IPMK regulates HDAC3 activity and histone H4 acetylation in human cells.

Histone deacetylases (HDACs) repress transcription by catalyzing the removal of acetyl groups from histones. Class 1 HDACs are activated by inositol phosphate signaling molecules in vitro , but it is unclear if this regulation occurs in human cells. Inositol Polyphosphate Multikinase (IPMK) is required for production of inositol hexakisphosphate (IP6), pentakisphosphate (IP5) and certain tetrakisphosphate (IP4) species, all known activators of Class 1 HDACs in vitro . Here, we generated IPMK knockout (IKO) human U251 glioblastoma cells, which decreased cellular inositol phosphate levels and increased histone H4-acetylation by mass spectrometry. ChIP-seq showed IKO increased H4-acetylation at IKO-upregulated genes, but H4-acetylation was unchanged at IKO-downregulated genes, suggesting gene-specific responses to IPMK knockout. HDAC deacetylase enzyme activity was decreased in HDAC3 immunoprecipitates from IKO vs . wild-type cells, while deacetylase activity of other Class 1 HDACs had no detectable changes in activity. Wild-type IPMK expression in IKO cells fully rescued HDAC3 deacetylase activity, while kinase-dead IPMK expression had no effect. Further, the deficiency in HDAC3 activity in immunoprecipitates from IKO cells could be fully rescued by addition of synthesized IP4 (Ins(1,4,5,6)P4) to the enzyme assay, while control inositol had no effect. These data suggest that cellular IPMK-dependent inositol phosphates are required for full HDAC3 enzyme activity and proper histone H4-acetylation. Implications for targeting IPMK in HDAC3-dependent diseases are discussed.

Design, synthesis and cellular characterization of a new class of IPMK kinase inhibitors.

Many genetic studies have established the kinase activity of inositol phosphate multikinase (IPMK) is required for the synthesis of higher-order inositol phosphate signaling molecules, the regulation of gene expression and control of the cell cycle. These genetic studies await orthogonal validation by specific IPMK inhibitors, but no such inhibitors have been synthesized. Here, we report complete chemical synthesis, cellular characterization, structure-activity relationships and rodent pharmacokinetics of a novel series of highly potent IPMK inhibitors. The first-generation compound 1 (UNC7437) decreased cellular proliferation and tritiated inositol phosphate levels in metabolically labeled human U251-MG glioblastoma cells. Compound 1 also regulated the transcriptome of these cells, selectively regulating genes that are enriched in cancer, inflammatory and viral infection pathways. Further optimization of compound 1 eventually led to compound 15 (UNC9750), which showed improved potency and pharmacokinetics in rodents. Compound 15 specifically inhibited cellular accumulation of InsP 5 , a direct product of IPMK kinase activity, while having no effect on InsP 6 levels, revealing a novel metabolic signature detected for the first time by rapid chemical attenuation of cellular IPMK activity. These studies designed, optimized and synthesized a new series of IPMK inhibitors, which reduces glioblastoma cell growth, induces a novel InsP 5 metabolic signature, and reveals novel aspects inositol phosphate cellular metabolism and signaling.

Multiple inositol phosphate species enhance stability of active mTOR.

Mechanistic Target of Rapamycin (mTOR) binds the small metabolite inositol hexakisphosphate (IP6) as shown in structures of mTOR, however it remains unclear if IP6, or any other inositol phosphate species, can activate mTOR kinase activity. Here, we show that multiple, exogenously added inositol phosphate species (IP6, IP5, IP4 and IP3) can all enhance the ability of mTOR and mTORC1 to auto-phosphorylate and incorporate radiolabeled phosphate into peptide substrates in in vitro kinase reactions. Although IP6 did not affect the apparent KM of mTORC1 for ATP, monitoring kinase activity over longer reaction times showed increased product formation, suggesting inositol phosphates stabilize an active form of mTORC1 in vitro. The effects of IP6 on mTOR were reversible, suggesting IP6 bound to mTOR can be exchanged dynamically with the free solvent. Interestingly, we also observed that IP6 could alter mTOR solubility and electrophoretic mobility in SDS-PAGE in the presence of manganese, suggesting divalent cations may play a role in inositol phosphate regulation of mTOR. Together, these data suggest for the first time that multiple inositol phosphate species (IP4, IP5 and IP6) can dynamically regulate mTOR and mTORC1 by promoting a stable, active state of the kinase. Our data suggest that studies of the dynamics of inositol phosphate regulation of mTOR are well justified.

