RESUMEN
"Helicopter research" refers to a practice where researchers from wealthier countries conduct studies in lower-income countries with little involvement of local researchers or community members. This practice also occurs domestically. In this Commentary, we outline strategies to curb domestic helicopter research and to foster equity-centered collaborations.
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Investigación Biomédica , Participación de la Comunidad , Humanos , Investigadores , Salud Global , National Institutes of Health (U.S.) , Estados Unidos , Poblaciones Minoritarias, Vulnerables y Desiguales en Salud , Inequidades en SaludRESUMEN
Neurotrophins and glucocorticoids are robust synaptic modifiers, and deregulation of their activities is a risk factor for developing stress-related disorders. Low levels of brain-derived neurotrophic factor (BDNF) increase the desensitization of glucocorticoid receptors (GR) and vulnerability to stress, whereas higher levels of BDNF facilitate GR-mediated signaling and the response to antidepressants. However, the molecular mechanism underlying neurotrophic-priming of GR function is poorly understood. Here we provide evidence that activation of a TrkB-MAPK pathway, when paired with the deactivation of a GR-protein phosphatase 5 pathway, resulted in sustained GR phosphorylation at BDNF-sensitive sites that is essential for the transcription of neuronal plasticity genes. Genetic strategies that disrupted GR phosphorylation or TrkB signaling in vivo impaired the neuroplasticity to chronic stress and the effects of the antidepressant fluoxetine. Our findings reveal that the coordinated actions of BDNF and glucocorticoids promote neuronal plasticity and that disruption in either pathway could set the stage for the development of stress-induced psychiatric diseases.
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Antidepresivos/farmacología , Plasticidad Neuronal/fisiología , Receptores de Glucocorticoides/fisiología , Transducción de Señal/fisiología , Estrés Psicológico/fisiopatología , Animales , Factor Neurotrófico Derivado del Encéfalo/fisiología , Femenino , Fluoxetina/farmacología , Sistema de Señalización de MAP Quinasas , Glicoproteínas de Membrana/fisiología , Ratones , Plasticidad Neuronal/efectos de los fármacos , Fosforilación , Proteínas Tirosina Quinasas/fisiología , Ratas , Ratas Sprague-Dawley , Receptor trkBRESUMEN
Well-defined as signaling hormones for the programming of cell type-specific and context-dependent gene expression signatures, glucocorticoids control experience-driven allostasis. One unifying model is that glucocorticoids help maintaining the integrity and plasticity of cellular networks in changing environments through the mobilization of cellular energy stores, profiling of gene expression, and changes in the electrical and morphological properties of cells. The nucleus is their primary site of action, yet recent discoveries point to additional gene transcription-independent functions at the plasma membrane of neuronal synapses. Glucocorticoids are secreted factors that reflect intrinsically the changes coming from the external world, temporally and regionally, during development and adulthood. In this review, we will enumerate the properties and signaling attributes of glucocorticoids and their receptors that characterize them as allostatic modulators. The molecular mechanisms used to support their role at the synapse will be highlighted.
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Glucocorticoides/metabolismo , Transducción de Señal , Regulación Alostérica , Animales , Disponibilidad Biológica , Humanos , Fosforilación , Receptores de Glucocorticoides/metabolismoRESUMEN
Regulation of the hypothalamic-pituitary-adrenal (HPA) axis is critical for adaptation to environmental changes. The principle regulator of the HPA axis is corticotrophin-releasing hormone (CRH), which is made in the parventricular nucleus and is an important target of negative feedback by glucocorticoids. However, the molecular mechanisms that regulate CRH are not fully understood. Disruption of normal HPA axis activity is a major risk factor of neuropsychiatric disorders in which decreased expression of the glucocorticoid receptor (GR) has been documented. To investigate the role of the GR in CRH neurons, we have targeted the deletion of the GR, specifically in the parventricular nucleus. Impairment of GR function in the parventricular nucleus resulted in an enhancement of CRH expression and an up-regulation of hypothalamic levels of BDNF and disinhibition of the HPA axis. BDNF is a stress and activity-dependent factor involved in many activities modulated by the HPA axis. Significantly, ectopic expression of BDNF in vivo increased CRH, whereas reduced expression of BDNF, or its receptor TrkB, decreased CRH expression and normal HPA functions. We find the differential regulation of CRH relies upon the cAMP response-element binding protein coactivator CRTC2, which serves as a switch for BDNF and glucocorticoids to direct the expression of CRH.
