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Although predictive associations between childhood executive control (EC) and adolescent substance use have been established in prior research, the developmental pathways involved in these long-term links have not been well understood. The goal of the current study was to investigate the degree to which aggressive behaviors, including both physical and relational aggression, and prosocial behaviors in elementary school operate as developmental pathways between preschool EC and adolescent substance use, while accounting for participants' age, sex, family history of substance use, and family socioeconomic status. Participants were 329 youth (49% male; 63.6% European American) who were recruited to participate in a study between 2006 and 2012 while youth were in preschool and elementary school and followed into adolescence. The sample was recruited from a small Midwestern city in the United States. EC was assessed with performance-based tasks when children were 5 years 3 months. Youth behaviors with peers were reported by teachers when participants were in elementary school. Self-reports of the substance use initiation (e-cigarettes, cigarettes, alcohol, and marijuana) were obtained in adolescence via phone surveys. Mediation analyses revealed a statistically significant indirect effect from preschool EC to adolescent substance use through youth's engagement in relational aggression in elementary school (

Child psychiatry access programs (CPAPs) provide primary care providers (PCPs) with assistance in mental health diagnosis, management, and resource navigation.Data collected from DC Mental Health Access in Pediatrics (MAP) included PCPs and patient demographics, clinical encounter information, and provider satisfaction.DC MAP consult volume increased 349.3% over the first 5 years. Services requested included care coordination (85.8%), psychiatric consultation (21.4%), and psychology/social work consultation (9.9%). Of psychiatry-involved consultations, PCPs managed patient medication care with DC MAP support 50.5% of the time. Most (94.1%) PCPs said they would recommend colleagues use DC MAP, and 29.6% reported diverting patients from the emergency departments using DC MAP.DC MAP grew quickly, highlighting program impact and need. Demand for care coordination required flexible staffing and highlighted the need for coordination in pediatrics. Child psychiatry access programs offer an innovative way to enhance PCP management of their patients' mental health needs.

Pd(ii) biladienes have been developed over the last five years as non-aromatic oligotetrapyrrole complexes that support a rich triplet photochemistry.

This article describes the current cooperation between Presença Karajá, aninterdisciplinary research project that maps and analyzes collections of Karajá dolls(ritxoko) in museum collections, and the GRASSI Museum for Ethnology in Leipzig,Germany, part of the Staatliche Kunstsammlungen Dresden (SKD). Together, theworking group analyzed the collection of ritxoko embedded in other Iny-Karajámaterials, gathered and documented by Dr. Fritz Krause (1881-1963) in 1908. Basedon Krause’s published works from his expedition, Iny-Karajá anthropological contributions, insights from Iny-Karajá representatives, and the ritxoko themselves, the working group investigated the provenance, ethnography, and anthropological data together, gathering valuable research results for the collection history as well asfor the Iny-Karajá themselves. Presença Karajá offered the Museum an opportunity to enhance the history of its collections as well as to support the goals of what the Museum calls “immaterial restitution”: strengthening Indigenous cultures and granting them greater sovereignty over their heritage.

Handheld ultrasound devices are increasingly used by clinicians for their ease of use and portability. Their utility for estimating right atrial pressure (RAP) is poorly described.This prospective study enrolled 50 consecutive patients presenting for outpatient right heart catheterization (RHC). A handheld ultrasound device was used to measure inferior vena cava size and collapsibility and estimate RAP to be 3, 8, or 15 mmHg according to American Society of Echocardiography recommendations for cardiac chamber quantification. Invasive pressure measurements were then performed using RHC. Spearman's correlation and linear regression analysis were used to evaluate the association between estimated RAP using ultrasound and invasive RAP.Fifty patients were enrolled (mean age 68 ± 8 years). Estimated RAP by ultrasound was significantly associated with invasive RAP (r 0.80; RHandheld ultrasonography is a useful tool that can accurately estimate RAP at the bedside.

Este artigo tem por objetivo introduzir os principais mecanismos que ensejaram o advento da antiarte e da poesia por outros meios ao longo das minhas atividades, pelo entendimento de que a sua pertinência pode se constituir num conjunto de ferramentas para o enfrentamento dos desafios do nosso tempo, permitindo que surjam possibilidades expressivas mais complexas e renovadoras.

Considering the social and ecological crises facing the planet, some may wonder if academia is an altogether useless enterprise, one irreparably fraught with colonial and extracting hierarchies; a project incapable of salvation. Skepticism over the coherence and usefulness of such categories as »religion« or »culture« and even the prospect of truly relevant knowledge production have been brought under harsh criticism by both the political right and left as »intellectually or ethically comprom...

