A high stable sample loading for analysis of adult alpha-thalassemia via the improved microarray isoelectric focusing of Hb species.

The isoelectric focusing has realized various improvements, including the protocols and creation of mIEF (microcolumn isoelectric focusing) instruments with excellent sensitivity for screening of diabetes and beta thalassemia. However, the problem of manual sample loading and hydration for the mIEF limits the operational capacity for stably detecting and quantitating most abnormal hemoglobin (Hb). Herein, we provided a high stable sample loading protocol for analysis of alpha thalassemia and Hb variants. In contrast to the previous volume of 20 µl, a 100 µl blood sample solution in this protocol was optimized with mixture of 6.4-7.5 and 3-10 pH carrier ampholytes, pI markers and loaded for 30 mins IPG microcolumn hydration. The hydrated microcolumn was then automatically loaded onto the mIEF chip array to which CH3COOH and NH4OH act as anodic and cathodic solutions. Lastly, the IEF was run for 9 mins. Hb H, Barts, A1c, F, A2 and CS were simultaneously separated and focused with higher resolution and sensitivity in quantifying H and Barts as low as 0.6 and 0.5 % respectively. Accordingly, there was an enhanced stability and linearity with a rapid assay time of 45 secs per sample. Moreover, analysis showed a fitting linear relationship with conventional technology at R2 = 0.9803 for H and R2 = 0.9728 for Barts thereby indicating greater accuracy confirmed by the AUC. Hence, the developed protocol could simply be employed for high stable and throughput batch sample loading of hydration, and accurate separation and quantitation of Hb variants for alpha and beta thalassemia.

Tumor necrosis factor-α-treated human adipose-derived stem cells enhance inherent radiation tolerance and alleviate in vivo radiation-induced capsular contracture.

INTRODUCTION: Post-mastectomy radiotherapy plays a crucial role in breast cancer treatment but can lead to an inflammatory response causing soft tissue damage, particularly radiation-induced capsular contracture (RICC), impacting breast reconstruction outcomes. Adipose-derived stem cells (ADSCs), known for their regenerative potential via paracrine capacity, exhibit inherent radiotolerance. The influence of tumor necrosis factor-alpha (TNF-α) on ADSCs has been reported to enhance the paracrine effect of ADSCs, promoting wound healing by modulating inflammatory responses. OBJECTIVE: This study investigates the potential of TNF-α-treated human ADSCs (T-hASCs) on silicone implants to alleviate RICC, hypothesizing to enhance suppressive effects on RICC by modulating inflammatory responses in a radiation-exposed environment. METHODS: In vitro, T-hASCs were cultured on various surfaces to assess viability after exposure to radiation up to 20 Gy. In vivo, T-hASC and non-TNF-α-treated hASC (C-hASCs)-coated membranes were implanted in mice before radiation exposure, and an evaluation of the RICC mitigation took place 4 and 8 weeks after implantation. In addition, the growth factors released from T-hASCs were assessed. RESULTS: In vitro, hASCs displayed significant radiotolerance, maintaining consistent viability after exposure to 10 Gy. TNF-α treatment further enhanced radiation tolerance, as evidenced by significantly higher viability than C-hASCs at 20 Gy. In vivo, T-hASC-coated implants effectively suppressed RICC, reducing capsule thickness. T-hASCs exhibited remarkable modulation of the inflammatory response, suppressing M1 macrophage polarization while enhancing M2 polarization. The elevated secretion of vascular endothelial growth factor from T-hASCs is believed to induce macrophage polarization, potentially reducing RICC. CONCLUSION: This study establishes T-hASCs as a promising strategy for ameliorating the adverse effects experienced by breast reconstruction patients after mastectomy and radiation therapy. The observed radiotolerance, anti-fibrotic effects, and immune modulation suggest the possibility of enhancing patient outcomes and quality of life. Further research and clinical trials are warranted for broader clinical uses.