Effects of ivermectin on development of Calliphora vicina, Robineau-Desvoidy 1830 (Diptera, Calliphoridae).

Ivermectin is one of the most widely used drugs for parasite control. Previous studies have shown a reduction in the abundance and diversity of "non-target" coprophilous organisms due to the presence of ivermectin (IVM) in bovine faecal matter (FM). Due to its breadth of behavioural habits, Calliphora vicina is a suitable dipteran species to evaluate the effects of IVM in FM. The aim of this work was to evaluate the effect of five concentrations of IVM in FM (3000, 300, 100, 30, and 3 ng/g) on the development of C. vicina. The following endpoints were evaluated: survival (between the first larval stage and emergence of new adults), larval development times to pupation and pupation times to adult, and adult emergence (% sex) and LC50. Sampling was performed from larval hatching at 60 and 120 min and at 3, 4, 5, and 12 h, and every 24 h specimens were weighed until pupae were observed. Data were analysed by ANOVA using a non-parametric Kruskal-Wallis test and as a function of elapsed development time and accumulated degree hours (ADH). Mortality at 3000 and 300 ng/g was 100% and 97%, respectively. There were statistically significant delays in adult emergence time (p = 0.0216) and in the ADH (p = 0.0431) between the control group (C) and 100 ng/g. The LC50 was determined at 5.6 ng/g. These results demonstrate the lethal and sub-lethal effects of IVM on C. vicina, while highlighting the usefulness of this species as a bioindicator for ecotoxicological studies.

Ferrostatin-1 mitigates cellular damage in a ferroptosis-like environment in Caenorhabditis elegans.

Although iron (Fe) is the most biologically abundant transition metal, it is highly toxic when it accumulates as Fe2+, forming a labile Fe pool and favoring the Fenton reaction. This oxidative scenario leads to a type of caspase-independent programmed cell death, referred to as ferroptosis, where following processes take place: 1) Fe2+ overload; 2) glutathione peroxidase 4 inactivation; 3) lipid peroxidation and 4) glutathione depletion. The present study sought to evaluate the consequences of Fe2+ administration on ferroptosis induction in Caenorhabditis elegans. We demonstrated higher mortality, increased lipid peroxidation, reduced glutathione peroxidase activity, and morphological damage in dopaminergic neurons upon Fe2+ overload. Pharmacological intervention at the level of lipid peroxidation with ferrostatin-1 (250 µM) mitigated the damage and returned the biochemical parameters to basal levels, revealing the potential of this therapeutical approach. Finally, to assess the relationship between ferroptosis and dopamine in a Parkinsonian background, we evaluated the UA44 worm strain which overexpresses the alpha-synuclein protein in cherry-labeled dopaminergic neurons. We demonstrated that Fe2+ administration reduced lethality associated with similar alterations in biochemical and dopaminergic morphological parameters in wild-type animals. These experiments provide mechanistic-based evidence on the efficacy of a pharmacological approach to mitigate the physiological, biochemical, and morphological consequences of Fe2+ overload. At the same time, they encourage further research on the impact of the combined effects resulting from the genetic background and dopamine signaling in a Parkinsonian phenotype.

Enduring Ethanol-Induced Behavioral Alterations in Caenorhabditis elegans After Developmental Lead Exposure.

The roundworm Caenorhabditis elegans (C. elegans) has become a powerful tool to evaluate the deleterious effects of early-life exposure to xenobiotics, including metals. The present chapter describes a detailed protocol for developmental lead (Pb)-exposure in C. elegans. Preliminary assays as well as the final procedure are described in detail. In addition, further protocols aimed to assess ethanol exposure at later stages of life demonstrate the impact of this drug on locomotor behavior, revealing the enduring effects that Pb can imprint on this organism when exposure occurs during development.

Visceral fat sympathectomy ameliorates systemic and local stress response related to chronic sleep restriction.

