RESUMEN
The brain's neuroreparative capacity after injuries such as ischemic stroke is partly contained in the brain's neurogenic niches, primarily the subventricular zone (SVZ), which lies in close contact with the cerebrospinal fluid (CSF) produced by the choroid plexus (ChP). Despite the wide range of their proposed functions, the ChP/CSF remain among the most understudied compartments of the central nervous system (CNS). Here, we report a mouse genetic tool (the ROSA26iDTR mouse line) for noninvasive, specific, and temporally controllable ablation of CSF-producing ChP epithelial cells to assess the roles of the ChP and CSF in brain homeostasis and injury. Using this model, we demonstrate that ChP ablation causes rapid and permanent CSF volume loss in both aged and young adult brains, accompanied by disruption of ependymal cilia bundles. Surprisingly, ChP ablation did not result in overt neurological deficits at 1 mo postablation. However, we observed a pronounced decrease in the pool of SVZ neuroblasts (NBs) following ChP ablation, which occurs due to their enhanced migration into the olfactory bulb. In the middle cerebral artery occlusion model of ischemic stroke, NB migration into the lesion site was also reduced in the CSF-depleted mice. Thus, our study establishes an important role of ChP/CSF in regulating the regenerative capacity of the adult brain under normal conditions and after ischemic stroke.
Asunto(s)
Plexo Coroideo , Ventrículos Laterales , Neurogénesis , Animales , Plexo Coroideo/metabolismo , Neurogénesis/fisiología , Ratones , Ventrículos Laterales/metabolismo , Ventrículos Laterales/citología , Células-Madre Neurales/metabolismo , Células-Madre Neurales/citología , Accidente Cerebrovascular/patología , Accidente Cerebrovascular/metabolismo , Accidente Cerebrovascular/fisiopatología , Masculino , Movimiento Celular , Ventrículos Cerebrales/metabolismoRESUMEN
The nucleolus has core functions in ribosome biosynthesis, but also acts as a regulatory hub in a plethora of non-canonical processes, including cellular stress. Upon DNA damage, several DNA repair factors shuttle between the nucleolus and the nucleoplasm. Yet, the molecular mechanisms underlying such spatio-temporal protein dynamics remain to be deciphered. Here, we present a novel imaging platform to investigate nucleolar-nucleoplasmic protein shuttling in living cells. For image acquisition, we used a commercially available automated fluorescence microscope and for image analysis, we developed a KNIME workflow with implementation of machine learning-based tools. We validated the method with different nucleolar proteins, i.e., PARP1, TARG1 and APE1, by monitoring their shuttling dynamics upon oxidative stress. As a paradigm, we analyzed PARP1 shuttling upon H2O2 treatment in combination with a range of pharmacological inhibitors in a novel reporter cell line. These experiments revealed that inhibition of SIRT7 results in a loss of nucleolar PARP1 localization. Finally, we unraveled specific differences in PARP1 shuttling dynamics after co-treatment with H2O2 and different clinical PARP inhibitors. Collectively, this work delineates a highly sensitive and versatile bioimaging platform to investigate swift nucleolar-nucleoplasmic protein shuttling in living cells, which can be employed for pharmacological screening and in-depth mechanistic analyses.
RESUMEN
The specific roles that different types of neurons play in recovery from injury is poorly understood. Here, we show that increasing the excitability of ipsilaterally projecting, excitatory V2a neurons using designer receptors exclusively activated by designer drugs (DREADDs) restores rhythmic bursting activity to a previously paralyzed diaphragm within hours, days, or weeks following a C2 hemisection injury. Further, decreasing the excitability of V2a neurons impairs tonic diaphragm activity after injury as well as activation of inspiratory activity by chemosensory stimulation, but does not impact breathing at rest in healthy animals. By examining the patterns of muscle activity produced by modulating the excitability of V2a neurons, we provide evidence that V2a neurons supply tonic drive to phrenic circuits rather than increase rhythmic inspiratory drive at the level of the brainstem. Our results demonstrate that the V2a class of neurons contribute to recovery of respiratory function following injury. We propose that altering V2a excitability is a potential strategy to prevent respiratory motor failure and promote recovery of breathing following spinal cord injury.
