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1.
Cell ; 161(2): 197-8, 2015 Apr 09.
Artículo en Inglés | MEDLINE | ID: mdl-25860602

RESUMEN

Lysosomes provide a major source for cellular cholesterol; however, most of this cholesterol is trafficked to the plasma membrane via unknown mechanisms. Chu et al. identify an unexpected role for peroxisomes in the transport of cholesterol from the lysosome to the plasma membrane via a lysosome-peroxisome membrane contact site.


Asunto(s)
Colesterol/metabolismo , Lisosomas/metabolismo , Peroxisomas/metabolismo , ARN Interferente Pequeño/metabolismo , Animales , Humanos
2.
Mol Cell ; 80(4): 736-743.e4, 2020 11 19.
Artículo en Inglés | MEDLINE | ID: mdl-33098764

RESUMEN

The phosphoinositide PI(3,5)P2, generated exclusively by the PIKfyve lipid kinase complex, is key for lysosomal biology. Here, we explore how PI(3,5)P2 levels within cells are regulated. We find the PIKfyve complex comprises five copies of the scaffolding protein Vac14 and one copy each of the lipid kinase PIKfyve, generating PI(3,5)P2 from PI3P and the lipid phosphatase Fig4, reversing the reaction. Fig4 is active as a lipid phosphatase in the ternary complex, whereas PIKfyve within the complex cannot access membrane-incorporated phosphoinositides due to steric constraints. We find further that the phosphoinositide-directed activities of both PIKfyve and Fig4 are regulated by protein-directed activities within the complex. PIKfyve autophosphorylation represses its lipid kinase activity and stimulates Fig4 lipid phosphatase activity. Further, Fig4 is also a protein phosphatase acting on PIKfyve to stimulate its lipid kinase activity, explaining why catalytically active Fig4 is required for maximal PI(3,5)P2 production by PIKfyve in vivo.


Asunto(s)
Membrana Celular/metabolismo , Flavoproteínas/metabolismo , Homeostasis , Lisosomas/metabolismo , Fosfatidilinositol 3-Quinasas/química , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfatos de Fosfatidilinositol/metabolismo , Monoéster Fosfórico Hidrolasas/metabolismo , Flavoproteínas/química , Flavoproteínas/genética , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Monoéster Fosfórico Hidrolasas/química , Monoéster Fosfórico Hidrolasas/genética , Fosforilación , Unión Proteica , Conformación Proteica , Transporte de Proteínas
3.
Proc Natl Acad Sci U S A ; 121(27): e2403777121, 2024 Jul 02.
Artículo en Inglés | MEDLINE | ID: mdl-38916998

RESUMEN

Spinal cord dorsal horn inhibition is critical to the processing of sensory inputs, and its impairment leads to mechanical allodynia. How this decreased inhibition occurs and whether its restoration alleviates allodynic pain are poorly understood. Here, we show that a critical step in the loss of inhibitory tone is the change in the firing pattern of inhibitory parvalbumin (PV)-expressing neurons (PVNs). Our results show that PV, a calcium-binding protein, controls the firing activity of PVNs by enabling them to sustain high-frequency tonic firing patterns. Upon nerve injury, PVNs transition to adaptive firing and decrease their PV expression. Interestingly, decreased PV is necessary and sufficient for the development of mechanical allodynia and the transition of PVNs to adaptive firing. This transition of the firing pattern is due to the recruitment of calcium-activated potassium (SK) channels, and blocking them during chronic pain restores normal tonic firing and alleviates chronic pain. Our findings indicate that PV is essential for controlling the firing pattern of PVNs and for preventing allodynia. Developing approaches to manipulate these mechanisms may lead to different strategies for chronic pain relief.


Asunto(s)
Dolor Crónico , Parvalbúminas , Parvalbúminas/metabolismo , Animales , Dolor Crónico/metabolismo , Dolor Crónico/fisiopatología , Ratones , Neuronas/metabolismo , Neuronas/fisiología , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatología , Masculino , Potenciales de Acción/fisiología , Canales de Potasio de Pequeña Conductancia Activados por el Calcio/metabolismo
4.
J Neurosci ; 43(31): 5608-5622, 2023 08 02.
Artículo en Inglés | MEDLINE | ID: mdl-37451982