Plant omega-3 fatty acids may lower the risk of atrial fibrillation in individuals with a low intake of marine omega-3 fatty acids.

BACKGROUND: Omega-3 fatty acids derived from seafood acids may influence cardiac arrhythmogenesis, while the role of the major plant-derived omega-3 fatty acid, alpha-linolenic acid (ALA), on atrial fibrillation (AF) is largely unknown. OBJECTIVE: To investigate the association between ALA intake and the risk of incident AF overall and in subjects with a low intake of marine omega-3 fatty acids. METHODS: We followed a total of 54,260 middle-aged men and women enrolled into the Danish Diet, Cancer and Health cohort for development of AF using nationwide registries. Intake of ALA was assessed using a validated food frequency questionnaire and modelled as a restricted cubic spline. Statistical analyses were conducted using Cox proportional hazards regression. RESULTS: We identified a total of 4,902 incident AF events during a median of 16.9 years of follow-up. In multivariable analyses, we observed indications of a statistically non-significant inverse association between ALA intake and the risk of AF up to an ALA intake of 2.5 g/day, whereas no appreciable association was found for higher intakes of ALA. A statistically significant dose-dependent negative association was found between ALA intake and risk of AF in individuals consuming less than 250mg of marine omega-3 fatty acids daily, while no association was found in those with a higher intake of marine omega-3 fatty acids. CONCLUSIONS: Intake of ALA was associated with a lower risk of AF in individuals consuming a low intake of marine omega-3 fatty acids. This finding is novel and warrants further investigation.

Effects of α-olefin sulfonate (AOS) on Tubifex tubifex: toxicodynamic-toxicokinetic inferences from the general unified threshold (GUTS) model, biomarker responses and molecular docking predictions.

We investigated the potential ecological risks and harm to aquatic organisms posed by anionic surfactants such as α-olefin sulfonate (AOS), which are commonly found in industrial and consumer products, including detergents. This study assessed acute (96-h) and subchronic (14-day) responses using antioxidant activity, protein levels, and histopathological changes in Tubifex tubifex exposed to different AOS concentrations (10% of the LC50, 20% of the LC50, and a control). Molecular docking was used to investigate the potential interactions between the key stress biomarker enzymes (superoxide dismutase, catalase, and cytochrome c oxidase) of Tubifex tubifex. Acute AOS exposure showed a concentration-dependent decrease in survival, and the general unified threshold (GUTS) model revealed that survivorship is linked to individual response patterns rather than random (stochastic) fluctuations. The GUTS model also revealed dose-dependent toxicity patterns in Tubifex tubifex exposed to α-olefin sulfonate (AOS), with adaptive mechanisms at lower concentrations but significant increases in mortality beyond a certain threshold, emphasizing the role of the AOS concentration in shaping its toxicological impact. Exposure to AOS disrupted antioxidant activity, inducing oxidative stress, with GST and GPx showing positive associations with surfactant concentration and increased lipid peroxidation (elevated MDA levels); moreover, AOS exposure decreased protein concentration, signifying disturbances in vital cellular processes. Histopathological examinations revealed various tissue-level alterations, including cellular vacuolation, cytoplasmic swelling, inflammation, necrosis, and apoptosis. Molecular docking analysis demonstrated interactions between AOS and enzymes (-catalase, superoxide dismutase, and cytochrome c oxidase) in Tubifex tubifex, including hydrophobic and hydrogen bond interactions, with the potential to disrupt enzyme structures and activities, leading to cellular process disruptions, oxidative stress, and tissue damage. According to the species sensitivity distribution (SSD), the difference in toxicity between Tilapia melanopleura (higher sensitivity) and Daphnia magna (low sensitivity) to AOS suggests distinct toxicokinetic and toxicodynamic mechanisms attributable to more complex physiology in Tilapia and efficient detoxification in Daphnia due to its smaller size.

Prediction of behavioral performance by alpha-band phase synchronization in working memory.

