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This study demonstrates the potential of an innovative anaerobic treatment technology for municipal biosolids (IntensiCarb), which relies on vacuum evaporation to decouple solids and hydraulic retention times (SRT and HRT). We present proof-of-concept experiments using primary sludge and thickened waste activated sludge (50-50 v/v mixture) as feed for fermentation and carbon upgrading with the IntensiCarb unit. IntensiCarb fully decoupled the HRT and SRT in continuously stirred anaerobic reactors (CSAR) to achieve two intensification factors, that is, 1.3 and 2, while keeping the SRT constant at 3 days (including in the control fermenter). The intensified CSARs were compared to a conventional control system to determine the yields of particulate hydrolysis, VFA production, and nitrogen partitioning between fermentate and condensate. The intensified CSAR operating at an intensification factor 2 achieved a 65% improvement in particulate solubilization. Almost 50% of total ammonia was extracted without pH adjustment, while carbon was retained in the fermentate. Based on these results, the IntensiCarb technology allows water resource recovery facilities to achieve a high degree of plant-wide intensification while partitioning nutrients into different streams and thickening solids. PRACTITIONER POINTS: The IntensiCarb reactor can decouple hydraulic (HRT) and solids (SRT) retention times in anaerobic systems while also increasing particulate hydrolysis and overall plant capacity. Using vacuum as driving force of the IntensiCarb technology, the system could achieve thickening, digestion, and partial dewatering in the same unit-thus eliminating the complexity of multi-stage biosolids treatment lines. The ability to partition nutrients between particulate, fermentate, and condensate assigns to the IntensiCarb unit a key role in recovery strategies for value-added products such as nitrogen, phosphorus, and carbon, which can be recovered separately and independently.
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Understanding long-run patterns in the incarceration of Black Americans requires integrating the study of racial inequality with the study of political economy. I offer a parsimonious framework describing how the Black incarceration rate has been affected by the dynamics of exploitation and exclusion over time and across space. This framework helps to explain otherwise puzzling facts, like why the Black incarceration rate was lower in the South than in the North for much of the 20th century, why it was lowest in the South's cotton belt, and why it began to tick upward when it did. It also enables us to better understand recent changes in racial and class inequality in incarceration in the United States.
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The present study reports on the microstructural evolution and room temperature plasticity of V(Si)B alloys with respect to the V solid solution (VSS)V3B2 phase region. To investigate the occurring effects systematically, different binary VB and ternary VSiB alloys were produced by conventional arc melting. Scanning electron microscope (SEM) analyses and X-ray diffraction (XRD) measurements were used to characterize the resulting as-cast microstructures. For the first time, the eutectic composition was systematically traced from the binary VB domain to the ternary VSiB system. The observations discover that the binary eutectic trough (VSSV3B2) seems to reach into the ternary system up to an alloy composition of V5Si9B. Room temperature compression tests were carried out in order to study the impact of single-phase and multi-phase microstructures on the strength and plasticity of binary and ternary alloys. The results indicate that the VSS phase controls the plastic deformability in the VSSV3B2 eutectic microstructure whereas the intermetallic V3B2 acts as a strong hardening phase.
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A highly negative glutathione redox potential (EGSH ) is maintained in the cytosol, plastids and mitochondria of plant cells to support fundamental processes, including antioxidant defence, redox regulation and iron-sulfur cluster biogenesis. Out of two glutathione reductase (GR) proteins in Arabidopsis, GR2 is predicted to be dual-targeted to plastids and mitochondria, but its differential roles in these organelles remain unclear. We dissected the role of GR2 in organelle glutathione redox homeostasis and plant development using a combination of genetic complementation and stacked mutants, biochemical activity studies, immunogold labelling and in vivo biosensing. Our data demonstrate that GR2 is dual-targeted to plastids and mitochondria, but embryo lethality of gr2 null mutants is caused specifically in plastids. Whereas lack of mitochondrial GR2 leads to a partially oxidised glutathione pool in the matrix, the ATP-binding cassette (ABC) transporter ATM3 and the mitochondrial thioredoxin system provide functional backup and maintain plant viability. We identify GR2 as essential in the plastid stroma, where it counters GSSG accumulation and developmental arrest. By contrast a functional triad of GR2, ATM3 and the thioredoxin system in the mitochondria provides resilience to excessive glutathione oxidation.
