Lesion Area Research Articles

Therapeutic effects of FGF21 mimetic bFKB1 on MASH and atherosclerosis in Ldlr-/-.Leiden mice.

Fibroblast growth factor 21 (FGF21) is a promising target for treatment of obesity-associated diseases including metabolic dysfunction-associated steatohepatitis (MASH) and atherosclerosis. We evaluated the effects of the bispecific anti-FGF21-β klotho (KLB) agonist antibody bFKB1 in a preclinical model of MASH and atherosclerosis. Low-density lipoprotein receptor knockout (Ldlr-/-).Leiden mice received a high-fat diet for 20 weeks, followed by treatment with an isotype control antibody or bFKB1 for 12 weeks. Effects on plasma risk markers and (histo)pathology of liver, adipose tissue, and heart were evaluated alongside hepatic transcriptomics analysis. bFKB1 lowered body weight (-21%) and adipose tissue mass (-22%) without reducing food intake. The treatment also improved plasma insulin (-80%), cholesterol (-48%), triglycerides (-76%), alanine transaminase (ALT: -79%), and liver weight (-43%). Hepatic steatosis and inflammation were strongly reduced (macrovesicular steatosis -34%; microvesicular steatosis -100%; inflammation -74%) and while the total amount of fibrosis was not affected, bFKB1 did decrease new collagen formation (-49%). Correspondingly, hepatic transcriptomics and pathway analysis revealed the mechanistic background underlying these histological improvements, demonstrating broad inactivation of inflammatory and profibrotic transcriptional programs by bFKB1. In epididymal white adipose tissue, bFKB1 reduced adipocyte size (-16%) and inflammation (-52%) and induced browning, signified by increased uncoupling protein-1 (UCP1) protein expression (8.5-fold increase). In the vasculature, bFKB1 had anti-atherogenic effects, lowering total atherosclerotic lesion area (-38%). bFKB1 has strong beneficial metabolic effects associated with a reduction in hepatic steatosis, inflammation, and atherosclerosis. Analysis of new collagen formation and profibrotic transcriptional programs indicate that bFKB1 treatment may have antifibrotic potential in a longer treatment duration as well.

Smooth muscle cell-specific deletion of S100A4 modifies smooth muscle cell fate and inflammation in murine atherosclerotic lesions

Abstract Background S100A4, a calcium-binding protein, is crucial in smooth muscle cell (SMC) phenotypic switch, yet its role in atherosclerotic plaque development and SMC plasticity remains unclear. Our previous experiments using an S100A4 neutralizing antibody approach in ApoE-/- atherosclerotic-prone mice showed reduced atherosclerotic burden but did not establish a direct link between the various S100A4-expressing cells and atherosclerosis. Methods/Results Herein, we show that aortic Oil RedO staining in ApoE-/-; S100A4-/- mice subjected to a 12-week high-cholesterol-diet (HCD) revealed reduced lesion areas compared to ApoE-/- mice (Figure 1, from 21.29% of the total aorta in ApoE-/-; S100A4+/+ mice to 13.27% in ApoE-/-; S100A4-/- mice), highlighting a pivotal role for S100A4 in atherosclerotic plaque development. We then used a lineage tracing ApoE-/- mouse model, in which we induced an SMC-specific deletion of S100A4 (SMC-S100A4Δ/Δ). After 12 weeks of HCD, SMC-S100A4Δ/Δ and control mice (SMC-S100A4wt/wt) were sacrificed, and aortas were processed for en face Oil Red O staining, immunohistochemistry, and single-cell RNA sequencing (scRNA-seq). SMC-specific deletion of S100A4 reduced the necrotic core area (from 29.75% of total plaque area in SMC-S100A4wt/wt to 18.23% in SMC-S100A4Δ/Δ mice) without affecting total atherosclerotic plaque size suggesting a more potent impact on plaque composition. ScRNA-seq analysis from SMC-S100A4Δ/Δ and SMC-S100A4wt/wt mice showed that the inflammatory macrophage-like SMC phenotype was highly suppressed in the plaque and associated with increased SMC repair phenotypes as well as a global reduction of myeloid inflammatory cells. SMCs also retained specific contractile SMC markers, namely Acta2 and Myh11 (fold change of 2.285 and 2.492, respectively) hinting towards a more stable fibrous cap. Immunofluorescence staining on aortic roots plaque (Figure 2) confirmed those results with an increase of SMCs (from 11.02% to 16.18%) as well as a-smooth muscle actin (a-SMA, Acta2)-positive SMCs (from 3.25% to 5.1%) in SMC-S100A4 Δ/Δ mice. Furthermore, the Gene Set Enrichment Analysis (GSEA) of scRNAseq data revealed that, in SMC-S100A4Δ/Δ mice, genes related to mitochondrial metabolism and oxidative respiration were highly downregulated in all SMC clusters. We investigated SMC mitochondrial fitness in vitro and showed that S100A4-/- SMCs have an increased basal oxygen consumption rate and an increased proton leak (fold change of 1.37 and 1.96 respectively) suggestive of differences in cellular metabolic adaptability. Conclusion Our research emphasizes the significant role of S100A4 in plaque development, demonstrating how SMC-derived S100A4 knockdown affects plaque evolution, reducing inflammation, and promoting stability likely through influencing SMC phenotypic switch through metabolic pathways.