Working memory (WM) is a cognitive system with limited capacity that can temporarily store and process information. The purpose of this study was to investigate functional connectivity based on phase synchronization during WM and its relationship with the behavioral response. In this regard, we recorded EEG/Eye tracking data of seventeen healthy subjects while performing a memory-guided saccade (MGS) task with two different positions (near eccentricity and far eccentricity). We computed saccade error as memory performance and measured functional connectivity using Phase Locking Value (PLV) in the alpha frequency band (8-12 Hz). The results showed that PLV is negatively correlated with saccade error. Our finding indicated that during the maintenance period, PLV between the frontal and visual area in trials with low saccade error increased significantly compared to trials with high saccade error. Furthermore, we observed a significant difference between PLV for near and far conditions in the delay period. The results suggest that PLV in memory maintenance, in addition to predicting saccade error as behavioral performance, can be related to the coding of spatial information in WM.

Galactose-1-phosphate inhibits cytochrome c oxidase and causes mitochondrial dysfunction in classic galactosemia.

Classic galactosemia is an inborn error of metabolism caused by mutations in the GALT gene resulting in the diminished activity of the galactose-1-phosphate uridyltransferase enzyme. This reduced GALT activity leads to the buildup of the toxic intermediate galactose-1-phosphate and a decrease in ATP levels upon exposure to galactose. In this work, we focused our attention on mitochondrial oxidative phosphorylation in the context of this metabolic disorder. We observed that galactose-1-phosphate accumulation reduced respiratory rates in vivo and changed mitochondrial function and morphology in yeast models of galactosemia. These alterations are harmful to yeast cells since the mitochondrial retrograde response is activated as part of the cellular adaptation to galactose toxicity. In addition, we found that galactose-1-phosphate directly impairs cytochrome c oxidase activity of mitochondrial preparations derived from yeast, rat liver, and human cell lines. These results highlight the evolutionary conservation of this biochemical effect. Finally, we discovered that two compounds - oleic acid and dihydrolipoic acid - that can improve the growth of cell models of mitochondrial diseases, were also able to improve galactose tolerance in this model of galactosemia. These results reveal a new molecular mechanism relevant to the pathophysiology of classic galactosemia - galactose-1-phosphate-dependent mitochondrial dysfunction - and suggest that therapies designed to treat mitochondrial diseases may be repurposed to treat galactosemia.

Screening (ant)agonistic activities of xenobiotics on the retinoic acid receptor alpha (RARα) using in vitro and in silico analysis.

Retinoic acid receptors (RARs) are known as crucial endocrine receptors that could mediate a broad diversity of biological processes. However, the data on endocrine disrupting effects of emerging chemicals by targeting RAR (ant)agonism are far from sufficient. Herein, we investigated the RARα agonistic or antagonistic activities for 75 emerging chemicals of concern, and explored their interactions with this receptor. A recombinant two-hybrid yeast assay was used to examine the RARα activities of the test chemicals, wherein 7 showed effects of RARα agonism and 54 exerted potentials of RARα antagonism. The representative chemicals with RARα agonistic activities, i.e. 4-hydroxylphenol (4-HP) and bisphenol AF (BPAF), significantly increased the mRNA levels of CRABP2 and CYP26A1, while 4 select chemicals with RARα antagonistic potentials, including bisphenol A (BPA), tetrabromobisphenol A (TBBPA), 4-tert-octylphenol (4-t-OP), and 4-n-nonylphenol (4-n-NP), conversely decreased the transcriptional levels of the test genes. The in silico molecular docking analysis using 3 different approaches further confirmed the substantial binding between the chemicals with RARα activities and this nuclear receptor protein. This work highlights the promising strategy for screening endocrine-disrupting effects of emerging chemicals of concern by targeting RARα (ant)agonism.

Paradoxical Psoriasis in Patients Receiving Therapy with Tumor Necrosis Factor Inhibitors: Potential Pathogenic Mechanisms and the Role of Genetic Factors.

