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L’Empire romain atteint à la fin de la République une étendue géographique qui englobe des aires culturelles très diverses, ce qui a une influence sur la typologie et les fonctions des maisons dans les différentes régions de la Méditerranée. Dans l’impossibilité de pouvoir donner une vue d’ensemble et laissant de côté pour cette même raison les provinces occidentales de l’Afrique du Nord et du Levant, nous allons évoquer, après un regard sur la description de la maison urbaine chez Vitruve, quelques exemples de Pompéi pour nous concentrer par la suite sur quelques maisons dans les provinces orientales, en particulier en Grèce et en Asie Mineure, pour mesurer l’influence ou non des Romains dans l’architecture privée. Il s’avère que cette dernière est bien restreinte, et que l’intégration de l’atrium est plutôt une référence qu’un élément structurel des maisons dont le péristyle reste l’élément central. L’étude est complétée par un excursus sur plusieurs maisons de l’Antiquité tardive à Athènes.

Prior work has identified a variety of factors that drive the way people identify and respond to misinformation. Such factors include confirmation bias, perceived credibility of the information source, individual media literacy, social norms, and others. This paper reviews the interventions designed to address misinformation and examines how various underlying mechanisms of response to misinformation are operationalized and implemented in the reviewed interventions. Key findings show that most prior work to address misinformation heavily focuses on individual pieces of misinformation and the actions individuals take in response to those individual pieces. These individualistic approaches, we argue, overlook the other drivers of responses to misinformation, such as individuals' prior beliefs and the social contexts in which misinformation is encountered. Additionally, the analysis shows that an individualistic focus on misinformation draws attention away from the systemic nature and consequences of misinformation. This paper argues that to overcome the limitation of individualistic approaches to addressing misinformation, future interventions need to expand their scope beyond individualistic approaches. As one way to do so, it discusses leveraging the impacts of community factors that impact the spread and impacts of misinformation. The paper concludes by using social norms as an example to illustrate how a focus on community factors might work in practice.

As AI-mediated communication (AI-MC) becomes more prevalent in everyday interactions, it becomes increasingly important to develop a rigorous understanding of its effects on interpersonal relationships and on society at large. Controlled experimental studies offer a key means of developing such an understanding, but various complexities make it difficult for experimental AI-MC research to simultaneously achieve the criteria of experimental realism, experimental control, and scalability. After outlining these methodological challenges, this paper offers the concept of methodological middle spaces as a means to address these challenges. This concept suggests that the key to simultaneously achieving all three of these criteria is to abandon the perfect attainment of any single criterion. This concept's utility is demonstrated via its use to guide the design of a platform for conducting text-based AI-MC experiments. Through a series of three example studies, the paper illustrates how the concept of methodological middle spaces can inform the design of specific experimental methods. Doing so enabled these studies to examine research questions that would have been either difficult or impossible to investigate using existing approaches. The paper concludes by describing how future research could similarly apply the concept of methodological middle spaces to expand methodological possibilities for AI-MC research in ways that enable contributions not currently possible.

While it is well known from numerous epidemiologic investigations that social determinants (socioeconomic, environmental, and psychosocial factors exposed to over the life-course) can dramatically impact cardiovascular health, the molecular mechanisms by which social determinants lead to poor cardiometabolic outcomes are not well understood. This review comprehensively summarizes a variety of current topics surrounding the biological effects of adverse social determinants (i.e., the biology of adversity), linking translational and laboratory studies with epidemiologic findings. With a strong focus on the biological effects of chronic stress, we highlight an array of studies on molecular and immunological signaling in the context of social determinants of health (SDoH). The main topics covered include biomarkers of sympathetic nervous system and hypothalamic–pituitary–adrenal axis activation, and the role of inflammation in the biology of adversity focusing on glucocorticoid resistance and key inflammatory cytokines linked to psychosocial and environmental stressors (PSES). We then further discuss the effect of SDoH on immune cell distribution and characterization by subset, receptor expression, and function. Lastly, we describe epigenetic regulation of the chronic stress response and effects of SDoH on telomere length and aging. Ultimately, we highlight critical knowledge gaps for future research as we strive to develop more targeted interventions that account for SDoH to improve cardiometabolic health for at-risk, vulnerable populations.

