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Injury responses in terminally differentiated cells such as neurons is tightly regulated by pathways aiding homeostatic maintenance. Cancer patients subjected to neuronal injury in brain radiation experience cognitive declines similar to those seen in primary neurodegenerative diseases. Numerous studies have investigated the effect of radiation in proliferating cells of the brain, yet the impact in differentiated, post-mitotic neurons, especially the structural and functional alterations remain largely elusive. We identified that microtubule-associated tau is a critical player in neuronal injury response via compartmentalized functions in both repair-centric and synaptic regulatory pathways. Ionizing radiation-induced injury acutely induces increase in phosphorylated tau in the nucleus and directly interacts with histone 2AX (H2AX), a DNA damage repair (DDR) marker. Loss of tau significantly reduced H2AX after irradiation, indicating that tau may play an important role in neuronal DDR response. We also observed that loss of tau increases eukaryotic elongation factor levels after irradiation, the latter being a positive regulator of protein translation. This cascades into a significant increase in synaptic proteins, resulting in disrupted homeostasis. Consequently, novel object recognition test showed decrease in learning and memory in tau-knockout mice after irradiation, and electroencephalographic activity showed increase in delta and theta band oscillations, often seen in dementia patients. Our findings demonstrate tau's previously undefined, multifunctional role in acute responses to injury, ranging from DDR response in the nucleus to synaptic function within a neuron. Such knowledge is vital to develop therapeutic strategies targeting neuronal injury in cognitive decline for at risk and vulnerable populations.

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Synaptic connections between neurons are essential for every facet of human cognition and are thus regulated with extreme precision. Rho-family GTPases, molecular switches that cycle between an active GTP-bound state and an inactive GDP-bound state, comprise a critical feature of synaptic regulation. Rho-GTPases are exquisitely controlled by an extensive suite of activators (GEFs) and inhibitors (GAPs and GDIs) and interact with many different signalling pathways to fulfill their roles in orchestrating the development, maintenance, and plasticity of excitatory synapses of the central nervous system. Among the mechanisms that control Rho-GTPase activity and signalling are cell surface receptors, GEF/GAP complexes that tightly regulate single Rho-GTPase dynamics, GEF/GAP and GEF/GEF functional complexes that coordinate multiple Rho-family GTPase activities, effector positive feedback loops, and mutual antagonism of opposing Rho-GTPase pathways. These complex regulatory mechanisms are employed by the cells of the nervous system in almost every step of development, and prominently figure into the processes of synaptic plasticity that underlie learning and memory. Finally, misregulation of Rho-GTPases plays critical roles in responses to neuronal injury, such as traumatic brain injury and neuropathic pain, and in neurodevelopmental and neurodegenerative disorders, including intellectual disability, autism spectrum disorder, schizophrenia, and Alzheimer's Disease. Thus, decoding the mechanisms of Rho-GTPase regulation and function at excitatory synapses has great potential for combatting many of the biggest current challenges in mental health.

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INTRODUCTION: Acute ischemic stroke (AIS) complicating cardiac interventions (CI) is well described. The use of mechanical thrombectomy (MT) for treatment of emergent large vessel occlusion (ELVO) in this setting, however, is not widely reported. METHODS: Cases of patients undergoing MT for AIS with ELVO at a single institution were reviewed. Cases preceded by recent CI were investigated retrospectively. Data was collected for patient demographics, type of cardiac intervention, stroke characteristics, neurovascular intervention, and patient outcomes. RESULTS: Between 2008 and 2017, registry analysis identified nine patients treated with MT for AIS complicating recent CI. Patients were more commonly male with a mean age of 67 years. A large majority had a known cardiac arrhythmia. Coronary artery bypass graft surgery (CABG) was the most identified CI, followed by valve repair, and cardiac ablations. Mean presenting NIHSS was 18. Most presented with hemiplegia. Seven cases were found to have MCA occlusions. Stent-retrievers were used in 6 cases with excellent recanalization in five MCA cases (TICI 2c or 3) and in two basilar cases. Despite immediate improvements in NIHSS scores in most cases, functional outcomes were poor in 7 cases (mRS of 4-6). Three cases were complicated by hemorrhage and three cases ended in mortality. CONCLUSION: AIS with ELVO following recent CI is associated with high rates of mortality and poor functional outcomes despite MT. Further work is needed to understand the key drivers to poor outcomes in this ELVO subgroup.

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BACKGROUND: Despite documented efficacy of surgical treatment in carefully selected patients, surgery is delayed and/or underutilized in both adult and children with focal onset epilepsy. The reasons for surgical delay are often assumed or theorized, and studies have predominantly targeted the adult population. To focus on a more targeted pediatric population and to determine identifiable reasons for intervention, this study aimed to investigate time to epilepsy surgery among pediatric patients with medically intractable epilepsy associated with focal cortical dysplasia and to identify sociodemographic and clinical associations in time to epilepsy surgery. METHODS: We reviewed 96 consecutive pediatric patients who underwent surgery for medically intractable epilepsy with a diagnosis of focal cortical dysplasia. Descriptive statistics, univariate and multivariate analyses were conducted to study the association of sociodemographic variables of patients with focal cortical dysplasia and time to epilepsy surgery and postoperative seizure control. RESULTS: We identified that non-white patients on average had a longer duration of epilepsy before surgery and traveled shorter distances for care. Non-white patients were more likely to have government-funded insurance. Patients who traveled the shortest distance to the surgical center underwent epilepsy surgery at an older age. CONCLUSIONS: Sociodemographic factors of travel distance, insurance, and race influenced time to epilepsy surgery for children with focal cortical dysplasia. Further research is warranted to target barriers in access to subspecialty care and develop ways to identify earlier the patients who may benefit from evaluation and deployment of surgical intervention.

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