Search Results (211)

Clinical reasoning over 3D CT scans is inherently compositional, requiring the integration of anatomical measurement, pathology assessment, spatial comparison, and clinical interpretation. We introduce MedToolica, a finetuning-free, role-based agentic framework for quantitative 3D abdominal CT reasoning that decomposes complex queries into structured sub-tasks coordinated through specialized expert tools. Empirical evaluation across quantitative reasoning benchmarks demonstrates that MedToolica is particularly effective in organ-centric measurement tasks when supported by reliable expert tools, achieving strong quantitative agreement (e.g., $CCC=0.99$ for organ HU estimation versus $0.46$ for finetuned baselines) and notable gains on multi-step visual reasoning tasks. In contrast, lesion-oriented tasks remain constrained by upstream tool limitations, indicating that reasoning sophistication alone cannot compensate for unreliable perception. Furthermore, we observe that the capability of the core language model substantially influences orchestration quality: smaller LLM orchestrators exhibit reduced overall accuracy due to higher execution failure rates ($25\%$ vs. $79\%$) and increased susceptibility to hallucination ($43\%$ vs. $2\%$). Collectively, these findings identify expert tool reliability and orchestration capability as critical determinants of performance in compositional medical AI and highlight both the promise and current limitations of finetuning-free agentic reasoning for quantitative 3D CT analysis. Full article

Background/Objectives: Dental metallic implants cause severe streaking artifacts in kilovoltage CT (kVCT), compromising dose calculation in radiotherapy (RT) treatment planning. The purpose of this study is to assess the dosimetric agreement of synthetic MVCT (sMVCT) images generated from artifact-affected kVCT using a deep learning network with respect to true MVCT (tMVCT) acquired at the treatment machine. Methods: Nineteen head and neck cancer patients with dental metallic implants treated with RT were included. Planning kVCT images were converted to sMVCT using Metal Artifact Reduction through Domain Transformation Network (MAR-DTN), a UNet-inspired deep learning network. The sMVCT images were rigidly registered to true MVCT (tMVCT) acquired on the Hi-Art II Tomotherapy system. Mean Hounsfield Unit (HU) values were compared across seven structures (thyroid, bilateral parotids, brainstem, spinal cord, GTV, PTV70) using pairwise Wilcoxon tests and Two One-Sided Tests (TOST) for statistical equivalence within a pre-specified margin of ±20 HU (corresponding to a 2% deviation in physical density). Dose distributions were recalculated on sMVCT using the AAA algorithm and compared to reference tMVCT-based plans via dose–volume histogram (DVH) metrics, evaluated for equivalence by TOST within a margin of ±2% of the prescribed dose (±142 cGy of 70.95 Gy), and via 3D gamma index, evaluated by one-sided non-inferiority test against the clinically accepted thresholds of 90% (2 mm/2%) and 95% (3 mm/3%). A pre-specified sensitivity analysis was performed by repeating all comparisons on the strictly independent sub-cohort (n = 16) excluding three patients drawn from the MAR-DTN training set. Results: All seven anatomical structures showed statistical equivalence between sMVCT and tMVCT under the ±20 HU margin (TOST p < 0.05; mean HU differences in the range −1.1 to +8.4 HU; all Wilcoxon p > 0.05). All nine DVH metrics achieved formal dosimetric equivalence within ±2% of the prescribed dose (TOST p < 0.05). Mean 3D gamma pass rates were 94.3% (95% CI: 89.3–97.1) for the 2 mm/2% criterion and 97.6% (95% CI: 94.8–99.0) for the 3 mm/3% criterion, both formally non-inferior to the respective clinical thresholds (p < 0.0001). Residual gamma failures were concentrated at the patient surface, consistent with inter-session repositioning uncertainty rather than errors in synthetic image generation. Sensitivity analysis on the n = 16 sub-cohort confirmed all conclusions, with mean HU and DVH differences smaller than in the full cohort for the structures showing the largest mean differences, and comparable for the remaining structures, with all TOST equivalence and gamma non-inferiority tests confirmed in both cohorts. Conclusions: sMVCT images generated via MAR-DTN show dosimetric agreement with physically acquired tMVCT in head and neck patients with dental implants, formally demonstrated by TOST equivalence within ±2% of prescribed dose for all DVH metrics. The combined HU and gamma index framework presented here represents a promising quality assurance approach for AI-based synthetic imaging tools in radiotherapy, pending validation in larger prospective multicentre cohorts. Full article