An easy to handle high-efficient approach to 5-polyfluoroalkyl-1,2,4-triazole-3-thiones (11 examples, up to 91% yield) is reported. The tautomerism of thione and thiol forms for the obtained products is discussed. A one step procedure for 6,6-dimethyl-3-(trifluoromethyl)-5,6-dihydro[1,3]thiazolo[2,3-c][1,2,4]triazole formation from trifluoroacetic acid and 4-methallylthiosemicarbazide has been developed. The structures of the products were unambiguously determined by complex NMR investigation and by single crystal X-ray diffraction.

Individuals with Down syndrome (DS) are at increased risk for being overweight/obese, but the associated cardiometabolic risk (CR) is not clear. Cross-sectional anthropometric and clinical laboratory data from a multi-site, international cohort of individuals with DS were analyzed to determine cardiometabolic risk by reporting observed distributions of cardiometabolic biomarkers in overweight/obese individuals with DS throughout the lifespan. Descriptive statistics and regression analyses by age categories determined the distributive percentiles for cardiometabolic biomarkers and tested for adiposity as a predictor of CR. Across seven DS clinics, data were collected on 240 patients between the ages of 3 and 63 years, with one quarter overweight and three quarters obese among children and nearly all adults being obese. In children and adults, most cardiometabolic biomarker profiles showed distributive values within normal ranges. Blood lipids were positively associated with body mass index (BMI) in children (high density lipid-cholesterol, p = 0.01; low density lipid-cholesterol, p = 0.02). Levels of hs-CRP were elevated in both children and adults, with BMI positively associated with hs-CRP in adults with DS (p = 0.04). Liver enzyme values were positively associated with BMI in children and adults. The data suggest that in contrast to the general population, in individuals with Down syndrome, being overweight and obese does not appear to confer a significantly increased risk for cardiometabolic disease by biomarker profile. Individuals with DS who are overweight/obese appear to have unique cardiometabolic profiles unrelated to adiposity, notable for increased hs-CRP and normal HA1c levels.

O presente artigo tem como tema "o trabalho dos estagiários das licenciaturas no processo de inclusão dos alunos com transtorno do espectro autista (TEA) no ensino regular da rede municipal de Criciúma/SC.". Tem como objetivo compreender quais as dificuldades encontradas pelos estagiários, entendendo o trabalho dos estagiários no estágio não obrigatório. A natureza é básica, sendo exploratória e qualitativa por meio de uma pesquisa de campo. A coleta de dados foi realizada a partir de um questionário com acadêmicos das licenciaturas da UNESC. Com os relatos apresentados pode-se perceber os desafios que eles encontram, muitas vezes por falta de conhecimento sobre a criança com autismo e a falta de orientação/formação, sendo que sua participação na inclusão do aluno com TEA é de extrema importância, pois é necessário que este aluno tenha consigo alguém que o acompanhe durante seu período de aprendizagem. A inclusão do aluno com autismo é prevista por leis, por isso é essencial que sua permanência seja garantida. O estudo revelou que é relevante que os estagiários recebam algum tipo de suporte e ajuda de profissionais qualificados que farão com que o trabalho seja realizado com confiança e sabedoria, pois todo esse aprendizado irá refletir na vida tanto dos alunos com TEA que estão ali para receber este acompanhamento quanto na do próprio estagiário, sendo que este período irá acrescentar em sua carreira, pois sabe-se que a criança com autismo precisa principalmente do apoio dos pais e uma boa educação, esta que é uma das exigências do acompanhamento. PALAVRAS-CHAVE: Inclusão. Estagiário. TEA. Ensino regular.

Research to guide clinicians in the management of the devastating regression which can affect adolescents and young adults with Down syndrome is limited. A multi-site, international, longitudinal cohort of individuals with a clinical diagnosis of Unexplained Regression in Down syndrome (URDS) was collated through seven Down syndrome clinics. Tiered medical evaluation, a 28-item core symptom list, and interim management are described naturalistically. Improvement-defined by the percentage of baseline function on a Parent-reported Functional Score, overall improvement in symptoms on a Clinician-administered Functional Assessment, or report of management type being associated with improvement-was analyzed. Improvement rates using ECT, IVIG, and others were compared. Across seven clinics, 51 patients with URDS had regression at age 17.6 years, on average, and showed an average 14.1 out of 28 symptoms. Longitudinal improvement in function was achieved in many patients and the medical management, types of treatment, and their impact on function are described. Management with intravenous immunoglobulin (IVIG) was significantly associated with higher rate of improvement in symptoms at the next visit (p = 0.001). Our longitudinal data demonstrates that URDS is treatable, with various forms of clinical management and has a variable course. The data suggests that IVIG may be an effective treatment in some individuals. Our description of the management approaches used in this cohort lays the groundwork for future research, such as development of standardized objective outcome measure and creation of a clinical practice guideline for URDS.

