Metabolic dysfunction-associated steatotic liver disease (MASLD) is a heterogeneous condition characterized by liver steatosis, inflammation, consequent fibrosis, and cirrhosis. Chronic impairment of lipid metabolism is closely related to oxidative stress, leading to cellular lipotoxicity, mitochondrial dysfunction, and endoplasmic reticulum stress. The detrimental effect of oxidative stress is usually accompanied by changes in antioxidant defense mechanisms, with the alterations in antioxidant enzymes expression/activities during MASLD development and progression reported in many clinical and experimental studies. This review will provide a comprehensive overview of the present research on MASLD-induced changes in the catalytic activity and expression of the main antioxidant enzymes (superoxide dismutases, catalase, glutathione peroxidases, glutathione S-transferases, glutathione reductase, NAD(P)H:quinone oxidoreductase) and in the level of non-enzymatic antioxidant glutathione. Furthermore, an overview of the therapeutic effects of vitamin E on antioxidant enzymes during the progression of MASLD will be presented. Generally, at the beginning of MASLD development, the expression/activity of antioxidant enzymes usually increases to protect organisms against the increased production of reactive oxygen species. However, in advanced stage of MASLD, the expression/activity of several antioxidants generally decreases due to damage to hepatic and extrahepatic cells, which further exacerbates the damage. Although the results obtained in patients, in various experimental animal or cell models have been inconsistent, taken together the importance of antioxidant enzymes in MASLD development and progression has been clearly shown.

• MeSH
• Antioxidants * metabolism   MeSH
• Glutathione metabolism   MeSH
• Humans MeSH
• Metabolic Diseases metabolism   MeSH
• Oxidative Stress * MeSH
• Reactive Oxygen Species metabolism   MeSH
• Vitamin E metabolism   MeSH
• Fatty Liver metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Plasma circulating donor-derived cell-free DNA (ddcfDNA) can be used to noninvasively monitor acute rejection of heart transplants (HTx). This study utilized digital droplet PCR to analyze ddcfDNA concentrations (measured in copies per milliliter) and the fractional abundance (%ddcfDNA) to differentiate between donor and recipient DNA on the basis of single nucleotide polymorphism (SNP) homozygosity. Seventy-seven patients participated in a study, providing 300 plasma samples. Both markers, mean ddcfDNA (cp/mL) and %ddcfDNA, showed similar decreasing trends following the HTx, (R2 < 0.2; p < 0.001). Significantly higher levels of ddcfDNA (cp/mL) and %ddcfDNA were observed during episodes of acute rejection (AR) compared to non-rejection samples (p < 0.001). Additionally, antibody-mediated rejection (AMR) was associated with increased %ddcfDNA levels compared to non-rejection and to acute cellular rejection samples (p < 0.001 and p < 0.01). A logistic regression model identified %ddcfDNA as an early predictor of AMR risk 10-19 days post-heart transplant (odds ratio 158, p < 0.02). Performance analysis established an optimal %ddcfDNA threshold of 0.125% for AMR detection, correctly identifying all patients without subsequent AMR. These findings suggest that early %ddcfDNA measurements post-HTx can accurately identify individuals unlikely to develop AMR during the first posttransplant year.

• MeSH
• Biomarkers * blood   MeSH
• Early Diagnosis MeSH
• Tissue Donors * MeSH
• Adult MeSH
• Isoantibodies * immunology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Follow-Up Studies MeSH
• Graft Survival MeSH
• Prognosis MeSH
• Graft Rejection * diagnosis   etiology   blood   MeSH
• Risk Factors MeSH
• Heart Transplantation * adverse effects   MeSH
• Cell-Free Nucleic Acids * blood   genetics   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Diplonemids are among the most abundant and species-rich protists in the oceans. Marine heterotrophic flagellates, including diplonemids, have been suggested to play important roles in global biogeochemical cycles. Diplonemids are also the sister taxon of kinetoplastids, home to trypanosomatid parasites of global health importance, and thus are informative about the evolution of kinetoplastid biology. However, the genomic and cellular complement that underpins diplonemids' highly successful lifestyle is underexplored. At the same time, our framework describing cellular processes may not be as broadly applicable as presumed, as it is largely derived from animal and fungal model organisms, a small subset of extant eukaryotic diversity. In addition to uniquely evolved machinery in animals and fungi, there exist components with sporadic (i.e., "patchy") distributions across other eukaryotes. A most intriguing subset are components ("jötnarlogs") stochastically present in a wide range of eukaryotes but lost in animal and/or fungal models. Such components are considered exotic curiosities but may be relevant to inferences about the complexity of the last eukaryotic common ancestor (LECA) and frameworks of modern cell biology. Here, we use comparative genomics and phylogenetics to comprehensively assess the membrane-trafficking system of diplonemids. They possess several proteins thought of as kinetoplastid specific, as well as an extensive set of patchy proteins, including jötnarlogs. Diplonemids apparently function with endomembrane machinery distinct from existing cell biological models but comparable with other free-living heterotrophic protists, highlighting the importance of including such exotic components when considering different models of ancient eukaryotic genomic complexity and the cell biology of non-opisthokont organisms.