Background/Objectives: Enteric glial cells (EGCs) are key players in regulating enteric neurons and gastrointestinal functions including disturbed gut motility in diabetic patients. Enteric neuronal damage has been shown in type 1 diabetes, but EGCs’ vulnerability to hyperglycaemic insults requires more investigation. Therefore, we aimed to study the quantitative changes in the EGC network enmeshing enteric plexuses, intestinal smooth muscle and mucosa in streptozotocin-induced acute (1-week) and chronic (10-weeks) diabetic rat models. Methods: Fluorescent immunohistochemistry using Sox10 glial and HuC/HuD pan-neuronal markers, immunogold electron microscopy and ELISA were performed on different gut segments. Results: In the submucosal ganglia of the ileum and colon, the density of Sox10-immunoreactive EGCs was significantly reduced in acute and increased in chronic hyperglycaemic rats without any changes in the duodenum. In the myenteric ganglia, regionally distinct alterations of glial density were noted in acute hyperglycaemia; however, a remarkable decrease was observed in chronic animals. Alterations of neuronal density did not follow the pattern of glial changes, resulting in shifts in the glia/neuron ratio. The presence of Sox10-HuC/HuD-immunoreactive cells and their diabetes-related quantitative changes were also revealed in enteric plexuses. The density of Sox10-labelling gold particles was significantly increased in the duodenal myenteric glia of diabetic rats. Muscular EGC density increased only in the colon after acute hyperglycaemia and changed in all segments after chronic hyperglycaemia. Glial fibrillary acidic protein levels decreased in the small intestine of chronic hyperglycaemic rats. Conclusions: Our present findings reveal time-dependent and regionally distinct changes in the EGC network in response to hyperglycaemia, contributing to diabetic enteric neuropathy and gut motility disturbances. Full article

The large yellow croaker (Larimichthys crocea) is a key mariculture species in China, however, its industry is threatened by visceral white nodules disease (VWND) caused by the bacterium Pseudomonas plecoglossicida. A significant challenge in breeding is the potential genetic trade-off between growth and disease resistance. To investigate their genetic relationship, we constructed a high-density SNP-based genetic linkage map for L. crocea using a F1 full-sib family (n = 150). The map comprised 24 linkage groups with 32,429 bin markers and an average interval of 0.051 cM. Based on this map, we conducted QTL mapping for one yield trait (body weight), eight morphological traits, and three VWND-resistance traits (survival time, AT; spleen and liver pathogen loads). Phenotypic analysis revealed strong integration among growth traits and a moderate positive correlation between growth traits and AT. QTL mapping identified 53 QTLs for growth (PVE = 0.14–5.83%) and 20 for resistance (PVE = 0.78–8.93%). Notably, only two genomic intervals exhibited co-localization between a morphological trait (AL or BL) and AT, each explaining a modest phenotypic variance (0.66–5.99%). The largest-effect QTLs for growth and resistance were mapped to distinct linkage groups, and candidate genes within the co-localized intervals (Unc5d, SCN5A, HUS1) are involved in fundamental cellular processes rather than core growth or immune pathways. These results suggest that yield, morphological, and VWND-resistance traits in L. crocea are largely under independent genetic control within the studied family, indicating that simultaneous improvement of growth and disease resistance is feasible. This study provides a molecular basis for breeding strategies aimed at overcoming the trait trade-off bottleneck in this economically vital species. Full article

