The Autoimmune Regulator (AIRE), Which Is Defective in Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy Patients, Is Expressed in Human Epidermal and Follicular Keratinocytes and Associates With the Intermediate Filament Protein Cytokeratin 17

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome, which is caused by mutation of the autoimmune regulator (AIRE) gene, is a highly variable disease characterized by multiple endocrine failure, chronic mucocutaneous candidiasis, and various ectodermal defects. AIRE is a transcriptional regulator classically expressed in medullary thymic epithelial cells, monocytes, macrophages, and dendritic cells. Previous studies have suggested that AIRE can shuttle between the nucleus and cytoplasm of cells, although its cytoplasmic functions are poorly characterized. Through mass spectrometry analysis of proteins co-immunoprecipitating with cytoplasmic AIRE, we identified a novel association of AIRE with the intermediate filament protein cytokeratin 17 (K17) in the THP-1 monocyte cell line. We confirmed AIRE expression in HaCaT epidermal keratinocytes, as well as its interaction with K17. Confocal microscopy of human fetal and adult scalp hair follicles demonstrated a cytoplasmic pattern of AIRE staining that moderately colocalized with K17. The cytoplasmic association of AIRE with the intermediate filament network in human epidermal and follicular keratinocytes may provide a new path to understanding the ectodermal abnormalities associated with the APECED syndrome. (Am J Pathol 2011, 178:983-988; DOI: 10.1016/j.ajpath.2010.12.007)

Epidemiology and control of frontier malaria in Brazil: lessons from community-based studies in rural Amazonia

We describe the epidemiology of malaria in a frontier agricultural settlement in Brazilian Amazonia. We analysed the incidence of slide-confirmed symptomatic infections diagnosed between 2001 and 2006 in a cohort of 531 individuals (2281.53 person-years of follow-up) and parasite prevalence data derived from four cross-sectional surveys. Overall, the incidence rates of Plasmodium vivax and P. falciparaum were 20.6/100 and 6.8/100 person-years at risk, respectively, with a marked decline in the incidence of both species (81.4 and 56.8%, respectively) observed between 2001 and 2006. PCR revealed 5.4-fold more infections than conventional microscopy in population-wide cross-sectional surveys carried out between 2004 and 2006 (average prevalence, 11.3 vs. 2.0%). Only 27.2% of PCR-positive (but 73.3% of slide-positive) individuals had symptoms when enrolled, indicating that asymptomatic carriage of low-grade parasitaemias is a common phenomenon in frontier settlements. A circular cluster comprising 22.3% of the households, all situated in the area of most recent occupation, comprised 69.1% of all malaria infections diagnosed during the follow-up, with malaria incidence decreasing exponentially with distance from the cluster centre. By targeting one-quarter of the households, with selective indoor spraying or other house-protection measures, malaria incidence could be reduced by more than two-thirds in this community. (C) 2010 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved.

Three-dimensional description and mathematical characterization of the parasellar internal carotid artery in human infants

Inside the `cavernous sinus` or `parasellar region` the human internal carotid artery takes the shape of a siphon that is twisted and torqued in three dimensions and surrounded by a network of veins. The parasellar section of the internal carotid artery is of broad biological and medical interest, as its peculiar shape is associated with temperature regulation in the brain and correlated with the occurrence of vascular pathologies. The present study aims to provide anatomical descriptions and objective mathematical characterizations of the shape of the parasellar section of the internal carotid artery in human infants and its modifications during ontogeny. Three-dimensional (3D) computer models of the parasellar section of the internal carotid artery of infants were generated with a state-of-the-art 3D reconstruction method and analysed using both traditional morphometric methods and novel mathematical algorithms. We show that four constant, demarcated bends can be described along the infant parasellar section of the internal carotid artery, and we provide measurements of their angles. We further provide calculations of the curvature and torsion energy, and the total complexity of the 3D skeleton of the parasellar section of the internal carotid artery, and compare the complexity of this in infants and adults. Finally, we examine the relationship between shape parameters of the parasellar section of the internal carotid artery in infants, and the occurrence of intima cushions, and evaluate the reliability of subjective angle measurements for characterizing the complexity of the parasellar section of the internal carotid artery in infants. The results can serve as objective reference data for comparative studies and for medical imaging diagnostics. They also form the basis for a new hypothesis that explains the mechanisms responsible for the ontogenetic transformation in the shape of the parasellar section of the internal carotid artery.

