significativa na comparação do comprimento telomérico de idosos e centenários comparados ao grupo jovem. Porém, não foi observada diferença entre os grupos idosos e centenários. Assim, nossos resultados mostram uma associação do processo de envelhecimento com a modulação de alguns genes da família RecQ helicase e participantes da via BER, e com o encurtamento telomérico. Os resultados gerados nesse trabalho são inéditos, sendo que relevantes para melhor compreensão do processo de envelhecimento. / Genomic instability plays a major role in the aging process due to the accumulation of DNA damage in somatic cells continuously exposed to endogenous and exogenous factors. A group of proteins essential in maintaining genome stability is composed by RecQ helicase, acting in several cell metabolism processes such as DNA replication, recombination, DNA repair and telomere maintenance. Some evidence related the aberrant expression of these proteins to premature aging. In order to determine the transcriptional expression profile of RecQ helicase gene family and some genes involved in the BER (Base excision repair) pathway, such as PARP1, POL and APEX1 in peripheral blood mononuclear cells (PBMCs), we compared groups of young (n = 20), elderly (n = 17) and centenarians (n = 27). Furthermore, it was also evaluated telomere length in DNA samples from these individuals. It was observed a decrease in the transcriptional expression of BLM gene in elderly and centenarians compared to the young group (p <0.05). It was also observed a decrease in expression of RECQL5 gene in the elderly compared to the younger group. For the BER genes, it was observed a transcriptional repression of PARP1 in the elderly group compared to the young group (p <0.05). Regarding the telomere length, our results demonstrated an association between reduction of telomere length and age. We obtained significant difference in comparing the telomere length of the elderly and centenarians compared to the younger group. However, no difference was observed between the elderly and centenarians groups. Thus, our results show an association of aging process with the modulation of certain genes from RecQ helicase family and participants of the BER pathway and the telomere shortening. The results generated in this study are promising, and relevant to better understanding the aging process.