Effects of a ciliary neurotrophic factor (CNTF) small-molecule peptide mimetic in an in vitro and in vivo model of CDKL5 deficiency disorder.

Background: Mutations in the X-linked CDKL5 gene underlie a severe epileptic encephalopathy, CDKL5 deficiency disorder (CDD), characterized by gross motor impairment, autistic features and intellectual disability. Absence of Cdkl5 negatively impacts neuronal proliferation, survival, and maturation in in vitro and in vivo models, resulting in behavioral deficits in the Cdkl5 KO mouse. While there is no targeted therapy for CDD, several studies showed that treatments enabling an increase in brain BDNF levels give rise to structural and behavioral improvements in Cdkl5 KO mice.

Characterisation of sleep apneas and respiratory circuitry in mice lacking CDKL5.

CDKL5 deficiency disorder is a rare genetic disease caused by mutations in the CDKL5 gene. Central apneas during wakefulness have been reported in patients with CDKL5 deficiency disorder. Studies on CDKL5-knockout mice, a CDKL5 deficiency disorder model, reported sleep apneas, but it is still unclear whether these events are central (central sleep apnea) or obstructive (obstructive sleep apnea) and may be related to alterations of brain circuits that modulate breathing rhythm.

Extravasation of brentuximab vedotin, an antibody-drug conjugate, in a patient with anaplastic large cell lymphoma.

Brentuximab vedotin (BV) is an antibody-drug conjugate, consisting of a CD30-directed antibody, conjugated by a protease-cleavable linker to a microtubule disrupting agent auristatin E (MMAE). Although the safety datasheet of BV does not warn of severe toxic effects of extravasation, we report a third case of a patient with anaplastic large cell lymphoma who developed severe epidermal necrosis after extravasation. The reason for what happened could be attributed to the fact that MMAE belongs to the group of vinca alkaloids so it should be handled like other tissue-necrotising chemotherapeutics.

Tracking flowpaths in a complex karst system through tracer test and hydrogeochemical monitoring: Implications for groundwater protection (Gran Sasso, Italy).

Groundwater in karst aquifers is frequently tapped for drinking purposes, due to frequent huge volumes of resources. Unfortunately, vulnerability of these aquifers can be high, due to possible fast transfer of recharge water on springs by the karst network. On Gran Sasso Mountain regional aquifer, several springs are subjected to drinking withdrawal and an updated evaluation of their potential is now a fundamental issue to be considered, facing climate change effects, which reflect on variation of discharge regimen and values.

Voluntary Running Improves Behavioral and Structural Abnormalities in a Mouse Model of CDKL5 Deficiency Disorder.

Cyclin-dependent kinase-like 5 () deficiency disorder (CDD) is a rare neurodevelopmental disease caused by mutations in the X-linked gene. CDD is characterized by a broad spectrum of clinical manifestations, including early-onset refractory epileptic seizures, intellectual disability, hypotonia, visual disturbances, and autism-like features. The knockout (KO) mouse recapitulates several features of CDD, including autistic-like behavior, impaired learning and memory, and motor stereotypies.

A T-cell antigen atlas for meningioma: novel options for immunotherapy.

Meningiomas are the most common primary intracranial tumors. Although most symptomatic cases can be managed by surgery and/or radiotherapy, a relevant number of patients experience an unfavorable clinical course and additional treatment options are needed. As meningiomas are often perfused by dural branches of the external carotid artery, which is located outside the blood-brain barrier, they might be an accessible target for immunotherapy.

Microbial peptides activate tumour-infiltrating lymphocytes in glioblastoma.

Microbial organisms have key roles in numerous physiological processes in the human body and have recently been shown to modify the response to immune checkpoint inhibitors. Here we aim to address the role of microbial organisms and their potential role in immune reactivity against glioblastoma. We demonstrate that HLA molecules of both glioblastoma tissues and tumour cell lines present bacteria-specific peptides.

Early-onset brain alterations during postnatal development in a mouse model of CDKL5 deficiency disorder.

Mutations in the CDKL5 gene are the cause of CDKL5 deficiency disorder (CDD), a rare and severe neurodevelopmental condition characterized by early-onset epilepsy, motor impairment, intellectual disability, and autistic features. A mouse model of CDD, the Cdkl5 KO mouse, that recapitulates several aspects of CDD symptomology, has helped to highlight brain alterations leading to CDD neurological defects. Studies of brain morphogenesis in adult Cdkl5 KO mice showed defects in dendritic arborization of pyramidal neurons and in synaptic connectivity, a hypocellularity of the hippocampal dentate gyrus, and a generalized microglia over-activation.