RESUMEN

Parvalbumin-expressing interneurons (PVINs) play a crucial role within the dorsal horn of the spinal cord by preventing touch inputs from activating pain circuits. In both male and female mice, nerve injury decreases PVINs' output via mechanisms that are not fully understood. In this study, we show that PVINs from nerve-injured male mice change their firing pattern from tonic to adaptive. To examine the ionic mechanisms responsible for this decreased output, we used a reparametrized Hodgkin-Huxley type model of PVINs, which predicted (1) the firing pattern transition is because of an increased contribution of small conductance calcium-activated potassium (SK) channels, enabled by (2) impairment in intracellular calcium buffering systems. Analyzing the dynamics of the Hodgkin-Huxley type model further demonstrated that a generalized Hopf bifurcation differentiates the two types of state transitions observed in the transient firing of PVINs. Importantly, this predicted mechanism holds true when we embed the PVIN model within the neuronal circuit model of the spinal dorsal horn. To experimentally validate this hypothesized mechanism, we used pharmacological modulators of SK channels and demonstrated that (1) tonic firing PVINs from naive male mice become adaptive when exposed to an SK channel activator, and (2) adapting PVINs from nerve-injured male mice return to tonic firing on SK channel blockade. Our work provides important insights into the cellular mechanism underlying the decreased output of PVINs in the spinal dorsal horn after nerve injury and highlights potential pharmacological targets for new and effective treatment approaches to neuropathic pain.SIGNIFICANCE STATEMENT Parvalbumin-expressing interneurons (PVINs) exert crucial inhibitory control over Aß fiber-mediated nociceptive pathways at the spinal dorsal horn. The loss of their inhibitory tone leads to neuropathic symptoms, such as mechanical allodynia, via mechanisms that are not fully understood. This study identifies the reduced intrinsic excitability of PVINs as a potential cause for their decreased inhibitory output in nerve-injured condition. Combining computational and experimental approaches, we predict a calcium-dependent mechanism that modulates PVINs' electrical activity following nerve injury: a depletion of cytosolic calcium buffer allows for the rapid accumulation of intracellular calcium through the active membranes, which in turn potentiates SK channels and impedes spike generation. Our results therefore pinpoint SK channels as potential therapeutic targets for treating neuropathic symptoms.


Asunto(s)
Calcio , Neuralgia , Ratones , Masculino , Femenino , Animales , Parvalbúminas/metabolismo , Neuralgia/metabolismo , Interneuronas/fisiología , Asta Dorsal de la Médula Espinal/metabolismo
5.
EMBO Rep ; 23(4): e53477, 2022 04 05.
Artículo en Inglés | MEDLINE | ID: mdl-35166010

RESUMEN

The vacuole/lysosome plays essential roles in the growth and proliferation of many eukaryotic cells via the activation of target of rapamycin complex 1 (TORC1). Moreover, the yeast vacuole/lysosome is necessary for progression of the cell division cycle, in part via signaling through the TORC1 pathway. Here, we show that an essential cyclin-dependent kinase, Bur1, plays a critical role in cell cycle progression in cooperation with TORC1. A mutation in BUR1 combined with a defect in vacuole inheritance shows a synthetic growth defect. Importantly, the double mutant, as well as a bur1-267 mutant on its own, has a severe defect in cell cycle progression from G1 phase. In further support that BUR1 functions with TORC1, mutation of bur1 alone results in high sensitivity to rapamycin, a TORC1 inhibitor. Mechanistic insight for Bur1 function comes from the findings that Bur1 directly phosphorylates Sch9, a target of TORC1, and that both Bur1 and TORC1 are required for the activation of Sch9. Together, these discoveries suggest that multiple signals converge on Sch9 to promote cell cycle progression.


Asunto(s)
Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae , Vacuolas , Ciclo Celular/genética , Quinasas Ciclina-Dependientes/genética , Quinasas Ciclina-Dependientes/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/genética , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Factores de Transcripción , Vacuolas/metabolismo
6.
Res Nurs Health ; 47(4): 369-383, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38804202

RESUMEN

When children experience extreme or persistent stressors (e.g., maltreatment, housing insecurity, intimate partner violence), prolonged elevation of the stress-response system can lead to disrupted development of multiple physiological systems. This response, known as toxic stress, is associated with poor physical and mental health across the life course. Emerging evidence suggests that the effects of toxic stress may be transmitted through generations, but the biological and behavioral mechanisms that link caregivers' childhood history with the health of the children they care for remain poorly understood. The purpose of this report is to describe the research protocol for The CARING (Childhood Adversity and Resilience In the Next Generation) Study, a cross-sectional study of caregivers with children aged 3-5 years designed to (1) examine the intergenerational transmission of toxic stress and protective factors; (2) explore three hypothesized pathways of transmission: parenting, daily routines, stressors, and supports; and (3) explore the extent to which genotypic variation in candidate genes related to caregiving and stress contribute to caregivers' and children's susceptibility to the effects of early childhood experiences (i.e., gene × environment interactions). We expect that findings from this study will provide critical data needed to identify targets for precision health interventions, reduce health disparities related to toxic stress, and prevent cycles of adversity among families at risk.