The worldwide prevalence of hypertension continues to rise, shortening lifespan and contributing to the risk of cardiovascular disease and stroke. Although there are numerous contributing risk factors, social adversity is believed to be one that may account, in part, for disparities in rates and treatment outcomes. We have recently begun to evaluate whether chronic social defeat stress (CSDS) can effectively model aspects of stress-induced cardiovascular disease. Adult male C57BL/6J mice were implanted with telemetry devices that recorded blood pressure, heart rate, core body temperature, and activity. Male CD1 mice were used to defeat C57BL/6J mice 1h before the onset of the dark cycle. Immediately following submission, the defeated mouse was housed in the same cage as the aggressor, physically separated by a perforated divider that allows for continuous visual, auditory, and olfactory contact. The C57BL/6J mouse was defeated and housed with a different CD1 mouse each day, to reduce the likelihood of habituation. Initial social defeat resulted in significant increases in blood pressure, activity, and temperature in comparison with control mice. Interestingly, while blood pressure returned to basal levels by the start of the light cycle for the first few days of defeat, chronic social defeat resulted in sustained elevations in blood pressure, lower activity and lower body temperature. Mice exposed to CSDS also exhibited anxiety-like behaviors, spending significantly more time in the closed arms of the elevated plus maze and less time in the center of an open field arena. At the end of the experiment, flow cytometry was performed on spleen and lung tissue from a subset of mice. Splenomegaly was observed in CSDS mice, with an increase in CD11b and monocytic and polymorphonuclear myeloid-derived suppressor cells (M-MDSCs and PMN-MDSCs), consistent with chronic inflammation. There were significant increases in PMN-MDSCs isolated from lung, a strong predictor of pulmonary hypertension, as well as enhanced immunosuppressive capability of MDSCs which is associated with the severity of disease. CSDS also resulted in increases in body, heart and adrenal weights and fluid retention. These data suggest that CSDS may be useful for modeling aspects of hypertension and immune dysfunction induced by chronic social stress, thereby enabling us to better understand the mechanisms that contribute to cardiovascular disease. R35HL150750 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Parallel career tracks have become more prevalent today, especially in Brazil, where more than a quarter of all postgrads have one. Despite its growing popularity, little research has tapped into this new career phenomenon. This study examines whether having a parallel career track leads to negative work outcomes related to sustainable careers, such as higher absenteeism and lower engagement, in comparison to a single career track. Cross-sectional and longitudinal data were gathered from 380 and 102 Brazilian professionals respectively, who filled out an online survey. A normal and a repeated-measures multivariate analysis of variance were used to examine whether work outcomes differed between those with parallel career tracks versus single career tracks. The findings indicate that parallel career tracks do not have different effects on individual sustainable employability outcomes when compared to single career tracks, including employability, engagement, absenteeism, presenteeism, and burnout. Therefore, organizations can face this new career trend without reluctance as it does not harm individual work outcomes related to sustainable careers. This study contributes significantly to improving the understanding of this new career format by examining the impact of parallel career tracks on individual work outcomes through a longitudinal design.

BACKGROUND: In the United States, African Americans (AAs) have greater risk for Class III obesity and cardiovascular disease (CVD). Previous reports suggest that AAs have a different immune cell profile when compared to Caucasians. METHODS: The immune cell profile of AAs was characterized by flow cytometry using two experimental setups: ex vivo (N=40) and in vitro (N=10). For ex vivo experiments, PBMC were treated with participant serum to understand how lipid contents may contribute to monocyte phenotypic differences. For in vitro experiments, monocytes were low-density lipoprotein (LDL)- or vehicle-treated for four hours and subsequently analyzed by flow cytometry and RT-qPCR. RESULTS: When PBMCs were treated with participant sera, subsequent multivariable regression analysis revealed that serum triglycerides and LDL levels were associated with monocyte subset differences. In vitro LDL treatment of monocytes induced a phenotypic switch in monocytes away from classical monocytes accompanied by subset-specific chemokine receptor CCR2 and CCR5 expression changes. These observed changes are partially translation-dependent as determined by co-incubation with cycloheximide. CONCLUSIONS: LDL treatment of monocytes induces a change in monocyte subsets and increases CCR2/CCR5 expression in a subset-specific manner. Understanding the molecular mechanisms could prove to have CVD-related therapeutic benefits, especially in high-risk populations with hyperlipidemia and increased risk for CVD.

