Search Results (78)

Background/Objectives: Long-term exposure to polychlorinated biphenyls (PCBs), including the mixture of PCBs in Aroclor1260 (Ar1260), results in metabolic dysfunction-associated steatotic liver disease (MASLD) in mice and humans. While the effects of PCBs on gene expression are well-documented using short-read RNA sequencing, the regulatory roles of alternative splicing (AS) and differential transcript usage (DTU) are uncharacterized. AS has been implicated in MASLD. Previously, we reported that chronic (34 wks.) exposure of normal, low-fat-diet (LFD)-fed male mice to Ar1260 resulted in 12 hepatic RNA modifications. Proteomic analysis of these same liver samples identified Ar1260 exposure-associated changes in selenoproteins: GPX4 and SELENBP2 were increased and SELENOS and SELENOF were reduced. Methods: Here we used long-read isoform sequencing (IsoSeq) to identify DTU in four genes in the Ar1260-exposed livers: Adpgk, Blvra, Mup2, and Ndufaf6. Results: Network analysis of the corresponding proteins revealed a strong association with pathways relevant to MASLD including lipid metabolism, glycolysis, and oxidative stress. Conclusions: These findings suggest that PCB exposure alters the transcript isoform landscape of key metabolic genes involved in MASLD. Full article

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disabling clinical condition, whose hallmark characteristic is post-exertional malaise (PEM). It can affect many organs and systems, leading to severe impairment of patients’ quality of life. Although numerous post-infectious, immunological, neurological, metabolic, and endocrine alterations have been documented, neither a definitive diagnostic marker nor approved treatments are available. The etiology and pathophysiology remain incompletely understood; however, emerging evidence suggests that the gut microbiome plays a role in immune responses and the development of ME/CFS. It is hypothesized that specific disturbances in gut microbiome composition, known as dysbiosis, may compromise the integrity of the intestinal barrier. This consequently leads to translocation of microbial components, which further triggers an immune response and systemic inflammation complicating the clinical presentation of ME/CFS. Furthermore, in terms of the so-called gut–brain axis, microbiome changes may lead to distinct neurocognitive impairments observed in ME/CFS patients. This review offers the readers a broad perspective on the topic on ME/CFS, with a particular emphasis on the interplay between the gut microbiome and disease mechanisms. Last but not least, recent data on potential treatment strategies for intestinal dysbiosis in ME/CFS patients have been included. Full article

Background: Chronic Fatigue Syndrome (CFS), also known as Myalgic Encephalomyelitis (ME), is a debilitating condition characterized by persistent fatigue and multisystemic symptoms, such as cognitive impairment, musculoskeletal pain, and post-exertional malaise. Recently, parallels have been drawn between ME/CFS and Long COVID, a post-viral syndrome following infection with SARS-CoV-2, which shares many clinical features with CFS. Both conditions involve chronic immune activation, raising questions about their immunopathological overlap. Objectives: This study aimed to compare immune biomarkers between patients with ME/CFS or Long COVID and healthy controls to explore shared immune dysfunction. Methods: We analyzed lymphocyte subsets, cytokine profiles, psychological status and their correlations in 190 participants, 65 with CFS, 54 with Long COVID, and 70 healthy controls. Results: When compared to healthy subjects, results in both conditions were marked by lower levels of lymphocytes (CFS—2.472 × 10⁹/L, p = 0.006, LC—2.051 × 10⁹/L, p = 0.009), CD8⁺ T cells (CFS—0.394 × 10⁹/L, p = 0.001, LC—0.404 × 10⁹/L, p = 0.001), and NK cells (CFS—0.205 × 10⁹/L, p = 0.001, LC—0.180 × 10⁹/L, p = 0.001), and higher levels of proinflammatory cytokines such as IL-6 (CFS—3.35 pg/mL, p = 0.050 LC—4.04 pg/mL, p = 0.001), TNF (CFS—2.64 pg/mL, p = 0.023, LC—2.50 pg/mL, p = 0.025), IL-4 (CFS—3.72 pg/mL, p = 0.041, LC—3.45 pg/mL, p = 0.048), and IL-10 (CFS—2.29 pg/mL, p = 0.039, LC—2.25 pg/mL, p = 0.018). Conclusions: Notably, there were no significant differences between CFS and Long COVID patients in the tested biomarkers. These results demonstrate that ME/CFS and Long COVID display comparable immune and inflammatory profiles, with no significant biomarker differences observed between the two groups. Full article