Asunto(s)
Cuidadores , Estrés Psicológico , Humanos , Femenino , Estudios Transversales , Masculino , Estrés Psicológico/psicología , Preescolar , Cuidadores/psicología , Cuidadores/estadística & datos numéricos , Adulto , Relaciones Intergeneracionales , Experiencias Adversas de la Infancia/estadística & datos numéricos , Responsabilidad Parental/psicología , Interacción Gen-Ambiente
7.
Public Health Nurs ; 40(5): 740-749, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37317821

RESUMEN

BACKGROUND AND OBJECTIVE: Virtual interviewing in qualitative research may promote inclusion, diversify samples, and maximize participation, but there is limited research regarding methodological best practices for marginalized study populations. Emerging adult (ages 18-29) and young adult (through age 40) mothers have ongoing stressors and competing responsibilities that may preclude participation with in-person interviews. The purpose of this article is to describe the processes and experiences of virtual interviewing among young adult mothers living in under-resourced communities, based on their responses to specific interview questions. DESIGN AND SAMPLE: As part of an explanatory sequential mixed methods study, qualitative interviews were conducted with a sample of young adult mothers who had previously participated in randomized controlled trials testing an intensive early home visiting intervention. Thirty-one participants (M = 29.7 years, SD = 2.5) who identified as Black (39%), Hispanic (55%), and White (7%), were interviewed using Zoom. RESULTS: The overarching theme was Zoom: Appreciating the New Norm. Identified categories were Practical Benefits of Virtual Interviewing, Sharing Stories, and Drawbacks of Virtual Interviewing. CONCLUSION: Findings support virtual interviewing as a feasible and potentially ideal method for qualitative studies with emerging/young adults. Further research to examine this approach with other marginalized populations may lead to more inclusive representation in qualitative research.


Asunto(s)
Madres , Femenino , Humanos , Adulto Joven , Adulto , Ensayos Clínicos Controlados Aleatorios como Asunto
8.
J Sch Nurs ; 39(3): 238-247, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-37154069

RESUMEN

This study explored adolescent perspectives on school-based health center (SBHC) services and how services differed from school nurses and community agencies. Six focus groups were conducted with adolescents, 13-19 years old, as part of a larger mixed-methods study. Data were analyzed for themes using content analysis. Adolescents (N = 30) described the accessibility, positive attitude of staff, competence of the nurse practitioner, confidentiality/privacy, and trusted relationships with staff as important aspects of SBHC care. SBHC services allowed adolescents to stay in school, provided confidentiality/privacy, were comfortable and convenient, fostered their independence, and adolescents felt SBHC staff knew them and they did not feel like strangers. SBHCs are adolescent-friendly resources that maximize school time and an important source for contraception, sexually transmitted infection testing, and mental health care. Additionally, SBHC services help support adolescents' transition from pediatric to adolescent-focused care and foster their growing self-awareness and empowerment related to their engagement in health care services.


Asunto(s)
Servicios de Salud del Adolescente , Servicios de Enfermería Escolar , Humanos , Adolescente , Niño , Adulto Joven , Adulto , Servicios de Salud Escolar , Grupos Focales , Confidencialidad
9.
J Sch Nurs ; : 10598405231179680, 2023 Jun 12.
Artículo en Inglés | MEDLINE | ID: mdl-37309163

RESUMEN

Sleep is critical to teen physical and mental health, daily function, and school performance. Yet, sleep deficiency is prevalent among ethnoracially diverse teens. The purpose of this community-engaged focus group study was to explore multilevel influences on teen sleep from teen and community stakeholder perspectives and to use this information to develop a tailored sleep health intervention. We conducted seven focus groups (N = 46) and analyzed data via content analysis. Five themes, each with subthemes, described sleep knowledge/attitudes, sleep habits, the multilevel causes and consequences of decreased nighttime sleep and suggestions for improving teen sleep. Teen health, mood, and school engagement were all impacted by inadequate nighttime sleep. Exhaustion emerged as an overarching theme and coincided with the transition to high school. The data from this study provide insight into important areas of focus for a sleep intervention tailored to the needs of ethnoracially diverse teens living in an urban community.

