The subtherapeutic dose of valproic acid induces the activity of cardiolipin-dependent proteins.

A mood-stabilizing anticonvulsant valproic acid (VPA) is a drug with a pleiotropic effect on cells. Here, we describe the impact of VPA on the metabolic function of human HAP1 cells. We show that VPA altered the biosynthetic pathway of cardiolipin (CL) and affected the activities of mitochondrial enzymes such as pyruvate dehydrogenase, α-ketoglutarate dehydrogenase and NADH dehydrogenase. We demonstrate that a therapeutic dose of VPA (0.6 mM) has a harmful effect on cell growth and increases the production of reactive oxygen species and superoxides. On the contrary, less concentrated VPA (0.06 mM) increased the activities of CL-dependent enzymes leading to an increased level of oxidative phosphorylation and ATP production. The effect of VPA was also tested on the Barth syndrome model, which is characterized by a reduced amount of CL and an increased level of monolyso-CL. In this model, VPA treatment slightly attenuated the mitochondrial defects by altering the activities of CL-dependent enzymes. However, the presence of CL was essential for the increase in ATP production by VPA. Our findings highlight the potential therapeutic role of VPA in normalizing mitochondrial function in BTHS and shed light on the intricate interplay between lipid metabolism and mitochondrial physiology in health and disease. SUMMARY: This study investigates the dose-dependent effect of valproate, a mood-stabilizing drug, on mitochondrial function. The therapeutic concentration reduced overall cellular metabolic activity, while a subtherapeutic concentration notably improved the function of cardiolipin-dependent proteins within mitochondria. These findings shed light on novel aspects of valproate's effect and suggest potential practical applications for its use. By elucidating the differential effects of valproate doses on mitochondrial activity, this research underscores the drug's multifaceted role in cellular metabolism and highlights avenues for further exploration in therapeutic interventions.

Global functional connectivity reorganization reflects cognitive processing speed deficits and fatigue in multiple sclerosis.

BACKGROUND AND PURPOSE: Cognitive impairment (CI) in multiple sclerosis (MS) is associated with bidirectional changes in resting-state centrality measures. However, practicable functional magnetic resonance imaging (fMRI) biomarkers of CI are still lacking. The aim of this study was to assess the graph-theory-based degree rank order disruption index (kD) and its association with cognitive processing speed as a marker of CI in patients with MS (PwMS) in a secondary cross-sectional fMRI analysis. METHODS: Differentiation between PwMS and healthy controls (HCs) using kD and its correlation with CI (Symbol Digit Modalities Test) was compared to established imaging biomarkers (regional degree, volumetry, diffusion-weighted imaging, lesion mapping). Additional associations were assessed for fatigue (Fatigue Scale for Motor and Cognitive Functions), gait and global disability. RESULTS: Analysis in 56 PwMS and 58 HCs (35/27 women, median age 45.1/40.5 years) showed lower kD in PwMS than in HCs (median -0.30/-0.06, interquartile range 0.55/0.54; p = 0.009, Mann-Whitney U test), yielding acceptable yet non-superior differentiation (area under curve 0.64). kD and degree in medial prefrontal cortex (MPFC) correlated with CI (kD/MPFC Spearman's ρ = 0.32/-0.45, p = 0.019/0.001, n = 55). kD also explained fatigue (ρ = -0.34, p = 0.010, n = 56) but neither gait nor disability. CONCLUSIONS: kD is a potential biomarker of CI and fatigue warranting further validation.

Intricate balance of dually-localized catalase modulates infectivity of Leptomonas seymouri (Kinetoplastea: Trypanosomatidae).

Nearly all aerobic organisms are equipped with catalases, powerful enzymes scavenging hydrogen peroxide and facilitating defense against harmful reactive oxygen species. In trypanosomatids, this enzyme was not present in the common ancestor, yet it had been independently acquired by different lineages of monoxenous trypanosomatids from different bacteria at least three times. This observation posited an obvious question: why was catalase so "sought after" if many trypanosomatid groups do just fine without it? In this work, we analyzed subcellular localization and function of catalase in Leptomonas seymouri. We demonstrated that this enzyme is present in the cytoplasm and a subset of glycosomes, and that its cytoplasmic retention is H2O2-dependent. The ablation of catalase in this parasite is not detrimental in vivo, while its overexpression resulted in a substantially higher parasite load in the experimental infection of Dysdercus peruvianus. We propose that the capacity of studied flagellates to modulate the catalase activity in the midgut of its insect host facilitates their development and protects them from oxidative damage at elevated temperatures.