• MeSH
• Biological Evolution MeSH
• Phylogeny MeSH
• Kinetoplastida * physiology   genetics   MeSH
• Publication type
• Journal Article MeSH

The cerebellum, a lateralised organ, plays a crucial role in motor control. Still, its involvement in hand and foot dominance remains inadequately understood, primarily in the right and left-side dominant population. A potential manifestation of this lateralisation is the neocerebellar extinction syndrome, previously linked to mild muscle hypotonia and moderate passivity in the non-preferred hand. A more precise understanding of the cerebellum's role in limb dominance patterns could provide valuable insights into motor learning, rehabilitation therapies, and neuroplasticity. This study explored the relationship between physiological neocerebellar extinction syndrome and hand/ft dominance in left and right-side dominant individuals. Data were collected from 80 university participants (40 left-side dominant, 40 right-side dominant, mean age = 24.7 ± 0.92 years) during controlled limb falls using 3D kinematic analysis. In these falls, theoretically suggested hypotonia in non-dominant limbs was analysed through attenuation coefficients and frequency differences. Using a linear mixed model, we found significantly lower hand attenuation in the non-dominant hand-(β = 0.10, p < 0.001), showing hypotonia compared to the dominant hand regardless of upper limb side dominance. Foot preference and dominance had minimal influence on leg attenuation or frequency, although right-footed, right-dominant individuals demonstrated significantly higher leg oscillation frequency, likely due to increased proximal muscle mass. Our findings suggest that distinct differences in cortical representation, lateralised control, and pathway specialisation exist due to the unique demands of each limb's motor functions, which are pronounced more neocerebellar extinction syndrome in the upper extremities. Therefore, the results showed potentially new perspectives on the cerebellum's nuanced role in motor control and laterality. The differential effects observed between the upper and lower limbs point to distinct cerebellar pathways and hypotonia. This work could significantly enhance the precision of therapeutic approaches and broaden our knowledge of laterality in motor function.

• MeSH
• Biomechanical Phenomena MeSH
• Adult MeSH
• Functional Laterality * physiology   MeSH
• Humans MeSH
• Young Adult MeSH
• Cerebellum * physiopathology   MeSH
• Foot physiology   MeSH
• Hand MeSH
• Muscle Hypotonia physiopathology   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Chronic Kidney Disease (CKD) is associated with heightened risk of thrombosis. Prescription of anticoagulants is key to manage it; however, CKD patients have shown an increased risk of bleeding under anticoagulation therapy compared to non-CKD patients. We hypothesized that the sex could modify the metabolism of indoxyl sulfate (IS), a uremic toxin and Apixaban. Our intoxication model shows that higher doses of IS and apixaban accumulate in the plasma of female mice because of expression differences in efflux transporters and cytochromes in the liver, ileum and kidneys, when compared to males. Furthermore, we found that accumulation of apixaban in females contributes to increased bleeding. Transcriptional analysis of liver samples revealed elevated Sult1a1 but reduced Abcg2 and Cyp3a11 in female mice, while in the kidneys the expression rates of Oat1 and Oat3 were respectively lower and higher than those observed in males, potentially affecting drug clearance. Whole proteomics liver analysis confirmed the previous transcriptional results at the protein level and revealed that sex had a major influence in regulating both coagulation and drug metabolism pathways. Thus, our findings underline the need for inclusive clinical and preclinical trials to accurately reflect sex-specific metabolic variations, and to consider CKD-specific changes to optimize dosing, minimize side effects, and improve patient outcomes.