Disturbance of sleep homeostasis encompasses health issues, including metabolic disorders like obesity, diabetes, and augmented stress vulnerability. Sleep and stress interact bidirectionally to influence the central nervous system and metabolism. Murine models demonstrate that decreased sleep time is associated with an increased systemic stress response, characterized by endocrinal imbalance, including the elevated activity of hypothalamic-pituitary-adrenal axis, augmented insulin, and reduced adiponectin, affecting peripheral organs physiology, mainly the white adipose tissue (WAT). Within peripheral organs, a local stress response can also be activated by promoting the formation of corticosterone. This local amplifying glucocorticoid signaling is favored through the activation of the enzyme 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1). In WAT, 11ß-HSD1 activity is upregulated by the sympathetic nervous system, suggesting a link between sleep loss, augmented stress response, and a potential WAT metabolic disturbance. To gain more understanding about this relationship, metabolic and stress responses of WAT-sympathectomized rats were analyzed to identify the contribution of the autonomic nervous system to stress response-related metabolic disorders during chronic sleep restriction. Male Wistar rats under sleep restriction were allowed just 6 h of daily sleep over eight weeks. Results showed that rats under sleep restriction presented higher serum corticosterone, increased adipose tissue 11ß-HSD1 activity, weight loss, decreased visceral fat, augmented adiponectin, lower leptin levels, glucose tolerance impairment, and mildly decreased daily body temperature. In contrast, sympathectomized rats under sleep restriction exhibited decreased stress response (lower serum corticosterone and 11ß-HSD1 activity). In addition, they maintained weight loss, explained by a reduced visceral fat pad, leptin, and adiponectin, improved glucose management, and persisting decline in body temperature. These results suggest autonomic nervous system is partially responsible for the WAT-exacerbated stress response and its metabolic and physiological disturbances.

25 Years of PI5P.

The accidental discovery of PI5P (phosphatidylinositol-5-phosphate) was published 25 years ago, when PIP5K type II (phosphoinositide-4-phosphate 5-kinase) was shown to actually be a 4-kinase that uses PI5P as a substrate to generate PI(4,5)P2. Consequently, PIP5K type II was renamed to PI5P4K, or PIP4K for short, and PI5P became the last of the 7 signaling phosphoinositides to be discovered. Much of what we know about PI5P comes from genetic studies of PIP4K, as the pathways for PI5P synthesis, the downstream targets of PI5P and how PI5P affects cellular function all remain largely enigmatic. Nevertheless, PI5P and PI5P-dependent PI(4,5)P2 synthesis have been clearly implicated in metabolic homeostasis and in diseases such as cancer. Here, we review the past 25 years of PI5P research, with particular emphasis on the impact this small signaling lipid has on human health.

ALDH2 inhibition by lead and ethanol elicits redox imbalance and mitochondrial dysfunction in SH-SY5Y human neuroblastoma cell line: Reversion by Alda-1.

Lead (Pb), a common environmental contaminant, and ethanol (EtOH), a widely available drug of abuse, are well-known neurotoxicants. In vivo, experimental evidence indicates that Pb exposure affects oxidative EtOH metabolism with a high impact on living organisms. On these bases, we evaluated the consequences of combined Pb and EtOH exposure on aldehyde dehydrogenase 2 (ALDH2) functionality. In vitro exposure to 10 µM Pb, 200 mM EtOH, or their combination for 24 h reduced ALDH2 activity and content in SH-SY5Y human neuroblastoma cells. In this scenario, we observed mitochondrial dysfunction characterized by reduced mass and membrane potential, decreased maximal respiration, and spare capacity. We also evaluated the oxidative balance in these cells finding a significant increase in reactive oxygen species (ROS) production and lipid peroxidation products under all treatments accompanied by an increase in catalase (CAT) activity and content. These data suggest that ALDH2 inhibition induces the activation of converging cytotoxic mechanisms resulting in an interplay between mitochondrial dysfunction and oxidative stress. Notably, NAD+ (1 mM for 24 h) restored ALDH2 activity in all groups, while an ALDH2 enhancer (Alda-1, 20 µM for 24 h) also reversed some of the deleterious effects resulting from impaired ALDH2 function. Overall, these results reveal the crucial role of this enzyme on the Pb and EtOH interaction and the potential of activators such as Alda-1 as therapeutic approaches against several conditions involving aldehydes accumulation.