In silico prediction of the metabolism of Blastocrithidia nonstop, a trypanosomatid with non-canonical genetic code.

BACKGROUND: Almost all extant organisms use the same, so-called canonical, genetic code with departures from it being very rare. Even more exceptional are the instances when a eukaryote with non-canonical code can be easily cultivated and has its whole genome and transcriptome sequenced. This is the case of Blastocrithidia nonstop, a trypanosomatid flagellate that reassigned all three stop codons to encode amino acids. RESULTS: We in silico predicted the metabolism of B. nonstop and compared it with that of the well-studied human parasites Trypanosoma brucei and Leishmania major. The mapped mitochondrial, glycosomal and cytosolic metabolism contains all typical features of these diverse and important parasites. We also provided experimental validation for some of the predicted observations, concerning, specifically presence of glycosomes, cellular respiration, and assembly of the respiratory complexes. CONCLUSIONS: In an unusual comparison of metabolism between a parasitic protist with a massively altered genetic code and its close relatives that rely on a canonical code we showed that the dramatic differences on the level of nucleic acids do not seem to be reflected in the metabolisms. Moreover, although the genome of B. nonstop is extremely AT-rich, we could not find any alterations of its pyrimidine synthesis pathway when compared to other trypanosomatids. Hence, we conclude that the dramatic alteration of the genetic code of B. nonstop has no significant repercussions on the metabolism of this flagellate.

Structural connectivity-based predictors of cognitive impairment in stroke patients attributable to aging.

Despite the rising global burden of stroke and its socio-economic implications, the neuroimaging predictors of subsequent cognitive impairment are still poorly understood. We address this issue by studying the relationship of white matter integrity assessed within ten days after stroke and patients' cognitive status one year after the attack. Using diffusion-weighted imaging, we apply the Tract-Based Spatial Statistics analysis and construct individual structural connectivity matrices by employing deterministic tractography. We further quantify the graph-theoretical properties of individual networks. The Tract-Based Spatial Statistic did identify lower fractional anisotropy as a predictor of cognitive status, although this effect was mostly attributable to the age-related white matter integrity decline. We further observed the effect of age propagating into other levels of analysis. Specifically, in the structural connectivity approach we identified pairs of regions significantly correlated with clinical scales, namely memory, attention, and visuospatial functions. However, none of them persisted after the age correction. Finally, the graph-theoretical measures appeared to be more robust towards the effect of age, but still were not sensitive enough to capture a relationship with clinical scales. In conclusion, the effect of age is a dominant confounder especially in older cohorts, and unless appropriately addressed, may falsely drive the results of the predictive modelling.

Multimodal-neuroimaging machine-learning analysis of motor disability in multiple sclerosis.

Motor disability is a dominant and restricting symptom in multiple sclerosis, yet its neuroimaging correlates are not fully understood. We apply statistical and machine learning techniques on multimodal neuroimaging data to discriminate between multiple sclerosis patients and healthy controls and to predict motor disability scores in the patients. We examine the data of sixty-four multiple sclerosis patients and sixty-five controls, who underwent the MRI examination and the evaluation of motor disability scales. The modalities used comprised regional fractional anisotropy, regional grey matter volumes, and functional connectivity. For analysis, we employ two approaches: high-dimensional support vector machines run on features selected by Fisher Score (aiming for maximal classification accuracy), and low-dimensional logistic regression on the principal components of data (aiming for increased interpretability). We apply analogous regression methods to predict symptom severity. While fractional anisotropy provides the classification accuracy of 96.1% and 89.9% with both approaches respectively, including other modalities did not bring further improvement. Concerning the prediction of motor impairment, the low-dimensional approach performed more reliably. The first grey matter volume component was significantly correlated (R = 0.28-0.46, p < 0.05) with most clinical scales. In summary, we identified the relationship between both white and grey matter changes and motor impairment in multiple sclerosis. Furthermore, we were able to achieve the highest classification accuracy based on quantitative MRI measures of tissue integrity between patients and controls yet reported, while also providing a low-dimensional classification approach with comparable results, paving the way to interpretable machine learning models of brain changes in multiple sclerosis.

