Hyperedge prediction and the statistical mechanisms of higher-order and lower-order interactions in complex networks.

Complex networked systems often exhibit higher-order interactions, beyond dyadic interactions, which can dramatically alter their observed behavior. Consequently, understanding hypergraphs from a structural perspective has become increasingly important. Statistical, group-based inference approaches are well suited for unveiling the underlying community structure and predicting unobserved interactions. However, these approaches often rely on two key assumptions: that the same groups can explain hyperedges of any order and that interactions are assortative, meaning that edges are formed by nodes with the same group memberships. To test these assumptions, we propose a group-based generative model for hypergraphs that does not impose an assortative mechanism to explain observed higher-order interactions, unlike current approaches. Our model allows us to explore the validity of the assumptions. Our results indicate that the first assumption appears to hold true for real networks. However, the second assumption is not necessarily accurate; we find that a combination of general statistical mechanisms can explain observed hyperedges. Finally, with our approach, we are also able to determine the importance of lower and high-order interactions for predicting unobserved interactions. Our research challenges the conventional assumptions of group-based inference methodologies and broadens our understanding of the underlying structure of hypergraphs.

Sirtuin 3 Mediated by Spinal cMyc-Enhancer of Zeste Homology 2 Pathway Plays an Important Role in Human Immunodeficiency Virus-Related Neuropathic Pain Model.

BACKGROUND: Clinical data demonstrate that chronic use of opioid analgesics increases neuropathic pain in people living with human immunodeficiency virus (HIV). Therefore, it is important to elucidate the molecular mechanisms of HIV-related chronic pain. In this study, we investigated the role of the transcription factor cMyc, epigenetic writer enhancer of zeste homology 2 (EZH2), and sirtuin 3 (Sirt3) pathway in HIV glycoprotein gp120 with morphine (gp120M)-induced neuropathic pain in rats. METHODS: Neuropathic pain was induced by intrathecal administration of recombinant gp120 with morphine. Mechanical withdrawal threshold was measured using von Frey filaments, and thermal latency using the hotplate test. Spinal expression of cMyc, EZH2, and Sirt3 were measured using Western blots. Antinociceptive effects of intrathecal administration of antisense oligodeoxynucleotide against cMyc, a selective inhibitor of EZH2, or recombinant Sirt3 were tested. RESULTS: In the spinal dorsal horn, gp120M upregulated expression of cMyc (ratio of gp120M versus control, 1.68 ± 0.08 vs 1.00 ± 0.14, P = .0132) and EZH2 (ratio of gp120M versus control, 1.76 ± 0.05 vs 1.00 ± 0.16, P = .006), and downregulated Sirt3 (ratio of control versus gp120M, 1.00 ± 0.13 vs 0.43 ± 0.10, P = .0069) compared to control. Treatment with intrathecal antisense oligodeoxynucleotide against cMyc, GSK126 (EZH2 selective inhibitor), or recombinant Sirt3 reduced mechanical allodynia and thermal hyperalgesia in this gp120M pain model. Knockdown of cMyc reduced spinal EZH2 expression in gp120M treated rats. Chromatin immunoprecipitation (ChIP) assay showed that enrichment of cMyc binding to the ezh2 gene promoter region was increased in the gp120M-treated rat spinal dorsal horn, and that intrathecal administration of antisense ODN against cMyc (AS-cMyc) reversed the increased enrichment of cMyc. Enrichment of trimethylation of histone 3 on lysine residue 27 (H3K27me3; an epigenetic mark associated with the downregulation of gene expression) binding to the sirt3 gene promoter region was upregulated in the gp120M-treated rat spinal dorsal horn; that intrathecal GSK126 reversed the increased enrichment of H3K27me3 in the sirt3 gene promoter. Luciferase reporter assay demonstrated that cMyc mediated ezh2 gene transcription at the ezh2 gene promoter region, and that H3K27me3 silenced sirt3 gene transcription at the gene promoter region. CONCLUSION: These results demonstrated that spinal Sirt3 decrease in gp120M-induced neuropathic pain was mediated by cMyc-EZH2/H3K27me3 activity in an epigenetic manner. This study provided new insight into the mechanisms of neuropathic pain in HIV patients with chronic opioids.

Clinical and neurodevelopmental predictors of psychotic disorders in children and adolescents at clinical high risk for psychosis: the CAPRIS study.