Low-dose N-acetyl cysteine prevents paraquat-induced mortality in Caenorhabditis elegans.

Exposure to the herbicide paraquat (PQ; 1,1'-dimethyl-4,4'-bipyridinium dichloride) affects the redox balance of the cell, an effect that can be restored by antioxidants, including N-acetyl cysteine (NAC). One hour of exposure to PQ (0 mM, 10 mM, 50 mM, or 100 mM) dose-dependently increased mortality in Caenorhabditis elegans after exposure (immediate toxicity), while this effect was more evident 24 hours thereafter (delayed toxicity). Importantly, pretreatment with NAC 0.5 mM for one hour partially prevented mortality in the immediate assay, while it had no effect in the delayed test, revealing the importance of long-term studies when evaluating toxicity.

Building bridges to care: the experience of peer navigation in enabling linkage to PrEP for adolescent men who have sex with men and transgender women.

Vulnerable populations are at increased risk for HIV/AIDS, especially adolescent men who have sex with men (AMSM) and adolescent travestis and transgender women (ATGW). Pre-exposure prophylaxis (PrEP) is one component of combination HIV prevention and is already available for these populations in Brazil. However, ensuring its uptake entails certain challenges since inequality and barriers have traditionally marked access and linkage to the related public health services. Peer navigation could be a way of mediating the linkage process because it involves peers keeping track of others' care schedules, dynamically fostering linkage to care according to the needs of users and the actors involved in their everyday care contexts. Therefore, this study proposes analyzing peer-navigator-mediated linkage to PrEP care for 15- to 19-year-old MSM and transgender women from the PrEP1519 project in Salvador, Bahia State, Brazil. In total, 15 field notebooks/diaries, written in April-July 2019, by four peer navigators were analyzed, as were the transcripts of one focal group and 20 semi-structured interviews with adolescents (17 MSM and three trans women) between June and December 2019. Linkage via peer navigator and participant is influenced by emotional dynamics and shared personal characteristics. It is fluid and unstable and calls for care practices to be shaped to meet each participant's needs. For peer navigation to be adopted as a care strategy for sexually transmitted infection prevention and treatment, it should envisage not only increased linkage to care but also sensitivity to service users' specific characteristics and lived experiences.

Hemoglobin increases leukocyte adhesion and initiates lung microvascular endothelial activation via Toll-like receptor 4 signaling.

Cell-free hemoglobin is a pathophysiological driver of endothelial injury during sepsis and acute respiratory distress syndrome (ARDS), but the precise mechanisms are not fully understood. We hypothesized that hemoglobin (Hb) increases leukocyte adhesion and endothelial activation in human lung microvascular endothelial cells (HLMVEC). We stimulated primary HLMVEC, or leukocytes isolated from healthy human donors, with Hb (0.5 mg/mL) and found that leukocyte adhesion to lung endothelium in response to Hb is an endothelial-dependent process. Next, we stimulated HLMVEC with Hb over time (1, 3, 6, and 24 h) and found increased transcription and release of inflammatory cytokines (IL-1ß, IL-8, and IL-6). In addition, Hb exposure variably upregulated transcription, total protein expression, and cell-surface localization of adhesion molecules E-selectin, P-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1). Since VCAM-1 was most upregulated by Hb, we further tested mechanisms for Hb-mediated upregulation of VCAM-1 in HLMVEC. Although upregulation of VCAM-1 was not prevented by hemoglobin scavenger haptoglobin, heme scavenger hemopexin, or inhibition of nod-like receptor protein 3 (NLRP3) signaling, blocking Toll-like receptor 4 (TLR4) with small molecule inhibitor TAK-242 (1 µM) prevented upregulation of VCAM-1 in response to Hb. Consistently, Hb increased nuclear factor-κB (NF-κB) activation and intracellular reactive oxygen species (ROS), which were both prevented by TLR4 inhibition. Together, these data demonstrate that Hb increases leukocyte-endothelial adhesion and activates HLMVEC through TLR4 signaling, indicating a potential mechanism for Hb-mediated pulmonary vascular injury during inflammatory and hemolytic conditions.