Brown adipose tissue (BAT) plays a key role in non-shivering thermogenesis and is a promising target for enhancing energy expenditure to combat obesity. Soluble epoxide hydrolase (sEH) is a cytosolic enzyme that catalyzes the conversion of epoxy fatty acids into less active diols. We have reported that local administration of the sEH inhibitor, t-TUCB, to the endogenous interscapular BAT (iBAT) of diet-induced obese mice decreased serum triglycerides and enhanced the expression of essential genes associated with lipid metabolism. Here, the effects of sEH inhibition by t-AUCB were assessed on human brown adipocyte (HuBr) differentiation and in nude mice transplanted with t-AUCB-treated HuBr. HuBr cells were differentiated with t-AUCB (1–10 µM) or the vehicle (0.1% DMSO). HuBr differentiated with t-AUCB at 5 μM (AUCB 5) or DMSO was mixed with matrix gel and transplanted into the nude mice. The mice were then fed a high-fat diet for eight weeks. The mice receiving AUCB 5-treated HuBr exhibited markedly reduced lipid accumulation in the iBAT compared with DMSO or matrix-only controls, along with increased protein expression of thermogenic PGC1α and UCP1, fatty acid transporter CD36, and CPT1A in the iBAT, while the NFκB inflammatory pathways were suppressed in both the AUCB 5 and DMSO groups. Moreover, the PGC1α and CPT1A protein levels were elevated, and the adipocyte sizes were decreased in the epididymal white adipose tissue of the AUCB 5 group. Our findings indicate that the transplantation of HuBr treated with AUCB 5 may stimulate thermogenesis, enhance lipid metabolism, and reduce inflammation in iBAT. Full article

This study investigates the effect of three-dimensional (3D) bioprinted collagen (Col) scaffolds (2% w/v collagen) loaded with autologous bone marrow stromal cells (BMSCs) and enriched with bone morphogenetic protein-2 (BMP-2) and hydroxyapatite-based particles (HAPPs) on bone regeneration in calvarial defects in rabbits. Three implant formulations, Col-(BMP-2) (at a concentration of 80 ng/mL), Col-HAPP (1% w/v) and a mixture of the two—Col-(BMP-2)-HAPP (40 ng/mL final concentration and 0.5% HAPP), were compared with a control group C-Per containing only periosteum to assess the influence of material structure, biochemical signals and cell component on osteogenesis. Histological analysis and quantitative computed tomography (CT) imaging parameters (HU values and residual defect diameter) showed significant differences between the groups, highlighting the role of combined strategies for optimal bone repair. The control group demonstrated the weakest regeneration, expressed by minimal lamellar bone and the largest residual defect. Col-(BMP-2) stimulated moderate osteoinduction with active osteoblasts but without a fully organised lamellar structure. Col-HAΡΡ provided more advanced regeneration, with histologically observed thick osteoid lamellae, early calcification, and structured lamellar architecture, emphasising the osteoconductive role of HAΡΡs. The strongest regeneration was reported with Col-(BMP-2)-HAΡΡ, where the synergy between BMP-2, HAΡΡs and BMSCs resulted in formed osteons, well-developed cancellous bone and minimal residual defects. The established negative correlation between bone density and residual calvarial defects emphasises the relationship between mineralisation and the degree of defect filling. The new data presented demonstrate that the combination of the abovementioned structural, biochemical and cellular factors in 3D bioprinted scaffolds offers a promising strategy for osteoregeneration of complex bone defects. Full article

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is initiated by the viral spike proteins, which are key structural components that mediate host cell binding and entry and alter downstream signaling through multiple interactions with endothelial surface receptors. Endothelial dysfunction is a central consequence of COVID-19, contributing to vascular inflammation, barrier disruption, thrombosis, and multi-organ injury affecting the pulmonary, cardiovascular, cerebral, and renal systems. Emerging evidence demonstrates that spike protein-mediated effects, independent of productive viral infection, disrupt endothelial homeostasis through angiotensin-converting enzyme 2 (ACE2) dysregulation, integrin engagement, altered calcium signaling, junctional protein remodeling, oxidative stress, and pro-inflammatory and pro-apoptotic pathways. This review is intentionally focused on spike (S) protein-driven mechanisms of endothelial dysfunction; pathogenic vascular effects attributed to other SARS-CoV-2 structural proteins, including the nucleocapsid (N) protein, are beyond the scope of this discussion. In this review, we synthesize current experimental and translational data detailing the molecular mechanisms by which the SARS-CoV-2 spike protein drives endothelial dysfunction across multiple organ systems and discuss potential therapeutic strategies aimed at preserving endothelial integrity in acute COVID-19 and its long-term vascular sequela. Full article