Conventional navigation systems use visually perceptible landmarks to navigate their users from a starting point to a destination. However, sometimes visual information is not enough for route guidance. Visually-impaired or elderly people may not be able to navigate using the visual sense. Furthermore, there may exist no outstanding (i.e., salient) visual landmarks that could be used to navigate. In such a case auditory information may be a helpful guide. We performed two online studies and a focus-group interview to identify possible sound classes in an urban environment. Based on our results, we gathered sounds in Augsburg and classified them according to their source. The findings support our notion that auditory information can be useful for spatial orientation and guidance in addition to or even replacing visual information.

Esse artigo revisita repertórios audiovisuais que abordaram desigualdades sociais brasileiras nas últimas décadas com o intuito de discutir a coincidência entre processos de inclusão social e a diversificação dos mecanismos de produção e circulação de imagens em movimento que ocorre com a transformação digital, um processo global. No Brasil, a diversificação de meios estimula a articulação e a diversificação de vozes anteriormente inaudíveis, e invisíveis no espaço público. Rastreio objetos audiovisuais que estenderam a amplitude da democracia brasileira ao introduzir questões éticas e estéticas sobre como filmar a desigualdade e a discriminação de classe, cor e gênero sem contribuir para reforçar a discriminação. Esse debate mobiliza a crítica, mas se dá na forma fílmica, articula memórias pessoais, coletivas, e/ou ancestrais, produz arquivos, onde eles inexistem ou são inacessíveis e envolve a imaginação de futuros inclusivos. Em um panorama de interlocuções fílmicas, me concentro em Branco sai, preto fica (2014) e A cidade é uma só? (2011), ambos de Adirley Queirós. O resgate dessas contribuições audiovisuais é uma forma de contribuir para a construção de alternativas a discursos de ódio que ocupam circuitos privativos nas redes sociais e desses bunkers virtuais ameaçam as possibilidades de “viver junto”, como diria Barthes.

Este artículo revisa los repertorios audiovisuales que han abordado las desigualdades sociales brasileñas en las últimas décadas con el objetivo de discutir la coincidencia entre los procesos de inclusión social y la diversificación de los mecanismos de producción y circulación de imágenes en movimiento que se produce con la transformación digital, un proceso global. En Brasil, la diversificación de medios estimula la articulación y diversificación de voces antes inaudibles e invisibles en el espacio público. Rastreo objetos audiovisuales que han extendido la amplitud de la democracia brasileña introduciendo cuestiones éticas y estéticas sobre cómo filmar la desigualdad y la discriminación de clase, color y género sin contribuir a reforzar la discriminación. Este debate moviliza la crítica, pero se desarrolla en forma fílmica, articula memorias personales, colectivas y/o ancestrales, produce archivos donde no existen o son inaccesibles, e involucra la imaginación de futuros inclusivos. En un panorama de interlocuciones fílmicas, me centraré en Branco sai, preto fica (2014) y en A cidade é uma só? (2011), ambas de Adirley Queirós. El rescate de estos aportes audiovisuales es una forma de contribuir a la construcción de alternativas a los discursos de odio que ocupan circuitos privados en las redes sociales, y de esos búnkeres virtuales que amenazan las posibilidades de “convivencia”, como diría Barthes.

While large earthquakes have been documented in stable continental regions, such as the central United States, they occur too infrequently to provide reliable observations of earthquake-related impacts. Using the state of Indiana as a case study, we investigate the impacts of five deterministic scenarios—three occurring outside the borders of the state and two within the state. They include a M7.3 Wabash Valley event in southern Illinois, a M7.6 New Madrid event in southeastern Missouri, a M6.2 event in west central Ohio, a M6.2 event near Evansville, Indiana, and a M5.8 Indianapolis event. The locations and magnitudes are based on known fault locations and credible interpretations of the earthquake history in the region. We use a combination of the US Geological Survey’s ShakeMap and the Federal Emergency Management Agency’s (FEMA) Hazus software packages to assess earthquake-triggered ground shaking and its effects on the built environment. We also use the United States Geological Survey (USGS) Ground Failure estimation tool to examine the spatial distribution of anticipated earthquake-induced landslides and liquefaction. The five main deterministic scenario models indicate that moderate-sized urban earthquakes may represent a greater threat to a state like Indiana than a large-magnitude event from the New Madrid seismic zone. To better understand the influence of earthquake source parameters on impacts, we conducted a sensitivity analysis for earthquakes near Indianapolis and Evansville, where we reviewed losses due to differences in magnitude, depth, strike, and dip. Based on the model projections, magnitude and depth have first-order and relatively predictable influence on losses. The orientation and dip of the causative fault in relation to populated areas can alter economic losses for an event of the same magnitude by 13%–32%. Deterministic scenario analyses, such as those presented here, can potentially be of widespread utility for understanding earthquake impacts in the central United States and other low-seismicity, stable continental regions.