[(13)C(2)]- Acetaldehyde Promotes Unequivocal Formation of 1,N(2)-Propano-2 `-deoxyguanosine in Human Cells

Acetaldehyde is an environmentally widespread genotoxic aldehyde present in tobacco smoke, vehicle exhaust and several food products. Endogenously, acetaldehyde is produced by the metabolic oxidation of ethanol by hepatic NAD-dependent alcohol dehydrogenase and during threonine catabolism. The formation of DNA adducts has been regarded as a critical factor in the mechanisms of acetaldehyde mutagenicity and carcinogenesis. Acetaldehyde reacts with 2`-deoxyguanosine in DNA to form primarily N(2)-ethylidene-2`-deoxyguanosine. The subsequent reaction of N(2)-ethylidenedGuo with another molecule of acetaldehyde gives rise to 1,N(2)-propano-2`-deoxyguanosine (1,N(2)-propanodGuo), an adduct also found as a product of the crotonaldehyde reaction with dGuo. However, adducts resulting from the reaction of more than one molecule of acetaldehyde in vivo are still controversial. In this study, the unequivocal formation of 1,N(2)-propanodGuo by acetaldehyde was assessed in human cells via treatment with [(13)C(2)]-acetaldehyde. Detection of labeled 1,N(2)-propanodGuo was performed by HPLC/MS/MS. Upon acetaldehyde exposure (703 mu M), increased levels of both 1,N(2)-etheno-2`-deoxyguanosine (1,N(2)-epsilon dGuo), which is produced from alpha,beta-unsaturated aldehydes formed during the lipid peroxidation process, and 1,N(2)-propanodGuo were observed. The unequivocal formation of 1,N(2)-propanodGuo in cells exposed to this aldehyde can be used to elucidate the mechanisms associated with acetaldehyde exposure and cancer risk.

Bcl-2 expression and apoptosis induction in human HL60 leukaemic cells treated with a novel organotellurium(IV) compound RT-04

Organotellurium(]V) compounds have been reported to have multiple biological activities including cysteine protease-inhibitory activity, mainly cathepsin B. As cathepsin B is a highly predictive indicator for prognosis and diagnosis of cancer, a possible antitumor potential for these new compounds is expected. In this work, it was investigated the effectiveness of organotellurium(IV) RT-04 to produce lethal effects in the human promyelocytic leukaemia cell line HL60. Using the MTT tetrazolium reduction test, and trypan blue exclusion assay, the IC50 for the compound after 24 h incubation was 6.8 and 0.35 mu M, respectively. Moreover, the compound was found to trigger apoptosis in HL60 cells, inducing DNA fragmentation and caspase-3, -6, and -9 activations. The apoptsosis-induced by RT-04 is probably related to the diminished Bcl-2 expression, observed by RT-PCR, in HL60-treated cells. In vivo studies demonstrated that the RT-04 treatment (2.76 mg/kg given for three consecutive days) produces no significant toxic effects for bone marrow and spleen CFU-GM. However, higher doses (5.0 and 10 mg/kg) produced a dose-dependent reduction in the number of CFU-GM of RT-04-treated mice. These results suggest that RT-04 is able to induce apoptosis in HL60 cells by Bcl-2 expression down-modulation. Further studies are necessary to better clarify the effects of this compound on bone marrow normal cells. (C) 2008 Elsevier Ltd. All rights reserved.