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Factor Neurotrófico Derivado del Encéfalo/metabolismo , Hormona Liberadora de Corticotropina/metabolismo , Glucocorticoides/metabolismo , Homeostasis/fisiología , Hipotálamo/fisiología , Receptores de Glucocorticoides/metabolismo , Transactivadores/metabolismo , Análisis de Varianza , Animales , Inmunoprecipitación de Cromatina , Sistema Hipotálamo-Hipofisario/fisiología , Inmunohistoquímica , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microscopía Confocal , Mutagénesis Sitio-Dirigida , Neuronas/metabolismo , Sistema Hipófiso-Suprarrenal/fisiología , Ratas , Ratas Sprague-Dawley , Reacción en Cadena en Tiempo Real de la Polimerasa , Factores de TranscripciónRESUMEN
To retain talented scientists in academia, there is a need for structural reform to postdoctoral researcher (postdoc) mentorship. These changes include mentorship training for postdocs and their mentors, formalizing postdoc mentorship networks and postdoc cohorts within a department, and incorporating mentorship development plans (MDPs) in funding decisions for principal investigators (PIs).
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Mentores , Investigadores , Humanos , Investigadores/educaciónRESUMEN
BACKGROUND: Mentorship is critical to success in postgraduate science, technology, engineering, math, and medicine (STEMM) settings. As such, the purpose of this study is to comprehensively explore the state of mentorship interventions in postgraduate STEMM settings to identify novel practices and future research directions. The selection criteria for reviewed articles included: 1) published between 2002 and 2022, 2) peer-reviewed, 3) in English, 4) postgraduate mentees, 5) a program where mentorship is a significant, explicit focus, and 6) a description of mentee outcomes related to the mentorship intervention. Overall, 2583 articles were screened, and 109 articles were reviewed. RESULTS: Most postgraduate STEMM mentorship intervention studies lack strong evidence to evaluate the effectiveness of the intervention, with only 5.5% of articles designed as randomized controlled trials. Most mentorship interventions (45.6%) were created for faculty, and few (4%) were for postdoctoral researchers. Also, only 18.8% of interventions focused on underrepresented groups in STEMM. Most interventions (53.7%) prescribed a dyadic structure, and there was more mentorship training for mentors than mentees. CONCLUSION: Overall, these findings identify gaps in mentorship interventions and provide step-by-step guidance for future interventions, including a consideration for underrepresented groups and postdoctoral scholars, robust mentorship training, and more randomized controlled trials.
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Mentores , Humanos , Tecnología/educación , Ingeniería/educación , Tutoría , Ciencia/educación , Matemática/educaciónRESUMEN
Many successful researchers in the biomedical sciences have benefitted from mentors and networks earlier in their career. However, early-career researchers from minoritized and underrepresented groups do not have the same access to potential mentors and networks as many of their peers. In this article we describe how 'cold emails' and social media platforms - notably Twitter/X and LinkedIn - can be used to build virtual networks, and stress the need to invest in maintaining networks once they have been established.
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Mentores , Red Social , Humanos , Medios de Comunicación SocialesRESUMEN
Over the past decade, institutions have earmarked more resources to diversity, equity, and inclusion (DEI). However, many struggle to measure the effectiveness of their efforts and communicate them to the scientific community. We offer suggestions for applying rigorous scientific methodology to DEI and ways to promote diversity in scientific journals.