Human brain structural connectivity matrices-ready for modelling.

The human brain represents a complex computational system, the function and structure of which may be measured using various neuroimaging techniques focusing on separate properties of the brain tissue and activity. We capture the organization of white matter fibers acquired by diffusion-weighted imaging using probabilistic diffusion tractography. By segmenting the results of tractography into larger anatomical units, it is possible to draw inferences about the structural relationships between these parts of the system. This pipeline results in a structural connectivity matrix, which contains an estimate of connection strength among all regions. However, raw data processing is complex, computationally intensive, and requires expert quality control, which may be discouraging for researchers with less experience in the field. We thus provide brain structural connectivity matrices in a form ready for modelling and analysis and thus usable by a wide community of scientists. The presented dataset contains brain structural connectivity matrices together with the underlying raw diffusion and structural data, as well as basic demographic data of 88 healthy subjects.

Highly flexible metabolism of the marine euglenozoan protist Diplonema papillatum.

BACKGROUND: The phylum Euglenozoa is a group of flagellated protists comprising the diplonemids, euglenids, symbiontids, and kinetoplastids. The diplonemids are highly abundant and speciose, and recent tools have rendered the best studied representative, Diplonema papillatum, genetically tractable. However, despite the high diversity of diplonemids, their lifestyles, ecological functions, and even primary energy source are mostly unknown. RESULTS: We designed a metabolic map of D. papillatum cellular bioenergetic pathways based on the alterations of transcriptomic, proteomic, and metabolomic profiles obtained from cells grown under different conditions. Comparative analysis in the nutrient-rich and nutrient-poor media, as well as the absence and presence of oxygen, revealed its capacity for extensive metabolic reprogramming that occurs predominantly on the proteomic rather than the transcriptomic level. D. papillatum is equipped with fundamental metabolic routes such as glycolysis, gluconeogenesis, TCA cycle, pentose phosphate pathway, respiratory complexes, ß-oxidation, and synthesis of fatty acids. Gluconeogenesis is uniquely dominant over glycolysis under all surveyed conditions, while the TCA cycle represents an eclectic combination of standard and unusual enzymes. CONCLUSIONS: The identification of conventional anaerobic enzymes reflects the ability of this protist to survive in low-oxygen environments. Furthermore, its metabolism quickly reacts to restricted carbon availability, suggesting a high metabolic flexibility of diplonemids, which is further reflected in cell morphology and motility, correlating well with their extreme ecological valence.

A Three-Arm Parallel-group Exploratory Trial documents balance improvement without much evidence of white matter integrity changes in people with multiple sclerosis following two months ambulatory neuroproprioceptive "facilitation and inhibition" physical therapy.

BACKGROUND: Changes of white matter integrity in people with multiple sclerosis (MS) were documented following mainly motor/skill acquisitions physical therapy, while following neuroproprioceptive "facilitation, inhibition" (neurofacilitation) only by two pilot studies. Neurofacilitation has potential to induce white matter changes due to the possibility of interfering with the neuronal tactility threshold. However stronger evidence is missing. AIM: This study investigates whether neurofacilitation (three physical therapy types) induce white matter changes and if they relate to clinical improvement. DESIGN: The Three-Arm Parallel-group Exploratory Trial (NCT04355663). SETTING: Each group underwent different kinds of two months ambulatory therapy (Motor Program Activating Therapy, Vojta's reflex locomotion and Functional Electric Stimulation in Posturally Corrected Position). POPULATION: MS people with moderate disability. METHODS: At baseline and after the program, participants underwent magnetic resonance diffusion tensor imaging (DTI) and clinical assessment. Fractional anisotropy maps obtained from DTI were further analyzed using tract-based spatial statistic exploring the mean values in the whole statistic skeleton. Moreover, additional exploratory analysis in 48 regions of white matter was done. RESULTS: Ninety-two people were recruited. DTI data from 61 people were analyzed. The neurofacilitation (irrespective type of therapy) resulted in significant improvement on the Berg Balance Scale (P=0.0089), mainly driven by the Motor Program Activating Therapy. No statistically significant change in the whole statistic skeleton was observed (only a trend for decrement of fractional anisotropy after Vojta's reflex locomotion). Additional exploratory analysis confirmed significant decrement of fractional anisotropy in the right anterior corona radiata. CONCLUSIONS: Neurofacilitation improved balance without much evidence of white matter integrity changes in people with MS. CLINICAL REHABILITATION IMPACT: The study results point to the importance of neuroproprioceptive "facilitation and inhibition" physical therapy in the management of balance in people with multiple sclerosis; and the potential to induce white matter changes due to the possibility of interfering with the neuronal tactility threshold.