BACKGROUND: The neurodevelopmental hypothesis of schizophrenia represents the disorder as an expression of an alteration during the brain development process early in life. Neurodevelopmental variables could become a trait marker, and the study of these variables in children and adolescents at clinical high risk for psychosis (CHR) could identify a specific cluster of patients who later developed psychosis. The aim of this study is to describe clinical and neurodevelopment predictors of transition to psychosis in child and adolescent participants at CHR. Naturalistic longitudinal two-center study of 101 CHR and 110 healthy controls (HC) aged 10-17. CHR participants were children and adolescents aged 10-17, meeting one or more of the CHR criteria assessed at baseline and at 18 months' follow-up. Neurodevelopmental variables assessed were obstetric complications, delay in principal development milestones, and presence of a neurodevelopment diagnosis. Pairwise comparisons, linear regressions, and binary logistic regression were performed.A transition rate of 23.3% at 1.5 years was observed. Participants who developed psychosis (CHR-P) showed higher rates of grandiosity and higher proportions of antipsychotic medication intake at baseline compared to participants who did not develop a psychotic disorder (CHR-NP). In terms of neurodevelopment alterations, CHR-P group showed a higher proportion of participants reporting delay in language development than the CHR-NP and HC groups. The odds of psychosis increased by 6.238 CI 95% [1.276-30.492] for a one-unit increase in having a positive score in grandiosity; they increased by 4.257 95% CI [1.293-14.023] for a one-unit increase in taking antipsychotic medication, and by 4.522 95% [1.185-64.180] for showing language development delay. However, the p-values did not reach significance after adjusting for multiple comparisons.A combination of clinical and neurodevelopmental alterations could help predict the transition to psychotic disorder in a CHR child and adolescent sample. Our results suggest the potential utility of collecting information about neurodevelopment and using these variable multifactorial models to predict psychosis disorders.

Role of Tumor Necrosis Factor Receptor 1-Reactive Oxygen Species-Caspase 11 Pathway in Neuropathic Pain Mediated by HIV gp120 With Morphine in Rats.

BACKGROUND: Recent clinical research suggests that repeated use of opioid pain medications can increase neuropathic pain in people living with human immunodeficiency virus (HIV; PLWH). Therefore, it is significant to elucidate the exact mechanisms of HIV-related chronic pain. HIV infection and chronic morphine induce proinflammatory factors, such as tumor necrosis factor (TNF)α acting through tumor necrosis factor receptor I (TNFRI). HIV coat proteins and/or chronic morphine increase mitochondrial superoxide in the spinal cord dorsal horn (SCDH). Recently, emerging cytoplasmic caspase-11 is defined as a noncanonical inflammasome and can be activated by reactive oxygen species (ROS). Here, we tested our hypothesis that HIV coat glycoprotein gp120 with chronic morphine activates a TNFRI-mtROS-caspase-11 pathway in rats, which increases neuroinflammation and neuropathic pain. METHODS: Neuropathic pain was induced by repeated administration of recombinant gp120 with morphine (gp120/M) in rats. Mechanical allodynia was assessed using von Frey filaments, and thermal latency using hotplate test. Protein expression of spinal TNFRI and cleaved caspase-11 was examined using western blots. The image of spinal mitochondrial superoxide was examined using MitoSox Red (mitochondrial superoxide indicator) image assay. Immunohistochemistry was used to examine the location of TNFRI and caspase-11 in the SCDH. Intrathecal administration of antisense oligodeoxynucleotide (AS-ODN) against TNFRI, caspase-11 siRNA, or a scavenger of mitochondrial superoxide was given for antinociceptive effects. Statistical tests were done using analysis of variance (1- or 2-way), or 2-tailed t test. RESULTS: Intrathecal gp120/M induced mechanical allodynia and thermal hyperalgesia lasting for 3 weeks ( P < .001). Gp120/M increased the expression of spinal TNFRI, mitochondrial superoxide, and cleaved caspase-11. Immunohistochemistry showed that TNFRI and caspase-11 were mainly expressed in the neurons of the SCDH. Intrathecal administration of antisense oligonucleotides against TNFRI, Mito-Tempol (a scavenger of mitochondrial superoxide), or caspase-11 siRNA reduced mechanical allodynia and thermal hyperalgesia in the gp120/M neuropathic pain model. Spinal knockdown of TNFRI reduced MitoSox profile cell number in the SCDH; intrathecal Mito-T decreased spinal caspase-11 expression in gp120/M rats. In the cultured B35 neurons treated with TNFα, pretreatment with Mito-Tempol reduced active caspase-11 in the neurons. CONCLUSIONS: These results suggest that spinal TNFRI-mtROS-caspase 11 signal pathway plays a critical role in the HIV-associated neuropathic pain state, providing a novel approach to treating chronic pain in PLWH with opioids.

Partnering to implement the Global Initiative for Childhood Cancer in the Americas: prioritizing systems strengthening.

Working with PAHO/WHO to prioritize childhood cancer in the context of systems strengthening is central to St. Jude Children's Research Hospital (SJCRH)'s role as WHO Collaborating Centre for Childhood Cancer. This manuscript focuses on how SJCRH and PAHO/WHO have partnered to apply C5 (Country Collaboration for Childhood Cancer Control) to define and implement priority actions regionally, strengthening Ministry programs for childhood cancer, while implementing the Global Initiative for Childhood Cancer since 2018. Using C5, a tool developed by SJCRH, PAHO/WHO and SJCRH co-hosted regional/national workshops engaging authorities, clinicians and other stakeholders across 10 countries to map health systems needs and prioritize strategic activities (spanning Central America, Dominican Republic, Haiti, Brazil and Uruguay). SJCRH provided English/Spanish/Portuguese C5 versions/templates for analysis/prioritization exercises, and worked with PAHO/WHO and country teams to implement C5, analyze findings, and develop outputs. In an eight-country regional workshop, countries defined priorities within national/regional initiatives and ranked their value and political will, incorporating country-specific surveys and stakeholder dialogues. Each country prioritized one strategic activity for 2022-2023, exchanged insights via storytelling, and disseminated and applied results to inform country-specific and regional action plans. National workshops analyses have been incorporated into cancer control planning activities and collaborative work regionally. Implementation success factors include engaging actors beyond the clinic, enabling flexibility, and focusing on co-design with stakeholders. Joint implementation of C5 catalyzed prioritization and accelerated strategic activities to improve policies, capacity, and quality of care for children in the Americas, supporting Ministries to integrate childhood cancer interventions as part of systems strengthening.