RESUMEN
BACKGROUND: The decision of whether to pursue a tenure-track faculty position has become increasingly difficult for undergraduate, graduate, and postdoctoral trainees considering a career in research. Trainees express concerns over job availability, financial insecurity, and other perceived challenges associated with pursuing an academic position. METHODS: To help further elucidate the benefits, challenges, and strategies for pursuing an academic career, a diverse sample of postdoctoral scholars ("postdocs") from across the United States were asked to provide advice on pursuing a research career in academia in response to an open-ended survey question. 994 responses were qualitatively analyzed using both content and thematic analyses. 177 unique codes, 20 categories, and 10 subthemes emerged from the data and were generalized into two thematic areas: Life in Academia and Strategies for Success. RESULTS: On life in academia, postdoc respondents overwhelmingly agree that academia is most rewarding when you are truly passionate about scientific research and discovery. 'Passion' emerged as the most frequently cited code, referenced 189 times. Financial insecurity, work-life balance, securing grant funding, academic politics, and a competitive job market emerged as challenges of academic research. The survey respondents note that while passion and hard work are necessary, they are not always sufficient to overcome these challenges. The postdocs encourage trainees to be realistic about career expectations and to prepare broadly for career paths that align with their interests, skills, and values. Strategies recommended for perseverance include periodic self-reflection, mental health support, and carefully selecting mentors. CONCLUSIONS: For early-career scientists along the training continuum, this advice deserves critical reflection before committing to an academic research career. For advisors and institutions, this work provides a unique perspective from postdoctoral scholars on elements of the academic training path that can be improved to increase retention, career satisfaction, and preparation for the scientific workforce.
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Selección de Profesión , Investigadores , Investigación , Encuestas y CuestionariosRESUMEN
The lack of diversity among faculty at universities and medical schools in the United States is a matter of growing concern. However, the factors that influence the career choices of underrepresented minority and female postdoctoral researchers have received relatively little attention. Here we report the results of a survey of 1284 postdocs working in the biomedical sciences in the US. Our findings highlight possible reasons why some underrepresented minority and female postdocs choose not to pursue careers in academic research, and suggest interventions that could be taken in the early stages of postdoctoral training to prevent this attrition of underrepresented groups.
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Selección de Profesión , Educación de Postgrado/estadística & datos numéricos , Grupos Minoritarios/estadística & datos numéricos , Investigadores/estadística & datos numéricos , Mujeres , Investigación Biomédica , Estados UnidosRESUMEN
In mouse models of atherosclerosis, normalization of hyperlipidemia promotes macrophage emigration and regression of atherosclerotic plaques in part by liver X receptor (LXR)-mediated induction of the chemokine receptor CCR7. Here we report that LXRα serine 198 (S198) phosphorylation modulates CCR7 expression. Low levels of S198 phosphorylation are observed in plaque macrophages in the regression environment where high levels of CCR7 expression are observed. Consistent with these findings, CCR7 gene expression in human and mouse macrophages cell lines is induced when LXRα at S198 is nonphosphorylated. In bone marrow-derived macrophages (BMDMs), we also observed induction of CCR7 by ligands that promote nonphosphorylated LXRα S198, and this was lost in LXR-deficient BMDMs. LXRα occupancy at the CCR7 promoter is enhanced and histone modifications associated with gene repression are reduced in RAW264.7 cells expressing nonphosphorylated LXRα (RAW-LXRα S198A) compared to RAW264.7 cells expressing wild-type (WT) phosphorylated LXRα (RAW-LXRα WT). Expression profiling of ligand-treated RAW-LXRα S198A cells compared to RAW-LXRα WT cells revealed induction of cell migratory and anti-inflammatory genes and repression of proinflammatory genes. Modeling of LXRα S198 in the nonphosphorylated and phosphorylated states identified phosphorylation-dependent conformational changes in the hinge region commensurate with the presence of sites for protein interaction. Therefore, gene transcription is regulated by LXRα S198 phosphorylation, including that of antiatherogenic genes such as CCR7.