A polymorphic transition as a result of grinding was found for 3-[1-(tert-butoxycarbonyl)azetidin-3-yl]-1,2-oxazole-4-carboxylic acid. The thorough study of polymorphic structures before and after crystal structure transformation has revealed some pre-conditions for a polymorphic transition and regularities of changes in molecular and crystal structure. In metastable polymorph 1a, the conformationally flexible molecule adopts a conformation with the higher energy and forms a less preferable linear supramolecular synthon. Additional energy imparted to a crystal structure during the grinding process proved to be enough to overcome low energy barriers for the nitrogen inversion and rotation of the oxazole ring around the sp 3–sp 2 single bond. As a result, polymorph 1b with a molecule adopting conformation with lower energy and forming a more preferable centrosymmetric supramolecular synthon was obtained. The study of pairwise interaction energies in the two polymorphs has shown that metastable polymorph 1a is organized by molecular building units and has a columnar-layered structure. A centrosymmetric dimer should be recognized as a complex building unit in more stable polymorph 1b, which has a layered structure.

The distributional extent of Pacific salmon (Oncorhynchus spp.) in the North American Arctic is unresolved. While adult Pacific salmon have a recurring presence across the Alaskan North Slope and into the Canadian Arctic, it is uncertain if these fish are part of established Arctic populations, vagrants from outside sources reproducing unsuccessfully, or both. Here we present the first confirmed record of a juvenile chum salmon (Oncorhynchus keta) captured in the nearshore marine ecosystem in the North American Arctic. This provides the first scientific evidence of successful spawning and early marine survival of Pacific salmon in the North American Arctic. It was caught near Kaktovik, Alaska, in August 2017 with a group of similarly sized age-0 Mackenzie River Arctic cisco (Coregonus autumnalis). Stable isotope and otolith microchemistry analyses are consistent with use of the nearshore estuarine corridor from the Mackenzie River west along the northern coast. This contributes critical information needed to identify, manage, and conserve biodiversity at the northern range edge and will help to clarify the status of Pacific salmon as potentially emerging fisheries develop in the North American Arctic due to climate warming.

The hemihydrate of 4-[(benzylamino)carbonyl]-1-methylpyridinium bromide, C14H15N2O+·Br−·0.5H2O, was studied by single-crystal and powder X-ray diffraction methods. In the asymmetric unit, two organic cations of similar conformation, two bromide anions and one water molecule are present. In the crystal, N—H...Br hydrogen bonds link the cations and anions. The formation of a set of intermolecular C—H...Br and C—H...π interactions result in double chains extending parallel to [011]. A Hirshfeld surface analysis showed high contributions of H...H and C...H/H...C short contacts to the total Hirshfeld surfaces of the cations.

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Social determinants of health (SDoH), which encompass the economic, social, environmental, and psychosocial factors that influence health, play a significant role in the development of cardiovascular disease (CVD) risk factors as well as CVD morbidity and mortality. The COVID-19 pandemic and the current social justice movement sparked by the death of George Floyd have laid bare long-existing health inequities in our society driven by SDoH. Despite a recent focus on these structural drivers of health disparities, the impact of SDoH on cardiovascular health and CVD outcomes remains understudied and incompletely understood. To further investigate the mechanisms connecting SDoH and CVD, and ultimately design targeted and effective interventions, it is important to foster interdisciplinary efforts that incorporate translational, epidemiological, and clinical research in examining SDoH-CVD relationships. This review aims to facilitate research coordination and intervention development by providing an evidence-based framework for SDoH rooted in the lived experiences of marginalized populations. Our framework highlights critical structural/socioeconomic, environmental, and psychosocial factors most strongly associated with CVD and explores several of the underlying biologic mechanisms connecting SDoH to CVD pathogenesis, including excess stress hormones, inflammation, immune cell function, and cellular aging. We present landmark studies and recent findings about SDoH in our framework, with careful consideration of the constructs and measures utilized. Finally, we provide a roadmap for future SDoH research focused on individual, clinical, and policy approaches directed towards developing multilevel community-engaged interventions to promote cardiovascular health.