La colaboración con la OPS/OMS para priorizar el cáncer infantil en el contexto del fortalecimiento de los sistemas es fundamental para la labor del St. Jude Children's Research Hospital (SJCRH) como centro colaborador de la OMS contra el cáncer infantil. Este artículo se centra en la alianza entre el SJCRH y la OPS/OMS en la aplicación de la herramienta C5 (colaboración nacional para el control del cáncer infantil) para definir y ejecutar medidas prioritarias a nivel regional, fortalecer los programas contra el cáncer infantil del ministerio y poner en marcha la Iniciativa Mundial contra el Cáncer Infantil desde el 2018. Con C5, una herramienta elaborada por el SJCRH, la OPS/OMS y este hospital organizaron conjuntamente talleres regionales y nacionales con autoridades, personal médico y otras partes interesadas en diez países para determinar cuáles son las necesidades de los sistemas de salud y priorizar las actividades estratégicas (en América Central, República Dominicana, Haití, Brasil y Uruguay). El SJCRH proporcionó versiones y plantillas de C5 en inglés, español y portugués para actividades de análisis y priorización y trabajó con la OPS/OMS y los equipos de país para ejecutar la herramienta C5, analizar los resultados y elaborar productos. En un taller regional de ocho países, se definieron las prioridades en las iniciativas regionales y nacionales, se clasificó su valor y la voluntad política y se incorporaron encuestas específicas para cada país y diálogos con las partes interesadas. Cada país priorizó una actividad estratégica para el período 2022-2023, intercambió ideas por medio de narrativas, y difundió y aplicó los resultados para fundamentar planes de acción tanto regionales como específicos para el país. Los análisis de los talleres nacionales se han incorporado a las actividades de planificación del control del cáncer y al trabajo colaborativo a nivel regional. Entre los factores de éxito de la ejecución se encuentra involucrar a los agentes más allá de lo clínico, permitir que haya flexibilidad y centrarse en un diseño elaborado en colaboración con las partes interesadas. La ejecución conjunta de la herramienta C5 catalizó la priorización y aceleró las actividades estratégicas para mejorar las políticas, la capacidad y la calidad de la atención infantil en la Región de las Américas y brindó apoyo a los ministerios para integrar las intervenciones contra el cáncer infantil en el fortalecimiento de los sistemas.

A colaboração com a OPAS/OMS para priorizar o câncer infantil no contexto do fortalecimento dos sistemas é fundamental para o papel do St. Jude Children's Research Hospital (SJCRH) como Centro Colaborador da OMS para o Câncer Infantil. Este artigo mostra como o SJCRH e a OPAS/OMS se associaram para aplicar a ferramenta C5 (Colaboração Nacional para Controle do Câncer Infantil), com o propósito de definir e implementar ações prioritárias regionalmente, fortalecendo programas ministeriais para o câncer na infância, durante a implementação da Iniciativa Global para o Câncer Infantil desde 2018. Com auxílio da C5, uma ferramenta desenvolvida pelo SJCRH, a OPAS/OMS e o SJCRH organizaram conjuntamente oficinas regionais/nacionais com a participação de autoridades, profissionais de saúde e outras partes interessadas em 10 países, com a finalidade de mapear as necessidades dos sistemas de saúde e priorizar atividades estratégicas (abrangendo América Central, República Dominicana, Haiti, Brasil e Uruguai). O SJCRH forneceu versões/modelos da C5 em inglês, espanhol e português para exercícios de análise/priorização e colaborou com a OPAS/OMS e as equipes dos países para implementar a C5, analisar resultados e desenvolver produtos. Em uma oficina regional com oito países, foram definidas as prioridades das iniciativas nacionais/regionais e classificados seu valor e vontade política, incorporando levantamentos nacionais e diálogos entre as partes interessadas. Cada país priorizou uma atividade estratégica para 2022-2023, trocou conhecimentos por meio da narração de histórias e disseminou e aplicou os resultados para informar planos de ação nacionais e regionais. As análises das oficinas nacionais foram incorporadas às atividades de planejamento para controle do câncer e ao trabalho conjunto no âmbito regional. Entre os fatores de êxito da implementação estão o engajamento de agentes de fora do segmento da saúde, a oferta de flexibilidade e a ênfase no planejamento conjunto com as partes interessadas. A implementação conjunta da C5 catalisou a priorização e acelerou atividades estratégicas para aprimorar as políticas, a capacidade e a qualidade da atenção às crianças nas Américas, apoiando os ministérios na integração das intervenções contra o câncer infantil como parte do fortalecimento dos sistemas.

Regional collaboration for the development of national childhood cancer plans in Latin America and the Caribbean.