The orchestration of coding and non-coding genes at the CDH13 locus in coronary artery disease

Abstract Background The CDH13 locus was associated with coronary artery disease (CAD) by genome-wide association studies (GWAS). However, the causal gene(s) and underlying disease mechanisms at this locus remain undetermined. Purpose We intended to pinpoint and functionally validate the causal coding and non-coding genes at the CDH13 locus and delineate the underlying mechanisms for CAD. Methods and results We conducted the transcriptome-wide association analysis (TWAS) using nine types of CAD-relevant tissues from Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task (STARNET) and Genotyped Tissue Expression (GTEx) projects and identified CDH13 (T-cadherin) and four long non-coding RNA (lncRNA) genes as candidate causal genes at The CDH13 locus. One of the antisense(AS) lncRNAs, CDH13-AS2, was predicted to bind on the 3’ untranslated region (UTR) of CDH13 using LncRRIsearch and RNAup servers. The binding interaction was validated by dCas13-medicated RNA immunoprecipitation. Weighted correlation network analysis (WGCNA) using transcriptomic data from CAD-relevant tissues of ~600 human subjects suggested a positive expression correlation between CDH13 and CDH13-AS2 in artery tissues. CRISPR/Cas9-based knockout (KO) of CDH13 or CDH13-AS2 in human umbilical vein endothelial cells (HUVECs) indicated synergistically atherogenic phenotypes, including reduced proliferation and migration, and increased apoptosis and monocyte adhesion. The data matched with the downregulation of CDH13 in artery samples of atherosclerosis patients. The cellular phenotypes were also in line with our in vivo data of Cdh13 and Apoe double-KO (Cdh13-/-/Apoe-/-) mice, which showed increased aortic lesion areas when fed on a high-fat diet compared to Apoe-/- mice. Furthermore, prediction using TargetScan, miRWalk, and scanMiRApp databases identified the potential binding of several EC-expression microRNAs (mir) on 3’UTR of CDH13. Several disease-associated variants were mapped to the predicted binding sites of a few microRNAs, including mir-let7, mir-30, and mir-125. The dual luciferase-based RNA interference (RNAi) assay confirmed the binding of mir-let7 on 3’UTR of CDH13. Transcriptional activation of CDH13-AS2 by the enzymatically inactivated Cas9 (dCas9) system diminished the binding of mir-let7 and increased CDH13 expression. Conclusions At the CDH13 locus, CDH13 and CDH13-AS2 are two causal genes, whose downregulation likely contributes to CAD. CDH13-AS2 bound and stabilized CDH13 partially by preventing mir-let7 mediated degradation of CDH13 mRNA, suggesting therapeutic potentials.

DMA‐Net: A dual branch encoder and multi‐scale cross attention fusion network for skin lesion segmentation

AbstractAutomatic segmentation of skin lesion is an important step in computer‐aided diagnosis. However, due to the significant variations in the size and shape of the lesion areas, as well as the low contrast with normal skin tissue, the boundaries are not clearly distinguishable, leading to a high possibility of incorrect segmentation. Therefore, this task is highly challenging. To overcome these difficulties, this paper proposes a medical image segmentation architecture named dual branch encoder and multi‐scale cross attention fusion network, which includes a dual‐branch encoder based on convolutional neural network and an improved channel‐enhanced Mamba to comprehensively extract local and global information from dermoscopy images. Additionally, to enhance the feature interaction and fusion of local and global information, a multi‐scale cross attention fusion module is adopted to cross‐merge features in different directions and at different scales, maximizing the advantages of the dual‐branch encoder and achieving precise segmentation of skin lesions. Extensive experiments are conducted on three public skin lesion datasets: ISIC‐2018, ISIC‐2017, and ISIC‐2016, to verify the effectiveness and superiority of the proposed method. The dice similarity coefficient scores on the three datasets reached 81.77%, 81.68% and 85.60%, respectively, surpassing most state‐of‐the‐art methods.