TNF inhibitors (TNFi) have revolutionized the therapeutic management of various chronic immune-mediated inflammatory diseases. Despite their known benefits, these therapies are related to paradoxical adverse effects (PAEs), including paradoxical psoriasis (PP). Although the underlying mechanism remains somewhat unclear, some theories suggest that genetic factors, particularly certain single-nucleotide polymorphisms (SNPs), may play an important role. The present review aimed to research and analyze recent findings regarding the pathomechanisms involved in the appearance of PP and the association between various genetic factors and PP in individuals treated with TNFi. We performed a literature search and found that certain genes (IL23R, TNF, FBXL19, CTLA4, SLC12A8, TAP1) are strongly associated with the occurrence of PP in pediatric and adult patients during therapy with TNFi. The identification of the specific SNPs involved in the appearance of PP and other PAEs in patients treated with TNFi for various diseases and in different populations may later favor the recognition of those patients at a high risk of developing such adverse effects and could guide personalized therapeutic strategies in future years.

The association between diet quality indices and oxidative stress biomarkers in male footballers and healthy active controls.

OBJECTIVE: The aim of the present study was the association between the relationship between Dietary Quality Index-International (DQI-I) and Healthy Eating Index (HEI) and the urinary levels of F2alpha-isoprostane (F2a-IP) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) was investigated as indicators of oxidative stress. RESULTS: Based on HEI (low, moderate, and good), the diet quality of both groups was classified as moderate. In all participants, HEI (ß=-0.29; P = 0.04) and DQI-I (ß=-0.46; P = 0.005) were inversely associated with 8-OHdG. Furthermore, a negative correlation was found between HEI (mean ß=-3.53; P = 0.04) and DQI-I (mean ß=-5.53; P = 0.004) with F2a-IP. The quality of the footballers' diet was higher than that of the control group. Following a high-quality diet, which is rich in antioxidants, is likely to effectively reduce oxidative stress.

A novel in vitro cell model of the proteinase/antiproteinase balance observed in alpha-1 antitrypsin deficiency.

Background: Alpha-1 antitrypsin deficiency (AATD) is a genetic condition resulting from mutations in the alpha-1 antitrypsin (AAT) protein, a major systemic antiproteinase, resulting in reduced/no release of AAT, disrupting the proteinase/antiproteinase balance. A sustained imbalance can cause structural changes to the lung parenchyma, leading to emphysema. Predicting and assessing human responses to potential therapeutic candidates from preclinical animal studies have been challenging. Our aims were to develop a more physiologically relevant in vitro model of the proteinase/antiproteinase balance and assess whether the data generated could better predict the efficacy of pharmacological candidates to inform decisions on clinical trials, together with expected biomarker responses. Methods: We developed an in vitro model assessing the proteinase/antiproteinase balance by the changes in the fibrinogen cleavage products of neutrophil elastase (NE) and proteinase 3 (PR3). This allowed the assessment of physiological and pharmaceutical neutrophil serine proteinase (NSP) inhibitors to determine the putative threshold at which the maximal effect is achieved. Results: AAT significantly reduced NE and PR3 activity footprints, with the maximal reduction achieved at concentrations above 10 µM. The inhibitor MPH966 alone also significantly reduced NE footprint generation in a concentration-dependent manner, leveling out above 100 nM but had no effect on the PR3 footprint. At levels of AAT consistent with AATD, MPH966 had an additive effect, reducing the NE activity footprint more than either inhibitor alone. Conclusion: Our results support an inhibitor threshold above which the activity footprint generation appears resistant to increasing dosage. Our model can support the testing of inhibitors, confirming activity biomarkers as indicators of likely pharmaceutical efficacy, the assessment of NSP activity in the pathophysiology of emphysema, and the likely function of biological or pharmacological inhibitors in disease management.