This article aims to describe the activities conducted by the National Childhood Cancer Plan Working Group to support the development of national childhood cancer plans in Latin America and the Caribbean in the period 2019-2022, and to present the stage of plan development. The Working Group activities were supported by the Pan American Health Organization and St. Jude Children's Research Hospital, which is the World Health Organization (WHO) Collaborating Centre for Childhood Cancer. Year after year, the workshops and activities developed with the Working Group mobilized key stakeholders: pediatric oncologists, representatives of the Ministry of Health, foundations supporting childhood cancer initiatives, and hospital administrators. As of February 2023, one regional framework is in place, approved by the Council of Ministries of Health of Central America and the Dominican Republic, nine countries are currently implementing national plans or laws that include childhood cancer, and ten countries are writing new plans. The WHO three-step framework helped to guide the Working Group activities. All plans were supported by a situational analysis, which highlighted the importance of having systematized data for evidence-based policies. To increase implementation success, an accompanying budget and timeline help to ensure the adequate implementation of the interventions. More than anything, committed stakeholders remain the most fundamental element to successfully write and approve a national childhood cancer plan. This is an opportunity to share these countries' experience so the strategy can be adapted to support other countries developing a childhood cancer plan and extended to other public health areas.

En este artículo se describen las actividades realizadas por el grupo de trabajo del plan nacional contra el cáncer infantil dirigidas a brindar apoyo para la formulación de planes nacionales contra el cáncer infantil en América Latina y el Caribe en el período 2019-2022, así como la presentación de la etapa de formulación de los planes. Las actividades del Grupo de Trabajo contaron con el apoyo de la Organización Panamericana de la Salud y el St. Jude Children's Research Hospital, que es el centro colaborador de la Organización Mundial de la Salud (OMS) contra el cáncer infantil. Año tras año, los talleres y actividades llevados a cabo con el grupo de trabajo han logrado convocar a las principales partes interesadas: especialistas en oncología pediátrica, representantes del Ministerio de Salud, fundaciones que apoyan iniciativas contra el cáncer infantil y gerentes de los hospitales. Desde febrero del 2023, existe un marco regional, aprobado por el Consejo de Ministerios de Salud de Centroamérica y República Dominicana; nueve países ya están aplicando planes o leyes nacionales en los que se incluye el cáncer infantil, y diez países están redactando nuevos planes. Para orientar las actividades del Grupo de Trabajo, se recurrió al marco en tres pasos de la OMS. Todos los planes se sustentaron en un análisis de situación lo que subraya la importancia de contar con datos sistematizados para que las políticas puedan estar basadas en evidencias. Asimismo, si se pretende aumentar el éxito de la aplicación, sería conveniente contar con un presupuesto y un cronograma que aseguren la aplicación adecuada de las intervenciones. Las partes interesadas implicadas siguen siendo, ante todo, el componente más trascendente en la redacción y aprobación exitosa de un plan nacional contra el cáncer infantil. Esta es una oportunidad para transmitir la experiencia de estos países, con el fin de que la estrategia pueda adaptarse para brindar apoyo a otros países que estén elaborando un plan contra el cáncer infantil y que puede hacerse extensiva a otros ámbitos de la salud pública.

Este artigo visa a descrever as atividades realizadas pelo Grupo de Trabalho para Planos Nacionais de Combate ao Câncer infantil a fim de prestar apoio ao desenvolvimento de planos nacionais de combate ao câncer infantil na América Latina e no Caribe no período de 2019 a 2022 e apresentar a atual fase de desenvolvimento dos planos. As atividades do Grupo de Trabalho receberam apoio da Organização Pan-Americana da Saúde e do St. Jude Children's Research Hospital, o Centro Colaborador em Câncer infantil da Organização Mundial da Saúde (OMS). Ano após ano, as oficinas e atividades desenvolvidas com o Grupo de Trabalho mobilizaram as principais partes interessadas: oncologistas pediátricos, representantes dos ministérios da saúde, fundações que apoiam iniciativas de combate ao câncer infantil e administradores de hospitais. Até fevereiro de 2023, havia uma estrutura regional em vigor aprovada pelo Conselho de Ministros da Saúde da América Central e da República Dominicana, nove países estavam implementando planos ou leis nacionais que incluíam o câncer infantil e dez países estavam elaborando novos planos. A estrutura de três etapas da OMS ajudou a orientar as atividades do Grupo de Trabalho. Todos os planos estavam embasados em uma análise situacional, o que destacou a importância de dispor de dados sistematizados para políticas baseadas em evidências. Para aumentar o sucesso da implementação, um orçamento e um cronograma correspondentes ajudam a garantir a implementação adequada das intervenções. Acima de tudo, o compromisso das partes interessadas continua sendo o elemento mais fundamental para elaborar e aprovar com sucesso um plano nacional de combate ao câncer infantil. Esta é uma oportunidade de compartilhar a experiência desses países para que a estratégia possa ser adaptada a fim de apoiar outros países na elaboração de um plano de combate ao câncer infantil e possa ser estendida a outras áreas de saúde pública.

Advances in the Global Initiative for Childhood Cancer: implementation in Latin America and the Caribbean.