The Impact of Intimate Partner Violence on Young Women's Educational Well-Being: A Systematic Review of Literature.

Research highlights that romantic relationships of young people are not all 'puppy love' but can be also abusive. Intimate partner violence (IPV) is a gendered phenomenon as it primarily affects women who are at a higher risk of more severe forms of violence and also suffer more severe consequences than young men. IPV leads to substantial negative outcomes such as mental health decline, economic insecurity and/or academic underachievement. Particularly for young females, education is a powerful protective factor against re-victimisation and economic dependence which often forces women to remain trapped in abusive relationships. This review was conducted to integrate and summarise research available on IPV and its impact on young women's educational well-being to fill a significant gap in the literature. Under the guidance of PRISMA, terms related to the criteria of young women aged 10-24, IPV and education were searched in the databases EBSCO, PsycINFO, Scopus, ProQuest and CINAHL. While the initial search yielded 6005 articles, we were left with only 10 articles for the analysis. In summary, the evidence suggests that females tend to display issues around concentration, absenteeism and academic disengagement, as well as decline in performance such as failing grades and higher drop out rates.

Building bridges to care: the experience of peer navigation in enabling linkage to PrEP for adolescent men who have sex with men and transgender women / Construindo pontes para o cuidado: a experiência da navegação de pares na habilitação do vínculo com a PrEP para homens adolescentes que fazem sexo com homens e mulheres transgêneros / Construcción de puentes hacia el cuidado: la experiencia de navegación entre pares para permitir la vinculación con la PrEP para hombres adolescentes que tienen relaciones sexuales con hombres y mujeres transgénero

Vulnerable populations are at increased risk for HIV/AIDS, especially adolescent men who have sex with men (AMSM) and adolescent travestis and transgender women (ATGW). Pre-exposure prophylaxis (PrEP) is one component of combination HIV prevention and is already available for these populations in Brazil. However, ensuring its uptake entails certain challenges since inequality and barriers have traditionally marked access and linkage to the related public health services. Peer navigation could be a way of mediating the linkage process because it involves peers keeping track of others' care schedules, dynamically fostering linkage to care according to the needs of users and the actors involved in their everyday care contexts. Therefore, this study proposes analyzing peer-navigator-mediated linkage to PrEP care for 15- to 19-year-old MSM and transgender women from the PrEP1519 project in Salvador, Bahia State, Brazil. In total, 15 field notebooks/diaries, written in April-July 2019, by four peer navigators were analyzed, as were the transcripts of one focal group and 20 semi-structured interviews with adolescents (17 MSM and three trans women) between June and December 2019. Linkage via peer navigator and participant is influenced by emotional dynamics and shared personal characteristics. It is fluid and unstable and calls for care practices to be shaped to meet each participant's needs. For peer navigation to be adopted as a care strategy for sexually transmitted infection prevention and treatment, it should envisage not only increased linkage to care but also sensitivity to service users' specific characteristics and lived experiences.

Populações vulneráveis têm maior risco de contrair HIV/aids, especialmente homens adolescentes que fazem sexo com homens (AHSH) e mulheres transgêneros adolescentes e travestis. A profilaxia pré-exposição (PrEP) é um componente da combinação de prevenção do HIV e já está disponível para essas populações no Brasil. No entanto, garantir a captação da PrEP implica certos desafios, uma vez que o acesso e a vinculação aos serviços públicos de saúde relacionados a ela tem sido tradicionalmente marcados pela desigualdade e por outras barreiras. A navegação de pares pode ser uma forma de mediar o processo de vinculação pois envolve os pares que acompanham as rotinas de cuidado dos outros, estimulando dinamicamente a vinculação ao cuidado de acordo com as necessidades dos usuários e dos atores envolvidos em seus cotidianos. Este estudo propõe, portanto, analisar a vinculação ao cuidado com a PrEP mediada por navegação de pares para homens que fazem sexo com homens e mulheres transgênero de 15 a 19 anos do projeto PrEP1519 em Salvador, Bahia, Brasil. Foram analisados 15 cadernos/diários de campo escritos por 4 navegadores(as) de pares em abril a julho de 2019 assim como as transcrições de um grupo focal e 20 entrevistas semiestruturadas com adolescentes (17 HSH e três mulheres trans) de junho a dezembro de 2019. O vínculo entre navegador e participante é influenciado pela dinâmica emocional e características pessoais compartilhadas. É fluido e instável e necessita que as práticas de cuidado sejam moldadas para atender às necessidades de cada participante. Para que a navegação de pares seja adotada como estratégia de cuidado para prevenir e tratar infecções sexualmente transmissíveis, o método deve prever não apenas o aumento da vinculação ao cuidado mas também a sensibilidade às características específicas dos usuários e as suas experiências de vida.