10.
Support Care Cancer ; 30(11): 8637-8653, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-35650456

RESUMEN

PURPOSE: Tumour blood vessels are structurally and functionally abnormal, resulting in areas of hypoxia and heterogeneous blood supply. Aerobic exercise may modulate tumour blood flow and normalise the tumour microenvironment to improve chemotherapy delivery. This systematic review and meta-analysis aimed to evaluate the effect of the aerobic exercise mode on tumour hypoxia, vascularisation and blood flow. METHODS: Four online databases were searched. Preclinical and clinical randomised controlled trials examining the effects of aerobic exercise training on hypoxia, vascularisation or blood flow in solid tumours were included. The risk of bias was assessed and a meta-analysis performed. RESULTS: Seventeen preclinical studies and one clinical study met criteria. Eleven studies assessed hypoxia, 15 studies assessed vascularisation and seven evaluated blood flow. There was large variability in measurement methods, tumour types and exercise program designs. The overall risk of bias was unclear in clinical and preclinical studies, owing to poor reporting. There was no significant effect of aerobic exercise on hypoxia (SMD = -0.17; 95% CI = -0.62, 0.28; I2 = 60%), vascularisation (SMD = 0.07; 95% CI = -0.40, 0.55; I2 = 71%) or blood flow (SMD = 0.01; 95% CI = -0.59, 0.61; I2 = 63%). CONCLUSION: There is heterogeneity in methodology, resulting in evidence that is inconsistent and inconclusive for the effects of aerobic exercise on hypoxia, vascularisation and blood flow. Most evidence of aerobic exercise effects on tumour blood flow is in animal models, with very limited evidence in humans.


Asunto(s)
Ejercicio Físico , Neoplasias , Humanos , Neoplasias/terapia , Hipoxia , Terapia por Ejercicio , Microambiente Tumoral
11.
Dev Psychopathol ; 34(1): 55-67, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-32907642

RESUMEN

Multiple interventions have been developed to improve the caregiver-child relationship as a buffer to the effects of early life adversity and toxic stress. However, relatively few studies have evaluated the long-term effects of these early childhood interventions, particularly on parenting and childhood behaviors. Here we describe the early school-age follow-up results of a randomized controlled trial of Minding the Baby ® (MTB), a reflective, attachment-based, trauma-informed, preventive home-visiting intervention for first-time mothers and their infants. Results indicate that mothers who participated in MTB are less likely to show impaired mentalizing compared to control mothers two to eight years after the intervention ended. Additionally, MTB mothers have lower levels of hostile and coercive parenting, and their children have lower total and externalizing problem behavior scores when compared to controls at follow-up. We discuss our findings in terms of their contribution to understanding the long-term parenting and childhood socio-emotional developmental effects of early preventive interventions for stressed populations.


Asunto(s)
Conducta Infantil , Visita Domiciliaria , Relaciones Madre-Hijo , Responsabilidad Parental , Experiencias Adversas de la Infancia/prevención & control , Niño , Conducta Infantil/psicología , Desarrollo Infantil , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Lactante , Relaciones Madre-Hijo/psicología , Madres/psicología , Responsabilidad Parental/psicología , Servicios Preventivos de Salud , Poblaciones Vulnerables/psicología
12.
Matern Child Health J ; 26(4): 941-952, 2022 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-34982339

RESUMEN

INTRODUCTION: Home visiting (HV) programs aim to promote child and family health through perinatal intervention. HV may benefit second children through improving subsequent pregnancy and birth outcomes. However, HV impacts on birth outcomes of second children have not been examined in a naturalistic setting. METHODS: Using data from Connecticut Nurturing Families Network (NFN) home visiting program of families enrolled from 2005 to 2015, we compared birth-related outcomes (birthweight, preterm birth, Cesarean section delivery, prenatal care utilization) of second children (n = 1758) to demographically similar propensity-score-matched families that were not enrolled in NFN (n = 5200). We examined whether the effects of NFN differed by maternal age, race and ethnicity, or visit attendance pattern. RESULTS: There was no program effect for the full sample. The effect of NFN did not differ by maternal age or visit attendance pattern but did differ by maternal race and ethnicity. Black women in NFN were more likely to receive adequate prenatal care during their second pregnancy (OR 1.05; 95% CI 1.01, 1.09) and Hispanic women in NFN were less likely to deliver by Cesarean section for their second birth (OR 0.97; 95% CI 0.94, 0.99), compared to Black and Hispanic women in the comparison group respectively. There was a protective program effect on prematurity of the second child (OR 0.92; 95% CI 0.85, 0.996) for women with a preterm first birth. DISCUSSION: These findings suggest that benefits of HV extend to subsequent birth-related outcomes for women from marginalized racial/ethnic groups. HV may help buffer some harmful social determinants of health.


