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IntroductionThrombotic events in neonates and children represent a rare although severe occurrence in view of the associated risk of mortality and sequelae. Quality evidence is limited in this field, and registry studies provide an essential base for research. The aim of this paper is to present the new Italian Registry of Infantile Thrombosis (RITI), set it into the scene of international thrombosis and stroke registries, and provide some insight on the challenges associated with registry management.MethodsWe present the detailed structure and content of the new RITI registry, a brief overview of its main data, and a reflection on its features, pitfalls and the main challenges related to its management.ResultsThe RITI, initially started in 2007 and officially re-launched in 2017 after structural modifications, is a non-interventional retrospective and prospective registry study collecting data on neonatal and pediatric patients (0–18 years) who experienced a systemic or cerebral thrombotic event in Italy. The RITI is managed by a multidisciplinary team with expertise in pediatric thrombosis, and participation is open to all Italian physicians, on a voluntary basis. The overall aim of the registry is to acquire new evidence to better characterize the population of children with thrombotic events and improve their management and outcome. 48 Italian pediatric and intensive care units are actively involved in the RITI, including 85 medical doctors from 16 Italian regions. A total of 1,001 neonates and children affected by cerebral or systemic thrombosis have been enrolled.DiscussionThe RITI is one of the largest available European registries of neonatal and pediatric thrombosis. National registries like the RITI represent a model for the study of rare conditions based on multidisciplinary and multicenter collaboration, aimed at overcoming the limitations due to small populations of patients, and creating a network of experts for patient referral and continuous education. Moreover, registry studies have a pivotal role in the research on pediatric thrombosis, due to the limited feasibility of high-quality studies. In our experience, the main critical stages, pitfalls and challenges in registry management include adequate registry designing, diffusion, data completeness and quality control.

Dopamine D3 receptors (D3Rs) modulate neuronal activity in several brain regions including the hippocampus. Although previous studies reported that blocking D3Rs exerts pro-cognitive effects, their involvement in hippocampal synaptic function and memory in the healthy and aged brain has not been thoroughly investigated. We demonstrated that in adult wild type (WT) mice, D3R pharmacological blockade or genetic deletion as in D3 knock out (KO) mice, converted the weak form of long-term potentiation (LTP1) into the stronger long-lasting LTP (LTP2) via the cAMP/PKA pathway, and allowed the formation of long-term memory. D3R effects were mainly mediated by post-synaptic mechanisms as their blockade enhanced basal synaptic transmission (BST), AMPAR-mediated currents, mEPSC amplitude, and the expression of the post-synaptic proteins PSD-95, phospho(p)GluA1 and p-CREB. Consistently, electron microscopy revealed a prevalent expression of D3Rs in post-synaptic dendrites. Interestingly, with age, D3Rs decreased in axon terminals while maintaining their levels in post-synaptic dendrites. Indeed, in aged WT mice, blocking D3Rs reversed the impairment of LTP, BST, memory, post-synaptic protein expression, and PSD length. Notably, aged D3-KO mice did not exhibit synaptic and memory deficits. In conclusion, we demonstrated the fundamental role of D3Rs in hippocampal synaptic function and memory, and their potential as a therapeutic target to counteract the age-related hippocampal cognitive decline., (© 2024 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Background: Reduction of adult hippocampal neurogenesis is an early critical event in Alzheimer's disease (AD), contributing to progressive memory loss and