OSSN in South India: Clinical presentation, treatment outcomes, and histopathologic correlations.

This study aimed to analyze the clinical presentation, treatment outcomes, and histopathology features of ocular surface squamous neoplasia (OSSN) in a South Indian population and correlate the area of lesions to the histopathological grade/severity of carcinoma in situ (CIN) and squamous cell carcinoma (SqCC) invasive and noninvasive tumors. The study was a retrospective cross-sectional study. The study reviewed electronic medical records (EMRs) of 99 eyes of 99 South Indian patients who underwent en bloc excision and biopsy for tumors in the corneal and conjunctival epithelium with suspicion of OSSN over 1 year from January 2019 to December 2019. Postoperatively, patients were treated with three cycles of topical 0.04% mitomycin C eye drops. Sixty-three had requisite EMR data with a follow-up period of 1 year. Patients had equal gender distribution with an age range of 28-83 years. The most common clinical variant was leukoplakic lesion, and the area of the lesion was the only predicting factor for SqCC and CIN. Bigger (T2) lesions should be strongly suspected for OSSN and promptly excised. Histopathologic analysis should be performed, and post-op topical mitomycin C or interferon alpha 2b is administered to avoid recurrence. In this study, by correlating the area of the lesion, we introduce a new variable that may aid in clinical prognostication alongside the AJCC classification.

Acute Administration of Edaravone Improves Cognitive Impairment in a Mouse Model of mPFC Ischemia: Crosstalk Between Necroptosis, Neuroinflammation, and Antioxidant Defense.

Edaravone (Eda), a well-known free radical scavenger, has been reported as a possible therapeutic agent for ischemic stroke patients' recovery. This study aimed to investigate the effects of time-dependent treatment with Eda on medial prefrontal cortex (mPFC) ischemia. Mice were randomly allocated into six groups: control, sham, normal saline, Eda-I, Eda-II, and Eda-III. After induction of a photothrombotic ischemia in the mPFC region, Eda-I, Eda-II, and Eda-III groups received 3mg/kg Eda intraperitoneally at the times of 0, 2, and 6h post-surgery. After 1day of recovery, the mice underwent behavioral tests (open field, novel object recognition, and T-maze). Next, necroptosis, NOD-like receptor protein 3 (NLRP3), and nuclear factor erythroid 2-related factor 2 (Nrf2) pathway-related protein levels were measured in the lesioned area using western blot analysis. For double confirmation, IL-1β and IL-18 were also assessed by immunofluorescence in the area. Further, histological evaluations were performed to measure tissue damage. The results showed that mPFC ischemia impaired recognition and spatial working memory without affecting locomotor activity, while immediate Eda administration improved cognitive impairments. Furthermore, acute Eda treatment reduced RIP1, RIP3, and MLKL levels, inhibited NLRP3 inflammasome proteins (NLRP3, ASC, and Cas1), decreased IL-1β and IL-18, upregulated Nrf2 and its targets (NQO-1 and HO-1), and diminished tissue damage. Our results highlighted the effects of acute administration of Eda post-stroke on improving cognitive impairments by suppressing necroptosis and NLRP3 inflammasome pathways and activating the Nrf2 antioxidant defense mechanism.

Evaluations of the deterioration characteristics of thermally treated wood samples from Corymbia citriodora and Eucalyptus urophylla caused by marine wood borers

The low natural durability properties of some types of wood indicate the need for treatments to enhance the resistance of these materials to biological decay. In the sea, this resistance is necessary due to the actions of wood-boring mollusks and crustaceans. These treatments must be effective without harming the environment. Wood thermal treatment should be evaluated for this purpose. Therefore, the aim of this study was to evaluate the deterioration characteristics of thermally treated wood samples from Corymbia citriodora and Eucalyptus urophylla under the actions of marine wood borers. A method was proposed to aid in this assessment. Ten samples of these woods, both untreated and thermally treated, were submerged in the sea, each at a depth of 2.5 meters, for five months. After this period, the external borehole number, mass loss, and central flat lesion parameters of the samples were evaluated. Both the thermally treated and untreated wood samples of C. citriodora showed less deterioration than those of E. urophylla, with fewer boreholes, smaller lesioned areas, and lower mass losses. Compared with untreated wood and E. urophylla wood, thermally treated C. citriodora wood exhibited some resistance to marine wood borers. It was concluded that C. citriodora wood was naturally more resistant to marine wood borers than E. urophylla wood. Moreover, thermal treatment increased the boring resistance of C. citriodora wood while increasing the susceptibility of E. urophylla wood. The digital measurement of flat lesions was proven to be an auxiliary and promising method for evaluating the deterioration process.