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Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Glutationa Redutase/metabolismo , Glutationa/metabolismo , Plastídeos/metabolismo , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Arabidopsis/genética , Arabidopsis/crescimento & desenvolvimento , Proteínas de Arabidopsis/genética , Teste de Complementação Genética , Glutationa Redutase/genética , Mitocôndrias/metabolismo , Mutação , Oxirredução , Plantas Geneticamente Modificadas , Plastídeos/genética , Sementes/genéticaRESUMO
In the first half of the twentieth century, the rate of death from infectious disease in the United States fell precipitously. Although this decline is well-known and well-documented, there is surprisingly little evidence about whether it took place uniformly across the regions of the United States. We use data on infectious disease deaths from all reporting U.S. cities to describe regional patterns in the decline of urban infectious mortality from 1900 to 1948. We report three main results. First, urban infectious mortality was higher in the South in every year from 1900 to 1948. Second, infectious mortality declined later in southern cities than in cities in the other regions. Third, comparatively high infectious mortality in southern cities was driven primarily by extremely high infectious mortality among African Americans. From 1906 to 1920, African Americans in cities experienced a rate of death from infectious disease that was greater than what urban whites experienced during the 1918 flu pandemic.
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Negro ou Afro-Americano/estatística & dados numéricos , Doenças Transmissíveis/etnologia , Doenças Transmissíveis/mortalidade , População Urbana/estatística & dados numéricos , População Branca/estatística & dados numéricos , Cidades/epidemiologia , Feminino , História do Século XX , Humanos , Influenza Pandêmica, 1918-1919/mortalidade , Masculino , Características de Residência/estatística & dados numéricos , Sudeste dos Estados Unidos/epidemiologia , Estados Unidos/epidemiologiaRESUMO
Background: The serotonin (5-HT) system has long been implicated in autism spectrum disorder (ASD) as indicated by elevated whole blood and platelet 5-HT, altered platelet and brain receptor and transporter binding, and genetic linkage and association findings. Based upon work in genetically modified mice, 5-HT is known to influence several aspects of brain development, but systematic neuroimaging studies have not previously been reported. In particular, the 5-HT transporter (serotonin transporter, SERT; 5-HTT) gene, Slc6a4, has been extensively studied. Methods: Using a 7-T MRI and deformation-based morphometry, we assessed neuroanatomical differences in an Slc6a4 knockout mouse on a C57BL/6 genetic background, along with an Slc6a4 Ala56 knockin mouse on two different genetic backgrounds (129S and C57BL/6). Results: Individually (same sex, same background, same genotype), the only differences found were in the female Slc6a4 knockout mouse; all the others had no significant differences. However, an analysis of variance across the whole study sample revealed a significant effect of Slc6a4 on the amygdala, thalamus, dorsal raphe nucleus, and lateral and frontal cortices. Conclusions: This work shows that an increase or decrease in SERT function has a significant effect on the neuroanatomy in 5-HT relevant regions, particularly the raphe nuclei. Notably, the Slc6a4 Ala56 knockin alone appears to have an insignificant, but suggestive, effect compared to the KO, which is consistent with Slc6a4 function. Despite the small number of 5-HT neurons and their localization to the brainstem, it is clear that 5-HT plays an important role in neuroanatomical organization.