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Expresión Génica/genética , Macrófagos/metabolismo , Receptores Nucleares Huérfanos/genética , Fosforilación/genética , Serina/genética , Animales , Aterosclerosis/genética , Línea Celular , Humanos , Ligandos , Receptores X del Hígado , Ratones , Ratones Endogámicos C57BL , Receptores CCR7RESUMEN
Abnormal glucocorticoid and neurotrophin signaling has been implicated in numerous psychiatric disorders. However, the impact of neurotrophic signaling on glucocorticoid receptor (GR)-dependent gene expression is not understood. We therefore examined the impact of brain-derived neurotrophic factor (BDNF) signaling on GR transcriptional regulatory function by gene expression profiling in primary rat cortical neurons stimulated with the selective GR agonist dexamethasone (Dex) and BDNF, alone or in combination. Simultaneous treatment with BDNF and Dex elicited a unique set of GR-responsive genes associated with neuronal growth and differentiation and also enhanced the induction of a large number of Dex-sensitive genes. BDNF via its receptor TrkB enhanced the transcriptional activity of a synthetic GR reporter, suggesting a direct effect of BDNF signaling on GR function. Indeed, BDNF treatment induces the phosphorylation of GR at serine 155 (S155) and serine 287 (S287). Expression of a nonphosphorylatable mutant (GR S155A/S287A) impaired the induction of a subset of BDNF- and Dex-regulated genes. Mechanistically, BDNF-induced GR phosphorylation increased GR occupancy and cofactor recruitment at the promoter of a BDNF-enhanced gene. GR phosphorylation in vivo is sensitive to changes in the levels of BDNF and TrkB as well as stress. Therefore, BDNF signaling specifies and amplifies the GR transcriptome through a coordinated GR phosphorylation-dependent detection mechanism.
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Factor Neurotrófico Derivado del Encéfalo/metabolismo , Glucocorticoides/metabolismo , Receptores de Glucocorticoides/metabolismo , Animales , Evolución Biológica , Factor Neurotrófico Derivado del Encéfalo/deficiencia , Factor Neurotrófico Derivado del Encéfalo/genética , Células Cultivadas , Secuencia Conservada , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Dexametasona/farmacología , Glucocorticoides/genética , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mutagénesis Sitio-Dirigida , Neuronas/metabolismo , Fosforilación , Regiones Promotoras Genéticas , Ratas , Receptor trkB/deficiencia , Receptor trkB/genética , Receptor trkB/metabolismo , Receptores de Glucocorticoides/deficiencia , Receptores de Glucocorticoides/genética , Transducción de Señal , TranscriptomaRESUMEN
p23 is a heat shock protein 90 (Hsp90) cochaperone located in both the cytoplasm and nucleus that stabilizes unliganded steroid receptors, controls the catalytic activity of certain kinases, regulates protein-DNA dynamics, and is upregulated in several cancers. We had previously shown that p23-overexpressing MCF-7 cells (MCF-7+p23) exhibit increased invasion without affecting the estrogen-dependent proliferative response, which suggests that p23 differentially regulates genes controlling processes linked to breast tumor metastasis. To gain a comprehensive view of the effects of p23 on estrogen receptor (ER)-dependent and -independent gene expression, we profiled mRNA expression from control versus MCF-7+p23 cells in the absence and presence of estrogen. A number of p23-sensitive target genes involved in metastasis and drug resistance were identified. Most striking is that many of these genes are also misregulated in invasive breast cancers, including PMP22, ABCC3, AGR2, Sox3, TM4SF1, and p8 (NUPR1). Upregulation of the ATP-dependent transporter ABCC3 by p23 conferred resistance to the chemotherapeutic agents etoposide and doxorubicin in MCF-7+p23 cells. MCF-7+p23 cells also displayed higher levels of activated Akt and an expanded phosphoproteome relative to control cells, suggesting that elevated p23 also enhances cytoplasmic signaling pathways. For breast cancer patients, tumor stage together with high cytoplasmic p23 expression more accurately predicted disease recurrence and mortality than did stage alone. High nuclear p23 was found to be associated with high cytoplasmic p23, therefore both may promote tumor progression and poor prognosis by increasing metastatic potential and drug resistance in breast cancer patients.