Transportation infrastructure underpins national mobility and economic growth, yet material sourcing for road construction imposes significant environmental and financial costs. As South Africa advances towards road construction, upcycling the reuse of reclaimed materials in higher-value applications offers opportunities to reduce waste and improve circular resource efficiency. This study assesses stakeholders’ perception and adoption of upcycling in the Material Utilisation Plans (MUPs) for road construction. A mixed-methods approach combined nine semi-structured interviews and thirty-two survey responses from professionals involved in the National Route 3 upgrade project. Thematic analysis identified key qualitative themes, while quantituative data from a five-point Likert scale were examined through descriptive statistics, reliability, and correlation analysis. Respondents supported existing downcycling practices (mean = 3.682, SD = 1.088) and expressed readiness to adopt upcycling for pavement surfacing, base, subbase, and subgrade (mean > 3.00, SD < 1.30). Major barriers included client specifications, limited awareness and material cost constraints. Reliability analysis (Cronbach’s α = 0.64–0.88) confirmed internal consistency across qualitative themes. Also, there was a positive correlation between reclaimed materials and cost, design specifications, and optimised cost (r > 0.30, p < 0.05), while downcycling correlated negatively with costs (r = −0.400, p < 0.05). This study provides new empirical evidence on the systemic barriers hindering upcycling adoption in South African road projects and offers a validated mixed-method framework linking perceptual, technical, and economic dimensions of material reuse. It recommends integrating upcycling criteria into design, testing, and procurement processes, shifting from compliance-based recycling to performance-based circular material management in national road infrastructure. Full article

Background/Objectives: Compaction of sustained release coated pellets into tablets is associated with damage to the functional coat and loss in sustained release. The influences of precompression, trilayering, and tableting rate on the compaction of sustained release coated pellets into tablets are not well defined and were herein investigated to enhance the current limited understanding of these factors. Methods: Pellets coated with acrylic polymer (AC) or ethylcellulose (EC) were combined with filler material and compacted into multi-unit pellet system (MUPS) tablets prepared using different levels of precompression, as a trilayered MUPS tablet and at different tableting rates. The physical properties of the resulting MUPS tablets were evaluated. Trilayering was achieved by adding cushioning layers at the top and bottom of the MUPS tablet to avoid direct contact of pellets with punch surfaces. Results: With precompression, slightly stronger MUPS tablets were made compared to the tablets without precompression for EC pellets but not AC pellets. However, precompression led to a slight reduction in pellet coat damage for AC pellets but not EC pellets. Trilayering led to significant reductions in pellet coat damage and significant increases in tablet tensile strength. When EC pellets were lubricated with sodium stearyl fumarate, pellet coat damage was significantly lower. Increasing the tableting rate from 20 to 100 rpm did not result in increased pellet coat damage but in significantly weaker tablets due to the shorter dwell time. Conclusions: This study provides key insights on how compaction parameters and techniques could be altered to produce better MUPS tablets. Full article

Background/Objectives: Acute ischemic stroke is a leading cause of mortality and long-term disability globally, with limited reliable early predictors of functional outcomes and survival. This study aimed to assess the prognostic value of two novel predictors: the hypoperfusion intensity ratio calculated from mean transit time and time-to-drain maps (HIR-MTT–TTD), derived from computed tomography perfusion (CTP) imaging parameters, and the Inflammation–Coagulation Index (ICI), which integrates systemic inflammatory (C-reactive protein and white blood cell count) and hemostatic (D-dimer) markers. Methods: This prospective, single-center observational study included 60 patients with acute ischemic stroke treated with intravenous thrombolysis and underwent pre-treatment CTP imaging. HIR-MTT–TTD evaluated collateral status and perfusion deficit severity, while ICI integrated C-reactive protein (CRP), white blood cell (WBC) count, and D-dimer levels. Functional outcomes were assessed using the National Institutes of Health Stroke Scale (NIHSS), Barthel Index, and modified Rankin Scale (mRS) at 24 h, 3 months, and 1 year. Results: Of 60 patients, 53.3% achieved functional independence (mRS 0–2) at 1 year. Unadjusted Cox models showed HIR-MTT–TTD (HR = 6.25, 95% CI: 1.48–26.30, p = 0.013) and ICI (HR = 1.08, 95% CI: 1.00–1.17, p = 0.052) were associated with higher 12-month mortality, worse mRS, and lower Barthel scores. After adjustment for age, BMI, smoking status, and sex, these associations became non-significant (HIR-MTT–TTD: HR = 2.83, 95% CI: 0.37–21.37, p = 0.314; ICI: HR = 1.07, 95% CI: 0.96–1.19, p = 0.211). Receiver operating characteristic (ROC) analysis indicated moderate predictive value, with ICI (AUC = 0.756, 95% CI: 0.600–0.867) outperforming HIR-MTT–TTD (AUC = 0.67, 95% CI: 0.48–0.83) for mortality prediction. Conclusions: The study introduces promising prognostic tools for functional outcomes. Elevated HIR-MTT–TTD and ICI values were independently associated with greater initial stroke severity, poorer functional recovery, and increased 1-year mortality. These findings underscore the prognostic significance of hypoperfusion intensity and systemic thrombo-inflammation in acute ischemic stroke. Combining the use of the presented indices may enhance early risk stratification and guide individualized treatment strategies. Full article