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Encéfalo/diagnóstico por imagem , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Animais , Encéfalo/metabolismo , Feminino , Imageamento por Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mutação , Neurônios/metabolismo , Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismoRESUMO
In the early twentieth century, the cotton-growing regions of the U.S. South were dominated by families of tenant farmers. Tenant farming created opportunities and incentives for prospective tenants to marry at young ages. These opportunities and incentives especially affected African Americans, who had few alternatives to working as tenants. Using complete-count Census of Population data from 1900-1930 and Census of Agriculture data from 1889-1929, we find that increases in tenancy over time increased the prevalence of marriage among young African Americans. We then study how marriage was affected by one of the most notorious disruptions to southern agriculture at the turn of the century: the boll weevil infestation of 1892-1922. Using historical Department of Agriculture maps, we show that the boll weevil's arrival reduced the share of farms worked by tenants as well as the share of African Americans who married at young ages. When the boll weevil infestation altered African Americans' opportunities and incentives to marry, the share of African Americans who married young fell accordingly. Our results provide new evidence about the effect of economic and political institutions on demographic transformations.
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Agricultura/história , Negro ou Afro-Americano/estatística & dados numéricos , Gossypium , Casamento/etnologia , Casamento/história , Gorgulhos , Adolescente , Adulto , Animais , Feminino , História do Século XIX , História do Século XX , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Estudos Prospectivos , Estados Unidos , Adulto JovemRESUMO
Biomarker, neuroimaging, and genetic findings implicate the serotonin transporter (SERT) in autism spectrum disorder (ASD). Previously, we found that adult male mice expressing the autism-associated SERT Ala56 variant have altered central serotonin (5-HT) system function, as well as elevated peripheral blood 5-HT levels. Early in gestation, before midbrain 5-HT projections have reached the cortex, peripheral sources supply 5-HT to the forebrain, suggesting that altered maternal or placenta 5-HT system function could impact the developing embryo. We therefore used different combinations of maternal and embryo SERT Ala56 genotypes to examine effects on blood, placenta and embryo serotonin levels and neurodevelopment at embryonic day E14.5, when peripheral sources of 5-HT predominate, and E18.5, when midbrain 5-HT projections have reached the forebrain. Maternal SERT Ala56 genotype was associated with decreased placenta and embryonic forebrain 5-HT levels at E14.5. Low 5-HT in the placenta persisted, but forebrain levels normalized by E18.5. Maternal SERT Ala56 genotype effects on forebrain 5-HT levels were accompanied by a broadening of 5-HT-sensitive thalamocortical axon projections. In contrast, no effect of embryo genotype was seen in concepti from heterozygous dams. Blood 5-HT levels were dynamic across pregnancy and were increased in SERT Ala56 dams at E14.5. Placenta RNA sequencing data at E14.5 indicated substantial impact of maternal SERT Ala56 genotype, with alterations in immune and metabolic-related pathways. Collectively, these findings indicate that maternal SERT function impacts offspring placental 5-HT levels, forebrain 5-HT levels, and neurodevelopment.
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Troca Materno-Fetal , Placenta/metabolismo , Prosencéfalo/embriologia , Prosencéfalo/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Serotonina/biossíntese , Animais , Feminino , Genótipo , Camundongos Endogâmicos , Camundongos Transgênicos , Gravidez , Rombencéfalo/metabolismo , Tálamo/embriologia , Tálamo/metabolismoRESUMO
This article reports estimates of the cumulative risk of imprisonment and parental imprisonment for demographic groups in four regions and four states. Regional and state-level cumulative risks were markedly higher for African Americans and Latinos than for whites. African Americans faced the highest cumulative risks of imprisonment in the Midwest, Northeast, and two southern states. Latinos were most likely to serve time in state prison in the West, where their cumulative risk was comparable to that of African Americans. Latino children had a relatively high risk of having a parent imprisoned in the Northeast as well. Racial disparities in the cumulative risk of imprisonment and parental imprisonment did not increase linearly with increases in the cumulative risk for all groups.
