BACKGROUND: Diffuse midline glioma, H3 K27-altered (DMG) is a fatal tumour that arises in the midline structures of the brain. When located in the pons, it is more commonly referred to as diffuse intrinsic pontine glioma (DIPG). DMG/DIPG is usually diagnosed when children are < 10 years, and it has a median overall survival of < 12 months after diagnosis. Radiological imaging is still the gold standard for DIPG diagnosis while the use of biopsy procedures led to our knowledge on its biology, such as with the identification of the canonical histone H3K27M mutation. However, the need to improve survival encourages the development of non-invasive, fast and inexpensive assays on biofluids for optimizing molecular diagnoses in DMG/DIPG. Here, we propose a rapid, new, imaging and epigenetics-based approach to diagnose DMG/DIPG in the plasma of paediatric patients. METHODS: A total of 20 healthy children (mean age: 10.5 years) and 24 children diagnosed with DMG/DIPG (mean age: 8.5 years) were recruited. Individual histones (H2A, H2B, H3, H4, macroH2A1.1 and macroH2A1.2), histone dimers and nucleosomes were assayed in biofluids by means of a new advanced flow cytometry ImageStream(X)-adapted method. RESULTS: We report a significant increase in circulating histone dimers and tetramers (macroH2A1.1/H2B versus control: p value < 0.0001; macroH2A1.2/H2B versus control: p value < 0.0001; H2A/H2B versus control: p value < 0.0001; H3/H4 versus control: p value = 0.008; H2A/H2B/H3/H4 versus control: p value < 0.0001) and a significant downregulation of individual histones (H2B versus control: p value < 0.0001; H3 versus control: p value < 0.0001; H4 versus control: p value < 0.0001). Moreover, histones were also detectable in the cerebrospinal fluid (CSF) of patients with DMG/DIPG and in the supernatant of SF8628, OPBG-DIPG002 and OPBG-DIPG004 DMG/DIPG cell lines, with patterns mostly similar to each other, but distinct compared to blood plasma. CONCLUSIONS: In summary, we identified circulating histone signatures able to detect the presence of DMG/DIPG in biofluids of children, using a rapid and non-invasive ImageStream(X)-based imaging technology, which may improve diagnosis and benefit the patients.

• MeSH
• Diffuse Intrinsic Pontine Glioma genetics   diagnosis   blood   MeSH
• Child MeSH
• Epigenesis, Genetic MeSH
• Glioma genetics   diagnosis   blood   pathology   diagnostic imaging   MeSH
• Histones * genetics   metabolism   blood   MeSH
• Humans MeSH
• Adolescent MeSH
• Mutation MeSH
• Biomarkers, Tumor blood   MeSH
• Brain Stem Neoplasms genetics   diagnosis   blood   diagnostic imaging   pathology   metabolism   MeSH
• Child, Preschool MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

BACKGROUND: Age-related neurodegenerative diseases (NDs) pose a formidable challenge to healthcare systems worldwide due to their complex pathogenesis, significant morbidity, and mortality. Scope and Approach: This comprehensive review aims to elucidate the central role of the microbiotagut- brain axis (MGBA) in ND pathogenesis. Specifically, it delves into the perturbations within the gut microbiota and its metabolomic landscape, as well as the structural and functional transformations of the gastrointestinal and blood-brain barrier interfaces in ND patients. Additionally, it provides a comprehensive overview of the recent advancements in medicinal and dietary interventions tailored to modulate the MGBA for ND therapy. CONCLUSION: Accumulating evidence underscores the pivotal role of the gut microbiota in ND pathogenesis through the MGBA. Dysbiosis of the gut microbiota and associated metabolites instigate structural modifications and augmented permeability of both the gastrointestinal barrier and the blood-brain barrier (BBB). These alterations facilitate the transit of microbial molecules from the gut to the brain via neural, endocrine, and immune pathways, potentially contributing to the etiology of NDs. Numerous investigational strategies, encompassing prebiotic and probiotic interventions, pharmaceutical trials, and dietary adaptations, are actively explored to harness the microbiota for ND treatment. This work endeavors to enhance our comprehension of the intricate mechanisms underpinning ND pathogenesis, offering valuable insights for the development of innovative therapeutic modalities targeting these debilitating disorders.

