RESUMEN
Translational control of gene expression is an important regulator of adult stem cell quiescence, activation and self-renewal. In skeletal muscle, quiescent satellite cells maintain low levels of protein synthesis, mediated in part through the phosphorylation of eIF2α (P-eIF2α). Pharmacological inhibition of the eIF2α phosphatase with the small molecule sal003 maintains P-eIF2α and permits the expansion of satellite cells ex vivo Paradoxically, P-eIF2α also increases the translation of specific mRNAs, which is mediated by P-eIF2α-dependent read-through of inhibitory upstream open reading frames (uORFs). Here, we ask whether P-eIF2α-dependent mRNA translation enables expansion of satellite cells. Using transcriptomic and proteomic analyses, we show a number of genes associated with the assembly of the spindle pole to be upregulated at the level of protein, without corresponding change in mRNA levels, in satellite cells expanded in the presence of sal003. We show that uORFs in the 5' UTR of mRNA for the mitotic spindle stability gene Tacc3 direct P-eIF2α-dependent translation. Satellite cells deficient for TACC3 exhibit defects in expansion, self-renewal and regeneration of skeletal muscle.
Asunto(s)
Factor 2 Eucariótico de Iniciación/metabolismo , Proteínas Fetales/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Biosíntesis de Proteínas , Células Satélite del Músculo Esquelético/citología , Células Satélite del Músculo Esquelético/metabolismo , Animales , Diferenciación Celular/genética , Proliferación Celular , Autorrenovación de las Células , Células Cultivadas , Regulación hacia Abajo/genética , Ratones Endogámicos C57BL , Factor de Transcripción PAX7/metabolismo , Fosforilación , Proteoma/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Regeneración , Transcriptoma/genética , Regulación hacia Arriba/genéticaRESUMEN
OBJECTIVE: There is a need to understand how family engagement in the intensive care unit (ICU) impacts patient outcomes. We reviewed the literature for randomized family-centered interventions with patient-related outcomes in the adult ICU. DATA SOURCES: The MEDLINE, EMBASE, PsycINFO, CINAHL, and the Cochrane Library databases were searched from inception until July 3, 2023. STUDY SELECTION: Articles involving randomized controlled trials (RCTs) in the adult critical care setting evaluating family-centered interventions and reporting patient-related outcomes. DATA EXTRACTION: Author, publication year, setting, number of participants, intervention category, intervention, and patient-related outcomes (patient-reported, physiological, clinical) were extracted. DATA SYNTHESIS: There were 28 RCTs (12,174 participants) included. The most common intervention types were receiving care and meeting needs (N = 10) and family presence (N = 7). 16 RCTs (57%) reported ≥1 positive outcome from the intervention; no studies reported worse outcomes. Studies reported improvements in patient-reported outcomes such as anxiety, satisfaction, post-traumatic stress symptoms, depression, and health-related quality of life. RCTs reported improvements in physiological indices, adverse events, mechanical ventilation duration, analgesia use, ICU length of stay, delirium, and time to withdrawal of life-sustaining treatments. CONCLUSIONS: Nearly two-thirds of RCTs evaluating family-centered interventions in the adult ICU reported positive patient-related outcomes. KEYPOINTS: Question: Do family-centered interventions improve patient outcomes in the adult intensive care unit (ICU)? FINDINGS: The systematic review found that nearly two-thirds of randomized clinical trials of family-centered interventions in the adult ICU improved patient outcomes. Studies found improvements in patient mental health, care satisfaction, physiological indices, and clinical outcomes. There were no studies reporting worse patient outcomes. Meaning: Many family-centered interventions can improve patient outcomes.
Asunto(s)
Familia , Unidades de Cuidados Intensivos , Ensayos Clínicos Controlados Aleatorios como Asunto , Humanos , Familia/psicología , Adulto , Cuidados Críticos , Medición de Resultados Informados por el PacienteRESUMEN
This study was conducted on five commercial farms across Victoria, Australia, between September 2018 and November 2019, where the TM status of ewes was within normal ranges before joining. Mix breed ewes (n = 1484) were randomly allocated to receive either nil treatment (Control) or two injections of an ITM product containing zinc (40 mg/mL), manganese (10 mg/mL), selenium (3 mg/mL), and copper (10 mg/mL); 0.2 mL per 10 kg BW (Multimin® plus Copper for Sheep, Virbac (Australia) Pty Ltd., Milperra, NSW, Australia) 30 days before the start of joining and 30 days before the start of lambing. Approximately 90 days after joining, pregnancy status and conception rate were determined by ultrasound. The marking rate was determined approximately four weeks after the end of lambing, and lamb weights were determined at weaning (12 weeks after the end of lambing). In all farms, ITM treatment did not affect the conception rate. The average conception rate was 156 ± 11.0% (p > 0.05). The marking rate of ITM ewes was 9% higher than control ewes (95% Confidence Interval 3−21%). Lambs born to ITM ewes were 2.31 kg heavier at weaning than lambs born to control ewes (p < 0.001). Although not significant, ewe mortality across farms was 1.3% lower in the ITM group than in the control group. On average, ewes treated with ITM pre-joining and pre-lambing produced more and heavier lambs that represent an extra AU$ 2338 per 100 ewes net benefit for the producer. These results help to understand strategic TM supplementation for animal health, performance and farm profitability beyond the treatment of clinical deficiencies.