Asunto(s)
Cesárea , Nacimiento Prematuro , Niño , Femenino , Humanos , Recién Nacido , Edad Materna , Padres , Embarazo , Atención Prenatal
13.
J Adv Nurs ; 78(11): 3495-3516, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-35774012

RESUMEN

AIMS: To enhance conceptual clarity and interdisciplinary understanding of structural violence, and to illuminate its implications for contemporary social justice and health equity research, by: (1) synthesizing scholarly literature pertaining to structural violence and health; (2) defining its key attributes, antecedents, consequences and characteristics; (3) contextually situating this phenomenon over time and across disciplines. DESIGN: A comprehensive review of scholarly health literature pertaining to 'structural violence' or its surrogate term 'structural determinants of health' was guided by a Research and Education Librarian. DATA SOURCES: In November 2019 and again in April 2021, CINAHL, Embase, Global Health, Medline, PsycINFO, PubMed and Scopus electronic databases were searched for peer-reviewed articles that described structural violence in the context of health. Of the 238 unique records identified, 32 articles were selected for inclusion and comprise the review sample. REVIEW METHODS: Using Beth Rodgers' evolutionary concept analysis method, articles were comparatively analysed to identify key attributes, antecedents and consequences associated with the concept's use in health research. RESULTS: The five interrelated attributes characterizing structural violence are: power, marginality, oppression, adversity and trauma. Hegemonic social, cultural, economic and political systems serve as antecedents, whilst the consequences of structural violence can be broadly classified as health inequity, injustice and indignity, and social disorganization. CONCLUSION: This analysis contributes to conceptual clarity and mutual understanding of the usage, application and significance of structural violence across health disciplines and provides a strong foundation for continued concept development and operationalization. Further research is needed to substantiate the relationship between structural violence and health inequity.


Asunto(s)
Formación de Concepto , Violencia , Humanos
14.
Res Nurs Health ; 45(3): 390-400, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35388528

RESUMEN

In retrospective cohort studies of interventions disseminated to communities, it is challenging to find comparison groups with high-quality data for evaluation. We present one methodological approach as part of our study of birth outcomes of second-born children in a home visiting (HV) program targeting first-time mothers. We used probabilistic record linkage to link Connecticut's Nurturing Families Network (NFN) HV program and birth-certificate data for children born from 2005 to 2015. We identified two potential comparison groups: a propensity-score-matched group from the remaining birth certificate sample and eligible-but-unenrolled families. An analysis of interpregnancy interval (IPI) is presented to exemplify the approach. We identified the birth certificates of 4822 NFN families. The propensity-score-matched group had 14,219 families (3-to-1 matching) and we identified 1101 eligible-but-unenrolled families. Covariates were well balanced for the propensity-score-matched group, but poorly balanced for the eligible-but-unenrolled group. No program effect on IPI was found. By combining propensity-score matching and probabilistic record linkage, we were able to retrospectively identify relatively large comparison groups for quasi-experimental research. Using birth certificate data, we accessed outcomes for all of these individuals from a single data source. Multiple comparison groups allow us to confirm findings when each method has some limitations. Other researchers seeking community-based comparison groups could consider a similar approach.


Asunto(s)
Exactitud de los Datos , Madres , Niño , Femenino , Humanos , Estudios Retrospectivos
15.
Aust Crit Care ; 35(4): 391-401, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-34474961

RESUMEN

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is a rescue treatment option for adult patients with severe cardiac dysfunction or respiratory failure. While short-term patient outcomes, such as in-hospital mortality and complications, have been widely described, little is known about the illness or recovery experience from the perspectives of survivors. Subjective reports of health are important indicators of the full, long-term impact of critical illness and treatment with ECMO on survivors' lives. OBJECTIVE: The objective of this study was to describe the experiences and needs of adults treated with ECMO, from onset of illness symptoms through the process of survivorship. METHODS: This study was guided by the qualitative method of interpretive description. We conducted in-depth, semistructured interviews with 16 adult survivors of ECMO who were treated at two participating regional ECMO centres in the northeast United States. Additional data were collected from demographic questionnaires, field notes, memos, and medical record review. Development of interview guides and data analysis were informed by the Family Management Style Framework. Qualitative data were analysed using thematic analysis techniques. RESULTS: The sample (n = 16) included 75% male participants; ages ranged from 23 to 65 years. Duration from hospital discharge to interviews ranged from 11 to 90 (M = 54; standard deviation = 28) months. Survivors progressed through three stages: Trauma and Vulnerability, Resiliency and Recovery, and Survivorship. Participants described short- and long-term impacts of the ECMO experience: all experienced physical challenges, two-thirds had at least one psychological or cognitive difficulty, and 25% were unable to return to work. All were deeply influenced by their own specific contexts, family support, and interactions with healthcare providers. CONCLUSIONS: The ECMO experience is traumatic and complex. Recovery requires considerable time, perseverance, and support. Long-term sequelae include impairments in cognitive, mental, emotional, physical, and social health. Survivors could likely benefit from specialised posthospital health services that include integrated, comprehensive follow-up care.