• MeSH
• ATP Binding Cassette Transporter, Subfamily G, Member 2 metabolism   genetics   MeSH
• Anticoagulants administration & dosage   metabolism   MeSH
• Renal Insufficiency, Chronic metabolism   drug therapy   MeSH
• Cytochrome P-450 CYP3A metabolism   genetics   MeSH
• Indican * metabolism   blood   MeSH
• Liver * metabolism   drug effects   MeSH
• Hemorrhage metabolism   MeSH
• Kidney metabolism   drug effects   MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Organic Anion Transporters, Sodium-Independent metabolism   genetics   MeSH
• Organic Anion Transport Protein 1 metabolism   genetics   MeSH
• Pyrazoles * pharmacology   MeSH
• Pyridones * administration & dosage   metabolism   pharmacology   MeSH
• Sex Factors MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Post-transplant cyclophosphamide (PTCY) is increasingly used as effective graft-versus-host disease (GvHD) prophylaxis in allogeneic hematopoietic-cell transplantation (allo-HCT). However, PTCY is associated with toxicities. Whether patients with specific comorbidities are more vulnerable to cyclophosphamide-induced toxicity is unclear. We retrospectively evaluated the impact of individual organ dysfunctions for non-relapse mortality (NRM) risk and overall survival (OS) among 5888 adults who underwent PTCY-based allo-HCT for acute myeloid leukemia between 2010 and 2023. In multivariable analyses 5 of the comorbidities (renal, moderate/severe hepatic, cardiac including arrhythmia/valvular disease, severe pulmonary, infection) were independently associated with adverse NRM and OS without influencing relapse rate. A simplified model using the absence (n = 4390), presence of 1 (n = 1229) or presence of 2 or 3 (n = 269) of the comorbidities which were determined individually to contribute to NRM stratified patients into 3 NRM risk (16.2% vs. 21.6% vs. 36%, retrospectively) and OS categories (64% vs. 56% vs. 36.4%, retrospectively). In Cox model, recipients with 2 or 3 comorbidities had an increased hazard ratio for NRM of 2.38 (95% confidence interval [CI], 1.89-3) and for OS of 1.96 (95% CI 1.64-2.33). Whether patients with concomitant diagnoses, as determined here, may benefit from a reduced PTCY dose remains to be evaluated in prospective clinical trials.

• MeSH
• Leukemia, Myeloid, Acute * therapy   mortality   MeSH
• Cyclophosphamide * therapeutic use   adverse effects   pharmacology   administration & dosage   MeSH
• Adult MeSH
• Comorbidity MeSH
• Middle Aged MeSH
• Humans MeSH
• Graft vs Host Disease prevention & control   mortality   MeSH
• Transplant Recipients MeSH
• Retrospective Studies MeSH
• Aged MeSH
• Hematopoietic Stem Cell Transplantation * methods   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Targeted alpha therapy (TAT) is an effective option for cancer treatment. To maximize its efficacy and minimize side effects, carriers must deliver radionuclides to target tissues. Most of the nuclides used in TAT decay via the alpha cascade, producing several radioactive daughter nuclei with sufficient energy to escape from the original carrier. Therefore, studying these daughter atoms is crucial in the search for new carriers. Nanoparticles have potential as carriers due to their structure, which can prevent the escape of daughter atoms and reduce radiation exposure to non-target tissues. This work focuses on determining the released activity of 221Fr and 213Bi resulting from the decay of 225Ac labelled TiO2 nanoparticles. RESULTS: Labelling of TiO2 nanoparticles has shown high sorption rates of 225Ac and its progeny, 221Fr and 213Bi, with over 92 % of activities sorbed on the nanoparticle surface for all measured radionuclides. However, in the quasi-dynamic in vitro system, the released activity of 221Fr and 213Bi is strongly dependent on the nanoparticles concentration, ranging from 15 % for a concentration of 1 mg/mL to approximately 50 % for a nanoparticle concentration of 10 μg/mL in saline solution. The released activities of 213Bi were lower, with a maximum value of around 20 % for concentrations of 0.05, 0.025, and 0.01 mg/mL. The leakage of 225Ac and its progeny was tested in various biological matrices. Minimal released activity was measured in saline at around 10 % after 48 h, while the maximum activity was measured in blood serum and plasma at 20 %. The amount of 225Ac released into the media was minimal (<3 %). The in vitro results were confirmed in a healthy mouse model. The difference in %ID/g was clearly visible immediately after dissection and again after 6 h when 213Bi reached equilibrium with 225Ac. CONCLUSION: The study verified the potential release of 225Ac progeny from the labelled TiO2 nanoparticles. Experiments were performed to determine the dependence of released activity on nanoparticle concentration and the biological environment. The results demonstrated the high stability of the prepared 225Ac@TiO2 NPs and the potential release of progeny over time. In vivo studies confirmed our hypothesis. The data obtained suggest that the daughter atoms can escape from the original carrier and follow their own biological pathways in the organism.