Predicting Sex From EEG: Validity and Generalizability of Deep-Learning-Based Interpretable Classifier.

Explainable artificial intelligence holds a great promise for neuroscience and plays an important role in the hypothesis generation process. We follow-up a recent machine learning-oriented study that constructed a deep convolutional neural network to automatically identify biological sex from EEG recordings in healthy individuals and highlighted the discriminative role of beta-band power. If generalizing, this finding would be relevant not only theoretically by pointing to some specific neurobiological sexual dimorphisms, but potentially also as a relevant confound in quantitative EEG diagnostic practice. To put this finding to test, we assess whether the automatic identification of biological sex generalizes to another dataset, particularly in the presence of a psychiatric disease, by testing the hypothesis of higher beta power in women compared to men on 134 patients suffering from Major Depressive Disorder. Moreover, we construct ROC curves and compare the performance of the classifiers in determining sex both before and after the antidepressant treatment. We replicate the observation of a significant difference in beta-band power between men and women, providing classification accuracy of nearly 77%. The difference was consistent across the majority of electrodes, however multivariate classification models did not generally improve the performance. Similar results were observed also after the antidepressant treatment (classification accuracy above 70%), further supporting the robustness of the initial finding.

The conversion factor for predicting adenoma detection rate from polyp detection rate varies according to colonoscopy indication and patient sex.

The adenoma detection rate (ADR) is the primary quality indicator for colonoscopies. The polyp detection rate (PDR) is available from administrative data and does not depend on histology verification. The correlation between PDR and ADR and the ADR/PDR conversion factor in preventive colonoscopies were evaluated. In the prospective study, asymptomatic individuals aged 45-75 years with preventive colonoscopy in 2012-2016 were included. Spearman's correlation coefficient was used to assess PDR/ADR for each endoscopist. Conversion factor predicting ADR from PDR was obtained by linear regression and subsequently compared with adenoma to polyp detection rate quotient. One thousand six hundred fourteen preventive colonoscopies performed by 16 endoscopists in 8 screening colonoscopy centres in the Czech Republic were analysed. Correlation between PDR and ADR in all preventive colonoscopies was high and statistically significant (Rs 0.82; P < 0.001). There was a strong correlation between PDR and ADR in men (Rs 0.74; P = 0.002) and in screening colonoscopies (Rs 0.85; P < 0.001). The conversion factor to convert ADR from PDR was 0.72 in all preventive colonoscopies, 0.76 in FOBT+ colonoscopies and 0.67 in screening colonoscopies. ADR may be replaced by PDR in the assessment of colonoscopy quality. The value of the conversion factor varies according to colonoscopy indication and gender of examined individuals; in this Czech study, it was 0.72 in all preventive colonoscopies. The minimum requested ADR of 25 % corresponds to a PDR of 35 %, when converted with the appropriate conversion factor.

Catalase and Ascorbate Peroxidase in Euglenozoan Protists.

In this work, we studied the biochemical properties and evolutionary histories of catalase (CAT) and ascorbate peroxidase (APX), two central enzymes of reactive oxygen species detoxification, across the highly diverse clade Eugenozoa. This clade encompasses free-living phototrophic and heterotrophic flagellates, as well as obligate parasites of insects, vertebrates, and plants. We present evidence of several independent acquisitions of CAT by horizontal gene transfers and evolutionary novelties associated with the APX presence. We posit that Euglenozoa recruit these detoxifying enzymes for specific molecular tasks, such as photosynthesis in euglenids and membrane-bound peroxidase activity in kinetoplastids and some diplonemids.