Investigating the characteristics of mild intervertebral disc degeneration at various age stages using single-cell genomics.

Introduction: Intervertebral disc degeneration often occurs in the elderly population, but in recent years, there has been an increasing incidence of disc degeneration in younger individuals, primarily with mild degeneration. Methods: In order to explore the underlying mechanisms of disc degeneration in both young and aging individuals, we collected four types of nucleus pulposus (NP) single-cell sequencing samples for analysis based on Pfirrmann grading: normal-young (NY) (Grade I), normal-old (NO) (Grade I), mild degenerative-young (MY) (Grade II-III), and mild degenerative-old (MO) (Grade II-III). Results: We found that most NP cells in NO and MY samples exhibited oxidative stress, which may be important pathogenic factors in NO and MY groups. On the other hand, NP cells in MO group exhibited endoplasmic reticulum stress. In terms of inflammation, myeloid cells were mainly present in the degenerative group, with the MY group showing a stronger immune response compared to the MO group. Interestingly, dendritic cells in the myeloid lineage played a critical role in the process of mild degeneration. Discussion: Our study investigated the molecular mechanisms of intervertebral disc degeneration from an age perspective, providing insights for improving treatment strategies for patients with disc degeneration at different age groups.

Perspective on solving the problem of declining interest in physical activity in Poland.

One of the leading areas of Polish research addressed in the physical culture sciences, is the declining interest in physical activity. The likely reason for this situation may be the inadequate communication of physical culture to today's generations: BB (baby boomers), X (great unknowns), Y (millennials), Z (snowflakes), Alpha (digital). Therefore, the aim of this article is to address the problem of declining interest in physical activity in Poland by identifying the appropriate approach of teachers, trainers and instructors to today's generations. The specifics of BB, X, Y, Z and Alpha generations are described and their expectations regarding physical activity are indicated. It was concluded that activating these social groups should be done by prompting topics that are important to them. Thus, BB value organizational stability, X need to see the purposefulness and attractiveness of the activities, Y equate physical activity with personal development, Z only take up useful forms of activities, and finally Alpha like smart technology-assisted activities.

Effect of preoperative alpha-blockers on ureteroscopy outcomes: A meta-analysis of randomised trials.

Objectives: This work aims to determine the efficacy and safety of preoperative alpha-blocker therapy on ureteroscopy (URS) outcomes. Methods: In this systematic review and meta-analysis of randomised trials of URS with or without preoperative alpha-blocker therapy, outcomes included the need for ureteral dilatation, stone access failure, procedure time, residual stone rate, hospital stay, and complications. Residual stone rates were reported with and without adjustments for spontaneous stone passage, medication noncompliance, or adverse events leading to patient withdrawal. Data were analysed using random-effects meta-analysis and meta-regression. Certainty of evidence was assessed using the GRADE criteria. Results: Among 15 randomised trials with 1653 patients, URS was effective and safe with a stone-free rate of 81.2% and rare (2.3%) serious complications. The addition of preoperative alpha-blockers reduced the need for ureteral dilatation (risk ratio [RR] = 0.48; 95% CI = 0.30 to 0.75; p = 0.002), access failure rate (RR = 0.36; 95% CI = 0.23 to 0.57; p < 0.001), procedure time (mean difference [MD] = -6 min; 95% CI = -8 to -3; p < 0.001), risk of residual stone in the primary (RR = 0.44; 95% CI = 0.33 to 0.66; p < 0.001) and adjusted (RR = 0.52; 95% CI = 0.40 to 0.68; p < 0.001) analyses, hospital stay (MD = -0.3 days; 95% CI = -0.4 to -0.1; p < 0.001), and complication rate (RR = 0.46; 95% CI = 0.35 to 0.59; p < 0.001). Alpha-blockers increased ejaculatory dysfunction risk and were less effective for renal/proximal ureter stones. The certainty of evidence was high or moderate for all outcomes. The main limitation of the review was inconsistency in residual stone assessment methods. Conclusion: While URS is an effective and safe treatment for stone disease, preoperative alpha-blocker therapy is well tolerated and can further improve patient outcomes.