Microglia overexpressing brain-derived neurotrophic factor promote vascular repair and functional recovery in mice after spinal cord injury.

Spinal cord injury represents a severe form of central nervous system trauma for which effective treatments remain limited. Microglia is the resident immune cells of the central nervous system, play a critical role in spinal cord injury. Previous studies have shown that microglia can promote neuronal survival by phagocytosing dead cells and debris and by releasing neuroprotective and anti-inflammatory factors. However, excessive activation of microglia can lead to persistent inflammation and contribute to the formation of glial scars, which hinder axonal regeneration. Despite this, the precise role and mechanisms of microglia during the acute phase of spinal cord injury remain controversial and poorly understood. To elucidate the role of microglia in spinal cord injury, we employed the colony-stimulating factor 1 receptor inhibitor PLX5622 to deplete microglia. We observed that sustained depletion of microglia resulted in an expansion of the lesion area, downregulation of brain-derived neurotrophic factor, and impaired functional recovery after spinal cord injury. Next, we generated a transgenic mouse line with conditional overexpression of brain-derived neurotrophic factor specifically in microglia. We found that brain-derived neurotrophic factor overexpression in microglia increased angiogenesis and blood flow following spinal cord injury and facilitated the recovery of hindlimb motor function. Additionally, brain-derived neurotrophic factor overexpression in microglia reduced inflammation and neuronal apoptosis during the acute phase of spinal cord injury. Furthermore, through using specific transgenic mouse lines, TMEM119, and the colony-stimulating factor 1 receptor inhibitor PLX73086, we demonstrated that the neuroprotective effects were predominantly due to brain-derived neurotrophic factor overexpression in microglia rather than macrophages. In conclusion, our findings suggest the critical role of microglia in the formation of protective glial scars. Depleting microglia is detrimental to recovery of spinal cord injury, whereas targeting brain-derived neurotrophic factor overexpression in microglia represents a promising and novel therapeutic strategy to enhance motor function recovery in patients with spinal cord injury.

A semi‐supervised segmentation network fusing pseudo‐label with multi‐level feature consistency correction for hard exudates

AbstractTimely detection of hard exudates in fundus images can effectively avoid the severity of the disease, but the labelling of small and numerous lesion areas requires a lot of labour costs. This paper proposes a semi‐supervised segmentation network, which integrates pseudo‐labels and multi‐level features consistency correction. It achieves accurate segmentation of hard exudates by making full use of a small amount of labelled data and a large amount of unlabelled data. The network effectively extracts features from the unlabelled data through knowledge transfer of the teacher‐student model, and incorporates a Transformer network for auxiliary training to promote the quality of transfer. In addition, three unsupervised losses are introduced to improve the performance: the perturbation loss improves the robustness of the model to noise by adding different noises to the same input; the multi‐level feature consistency correction loss ensures the consistency of features of the student model at different scales; and the pseudo‐labelling cross‐supervision loss utilizes the generated pseudo‐labels for supervision between CNN and Transformer. By comparing the segmentation results with different proportion of the labelled data, it has better segmentation performance compared to other methods. The proposed methods can totally increase dice by 16.56% and mean intersection over union (MIoU) by 25.11%.

Cap2Seg: leveraging caption generation for enhanced segmentation of COVID-19 medical images