Accuracy of Colon Capsule Endoscopy for Colorectal Neoplasia Detection in Individuals Referred for a Screening Colonoscopy.

BACKROUND: Capsule colonoscopy might present an alternative to colonoscopy for colorectal neoplasia screening. AIM: To assess the accuracy of second-generation capsule colonoscopy (CCE2) for colorectal neoplasia detection compared with conventional colonoscopy (CC). METHODS: From 2011-2015, we performed a multicenter, prospective, cross-over study evaluating the use of CCE2 as a possible colorectal cancer (CRC) screening test based on the assessment of the method's characteristics (accuracy) and safety and patient acceptance of the routine. Enrolled participants fulfilled the CRC screening population criteria if they were asymptomatic, were older than 50, and had no personal or familial history of colorectal neoplasia. The primary outcome was accuracy for the detection of polyps ≥ 6 mm. Secondary outcomes were accuracy for all polyps, polyps ≥ 10 mm, adenomas ≥ 10 mm, and cancers, the quality of bowel cleansing, safety, and CCE2 acceptability by the screening population. RESULTS: A total of 236 individuals were examined; 11 patients (5%) were excluded. Therefore, 225 subjects (95%) were considered in the intention-to-screen (ITS) group. A total of 201 patients (89%) completed both examinations successfully (per protocol group). In the ITS group, polyps were diagnosed during CC in 114 subjects (51%); polyps ≥ 6 mm, polyps ≥ 10 mm, and adenomas ≥ 10 mm were diagnosed in 34 (15%), 16 (7%), and 11 (5%) patients, respectively. The sensitivity of CCE2 for polyps ≥ 6 mm, polyps ≥ 10 mm, and adenomas ≥ 10 mm was 79% (95% confidence interval (CI): 62-91%), 88% (95% CI: 62-98%), and 100% (95% CI: 72-100%), respectively. CONCLUSION: Second-generation capsule colonoscopy is a safe, noninvasive, and sensitive method for colorectal neoplasia detection although CC remains the preferred method for considerable proportion of subjects. CCE2 may therefore be accepted as the primary screening test for colorectal cancer screening.

Effect of probiotic bacteria on phagocytosis and respiratory burst activity of blood polymorphonuclear leukocytes (PMNL) in mice infected with Trichinella spiralis.

This study focusses on the effect of probiotic (bacteriocinogenic) strains on parasite infection and innate immunity - phagocytosis and oxidative burst of blood monocytes and polymorphonuclear leukocytes (PMNL) in mice infected with Trichinella spiralis. Bacteriocinogenic and probiotic strains of different origin (Enterococcus faecium AL41=CCM8558, Enterococcus durans ED26E/7, Lactobacillus fermentum AD1=CCM7421, Lactobacillus plantarum 17L/1) were administered daily in dose of 109CFU/ml in 100µl and mice were infected with 400 larvae of T. spiralis on 7th day of treatment. Phagocytic activity of blood leukocytes was inhibited at week 3 and 4 post infection (p.i.), i.e. in the time of massive muscle invasion with larvae T. spiralis. Administration of bacterial strains to mice prior to T. spiralis infection elevated and prolonged phagocytic activity of blood leukocytes and their ingestion capability from week 1 to 3 of the infection and the phagocytosis was inhibited only at week 4 p.i. The highest stimulative effect on phagocytosis was induced by strains E. durans ED26E/7, L. fermentum AD1=CCM7421, and L. plantarum 17L/1. The percentage of cells with respiratory burst and their enzymatic activity was increased after T. spiralis infection with the exception of week 3 p.i. In contrast, in all mice treated with bacterial strains the enzymatic stimulation was observed after the infection, with the highest intensity caused by strains E. durans ED26E/7, L. fermentum AD1=CCM7421 and L. plantarum 17L/1. The administration of probiotic strains stimulated phagocytosis and respiratory burst of blood PMNL that could contribute to a decreased larval migration and a destruction of muscle larvae and then reduced parasite burden in the host. The protective effect against T. spiralis infection was induced by all strains, but the highest reduction was recorded by E. faecium AL41=CCM8558.