Asunto(s)
Oxigenación por Membrana Extracorpórea , Insuficiencia Respiratoria , Adulto , Anciano , Enfermedad Crítica , Oxigenación por Membrana Extracorpórea/efectos adversos , Oxigenación por Membrana Extracorpórea/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Calidad de Vida , Insuficiencia Respiratoria/terapia , Estudios Retrospectivos , Sobrevivientes/psicología , Adulto Joven
16.
J Cell Sci ; 132(5)2019 02 28.
Artículo en Inglés | MEDLINE | ID: mdl-30709920

RESUMEN

The metabolism of PI(3,5)P2 is regulated by the PIKfyve, VAC14 and FIG4 complex, mutations in which are associated with hypopigmentation in mice. These pigmentation defects indicate a key, but as yet unexplored, physiological relevance of this complex in the biogenesis of melanosomes. Here, we show that PIKfyve activity regulates formation of amyloid matrix composed of PMEL protein within the early endosomes in melanocytes, called stage I melanosomes. PIKfyve activity controls the membrane remodeling of stage I melanosomes, which regulates PMEL abundance, sorting and processing. PIKfyve activity also affects stage I melanosome kiss-and-run interactions with lysosomes, which are required for PMEL amyloidogenesis and the establishment of melanosome identity. Mechanistically, PIKfyve activity promotes both the formation of membrane tubules from stage I melanosomes and their release by modulating endosomal actin branching. Taken together, our data indicate that PIKfyve activity is a key regulator of the melanosomal import-export machinery that fine tunes the formation of functional amyloid fibrils in melanosomes and the maintenance of melanosome identity.This article has an associated First Person interview with the first author of the paper.


Asunto(s)
Flavoproteínas/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Lisosomas/metabolismo , Melanocitos/metabolismo , Melanosomas/metabolismo , Proteínas de la Membrana/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfoinosítido Fosfatasas/metabolismo , Epitelio Pigmentado de la Retina/metabolismo , Amiloide/metabolismo , Animales , Células Cultivadas , Flavoproteínas/genética , Homeostasis , Péptidos y Proteínas de Señalización Intracelular/genética , Melanocitos/patología , Melanosomas/ultraestructura , Proteínas de la Membrana/genética , Ratones , Ratones Noqueados , Fosfatidilinositol 3-Quinasas/genética , Fosfoinosítido Fosfatasas/genética , Transporte de Proteínas , Epitelio Pigmentado de la Retina/patología , Antígeno gp100 del Melanoma/metabolismo
17.
Curr Genet ; 67(6): 865-869, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34110447

RESUMEN

A major question in cell biology is, how are organelles and macromolecular machines moved within a cell? The delivery of cargoes to the right place at the right time within a cell is critical to cellular health. Failure to do so is often catastrophic for animal physiology and results in diseases of the gut, brain, and skin. In budding yeast, a myosin V motor, Myo2, moves cellular materials from the mother cell into the growing daughter bud. Myo2-based transport ensures that cellular contents are shared during cell division. During transport, Myo2 is often linked to its cargo via cargo-specific adaptor proteins. This simple organism thus serves as a powerful tool to study how myosin V moves cargo, such as organelles. Some critical questions include how myosin V moves along the actin cytoskeleton, or how myosin V attaches to cargo in the mother. Other critical questions include how the cargo is released from myosin V when it reaches its final destination in the bud. Here, we review the mechanisms that regulate the vacuole-specific adaptor protein, Vac17, to ensure that Myo2 delivers the vacuole to the bud and releases it at the right place and the right time. Recent studies have revealed that Vac17 is regulated by ubiquitylation and phosphorylation events that coordinate its degradation and the detachment of the vacuole from Myo2. Thus, multiple post-translational modifications tightly coordinate cargo delivery with cellular events. It is tempting to speculate that similar mechanisms regulate other cargoes and molecular motors.