• MeSH
• Dysbiosis metabolism   MeSH
• Blood-Brain Barrier metabolism   MeSH
• Humans MeSH
• Brain * metabolism   MeSH
• Neurodegenerative Diseases * microbiology   metabolism   MeSH
• Brain-Gut Axis * physiology   MeSH
• Probiotics MeSH
• Aging * MeSH
• Gastrointestinal Microbiome * physiology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Obezita a diabetes mellitus 2. typu (DM2T) sú významnými rizikovými faktormi rozvoja kognitívnej dysfunkcie a neurodegeneratívnych ochorení. Ich spoločný patofyziologický základ zahŕňa inzulínovú rezistenciu, chronický subklinický systémový zápal a neurozápal, poruchy mikrobiómu, hormonálnu dysreguláciu a štrukturálne zmeny mozgu. Tieto faktory vedú k zhoršeniu pamäte, exekutívnych funkcií a k akcelerácii neurodegenerácie. Pozitívne účinky úpravy životného štýlu – vrátane zníženia telesnej hmotnosti, zvýšenia fyzickej aktivity a úpravy výživy a stravovacích návykov – sa prejavujú zlepšením inzulínovej senzitivity v mozgu, zvýšením neurotrofických faktorov, redukciou systémového zápalu a neurozápalu a zlepšením metabolizmu. Kombinácia behaviorálnych a farmakologických intervencií môže spomaliť kognitívny pokles a znížiť riziko demencie u populácie s obezitou a poruchou metabolizmu glukózy.

Obesity and type 2 diabetes (T2D) are important risk factors for the development of cognitive dysfunction and neurodegenerative diseases. Their common pathophysiological substrate includes insulin resistance, chronic subclinical systemic inflammation, neuroinflammation, shifts in the intestinal microbiome composition, hormonal dysregulation, and structural changes of the brain. These factors lead to impaired memory, executive functions, and accelerated neurodegeneration. The positive effects of lifestyle modifications — including weight loss, increased physical activity, and improved dietary composition — are manifested by improved insulin sensitivity in the brain, increased neurotrophic factors, reduced systemic inflammation and neuroinflammation, and improved metabolism. A combination of behavioral and pharmacological interventions may slow cognitive decline and reduce the risk of dementia in patients with obesity, prediabetes and T2D.

• MeSH
• Exercise MeSH
• Diabetes Mellitus, Type 2 complications   MeSH
• Weight Loss MeSH
• Cognition Disorders * etiology   MeSH
• Humans MeSH
• Neurodegenerative Diseases etiology   MeSH
• Obesity * complications   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Review MeSH

Bats are the natural reservoirs for a variety of emerging and re-emerging viruses. Among them, rabies virus (genus Lyssavirus, family Rhabdoviridae) is one of the first and most emblematic described in these animals. Since its first description, several new bat lyssaviruses have been regularly identified. In addition to lyssaviruses, other bat rhabdoviruses have also been discovered, including members of the genera Vesiculovirus, Ledantevirus and, more recently, Alphanemrhavirus and Tupavirus. However, the family Rhabdoviridae is one of the most abundant and diverse viral families, with 434 officially recognized species, divided into 5 subfamilies and 56 different genera. The number of rhabdoviruses associated with bats is therefore probably higher than that currently available. In this study, we first developed and validated a combined nested RT-qPCR technique (pan-rhabdo RT-nqPCR) dedicated to the broad detection of animal rhabdoviruses. After validation, this technique was used for a large retrospective screening of archival bat samples (n = 1962), including blood (n = 816), brain (n = 723) and oral swab (n = 423). These samples were collected from various bat species over a 12-year period (2007-2019) in 9 different countries in Europe and Africa. A total of 23 samples (1.2%) from bat species Miniopterus schreibersii, Rhinolophus euryale and Rhinolophus ferrumequinum tested positive for rhabdovirus infection, including 17 (2.1%) blood and 6 (1.4%) oral swab samples, all collected from bats originating from the Mediterranean region. Complete virus genome sequences were obtained by next-generation sequencing for most of the positive samples. Molecular and phylogenetic analysis of these sequences demonstrated that the virus isolates, named Mediterranean bat virus (MBV), were closely related and represented a new species, Mediterranean vesiculovirus, within the genus Vesiculovirus. MBV was more specifically related to other bat vesiculoviruses previously described from China and North America, together clustering into a distinct group of bat viruses within this genus. Interestingly, our results suggest that MBV is widespread, at least in the western part of the Mediterranean region, where it circulates in the blood of several bat species. These results expand the host range and viral diversity of bat vesiculoviruses, and pave the way for further studies to determine the transmission route and dissemination dynamics of these viruses in bat colonies, as well as to assess their potential threat to public health.