RESUMEN
Activation of microglia in the spinal cord dorsal horn after peripheral nerve injury contributes to the development of pain hypersensitivity. How activated microglia selectively enhance the activity of spinal nociceptive circuits is not well understood. We discovered that after peripheral nerve injury, microglia degrade extracellular matrix structures, perineuronal nets (PNNs), in lamina I of the spinal cord dorsal horn. Lamina I PNNs selectively enwrap spinoparabrachial projection neurons, which integrate nociceptive information in the spinal cord and convey it to supraspinal brain regions to induce pain sensation. Degradation of PNNs by microglia enhances the activity of projection neurons and induces pain-related behaviors. Thus, nerve injury-induced degradation of PNNs is a mechanism by which microglia selectively augment the output of spinal nociceptive circuits and cause pain hypersensitivity.
Asunto(s)
Hiperalgesia , Microglía , Dolor , Traumatismos de los Nervios Periféricos , Asta Dorsal de la Médula Espinal , Animales , Matriz Extracelular/patología , Hiperalgesia/etiología , Hiperalgesia/patología , Hiperalgesia/fisiopatología , Microglía/patología , Dolor/patología , Dolor/fisiopatología , Traumatismos de los Nervios Periféricos/complicaciones , Traumatismos de los Nervios Periféricos/patología , Ratas , Ratas Sprague-Dawley , Asta Dorsal de la Médula Espinal/patología , Asta Dorsal de la Médula Espinal/fisiopatologíaRESUMEN
Magnocellular vasopressin (VP) neurones are activated by increases in blood osmolality, leading to the secretion of VP into the circulation to promote water retention in the kidney, thus constituting a key mechanism for the regulation of body fluid homeostasis. However, chronic high salt intake can lead to excessive activation of VP neurones and increased circulating levels of VP, contributing to an elevation in blood pressure. Multiple extrinsic factors, such as synaptic inputs and glial cells, modulate the activity of VP neurones. Moreover, magnocellular neurones are intrinsically osmosensitive, and are activated by hypertonicity in the absence of neighbouring cells or synaptic contacts. Hypertonicity triggers cell shrinking, leading to the activation of VP neurones. This cell-autonomous activation is mediated by a scaffold of dense somatic microtubules, uniquely present in VP magnocellular neurones. Treating isolated magnocellular neurones with drugs modulating microtubule stability modifies the sensitivity of neuronal activation in response to acute hypertonic stimuli. However, whether the microtubule network is altered in conditions associated with enhanced neuronal activation and increased VP release, such as chronic high salt intake, remains unknown. We examined the organisation of microtubules in VP neurones of the supraoptic and paraventricular hypothalamic nuclei (SON and PVN, respectively) of rats subjected to salt-loading (drinking 2% NaCl for 7 days). Using super-resolution imaging, we found that the density of microtubules in magnocellular VP neurones from the SON and PVN was significantly increased, whereas the density and organisation of microtubules remain unchanged in other hypothalamic neurones, as well as in neurones from other brain areas (e.g., hippocampus, cortex). We propose that the increase in microtubule density in magnocellular VP neurones in salt-loading promotes their enhanced activation, possibly contributing to elevated blood pressure in this condition.
Asunto(s)
Microtúbulos/metabolismo , Neuronas/metabolismo , Núcleo Hipotalámico Paraventricular/metabolismo , Cloruro de Sodio/administración & dosificación , Núcleo Supraóptico/metabolismo , Vasopresinas/metabolismo , Animales , Masculino , Concentración Osmolar , Ratas Wistar , Cloruro de Sodio/metabolismoRESUMEN
Magnocellular neurosecretory cells (MNCs) are intrinsically osmosensitive and can be activated by increases in blood osmolality, triggering the release of antidiuretic hormone vasopressin (VP) to promote water retention. Hence, the activity of magnocellular VP neurons is one of the key elements contributing to the regulation of body fluid homeostasis in healthy organisms. Chronic exposure to high dietary salt leads to excessive activation of VP neurons, thereby elevating levels of circulating VP, which can cause increases in blood pressure contributing to salt-dependent hypertension. However, the molecular basis underlying high-salt diet-induced hyperactivation of magnocellular VP neurons remains not fully understood. Previous studies suggest that magnocellular neurosecretory neurons contain a subcortical layer of actin filaments and pharmacological stabilization of this actin network potentiates osmotically-induced activation of magnocellular neurons. Using super-resolution imaging in situ, we investigated the organization of the actin cytoskeleton in rat MNCs under normal physiological conditions and after a chronic increase in blood osmolality following 7 d of salt-loading (SL). We found that, in addition to the subcortical layer of actin filaments, magnocellular VP neurons are endowed with a unique network of cytoplasmic actin filaments throughout their somata. Moreover, we revealed that the density of both subcortical and cytoplasmic actin networks in magnocellular VP neurons is dramatically increased following SL. These results suggest that increased osmo-responsiveness of VP neurons following chronic exposure to high dietary salt may be mediated by the modulation of unique actin networks in magnocellular VP neurons, possibly contributing to elevated blood pressure in this condition.