This report describes the status of childhood cancer control initiatives in Latin America and the Caribbean (LAC). Progress between 2017 and 2023 is measured using the outcome indicators from the Pan American Health Organization (PAHO) childhood cancer logic model aligned with the World Health Organization Global Initiative for Childhood Cancer (GICC). This report also describes the advances, barriers, and facilitators for the implementation of the GICC at the Regional level. Methods used in this report encompassed a comprehensive approach, incorporating a literature review, interviews, surveys, and a Delphi study developed by the technical team of the PAHO Non-Communicable Diseases and Mental Health Department and by the GICC LAC working group. Since 2017, there has been a substantial increase in the number of countries that have included childhood cancer in their national regulations. Currently, 21 LAC countries are involved in the GICC implementation, activities, and dialogues. However, the objectives for 2030 will only be achieved if Member States overcome the barriers to accelerating the pace of initiative implementation. There is an urgent need to increase the efforts in childhood cancer control in LAC, especially regarding the prioritization of timely detection, essential diagnostics, access to cancer treatment, palliative care, and close follow-up of children and adolescents with cancer.

En este artículo se describe la situación de las iniciativas para el control del cáncer infantil en América Latina y el Caribe. Para medir los progresos entre el 2017 y el 2023, se utilizan los indicadores de resultados del modelo lógico del cáncer infantil de la Organización Panamericana de la Salud (OPS) que es coherente con la Iniciativa Mundial contra el Cáncer Infantil de la Organización Mundial de la Salud. También se describen los avances, los obstáculos y los elementos que han facilitado la aplicación de esa iniciativa en la Región Los métodos utilizados en este trabajo incluyeron un enfoque integral que incorporó una revisión bibliográfica, entrevistas, encuestas y un estudio de tipo Delfos llevado a cabo por el equipo técnico del Departamento de Enfermedades No Transmisibles y Salud Mental de la OPS y por el grupo de trabajo de América Latina y el Caribe de la Iniciativa Mundial contra el Cáncer Infantil de la Organización Mundial de la Salud.Desde el 2017 ha habido un incremento considerable en el número de países que incorporan el cáncer infantil en sus regulaciones nacionales. En la actualidad, 21 países de América Latina y el Caribe participan en la puesta en práctica, las actividades y las deliberaciones de la Iniciativa Mundial contra el Cáncer Infantil de la Organización Mundial de la Salud. No obstante, los objetivos para el 2030 solo podrán alcanzarse si los Estados Miembros son capaces de superar los obstáculos que dificultan la aceleración del ritmo de aplicación de esta iniciativa. Existe una necesidad urgente de aumentar las actividades dirigidas al control del cáncer infantil en América Latina y el Caribe, en especial en lo que respecta a priorizar la detección temprana, los medios de diagnóstico esenciales, el acceso a los tratamientos oncológicos, los cuidados paliativos y el seguimiento estricto de la población infantil y adolescente con cáncer.

Este relatório descreve a situação das iniciativas de controle do câncer infantil na Região da América Latina e do Caribe (ALC). O progresso alcançado entre 2017 e 2023 foi medido usando os indicadores de resultados intermediários do modelo lógico de câncer infantil da Organização Pan-Americana da Saúde (OPAS), em linha com a Iniciativa Global para o Câncer Infantil (GICC) da Organização Mundial da Saúde. O relatório também descreve os avanços, as barreiras e os facilitadores para a implementação da iniciativa em nível regional. Os métodos utilizados neste relatório aplicaram uma abordagem abrangente que incluiu revisão da literatura, entrevistas, levantamentos e um estudo Delphi desenvolvido pela equipe técnica do Departamento de Doenças Não Transmissíveis e Saúde Mental da OPAS e pelo grupo de trabalho da GICC para a ALC.Desde 2017, houve um aumento significativo no número de países que passaram a incluir o câncer infantil em regulamentações nacionais. Atualmente, 21 países da América Latina e do Caribe estão envolvidos na implementação da GICC, bem como em atividades e diálogos relacionados. No entanto, os objetivos para 2030 só serão alcançados se os Estados Membros superarem as barreiras ao aceleramento do ritmo de implementação da iniciativa. Existe uma necessidade urgente de intensificar os esforços de controle do câncer infantil na ALC, especialmente no tocante à priorização da detecção em tempo hábil, diagnósticos essenciais, acesso a tratamentos oncológicos, cuidados paliativos e acompanhamento cuidadoso de crianças e adolescentes com câncer.

Major depressive disorder and attenuated negative symptoms in a child and adolescent sample with psychosis risk syndrome: the CAPRIS study.

Some 70-80% of subjects with psychotic risk syndrome (PRS) have lifetime comorbidity, with depressive disorders being the most common. A high proportion of patients with PRS present nonspecific symptoms which can be confounding factors for diagnosis. Depressive and negative symptoms may be difficult to distinguish and it is important to differentiate them. The aim of this study is to assess the presence of depressive disorder in a child and adolescent sample of PRS and to examine the presence of negative symptoms and detect possible confounding characteristics between them and depressive symptoms. This is a naturalistic multi-site study with subjects who met PRS criteria. A sample of 89 PRS adolescent patients was included. Major depressive disorder (MDD) is the most prevalent comorbid disorder (34.83%). The sample was divided into patients who met criteria for MDD (PRS-MDD, n = 31) and those who did not have this disorder (PRS-ND, n = 44). We obtained significant differences in the attenuated negative symptoms (ANS) between PRS-MDD and PRS-ND (68.18 vs. 90.32%, respectively, p = 0.021). Subjects with MDD presented a higher score in ANS and Hamilton Depression Rating Scale (HDRS). Moreover, we obtained a correlation between negative symptomatology and HDRS score with a higher score on HDRS in subjects with higher negative symptom scores (r = 0.533, p < 0.001). More research is needed to fine tune differentiation between depressive and negative symptoms and learn more about the possible impact of MDD on PRS children and adolescents.