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Pais , Prisões/estatística & dados numéricos , Grupos Raciais/estatística & dados numéricos , Negro ou Afro-Americano/estatística & dados numéricos , Pai/estatística & dados numéricos , Feminino , Hispânico ou Latino/estatística & dados numéricos , Humanos , Masculino , Características de Residência , Fatores de Risco , Fatores Socioeconômicos , Estados Unidos , População Branca/estatística & dados numéricosRESUMO
The pervasiveness of tenancy in the postbellum South had countervailing effects on marriage between African Americans. Tenancy placed severe constraints on African American women's ability to find independent agricultural work. Freedwomen confronted not only planters' reluctance to contract directly with women but also whites' refusal to sell land to African Americans. Marriage consequently became one of African American women's few viable routes into the agricultural labor market. We find that the more counties relied on tenant farming, the more common was marriage among their youngest and oldest African American residents. However, many freedwomen resented their subordinate status within tenant marriages. Thus, we find that tenancy contributed to union dissolution as well as union formation among freedpeople. Microdata tracing individuals' marital transitions are consistent with these county-level results.
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Agricultura/história , Negro ou Afro-Americano/história , Emprego/história , Casamento/história , Adolescente , Adulto , Negro ou Afro-Americano/etnologia , Negro ou Afro-Americano/estatística & dados numéricos , Fatores Etários , Divórcio/história , Divórcio/estatística & dados numéricos , Emprego/estatística & dados numéricos , Escravização , Etnicidade/história , Etnicidade/estatística & dados numéricos , Feminino , História do Século XIX , Humanos , Masculino , Casamento/estatística & dados numéricos , Pessoa de Meia-Idade , Dinâmica Populacional , Racismo , Sexismo , Fatores Socioeconômicos , Adulto JovemRESUMO
Subtropical ecosystems are often characterized by high N cycling rates, but net nitrification rates are often low in subtropical acid soils. NO3(-)-N immobilization into organic N may be a contributing factor to understand the observed low net nitrification rates in these acid soils. The effects of Fe oxide and organic matter on soil N transformations were evaluated using a (15)N tracing study. Soil net nitrification was low for highly acidic yellow soil (Ferralsols), but gross ammonia oxidation was 7 times higher than net nitrification. In weakly acidic purple soil (Cambisols), net nitrification was 8 times higher than in Ferralsols. The addition of 5% Fe oxide to Cambisols, reduced the net nitrification rate to a negative rate, while NO3(-)-N immobilization rate increased 8 fold. NO3(-)-N immobilization was also observed in Ferralsols which contained high Fe oxides levels. A possible mechanism for these reactions could be stimulation of NO3(-)-N immobilization by Fe oxide which promoted the abiotic formation of nitrogenous polymers, suggesting that the absence of net nitrification in some highly acid soils may be due to high rates of NO3(-)-N immobilization caused by high Fe oxide content rather than a low pH.
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Several lines of evidence implicate dysfunction of the serotonin (5-HT) system in autism spectrum disorder (ASD). Specifically, the serotonin transporter (5-HTT, SERT) has been scrutinized as an ASD candidate risk gene. SERT plays key roles in the development of circuits that underlie sensory function, particularly in the somatosensory system. One previous study in ASD found association of a rare, hyperfunctional SERT variant with sensory aversion, but studies of common SERT variants have never examined sensory symptoms in ASD. Using standardized caregiver assessments of sensory function in children, we evaluated patterns of sensory responsiveness in 47 children with ASD and 38 typically developing (TD) children. Study participants were genotyped for the functional SERT promoter polymorphisms, 5-HTTLPR and rs25531, to test the hypothesis that the higher expressing genotypes would be associated with hyperresponsiveness to touch, a common sensory aversion in ASD. All measures of sensory hypo- and hyperresponsiveness were increased in children with ASD, with hyporesponsive sensory patterns negatively correlated to age and hyperresponsive sensory patterns positively correlated to repetitive behavior. Strikingly, high-expressing SERT genotypes were associated with increased tactile hyperresponsiveness in the ASD group. Our findings indicate genetic variation that increases SERT function may specifically impact somatosensory processing in ASD.