In this study, we constructed plasmids to increase the overall expression level of the SARS-CoV-2 S-protein and its presentation on the cell surface. To this end, we designed a series of plasmid constructs encoding the SARS-CoV-2 S-protein with modifications to its cytoplasmic domain and containing various 5′ and 3′ untranslated regions. Our results confirmed the critical role of the S-protein cytoplasmic domain in limiting its localization to the cell surface. We confirmed that deletion of the 19 C-terminal amino acids, which contain an endoplasmic reticulum retrieval signal, significantly increased S-protein presentation on the cell surface. Furthermore, introducing the HuR-binding site from the CD47 3′ untranslated region and replacing the 19 C-terminal amino acids of the S-protein with the CD47 cytoplasmic tail significantly enhanced total S-protein expression compared to the wild-type S-protein and constructs with the 19-amino-acid deletion. Unfortunately, for the plasmid constructs bearing CD47 elements, their higher surface expression compared to the wild-type S-protein correlated with a high total protein expression level. Full article

Microglia-derived small extracellular vesicles (MGEVs) are key mediators of neuroimmune communication, yet their cross-species comparability and translational relevance remain poorly defined. Here, we establish a harmonized framework to compare the molecular and biochemical signatures of sEVs derived from immortalized mouse (BV2) and human (HMC3) microglial cells as well as assess their bioactivity on a human Schwann cell (HuSC) line. MGEVs were isolated via MISEV-aligned size-exclusion chromatography (SEC) and characterized by nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM), and immunoblotting for canonical EV markers CD9, CD63, CD81, TSG101. Human and mouse MGEVs exhibited similar morphology but displayed distinct membrane tetraspanin protein enrichment patterns. Functionally, mouse and human MGEVs attenuated HuSC migration while enhancing HuSC proliferation and their resistance to H₂O₂-induced oxidative stress, with human MGEVs providing stronger protective effects, suggesting they retain similar core functional properties. Short, non-coding-miRNA sequencing analysis identified 196 shared miRNAs (Spearman ρ = 0.72) with species-specific enrichment: human MGEVs-derived miRNAs favored regenerative and metabolic pathways, whereas mouse MGEVs-derived miRNAs aligned more so with inflammatory signaling. This study delivers the first integrated cross-species blueprint of MGEVs, revealing conserved neuroprotective actions alongside species-biased miRNA cargo that define translational boundaries and highlight human-relevant MGEV signatures for therapeutic innovation, therefore contributing to the importance of considering these differences in translational research. Full article

Coordination polymers (CPs) are garnering attention in the field of medicine day by day. The goal is to develop a CP with biosafe and environment-friendly characteristics. Herein, we report two such novel 3D coordination polymers of zinc-inosine-5′-monophosphate (Zn-IMP) and bpe/azpy (as linkers) which were engineered as metal–organic frameworks that can be used as drug carriers for hydroxyurea (HU). We employed SCXRD, PXRD, solid-state CD, FTIR and TGA for crystal structure characterizations; the results achieved 3D coordination polymers which contain a P2₁ space group with chiral distorted tetrahedral geometry. Solution phase studies like UV–vis and CD were carried out to understand mechanistic pathways for interaction and chirality, respectively. We have also performed computational studies to evaluate the drug delivery capacity of both 3D CPs. Molecular docking and multi-pH molecular dynamics (MD) quantify that HU binds more strongly with CP−1 (ΔG =−10.87 ± 0.12) as compared to CP−2 (ΔG = −7.59 ± 0.26 kcal·mol⁻¹), at normal and basic pH. MD simulation analysis indicated that a more compact and rigid cavity is observed by CP−1 as compared to CP−2 at physiological pH. Across acidic pH, for CP−1 the ligand RMSD increases markedly and U becomes slightly less negative, which indicated partial loss of contacts, thus releasing drugs in a tumor-like environment more easily. These result showed that CP−1 offers stronger binding, higher structural stability and a more pronounced pH-responsive release profile than CP−2, making CP-1 more promising candidate for targeted HU drug delivery, while CP−2 may serve as a weaker-binding, faster-release complement. Full article