Association of circulating Z-polymer with adverse clinical outcomes and liver fibrosis in adults with alpha-1 antitrypsin deficiency.

BACKGROUND: Circulating polymerized mutant Z-alpha-1 antitrypsin (Z-polymer) constitutes a characteristic feature in alpha-1 antitrypsin deficiency (AATD), but there is limited knowledge about its association with adverse clinical outcomes and liver fibrosis. We explored this association using data from a large cohort of adults with AATD. METHODS: A total of 836 (431 PiZZ, 405 PiMZ) adults with AATD and 312 controls (PiMM) from the European Alpha-1 Liver Cohort (2015-2020) were included. Time-to-event analyses were conducted for adults with the PiZZ genotype followed for adverse clinical outcomes (earliest occurrence of liver-related hospitalization, liver transplant or all-cause mortality). Cox proportional hazard models were used to describe the association between binary circulating Z-polymer levels and adverse clinical outcomes. Correlations between baseline circulating Z-polymer levels and baseline liver fibrosis (liver stiffness measurement [LSM] determined by transient elastography [FibroScan®]) were evaluated. The analyses were stratified by augmentation therapy status. RESULTS: Of 324 adults with the PiZZ genotype and longitudinal follow-up data, 28 reported adverse clinical outcomes. Higher baseline circulating Z-polymer levels were associated with an increased risk of adverse clinical outcomes in both crude (hazard ratio [95% confidence interval, CI], 2.88 [1.21, 6.87]) and age-adjusted (1.96 [0.78, 4.94]) analyses. In adults with the PiZZ genotype, circulating Z-polymer levels were weakly positively correlated with baseline LSM (Spearman's rho [95% CI]: 0.21 [0.11, 0.31]). Similar results were observed after stratification by augmentation therapy status. CONCLUSIONS: In adults with the PiZZ genotype, higher circulating Z-polymer levels were associated with a shorter time to adverse clinical outcome, and positively correlated with baseline LSM. Circulating Z-polymer levels may be a prognostic biomarker of clinically relevant disease in AATD.

The most commonly used spices in Thai traditional medicine: in vitro evaluation of anti-hyperglycemic, antioxidant, polyphenol content, and nitric oxide production inhibitory activities.

Background and purpose: Diabetes mellitus is a persistent hyperglycemic condition. Thai cuisine and medicine incorporate spices: nutmeg, mace, clove buds, cardamom, cinnamon, and coriander. The in vitro impacts of these spices on anti-diabetic, antioxidant, anti-inflammatory, and total phenolic and flavonoid content were assessed. Experimental approach: Alpha-amylase and alpha-glucosidase inhibition assays were conducted. Antioxidant potential was measured through DPPH and ABTS assays. Anti-inflammatory activity was determined by inhibiting nitric oxide generation in RAW 264.7 cells. Total phenolic content was quantified using the Folin Ciocalteu method, while total flavonoid content was estimated via the aluminum chloride colorimetric method. Findings/Results: Ethanolic and aqueous extracts of a blend of spices (Siam cardamom, nutmeg, mace, and clove buds), denoted as 4-GlurE and 4-GlurA, displayed concentration-dependent inhibition of alpha-glucosidase, with IC50 values of 0.373 and 0.435 mg/mL, respectively. 4-GlurE and 4-GlurA exhibited antioxidant activity, by ABTS·+ radical and DPPH scavenging capabilities. 4-GlurE demonstrated anti-inflammatory potential by reducing nitric oxide generation (IC50: 43.95 ± 2.47 µg/mL). 4-GlurE and 4-GlurA possessed total phenolic content (TPC) of 122.47 ± 1.12 and 148.72 ± 0.14 mg GAE/g, respectively. 4-GlurE exhibited a higher total flavonoid content (TFC) compared to the aqueous extract (340.33 ± 4.77 and 94.17 ± 3.36 mg QE/g). Cinnamon and clove aqueous extracts were more potent than acarbose in alpha-glucosidase inhibition with the highest antioxidant activity. Polyphenol levels (TPC and TFC) exhibited strong correlations with antioxidant capacity. Conclusions and implications: Findings are consistent with the traditional use of 4-Glur, with cinnamon, for diabetes prevention and treatment.