Background: Melanoma of unknown primary (MUP) is a rare and distinct clinical subtype of metastatic melanoma, in which no identifiable primary tumor is found. The prognosis of MUP compared to melanoma with known primary (MKP) remains unclear, especially in the era of novel therapies like immune checkpoint inhibitors (ICIs) and targeted therapies. This meta-analysis aims to compare the overall survival (OS) of MUP and MKP patients under these therapies. Methods: This systematic review was conducted in line with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA). A systematic search of major databases was conducted, yielding six eligible studies (nine study arms) that assessed the survival outcomes of MUP and MKP patients treated with immunotherapies and targeted therapies. We pooled the hazard ratios (HRs) for OS using both fixed and random effects models. Heterogeneity was assessed with the I² statistic followed by a Baujat plot, and publication bias was evaluated using funnel plots and Egger’s test. Results: Our analysis revealed a borderline significant HR of 0.90 (95% CI: [0.81, 1.00], p = 0.04) under the fixed effect model, suggesting a potential survival benefit for MUP patients. However, the random effects model, accounting for study heterogeneity, showed no significant difference in OS between MUP and MKP (HR = 0.87, 95% CI: [0.73, 1.05], p = 0.15). Significant heterogeneity (I² = 66.9%, p = 0.0022) was observed across studies. No substantial publication bias was detected. Conclusion: While the trend observed in the fixed effect model suggests a potential benefit for MUP patients, the random effects analysis indicates no significant difference between MUP and MKP in terms of OS. These findings underscore the importance of accounting for study heterogeneity and highlight the need for further prospective studies to better understand the impact of novel therapies on MUP. Full article

Background/Objectives: Worldwide, glaucomas are the leading cause of irreversible blindness in adults. On the ocular level, they are fairly well understood; however, the functional and structural changes that occur in the brain have become a subject of great interest lately, mostly owing to improved accessibility and effectiveness of functional magnetic resonance imaging (fMRI). This, coupled with the non-invasive nature of the methodology, has contributed to an ever-growing body of research published on the topic. In this systematic review, we gather, systematize, and compare the results and methodologies reported in the literature, as pertaining to resting-state fMRI brain changes in primary open-angle glaucoma (POAG). Methods: A systematic search in PubMed, Scopus, and Web of Science was carried out, resulting in a total of 290 records identified, with 67 assessed for eligibility and 24 selected for inclusion. Results: The main findings include worse functional parameters in the early visual centers in POAG across all methodologies, reduced functional connectivity between V1 and other parts of the visual cortex, functional aberrations in higher levels of the visual system, predominantly in the ventral stream and in extravisual networks, among others. Moreover, the majority of these changes are shown to be correlated with ophthalmological measurements. Conclusions: Although studies on this matter tend to suffer from a limited sample size and a lack of methodological standardization, we nevertheless manage to present common results and conclusions regarding the effects of POAG on brain function. Full article