• MeSH
• Actinium * chemistry   MeSH
• Isotope Labeling MeSH
• Mice MeSH
• Nanoparticles * chemistry   MeSH
• Radioisotopes chemistry   MeSH
• Titanium * chemistry   MeSH
• Tissue Distribution MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

OBJECTIVE: This study aims to evaluate the efficacy of the Uniform Data Set (UDS) 2 battery in distinguishing between individuals with mild cognitive impairment (MCI) attributable to Alzheimer's disease (MCI-AD) and those with MCI due to other causes (MCI-nonAD), based on contemporary AT(N) biomarker criteria. Despite the implementation of the novel UDS 3 battery, the UDS 2 battery is still used in several non-English-speaking countries. METHODS: We employed a cross-sectional design. A total of 113 Czech participants with MCI underwent a comprehensive diagnostic assessment, including cerebrospinal fluid biomarker evaluation, resulting in two groups: 45 individuals with prodromal AD (A+T+) and 68 participants with non-Alzheimer's pathological changes or normal AD biomarkers (A-). Multivariable logistic regression analyses were employed with neuropsychological test scores and demographic variables as predictors and AD status as an outcome. Model 1 included UDS 2 scores that differed between AD and non-AD groups (Logical Memory delayed recall), Model 2 employed also Letter Fluency and Rey's Auditory Verbal Learning Test (RAVLT). The two models were compared using area under the receiver operating characteristic curves. We also created separate logistic regression models for each of the UDS 2 scores. RESULTS: Worse performance in delayed recall of Logical Memory significantly predicted the presence of positive AD biomarkers. In addition, the inclusion of Letter Fluency RAVLT into the model significantly enhanced its discriminative capacity. CONCLUSION: Our findings demonstrate that using Letter Fluency and RAVLT alongside the UDS 2 battery can enhance its potential for differential diagnostics.

• MeSH
• Alzheimer Disease * diagnosis   cerebrospinal fluid   MeSH
• Amyloid beta-Peptides cerebrospinal fluid   MeSH
• Biomarkers * cerebrospinal fluid   MeSH
• Diagnosis, Differential MeSH
• Cognitive Dysfunction * diagnosis   etiology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Neuropsychological Tests * standards   statistics & numerical data   MeSH
• tau Proteins cerebrospinal fluid   MeSH
• Cross-Sectional Studies MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Protein cross-linking has assumed an irreplaceable role in structural proteomics. Recently, significant efforts have been made to develop novel mass spectrometry (MS)-cleavable reagents. At present, only water-insoluble MS-cleavable cross-linkers are commercially available. However, to comprehensively analyse the various chemical and structural motifs making up proteins, it is necessary to target different protein sites with varying degrees of hydrophilicity. Here we introduce the new MS-cleavable cross-linker disulfodisuccinimidyl dibutyric urea (DSSBU), which we have developed in-house for this purpose. DSSBU contains an N-hydroxysulfosuccinimide (sulfo-NHS) reactive group, so it can serve as a water-soluble counterpart to the widely used cross-linker disuccinimidyl dibutyric urea (DSBU). To investigate the applicability of DSSBU, we compared the efficacy of four similar cross-linkers: bis[sulfosuccinimidyl] suberate (BS3), disuccinimidyl suberate (DSS), DSBU and DSSBU with bovine serum albumin. In addition, we compared the efficacy of DSBU and DSSBU with human haemoglobin. Our results demonstrate that the sulfo-NHS group ensures the superior water solubility of DSSBU and thus negates the need for organic solvents such as dimethyl sulfoxide while preserving the effectivity of urea-based MS-cleavable crosslinkers such as DSBU. Additionally, it makes it possible to target polar regions in proteins. The data gathered are available via ProteomeXchange under identifier PXD055284. SIGNIFICANCE: We have synthesized the novel protein cross-linker DSSBU, which combines sulfo-NHS ester chemistry with a mass spectrometry-cleavable urea group. This makes DSSBU a water-soluble, MS-cleavable cross-linker that reacts with amino groups. To our knowledge, it is the first cross-linker which combines all three of these characteristics. We have tested the performance of our novel cross-linker on bovine serum albumin, a model widely used by the cross-linking mass spectrometry community, and on human haemoglobin. We have comprehensively assessed the performance of DSSBU and compared its efficacy with that of three other cross-linkers in current use (BS3, DSS and DSBU). We conclude that our novel cross-linker surpasses its MS-non-cleavable analogue BS3 in performance and that its water solubility eliminates the need for organic solvents while its hydrophilicity allows for the targetting of polar regions in proteins. Therefore, it will likely become a significant addition to the portfolio of N-hydroxysuccinimide ester cross-linkers.