• MeSH
• Chiroptera * virology   MeSH
• Phylogeny MeSH
• Genome, Viral MeSH
• Rhabdoviridae Infections * veterinary   epidemiology   virology   MeSH
• Real-Time Polymerase Chain Reaction MeSH
• Vesiculovirus * genetics   isolation & purification   classification   MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Mediterranean Region MeSH

Intracranial human brain recordings from multiple implanted depth electrodes using stereo-EEG (sEEG) technology for seizure localization provide unique local field potential signals (LFP) sampled with standard macro- and special micro-electrode contacts. Over one hundred macro- and micro-contact LFP signals localized in particular brain regions were recorded from each sEEG monitoring case as patients engaged in an automated battery of verbal memory and non-verbal gaze movement tasks. Subject eye and vocal responses in both visual and auditory task versions were automatically detected in Polish, Czech, and Slovak languages with accurate timing of the correct and incorrect verbal responses using our web-based transcription tool. The behavioral events, LFP and pupillometric signals were synchronized and stored in a standard BIDS data structure with corresponding metadata. Each dataset contains recordings from at least one battery task performed over at least one day. The same set of 180 common nouns in the three languages was used across different battery tasks and recording days to enable the analysis of selective responses to specific word stimuli.

• MeSH
• Electroencephalography MeSH
• Language MeSH
• Cognition * MeSH
• Humans MeSH
• Brain * physiology   MeSH
• Eye Movements MeSH
• Eye-Tracking Technology MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Dataset MeSH

Nedd4-2 E3 ligase regulates Na+ homeostasis by ubiquitinating various channels and membrane transporters, including the epithelial sodium channel ENaC. In turn, Nedd4-2 dysregulation leads to various conditions, including electrolytic imbalance, respiratory distress, hypertension, and kidney diseases. However, Nedd4-2 regulation remains mostly unclear. The present study aims at elucidating Nedd4-2 regulation by structurally characterizing Nedd4-2 and its complexes using several biophysical techniques. Our cryo-EM reconstruction shows that the C2 domain blocks the E2-binding surface of the HECT domain. This blockage, ubiquitin-binding exosite masking by the WW1 domain, catalytic C922 blockage and HECT domain stabilization provide the structural basis for Nedd4-2 autoinhibition. Furthermore, Ca2+-dependent C2 membrane binding disrupts C2/HECT interactions, but not Ca2+ alone, whereas 14-3-3 protein binds to a flexible region of Nedd4-2 containing the WW2 and WW3 domains, thereby inhibiting its catalytic activity and membrane binding. Overall, our data provide key mechanistic insights into Nedd4-2 regulation toward fostering the development of strategies targeting Nedd4-2 function.

• MeSH
• Cryoelectron Microscopy MeSH
• HEK293 Cells MeSH
• Humans MeSH
• Models, Molecular MeSH
• Protein Domains MeSH
• 14-3-3 Proteins * metabolism   chemistry   MeSH
• Ubiquitination MeSH
• Nedd4 Ubiquitin Protein Ligases * metabolism   chemistry   genetics   ultrastructure   MeSH
• Calcium * metabolism   MeSH
• Protein Binding MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

This study presents a systematic review conducted according to the PRISMA 2020 guidelines, evaluating pharmacokinetic-pharmacodynamic (PK-PD) models for target-controlled infusion (TCI) of propofol. A structured search was performed across PubMed, Summon, Google Scholar, Web of Science, and Scopus, identifying 427 sources, of which 17 met the inclusion criteria. The analysis revealed that nine studies compared existing models, six focused on the development of new PK-PD models, and two explored broader implications of TCI in anesthesia. Comparative studies indicate that while the Eleveld model generally offers superior predictive accuracy, it does not consistently outperform the Marsh and Schnider models across all populations. The Schnider model demonstrated better bias control in elderly patients, while the Eleveld model improved drug clearance estimation in obese patients. However, inconsistencies remain in predicting brain concentrations of propofol. Newly proposed models introduce adaptive dosing strategies, incorporating allometric scaling, lean body weight, and machine learning techniques, yet require further external validation. The results highlight ongoing challenges in achieving universal applicability of TCI models, underscoring the need for future research in refining precision dosing and personalized anesthesia management.