Incorporating medical text annotations compensates for the quality deficiencies of image data, effectively overcoming the limitations of medical image segmentation. Many existing approaches achieve high-quality segmentation results by integrating text into the image modality. However, these approaches require matched image-text pairs during inference to maintain their performance, and the absence of corresponding text annotations results in degraded model performance. Additionally, these methods often assume that the input text annotations are ideal, overlooking the impact of poor-quality text on model performance in practical scenarios. To address these issues, we propose a novel generative medical image segmentation model, Cap2Seg (Leveraging Caption Generation for Enhanced Segmentation of COVID-19 Medical Images). Cap2Seg not only segments lesion areas but also generates related medical text descriptions, guiding the segmentation process. This design enables the model to perform optimal segmentation without requiring text input during inference. To mitigate the impact of inaccurate text on model performance, we consider the consistency between generated textual features and visual features and introduce the Scale-aware Textual Attention Module (SATaM), which reduces the model’s dependency on irrelevant or misleading text information. Subsequently, we design a word-pixel fusion decoding mechanism that effectively integrates textual features into visual features, ensuring that the text information effectively supplements and enhances the image segmentation task. Extensive experiments on two public datasets, MosMedData+ and QaTa-COV19, demonstrate that our method outperforms the current state-of-the-art models under the same conditions. Additionally, ablation studies have been conducted to demonstrate the effectiveness of each proposed module. The code is available at https://github.com/AllenZzzzzzzz/Cap2Seg.

Simulation analysis of different types of balloon dilatation catheters for the treatment of intracranial arterial stenosis.

The application of balloon dilation catheters in the management of intracranial arterial stenosis has been gradually increasing. However, studies on the feasibility and effectiveness of different types of balloons remain relatively scarce. In this study, catheter models of three different materials were designed to simulate balloon crimping,splitting, and dilatation processes. A compliant balloon produces large deformations with poor dilatation and a stress concentration phenomenon. During dilatation, the shear stress generated in the intima and lesion area by the semi-compliant balloon was smaller than that generated by the non-compliant balloon. These results demonstrate the feasibility of using semi-compatible balloons.

Kaposiform haemangioendothelioma: ultrasonographic features and risk factors for the Kasabach-Merritt phenomenon.

Kaposiform hemangioendothelioma (KHE) is a rare, locally aggressive vascular tumor with high morbidity and mortality. The aim of this study was to evaluate ultrasonographic findings associated with KHE.The clinical and ultrasonographic findings of a cohort of 64 cases with pathologically proven KHE were retrospectively reviewed and analyzed between November 2014 and February 2021. Two subtypes were divided according to the presence or absence of the Kasabach-Merritt phenomenon (KMP). The KMP risk factors in patients with KHE were analyzed statistically.Among the 64 cases of KHE, 43 (67.2%) were accompanied by KMP. There was a positive correlation between the appearance of KMP and tumor size. KHEs had an increased risk of developing KMP if the lesions measured were >6 cm and if they belonged to the deep or mixed subtype. On ultrasonography, all KHE lesions were heterogeneous, and 81.3% were hypoechoic; 93.8% of KHEs exhibited ill-defined margins, 68.7% had strands branching into the adjacent tissue, and 84.4% presented marked hypervascularity. Elastography showed that central hypoechogenic lesion areas were hard, and surrounding hyperechogenic lesion areas were soft.KHEs can occur in different parts of childrens' bodies. On ultrasonography, the main findings are heterogeneous low erosions, indistinct margins, branching strangulation into adjacent tissues, and obvious hypervascularity. Patients with lesions larger than 6 cm or belonging to deep or mixed subtypes (musculoskeletal infiltrates) are at risk for developing KMP, and clinicians should be vigilant.

Weakly supervised deep learning for diagnosis of prostate cancer after radical prostatectomy: a population- based, multicenter study

Abstract Introduction/Objective The pathological diagnosis of prostate cancer after radical prostatectomy (RP) is a challenging and time-consuming process. Artificial intelligence has the potential to enhance this situation significantly. Our study aimed to assess the efficacy of weakly supervised deep learning, specifically focusing on practical diagnostic tasks for RP specimens. Methods/Case Report We obtained slices from clinical centers across four regions in China. The model was developed based on a multiple instance learning framework. We evaluated the model’s predictive accuracy, covering both slice-level and lesion-level diagnoses. Additionally, we investigated lesion localization using attention visualization. Slice-level diagnosis included prostate cancer detection and Gleason grading, while lesion-level diagnosis involved recognizing index lesions and non-index lesions. Results (if a Case Study enter NA) The study involved 13,245 slides from 304 patients. The area under the curve values in four validation sets ranged from 0.921 (95% CI 0.913–0.930) to 0.964 (95% CI 0.959–0.968). Regarding Gleason grading, the model demonstrated quadratic Weighted Kappa values of 0.748 and 0.720 for internal and external validation, respectively. The model predicted 1,683 (35.3%) positive and 3,081 (64.7%) negative slices in all validation sets. The median area of index lesions and non-index lesions was 92.6mm2 (IQR: 54.2–130.0mm2) and 3.5mm2 (IQR: 1.4–10.9mm2) (p<0.001), respectively. The model accurately predicted index lesions in all cases for three validation sets. Furthermore, the model achieved 100% accuracy in predicting slides with the maximum tumor area for index lesions in two validation sets. In visual assessment, 200 randomly selected slices predicted as true positive demonstrated that the model could identify 97.5% (195/200) of the index lesions. Conclusion The weakly supervised deep learning model demonstrated remarkably high diagnostic and localization capabilities in identifying index lesions within RP specimens. This targeted approach would effectively alleviate the diagnostic workload associated with pathology assessments for prostate cancer.