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OBJECTIVES: The purpose of this study was to examine the beneficial effects on cognitive function by a cognitive intervention program designed for dementia care called Learning Therapy in Japan and SAIDO Learning in the United States (hereinafter "SAIDO Learning," as appropriate). SAIDO Learning is a working memory training program that uses systematized basic problems in arithmetic and language, including reading aloud, as well as writing. DESIGN, SETTING, PARTICIPANTS, AND INTERVENTION: Twenty-three nursing home residents with dementia were assigned as an intervention group, and another 24 people with dementia at another nursing home were assigned as a control group. Both nursing homes were operated by the same organization, and residents of both nursing homes received essentially the same nursing care. Thirteen and 6 subjects of the intervention and control groups, respectively, were clinically diagnosed as Alzheimer disease (AD). RESULTS: After the 6-month intervention, the participants with AD of the intervention group showed statistically significant improvement in cognitive function, as measured by the Mini-Mental State Examination (MMSE) compared with the control participants. In addition, post hoc analysis revealed that the Frontal Assessment Battery at Bedside (FAB) scores of the intervention group tended to improve after 6-month intervention. Based on MDS scores, improvements in total mood severity scores also were observed, but only in the intervention group of the participants with AD. CONCLUSION: These results suggest that SAIDO Learning is an effective cognitive intervention and is useful for dementia care. An additional outcome of this intervention, which has not yet been evaluated in detail, appears to be that it promotes greater positive engagement of a diversity of nursing home staff in the residents' individual progress and care needs.
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Doença de Alzheimer/reabilitação , Terapia Cognitivo-Comportamental/métodos , Aprendizagem , Casas de Saúde , Atividades Cotidianas , Idoso , Idoso de 80 Anos ou mais , Feminino , Avaliação Geriátrica , Humanos , Masculino , Testes Neuropsicológicos , Resultado do TratamentoRESUMO
Human psychophysical and animal behavioral studies have illustrated the benefits that can be conferred from having information available from multiple senses. Given the central role of multisensory integration for perceptual and cognitive function, it is important to design behavioral paradigms for animal models to provide mechanistic insights into the neural bases of these multisensory processes. Prior studies have focused on large mammals, yet the mouse offers a host of advantages, most importantly the wealth of available genetic manipulations relevant to human disease. To begin to employ this model species for multisensory research it is necessary to first establish and validate a robust behavioral assay for the mouse. Two common mouse strains (C57BL/6J and 129S6/SvEv) were first trained to respond to unisensory (visual and auditory) stimuli separately. Once trained, performance with paired audiovisual stimuli was then examined with a focus on response accuracy and behavioral gain. Stimulus durations varied from 50 ms to 1 s in order to modulate the effectiveness of the stimuli and to determine if the well-established "principle of inverse effectiveness" held in this model. Response accuracy in the multisensory condition was greater than for either unisensory condition for all stimulus durations, with significant gains observed at the 300 ms and 100 ms durations. Main effects of stimulus duration, stimulus modality and a significant interaction between these factors were observed. The greatest behavioral gain was seen for the 100 ms duration condition, with a trend observed that as the stimuli became less effective, larger behavioral gains were observed upon their pairing (i.e., inverse effectiveness). These results are the first to validate the mouse as a species that shows demonstrable behavioral facilitations under multisensory conditions and provides a platform for future mechanistically directed studies to examine the neural bases of multisensory integration.