• MeSH
• Anesthetics, Intravenous * administration & dosage   pharmacokinetics   pharmacology   MeSH
• Models, Biological MeSH
• Infusions, Intravenous MeSH
• Humans MeSH
• Propofol * administration & dosage   pharmacokinetics   pharmacology   MeSH
• Machine Learning MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Systematic Review MeSH

Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder for which current treatments provide only symptomatic relief, primarily through cholinesterase (ChE) inhibition and N-methyl-d-aspartate receptor (NMDAR) antagonism. To improve therapeutic efficacy and safety, we designed and synthesized 16 novel tacrine derivatives modified at position 7 with various (hetero)aryl groups or deuterium substitution. Initially, in silico screening predicted favorable CNS permeability and oral bioavailability. Subsequent in vitro evaluations demonstrated significant inhibitory potency against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), with derivatives 5i and 5m displaying particularly promising profiles. Metabolic stability assessed using human liver microsomes revealed enhanced stability for compound 5e, whereas 5i and 5m underwent rapid metabolism. Notably, compound 7 showed improved metabolic stability attributed to deuterium incorporation. The newly synthesized compounds were further tested for antagonistic activity on the GluN1/GluN2B subtype of NMDAR, with compound 5m exhibiting the most potent and voltage-independent inhibition. The ability of these compounds to permeate the blood-brain barrier (BBB) was confirmed through in vitro PAMPA assays. In preliminary hepatotoxicity screening (HepG2 cells), most derivatives exhibited higher cytotoxicity than tacrine, emphasizing the ongoing challenge in hepatotoxicity management. Based on its overall favorable profile, compound 5m advanced to in vivo pharmacokinetic studies in mice, demonstrating efficient CNS penetration, with brain concentrations exceeding plasma levels (brain-to-plasma ratio 2.36), indicating active transport across the BBB. These findings highlight compound 5m as a promising tacrine-based multi-target-directed ligand, supporting further preclinical development as a potential therapeutic candidate for AD.

• MeSH
• Acetylcholinesterase metabolism   MeSH
• Alzheimer Disease * drug therapy   metabolism   MeSH
• Biological Availability MeSH
• Butyrylcholinesterase metabolism   MeSH
• Cholinesterase Inhibitors * pharmacology   chemistry   chemical synthesis   MeSH
• Blood-Brain Barrier metabolism   MeSH
• Microsomes, Liver metabolism   MeSH
• Humans MeSH
• Ligands MeSH
• Molecular Structure MeSH
• Mice MeSH
• Receptors, N-Methyl-D-Aspartate * antagonists & inhibitors   metabolism   MeSH
• Tacrine * pharmacology   chemistry   chemical synthesis   MeSH
• Dose-Response Relationship, Drug MeSH
• Structure-Activity Relationship MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Temporal interference (TI) is a method of non-invasive brain stimulation using transcutaneous electrodes which allows the targeting and modulation of deeper brain structures, not normally associated with non-invasive simulation, while avoiding unwanted stimulation of shallower cortical structures. The properties of TI have been previously demonstrated, however, the problem of decoupling stimulation focality from stimulation intensity has not yet been well addressed. In this paper, we provide a possible novel solution, multipolar TI (mTI), which allows increased independent control over both the size of the stimulated region and the stimulation intensity. The mTI method uses multiple carrier frequencies to create multiple overlapping amplitude-modulated envelopes, rather than using one envelope as in standard TI. The study presents an explanation of the concept of mTI along with experimental data gathered from Rhesus macaques and mice. We improved the focality at depth in anesthetized mice and monkeys, and using the new focality in awake monkeys, evoked targeted activity at depth in the superior colliculus. The mTI method could be an interesting and potentially useful new tool alongside other forms of non-invasive brain stimulation. Teaser Multipolar Temporal Interference Stimulation can produce a more focal brain stimulation at depth compared to Temporal Interference.

• Publication type
• Journal Article MeSH

Mutations in CACNA1C, the gene encoding Cav1.2 voltage-gated calcium channels, are associated with a spectrum of disorders, including Timothy syndrome and other neurodevelopmental and cardiac conditions. In this study, we report a child with a de novo heterozygous missense variant (c.1973T > C; L658P) in CACNA1C, presenting with refractory epilepsy, global developmental delay, hypotonia, and multiple systemic abnormalities, but without overt cardiac dysfunction. Electrophysiological analysis of the recombinant Cav1.2 L658P variant revealed profound gating alterations, most notably a significant hyperpolarizing shift in the voltage dependence of activation and inactivation. Additionally, molecular modeling suggested that the L658P mutation disrupts interactions within the IIS5 transmembrane segment, reducing the energy barrier for state transitions and facilitating channel opening at more negative voltages. These findings establish L658P as a pathogenic CACNA1C variant primarily associated with severe neurological dysfunction and expands the phenotypic spectrum of CACNA1C-related disorders.

• MeSH
• Child MeSH
• Ion Channel Gating * MeSH
• Humans MeSH
• Mutation, Missense genetics   MeSH
• Models, Molecular MeSH
• Neurodevelopmental Disorders * genetics   MeSH
• Child, Preschool MeSH
• Amino Acid Sequence MeSH
• Calcium Channels, L-Type * genetics   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH