Search

The potassium-chloride co-transporter 2, KCC2, is a neuron-specific ion transporter that plays a multifunctional role in neuronal development. In mature neurons, KCC2 maintains a low enough intracellular chloride concentration essential for inhibitory neurotransmission. During recent years, pathogenic variants in the KCC2 encoding gene SLC12A5 affecting the functionality or expression of the transporter protein have been described in several patients with epilepsy of infancy with migrating focal seizures (EIMFS), a devastating early-onset developmental and epileptic encephalopathy. In this study, we identified a novel recessively inherited SLC12A5 c.692G>A, p. (R231H) variant in a patient diagnosed with severe and drug-resistant EIMFS and profound intellectual disability. The functionality of the variant was assessed in vitro by means of gramicidin-perforated patch-clamp experiments and ammonium flux assay, both of which indicated a significant reduction in chloride extrusion. Based on surface immunolabeling, the variant showed a reduction in membrane expression. These findings implicate pathogenicity of the SLC12A5 variant that leads to impaired inhibitory neurotransmission, increasing probability for hyperexcitability and epileptogenesis.

Summary: Brain functionality relies on finely tuned regulation of gene expression by networks of non-coding RNAs (ncRNAs) such as the one composed by the circular RNA ciRS-7 (also known as CDR1as), the microRNA miR-7, and the long ncRNA Cyrano. We describe ischemia-induced alterations in the ncRNA network both in vitro and in vivo and in transgenic mice lacking ciRS-7 or miR-7. Our data show that cortical neurons downregulate ciRS-7 and Cyrano and upregulate miR-7 expression during ischemia. Mice lacking ciRS-7 exhibit reduced lesion size and motor impairment, while the absence of miR-7 alone results in increased ischemia-induced neuronal death. Moreover, miR-7 levels in pyramidal excitatory neurons regulate neurite morphology and glutamatergic signaling, suggesting a potential molecular link to the in vivo phenotype. Our data reveal the role of ciRS-7 and miR-7 in modulating ischemic stroke outcome, shedding light on the pathophysiological function of intracellular ncRNA networks in the brain.

Introduction: The left (LV) and right (RV) ventricles are linked biologically, hemodynamically, and mechanically, a phenomenon known as ventricular interdependence. While LV function has long been known to impact RV function, the reverse is increasingly being realized to have clinical importance. Investigating ventricular interdependence clinically is challenging given the invasive measurements required, including biventricular catheterization, and confounding factors such as comorbidities, volume status, and other aspects of subject variability.Methods: Computational modeling allows investigation of mechanical and hemodynamic interactions in the absence of these confounding factors. Here, we use a threesegment biventricular heart model and simple circulatory system to investigate ventricular interdependence under conditions of systolic and diastolic dysfunction of the LV and RV in the presence of compensatory volume loading. We use the end-diastolic pressure-volume relationship, end-systolic pressure-volume relationship, Frank Starling curves, and cardiac power output as metrics.Results: The results demonstrate that LV systolic and diastolic dysfunction lead to RV compensation as indicated by increases in RV power. Additionally, RV systolic and diastolic dysfunction lead to impaired LV filling, interpretable as LV stiffening especially with volume loading to maintain systemic pressure.Discussion: These results suggest that a subset of patients with intact LV systolic function and diagnosed to have impaired LV diastolic function, categorized as heart failure with preserved ejection fraction (HFpEF), may in fact have primary RV failure. Application of this computational approach to clinical data sets, especially for HFpEF, may lead to improved diagnosis and treatment strategies and consequently improved outcomes.

Abstract Objective The aim of this study was to analyze the usefulness of myeloid-related protein 8/14 (MRP8/14) in the prediction of disease course in a real-world setting for patients with new-onset juvenile idiopathic arthritis (JIA), to identify the relationship between MRP8/14 and disease activity using the physician’s global assessment of disease activity (PGA), and determine whether the MRP8/14 levels measured in serum and plasma are equally useful. Methods In this prospective follow-up study, 87 new-onset non-systemic JIA patients were studied. Blood and synovial fluid samples were collected prior to any antirheumatic medication use. MRP8/14 was measured from serum (S-MRP8/14), plasma (P-MRP8/14), and synovial fluid samples using ELISA. Results The baseline MRP8/14 blood levels were significantly higher in patients using synthetic antirheumatic drugs than in patients with no systemic medications at 1 year after diagnosis in serum (mean 298 vs. 198 ng/ml, P

