Phosphofurin acidic cluster sorting protein 2 (PACS2) plays a vital role in maintaining cellular homeostasis by regulating protein trafficking between cellular membranes. This function impacts crucial processes like apoptosis, mitochondria-endoplasmic reticulum interaction, and subsequently Ca2+ flux, lipid biosynthesis, and autophagy. Missense mutations, particularly E209K and E211K, are linked to developmental and epileptic encephalopathy-66 (DEE66), known as PACS2 syndrome. Individuals with this syndrome exhibit neurodevelopmental delay, seizures, facial dysmorphism, hypotonia, and delayed motor skills.Understanding the impact of these missense mutations on molecular processes is crucial. Studies suggest that E209K mutation decreases phosphorylation, increases the survival time of protein, and modifies protein-protein interaction, consequently leading to disruption of calcium flux and lower resistance to apoptosis induction. Unfortunately, to date, only a limited number of research groups have investigated the effects of mutations in the PACS2 gene. Current research on PACS2 syndrome is hampered by the lack of suitable models. While in vitro models using transfected cell lines offer insights, they cannot fully capture the disease's complexity.To address this, utilizing cells from individuals with PACS2 syndrome, specifically induced pluripotent stem cells (iPSCs), holds promise for understanding phenotypic diversity and developing personalized therapies. However, iPSC models may not fully capture tissue-specific effects of the E209K/E211K mutation. In vivo studies using animal models, particularly mice, could overcome these limitations.This review summarizes current knowledge about PACS2 structure and functions, explores the cellular consequences of E209K and E211K mutations, and highlights the potential of iPSC and mouse models in advancing our understanding of PACS2 syndrome.

• MeSH
• Induced Pluripotent Stem Cells metabolism   MeSH
• Humans MeSH
• Mutation, Missense * MeSH
• Mutation MeSH
• Vesicular Transport Proteins * genetics   metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

The ABCB1 gene, encoding the ATP-dependent translocase ABCB1, plays a crucial role in the clearance of amyloid-beta (Aβ) peptides and the transport of cholesterol, implicating it in the pathogenesis of Alzheimer's disease. The study aims to investigate the association between polymorphisms in the ABCB1 gene and cognitive decline in individuals with mild cognitive impairment (MCI), particularly focusing on language function. A longitudinal cohort study involving 1 005 participants from the Czech Brain Aging Study was conducted. Participants included individuals with Alzheimer's disease, amnestic MCI, non-amnestic MCI, subjective cognitive decline, and healthy controls. Next-generation sequencing was utilized to analyze the entire ABCB1 gene. Cognitive performance was assessed using a comprehensive battery of neuropsychological tests, including the Boston Naming Test and the semantic verbal fluency test. Ten ABCB1 polymorphisms (rs55912869, rs56243536, rs10225473, rs10274587, rs2235040, rs12720067, rs12334183, rs10260862, rs201620488, and rs28718458) were significantly associated with cognitive performance, particularly in language decline among amnestic MCI patients. In silico analyses revealed that some of these polymorphisms may affect the binding sites for transcription factors (HNF-3alpha, C/EBPβ, GR-alpha) and the generation of novel exonic splicing enhancers. Additionally, polymorphism rs55912869 was identified as a potential binding site for the microRNA hsa-mir-3163. Our findings highlight the significant role of ABCB1 polymorphisms in cognitive decline, particularly in language function, among individuals with amnestic MCI. These polymorphisms may influence gene expression and function through interactions with miRNAs, transcription factors, and alternative splicing mechanisms.

• MeSH
• Alzheimer Disease genetics   MeSH
• Polymorphism, Single Nucleotide * MeSH
• Cognitive Dysfunction * genetics   MeSH
• Humans MeSH
• Longitudinal Studies MeSH
• Neuropsychological Tests MeSH
• ATP Binding Cassette Transporter, Subfamily B genetics   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• High-Throughput Nucleotide Sequencing MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Czech Republic MeSH

Full recovery from spinal cord injury requires axon regeneration to re-establish motor and sensory pathways. In mammals, the failure of sensory and motor axon regeneration has many causes intrinsic and extrinsic to neurons, amongst which is the lack of adhesion molecules needed to interact with the damaged spinal cord. This study addressed this limitation by expressing the integrin adhesion molecule α9, along with its activator kindlin-1, in sensory neurons via adeno-associated viral (AAV) vectors. This enabled sensory axons to regenerate through spinal cord injuries and extend to the brainstem, restoring sensory pathways, touch sensation and sensory behaviours. One of the integrin ligands in the injured spinal cord is tenascin-C, which serves as a substrate for α9β1 integrin, a key receptor in developmental axon guidance. However, the adult PNS and CNS neurons lack this receptor. Sensory neurons were transduced with α9 integrin (which pairs with endogenous β1 to form a α9β1 tenascin receptor) together with the integrin activator kindlin-1. Regeneration from sensory neurons transduced with α9integrin and kindlin-1 was examined after C4 and after T10 dorsal column lesions with C6,7 and L4,5 sensory ganglia injected with AAV1 vectors. In animals treated with α9 integrin and kindlin-1, sensory axons regenerated through tenascin-C-expressing connective tissue strands and bridges across the lesions and then re-entered the CNS tissue. Many axons regenerated rostrally to the level of the medulla. Axons grew through the dorsal grey matter rather than their normal pathway the dorsal columns. Growth was slow, axons taking 12 weeks to grow from T10 to the medulla, a distance of 4-5 cm. Functional recovery was confirmed through cFos activation in neurons rostral to the injury after nerve stimulation and VGLUT1/2 staining indicating new synapse formation above the lesion. Behavioural recovery was seen in both heat and mechanical sensation, as well as tape removal tests. This approach demonstrates the potential of integrin-based therapies for long distance sensory axon regeneration and functional recovery following thoracic and partial recovery after cervical spinal cord injury.

• MeSH
• Axons MeSH
• Dependovirus genetics   MeSH
• Genetic Vectors MeSH
• Rats MeSH
• Disease Models, Animal MeSH
• Mice MeSH
• Sensory Receptor Cells * metabolism   physiology   pathology   MeSH
• Recovery of Function physiology   MeSH
• Spinal Cord Injuries * pathology   physiopathology   metabolism   MeSH
• Rats, Sprague-Dawley MeSH
• Nerve Tissue Proteins metabolism   genetics   MeSH
• Nerve Regeneration * physiology   MeSH
• Tenascin metabolism   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH

AIMS: The cardiac conduction system (CCS) is progressively specified during development by interactions among a discrete number of transcription factors (TFs) that ensure its proper patterning and the emergence of its functional properties. Meis genes encode homeodomain TFs with multiple roles in mammalian development. In humans, Meis genes associate with congenital cardiac malformations and alterations of cardiac electrical activity; however, the basis for these alterations has not been established. Here, we studied the role of Meis TFs in cardiomyocyte development and function during mouse development and adult life. METHODS AND RESULTS: We studied Meis1 and Meis2 conditional deletion mouse models that allowed cardiomyocyte-specific elimination of Meis function during development and inducible elimination of Meis function in cardiomyocytes of the adult CCS. We studied cardiac anatomy, contractility, and conduction. We report that Meis factors are global regulators of cardiac conduction, with a predominant role in the CCS. While constitutive Meis deletion in cardiomyocytes led to congenital malformations of the arterial pole and atria, as well as defects in ventricular conduction, Meis elimination in cardiomyocytes of the adult CCS produced sinus node dysfunction and delayed atrio-ventricular conduction. Molecular analyses unravelled Meis-controlled molecular pathways associated with these defects. Finally, we studied in transgenic mice the activity of a Meis1 human enhancer related to an single-nucleotide polymorphism (SNP) associated by Genome-wide association studies (GWAS) to PR (P and R waves of the electrocardiogram) elongation and found that the transgene drives expression in components of the atrio-ventricular conduction system. CONCLUSION: Our study identifies Meis TFs as essential regulators of the establishment of cardiac conduction function during development and its maintenance during adult life. In addition, we generated animal models and identified molecular alterations that will ease the study of Meis-associated conduction defects and congenital malformations in humans.

• MeSH
• Action Potentials MeSH
• Phenotype MeSH
• Homeodomain Proteins * genetics   metabolism   MeSH
• Myocytes, Cardiac * metabolism   pathology   MeSH
• Myocardial Contraction MeSH
• Mice, Knockout MeSH
• Sinoatrial Node metabolism   physiopathology   MeSH
• Heart Conduction System * metabolism   physiopathology   growth & development   MeSH
• Arrhythmias, Cardiac physiopathology   metabolism   genetics   MeSH
• Heart Rate * MeSH
• Myeloid Ecotropic Viral Integration Site 1 Protein * genetics   metabolism   deficiency   MeSH
• Age Factors MeSH
• Heart Defects, Congenital metabolism   genetics   physiopathology   MeSH
• Gene Expression Regulation, Developmental MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH

Current diagnostic methods for dyslexia primarily rely on traditional paper-and-pencil tasks. Advanced technological approaches, including eye-tracking and artificial intelligence (AI), offer enhanced diagnostic capabilities. In this paper, we bridge the gap between scientific and diagnostic concepts by proposing a novel dyslexia detection method, called INSIGHT, which combines a visualisation phase and a neural network-based classification phase. The first phase involves transforming eye-tracking fixation data into 2D visualisations called Fix-images, which clearly depict reading difficulties. The second phase utilises the ResNet18 convolutional neural network for classifying these images. The INSIGHT method was tested on 35 child participants (13 dyslexic and 22 control readers) using three text-reading tasks, achieving a highest accuracy of 86.65%. Additionally, we cross-tested the method on an independent dataset of Danish readers, confirming the robustness and generalizability of our approach with a notable accuracy of 86.11%. This innovative approach not only provides detailed insight into eye movement patterns when reading but also offers a robust framework for the early and accurate diagnosis of dyslexia, supporting the potential for more personalised and effective interventions.

• MeSH
• Reading MeSH
• Child MeSH
• Dyslexia * physiopathology   diagnosis   classification   MeSH
• Humans MeSH
• Neural Networks, Computer * MeSH
• Fixation, Ocular * physiology   MeSH
• Eye Movements physiology   MeSH
• Eye-Tracking Technology * MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Sociální sítě se staly běžnou součástí našich životů. Jejich možný vliv na lidskou psychiku, obzvláště u dětí a dospívajících, se stává opakovaně předmětem vzrušených debat jak u laické, tak odborné veřejnosti. některé aspekty sociálních sítí mohou mít negativní dopady na psychiku. Často zmiňované je sociální srovnávání, zejména srovnávání se s těmi, kteří jsou vnímáni jako úspěšnější, což může vést k pocitům méněcennosti a frustrace. dalším negativním faktorem je strach z promeškání, tedy obava, že ostatní prožívají zajímavější a hodnotnější události než my sami. tento strach může vést k úzkosti a stresu. Za problematické je považováno i nadměrné užívání sociálních sítí, které se projevuje silným zaujetím, neschopností kontrolovat čas strávený na sítích a negativním dopadem na důležité oblasti života, jako jsou vztahy, práce nebo studium. sociální sítě však mohou mít i pozitivní vliv na psychiku. Budování sociálního kapitálu, tedy sítě vztahů a kontaktů, může vést k pocitům sounáležitosti a podpory, a tím přispívat k celkové psychické pohodě. Výzkumy zaměřené na vliv sociálních sítí na psychiku dospívajících přinášejí mnohdy rozporuplné výsledky. některé naznačují mírný negativní vliv, jako je nárůst deprese a úzkosti, zatímco jiné poukazují na mírný pozitivní vliv, jako je vyšší spokojenost se životem. Vliv sociálních sítí se liší v závislosti na individuálních, sociálních a vývojových faktorech. některé studie poukazují na existenci vývojově podmíněných tzv. období citlivosti, během nichž je vliv sociálních sítí na psychiku dospívajících významnější. další výzkumy prokázaly souvislost mezi užíváním sociálních sítí a rizikovým chováním, jako je sebepoškozování a poruchy příjmu potravy. Účinnost intervencí zaměřených na omezení používání sociálních sítí, jako je například „digitální detox“, je nejasná. dosavadní studie naznačují, že pozitivnější vliv na celkovou psychickou pohodu má zkrácení času stráveného na sociálních sítích, nikoliv jejich úplné opuštění.

Social networking sites have become a reality in our lives. their potential impact on the human psyche, especially for children and adolescents, has repeatedly become a subject of enthusiastic debate among both the general public and academics. some aspects of social networking can have negative effects on the psyche. social comparison is often cited, particularly comparison with those who are perceived to be more successful, which can lead to feelings of inferiority and frustration. another negative factor is the fear of missing out, i.e. the fear that others are experiencing more interesting and worthwhile events than oneself. this fear can lead to anxiety and stress. excessive use of social networking sites is also considered problematic, with strong preoccupations, an inability to control time spent on the sites and a negative impact on important areas of life such as relationships, work or study. However, social networking can also have a positive effect on the psyche. Building social capital, i.e. a network of relationships and contacts, can lead to feelings of belonging and support, thus contributing to overall psychological well-being. research on the impact of social networks on adolescents‘ psyche has often produced contradictory results. some suggest a slight negative effect, such as an increase in depression and anxiety, while others point to a slight positive effect, such as increased life satisfaction. the impact of social networks varies depending on individual, social and developmental factors. some studies point to the existence of ‚developmental windows of sensitivity‘ during which the influence of social networks on the adolescent psyche is more significant. other research has shown a link between social networking use and risky behaviors such as self-harm and eating disorders. the effectiveness of interventions aimed at reducing social networking use, such as ‚digital detox‘, is still unclear. studies to date suggest that reducing time spent on social networking sites has a more positive effect on overall psychological well-being than leaving them altogether.

• MeSH
• Depressive Disorder etiology   MeSH
• Mental Health * MeSH
• Humans MeSH
• Adolescent * MeSH
• Feeding and Eating Disorders of Childhood etiology   MeSH
• Self Mutilation etiology   psychology   MeSH
• Social Media MeSH
• Social Networking * MeSH
• Check Tag
• Humans MeSH
• Adolescent * MeSH

Epileptické záchvaty jsou nejčastější urgentní událostí v dětském věku, a to zejména v prvním roce života. u čtyř procent dětí se vyskytnou febrilní křeče, 1 % dětí trpí chronickou epilepsií, 1 % prodělá ojedinělý epileptický záchvat a přibližně 2 % dětí mají různé formy křečí či poruch vědomí připomínající či imitující záchvaty epileptické. obvykle se jako první se záchvatem setká pediatr, který dle předpokládané diagnózy rozhoduje o dalším postupu. ne vždy a všude je dostupné vyšetření dětským neurologem, proto je základní znalost sémiologie epileptických záchvatů a syndromů pro pediatry užitečná. následné krátké komentované kazuistiky si kladou za cíl upozornit na možná diferenciálně diagnostická úskalí záchvatů a věkově vázaných syndromů v jednotlivých vývojových etapách.

Epileptic seizures are the most common urgent events in childhood, particularly during the first year of life. less than 1% of children suffer from chronic epilepsy, 1% experience a single epileptic seizure, 4% have febrile seizures, and approximately 2% of children exhibit various forms of convulsions or consciousness disorders resembling or mimicking epileptic seizures. pediatricians are usually the first to encounter a seizure and must decide on further steps based on the presumed diagnosis. since access to pediatric neurologists is not always available, a basic understanding of the semiology of epileptic seizures and syndromes can be beneficial for pediatricians. the following brief case studies aim to highlight potential differential diagnostic challenges of seizures and age-related syndromes at various developmental stages.

• MeSH
• Anticonvulsants pharmacology   therapeutic use   MeSH
• Diagnosis, Differential * MeSH
• Child MeSH
• Epilepsy diagnosis   MeSH
• Epileptic Syndromes diagnosis   MeSH
• Humans MeSH
• Seizures * diagnosis   etiology   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Case Reports MeSH

BACKGROUND: Previous research has demonstrated impaired proprioception and poorer responses to tactile deep pressure, visual-tactile integration, and vestibular stimuli in individuals with generalized hypermobility, potentially leading to sensory processing issues. Therefore, we aimed to explore the influence of hypermobility on somatognosia and stereognosia. METHODS: Forty-six participants were assessed using the Beighton score and categorized into three groups: non-hypermobile (n = 20), symptomatic hypermobile (n = 13), and asymptomatic hypermobile (n = 13). Somatognosia was evaluated using the shoulder width test in the vertical plane and pelvic width test in the vertical and horizontal planes. Stereognosia was assessed with Petrie's test. Spearman's rank correlation coefficient was examined the relationship between the Beighton score and measures of somatognosia and stereognosia. An unpaired t-test was used to compare variables between hypermobile (both symptomatic and asymptomatic) and non-hypermobile individuals, while a one-way ANOVA was used to compare data between the three groups. RESULTS: No significant relationship was observed between Beighton scores and measures of somatognosia and stereognosia. The t-test revealed no statistically significant differences between hypermobile and non-hypermobile groups in the shoulder width, two pelvic widths, and Petrie's tests (all p ≥ 0.105). Similarly, one-way ANOVA showed no statistically significant differences between the three groups across these tests (all p ≥ 0.177). CONCLUSIONS: The results indicate that somatognosia and stereognosia are not significantly related to the Beighton score and do not significantly differ between the groups studied. These sensory processing functions are unlikely to contribute to the common complaints reported by hypermobile individuals. CLINICAL TRIAL NUMBER: Not applicable.

