A hub-and-spoke nuclear lamina architecture in trypanosomes.
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ABSTRACT:
SUBMITTER: Padilla-Mejia NE
PROVIDER: S-EPMC8255026 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Jacob is a synapto-nuclear messenger protein that couples NMDAR activity to CREB-dependent gene expression. In this study, we investigated the nuclear distribution of Jacob and report a prominent targeting to the nuclear envelope that requires NMDAR activity and nuclear import. Immunogold electron microscopy and proximity ligation assay combined with STED imaging revealed preferential association of Jacob with the inner nuclear membrane where it directly binds to LaminB1, an intermediate filament and core component of the inner nuclear membrane (INM). The association with the INM is transient; it involves a functional nuclear export signal in Jacob and a canonical CRM1-RanGTP-dependent export mechanism that defines the residing time of the protein at the INM. Taken together, the data suggest a stepwise redistribution of Jacob within the nucleus following nuclear import and prior to nuclear export.
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Project description:Glaucoma is an extremely significant public health issue, since it is the most common cause of irreversible blindness worldwide, nevertheless it is still widely undiagnosed because of its devious nature. Glaucoma diagnosis criteria are well-defined and have to be strictly observed and recognized: the earlier the disease is diagnosed, the earlier the patient can undergo the most suitable treatment, the better can be the prognosis. The three levels of prevention are essential in the approach to the disease and its pathophysiological features make it eligible for screening. This review provides an overview of the current state of the art in glaucoma management, starting from its prevention and coming to the hub-and-spoke organization. This model applied to glaucoma aims to direct patients toward professional and not professional figures who may guide them in integrated care pathway. This path should be designed in accordance with best practice to coordinate glaucoma prevention, diagnosis, treatment and follow up with the best cost-benefit ratio, protecting both the interests of the patient and of the society.
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Project description:In the interphase nucleus, chromatin is organized into three-dimensional conformation to coordinate genome functions. The lamina-chromatin association is important to facilitate higher-order chromatin in mammalian cells, but its biological significances and molecular mechanisms remain poorly understood. One obstacle is that the list of lamina-associated proteins remains limited, presumably due to the inherent insolubility of lamina proteins. In this report, we identified 182 proteins associated with lamin B1 (a constitutive component of lamina) in mouse hepatocytes, by adopting virus-based proximity-dependent biotin identification. These proteins are functionally related to biological processes such as chromatin organization. As an example, we validated the association between lamin B1 and core histone macroH2A1, a histone associated with repressive chromatin. Furthermore, we mapped Lamina-associated domains (LADs) in mouse liver cells and found that boundaries of LADs are enriched for macroH2A. More interestingly, knocking-down of macroH2A1 resulted in the release of heterochromatin foci marked by histone lysine 9 trimethylation (H3K9me3) and the decondensation of global chromatin structure. However, down-regulation of lamin B1 led to redistribution of macroH2A1. Taken together, our data indicated that macroH2A1 is associated with lamina and is required to maintain chromatin architecture in mouse liver cells.
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Project description:For acute ischemic stroke patients, shorter time to thrombolytic (tissue plasminogen activator [tPA]) is associated with improved outcomes.Telestroke increases tPA use at spoke hospitals, yet its effect on door-to-needle (DTN) times for tPA administration is unknown. We hypothesize that spoke hospitals with more frequent contact to a hub hospital will have shorter DTN times than those with less frequent contact.We identified 375 patients treated with tPA by conventional or telestroke methods in an academic hub-and-spoke telestroke network for whom date and time data were available. Strength of the spoke-hub connection was the primary predictor variable, defined as the number of all telestroke consults (tPA and non-tPA) done at each spoke hospital during the year of the patient's presentation. Patient-level regression analyses examined the relationship between DTN time and spoke-hub connection during the year of the patient's presentation, controlling for temporal trends and clustering within hospitals.Sixteen spoke hospitals contributed data on 375 tPA-treated patients from 2006-2015. Hospitals treated a median of 13.5 patients with tPA per year; median hospital-level DTN was 78.8?min (interquartile range [IQR] 71.3-85). Median number of telestroke consults per year was 34 (range 3-137). Among all 375 patients, median DTN was 76?min (IQR 60-97). Strength of spoke-hub connection was significantly associated with faster DTN time for patients (1.3?min gain per 10 additional consults, p?=?0.048).More frequent contact between a telestroke spoke and its hub was associated with faster tPA delivery for patients, even after accounting for secular trends in DTN improvements.