This review summarizes a growing collection of data on adult neurogenesis in various vertebrate species, with a focus on teleost fish and mammals. Teleost fish serve as exceptional models for studying the dynamics of the cell cycle and the functions of adult neural stem progenitor cells (aNSPCs) throughout the central nervous system (CNS). New information about the characteristics of cells in various areas of the telencephalon of non-model objects—juvenile masu salmon Oncorhynchus masou and chum salmon Oncorhynchus keta—during postembryonic ontogenesis and after traumatic injury expands the current understanding of the issue. The expression of molecular markers of adult-type glial precursors in the model zebrafish and non-model objects, juveniles O. masou and O. keta, was presented. Immunohistochemical (IHC) verification of BrdU and PCNA made it possible to identify a population of rapidly and slowly proliferating cells in the pallium of intact O. masou and after traumatic brain injury (TBI). In salmonids, unlike in mammals, progenitor cells are able to differentiate into neurons after injury. The expression of vimentin and GFAP in the aNSCPs has functional specificity. A comparative analysis of the expression of Pax transcription factors in various vertebrates and juveniles O. masou is presented. Pax genes maintain cells in an undifferentiated state and ensure the spatiotemporal formation of mature cell types in changing developing neurogenic niches. The functions of glutamine synthetase (GS) and H₂S in the brains of vertebrates and juvenile chum salmon under intact conditions and after TBI are characterized. In fish, unlike mammals, as a result of TBI, neuronal conduction is restored in the injury area, whereas in mammals the regenerative process is complicated by neuroinflammation and culminates in the formation of a glial scar. Full article

Objective: Axillary lymph node changes are frequently observed in patients with HIV, yet their radiological characteristics and clinical significance remain underexplored. This study aimed to evaluate the association between axillary lymph node computed tomography (CT) features and clinical markers of immune function, including CD4 lymphocyte count and plasma viral load, in HIV-positive patients. Materials and Methods: In this retrospective study, 113 HIV-positive patients who underwent contrast-enhanced chest CT were included. Patients were stratified by CD4 count (<200, 200–500, >500 cells/μL) and plasma viral load (<100,000 or >100,000 copies/mL). Axillary lymph node parameters—including maximum and minimum diameters, cortical thickness, hilar width, and density (Hounsfield units, HU)—were measured on multiplanar reconstructed CT images. Group differences were assessed using the Kruskal–Wallis and Mann–Whitney U tests, and Spearman’s correlation was used to evaluate associations between imaging and laboratory findings. Receiver operating characteristic (ROC) curve analysis identified optimal density thresholds. Results: Lymph node diameters, cortical thickness, and hilar width did not significantly differ between CD4 groups. However, mean lymph node density was higher in patients with CD4 < 200 cells/μL (p = 0.024). A density threshold of 84.5 HU distinguished impaired from preserved immune function (sensitivity 61.1%, specificity 71.2%). Patients with viral load >100,000 copies/mL showed increased lymph node density, minimal diameter, and cortical thickness. Conclusions: Elevated axillary lymph node density correlates with immune suppression and high viral load, suggesting its potential as a non-invasive prognostic imaging biomarker in HIV infection. Full article

Background/Objectives: SARS-CoV-2 continues to generate antigenically divergent variants that reduce the breadth of existing vaccine-induced antibody responses. Fc-fusion subunit vaccines offer advantages in stability, antigen display, and Fc-mediated immune engagement. This study aimed to design and evaluate a tetravalent RBD–Fc fusion construct incorporating RBDs from Wuhan-Hu-1 and Omicron BA.4/BA.5 and to determine whether this configuration can induce broad antibody recognition across SARS-CoV-2 variants. The objective was to assess its feasibility, biochemical properties, and initial immunogenicity. Methods: Immune responses to the construct were first assessed using the C-ImmSim simulation platform. The full-length fusion was synthesized, subcloned into pcDNA3.1(+), expressed in HEK293 cells, and purified by Protein G affinity chromatography. Protein integrity was evaluated by reducing SDS–PAGE. BALB/c mice (female, 8 weeks) were immunized with a prime–boost–boost schedule, and sera were analyzed by ELISA, considering binding to Wuhan-Hu-1, Omicron BA.4/BA.5, and a panel of RBD variants. Results: In silico analysis predicted coordinated antigen clearance, class switching, memory B- and CD4⁺ T-cell formation, and transient cytokine induction. The recombinant protein was expressed efficiently, yielding a major ~56 kDa band and a ~23 kDa RBD fragment. Vaccinated mice generated strong IgG responses to Wuhan-Hu-1 and BA.4/BA.5 RBDs and showed broad binding to major variant RBDs. Conclusions: The tetravalent RBD–Fc fusion vaccine was successfully produced and elicited broad antibody binding across SARS-CoV-2 variants, supporting its potential as a versatile protein-based vaccine platform. Full article