Asunto(s)
Diafragma , Traumatismos de la Médula Espinal , Animales , Ratones , Tronco Encefálico , Cafeína , Neuronas , NiacinamidaRESUMEN
The brain's neuroreparative capacity after injuries such as ischemic stroke is contained in the brain's neurogenic niches, primarily the subventricular zone (SVZ), which lies in close contact with the cerebrospinal fluid (CSF) produced by the choroid plexus (ChP). Despite the wide range of their proposed functions, the ChP/CSF remain among the most understudied compartments of the central nervous system (CNS). Here we report a mouse genetic tool (the ROSA26iDTR mouse line) for non-invasive, specific, and temporally controllable ablation of CSF-producing ChP epithelial cells to assess the roles of the ChP and CSF in brain homeostasis and injury. Using this model, we demonstrate that ChP ablation causes rapid and permanent CSF volume loss accompanied by disruption of ependymal cilia bundles. Surprisingly, ChP ablation did not result in overt neurological deficits at one-month post-ablation. However, we observed a pronounced decrease in the pool of SVZ neuroblasts following ChP ablation, which occurs due to their enhanced migration into the olfactory bulb. In the MCAo model of ischemic stroke, neuroblast migration into the lesion site was also reduced in the CSF-depleted mice. Thus, our study establishes an important and novel role of ChP/CSF in regulating the regenerative capacity of the adult brain under normal conditions and after ischemic stroke.
RESUMEN
INTRODUCTION: The present study examined the efficacy of a CogSMART-based program in improving cognitive and emotional functioning in a clinic-based sample of Veterans presenting with cognitive concerns and history of mental health diagnoses. METHOD: Forty Veterans (Mage = 61.2 years, 85% male) completed a weekly CogSMART-based group program as well as a battery of neuropsychological and psychological measures at both pre- and post-group evaluations. Participants met DSM-5 criteria for at least one mental health diagnosis. RESULTS: Significant improvements on global cognition as well as measures of learning/memory and attention were observed from pre- to post-group (p < .05, cohen's d range = .48-1.01). As many as 33.3% of participants showed significant improvement, depending on the cognitive domain. Significant overall improvements were observed in depression symptoms and life satisfaction (p < .01, cohen's d = .67 and .59, respectively). Over one-third of the sample demonstrated a reliable improvement in depressive symptoms, 25% in anxiety symptoms, and 18% in life satisfaction. CONCLUSIONS: Among individuals with mental health diagnosis but without major neurocognitive disorders, CogSMART-based interventions may be an effective treatment for improving aspects of cognition, depression, and life satisfaction.
RESUMEN
Ten bacterial isolates belonging to the genus Vagococcus were obtained from Malian sour milk fènè produced from spontaneously fermented cow milk. However, these isolates could not be assigned to a species upon initial comparative 16S rRNA gene sequence analysis and were therefore further characterized. Rep-PCR fingerprinting of the isolates yielded four strain clusters represented by strains CG-21T (=DSM 21459T), 24CA, CM21 and 9H. Sequence identity of the 16S rRNA gene of DSM 21459T to its closest relative species Vagococcus penaei was 97.9%. Among the four rep strain clusters, DSM 21459T and 24CA shared highest 16S rRNA gene sequence identity of 99.6% while CM21 and 9H shared 98.6-98.8% with DSM 21459T and V. penaei CD276T. DSM 21459T and 24CA were thus subjected to a polyphasic typing approach. The genome of DSM 21459T featured a G+C content of 34.1mol% for a 2.17-bp chromosome and a 15-kbp plasmid. Average nucleotide identity (ANI) of DSM 21459T to Vagococcus fluvialis bH819, V. penaei CD276T were 72.88%, 72.63%, respectively. DNA-DNA hybridization (DDH) similarities of strain DSM 21459T to other Vagococcus species were <42.0%. ANI and DDH findings strongly supported the 16S rRNA gene phylogenetic tree delineations. The fatty acid patterns of DSM 21459T was palmitic acid (C 16:0, 24.5%), oleic acid (C 18:1-ω9c, 32.8%), stearic acid (C 18:0, 18.9%). General physiological characterization of DSM 21459T and 24CA were consistent with those of the genus Vagococcus. Strain DSM 21459T and further strains are therefore considered to belong to a novel species, for which the nomenclature Vagococcus teuberi sp. nov. is proposed. The type strain is named CG-21T (=DSM 21459T and LMG 24695T).