Heterozygote Dopamine Transporter Knockout Rats Display Enhanced Cocaine Locomotion in Adolescent Females.

Cocaine is a powerful psychostimulant that is one of the most widely used illicit addictive. The dopamine transporter (DAT) plays a major role in mediating cocaine's reward effect. Decreases in DAT expression increase rates of drug abuse and vulnerability to comorbid psychiatric disorders. We used the novel DAT transgenic rat model to study the effects of cocaine on locomotor behaviors in adolescent rats, with an emphasis on sex. Female rats showed higher response rates to cocaine at lower acute and chronic doses, highlighting a higher vulnerability and perceived gender effects. In contrast, locomotor responses to an acute high dose of cocaine were more marked and sustained in male DAT heterozygous (HET) adolescents. The results demonstrate the augmented effects of chronic cocaine in HET DAT adolescent female rats. Knockout (KO) DAT led to a level of hyperdopaminergia which caused a marked basal hyperactivity that was unchanged, consistent with a possible ceiling effect. We suggest a role of alpha synuclein (α-syn) and PICK 1 protein expressions to the increased vulnerability in female rats. These proteins showed a lower expression in female HET and KO rats. This study highlights gender differences associated with mutations which affect DAT expression and can increase susceptibility to cocaine abuse in adolescence.

Size-dependent intranasal administration of magnetoelectric nanoparticles for targeted brain localization.

The brain is a massive network of neurons which are interconnected through chemical and electrical field oscillations. It is hard to overestimate the significance of the ability to control chemical and physical properties of the network at both the collective and single-cell levels. Most psychiatric and neurodegenerative diseases are typically characterized by certain aberrations of these oscillations. Recently, magnetoelectric nanoparticles (MENs) have been introduced to achieve the desired control. MENs effectively enable wirelessly controlled nanoelectrodes deep in the brain. Although MENs have been shown to cross the blood-brain barrier via intravenous (IV) administration, achieving adequate efficacy of the delivery remains an open question. Herein, through in vivo studies on a mouse model, we demonstrate at least a 4-fold improved efficacy of the targeted delivery of MENs across BBB via intranasal administration compared to an equivalent IV administration.

Depressive symptoms and their relationship with negative and other psychotic symptoms in early onset psychosis.

The importance of depression in adult people with first-episode psychosis (FEP) has been demonstrated. However, it has hardly been studied in children and adolescents. There is a need to broaden knowledge of the relationship between psychotic symptoms and specific depression symptomatology. The aims of study were (a) to examine the frequency of presence and type of depressive symptoms in early onset FEP, and (b) to assess the relationship between depressive symptoms and psychotic symptomatology, and specifically negative symptoms. An observational cross-sectional study was performed in 62 FEP cases. Inclusion criteria were two or more psychotic symptoms, age 7-17 years old, first mental health service consultation, and fewer than 6 months from the first contact with the service. Participants were assessed with clinical and socio-demographic questionnaires: the Positive and Negative Syndrome Scale (PANSS) and the Children Depression Inventory (CDI). A Student t test was performed to compare psychotic symptoms in both groups: presence of depression and the absence of depression. A Pearson correlation was performed in order to relate subscales of the PANSS and each of the depression subscales and factors, as well the relation between negative and depressive symptoms. Our results show that a high percentage of people with an early onset of a FEP scored positively for depression. The most prevalent depressive symptoms were associated with schooling. The presence of depression was associated with negative, affective, and excited symptoms. Self-esteem, school problems, negative affect, and biological dysregulation were associated with psychotic symptoms. Finally, depressive items related to social functioning were more closely associated with negative symptoms of the PANSS. In conclusion, owing to the high incidence of depression in FEP in those suffering early onset of psychosis, there is a need for instruments to measure the depression more specifically in children and adolescent, and to uncover the clinical characteristics of depression in this population.

CliqueMS: a computational tool for annotating in-source metabolite ions from LC-MS untargeted metabolomics data based on a coelution similarity network.