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Project description:The American Stroke Association guidelines emphasized the need for further high-quality studies that assess agreement by radiologists and nonradiologists engaged in emergency telestroke assessments and decision-making. Therefore, the objective of this study was to determine the level of agreement of baseline brain CT scan interpretations of patients with acute stroke presenting to telestroke spoke hospitals between central reading committee neuroradiologists and each of 2 groups, spoke hospital radiologists and hub hospital vascular neurologists (telestrokologists).The Stroke Team Remote Evaluation Using a Digital Observation Camera Arizona trial was a prospective, urban single-hub, rural 2-spoke, randomized, blinded, controlled trial of a 2-way, site-independent, audiovisual telemedicine and teleradiology system designed for remote evaluation of adult patients with acute stroke versus telephone consultation to assess eligibility for treatment with intravenous thrombolysis. In the telemedicine arm, the subjects' CT scans were interpreted by the hub telestrokologist and in the telephone arm by the spoke radiologist. All subjects' CT scans were subsequently interpreted centrally, independently, and blindly by 2 hub neuroradiologists. The primary CT outcome was determination of a CT-based contraindication to thrombolytic treatment. Kappa statistics and exact agreement rates were used to analyze interobserver agreement.Fifty-four subjects underwent random assignment. The overall agreement for the presence of radiological contraindications to thrombolysis was excellent (0.91) and did not differ substantially between the hub telestrokologist to neuroradiologist and spoke radiologist to neuroradiologist (0.92 and 0.89, respectively).In the context of a telestroke network designed to assess patients with acute stroke syndromes, agreement over the presence or absence of radiological contraindications to thrombolysis was excellent whether the comparisons were between a telestrokologist and neuroradiologist or between spoke radiologist and neuroradiologist.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00623350.
| S-EPMC3502613 | biostudies-literature
Project description:The nuclear lamina is a complex protein mesh attached to the inner nuclear membrane (INM), which is also associated with nuclear pore complexes. It provides mechanical support to the nucleus and nuclear envelope, and as well as facilitating the connection of the nucleoskeleton to the cytoskeleton, it is also involved in chromatin organization, gene regulation, and signaling. In metazoans, the nuclear lamina consists of a polymeric layer of lamins and other interacting proteins responsible for its association with the INM and chromatin. In plants, field emission scanning electron microscopy of nuclei, and thin section transmission electron microscopy of isolated nucleoskeletons, reveals the lamina to have a similar structure to that of metazoans. Moreover, although plants lack lamin genes and the genes encoding most lamin-binding proteins, the main functions of the lamina are fulfilled in plants. Hence, it would appear that the plant lamina is not based on lamins and that other proteins substitute for lamins in plant cells. The nuclear matrix constituent proteins are the best characterized structural proteins in the plant lamina. Although these proteins do not display strong sequence similarity to lamins, their predicted secondary structure and sub-nuclear distribution, as well as their influence on nuclear size and shape, and on heterochromatin organization, suggest they could be functional lamin analogs. In this review we shall summarize what is currently known about the organization and composition of the plant nuclear lamina and its interacting complexes, and we will discuss the activity of this structure in the plant cell and its nucleus.
| S-EPMC4010787 | biostudies-literature
Project description:Macroautophagy (hereafter referred to as autophagy) is a catabolic membrane trafficking process that degrades a variety of cellular constituents and is associated with human diseases. Although extensive studies have focused on autophagic turnover of cytoplasmic materials, little is known about the role of autophagy in degrading nuclear components. Here we report that the autophagy machinery mediates degradation of nuclear lamina components in mammals. The autophagy protein LC3/Atg8, which is involved in autophagy membrane trafficking and substrate delivery, is present in the nucleus and directly interacts with the nuclear lamina protein lamin B1, and binds to lamin-associated domains on chromatin. This LC3-lamin B1 interaction does not downregulate lamin B1 during starvation, but mediates its degradation upon oncogenic insults, such as by activated RAS. Lamin B1 degradation is achieved by nucleus-to-cytoplasm transport that delivers lamin B1 to the lysosome. Inhibiting autophagy or the LC3-lamin B1 interaction prevents activated RAS-induced lamin B1 loss and attenuates oncogene-induced senescence in primary human cells. Our study suggests that this new function of autophagy acts as a guarding mechanism protecting cells from tumorigenesis.