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BACKGROUND: Previously, we identified multiple, rare serotonin (5-HT) transporter (SERT) variants in children with autism spectrum disorder (ASD). Although in our study the SERT Ala56 variant was over-transmitted to ASD probands, it was also seen in some unaffected individuals, suggesting that associated ASD risk is influenced by the epistatic effects of other genetic variation. Subsequently, we established that mice expressing the SERT Ala56 variant on a 129S6/S4 genetic background display multiple biochemical, physiological and behavioral changes, including hyperserotonemia, altered 5-HT receptor sensitivity, and altered social, communication, and repetitive behavior. Here we explore the effects of genetic background on SERT Ala56 knock-in phenotypes. METHODS: To explore the effects of genetic background, we backcrossed SERT Ala56 mice on the 129 background into a C57BL/6 (B6) background to achieve congenic B6 SERT Ala56 mice, and assessed autism-relevant behavior, including sociability, ultrasonic vocalizations, and repetitive behavior in the home cage, as well as serotonergic phenotypes, including whole blood serotonin levels and serotonin receptor sensitivity. RESULTS: One consistent phenotype between the two strains was performance in the tube test for dominance, where mutant mice displayed a greater tendency to withdraw from a social encounter in a narrow tube as compared to wildtype littermate controls. On the B6 background, mutant pup ultrasonic vocalizations were significantly increased, in contrast to decreased vocalizations seen previously on the 129 background. Several phenotypes seen on the 129 background were reduced or absent when the mutation was placed on the B6 background, including hyperserotonemia, 5-HT receptor hypersensivity, and repetitive behavior. CONCLUSIONS: Our findings provide a cogent example of how epistatic interactions can modulate the impact of functional genetic variation and suggest that some aspects of social behavior may be especially sensitive to changes in SERT function. Finally, these results provide a platform for the identification of genes that may modulate the risk of ASD in humans.
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Recent interest in carbon-neutral biofuels has revived interest in co-digestion for methane generation. At wastewater treatment facilities, organic wastes may be co-digested with sludge using established anaerobic digesters. However, changes to organic loadings may induce digester instability, particularly for thermophilic digesters. To examine this problem, thermophilic (55 degrees C) co-digestion was studied for two food-industry wastes in semi-continuous laboratory digesters; in addition, the wastes' biochemical methane potentials were tested. Wastes with high chemical oxygen demand (COD) content were selected as feedstocks allowing increased input of potential energy to reactors without substantially altering volumetric loadings. Methane generation increased while reactor pH and volatile solids remained stable. Lag periods observed prior to methane stimulation suggested that acclimation of the microbial community may be critical to performance during co-digestion. Chemical oxygen demand mass balances in the experimental and control reactors indicated that all of the food industry waste COD was converted to methane.
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Biocombustíveis/análise , Reatores Biológicos , Resíduos de Alimentos , Metano/análise , Esgotos , Indústria Alimentícia , Resíduos IndustriaisRESUMO
To identify potentially novel and essential components of plant membrane trafficking mechanisms we performed a GFP-based forward genetic screen for seedling-lethal biosynthetic membrane trafficking mutants in Arabidopsis thaliana. Amongst these mutants, four recessive alleles of GSH2, which encodes glutathione synthase (GSH2), were recovered. Each allele was characterized by loss of the typical polygonal endoplasmic reticulum (ER) network and the accumulation of swollen ER-derived bodies which accumulated a soluble secretory marker. Since GSH2 is responsible for converting γ-glutamylcysteine (γ-EC) to glutathione (GSH) in the glutathione biosynthesis pathway, gsh2 mutants exhibited γ-EC hyperaccumulation and GSH deficiency. Redox-sensitive GFP revealed that gsh2 seedlings maintained redox poise in the cytoplasm but were more sensitive to oxidative challenge. Genetic and pharmacological evidence indicated that γ-EC accumulation rather than GSH deficiency was responsible for the perturbation of ER morphology. Use of soluble and membrane-bound ER markers suggested that the swollen ER bodies were derived from ER fusiform bodies. Despite the gross perturbation of ER morphology, gsh2 seedlings did not suffer from constitutive oxidative ER stress or lack of an unfolded protein response, and homozygotes for the weakest allele could be propagated. The link between glutathione biosynthesis and ER morphology and function is discussed.