cognitive decline. Reduced levels of the nucleoporin 153 (Nup153), a key epigenetic regulator of NSC stemness, characterize the neural stem cells isolated from a mouse model of AD (3×Tg) (AD-NSCs) and determine their altered plasticity and gene expression., Methods: Nup153-regulated mechanisms contributing to NSC function were investigated: (1) in cultured NSCs isolated from AD and wild type (WT) mice by proteomics; (2) in vivo by lentiviral-mediated delivery of Nup153 or GFP in the hippocampus of AD and control mice analyzing neurogenesis and cognitive function; (3) in human iPSC-derived brain organoids obtained from AD patients and control subjects as a model of neurodevelopment., Results: Proteomic approach identified Nup153 interactors in WT- and AD-NSCs potentially implicated in neurogenesis regulation. Gene ontology (GO) analysis showed that Nup153-bound proteins in WT-NSCs were involved in RNA metabolism, nuclear import and epigenetic mechanisms. Nup153-bound proteins in AD-NSCs were involved in pathways of neurodegeneration, mitochondrial dysfunction, proteasomal processing and RNA degradation. Furthermore, recovery of Nup153 levels in AD-NSCs reduced the levels of oxidative stress markers and recovered proteasomal activity. Lentiviral-mediated delivery of Nup153 in the hippocampal niche of AD mice increased the proliferation of early progenitors, marked by BrdU/DCX and BrdU/PSANCAM positivity and, later, the integration of differentiating neurons in the cell granule layer (BrdU/NeuN + cells) compared with GFP-injected AD mice. Consistently, Nup153-injected AD mice showed an improvement of cognitive performance in comparison to AD-GFP mice at 1 month after virus delivery assessed by Morris Water Maze. To validate the role of Nup153 in neurogenesis we took advantage of brain organoids derived from AD-iPSCs characterized by fewer neuroepithelial progenitor loops and reduced differentiation areas. The upregulation of Nup153 in AD organoids recovered the formation of neural-like tubes and differentiation., Conclusions: Our data suggest that the positive effect of Nup153 on neurogenesis is based on a complex regulatory network orchestrated by Nup153 and that this protein is a valuable disease target., (© 2024. The Author(s).)

It has been recently established that GPR158, a class C orphan G protein-coupled receptor, serves as a metabotropic glycine receptor. GPR158 is highly expressed in the nucleus accumbens (NAc), a major input structure of the basal ganglia that integrates information from cortical and subcortical structures to mediate goal-directed behaviors. However, whether glycine modulates neuronal activity in the NAc through GPR158 activation has not been investigated yet. Using whole-cell patch-clamp recordings, we found that glycine-dependent activation of GPR158 increased the firing rate of NAc medium spiny neurons (MSNs) while it failed to significantly affect the excitability of cholinergic interneurons (CIN). In MSNs GPR158 activation reduced the latency to fire, increased the action potential half-width, and reduced action potential afterhyperpolarization, effects that are all consistent with negative modulation of potassium M-currents, that in the central nervous system are mainly carried out by Kv7/KCNQ-channels. Indeed, we found that the GPR158-induced increase in MSN excitability was associated with decreased M-current amplitude, and selective pharmacological inhibition of the M-current mimicked and occluded the effects of GPR158 activation. In addition, when the protein kinase A (PKA) or extracellular signal-regulated kinase (ERK) signaling was pharmacologically blocked, modulation of MSN excitability by GPR158 activation was suppressed. Moreover, GPR158 activation increased the phosphorylation of ERK and Kv7.2 serine residues. Collectively, our findings suggest that GPR158/PKA/ERK signaling controls MSN excitability via Kv7.2 modulation. Glycine-dependent activation of GPR158 may significantly affect MSN firing in vivo, thus potentially mediating specific aspects of goal-induced behaviors., (© 2024. The Author(s).)