Consumed by Faith: The development of Christian Fundamentalism and its applications in contemporary society

My research aims to understand how and why fundamentalists justify violence against people who do not fit their profile of "righteous" or "saved" persons, such as abortion doctors and clinic workers, gays and lesbians, and Jews. The first section of this paper travels through the history of fundamentalism since its origins in the British and American apocalipticism, or belief in the Second Coming of Jesus Christ. However, my history of Protestant Fundamentalism in the United States will focus on the ways in which Fundamentalism developed in response to many changes in American social structure. I interpret Fundamentalism as an anti-modern movement seeking to reassert "traditional" Christian values.

Quantifying epistemic actions in human-computer interaction

As digital systems move away from traditional desktop setups, new interaction paradigms are emerging that better integrate with users’ realworld surroundings, and better support users’ individual needs. While promising, these modern interaction paradigms also present new challenges, such as a lack of paradigm-specific tools to systematically evaluate and fully understand their use. This dissertation tackles this issue by framing empirical studies of three novel digital systems in embodied cognition – an exciting new perspective in cognitive science where the body and its interactions with the physical world take a central role in human cognition. This is achieved by first, focusing the design of all these systems on a contemporary interaction paradigm that emphasizes physical interaction on tangible interaction, a contemporary interaction paradigm; and second, by comprehensively studying user performance in these systems through a set of novel performance metrics grounded on epistemic actions, a relatively well established and studied construct in the literature on embodied cognition. The first system presented in this dissertation is an augmented Four-in-a-row board game. Three different versions of the game were developed, based on three different interaction paradigms (tangible, touch and mouse), and a repeated measures study involving 36 participants measured the occurrence of three simple epistemic actions across these three interfaces. The results highlight the relevance of epistemic actions in such a task and suggest that the different interaction paradigms afford instantiation of these actions in different ways. Additionally, the tangible version of the system supports the most rapid execution of these actions, providing novel quantitative insights into the real benefits of tangible systems. The second system presented in this dissertation is a tangible tabletop scheduling application. Two studies with single and paired users provide several insights into the impact of epistemic actions on the user experience when these are performed outside of a system’s sensing boundaries. These insights are clustered by the form, size and location of ideal interface areas for such offline epistemic actions to occur, as well as how can physical tokens be designed to better support them. Finally, and based on the results obtained to this point, the last study presented in this dissertation directly addresses the lack of empirical tools to formally evaluate tangible interaction. It presents a video-coding framework grounded on a systematic literature review of 78 papers, and evaluates its value as metric through a 60 participant study performed across three different research laboratories. The results highlight the usefulness and power of epistemic actions as a performance metric for tangible systems. In sum, through the use of such novel metrics in each of the three studies presented, this dissertation provides a better understanding of the real impact and benefits of designing and developing systems that feature tangible interaction.

Non invasive methods for genetic analysis applied to ecological and behavioral studies in Latino-America

Documenting the presence and abundance of the neotropical mammals is the first step for understanding their population ecology, behavior and genetic dynamics in designing conservation plans. The combination of field research with molecular genetics techniques are new tools that provide valuable biological information avoiding the disturbance in the ecosystems, trying to minimize the human impact in the process to gather biological information. The objective of this paper is to review the available non invasive sampling techniques that have been used in Neotropical mammal studies to apply to determine the presence and abundance, population structure, sex ratio, taxonomic diagnostic using mitochondrial markers, and assessing genetic variability using nuclear markers. There are a wide range of non invasive sampling techniques used to determine the species identification that inhabit an area such as searching for tracks, feces, and carcasses. Other useful equipment is the camera traps that can generate an image bank that can be valuable to assess species presence and abundance by morphology. With recent advances in molecular biology, it is now possible to use the trace amounts of DNA in feces and amplify it to analyze the species diversity in an area, and the genetic variability at intraspecific level. This is particularly helpful in cases of sympatric and cryptic species in which morphology failed to diagnose the taxonomic status of several species of brocket deer of the genus Mazama.