• MeSH
• Mass Spectrometry methods   MeSH
• Humans MeSH
• Urea chemistry   MeSH
• Proteomics methods   MeSH
• Cross-Linking Reagents * chemistry   MeSH
• Serum Albumin, Bovine chemistry   MeSH
• Cattle MeSH
• Succinimides * chemistry   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Cattle MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Medication non-adherence is a common issue in chronic illness. The World Health Organization has recognized a need for a valid and reliable method of measuring adherence to understand and mitigate non-adherence. This study aimed to psychometrically evaluate the English version of the Adelphi Adherence Questionnaire (ADAQ©), a questionnaire designed to assess patient-reported medication adherence across multiple therapy areas, in patients with Osteoarthritis (OA). METHODOLOGY: Data from the Adelphi OA Disease Specific ProgrammeTM, a survey of physicians and their consulting adult patients with OA conducted in the United States, November 2020 to March 2021, was used to assess the psychometric properties of the ADAQ. Patients completed the ADAQ, Adherence to Refills and Medication Scale (ARMS), Western Ontario and McMaster Universities Arthritis Index (WOMAC), and EQ-5D-3L. The measurement model of the 13-item ADAQ was assessed and refined using latent variable modelling (Multiple Indicator Multiple Cause, confirmatory and exploratory factor analyses, item response theory, Mokken scaling, and bifactor analyses). Correlational analyses (Spearman's rank and polyserial as appropriate) with ARMS, WOMAC, and EQ-5D-3L scores assessed construct validity. Anchor- and distribution-based analyses were performed to estimate between-group clinically important differences (CID). RESULTS: Overall, 723 patients were included in this analysis (54.5% female, 69.0% aged ≥ 60). Latent variable modelling indicated a unidimensional reflective model was appropriate, with a bifactor model confirming an 11-item essentially unidimensional score. Items 12 and 13 were excluded from scoring as they measured a different concept. The ADAQ had high internal reliability with omega hierarchical and Cronbach's alpha coefficients of 0.89 and 0.97, respectively. Convergent validity was supported by moderate correlations with items of the ARMS, and physician-reported adherence and compliance. Mean differences in ADAQ score between high and low adherence groups yielded CID estimates between 0.49 and 1.05 points, with a correlation-weighted average of 0.81 points. CONCLUSION: This scoring model showed strong construct validity and internal consistency reliability when assessing medication adherence in OA. Future work should focus on confirming validity across a range of disease areas.

• MeSH
• Medication Adherence * psychology   MeSH
• Adult MeSH
• Assessment of Medication Adherence * MeSH
• Middle Aged MeSH
• Humans MeSH
• Osteoarthritis * drug therapy   psychology   MeSH
• Surveys and Questionnaires MeSH
• Psychometrics * methods   MeSH
• Reproducibility of Results MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• United States MeSH