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Productos Lácteos Cultivados/microbiología , Enterococcaceae/genética , Enterococcaceae/aislamiento & purificación , Leche/microbiología , Filogenia , Animales , Técnicas de Tipificación Bacteriana , Composición de Base , Bovinos/microbiología , ADN Bacteriano/genética , Enterococcaceae/clasificación , Ácidos Grasos/química , Malí , Hibridación de Ácido Nucleico , ARN Ribosómico 16S/genética , Análisis de Secuencia de ADNRESUMEN
The current project examined the impact of caregiving and caregiving-work conflict on employees' well-being. A sequential explanatory mixed-methods design (QUANâqual) was utilized, and a total of 880 employees from a large health-care plan employer completed an online survey. Forty-five caregivers who completed the survey also participated in one of the five focus groups held 1 to 2 months later. Employed caregivers were significantly ( p < .05) more likely to indicate poorer physical and mental health than noncaregivers; among caregivers ( n = 370), caregiving-work conflict emerged as the most significant predictor of well-being and fully mediated the empirical relationship between burden and well-being. The focus group findings complemented the quantitative results; many of the challenges employed caregivers experience stem from their ability or inability to effectively balance their employment and caregiving roles. The results suggest the need to focus on caregiving-work conflict when constructing new or translating existing evidence-based caregiver interventions.
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Cuidadores/psicología , Familia/psicología , Satisfacción en el Trabajo , Salud Mental , Adulto , Empleo , Femenino , Grupos Focales , Humanos , Masculino , Persona de Mediana Edad , Encuestas y CuestionariosRESUMEN
PURPOSE: To analyse prognostic factors for long term seizure remission in patients with childhood (CAE) and juvenile absence epilepsy (JAE). STUDY DESIGN: A retrospective analysis of a hospital based prevalence cohort. METHODS: The cohort consisted of 163 patients (104 females, 59 males) treated at the Universitatsklinik fur Neurologie, Innsbruck between 1970 and 1997. All had absences according to the ILAE classification. Follow up was in 1999 to 2000. We assessed multiple clinical and EEG factors as predictors of outcome and compared a classification according to the predominant pattern of seizure recurrence (pyknoleptic, PA or non pyknoleptic absence, NPA) with the ILAE classification with respect to prognosis. RESULTS: The mean age at seizure onset was 10.9 years (range, 3 to 27); age at follow up was 36.7 years (range, 13 to 81); duration of follow up was 25.8 years (range, 3 to 69). Sixty four patients (39 %) had CAE and 64 (39 %) JAE, while 35 (22%) had typical absences but could not be clearly defined as either CAE or JAE, and were therefore called "the overlap group". Patients with JAE or patients in the overlap group developed more often generalized tonic clonic seizures (GTCS) (p<0.001) and myoclonic attacks (p<0.05) during the course of the disease. At follow up 36 (56 %) of patients with CAE, 40 (62%) with JAE and 19 (54 %) of the overlap group were seizure free for at least two years (p=ns). When classified according to the predominant absence pattern at seizure onset 42 (51%) patients with PA and 53 (65%) with NPA were in remission (p=ns). In a stepwise binary logistic regression analysis the pattern of absence (PA or NPA) together with the later development of additional seizure types (myoclonias or GTCS), but not the CAE/JAE classification was predictive for long term lack of remission with a correct prediction of 66% of all patients. CONCLUSION: Only 58% of patients with absences were in remission after a long term follow up. CAE and JAE are closely related syndromes with large overlap of the age of onset. A classification according to the predominant seizure pattern at onset, together with later development of myoclonic attacks or GTCS is useful in predicting seizure remission in absence epilepsies.