Las poblaciones vulnerables tienen mayor riesgo de contraer el VIH/SIDA, especialmente los hombres adolescentes que tienen sexo con hombres (AHSH) y las mujeres adolescentes transgénero y travestis. La profilaxis previa a la exposición (PrEP) es un componente de la combinación de prevención del VIH y ahora está disponible para estas poblaciones en Brasil. Sin embargo, la obtención de la PrEP implica ciertos desafíos, ya que el acceso y los vínculos con los servicios de salud pública relacionados con la PrEP han sido marcados en general por la desigualdad y otras barreras. La navegación entre pares puede ser una forma de mediar el proceso de vinculación, puesto que involucra a los pares acompañando las rutinas de cuidado de los demás, estimulando dinámicamente el vínculo del cuidado según las necesidades de los usuarios y actores involucrados en su cotidiano. Este estudio propone analizar el vínculo del cuidado de la PrEP mediada por la navegación entre pares para hombres que tienen relaciones sexuales con hombres y mujeres transgénero, con edades entre los 15 y los 19 años y que participan en el proyecto PrEP1519 en Salvador, Bahia, Brasil. Cuatro navegantes pares analizaron 15 cuadernos/diarios de campo escritos entre abril y julio de 2019, así como las transcripciones de un grupo focal y 20 entrevistas semiestructuradas con adolescentes (17 HSH y tres mujeres trans) realizadas de junio a diciembre de 2019. El vínculo entre el navegador y el participante estuvo influenciado por dinámicas emocionales y características personales compartidas. Este vínculo es fluido e inestable, además requiere que las prácticas de cuidado sean capaces de satisfacer las necesidades de cada participante. Para que la navegación entre pares sea una estrategia de cuidado en la prevención y tratamiento de las infecciones de transmisión sexual, el método necesita proporcionar no solo una mayor vinculación con el cuidado, sino también una concientización de las características específicas de los usuarios y sus experiencias de vida.

Building bridges to care: the experience of peer navigation in enabling linkage to PrEP for adolescent men who have sex with men and transgender women / Construindo pontes para o cuidado: a experiência da navegação de pares na habilitação do vínculo com a PrEP para homens adolescentes que fazem sexo com homens e mulheres transgêneros / Construcción de puentes hacia el cuidado: la experiencia de navegación entre pares para permitir la vinculación con la PrEP para hombres adolescentes que tienen relaciones sexuales con hombres y mujeres transgénero

Vulnerable populations are at increased risk for HIV/AIDS, especially adolescent men who have sex with men (AMSM) and adolescent travestis and transgender women (ATGW). Pre-exposure prophylaxis (PrEP) is one component of combination HIV prevention and is already available for these populations in Brazil. However, ensuring its uptake entails certain challenges since inequality and barriers have traditionally marked access and linkage to the related public health services. Peer navigation could be a way of mediating the linkage process because it involves peers keeping track of others' care schedules, dynamically fostering linkage to care according to the needs of users and the actors involved in their everyday care contexts. Therefore, this study proposes analyzing peer-navigator-mediated linkage to PrEP care for 15- to 19-year-old MSM and transgender women from the PrEP1519 project in Salvador, Bahia State, Brazil. In total, 15 field notebooks/diaries, written in April-July 2019, by four peer navigators were analyzed, as were the transcripts of one focal group and 20 semi-structured interviews with adolescents (17 MSM and three trans women) between June and December 2019. Linkage via peer navigator and participant is influenced by emotional dynamics and shared personal characteristics. It is fluid and unstable and calls for care practices to be shaped to meet each participant's needs. For peer navigation to be adopted as a care strategy for sexually transmitted infection prevention and treatment, it should envisage not only increased linkage to care but also sensitivity to service users' specific characteristics and lived experiences.