No relationship found between point heteroplasmy in mitochondrial DNA control region and age range, sex and haplogroup in human hairs

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

MicroRNA-100 Acts as a Tumor Suppressor in Human Bladder Carcinoma 5637 Cells

Bladder carcinoma is one of the most common tumors in the world and, despite the therapy currently available, most of the patients relapse. Better understanding of the factors involved in disease pathogenesis would provide insights for the development of more effective strategies in treatment. Recently, differential miRNA expression profiles in bladder urothelial carcinomas identified miR-100 down-regulation and miR-708 up-regulation among the most common alterations, although the possible influence of these miRNAs in the control of basic mechanisms in bladder tumors has not been addressed. In this context, the present study aimed to evaluate the in vitro effects of miR-100 forced expression and miR-708 inhibition in the bladder carcinoma cell line 5637. Our results showed that overexpression of miR-100 significantly inhibited growth when compared to controls at both times tested (72 and 96 hours, p<0.01) with a maximum effect at 72 hours reducing proliferation in 29.6 %. Conversely, no effects on cell growth were observed after inhibition of miR-708. MiR-100 also reduced colony formation capacity of 5637 cells by 24.4%. No alterations in cell cycle progression or apoptosis induction were observed. The effects of miR-100 on growth and clonogenicity capacity in 5637 cells evince a possible role of this miRNA in bladder carcinoma pathogenesis. Further studies are necessary to corroborate our findings and examine the potential use of this microRNA in future therapeutic interventions.

Stress hormones increase cell proliferation and regulates interleukin-6 secretion in human oral squamous cell carcinoma cells

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Role of TLR2 and TLR4 in Human Neutrophil Functions Against Paracoccidioides brasiliensis

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

ORGANOCHLORINE PESTICIDE-RESIDUES IN HUMAN-MILK IN THE RIBEIRAO-PRETO REGION, STATE OF SAO-PAULO, BRAZIL

Thirty-seven samples of human milk (colostrum) from donors living in the Ribeirao Preto region were analyzed to determine the levels of organochlorine pesticide residues. Donors were classified into two groups, i.e., occupationally exposed and non-exposed to pesticides. Other factors such as age, previous lactations, race, smoking habit, occupation, family income and educational level were also considered. Analysis was performed by preliminary lipid extraction followed by fractional partition on a column and finally by gas chromatography with an electron capture detector. Lindane was found in 32% of the samples in amounts of less than 0.001 mg/kg; heptachlor was found in 65% of the samples at mean levels of 0.001 mg/kg, i.e., a level five-fold lower than that established by FAO/WHO (1970) for cow's milk. Aldrin and endrin were not detected in any of the samples. Dieldrin was detected in only one sample at a level of 0.038 mg/kg, which is considered high. DDT and DDE amounts are reported as total DDT and at least one of these compounds was present in every sample. Amounts detected in donors occupationally exposed to pesticides ranged from 0.008 to 0.455 mg/kg (mean, 0.149 mg/kg), i.e., three times the limit established by FAO/WHO (1970), while values for donors who had not been exposed ranged from 0.002 to 0.072 mg/kg (mean, 0.025 mg/kg), i.e., half the limit. Considering the level of acceptable daily intake proposed by FAO/WHO (1973), lactents ingested 1% of the acceptable intake of lindane (all donors), 30% of the acceptable intake of heptachlor (all donors), 60% of the acceptable intake of DDT (non-exposed donors), and 3.7 times the acceptable intake of DDT (exposed donors). Comparing the present results with those obtained 10 years ago, the total DDT level in human milk is decreasing in this part of the country. The mean amount of organochlorine residues in non-exposed women's milk was one of the lowest levels among those recorded in the literature. DDT levels of occupationally exposed women's milk were comparable with those reported for developed countries and lower than those detected in Latin American countries. When the results of this survey are considered in relation to the advantages of breast-feeding, the risk-benefit balance is still favorable to breast-feeding. However, given the lack of long-term epidemiological studies, undesirable or harmful long-lasting effects cannot be excluded.