S.Figures 1-5 and S.Table 1

Supplementary Table S2 from EBP1, an ErbB3-binding protein, is decreased in prostate cancer and implicated in hormone resistance

Serum concentration of intact sacituzumab govitecan and hRS7 IgG taken 30 min after injection for each of the 4 dose levels tested.

This file contains additional methods, including eligibility criteria, study design, pharmacokinetics and immunogenicity, and immunohistology, as well as additional results related to several notable patient narratives.

Aberrant activation of the androgen receptor (AR) by the ErbB2/ErbB3 heterodimer contributes to the development of hormone resistance in prostate cancer. EBP1, an ErbB3-binding protein, acts as an AR corepressor. As EBP1 is decreased in preclinical models of hormone-refractory prostate cancer, we studied the expression of EBP1 in human prostate cancer. We found that the expression of the EBP1 gene was significantly decreased in prostate cancer tissues compared with benign prostate at both mRNA and protein levels. Restoration of EBP1 expression in the hormone-refractory LNCaP C81 cell line led to an amelioration of the androgen-independent phenotype based on established biological criteria and a reduction in the expression of a cohort of AR target genes. The ability of the ErbB3 ligand heregulin (HRG) to stimulate growth and AKT phosphorylation of hormone-refractory prostate cancer cells was abolished. Abrogation of EBP1 expression by short hairpin RNA in hormone-dependent LNCaP cells, which undergo apoptosis in response to HRG, resulted in HRG-stimulated cell growth. Restoration of EBP1 expression decreased the tumorigenicity of C81 xenografts in female mice, whereas elimination of EBP1 expression enhanced the ability of LNCaP cells to grow in female mice. Our data support a role for EBP1 in the development of hormone-refractory prostate cancer via inhibition of both AR- and HRG-stimulated growth and present a novel strategy for treating androgen-refractory prostate cancer. [Mol Cancer Ther 2008;7(10):3176–86]

Supplementary Table S1 from EBP1, an ErbB3-binding protein, is decreased in prostate cancer and implicated in hormone resistance

Safe medications for mild mental diseases in pregnancy are needed. Phytomedicines from St. John’s wort and valerian are valid candidates, but safety data in pregnancy are lacking. The transplacental transport of hyperforin and hypericin (from St. John’s wort), and valerenic acid (from valerian) was evaluated using the ex vivo cotyledon perfusion model (4 h perfusions, term placentae) and, in part, the in vitro Transwell assay with BeWo b30 cells. Antipyrine was used for comparison in both models. U(H)PLC-MS/MS bioanalytical methods were developed to quantify the compounds. Perfusion data obtained with term placentae showed that only minor amounts of hyperforin passed into the fetal circuit, while hypericin did not cross the placental barrier and valerenic acid equilibrated between the maternal and fetal compartments. None of the investigated compounds affected metabolic, functional, and histopathological parameters of the placenta during the perfusion experiments. Data from the Transwell model suggested that valerenic acid does not cross the placental cell layer. Taken together, our data suggest that throughout the pregnancy the potential fetal exposure to hypericin and hyperforin – but not to valerenic acid – is likely to be minimal.

Supplementary Fig. S1 from EBP1, an ErbB3-binding protein, is decreased in prostate cancer and implicated in hormone resistance

Purpose: Sacituzumab govitecan (IMMU-132) is an antibody–drug conjugate (ADC) targeting Trop-2, a surface glycoprotein expressed on many epithelial tumors, for delivery of SN-38, the active metabolite of irinotecan. This phase I trial evaluated this ADC as a potential therapeutic for pretreated patients with a variety of metastatic solid cancers.Experimental Design: Sacituzumab govitecan was administered on days 1 and 8 of 21-day cycles, with cycles repeated until dose-limiting toxicity or progression. Dose escalation followed a standard 3 + 3 scheme with 4 planned dose levels and dose delay or reduction allowed.Results: Twenty-five patients (52–60 years old, 3 median prior chemotherapy regimens) were treated at dose levels of 8 (n = 7), 10 (n = 6), 12 (n = 9), and 18 (n = 3) mg/kg. Neutropenia was dose limiting, with 12 mg/kg the maximum tolerated dose for cycle 1, but too toxic with repeated cycles. Lower doses were acceptable for extended treatment with no treatment-related grade 4 toxicities and grade 3 toxicities limited to fatigue (n = 3), neutropenia (n = 2), diarrhea (n = 1), and leukopenia (n = 1). Using CT-based RECIST 1.1, two patients achieved partial responses (triple-negative breast cancer, colon cancer) and 16 others had stable disease as best response. Twelve patients maintained disease control with continued treatment for 16 to 36 weeks; 6 survived 15 to 20+ months. No preselection of patients based on tumor Trop-2 expression was done.Conclusions: Sacituzumab govitecan had acceptable toxicity and encouraging therapeutic activity in patients with difficult-to-treat cancers. The 8 and 10 mg/kg doses were selected for phase II studies. Clin Cancer Res; 21(17); 3870–8. ©2015 AACR.