Improving the manufacturability of drug formulations via direct compression has been of great interest for the pharmaceutical industry. Selecting excipients plays a vital role in obtaining a high-quality product without the wet granulation processing step. In particular, for diluents which are usually present in a larger amount in a formulation, choosing the correct one is of utmost importance in the production of tablets via any method. In this work, we assessed the possibility of manufacturing a small-molecule drug product, omeprazole, which has been historically manufactured via a multi-step processes such as wet granulation and multiple-unit pellet system (MUPS). For this purpose, four prototypes were developed using several diluents: a co-processed excipient (Microcelac^®), two granulated forms of alpha-lactose monohydrate (Tablettose^® 70 and Tabletose^® 100), and a preparation of microcrystalline cellulose (Avicel^® PH102) and lactose (DuraLac^® H), both of which are common excipients without any enhancement. The tablets were produced using a single punch tablet press and thoroughly characterized physically and chemically in order to assess their functionality and adherence to drug product specifications. The direct compression process was used for the manufacturing of all proposed formulations, and the prototype formulated using Microcelac^® showed the best results and performance during the compression process. In addition, it remained stable over twelve months under 25 °C/60% RH conditions. Full article

The rapid and ultrasensitive detection of Salmonella holds strategic significance for food safety surveillance and public health protection systems. This study innovatively developed a label-free biosensing platform based on the synergistic integration of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas12a and the fluorescent deoxyribozyme Aurora for the efficient detection of foodborne Salmonella. The detection mechanism operates through a molecular cascade reaction: target-activated Cas12a protein specifically degrades Aurora deoxyribozyme via its trans-cleavage activity, thereby abolishing the enzyme’s catalytic capability to convert 4-methylumbelliferyl phosphate (4-MUP) into the highly fluorescent product 4-methylumbelliferone (4-MU). This cascade ultimately enables quantitative target analysis through fluorescence signal attenuation. Following systematic optimization of critical reaction parameters, the biosensing system demonstrated exceptional analytical performance: a detection limit of 1.29 CFU/mL with excellent linearity (R² = 0.992) spanning six orders of magnitude (1.65 × 10¹–10⁶ CFU/mL), along with high specificity against multiple interfering bacterial strains. Spike-and-recovery tests in complex food matrices (milk, chicken, and lettuce) yielded recoveries of 90.91–99.40% (RSD = 3.55–4.72%), confirming robust practical applicability. Notably, the platform design allows flexible detection of other pathogens through simple replacement of CRISPR guide sequences. Full article

Background: Chronic insomnia (CID) is a highly prevalent sleep disorder, yet the precise mechanisms underlying it remain incompletely understood. The aim of this study is to analyze effective connectivity between key regions of the default mode network (DMN), executive control network (ECN), and salience network (SN) in patients with CID as potential neurologic correlates of the hyperarousal state. Methods: Thirty-one CID patients and 24 healthy controls (HC) were recruited. All the subjects filled out the Insomnia severity index scale (ISI), Beck depression inventory (BDI), and Epworth sleepiness scale (ESS), underwent polysomnography, and were scanned on functional magnetic resonance imaging. Statistical Parametric Mapping 12 was used to analyze the results. Spectral dynamic causal modeling was applied to the chosen regions of interest. Results: There were three significant connections present in the CID group—inhibitory from the dorsolateral prefrontal cortex (DLPFC) to the right hippocampus (Hippocamp R); excitatory from the dorsomedial prefrontal cortex to the ventromedial prefrontal cortex; and excitatory from the common medial prefrontal cortex to the right anterior insula (AIR). Two statistically significant excitatory connections were lacking in the patients’ group—from the posterior cingulate cortex (PCC) to AIR, and from precuneus to PCC. CID patients scored higher on the ISI and BDI. Significant negative correlations between DLPFC-Hippocamp R connectivity and both ISI and BDI scores were identified. Conclusions: Disruptions within the DMN and between the DMN, SN, and ECN reflect an impaired ability to appropriately shift between internally and externally directed cognitive states—an imbalance that potentially underlies the hyperarousal state of CID. Full article

Standardizing socket design and maintaining a default socket alignment in transtibial prostheses are innovations that aim to simplify fitting procedures and reduce prosthetic service costs, particularly in low-income countries. Objectives: This study evaluated the Mercer Universal Prosthesis (MUP) with a standardized “neutral alignment” against custom-made conventional prostheses (CVPs). Methods: Twenty transtibial amputees (n = 20) completed gait assessments using their CVP and immediately after fitting with an MUP. Temporal–spatial and sagittal plane kinematics (hip, knee, and ankle angles) were analyzed, along with a gait symmetry index. Results: the MUP group reported a significant difference between the prosthetic and the intact limb for both hip and knee kinematics (p < 0.05), but there was no change in the CVP group. When compared with the sound limb in the MUP group, post hoc analysis showed that both hip flexion and the hip range of motion (ROM) in the MUP limb significantly increased by 5.7° and 7.3° (p = 0.002 and p < 0.001, respectively). Spatial and temporal gait parameters were comparable between the MUP and CVP groups, and gait symmetry showed no significant differences. The CVP showed greater symmetry in terms of hip (19%, p = 0.012) and knee flexion (8%, p = 0.026) compared to the MUP, while the MUP had higher plantarflexion symmetry (24.4%, p = 0.013). Conclusions: Immediately post fitting, MUP improved joint mobility in the prosthetic limb, potentially enhancing kinematics. While short-term benefits are evident, further research is needed to assess long-term gait adaptation and quality of life impacts. Full article