Cardiac Functional and Structural Abnormalities in a Mouse Model of CDKL5 Deficiency Disorder.

CDKL5 (cyclin-dependent kinase-like 5) deficiency disorder (CDD) is a severe neurodevelopmental disease that mostly affects girls, who are heterozygous for mutations in the X-linked gene. Mutations in the gene lead to a lack of CDKL5 protein expression or function and cause numerous clinical features, including early-onset seizures, marked hypotonia, autistic features, gastrointestinal problems, and severe neurodevelopmental impairment. Mouse models of CDD recapitulate several aspects of CDD symptomology, including cognitive impairments, motor deficits, and autistic-like features, and have been useful to dissect the role of CDKL5 in brain development and function.

Vaccination with Designed Neopeptides Induces Intratumoral, Cross-reactive CD4+ T-cell Responses in Glioblastoma.

Purpose: The low mutational load of some cancers is considered one reason for the difficulty to develop effective tumor vaccines. To overcome this problem, we developed a strategy to design neopeptides through single amino acid mutations to enhance their immunogenicity.

Experimental Design: Exome and RNA sequencing as well as in silico HLA-binding predictions to autologous HLA molecules were used to identify candidate neopeptides.

Expression of a Secretable, Cell-Penetrating CDKL5 Protein Enhances the Efficacy of Gene Therapy for CDKL5 Deficiency Disorder.

Although delivery of a wild-type copy of the mutated gene to cells represents the most effective approach for a monogenic disease, proof-of-concept studies highlight significant efficacy caveats for treatment of brain disorders. Herein, we develop a cross-correction-based strategy to enhance the efficiency of a gene therapy for CDKL5 deficiency disorder, a severe neurodevelopmental disorder caused by CDKL5 gene mutations. We created a gene therapy vector that produces an Igk-TATk-CDKL5 fusion protein that can be secreted via constitutive secretory pathways and, due to the cell-penetration property of the TATk peptide, internalized by cells.

Luteolin Treatment Ameliorates Brain Development and Behavioral Performance in a Mouse Model of CDKL5 Deficiency Disorder.

CDKL5 deficiency disorder (CDD), a rare and severe neurodevelopmental disease caused by mutations in the X-linked 5 gene, is characterized by early-onset epilepsy, intellectual disability, and autistic features. Although pharmacotherapy has shown promise in the CDD mouse model, safe and effective clinical treatments are still far off. Recently, we found increased microglial activation in the brain of a mouse model of CDD, the 5 KO mouse, suggesting that a neuroinflammatory state, known to be involved in brain maturation and neuronal dysfunctions, may contribute to the pathophysiology of CDD.

Treatment with FRAX486 rescues neurobehavioral and metabolic alterations in a female mouse model of CDKL5 deficiency disorder.

Introduction: CDKL5 deficiency disorder (CDD) is a rare neurodevelopmental condition, primarily affecting girls for which no cure currently exists. Neuronal morphogenesis and plasticity impairments as well as metabolic dysfunctions occur in CDD patients. The present study explored the potential therapeutic value for CDD of FRAX486, a brain-penetrant molecule that was reported to selectively inhibit group I p21-activated kinases (PAKs), serine/threonine kinases critically involved in the regulation of neuronal morphology and glucose homeostasis.

Inhibition of microglia overactivation restores neuronal survival in a mouse model of CDKL5 deficiency disorder.

Background: CDKL5 deficiency disorder (CDD), a severe neurodevelopmental disorder characterized by early onset epilepsy, intellectual disability, and autistic features, is caused by mutations in the CDKL5 gene. Evidence in animal models of CDD showed that absence of CDKL5 negatively affects neuronal survival, as well as neuronal maturation and dendritic outgrowth; however, knowledge of the substrates underlying these alterations is still limited. Neuroinflammatory processes are known to contribute to neuronal dysfunction and death.

Groundwater flow velocities in karst aquifers; importance of spatial observation scale and hydraulic testing for contaminant transport prediction.

We review scale dependence of hydraulic conductivities and effective porosities for prediction of contaminant transport in four UK karst aquifers. Approaches for obtaining hydraulic parameters include core plug, slug, pumping and pulse tests, calibration of groundwater flow models and spring recession curves. Core plug and slug tests are unsuitable because they do not characterize a large enough volume to include a representative fracture network.