Time to progression in relation to the immunohistological score in 16 patients with diverse cancers enrolled in the sacituzumab govitecan trial who provided archival tissue specimens.

Trop-2 expression in archived tissue specimens from 6 patients enrolled in the clinical trial with sacituzumab govitecan.

We developed a novel cardiac critical care bootcamp consisting of didactic, small group, and simulation sessions. The bootcamp was remote due to the COVID-19 pandemic and included telesimulation. We aimed to assess learners' reactions to the bootcamp and their perception of telesimulation. Paired anonymous surveys were administered before and after participation. Surveys assessed participants' comfort in independently managing cardiac critical care scenarios, perceptions of telesimulation, barriers to its effectiveness, and specific feedback on course components. Forty-three fellows from 10 institutions joined the bootcamp over 2 years. Thirty-eight pre- and 28 postcourse surveys were completed. The course was rated good or excellent by all respondents, and 27/28 rated the material as appropriate to their level of training. Based on feedback from 2020, the electrophysiology sessions were converted to a small group format in 2021; positive assessment of these sessions improved from 65 to 90–100%. The telesimulations were highly rated, with 83–94% of participants in 2020 and 90–100% in 2021 rating them as good or excellent. Participants' views on telesimulation improved following the course, with 78% (14/18) post- versus 50% preparticipation agreeing that telesimulation is an effective educational tool (p = 0.06) and 56% (10/18) post- versus 67% (12/18) pre-rating telesimulation as less effective than in person simulation (p = 0.04). Identified limitations of telesimulation were limited active participation, lack of realism, impaired flow of conversation, and audiovisual and technical concerns. Telesimulation is feasible in cardiac critical care education and was an acceptable alternative to in person simulation for course participants.

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PDF file - 9.8MB, Supplementary Figure S1. TCF3 expression levels in breast cancer cell lines. Supplementary Figure S2. Effects of TCF3 on cell proliferation, apoptosis and tumor growth. Supplementary Figure S3. TCF3 induces changes in the expression of EMT-associated genes. Supplementary Figure S4. Gene expression changes in TCF3-silenced cells. Supplementary Figure S5. Wnt-related gene expression changes in TCF3 silenced cells. Supplementary Figure S6. Inducible Tcf3 transgenic mice. Supplementary Figure S7. Tcf3 inhibition of ductal growth is reversible. Supplementary Figure S8. Tcf3 induces EMT-associated genes in the mouse mammary gland

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We examined whether the Strange Situation Procedure (SSP) is applicable not only for assessing children with Autism Spectrum Disorder (ASD) and their mothers but also with their fathers. Forty preschoolers with ASD were observed in the SSP with their mothers and 39 with their fathers. Unexpectedly, the SSP was found to be not applicable (NA) to 25% of the SSPs with fathers because levels of attachment behavior were minimal, but all SSPs with mothers were codable. NA children had lower cognitive functioning and more severe symptoms than those not so coded. Insecure children with their fathers had more severe symptoms than secure children, but were not different in their cognitive functioning. No associations between attachment with mother and severity of symptoms/cognitive functioning were found. Attachment was unrelated to parents' distress or Broad Autism Phenotype. The study raises questions regarding the applicability of the SSP with fathers of children with ASD.

We present polynomials for the eigenprojections or Frobenius covariants of a matrix A є Cnxn. They allow for a computation of a function of A by a generalization of the Sylvester formula.