Asunto(s)
Miosina Tipo V/metabolismo , Vacuolas/metabolismo , Levaduras/fisiología , Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Proteínas Fúngicas/metabolismo , Miosina Tipo V/genética , Fosforilación , Transporte de Proteínas , Proteolisis , Ubiquitinación
18.
Nurs Res ; 70(5S Suppl 1): S43-S52, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34173377

RESUMEN

BACKGROUND: Racism is a significant source of toxic stress and a root cause of health inequities. Emerging evidence suggests that exposure to vicarious racism (i.e., racism experienced by a caregiver) is associated with poor child health and development, but associations with biological indicators of toxic stress have not been well studied. It is also unknown whether two-generation interventions, such as early home visiting programs, may help to mitigate the harmful effects of vicarious racism. OBJECTIVE: The purpose of this study was to examine associations between maternal experiences of racial discrimination and child indicators of toxic stress and to test whether relationships are moderated by prior participation in Minding the Baby (MTB), an attachment-based early home visiting intervention. METHODS: Ninety-seven maternal-child dyads (n = 43 intervention dyads, n = 54 control dyads) enrolled in the MTB Early School Age follow-up study. Mothers reported on racial discrimination using the Experiences of Discrimination Scale. Child indicators of toxic stress included salivary biomarkers of inflammation (e.g., C-reactive protein, panel of pro-inflammatory cytokines), body mass index, and maternally reported child behavioral problems. We used linear regression to examine associations between maternal experiences of racial discrimination and child indicators of toxic stress and included an interaction term between experiences of discrimination and MTB group assignment (intervention vs. control) to test moderating effects of the MTB intervention. RESULTS: Mothers identified as Black/African American (33%) and Hispanic/Latina (64%). In adjusted models, maternal experiences of racial discrimination were associated with elevated salivary interleukin-6 and tumor necrosis factor-α levels in children, but not child body mass index or behavior. Prior participation in the MTB intervention moderated the relationship between maternal experiences of discrimination and child interleukin-6 levels. DISCUSSION: Results of this study suggest that racism may contribute to the biological embedding of early adversity through influences on inflammation, but additional research with serum markers is needed to better understand this relationship. Improved understanding of the relationships among vicarious racism, protective factors, and childhood toxic stress is necessary to inform family and systemic-level intervention.


Asunto(s)
Relaciones Madre-Hijo , Madres/psicología , Racismo/psicología , Estrés Psicológico/complicaciones , Biomarcadores/análisis , Índice de Masa Corporal , Niño , Preescolar , Femenino , Visita Domiciliaria/estadística & datos numéricos , Humanos , Madres/estadística & datos numéricos , Psicometría/instrumentación , Psicometría/métodos , Racismo/etnología , Racismo/estadística & datos numéricos , Saliva , Estrés Psicológico/psicología
19.
Prev Sci ; 22(8): 1108-1119, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-33730259

RESUMEN

Prevention of child maltreatment is a goal of home visiting (HV) for new mothers. How home visitors and their clinical supervisors manage concerns about child maltreatment may impact both the families' and the home visitors' engagement with the program. We sought to understand how HV personnel encounter and respond to concerns of child maltreatment and how these concerns are related to their work with families. We conducted an interpretive descriptive qualitative study of home visitors and supervisors in a statewide HV program, using the Parents as Teachers curriculum, to describe the experience of HV personnel. Two researchers conducted semi-structured interviews March 2016 to October 2017. Interviews were concurrently transcribed, coded, and analyzed, using thematic analysis. After 13 interviews with home visitors and 13 interviews with supervisors, codes and themes were saturated. We identified three themes: Decision to Call Child Protective Services (CPS), Relationships, and Collaborating with CPS. The decision to call CPS was described as difficult, and there was substantial variation in the details of this decision. The relationship between home visitor and family was consistently the most important. Variations were seen in how home visitors and supervisors collaborated with CPS, ranging from strong connections through liaisons to frustrations due to poor communication and perceived variation in how cases were handled. The decision to report a family to CPS is a challenging clinical issue; additional training and connections with CPS may improve consistency across sites for home visitors.