The growing challenge of antibiotic resistance has intensified the search for new antimicrobial agents. Promising alternatives include peptidoglycan hydrolases (PGHs) and certain ribosomal proteins, both of which exhibit antimicrobial activity. This study focuses on a Lactiplantibacillus paraplantarum strain, isolated from fermented meat, capable of inhibiting pathogens such as Listeria innocua, Salmonella Typhimurium, Escherichia coli, Staphylococcus aureus, and Weissella viridescens. The highest growth and antimicrobial activity were observed at a high nitrogen concentration (5.7 g/L). Two antimicrobial proteins were identified: the 50S ribosomal protein L14 (RP uL14) and 6-phospho-N-acetylmuramidase (MupG), a PGH. Partial purification and characterization of these proteins were achieved using SDS-PAGE, zymography, and LC-MS/MS. Transcriptional data (RT-qPCR) showed that higher nitrogen concentrations enhanced MupG expression, while increased carbon concentrations boosted RP uL14 expression. These findings highlight the importance of nutritional sources in maximizing the production of novel antimicrobial proteins, offering a potential path to develop effective alternatives against antibiotic-resistant bacteria. Full article

Background/Objectives: The aim of the present study was to develop lactose-free formulations of rivaroxaban, a novel oral anticoagulant used for the treatment and prevention of blood clotting. As a BCS Class II drug, rivaroxaban is characterized by poor solubility in aqueous media, posing a significant formulation challenge. Methods: To address this, phosphate-based excipients were employed to prepare both traditional single-unit dosage forms (tablets) and modern multiple-unit pellet systems (MUPS). These formulations were successfully developed and thoroughly evaluated for their physical properties and performance. Results: The resulting formulations demonstrated very good mechanical strength, including appropriate hardness and friability, alongside strong chemical stability. Their dissolution profiles met the requirements of the compendial monograph for Rivaroxaban Tablets and were comparable to those of the reference product, Xarelto^® film-coated tablets. Conclusions: This study shows the potential for producing effective, stable, and patient-friendly medications that meet the needs of contemporary society, where an increasing number of individuals suffer from lactose intolerance or seek vegan-friendly alternatives. Full article

Melanoma is one of the most aggressive forms of skin cancer. While most melanomas have a discernible primary site, a small subset, approximately 3.2%, present as a metastatic disease without an identifiable primary origin, a condition known as melanoma of unknown primary (MUP). Unusual cases of primary melanoma have also been previously reported in the respiratory, gastrointestinal, and urogenital tracts. MUP typically is found in lymph nodes, subcutaneous sites, and visceral organs, with hypotheses about its origin including spontaneous primary tumor regression and ectopic melanocytes. MUP presents unique challenges in diagnosis and treatment due to the absence of a detectable primary tumor. Understanding its genetic and molecular features, epidemiology, prognostic factors, and treatment options is crucial for optimizing patient care and outcomes in this subset of melanoma patients. We conducted an extensive literature review triggered by a case report of a patient with suspected MUP. A 51-year-old woman was transferred from another hospital where an incision was performed for a suspected superinfected hematoma of the left thigh. Since the patient showed high leukocytosis and redness and swelling of the thigh, local debridement, drainage, and excisional biopsy of the tumor mass were performed in our unit in the emergency setting, and the tumor was taken for histopathology evaluation. Intraoperatively, the mass appeared nonspecific. The permanent histopathology report established a diagnosis of melanoma, with tumor proliferation also involving lymphoid tissue, and despite broad clinical and imagistic assessments, the primary melanoma could not be identified. Clinicians must be aware of the varied clinical manifestations of malignant melanoma, especially in cases of occult melanoma where the primary site is not evident. Full article