The incidence of melanoma, the most fatal dermatological cancer, has dramatically increased over the last few decades. Modern targeted therapy with kinase inhibitors induces potent clinical responses, but drug resistance quickly develops. Combination therapy improves treatment outcomes. Therefore, novel inhibitors targeting aberrant proliferative signaling in melanoma via the MAPK/ERK and PI3K/AKT pathways are urgently needed. Biosensors were combined that report on ERK/AKT activity with image-based high-content screening and HPLC-based activity profiling. An in-house library of 2576 plant extracts was screened on two melanoma cell lines with different oncogenic mutations leading to pathological ERK/AKT activity. Out of 140 plant extract hits, 44 were selected for HPLC activity profiling. Active thymol derivatives and piperamides from Arnica montana and Piper nigrum were identified that inhibited pathological ERK and/or AKT activity. The pipeline used enabled an efficient identification of natural products targeting oncogenic signaling in melanoma.

Cystic fibrosis (CF) is a multisystem disease that often requires otolaryngology care. Individuals with CF commonly have chronic rhinosinusitis but also present with hearing loss and dysphonia. Given these manifestations of CF, otolaryngologists are frequently involved in the care of patients with CF; however, there is limited consensus on optimal management of sinonasal, otologic, and laryngologic symptoms.The Cystic Fibrosis Foundation convened a multidisciplinary team of otolaryngologists, pulmonologists, audiologists, pharmacists, a social worker, a nurse coordinator, a respiratory therapist, two adults with CF, and a caregiver of a child with CF to develop consensus recommendations. Workgroups developed draft recommendation statements based on a systematic literature review, and a ≥80% consensus was required for acceptance of each recommendation statement.The committee voted on 25 statements. Eleven statements were adopted recommending a treatment or intervention, while five statements were formulated recommending against a specific treatment or intervention. The committee recommended eight statements as an option for select patients in certain circumstances, and one statement did not reach consensus.These multidisciplinary consensus recommendations will help providers navigate decisions related to otolaryngology consultation, medical and surgical management of CF-CRS, hearing, and voice in individuals with CF. A collaborative and multidisciplinary approach is advocated to best care for our patients with CF. Future clinical research is needed utilizing standardized, validated outcomes with comprehensive reporting of patient outcome, effects of modulator therapies, and genetic characteristics to help continue to advance care, decrease morbidity, and improve the quality of life for individuals with CF.

Apresentação da edição 57 da Significação feita pela editora Esther Império Hamburger. Apresentação da edição 57 da Significação feita pela editora Esther Império Hamburger. Apresentação da edição 57 da Significação feita pela editora Esther Império Hamburger.

Neoantigens are among the most intriguing potential immuno-oncology targets because, unlike many cancer targets that are expressed on normal tissues, they are by definition restricted to cancer cells. Medicines directed at common neoantigens such as mutant KRAS are especially interesting because they may offer the convenience and cost of an off-the-shelf therapy. However, all common KRAS mutations produce proteins that differ from the wild type at a single amino acid, creating challenges for molecular discrimination. We have undertaken an effort to optimize single-chain variable fragments (scFv) against peptide/major histocompatibility antigen complexes composed of HLA-A*11 and either G12V- or G12D-mutant KRAS peptides. These scFvs could in principle be used in chimeric antigen receptor (CAR) T-cell therapies for selected patients whose tumors bear either of these mutations. Here we show that optimization of such CARs involves a trade-off between potency and selectivity. We further show that targeting this family without high selectivity engenders risks of cross-reactivity against other members of the G-protein family to which KRAS belongs.Significance:We report an effort to generate high potency, selective CARs directed at mutant KRAS peptides. Although the heavily optimized CARs maintain high selectivity against wild-type KRAS, they lose selectivity against other KRAS-related peptides derived from human proteins. To our knowledge, this work is the first to examine the trade-off between potency and selectivity with regard to KRAS pMHC-directed CARs, illustrating the challenge to achieve both sufficient potency and high selectivity.

In our daily life navigation systems play a pivotal role. These technical aids are used to find a way in unknown environments. Nowadays, they are already integrated into cars or available as smartphone apps. However, navigation is not necessarily successful when using such navigation aids. A highly debated but widely accepted consensus is that the increased use of navigation aids is associated with decreasing navigation skills (i.e., cognitive skills) and social interaction. In the current discussion paper, we therefore want to focus on how to reduce such (possibly) detrimental effects while engaging people in active spatial learning during the use of a navigation device. As we will demonstrate, such an active engagement can be realized rather easily and in a very simple manner: an explicit instruction (and people’s will to follow it). The way the instruction and the task are presented does not seem to matter (i.e., self-read, experimenter-read, or AI-read). The most simple but decisive element for effective wayfinding may be found on the individual psychological level, rather than on the design level for artificial systems. Thus, our discussion paper wants to 1) provide ideas on how to reduce possible detrimental effects in wayfinding (short-term and long-term) and 2) stimulate research on the psychological issues in addition to the technical issues.