Immediate Destiny of Bifurcation Lesions Treated with Biomatrix Alpha Stents.

BACKGROUND: About 15% of coronary artery interventions are performed on coronary artery bifurcation. Managing these lesions presents a significant therapeutic obstacle in the context of coronary artery issues. Addressing both immediate and lasting side effects of these lesions demands ongoing monitoring and action. The introduction of drug-eluting stents has raised hopes for better outcomes in patients experiencing cardiovascular events. METHODS: In this study, we selected 51 patients (out of 850) who had received ≥1 cobalt-chromium, biodegradable polymer, Biolimus A9-eluting stent (CoCr-BP-BES) Biomatrix Alpha stent. Immediately after stenting, thrombolysis in myocardial infarction (TIMI) flow score in the coronary artery and its bypass branch, plaque shift, and lateral dissection immediately after angioplasty were evaluated. RESULTS: The mean age for patients was 65 (±10.35) years, where 49.02% of them were male and 45.1% had diabetes. No lateral dissection and death were reported in any of the patients. Also, the TIMI flow grade was 3 for the main branch in all patients. Plaque shifts were compared at different degrees of the TIMI flow coronary artery bypass graft. A statistical study revealed a noteworthy distinction between the groups. There was no discernible change when gender, diabetes, systolic and diastolic blood pressure with plaque changes were all controlled for. CONCLUSION: We discovered that the Biomatrix Alpha stents' instant clinical results are admissible. Our findings confirm the clinical utility of the recently developed biolimus-eluting (BES) stent technology, which combines the BA-9 medication, a thin-strut CoCr stent platform, and a biodegradable polymer. This aligns with the existing body of research on the most recent generation of drug-eluting stents (DES).

Effects of endogenous testosterone on oscillatory activity during verbal working memory in youth.

Testosterone levels sharply rise during the transition from childhood to adolescence and these changes are known to be associated with changes in human brain structure. During this same developmental window, there are also robust changes in the neural oscillatory dynamics serving verbal working memory processing. Surprisingly, whereas many studies have investigated the effects of chronological age on the neural oscillations supporting verbal working memory, none have probed the impact of endogenous testosterone levels during this developmental period. Using a sample of 89 youth aged 6-14 years-old, we collected salivary testosterone samples and recorded magnetoencephalography during a modified Sternberg verbal working memory task. Significant oscillatory responses were identified and imaged using a beamforming approach and the resulting maps were subjected to whole-brain ANCOVAs examining the effects of testosterone and sex, controlling for age, during verbal working memory encoding and maintenance. Our primary results indicated robust testosterone-related effects in theta (4-7 Hz) and alpha (8-14 Hz) oscillatory activity, controlling for age. During encoding, females exhibited weaker theta oscillations than males in right cerebellar cortices and stronger alpha oscillations in left temporal cortices. During maintenance, youth with greater testosterone exhibited weaker alpha oscillations in right parahippocampal and cerebellar cortices, as well as regions across the left-lateralized language network. These results extend the existing literature on the development of verbal working memory processing by showing region and sex-specific effects of testosterone, and are the first results to link endogenous testosterone levels to the neural oscillatory activity serving verbal working memory, above and beyond the effects of chronological age.

The Use of TNF-α Inhibitors in Active Ankylosing Spondylitis Treatment.