Background: Systems capable of automating and enhancing the management of research and clinical data represent a significant contribution of information and communication technologies to health care. A recent advancement is the development of imaging biobanks, which are now enabling the collection and storage of diagnostic images, clinical reports, and demographic data to allow researchers identify associations between lifestyle and genetic factors and imaging-derived phenotypes., Objective: The aim of this study was to design and evaluate the system performance of a network for an operating biobank of diagnostic images, the Bio Check Up Srl (BCU) Imaging Biobank, based on the Extensible Neuroimaging Archive Toolkit open-source platform., Methods: Three usage cases were designed focusing on evaluation of the memory and computing consumption during imaging collections upload and during interactions between two kinds of users (researchers and radiologists) who inspect chest computed tomography scans of a COVID-19 cohort. The experiments considered three network setups: (1) a local area network, (2) virtual private network, and (3) wide area network. The experimental setup recorded the activity of a human user interacting with the biobank system, which was continuously replayed multiple times. Several metrics were extracted from network traffic traces and server logs captured during the activity replay., Results: Regarding the diagnostic data transfer, two types of containers were considered: the Web and the Database containers. The Web appeared to be the more memory-hungry container with a higher computational load (average 2.7 GB of RAM) compared to that of the database. With respect to user access, both users demonstrated the same network performance level, although higher resource consumption was registered for two different actions: DOWNLOAD & LOGOUT (100%) for the researcher and OPEN VIEWER (20%-50%) for the radiologist., Conclusions: This analysis shows that the current setup of BCU Imaging Biobank is well provisioned for satisfying the planned number of concurrent users. More importantly, this study further highlights and quantifies the resource demands of specific user actions, providing a guideline for planning, setting up, and using an image biobanking system., (©Giuseppina Esposito, Ciro Allarà, Marco Randon, Marco Aiello, Marco Salvatore, Giuseppe Aceto, Antonio Pescapè. Originally published in JMIR Formative Research (https://formative.jmir.org), 21.12.2023.)

Background: In amyotrophic lateral sclerosis (ALS), gait abnormalities contribute to poor mobility and represent a relevant risk for falls. To date, gait studies in ALS patients have focused on the motor dimension of the disease, underestimating the cognitive aspects., Methods: Using a wearable gait analysis device, we compared gait patterns in ambulatory ALS patients with mild cognitive impairment (ALS MCI+; n = 18), and without MCI (ALS MCI-; n = 24), and healthy subjects (HS; n = 16) under two conditions: (1) normal gait (single task) and (2) walking while counting backward (dual task). Finally, we examined if the occurrence and number of falls in the 3 months following the baseline test were related to cognition., Results: In the single task condition, ALS patients, regardless of cognition, displayed higher gait variability than HS, especially for stance and swing time (p < 0.001). The dual task condition revealed additional differences in gait variability parameters between ALS MCI+ and ALS MCI- for cadence (p = 0.005), stance time (p = 0.04), swing time (p = 0.04) and stability index (p = 0.02). Moreover, ALS MCI+ showed a higher occurrence (p = 0.001) and number of falls (p < 0.001) at the follow-up. Regression analyses demonstrated that MCI condition predicted the occurrence of future falls (β = 3.649; p = 0.01) and, together with executive dysfunction, was associated with the number of falls (cognitive impairment: β = 0.63; p < 0.001; executive dysfunction: β = 0.39; p = 0.03), regardless of motor impairment at clinical examination., Conclusion: In ALS, MCI is associated with exaggerated gait variability and predicts the occurrence and number of short-term falls., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Several studies including ours reported the detrimental effects of extracellular tau oligomers (ex-oTau) on glutamatergic synaptic transmission and plasticity. Astrocytes greatly internalize ex-oTau whose intracellular accumulation alters neuro/gliotransmitter handling thereby negatively affecting synaptic function. Both amyloid precursor protein (APP) and heparan sulfate proteoglycans (HSPGs) are required for oTau internalization in astrocytes but the molecular mechanisms underlying this phenomenon have not been clearly identified yet. Here we found that a specific antibody anti-glypican 4 (GPC4), a receptor belonging to the HSPG family, significantly reduced oTau uploading from astrocytes and prevented oTau-induced alterations of Ca 2+ -dependent gliotransmitter release. As such, anti-GPC4 spared neurons co-cultured with astrocytes from the astrocyte-mediated synaptotoxic action of ex-oTau, thus preserving synaptic vesicular release, synaptic protein expression and hippocampal LTP at CA3-CA1 synapses. Of note, the expression of GPC4 depended on APP and, in particular, on its C-terminal domain, AICD, that we found to bind Gpc4 promoter. Accordingly, GPC4 expression was significantly reduced in mice in which either APP was knocked-out or it contained the non-phosphorylatable amino acid alanine replacing threonine 688, thus becoming unable to produce AICD. Collectively, our data indicate that GPC4 expression is APP/AICD-dependent, it mediates oTau accumulation in astrocytes and the resulting synaptotoxic effects., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

SMARCA4 (BRG1) and SMARCA2 (BRM) are the two paralogous ATPases of the SWI/SNF chromatin remodeling complexes frequently inactivated in cancers. Cells deficient in either ATPase have been shown to depend on the remaining counterpart for survival. Contrary to this paralog synthetic lethality, concomitant loss of SMARCA4/2 occurs in a subset of cancers associated with very poor outcomes. Here, we uncover that SMARCA4/2-loss represses expression of the glucose transporter GLUT1, causing reduced glucose uptake and glycolysis accompanied with increased dependency on oxidative phosphorylation (OXPHOS); adapting to this, these SMARCA4/2-deficient cells rely on elevated SLC38A2, an amino acid transporter, to increase glutamine import for fueling OXPHOS. Consequently, SMARCA4/2-deficient cells and tumors are highly sensitive to inhibitors targeting OXPHOS or glutamine metabolism. Furthermore, supplementation of alanine, also imported by SLC38A2, restricts glutamine uptake through competition and selectively induces death in SMARCA4/2-deficient cancer cells. At a clinically relevant dose, alanine supplementation synergizes with OXPHOS inhibition or conventional chemotherapy eliciting marked antitumor activity in patient-derived xenografts. Our findings reveal multiple druggable vulnerabilities of SMARCA4/2-loss exploiting a GLUT1/SLC38A2-mediated metabolic shift. Particularly, unlike dietary deprivation approaches, alanine supplementation can be readily applied to current regimens for better treatment of these aggressive cancers., (© 2023. The Author(s).)

Aims: Early dysfunction in Alzheimer's disease (AD) is characterised by alterations of synapse structure and function leading to dysmorphic neurites, decreased spine density, impaired synaptic plasticity and cognitive deficits. The class II member HDAC4, which recently emerged as a crucial factor in shaping synaptic plasticity and memory, was found to be altered in AD. We investigated how the modulation of HDAC4 may contribute to counteracting AD pathogenesis., Methods: Using a cytoplasmic HDAC4 mutant (HDAC4 SD ), we studied the recovery of synaptic function in hippocampal tissue and primary neurons from the triple-transgenic mouse model of AD (3×Tg-AD)., Results: Here, we report that in wild-type mice, HDAC4 is localised at synapses and interacts with postsynaptic proteins, whereas in the 3×Tg-AD, it undergoes nuclear import, reducing its interaction with synaptic proteins. Of note, HDAC4 delocalisation was induced by both amyloid-β and tau accumulation. Overexpression of the HDAC4 SD mutant in CA1 pyramidal neurons of organotypic hippocampal slices obtained from 3×Tg-AD mice increased dendritic length and promoted the enrichment of N-cadherin, GluA1, PSD95 and CaMKII proteins at the synaptic level compared with AD neurons transfected with the empty vector. Moreover, HDAC4 overexpression recovered the level of SUMO2/3ylation of PSD95 in AD hippocampal tissue, and in AD organotypic hippocampal slices, the HDAC4 SD rescued spine density and synaptic transmission., Conclusions: These results highlight a new role of cytoplasmic HDAC4 in providing a structural and enzymatic regulation of postsynaptic proteins. Our findings suggest that controlling HDAC4 localisation may represent a promising strategy to rescue synaptic function in AD, potentially leading to memory improvement., (© 2022 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.)

Down syndrome (DS) is the most frequent genetic cause of intellectual disability and is strongly associated with Alzheimer's disease (AD). Brain insulin resistance greatly contributes to AD development in the general population and previous studies from our group showed an early accumulation of insulin resistance markers in DS brain, already in childhood, and even before AD onset. Here we tested the effects promoted in Ts2Cje mice by the intranasal administration of the KYCCSRK peptide known to foster insulin signaling activation by directly interacting and activating the insulin receptor (IR) and the AKT protein. Therefore, the KYCCSRK peptide might represent a promising molecule to overcome insulin resistance. Our results show that KYCCSRK rescued insulin signaling activation, increased mitochondrial complexes levels (OXPHOS) and reduced oxidative stress levels in the brain of Ts2Cje mice. Moreover, we uncovered novel characteristics of the KYCCSRK peptide, including its efficacy in reducing DYRK1A (triplicated in DS) and BACE1 protein levels, which resulted in reduced AD-like neuropathology in Ts2Cje mice. Finally, the peptide elicited neuroprotective effects by ameliorating synaptic plasticity mechanisms that are altered in DS due to the imbalance between inhibitory vs. excitatory currents. Overall, our results represent a step forward in searching for new molecules useful to reduce intellectual disability and counteract AD development in DS.

Multiple sclerosis (MS) is a chronic, debilitating disease characterised by demyelination of the nerves of the central nervous system that results in patients progressively losing the ability to perform daily tasks. As there is no cure for this disease, rehabilitation therapy is an important aspect of care; assisting patients to regain or retain function and improve their physical, mental and social wellbeing. At present there is no current consistent model of care for MS, likely due to the variable symptom presentation. Various forms of rehabilitation therapy are available, and these include physical rehabilitation methods, such as balance and gait therapy, speech and respiration rehabilitation, and occupational therapy. Contrary to previous understanding, exercise-based therapies have shown various benefits for patients with MS, and in addition to improving MS-related physical symptoms, have been shown to reduce the risk of developing cardiovascular disease and can improve cognitive function. Cognition rehabilitation therapy specifically focuses on behavioural tasks and is divided into two main forms: compensatory rehabilitation, which offers cognitive functioning benefits, and restorative rehabilitation, which offers memory benefits. Excitation therapies include cranial stimulation and other stimulation rehabilitation methods such as focal muscle vibration therapy and these non-invasive techniques may improve patient's physical ability. Additionally, more novel rehabilitation methods include robot-assisted gait therapy and telerehabilitation, both of which are expected to play progressively more prominent roles in the future of rehabilitation therapy. The structure of the care team has been found to impact patient outcomes, and both in- and out-patient care settings have been found to be beneficial, dependant on the patient's circumstances, with certain patients better suited to a particular setting. While a single point of care is recommended for patients, a multidisciplinary care team and regular reassessment is recommended to manage changing symptoms and ensure continuity of care. The importance of the critical components of rehabilitation have been identified, and these are of vital importance in achieving beneficial outcomes. These components include the patients' participation in the treatment, goal setting with a multidisciplinary care team, a guiding-light purpose for the patient, which focusses on recognizing their personal potential and obtaining improvements through a tailored plan. The final critical component of rehabilitation is the results measurement, which highlights the need for a quantifiable reduction in impairment and improvement in activity and participation. Overall, a lack of standardisation in outcome measurements makes comparison challenging. This is particularly important when comparing standard methods of care with more novel rehabilitation techniques. However, within the broad area of rehabilitation therapies, it is clear that patients with MS can benefit from rehabilitation practices; physically, mentally and socially., Competing Interests: Declaration of Competing Interest None, (Copyright © 2022. Published by Elsevier B.V.)

The COVID-19 pandemic has reshaped Internet traffic due to the huge modifications imposed to lifestyle of people resorting more and more to collaboration and communication apps to accomplish daily tasks. Accordingly, these dramatic changes call for novel traffic management solutions to adequately countermeasure such unexpected and massive changes in traffic characteristics. In this paper, we focus on communication and collaboration apps whose traffic experienced a sudden growth during the last two years. Specifically, we consider nine apps whose traffic we collect, reliably label, and publicly release as a new dataset (MIRAGE-COVID-CCMA-2022) to the scientific community. First, we investigate the capability of state-of-art single-modal and multimodal Deep Learning-based classifiers in telling the specific app, the activity performed by the user, or both. While we highlight that state-of-art solutions reports a more-than-satisfactory performance in addressing app classification (96%-98% F-measure), evident shortcomings stem out when tackling activity classification (56%-65% F-measure) when using approaches that leverage the transport-layer payload and/or per-packet information attainable from the initial part of the biflows. In line with these limitations, we design a novel set of inputs (namely Context Inputs) providing clues about the nature of a biflow by observing the biflows coexisting simultaneously. Based on these considerations, we propose Mimetic-All a novel early traffic classification multimodal solution that leverages Context Inputs as an additional modality, achieving ≥ 82 % F-measure in activity classification. Also, capitalizing the multimodal nature of Mimetic-All, we evaluate different combinations of the inputs. Interestingly, experimental results witness that Mimetic-ConSeq-a variant that uses the Context Inputs but does not rely on payload information (thus gaining greater robustness to more opaque encryption sub-layers possibly going to be adopted in the future)-experiences only ≈ 1 % F-measure drop in performance w.r.t. Mimetic-All and results in a shorter training time., (© 2022 Elsevier B.V. All rights reserved.)

Histamine, a monoamine implicated in stress-related arousal states, is synthesized in neurons exclusively located in the hypothalamic tuberomammillary nucleus (TMN) from where they diffusely innervate striatal and mesolimbic networks including the nucleus accumbens (NAc), a vital node in the limbic loop. Since histamine-containing TMN neuron output increases during stress, we hypothesized that exposure of mice to acute restrain stress (ARS) recruits endogenous histamine type 2 receptor (H2R) signaling in the NAc, whose activation increases medium spiny neurons (MSNs) intrinsic excitability via downregulation of A-type K + currents. We employed an ARS paradigm in which mice were restrained for 120 min, followed by a 20-min recovery period, after which brain slices were prepared for ex vivo electrophysiology. Using whole-cell patch-clamp recordings, we found that pharmacological activation of H2R failed to affect MSN excitability and A-type K + currents in mice that underwent ARS. Interestingly, in mice treated with H2R-antagonist prior to ARS paradigm, H2R activation increased evoked firing and decreased A-type K + currents similarly to what observed in control mice. Furthermore, H2R-antagonist treatment ameliorated anxiety-like behavior in ARS mice. Together, our findings indicate that ARS paradigm recruits endogenous H2R signaling in MSNs and suggest the involvement of H2R signaling in stress-related motivational states., Competing Interests: Declaration of competing interest All authors declare that the research was conducted in the absence of any commercial and financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Histaminergic neurons are exclusively located in the hypothalamic tuberomammillary nucleus, from where they project to many brain areas including the nucleus accumbens (NAc), a brain area that integrates diverse monoaminergic inputs to coordinate motivated behaviours. While the NAc expresses various histamine receptor subtypes, the mechanisms by which histamine modulates NAc activity are still poorly understood. Using whole-cell patch-clamp recordings, we found that pharmacological activation of histamine 2 (H2) receptors elevates the excitability of NAc medium spiny neurons (MSNs), while activation of H1 receptors failed to significantly affect MSN excitability. The evoked firing of MSNs increased after seconds of local H2 agonist administration and remained elevated for minutes. H2 receptor (H2R) activation accelerated subthreshold depolarization in response to current injection, reduced the latency to fire, diminished action potential afterhyperpolarization and increased the action potential half-width. The increased excitability was protein kinase A-dependent and associated with decreased A-type K + currents. In addition, selective pharmacological inhibition of the Kv4.2 channel, the main molecular determinant of A-type K + currents in MSNs, mimicked and occluded the increased excitability induced by H2R activation. Our results indicate that histaminergic transmission in the NAc increases MSN intrinsic excitability through H2R-dependent modulation of Kv4.2 channels. Activation of H2R will significantly alter spike firing in MSNs in vivo, and this effect could be an important mechanism by which these receptors mediate certain aspects of goal-induced behaviours. KEY POINTS: Histamine is synthesized and released by hypothalamic neurons of the tuberomammillary nucleus and serves as a general modulator for whole-brain activity including the nucleus accumbens. Histamine receptors type 2 (HR2), which are expressed in the nucleus accumbens, couple to Gαs/off proteins which elevate cyclic adenosine monophosphate levels and activate protein kinase A. Whole-cell patch-clamp recordings revealed that H2R activation increased the evoked firing in medium spiny neurons of the nucleus accumbens via protein kinase A-dependent mechanisms. HR2 activation accelerated subthreshold depolarization in response to current injection, reduced the latency to fire, diminished action potential medium after-hyperpolarization and increased the action potential half-width. HR2 activation also reduced A-type potassium current. Selective pharmacological inhibition of the Kv4.2 channel mimicked and occluded the increased excitability induced by H2R activation., (© 2022 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Glycogen synthase kinase 3β (GSK3) is a multifaceted serine/threonine (S/T) kinase expressed in all eukaryotic cells. GSK3β is highly enriched in neurons in the central nervous system where it acts as a central hub for intracellular signaling downstream of receptors critical for neuronal function. Unlike other kinases, GSK3β is constitutively active, and its modulation mainly involves inhibition via upstream regulatory pathways rather than increased activation. Through an intricate converging signaling system, a fine-tuned balance of active and inactive GSK3β acts as a central point for the phosphorylation of numerous primed and unprimed substrates. Although the full range of molecular targets is still unknown, recent results show that voltage-gated ion channels are among the downstream targets of GSK3β. Here, we discuss the direct and indirect mechanisms by which GSK3β phosphorylates voltage-gated Na + channels (Na v 1.2 and Na v 1.6) and voltage-gated K + channels (K v 4 and K v 7) and their physiological effects on intrinsic excitability, neuronal plasticity, and behavior. We also present evidence for how unbalanced GSK3β activity can lead to maladaptive plasticity that ultimately renders neuronal circuitry more vulnerable, increasing the risk for developing neuropsychiatric disorders. In conclusion, GSK3β-dependent modulation of voltage-gated ion channels may serve as an important pharmacological target for neurotherapeutic development.

This paper is designed to evaluate the results (at long-term follow-up of) children affected by dilating VUR. Our attention was focused on how VUR grade, laterality, bladder dysfunction (BD), the double renal system, and the type of bulking substance may affect VUR resolution in the long-term period. The charts of 93 children with dilating VUR who underwent endoscopic treatment (ET) and with a minimum post-operative follow-up of 7 years were reviewed (mean follow-up time was 9.6 + 1.4). The majority of patients had severe and bilateral VUR. Polydimetilsiloxane or hyaluronic acid/dextranomer (PDS or Ha/Dx) were used as bulking agents. VUR persistence following endoscopic injection was independent with respect to grade, laterality, duplex renal system, and BD. However, the rate of VUR persistence was significantly higher in children with BD. Children treated with Ha/Dx had a higher rate of VUR persistence. This research demonstrated that ET of VUR is also effective at very long term follow up (and without the development of significant complications). We also showed that patients treated with absorbable bulking agents such as Ha/Dx may experience a higher recurrence rate at the long-term follow-up). We also confirm that the only preoperative condition affecting VUR recurrence was bladder dysfunction.