Abstract Background Transcriptomic and proteomic profiling of human brain tissue is hindered by the availability of fresh samples from living patients. Postmortem samples usually represent the advanced disease stage of the patient. Furthermore, the postmortem interval can affect the transcriptomic and proteomic profiles. Therefore, fresh brain tissue samples from living patients represent a valuable resource of metabolically intact tissue. Implantation of deep brain stimulation (DBS) electrodes into the human brain is a neurosurgical treatment for, e.g., movement disorders. Here, we describe an improved approach to collecting brain tissues from surgical instruments used in implantation of DBS device for transcriptomics and proteomics analyses. Methods Samples were extracted from guide tubes and recording electrodes used in routine DBS implantation procedure to treat patients with Parkinson’s disease, genetic dystonia and tremor. RNA sequencing was performed in tissues extracted from the recording microelectrodes and liquid chromatography-mass spectrometry (LC-MS) performed in tissues from guide tubes. To assess the performance of the current approach, the obtained datasets were compared with previously published datasets representing brain tissues. Results Altogether, 32,034 RNA transcripts representing the unique Ensembl gene identifiers were detected from eight samples representing both hemispheres of four patients. By using LC-MS, we identified 734 unique proteins from 31 samples collected from 14 patients. The datasets are available in the BioStudies database (accession number S-BSST667). Our results indicate that surgical instruments used in DBS installation retain brain material sufficient for protein and gene expression studies. Comparison with previously published datasets obtained with similar approach proved the robustness and reproducibility of the protocol. Conclusions The instruments used during routine DBS surgery are a useful source for obtaining fresh brain tissues from living patients. This approach overcomes the issues that arise from using postmortem tissues, such as the effect of postmortem interval on transcriptomic and proteomic landscape of the brain, and can be used for studying molecular aspects of DBS-treatable diseases.

Abstract Background FINCA disease is a pediatric cerebropulmonary disease caused by variants in the NHL repeat-containing 2 (NHLRC2) gene. Neurological symptoms are among the first manifestations of FINCA disease, but the consequences of NHLRC2 deficiency in the central nervous system are currently unexplored. Methods The orthologous mouse gene is essential for development, and its complete loss leads to early embryonic lethality. In the current study, we used CRISPR/Cas9 to generate an Nhlrc2 knockin (KI) mouse line, harboring the FINCA patient missense mutation (c.442G > T, p.Asp148Tyr). A FINCA mouse model, resembling the compound heterozygote genotype of FINCA patients, was obtained by crossing the KI and Nhlrc2 knockout mouse lines. To reveal NHLRC2-interacting proteins in developing neurons, we compared cortical neuronal precursor cells of E13.5 FINCA and wild-type mouse embryos by two-dimensional difference gel electrophoresis. Results Despite the significant decrease in NHLRC2, the mice did not develop severe early onset multiorgan disease in either sex. We discovered 19 altered proteins in FINCA neuronal precursor cells; several of which are involved in vesicular transport pathways and actin dynamics which have been previously reported in other cell types including human to have an association with dysfunctional NHLRC2. Interestingly, isoform C2 of hnRNP C1/C2 was significantly increased in both developing neurons and the hippocampus of adult female FINCA mice, connecting NHLRC2 dysfunction with accumulation of RNA binding protein. Conclusions We describe here the first NHLRC2-deficient mouse model to overcome embryonic lethality, enabling further studies on predisposing and causative mechanisms behind FINCA disease. Our novel findings suggest that disrupted RNA metabolism may contribute to the neurodegeneration observed in FINCA patients.

Clara Paz,1 Mari Aguilera,2 Marta Salla,3 Victoria Compañ,3 Joan C Medina,3,4 Arturo Bados,3 Eugeni García-Grau,3 Antoni Castel,5 José Cañete Crespillo,6 Adrián Montesano,7 Leticia Medeiros-Ferreira,8 Guillem Feixas3,4 1School of Psychology, Universidad de Las Américas, Quito, Ecuador; 2Department of Cognition, Development and Educational Psychology, Faculty of Psychology, Universitat de Barcelona, Barcelona, Spain; 3Department of Clinical Psychology and Psychobiology, Faculty of Psychology, Universitat de Barcelona, Barcelona, Spain; 4The Institute of Neurosciences, Universitat de Barcelona, Barcelona, Spain; 5Hospital Universitari de Tarragona Joan XXIII, Tarragona, Spain; 6Department of Psychiatry, Hospital de Mataró, Mataró, Spain; 7Faculty of Psychology and Educational Sciences, Universitat Oberta de Catalunya, Barcelona, Spain; 8Nou Barris Nord Adult Mental Health Centre, Barcelona, SpainCorrespondence: Clara Paz Jose Queri y Av, De Los Granados, Quito EC170125, EcuadorTel +593 2 3981000 ext. 2518Email clara.paz@udla.edu.ecBackground: Fibromyalgia (FM) is a debilitating syndrome, more prevalent in women, which is aggravated by the presence of depressive symptoms. In the last decade, cognitive behavioral therapy (CBT) has demonstrated to reduce such depressive symptoms and pain in these patients, but there are still a considerable number of them who do not respond to interventions. The complexity of the disorder requires the consideration of the unique psychological characteristics of each patient to attain good outcomes. One approach that could accomplish this goal might be personal construct therapy (PCT), an idiographic approach that considers identity features and interpersonal meanings as their main target of intervention. Then, the aim of the study is to test the efficacy of PCT as compared to a well-established treatment in the reduction of depressive symptoms in women with fibromyalgia.Methods and Analysis: This is a multicenter randomized controlled trial. In each condition participants will attend up to eighteen 1-hr weekly therapy sessions and up to three 1-hr booster sessions during the following 3– 5 months after the end of treatment. The depression subscale of the Hospital Anxiety and Depression Scale (HADS-D) will be the primary outcome measure and it will be assessed at baseline, at the end of therapy, and at 6-month follow-up. Other secondary measures will be applied following the same schedule. Participants will be 18- to 70-years-old women with a diagnosis of FM, presenting depressive symptoms evinced by scores above seven in depression items of the HADS-D. Intention-to-treat and complete case analyses will be performed for the main statistical tests. Linear mixed models will be used to analyze and to compare the treatment effects of both conditions.Trial Registration: ClinicalTrials.gov: NCT02711020.Keywords: psychotherapy, pain, repertory grid technique, study protocol, CBT, personal construct therapy

The modification of genes in animal models has evidently and comprehensively improved our knowledge on proteins and signaling pathways in human physiology and pathology. In this review, we discuss almost 40 monogenic rare diseases that are enriched in the Finnish population and defined as the Finnish disease heritage (FDH). We will highlight how gene-modified mouse models have greatly facilitated the understanding of the pathological manifestations of these diseases and how some of the diseases still lack proper models. We urge the establishment of subsequent international consortiums to cooperatively plan and carry out future human disease modeling strategies. Detailed information on disease mechanisms brings along broader understanding of the molecular pathways they act along both parallel and transverse to the proteins affected in rare diseases, therefore also aiding understanding of common disease pathologies.

Aim: To describe the specific brain magnetic resonance imaging (MRI) patterns of the paediatric genetic disorders associated with white matter abnormalities in Northern Finland. Method: In this retrospective population‐based longitudinal study, brain MRI scans accumulated from 1990 to 2019 at Oulu University Hospital, Finland, were assessed. Inclusion criteria were defined as leukodystrophies or genetic diseases with significant white matter abnormalities that did not meet the criteria for leukodystrophy, at least one brain MRI, and age under 18 years at diagnosis. Results: A total of 83 patients (48 males, 35 females) were found with 52 different diseases. The median age at the time of the brain MRI was 22 months (interquartile range [IQR] = 46 months). In 72 (87%) of the children, brain MRIs revealed abnormal findings, including cerebral white matter abnormalities (n = 49, 59%), brainstem signal abnormalities (n = 28, 34%), thinning of the corpus callosum (n = 30, 36%), delayed myelination (n = 11, 13%), and permanent hypomyelination (n = 9, 11%). Interpretation: Symmetrical and bilateral white matter signal patterns of the brain MRI should raise suspicion of genetic disorders when the clinical symptoms are compatible. This study illustrates brain imaging patterns of childhood‐onset genetic disorders in a population in Northern Finland and improves the diagnostic accuracy of rare genetic disorders. [ABSTRACT FROM AUTHOR]