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Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Retículo Endoplasmático/ultraestrutura , Glutationa/biossíntese , Via Secretória , Resposta a Proteínas não Dobradas , Sequência de Aminoácidos , Arabidopsis/genética , Arabidopsis/ultraestrutura , Proteínas de Arabidopsis/genética , Dipeptídeos/metabolismo , Retículo Endoplasmático/metabolismo , Loci Gênicos , Glutationa/genética , Glutationa Sintase/genética , Glutationa Sintase/metabolismo , Proteínas de Fluorescência Verde , Hipocótilo/genética , Hipocótilo/metabolismo , Hipocótilo/ultraestrutura , Dados de Sequência Molecular , Mutação , Oxirredução , Estresse Oxidativo , Fenótipo , Epiderme Vegetal/genética , Epiderme Vegetal/metabolismo , Epiderme Vegetal/ultraestrutura , Raízes de Plantas/genética , Raízes de Plantas/metabolismo , Raízes de Plantas/ultraestrutura , Estrutura Terciária de Proteína , Plântula/genética , Plântula/metabolismo , Plântula/ultraestrutura , Alinhamento de Sequência , Compostos de Sulfidrila/análise , Compostos de Sulfidrila/metabolismoRESUMO
Fifty years ago, increased whole-blood serotonin levels, or hyperserotonemia, first linked disrupted 5-HT homeostasis to Autism Spectrum Disorders (ASDs). The 5-HT transporter (SERT) gene (SLC6A4) has been associated with whole blood 5-HT levels and ASD susceptibility. Previously, we identified multiple gain-of-function SERT coding variants in children with ASD. Here we establish that transgenic mice expressing the most common of these variants, SERT Ala56, exhibit elevated, p38 MAPK-dependent transporter phosphorylation, enhanced 5-HT clearance rates and hyperserotonemia. These effects are accompanied by altered basal firing of raphe 5-HT neurons, as well as 5HT(1A) and 5HT(2A) receptor hypersensitivity. Strikingly, SERT Ala56 mice display alterations in social function, communication, and repetitive behavior. Our efforts provide strong support for the hypothesis that altered 5-HT homeostasis can impact risk for ASD traits and provide a model with construct and face validity that can support further analysis of ASD mechanisms and potentially novel treatments.
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Transtorno Autístico/genética , Receptores de Serotonina/fisiologia , Serotonina/sangue , Comportamento Social , Comportamento Estereotipado , Animais , Transtorno Autístico/sangue , Transtorno Autístico/fisiopatologia , Modelos Animais de Doenças , Homeostase , CamundongosRESUMO
Elevated whole blood serotonin 5-HT, or hyperserotonemia, is a common biomarker in autism spectrum disorder (ASD). The integrin ß3 receptor subunit gene (ITGB3) is a quantitative trait locus for whole blood 5-HT levels. Recent work shows that integrin ß3 interacts with the serotonin transporter (SERT) in both platelets and in the midbrain. Furthermore, multiple studies have now reported gene-gene interaction between the integrin ß3 and SERT genes in association with ASD. Given the lack of previous data on the impact of integrin ß3 on brain or behavioral phenotypes, we sought to compare mice with decreased or absent expression of the integrin ß3 receptor subunit (Itgb3 +/- and -/-) with wildtype littermate controls in behavioral tasks relevant to ASD. These mice did not show deficits in activity level in the open field or anxiety-like behavior on the elevated plus maze, two potential confounds in the evaluation of mouse social behavior. In the three-chamber social test, mice lacking integrin ß3 were shown to have normal sociability but did not show a preference for social novelty. Importantly, the absence of integrin ß3 did not impair olfaction or the ability to recall familiar social odors. Additionally, mice lacking integrin ß3 showed increased grooming behavior in novel environments. These preliminary studies reveal altered social and repetitive behavior in these mice, which suggests that the integrin ß3 subunit may be involved in brain systems relevant to ASD. Further work is needed to fully characterize these behavioral changes and the underlying brain mechanisms.