Shiga toxin-producing Escherichia coli (STEC) is a major foodborne pathogen, responsible for severe gastrointestinal disease and hemolytic uremic syndrome (HUS). Here, we report Click Detect, a novel diagnostic platform that leverages click display to efficiently produce sensing probes for sandwich-style antigen detection. Click display is an in vitro protein display technology that generates uniform and covalently linked protein–cDNA conjugates in a simple one-pot reaction format within 2 h. The captured sensing probe can be quantified by standard nucleic acid amplification assays. Using click displayed DARPin (D_#20) as the sensing probe and a high-affinity nanobody (N_G1) as the capture reagent, Click Detect reliably detected Shiga toxin 2 (Stx2) at 600 fM by quantitative PCR (qPCR) and 6 pM by loop-mediated isothermal amplification (LAMP). The assay maintained comparable sensitivity in matrices containing up to 40% public swimming pool water or lettuce extract, highlighting robustness for real-world surveillance applications. Key advantages of Click Detect include simple, rapid, and cost-effective (~USD 0.04 per assay) sensing probe preparation, as well as a versatile plug-and-play probe format for detecting other targets. We believe that Click Detect has great potential as a novel sensing platform for food/environmental monitoring and point-of-care diagnostics, with potentially broad applicability to other toxins and protein targets. Full article

Introduction: Hyperuricemia is increasingly recognized as a metabolic disorder linked to dyslipidemia, insulin resistance, and vascular complications. In Saudi Arabia, the prevalence of hyperuricemia is rising with obesity and diabetes, yet its relationship with lipid-derived cardiometabolic indices remained understudied. This study aimed to examine the associations between uricemia status and lipid-derived cardiometabolic indices in a large adult cohort. Methods: This retrospective cross-sectional study analyzed data from 7652 adults, including 5385 normouricemic (NU) and 2267 hyperuricemic (HU). Key cardiometabolic indices, including the triglyceride-glucose index (TyG), non-high-density lipoprotein cholesterol (non-HDL-C), remnant cholesterol (RC), atherogenic index of plasma (AIP), and Castelli risk indices I and II (CRI-I, CRI-II), were calculated. Associations were evaluated treating HU as the exposure and the lipid-derived cardiometabolic indices as the outcomes. Multivariable regression analyses, receiver operating characteristic (ROC) curves, and prevalence-based association estimates were used to assess these relationships. Results: HU individuals exhibited significantly higher TG along with lowered HDL-C. Median TyG (4.61), AIP (0.38), non-HDL-C (147 mg/dL), RC (18 mg/dL), CRI-I (4.30), and CRI-II (2.85) were higher in the HU group compared to NU group, with non-HDL-C and CRI-I falling within the abnormal range, AIP in the high-risk range, and TyG and CRI-II at borderline levels. Across the separately adjusted models, hyperuricemia showed consistent positive associations with RC, AIP, CRI-I, and CRI-II, whereas associations with TyG and non-HDL-C diminished after adjustment for renal or liver markers. ROC analysis demonstrated modest discriminatory ability of uric acid for elevated indices, with AIP (AUC = 0.641) and CRI-I (AUC = 0.640) exhibiting the highest performance. The prevalence of elevated indices was substantially higher in HU, particularly for CRI-II (44.0% vs. 25.9%) and CRI-I (28.2% vs. 13.7%). Conclusions: These findings highlight associations between HU and lipid-derived cardiometabolic indices, but further longitudinal research is required to determine whether HU has a clinical predictive value in cardiovascular risk assessment. Full article