Background: Genetic syndromes of hyperkinetic movement disorders associated with epileptic encephalopathy and intellectual disability are becoming increasingly recognized. Recently, a de novo heterozygous NACC1 (nucleus accumbens‐associated 1) missense variant was described in a patient cohort including one patient with a combined mitochondrial oxidative phosphorylation (OXPHOS) deficiency. Objectives: The objective is to characterize the movement disorder in affected patients with the recurrent c.892C>T NACC1 variant and study the NACC1 protein and mitochondrial function at the cellular level. Methods: The movement disorder was analyzed on four patients with the NACC1 c.892C>T (p.Arg298Trp) variant. Studies on NACC1 protein and mitochondrial function were performed on patient‐derived fibroblasts. Results: All patients had a generalized hyperkinetic movement disorder with chorea and dystonia, which occurred cyclically and during sleep. Complex I was found altered, whereas the other OXPHOS enzymes and the mitochondria network seemed intact in one patient. Conclusions: The movement disorder is a prominent feature of NACC1‐related disease. [ABSTRACT FROM AUTHOR]

This study critically examines gender equality planning (GEP), which has been obligatory in all Finnish comprehensive schools since 2015. GEP has been welcomed as a promising method of systemizing perspectives on gender in Finnish basic education. A regionally representative, discretional sample of gender equality plans (N = 140) was analysed using a critical discourse approach to examine how these plans discursively bent, stretched, fixed or shrank the meaning of gender equality along with the consequences of these approaches for equality promotion. The analysis shows that the GE plans constantly bent and stretched equality to separate it from gender and fixed it to free-floating gender equality measures, which left gendered power relations undisturbed. Consequently, equality promotion was represented as depoliticized. However, through the shrinking, the contextual construction of gendered power relations was recognized, and GEP exhibited the potential to politicize gender equality. In this paper, we argue that GEP has potential in gender equality promotion if the planning processes recognize contextual construction of gendered power relations and if equality promotion is not reduced to technical measures. Otherwise, the tool might actually impede equality rather than promoting it.

HLA typing and matching have been crucial in kidney transplantation, but methods for assessing tissue histocompatibility have advanced significantly. While serological-level HLA typing remains common, it captures only a small fraction of true HLA variation, and molecular matching is already replacing traditional HLA matching. Recent studies have expanded our understanding of genetic tissue compatibility beyond HLA loci. Candidate gene analyses and genome-wide association studies (GWAS) have identified genetic factors linked to post-transplant complications, though replication of these findings is challenging. An alternative approach involves genome-wide matching of genes or genetic variations. This method has shown promise in hematopoietic stem cell and kidney transplantation. For instance, homozygous gene deletions in LIMS1 or complement factor H (CFH) genes have been associated with acute rejection risk. This may be due to alloimmune responses against proteins absent in the patient but present in the graft, or due to the missing protein’s function. Genetic studies in clinical medicine face challenges due to the interplay of genetic and environmental factors, necessitating large datasets for meaningful associations. International collaboration and large consortia, like iGeneTRAin, are essential for validating findings and advancing the field. This review highlights recent advancements in immunogenetics and tissue histocompatibility, emphasizing future research directions.

Establishes whether students in a variety of educational environments differ in their attitudes toward nature and the environment. Identifies students' nature and environment-related activities and knowledge. (Author/CCM)

Abstract It has been described that many puppy owners experience a state called puppy blues involving stress, worry, anxiety, strain, frustration, or regret. While puppy blues is a commonly used term among dog owners, the term is nearly nonexistent in scientific literature. In turn, analogous phenomenon, postpartum affective disturbance of infant caregivers, is well described in the literature. This study aimed to develop and validate the first questionnaire to evaluate puppy blues. The methodology involved generating scale items based on a qualitative review of 135 pilot survey responses from people who had experienced distress during the puppy period, conducting exploratory factor analysis for the final scale items from a dataset of 1801 answers from Finnish dog owners (92% women), and collecting test-retest data from 265 individuals to assess the consistency of the measurement of items and factor structure across time. In addition, we collected an independent sample of 326 owners of 1–2-year-old dogs who answered the survey both regarding puppy period and current moment. The results indicate that the scale is a valid and reliable tool for measuring dog owners’ negative experiences and feelings related to puppyhood. We discovered three factors that describe different aspects of puppy blues: Frustration, Anxiety, and Weariness, which accounted for a significant proportion of the variance in puppy blues. The study demonstrated good internal consistency and consistency across two independent samples for the three identified factors. The test-retest reliability of the factors was good. Responses for the current timeframe compared to puppyhood experiences revealed significantly lower current scores across all factors for the current period, validating that the scale captures distress during puppyhood that diminishes over time. Interestingly, we found a fading affect bias where recollections of the experiences in the puppy period became more positive with time. Our findings shed light on the characteristics of puppy blues and provide a useful retrospective tool for measuring it.