MOTIVATION: The analysis of biological samples in untargeted metabolomic studies using LC-MS yields tens of thousands of ion signals. Annotating these features is of the utmost importance for answering questions as fundamental as, e.g. how many metabolites are there in a given sample. RESULTS: Here, we introduce CliqueMS, a new algorithm for annotating in-source LC-MS1 data. CliqueMS is based on the similarity between coelution profiles and therefore, as opposed to most methods, allows for the annotation of a single spectrum. Furthermore, CliqueMS improves upon the state of the art in several dimensions: (i) it uses a more discriminatory feature similarity metric; (ii) it treats the similarities between features in a transparent way by means of a simple generative model; (iii) it uses a well-grounded maximum likelihood inference approach to group features; (iv) it uses empirical adduct frequencies to identify the parental mass and (v) it deals more flexibly with the identification of the parental mass by proposing and ranking alternative annotations. We validate our approach with simple mixtures of standards and with real complex biological samples. CliqueMS reduces the thousands of features typically obtained in complex samples to hundreds of metabolites, and it is able to correctly annotate more metabolites and adducts from a single spectrum than available tools. AVAILABILITY AND IMPLEMENTATION: https://CRAN.R-project.org/package=cliqueMS and https://github.com/osenan/cliqueMS. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Bayesian Machine Scientist to Compare Data Collapses for the Nikuradse Dataset.

Ever since Nikuradse's experiments on turbulent friction in 1933, there have been theoretical attempts to describe his measurements by collapsing the data into single-variable functions. However, this approach, which is common in other areas of physics and in other fields, is limited by the lack of rigorous quantitative methods to compare alternative data collapses. Here, we address this limitation by using an unsupervised method to find analytic functions that optimally describe each of the data collapses for the Nikuradse dataset. By descaling these analytic functions, we show that a low dispersion of the scaled data does not guarantee that a data collapse is a good description of the original data. In fact, we find that, out of all the proposed data collapses, the original one proposed by Prandtl and Nikuradse over 80 years ago provides the best description of the data so far, and that it also agrees well with recent experimental data, provided that some model parameters are allowed to vary across experiments.

Preference for vigorous exercise versus sedentary sucrose drinking: an animal model of anergia induced by dopamine receptor antagonism.

Motivation has activational and directional components. Mesolimbic dopamine is critical for the regulation of behavioral activation and effort-related processes in motivated behaviors. Impairing mesolimbic dopamine function leads to fatigue and anergia, but leaves intact other aspects of reinforce seeking behaviors, such as the consummatory or hedonic component. In male Swiss mice, we characterized the impact of dopamine antagonism on the selection of concurrently presented stimuli that have different vigor requirements. We analyzed running wheel activity versus sucrose solution intake, typically used as a measure of anhedonia. Results are compared with data from nonconcurrent presentation to those stimuli. In the concurrent presentation experiment, control mice preferred to spend time running compared to sucrose intake. Dopamine antagonism shifted relative reinforcer preference, reducing time spent on the running wheel, but actually increasing time-consuming sucrose. Mice increased frequency of bouts for both reinforcers, suggesting that there was fatigue in the running wheel rather than aversion. Moreover, satiation or habituation by preexposing animals to both reinforcers did not shift preferences. In the nonconcurrent experiments, haloperidol reduced running wheel but had no impact on sucrose consumption. Dopamine antagonism did not change preference for sucrose or total volume consumed. Additional correlational analyses indicated that baseline differences in sucrose consumption were independent of baseline running or novelty exploration. Thus, dopamine antagonism seems to have anergic rather than anhedonic effects, and the concurrent presentation in this setting could be useful for assessing preferences based on effort requirements.

Own or dam's genotype? Classical colony breeding may bias spontaneous and stress-challenged activity in DAT-mutant rats.

There is considerable interest in understanding what makes an individual vulnerable or resilient to the deleterious effects of stressful events. From candidate genes, dopamine (DA) and dopamine transporter (DAT) have been linked to anxiety, depression, and post-traumatic stress disorder. We investigated role of DAT using the new DAT heterozygous (DAT-HET) and homozygous mutant (DAT-KO) rat models of hyperdopaminergia. We studied the impact of two breeding conditions in spontaneous locomotor behavior of female rats. The classical colony, through mating DAT-HET males × DAT-HET females (breeding HET-HET), was used. A second WT colony was derived and maintained (breeding WT-WT). Additionally, a subgroup of rats was bred through mating DAT-KO males × WT females (atypical HET, breeding KO-WT). We studied the effects of genotype and its interaction with maternal care (depending by breeding condition). HET-HET breeding led to reduced activity in HET females compared to WT rats (from WT-WT breeding). However, HET females from KO-WT breeding did not differ so much from WT rats (WT-WT breeding). The maternal-care impact was then confirmed: HET mothers (breeding HET-HET) showed reduced liking/grooming of pups and increased digging away from nest, compared to WT mothers (breeding WT-WT). In their female offspring (HET, breeding HET-HET vs. WT, breeding WT-WT), isolation plus wet bedding induced higher and more persistent impact on activity of HET rats, even when the stressor was removed. Our results highlight the importance of epigenetic factors (e.g., maternal care) in responses to stress expressed by offspring at adulthood, quite independently of genotype. DAT hypofunction could determinate vulnerability to stressful agents via altered maternal care.

Neuropsychological profile of children and adolescents with psychosis risk syndrome: the CAPRIS study.