• MeSH
• Agnosia * diagnosis   MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Joint Instability * diagnosis   physiopathology   psychology   complications   epidemiology   MeSH
• Proprioception physiology   MeSH
• Stereognosis * physiology   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

OBJECTIVE: Standard resective treatment of mesial temporal lobe epilepsy (MTLE) includes anteromesial temporal resection or amygdalohippocampectomy. One potential risk of these surgeries, especially in patients with magnetic resonance imaging (MRI)-negative findings, is postoperative memory impairment. An alternative to resective procedures that aim to preserve the neuropsychological profile are multiple hippocampal transections (MHTs). The objective of transections is to interrupt the longitudinal pathways of the hippocampus to prevent the spread of epileptic seizures while preserving the memory circuits. Previously performed MHT procedures were guided by questionable intraoperative electrocorticography. At our institution, we have developed and tested a modified technique to achieve complete MHTs. METHODS: Patients with pharmacoresistant unilaterally lateralized MTLE and MRI-negative findings with high risk of neuropsychologic deterioration were indicated for complete MHT. Comprehensive neuropsychological and epileptological evaluations and MRI follow-ups were conducted 1 year and 2 years postoperatively. The primary evaluated parameters were seizure reduction and significant changes in neuropsychological performance (± 1 SD). RESULTS: Complete MHTs were performed on 3 patients who completed 2-year follow-up. Two MHTs were performed on the right and 1 on the left side. Two patients are classified as Engel 1 and one patient as Engel 3. Two years after surgery, neuropsychologic evaluation did not show significant decrease in memory performance and performance in majority of cognitive tests. One-year MRI follow-up showed decrease of volume of hippocampus in all 3 patients. CONCLUSIONS: This modified technique of MHT in patients with MTLE and MRI-negative findings led to seizure reduction while preserving their neuropsychologic performance.

• MeSH
• Adult MeSH
• Epilepsy, Temporal Lobe * surgery   diagnostic imaging   MeSH
• Hippocampus * surgery   diagnostic imaging   MeSH
• Middle Aged MeSH
• Humans MeSH
• Magnetic Resonance Imaging MeSH
• Young Adult MeSH
• Follow-Up Studies MeSH
• Neurosurgical Procedures * methods   MeSH
• Neuropsychological Tests MeSH
• Drug Resistant Epilepsy * surgery   diagnostic imaging   MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Patients with schizophrenia frequently encounter challenges related to sexuality and intimacy; however, the underlying causes of these difficulties remain unknown and unexplored. AIM: This narrative review aims to explore how the biological/hormonal and psychological/behavioral developmental trajectories in schizophrenia patients deviate from the normal course and to examine their connection to difficulties in sexual and romantic functioning. METHODS: A comprehensive literature search was conducted using PubMed and Google Scholar, with key terms related to schizophrenia and sexual development without restriction on publication year. Articles discussing behavioral, sexual, or psychological/behavioral development before the onset of schizophrenia were included. Articles were divided into biological/hormonal and psychological/behavioral precursor categories. Additional searches were conducted to explore the broader sociocognitive context of schizophrenia, such as deficits in empathy, emotional processing, and theory of mind. OUTCOMES: The review highlights deviations in both biological/hormonal and psychological/behavioral development in schizophrenia that contribute to difficulties in romantic and sexual relationships. RESULTS: This narrative review addresses the extent to which biological, psychological, and social factors in schizophrenia may be closely intertwined. Abnormalities in the hypothalamic-pituitary-gonadal and hypothalamic-pituitary-adrenal axes have been documented in individuals with schizophrenia, potentially impairing sociosexual competencies and leading to behavioral challenges in forming sexual relationships. Deficits in theory of mind, emotional processing, and empathy may further hinder the ability to form and sustain intimate relationships, amplifying the social difficulties associated with schizophrenia. Additionally, early life traumas, especially sexual abuse, can contribute to sexual difficulties and worsen the disorder. CLINICAL TRANSLATION: Understanding the deviations from the normal developmental course in schizophrenia patients may offer valuable insights for potential intervention strategies and remediation approaches and contribute to improvements in sexual/romantic functioning and overall sexual health in schizophrenia patients. STRENGTHS AND LIMITATIONS: This review provides an overview of the developmental precursors of schizophrenia-related sexual/romantic difficulties. Further research is needed to elucidate the specific mechanisms underlying these difficulties, particularly in determining the emotional and motivational salience of sexual stimuli and the capacity to engage in and maintain communication of sexual interest. The reader should bear in mind that narrative reviews lack systematic methods for selecting and evaluating studies, which can lead to author bias in choosing or interpreting sources. CONCLUSION: The narrative review identified deviations in the biological/hormonal and psychological/behavioral developmental trajectories of schizophrenia patients, linking these abnormalities to difficulties in sexual and romantic functioning, and highlighting the need for sexological remediation strategies to improve sociosexual competencies and overall sexual health.

• Publication type
• Journal Article MeSH
• Review MeSH