Age-Related Cognitive and Motor Decline in a Mouse Model of CDKL5 Deficiency Disorder is Associated with Increased Neuronal Senescence and Death.

CDKL5 deficiency disorder (CDD) is a severe neurodevelopmental disease caused by mutations in the X-linked gene. Children affected by CDD display a clinical phenotype characterized by early-onset epilepsy, intellectual disability, motor impairment, and autistic-like features. Although the clinical aspects associated with mutations are well described in children, adults with CDD are still under-characterized.

Treatment with a GSK-3β/HDAC Dual Inhibitor Restores Neuronal Survival and Maturation in an In Vitro and In Vivo Model of Deficiency Disorder.

Mutations in the X-linked cyclin-dependent kinase-like 5 () gene cause a rare neurodevelopmental disorder characterized by early-onset seizures and severe cognitive, motor, and visual impairments. To date there are no therapies for deficiency disorder (CDD). In view of the severity of the neurological phenotype of CDD patients it is widely assumed that may influence the activity of a variety of cellular pathways, suggesting that an approach aimed at targeting multiple cellular pathways simultaneously might be more effective for CDD.

A GABA receptor antagonist rescues functional and structural impairments in the perirhinal cortex of a mouse model of CDKL5 deficiency disorder.

CDKL5 (cyclin-dependent kinase-like 5) deficiency disorder (CDD) is a severe neurodevelopmental encephalopathy characterized by early-onset epilepsy and intellectual disability. Studies in mouse models have linked CDKL5 deficiency to defects in neuronal maturation and synaptic plasticity, and disruption of the excitatory/inhibitory balance. Interestingly, increased density of both GABAergic synaptic terminals and parvalbumin inhibitory interneurons was recently observed in the primary visual cortex of Cdkl5 knockout (KO) mice, suggesting that excessive GABAergic transmission might contribute to the visual deficits characteristic of CDD.

Review of Modeling Approaches to Groundwater Flow in Deformed Carbonate Aquifers.

We discuss techniques to represent groundwater flow in carbonate aquifers using the three existing modeling approaches: equivalent porous medium, conduit network, and discrete fracture network. Fractures in faulted stratigraphic successions are characterized by dominant sets of sub-vertical joints. Grid rotation is recommended using the equivalent porous medium to match higher hydraulic conductivity with the dominant orientation of the joints.

Correction to: Increased DNA Damage and Apoptosis in CDKL5-Deficient Neurons.

The original version of this article unfortunately contained error in Fig. 5a to where a panel is missing.

Increased DNA Damage and Apoptosis in CDKL5-Deficient Neurons.

Mutations in the CDKL5 gene, which encodes a serine/threonine kinase, causes a rare encephalopathy, characterized by early-onset epilepsy and severe intellectual disability, named CDKL5 deficiency disorder (CDD). In vitro and in vivo studies in mouse models of Cdkl5 deficiency have highlighted the role of CDKL5 in brain development and, in particular, in the morphogenesis and synaptic connectivity of hippocampal and cortical neurons. Interestingly, Cdkl5 deficiency in mice increases vulnerability to excitotoxic stress in hippocampal neurons.

Pharmacotherapy with sertraline rescues brain development and behavior in a mouse model of CDKL5 deficiency disorder.

Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene cause a severe neurodevelopmental disorder, CDKL5 deficiency disorder (CDD). CDKL5 is fundamental for correct brain development and function, but the molecular mechanisms underlying aberrant neurologic dysfunction in CDD are incompletely understood. Here we show a dysregulation of hippocampal and cortical serotonergic (5-HT) receptor expression in heterozygous Cdkl5 knockout (KO) female mice, suggesting that impaired 5-HT neurotransmission contributes to CDD.

Prediction of contaminant transport in fractured carbonate aquifer types: a case study of the Permian Magnesian Limestone Group (NE England, UK).

Viruses and bacteria which are characterized by finite lives in the subsurface are rapidly transported via fractures and cavities in fractured and karst aquifers. Here, we demonstrate how the coupling of a robust outcrop characterization and hydrogeophysical borehole testing is essential for prediction of contaminant velocities and hence wellhead protection areas. To show this, we use the dolostones of the Permian Magnesian Limestone aquifer in NE England, where we incorporated such information in a groundwater flow and particle tracking model.