Asunto(s)
Maltrato a los Niños , Visita Domiciliaria , Niño , Maltrato a los Niños/prevención & control , Femenino , Humanos , Madres , Atención Posnatal , Embarazo , Investigación Cualitativa
20.
Infant Ment Health J ; 42(1): 60-73, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-32816335

RESUMEN

This article presents the results of a small pilot study examining links between Hostile/Helpless (HH) representations of caregiving in pregnancy and later child removal by child protective services. The sample was drawn from a replication study of the Minding the Baby® attachment-based home-visiting intervention conducted in the United Kingdom, serving young first-time mothers in under resourced communities. The HH classification system (Lyons-Ruth et al.) was adapted for use with the Pregnancy Interview (PI) (Slade); 26 PIs were assessed (coders blinded) in a sample that included 13 mothers whose infants were removed from custody due to anticipated or documented maltreatment within 2 years of childbirth, and 13 mothers who did not have their infants removed. Mothers whose infants were removed from their custody had significantly higher HH scores than mothers of infants who were not removed from their care (F(1, 24) = 14.500, p < .001), and the relation between overall HH classification and infant removal status was also significant (χ2 (1, N = 26) = 12.462, p < .001). Results suggest that prenatal maternal caregiving representations may predict postnatal relationship disruptions, and indicate the need for larger studies further testing this prenatal approach to maltreatment risk assessment in at-risk populations.


Este artículo presenta los resultados de un pequeño estudio piloto que examina las conexiones entre las representaciones Hostiles/Indefensas de la prestación de cuidado durante el embarazo y más tarde cuando los servicios de protección a la niñez han separado al niño. El grupo muestra fue seleccionado de un estudio de replicación de la intervención Cuidando al Bebé (Minding the Baby® -MTB) de visita a casa con base en la afectividad, llevada a cabo en el Reino Unido para servirles a madres jóvenes en comunidades de pocos recursos. El sistema de clasificación Hostil/Indefensa (HH) (Lyons-Ruth et al., 1995-2005) se adaptó para el uso con la Entrevista del Embarazo (PI) (Slade, 2011); se evaluaron 26 entrevistas PI (los codificadores lo hicieron de manera ciega), de un grupo muestra que incluía 13 madres cuyos infantes fueron separados de su custodia debido al anticipado o documentado maltrato dentro de los 2 años anteriores al parto, y 13 madre cuyos infantes no habían sido separados. Las madres cuyos infantes habían sido separado de su custodia presentaron significativamente más altos puntajes HH que las madres de infantes no separados del cuidado materno (F(1, 24) = 14.500, p < .001), y la relación entre la clasificación general HH y la condición de separación del infante fue también significativa (c2(1, N = 26) = 12.462, p < .001). Los resultados sugieren que las representaciones prenatales del cuidado materno pudieran predecir las interrupciones de la relación postnatal, y apuntan a la necesidad de estudios más comprensivos que continúen examinando este acercamiento prenatal a la evaluación del riesgo de maltrato en grupos bajo riesgo.


Cet article présente les résultats d'une petite étude pilote examinant les liens entre les représentations Hostile/Impuissant du mode de soin durant la grossesse et plus tard durant le retrait de l'enfant par les services de protection de l'enfance. Cet échantillon a été retiré d'une étude de réplication de l'intervention sur l'attachement et faite à domicile Minding the Baby (MTB), faite au Royaume Unis, servant de jeunes mères n'ayant pas eu d'enfant auparavant dans des communautés n'ayant pas beaucoup de ressources. Le système de classification HI suivant les initiales en français Hostile/Impuissant (Lyons-Ruth et al., 1995-2005) a été adapté pour une utilisation durant l'Entretien de Grossesse (abrégé selon le français EG ici, Slade, 2011). 26 EG ont été évalués (codage à l'aveugle) dans un échantillon qui a inclus 13 mères dont les bébés avaient été retirés de leur garde pour maltraitance documentée ou anticipée dans les deux ans après la naissance, et 13 mères dont les bébés n'avaient pas été retirés. Les mères dont les bébés avaient été retirés de leur garde avaient des scores HI bien plus élevés que les mères de bébés n'avaient pas été retirés de leur garde (F(1, 24) = 14,500, p <,001), et la relation entre la classification générale HI et le statut de retrait du bébé était aussi importante (c2(1, N = 26) = 12,462, p <,001). Les résultats suggèrent que les représentations de mode de soin maternel prénatal peuvent prédire des perturbations de la relation postnatale, et indiquent le besoin d'études plus grandes testant plus profondément cette approche prétanale de l'évaluation de risque de maltraitance chez des populations à risque.


Asunto(s)
Relaciones Madre-Hijo , Madres , Niño , Emociones , Femenino , Visita Domiciliaria , Humanos , Lactante , Proyectos Piloto , Embarazo
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