Populações vulneráveis têm maior risco de contrair HIV/aids, especialmente homens adolescentes que fazem sexo com homens (AHSH) e mulheres transgêneros adolescentes e travestis. A profilaxia pré-exposição (PrEP) é um componente da combinação de prevenção do HIV e já está disponível para essas populações no Brasil. No entanto, garantir a captação da PrEP implica certos desafios, uma vez que o acesso e a vinculação aos serviços públicos de saúde relacionados a ela tem sido tradicionalmente marcados pela desigualdade e por outras barreiras. A navegação de pares pode ser uma forma de mediar o processo de vinculação pois envolve os pares que acompanham as rotinas de cuidado dos outros, estimulando dinamicamente a vinculação ao cuidado de acordo com as necessidades dos usuários e dos atores envolvidos em seus cotidianos. Este estudo propõe, portanto, analisar a vinculação ao cuidado com a PrEP mediada por navegação de pares para homens que fazem sexo com homens e mulheres transgênero de 15 a 19 anos do projeto PrEP1519 em Salvador, Bahia, Brasil. Foram analisados 15 cadernos/diários de campo escritos por 4 navegadores(as) de pares em abril a julho de 2019 assim como as transcrições de um grupo focal e 20 entrevistas semiestruturadas com adolescentes (17 HSH e três mulheres trans) de junho a dezembro de 2019. O vínculo entre navegador e participante é influenciado pela dinâmica emocional e características pessoais compartilhadas. É fluido e instável e necessita que as práticas de cuidado sejam moldadas para atender às necessidades de cada participante. Para que a navegação de pares seja adotada como estratégia de cuidado para prevenir e tratar infecções sexualmente transmissíveis, o método deve prever não apenas o aumento da vinculação ao cuidado mas também a sensibilidade às características específicas dos usuários e as suas experiências de vida.

Las poblaciones vulnerables tienen mayor riesgo de contraer el VIH/SIDA, especialmente los hombres adolescentes que tienen sexo con hombres (AHSH) y las mujeres adolescentes transgénero y travestis. La profilaxis previa a la exposición (PrEP) es un componente de la combinación de prevención del VIH y ahora está disponible para estas poblaciones en Brasil. Sin embargo, la obtención de la PrEP implica ciertos desafíos, ya que el acceso y los vínculos con los servicios de salud pública relacionados con la PrEP han sido marcados en general por la desigualdad y otras barreras. La navegación entre pares puede ser una forma de mediar el proceso de vinculación, puesto que involucra a los pares acompañando las rutinas de cuidado de los demás, estimulando dinámicamente el vínculo del cuidado según las necesidades de los usuarios y actores involucrados en su cotidiano. Este estudio propone analizar el vínculo del cuidado de la PrEP mediada por la navegación entre pares para hombres que tienen relaciones sexuales con hombres y mujeres transgénero, con edades entre los 15 y los 19 años y que participan en el proyecto PrEP1519 en Salvador, Bahia, Brasil. Cuatro navegantes pares analizaron 15 cuadernos/diarios de campo escritos entre abril y julio de 2019, así como las transcripciones de un grupo focal y 20 entrevistas semiestructuradas con adolescentes (17 HSH y tres mujeres trans) realizadas de junio a diciembre de 2019. El vínculo entre el navegador y el participante estuvo influenciado por dinámicas emocionales y características personales compartidas. Este vínculo es fluido e inestable, además requiere que las prácticas de cuidado sean capaces de satisfacer las necesidades de cada participante. Para que la navegación entre pares sea una estrategia de cuidado en la prevención y tratamiento de las infecciones de transmisión sexual, el método necesita proporcionar no solo una mayor vinculación con el cuidado, sino también una concientización de las características específicas de los usuarios y sus experiencias de vida.