In the paper, synthesis process of the TiO2 particles was discussed, from the fluoride solution, through TiO2·nH2O gel thermal precipitation and decomposition, and its impact on the further sintering of the obtained powders. It was demonstrated that the main phase of the obtained titania was anatase. Morphology of the obtained TiO2 can be controlled through variations of the precipitation temperature and the emulsifier concentration. It was found that the addition of the chloride ions during gel formation caused crystallization of the (NH4)2TiOF4 phase. When it underwent decomposition under heating, agglomerated particles in form of rods several micrometers long were synthesized. Obtained powders were sintered, and both the sintering process and the final bulk structures were examined. The results indicated the lowest microhardness of 540 kg/mm2 in the specimens prepared out of the powders synthesized without emulsifier, while the highest hardness of 1450 kg/mm2 was reached when the TiO2 particles had been precipitated at room temperature with emulsifier proportion С(Ti):C(OР9) = 1:0.5. However, further increase of the emulsifier concentration led to the decrease of hardness.

Protocols for the construction of large, deeply mutagenized protein encoding libraries via Golden Gate assembly of synthetic DNA cassettes employ disparate, system specific methodology. Here we benchmark a broadly applicable Golden Gate method for building user-defined libraries. We demonstrate that a 25 μl reaction, using 40 fmol of input DNA, can generate a library on the order of 1×106members and that reaction volume or input DNA concentration can be scaled up with no losses in transformation efficiency. Such libraries can be constructed from dsDNA cassettes generated either by degenerate oligonucleotides or oligo pools. We demonstrate its real-world effectiveness by building custom, user-defined libraries on the order of 104to 107unique protein encoding variants for two orthogonal protein engineering systems. We include a detailed protocol and provide several general-use destination vectors.

Pathogenic heterozygous variants in SCN2A, which encodes the neuronal sodium channel Na(V)1.2, cause different types of epilepsy or intellectual disability (ID)/autism without seizures. Previous studies using mouse models or heterologous systems suggest that Na(V)1.2 channel gain-of-function typically causes epilepsy, whereas loss-of-function leads to ID/autism. How altered channel biophysics translate into patient neurons remains unknown. Here, we investigated iPSC-derived early-stage cortical neurons from ID patients harboring diverse pathogenic SCN2A variants [p.(Leu611Valfs*35); p.(Arg937Cys); p.(Trp1716*)] and compared them with neurons from an epileptic encephalopathy (EE) patient [p.(Glu1803Gly)] and controls. ID neurons consistently expressed lower Na(V)1.2 protein levels. In neurons with the frameshift variant, Na(V)1.2 mRNA and protein levels were reduced by similar to 50%, suggesting nonsense-mediated decay and haploinsufficiency. In other ID neurons, only protein levels were reduced implying Na(V)1.2 instability. Electrophysiological analysis revealed decreased sodium current density and impaired action potential (AP) firing in ID neurons, consistent with reduced Na(V)1.2 levels. In contrast, epilepsy neurons displayed no change in Na(V)1.2 levels or sodium current density, but impaired sodium channel inactivation. Single-cell transcriptomics identified dysregulation of distinct molecular pathways including inhibition of oxidative phosphorylation in neurons with SCN2A haploinsufficiency and activation of calcium signaling and neurotransmission in epilepsy neurons. Together, our patient iPSC-derived neurons reveal characteristic sodium channel dysfunction consistent with biophysical changes previously observed in heterologous systems. Additionally, our model links the channel dysfunction in ID to reduced Na(V)1.2 levels and uncovers impaired AP firing in early-stage neurons. The altered molecular pathways may reflect a homeostatic response to Na(V)1.2 dysfunction and can guide further investigations., Human Molecular Genetics, 32 (13), ISSN:0964-6906, ISSN:1460-2083

Supplementary Figures 1-7 from p18Ink4c and p53 Act as Tumor Suppressors in Cyclin D1–Driven Primitive Neuroectodermal Tumor