Ankylosing spondylitis (AS) is a challenging disease, characterized by chronic inflammation and structural damage primarily affecting the axial skeleton, while extra-articular manifestations may also appear. This results in the deterioration of patients' quality of life. Over the past few decades, tumor necrosis factor-α (TNF-α) inhibitors have revolutionized the management of AS, offering substantial relief from symptoms and improving patient outcomes. The aim of this review is to assess the efficacy of TNF-α inhibitors in patients with active AS. A search was performed in the PubMed database using the following keywords: ("TNF alpha inhibitors" OR "anti TNF-a" OR "TNF-a inhibitors" OR "anti TNF-alpha" OR "Etanercept " OR "Golimumab" OR "Infliximab" OR "Certolizumab pegol" OR "Adalimumab") AND "ankylosing spondylitis". The search was completed in February 2024, and 35 studies were included in this review following PRISMA guidelines. The findings reveal evidence supporting the efficacy of TNF-α inhibitors in reducing inflammation, preventing structural damage, and enhancing overall well-being in AS patients. Overall, TNF-α inhibitors have emerged as a cornerstone in the therapeutic algorithm against AS with a very satisfactory safety profile.

When the Belly Looks Okay but Is Actually Not: A Case of Hepatoblastoma in a Well-Appearing Child.

Hepatoblastoma is one of the pediatric tumors with genetic and intrauterine risk factors. It is typically asymptomatic at diagnosis, at which time most patients have metastasis to the lungs and are in an advanced stage of liver disease. We report an interesting case of a 13-month-old child who presented with a one-month history of abdominal distention. A review of the systems was unremarkable but a physical examination revealed a well-appearing child with abdominal distention, normal vital signs, and an abdominal mass. Abdominal imaging revealed a well-defined heterogeneously-enhancing mass arising from the right hepatic lobe and laboratory results were consistent with a diagnosis of hepatoblastoma. The mass was resected and the patient underwent chemotherapy with continued follow-up management. We shed light on pediatric hepatoblastoma and its clinical presentation, pathology, and laboratory and imaging findings, to aid clinicians in diagnosing the condition correctly.

Efficient characterization of multiple binding sites of small molecule imaging ligands on amyloid-beta, tau and alpha-synuclein.

PURPOSE: There is an unmet need for compounds to detect fibrillar forms of alpha-synuclein (αSyn) and 4-repeat tau, which are critical in many neurodegenerative diseases. Here, we aim to develop an efficient surface plasmon resonance (SPR)-based assay to facilitate the characterization of small molecules that can bind these fibrils. METHODS: SPR measurements were conducted to characterize the binding properties of fluorescent ligands/compounds toward recombinant amyloid-beta (Aß)42, K18-tau, full-length 2N4R-tau and αSyn fibrils. In silico modeling was performed to examine the binding pockets of ligands on αSyn fibrils. Immunofluorescence staining of postmortem brain tissue slices from Parkinson's disease patients and mouse models was performed with fluorescence ligands and specific antibodies. RESULTS: We optimized the protocol for the immobilization of Aß42, K18-tau, full-length 2N4R-tau and αSyn fibrils in a controlled aggregation state on SPR-sensor chips and for assessing their binding to ligands. The SPR results from the analysis of binding kinetics suggested the presence of at least two binding sites for all fibrils, including luminescent conjugated oligothiophenes, benzothiazole derivatives, nonfluorescent methylene blue and lansoprazole. In silico modeling studies for αSyn (6H6B) revealed four binding sites with a preference for one site on the surface. Immunofluorescence staining validated the detection of pS129-αSyn positivity in the brains of Parkinson's disease patients and αSyn preformed-fibril injected mice, 6E10-positive Aß in arcAß mice, and AT-8/AT-100-positivity in pR5 mice. CONCLUSION: SPR measurements of small molecules binding to Aß42, K18/full-length 2N4R-tau and αSyn fibrils suggested the existence of multiple binding sites. This approach may provide efficient characterization of compounds for neurodegenerative disease-relevant proteinopathies.