Reduced acute functional tolerance and enhanced preference for ethanol in Caenorhabditis elegans exposed to lead during development: Potential role of alcohol dehydrogenase.

Despite its relative simplicity, the invertebrate Caenorhabditis elegans (C. elegans) has become a powerful tool to evaluate toxicity. Lead (Pb) persistence in the environment and its distinctive characteristic as a neurodevelopmental toxicant determine the potential effects of this metal against challenging events later in life. Additionally, among other psychoactive substances, low to moderate ethanol (EtOH) doses have been pointed out to induce behaviors such as acute functional tolerance (AFT) and drug-induced chemotaxis. In the present study, we aimed to study the impact of early-life Pb exposure on EtOH-induced motivational and stimulant effects in C. elegans by assessing the preference for EtOH and the participation of alcohol dehydrogenase (ADH, sorbitol dehydrogenase -SODH in worms) in the AFT response. Thus, N2 (wild type) and RB2114 (sod-1 -/-) strains developmentally exposed to 24 µM Pb were evaluated in their AFT to 200 mM EtOH alone and in combination with acetaldehyde (ACD). We ascribed the enhanced EtOH-induced AFT observed in the N2 Pb-exposed animals to a reduced ADH functionality as evaluated by both, ADH activity determination and the allyl alcohol test, which altogether suggest excess EtOH accumulation rather than low ACD formation in these animals. Moreover, the Pb-induced preference for EtOH indicates enhanced motivational effects of this drug as a consequence of early-life exposure to Pb, results that resemble our previous reports in rodents and provide a close association between EtOH stimulant and motivational effects in these animals.

Mitochondrial transporter expression patterns distinguish tumor from normal tissue and identify cancer subtypes with different survival and metabolism.

Transporters of the inner mitochondrial membrane are essential to metabolism. We demonstrate that metabolism as represented by expression of genes encoding SLC25 transporters differentiates human cancers. Tumor to normal tissue expression ratios for clear cell renal cell carcinoma, colon adenocarcinoma, lung adenocarcinoma and breast invasive carcinoma were found to be highly significant. Affinity propagation trained on SLC25 gene expression patterns from 19 human cancer types (6825 TCGA samples) and normal tissues (2322 GTEx samples) was used to generate clusters. They differentiate cancers from normal tissues. They also indicate cancer subtypes with survivals distinct from the total patient population of the cancer type. Probing the kidney, colon, lung, and breast cancer clusters, subtype pairs of cancers were identified with distinct prognoses and differing in expression of protein coding genes from among 2080 metabolic enzymes assayed. We demonstrate that SLC25 expression clusters facilitate the identification of the tissue-of-origin, essential to efficacy of most cancer therapies, of CUPs (cancer-unknown-primary) known to have poor prognoses. Different cancer types within a single cluster have similar metabolic patterns and this raises the possibility that such cancers may respond similarly to existing and new anti-cancer therapies.

Developmental lead exposure affects dopaminergic neuron morphology and modifies basal slowing response in Caenorhabditis elegans: Effects of ethanol.

Lead (Pb) and ethanol (EtOH) are neurotoxicants that affect the dopaminergic (DAergic) system. We first sought to assess the morphology of the DAergic neurons in the Caenorhabditis elegans BY200 strain. The results demonstrated dose-dependent damage in these neurons induced by developmental Pb exposure. Secondly, transgenic worms exposed to 24 µM Pb and administered with 200 mM EtOH were evaluated in the basal slowing response (BSR). Pb induced impairment in the BSR in the wild-type strain that did not improve in response to EtOH, an effect also observed in strains that lack the DOP-1, DOP-2, and DOP-3 receptors. The animals that overexpress tyrosine hydroxylase (TH), or lack the vesicular transport (VMAT) showed a Pb-induced impairment in the BSR that seemed to improve after EtOH. Interestingly, a dramatic impairment in the BSR was observed in the Pb group in strains lacking the DOP-4 receptor, resembling the response of the TH-deficient strain, an effect that in both cases showed a non-significant reversal by EtOH. These results suggest that the facilitatory effect of EtOH on the impaired BSR observed in Pb-exposed null mutant strains may be the result of a compensatory effect in the altered DAergic synapse present in these animals.