Ewing's sarcoma family tumors (ESFT) express the EWS-FLI-1 fusion gene generated by the chromosomal translocation t(11;22)(q24;q12). Expression of the EWS-FLI-1 fusion protein in a permissive cellular environment is believed to play a key role in ESFT pathogenesis. However, EWS-FLI-1 induces growth arrest or apoptosis in differentiated primary cells, and the identity of permissive primary human cells that can support its expression and function has until now remained elusive. Here we show that expression of EWS-FLI-1 in human mesenchymal stem cells (hMSC) is not only stably maintained without inhibiting proliferation but also induces a gene expression profile bearing striking similarity to that of ESFT, including genes that are among the highest ESFT discriminators. Expression of EWS-FLI-1 in hMSCs may recapitulate the initial steps of Ewing's sarcoma development, allowing identification of genes that play an important role early in its pathogenesis. Among relevant candidate transcripts induced by EWS-FLI-1 in hMSCs, we found the polycomb group gene EZH2, which we show to play a critical role in Ewing's sarcoma growth. These observations are consistent with our recent findings using mouse mesenchymal progenitor cells and provide compelling evidence that hMSCs are candidate cells of origin of ESFT. [Cancer Res 2008;68(7):2176–85]

Supplementary Data 3 from Expression of the FUS-CHOP Fusion Protein in Primary Mesenchymal Progenitor Cells Gives Rise to a Model of Myxoid Liposarcoma

Supplementary Data 2 from EZH2 Is Essential for Glioblastoma Cancer Stem Cell Maintenance

Supplementary Data 1 from Expression of the FUS-CHOP Fusion Protein in Primary Mesenchymal Progenitor Cells Gives Rise to a Model of Myxoid Liposarcoma

Supplementary Data 1 from EWS-FLI-1 Expression Triggers a Ewing's Sarcoma Initiation Program in Primary Human Mesenchymal Stem Cells

A subset of sarcomas is associated with specific chromosomal translocations that give rise to fusion genes believed to participate in transformation and oncogenesis. Identification of the primary cell environment that provides permissiveness for the oncogenic potential of these fusion genes is essential to understand sarcoma pathogenesis. We have recently shown that expression of the EWS-FLI-1 fusion protein in primary mesenchymal progenitor cells (MPCs) suffices to develop Ewing's sarcoma-like tumors in mice. Because most sarcomas bearing unique chromosomal translocations are believed to originate from common progenitor cells, and because MPCs populate most organs, we expressed the sarcoma-associated fusion proteins FUS/TLS-CHOP, EWS-ATF1, and SYT-SSX1 in MPCs and tested the tumorigenic potential of these cells in vivo. Whereas expression of EWS-ATF1 and SYT-SSX1 failed to transform MPCs, FUS-CHOP–expressing cells formed tumors resembling human myxoid liposarcoma. Transcription profile analysis of these tumors revealed induction of transcripts known to be associated with myxoid liposarcoma and novel candidate genes, including PDGFA, whose expression was confirmed in human tumor samples. MPCFUS-CHOP and the previously described MPCEWS-FLI-1 tumors displayed distinct transcription profiles, consistent with the different target gene repertoires of their respective fusion proteins. Unexpectedly, a set of genes implicated in cell survival and adhesion displayed similar behavior in the two tumors, suggesting events that may be common to primary MPC transformation. Taken together, our observations suggest that expression of FUS-CHOP may be the initiating event in myxoid liposarcoma pathogenesis, and that MPCs may constitute one cell type from which these tumors originate. (Cancer Res 2006; 66(14): 7016-23)

Supplementary Data 2 from Expression of the FUS-CHOP Fusion Protein in Primary Mesenchymal Progenitor Cells Gives Rise to a Model of Myxoid Liposarcoma

Supplementary Data 3 from EWS-FLI-1 Expression Triggers a Ewing's Sarcoma Initiation Program in Primary Human Mesenchymal Stem Cells

Overexpression of the polycomb group protein enhancer of zeste homologue 2 (EZH2) occurs in diverse malignancies, including prostate cancer, breast cancer, and glioblastoma multiforme (GBM). Based on its ability to modulate transcription of key genes implicated in cell cycle control, DNA repair, and cell differentiation, EZH2 is believed to play a crucial role in tissue-specific stem cell maintenance and tumor development. Here, we show that targeted pharmacologic disruption of EZH2 by the S-adenosylhomocysteine hydrolase inhibitor 3-deazaneplanocin A (DZNep), or its specific downregulation by short hairpin RNA (shRNA), strongly impairs GBM cancer stem cell (CSC) self-renewal in vitro and tumor-initiating capacity in vivo. Using genome-wide expression analysis of DZNep-treated GBM CSCs, we found the expression of c-myc, recently reported to be essential for GBM CSCs, to be strongly repressed upon EZH2 depletion. Specific shRNA-mediated downregulation of EZH2 in combination with chromatin immunoprecipitation experiments revealed that c-myc is a direct target of EZH2 in GBM CSCs. Taken together, our observations provide evidence that direct transcriptional regulation of c-myc by EZH2 may constitute a novel mechanism underlying GBM CSC maintenance and suggest that EZH2 may be a valuable new therapeutic target for GBM management. [Cancer Res 2009;69(24):9211–8]