| S-EPMC4824414 | biostudies-literature
Project description:The hub-and-spoke semantic representation theory posits that semantic knowledge is processed in a neural network, which contains an amodal hub, the sensorimotor modality-specific regions, and the connections between them. The exact neural basis of the hub, regions and connectivity remains unclear. Semantic dementia could be an ideal lesion model to construct the semantic network as this disease presents both amodal and modality-specific semantic processing (e.g. colour) deficits. The goal of the present study was to identify, using an unbiased data-driven approach, the semantic hub and its general and modality-specific semantic white matter connections by investigating the relationship between the lesion degree of the network and the severity of semantic deficits in 33 patients with semantic dementia. Data of diffusion-weighted imaging and behavioural performance in processing knowledge of general semantic and six sensorimotor modalities (i.e. object form, colour, motion, sound, manipulation and function) were collected from each subject. Specifically, to identify the semantic hub, we mapped the white matter nodal degree value (a graph theoretical index) of the 90 regions in the automated anatomical labelling atlas with the general semantic abilities of the patients. Of the regions, only the left fusiform gyrus was identified as the hub because its structural connectivity strength (i.e. nodal degree value) could significantly predict the general semantic processing of the patients. To identify the general and modality-specific semantic connections of the semantic hub, we separately correlated the white matter integrity values of each tract connected with the left fusiform gyrus, with the performance for general semantic processing and each of six semantic modality processing. The results showed that the hub region worked in concert with nine other regions in the semantic memory network for general semantic processing. Moreover, the connection between the hub and the left calcarine was associated with colour-specific semantic processing. The observed effects could not be accounted for by potential confounding variables (e.g. total grey matter volume, regional grey matter volume and performance on non-semantic control tasks). Our findings refine the neuroanatomical structure of the semantic network and underline the critical role of the left fusiform gyrus and its connectivity in the network.
| S-EPMC7191302 | biostudies-literature
Project description:Background and purposeTelestroke networks support screening for patients with emergent large-vessel occlusions who are eligible for endovascular thrombectomy. Ideal triage processes within telestroke networks remain uncertain. We characterize the impact of implementing a routine spoke hospital CTA protocol in our integrated telestroke network on transfer and thrombectomy patterns.Materials and methodsA protocol-driven CTA process was introduced at 22 spoke hospitals in November 2017. We retrospectively identified prospectively collected patients who presented to a spoke hospital with National Institutes of Health Stroke Scale scores ≥6 between March 1, 2016 and March 1, 2017 (pre-CTA), and March 1, 2018 and March 1, 2019 (post-CTA). We describe the demographics, CTA utilization, spoke hospital retention rates, emergent large-vessel occlusion identification, and rates of endovascular thrombectomy.ResultsThere were 167 patients pre-CTA and 207 post-CTA. The rate of CTA at spoke hospitals increased from 15% to 70% (P < .001). Despite increased endovascular thrombectomy screening in the extended window, the overall rates of transfer out of spoke hospitals remained similar (56% versus 54%; P = .83). There was a nonsignificant increase in transfers to our hub hospital for endovascular thrombectomy (26% versus 35%; P = .12), but patients transferred >4.5 hours from last known well increased nearly 5-fold (7% versus 34%; P < .001). The rate of endovascular thrombectomy performed on patients transferred for possible endovascular thrombectomy more than doubled (22% versus 47%; P = .011).ConclusionsImplementation of CTA at spoke hospitals in our telestroke network was feasible and improved the efficiency of stroke triage. Rates of patients retained at spoke hospitals remained stable despite higher numbers of patients screened. Emergent large-vessel occlusion confirmation at the spoke hospital lead to a more than 2-fold increase in thrombectomy rates among transferred patients at the hub.
| S-EPMC7959422 | biostudies-literature
Project description:Extracorporeal membrane oxygenation (ECMO) implantation for neonates with severe cardiorespiratory life-threatening conditions is highly effective. However, since ECMO is a high-risk and complex therapy, this treatment is usually performed in centers with proven expertise. A retrospective review of neonates, from January 2014 to January 2020, presenting with life-threatening conditions and treated by means of Hub and Spoke (HandS) ECMO in peripheral (spoke) hospitals. Data were retrieved from our internal ECMO registry. Protocols and checklists were revised and shared with all spoke hospitals located in North-Eastern Italy. Eleven neonates receiving maximal respiratory and cardiovascular support at a spoke hospital underwent HandS ECMO management. All but three patients were affected by life-threatening meconium aspiration syndrome (MAS). The median ECMO support duration and hospitalization were four (range 2-32) and 30 days (range 8-50), respectively. All but two patients (with congenital diaphragmatic hernia), were weaned off ECMO and discharged home. At a mean follow up of 33.7 ± 29.2 months, all survivors were alive and well, without medications, and normal somatic growth. All but one had normal neuropsychological development. HandS ECMO model for neonates with life-threatening conditions is effective and successful. A specialized multidisciplinary team and close cooperation between Hub and Spoke centers are essential for success.
| S-EPMC7824856 | biostudies-literature