Neuropsychological underperformance is well described in young adults at clinical high risk for psychosis, but the literature is scarce on the cognitive profile of at-risk children and adolescents. The aim of this study is to describe the neuropsychological profile of a child and adolescent sample of patients with psychosis risk syndrome (PRS) compared to healthy controls and to analyze associations between attenuated psychotic symptoms and cognitive impairment. Cross-sectional baseline data analysis from a longitudinal, naturalistic, case-control, two-site study is presented. Eighty-one help-seeking subjects with PRS and 39 healthy controls (HC) aged between 10 and 17 years of age were recruited. PRS was defined by: positive or negative attenuated symptoms, Brief Limited Intermittent Psychotic Symptoms (BLIPS), genetic risk (first- or second-degree relative), or schizotypal personality disorder plus impairment in functioning. A neuropsychological battery was administered to assess general intelligence, verbal and visual memory, visuospatial abilities, speed processing, attention, and executive functions. The PRS group showed lower general neuropsychological performance scores at a multivariate level and lower scores than controls in general intelligence and executive functions. Lower scores on executive function and poorer attention were associated with high scores of positive attenuated psychotic symptoms. No association with attenuated negative symptoms was found. This study provides evidence of cognitive impairment in PRS children and adolescents and shows a relationship between greater cognitive impairment in executive functions and attention tasks and severe attenuated positive symptoms. However, longitudinal studies are needed to clarify the nature of cognitive impairment as a possible vulnerability marker.

Differences in Collaboration Patterns across Discipline, Career Stage, and Gender.

Collaboration plays an increasingly important role in promoting research productivity and impact. What remains unclear is whether female and male researchers in science, technology, engineering, and mathematical (STEM) disciplines differ in their collaboration propensity. Here, we report on an empirical analysis of the complete publication records of 3,980 faculty members in six STEM disciplines at select U.S. research universities. We find that female faculty have significantly fewer distinct co-authors over their careers than males, but that this difference can be fully accounted for by females' lower publication rate and shorter career lengths. Next, we find that female scientists have a lower probability of repeating previous co-authors than males, an intriguing result because prior research shows that teams involving new collaborations produce work with higher impact. Finally, we find evidence for gender segregation in some sub-disciplines in molecular biology, in particular in genomics where we find female faculty to be clearly under-represented.

ATP: The crucial component of secretory vesicles.

The colligative properties of ATP and catecholamines demonstrated in vitro are thought to be responsible for the extraordinary accumulation of solutes inside chromaffin cell secretory vesicles, although this has yet to be demonstrated in living cells. Because functional cells cannot be deprived of ATP, we have knocked down the expression of the vesicular nucleotide carrier, the VNUT, to show that a reduction in vesicular ATP is accompanied by a drastic fall in the quantal release of catecholamines. This phenomenon is particularly evident in newly synthesized vesicles, which we show are the first to be released. Surprisingly, we find that inhibiting VNUT expression also reduces the frequency of exocytosis, whereas the overexpression of VNUT drastically increases the quantal size of exocytotic events. To our knowledge, our data provide the first demonstration that ATP, in addition to serving as an energy source and purinergic transmitter, is an essential element in the concentration of catecholamines in secretory vesicles. In this way, cells can use ATP to accumulate neurotransmitters and other secreted substances at high concentrations, supporting quantal transmission.

Accurate and scalable social recommendation using mixed-membership stochastic block models.

With increasing amounts of information available, modeling and predicting user preferences-for books or articles, for example-are becoming more important. We present a collaborative filtering model, with an associated scalable algorithm, that makes accurate predictions of users' ratings. Like previous approaches, we assume that there are groups of users and of items and that the rating a user gives an item is determined by their respective group memberships. However, we allow each user and each item to belong simultaneously to mixtures of different groups and, unlike many popular approaches such as matrix factorization, we do not assume that users in each group prefer a single group of items. In particular, we do not assume that ratings depend linearly on a measure of similarity, but allow probability distributions of ratings to depend freely on the user's and item's groups. The resulting overlapping groups and predicted ratings can be inferred with an expectation-maximization algorithm whose running time scales linearly with the number of observed ratings. Our approach enables us to predict user preferences in large datasets and is considerably more accurate than the current algorithms for such large datasets.

Clinical high risk for psychosis in children and adolescents: a systematic review.

The concept of being at risk for psychosis has been introduced both for adults and children and adolescents, but fewer studies have been conducted in the latter population. The aim of this study is to systematically review the articles associated with clinical description, interventions, outcome and other areas in children and adolescents at risk for psychosis. We searched in MEDLINE/PubMed and PsycINFO databases for articles published up to 30/06/16. Reviewed articles were prospective studies; written in English; original articles with Clinical High Risk (CHR) for psychosis samples; and mean age of samples younger than 18 years. From 103 studies initially selected, 48 met inclusion criteria and were systematically reviewed. Studies show that CHR children and adolescents present several clinical characteristics at baseline, with most attenuated positive-symptom inclusion criteria observed, reporting mostly perceptual abnormalities and suspiciousness, and presenting comorbid conditions such as depressive and anxiety disorders. CHR children and adolescents show lower general intelligence and no structural brain changes compared with controls. Original articles reviewed show rates of conversion to psychosis between 17 and 20% at 1 year follow-up and between 7 and 21% at 2 years. While 36% of patients recovered from their CHR status at 6-year follow-up, 40% still met CHR criteria. Studies in children and adolescents with CHR were conducted with different methodologies, assessments tools and small samples. It is important to conduct studies on psychopharmacological and psychological treatment, as well as replication of the few studies found.