Supplementary Data Legends 1-3 from EWS-FLI-1 Expression Triggers a Ewing's Sarcoma Initiation Program in Primary Human Mesenchymal Stem Cells

Background Down syndrome (DS) is one of the most common genetic causes of intellectual disability, and it is associated with an increased incidence of numerous co-occurring conditions. Autism spectrum disorder (ASD) is common in persons with DS, with rates reported as high as 39%. However, little is known regarding co-occurring conditions in children with both DS and ASD. Methods A single-center retrospective review of prospective longitudinally collected clinical data was performed. Any patient with a confirmed diagnosis of DS evaluated at a large, specialized Down Syndrome Program in a tertiary pediatric medical center between March 2018 and March 2022 was included. A standardized survey which included demographic and clinical questions was administered during each clinical evaluation. Results In total, 562 individuals with DS were included. The median age was 10 years (IQR: 6.18–13.92). Of this group, 72 (13%) had a co-occurring diagnosis of ASD (DS+ASD). Individuals with DS+ASD were more likely to be male (OR 2.23, CI 1.29–3.84) and had higher odds of a current or prior diagnosis of constipation (OR 2.19, CI 1.31–3.65), gastroesophageal reflux (OR 1.91, CI 1.14–3.21), behavioral feeding difficulties (OR 2.71, CI 1.02–7.19), infantile spasms (OR 6.03, CI 1.79–20.34) and scoliosis (OR 2.73, CI 1.16–6.40). There were lower odds of congenital heart disease in the DS+ASD group (OR 0.56, CI 0.34–0.93). There was no observed difference in prematurity or Neonatal Intensive Care Unit complications between groups. Individuals with DS+ASD had similar odds of having a history of congenital heart defect requiring surgery to those with DS only. Furthermore, there was no difference in rates of autoimmune thyroiditis or celiac disease. There was also no difference in rates of diagnosed co-occurring neurodevelopmental or mental health conditions in this cohort, including anxiety disorders and attention-deficit/hyperactivity disorder. Conclusions This study identifies a variety of medical conditions which are more frequent in children with DS+ASD than DS alone, providing important information for the clinical management of these patients. Future research should investigate the role of some of these medical conditions in the development of ASD phenotypes, and whether there may be distinct genetic and metabolic contributions towards these conditions.

Introduction: Chronic psychosocial stressors are associated with inflammation and cardiovascular (CV) risk, including insulin resistance (IR); however, potential DNA methylation (DNAm) mediators between stress-related inflammation and IR are not known. Hypothesis: DNAm biomarkers mediate the relationship between stress-related inflammation and IR. Methods: Participants from the DC Cardiovascular Health and Needs Assessment (DC-CHNA) underwent phenotyping at the NIH Clinical Center. Homeostatic Model Assessment for Insulin Resistance was calculated using insulin and glucose values. Social isolation, loneliness, and depression were determined using validated surveys. IL-8 was measured using an ELISA-based method. Principal component DNAm-based surrogate markers of leptin, cystatin C, and plasminogen activator inhibitor-1 were calculated from DNAm data obtained from participants' buffy coat samples. We examined relationships of interest with regression models adjusted for atherosclerotic cardiovascular disease (ASCVD) risk score and body mass index (BMI). Mediation analysis was used to evaluate DNAm measures as possible mediators. Results: The DC-CHNA consisted of 60 African American participants (mean age 61±11 years, 93% female) with ASCVD risk. Social isolation (β=0.34, p=0.009) and depression (β=0.30, p=0.04) associated with IL-8. IL-8 then inversely associated with DNAm-based surrogate leptin levels and directly associated with IR; leptin DNAm mediated the IL-8-IR relationship ( Figure ). Conclusions: We show a relationship between stress-associated IL-8 and IR mediated by DNAm-based surrogate leptin levels. While relationships between inflammation, serum leptin, and IR are documented, the impact of chronic stress on leptin DNAm in the context of CV risk requires further investigation in larger, diverse cohorts. DNAm-based surrogate markers of plasma proteins, such as leptin, could serve as a marker for increased CV risk in populations disproportionately exposed to chronic stress.