Combined fractional CO2 laser with dimethyl sulfoxide (DMSO) 50% versus fractional CO2 Laser alone in the treatment of macular amyloidosis: clinical and histopathological assessment.

Macular amyloidosis (MA) could be of cosmetic concern with a significant psychological impact for patients, and its treatment is challenging. To compare the efficacy and safety of combined fractional CO2 laser with dimethyl sulfoxide (DMSO) 50% versus fractional CO2 laser alone in the treatment of macular amyloidosis. Twenty patients with macular amyloidosis were treated with monthly session of fractional CO2 laser only in one side of the lesion (area A), and fractional laser followed by application of DMSO 50% solution in the other side of the lesion (area B). All patients were evaluated clinically, by dermoscope and histopathology before and 3months after the end of 4 treatment sessions. Both treatments showed significant decrease of pigmentation after treatment (p < 0.001). There was non-significant decrease in rippling on both sides (p = 0.06). The median itching score dropped significantly after treatment from 9 to 3.5 in area A (laser only) and to 2 in area B (laser and DMSO), with non-significant difference between both areas (P = 0.244). Dermoscopic features after treatment showed fading and decreasing in multiple features in both areas A and B, with non-significant difference between the 2 areas. Histopathologically, there was significant reduction in the amyloid deposition after treatment in both areas A and B without significant difference between both areas. both fractional CO2 laser combined with topical DMSO 50% and fractional CO2 laser alone are safe and effective treatment options for MA with significant clinical improvement.

Microbial imbalance in Darier disease: Dominance of various staphylococcal species and absence of Cutibacteria

Darier disease (DD) is a rare autosomal dominant genodermatosis characterized by erythematous papules and plaques mainly involving sebaceous areas, such as the face, chest and back. Skin microbiome plays an essential role in maintaining skin homeostasis. A disturbed skin microbiome may contribute to the exacerbation of DD. We investigated the bacterial composition of two predilectional sites in DD patients and healthy individuals. We also measured the microbiome composition of deeper skin layers, where diversity was significantly reduced compared to the superficial layer of the skin from the same area. The microbiome of DD patients at lesional sites differed from that of non-lesional skin areas; moreover, non-lesional sites were different from those of the controls. Lesional areas were dominated by Staphylococcus species, such as S. aureus, S. epidermidis, S. hominis, S. sciuri, and S. equorum. However, levels of Cutibacterium acnes (formerly Propionibacterium acnes) and C. acnes subspecies defendens were significantly lower in lesional sites than in non-lesional sites. A significant decrease was measured in the levels of these two bacteria between non-lesional and control samples. Our findings may indicate that alterations in the skin microbiome could contribute to the inflammation of skin lesions in DD.

Isoorientin Improves Excisional Skin Wound Healing in Mice

Background/Objectives: Wound healing relies on a coordinated process with the participation of different mediators. Natural products are a source of active compounds with healing potential. Isoorientin is a natural flavone recognized as having several pharmacological properties, such as anti-inflammatory effects, making it a potential treatment for wounds. We investigated the effect of isoorientin on the healing of excisional skin wounds. Methods: Male Swiss mice were subjected to the induction of excisional skin wounds (6 mm diameter) and treated with a vehicle (2% dimethyl sulfoxide in propylene glycol) or 2.5% isoorientin applied topically once a day for 14 days. The wound area was measured on days 0, 3, 7, and 14. Histopathological analyses were performed on the cicatricial tissue after 14 days. The myeloperoxidase activity and the interleukin-1β, tumoral necrosis factor (TNF)-α, and interleukin-6 concentrations were determined on the third day. Results: We observed that 3 days after the topical application of isoorientin, the lesion area was significantly smaller when compared to those of the vehicle (p &lt; 0.01) and control (p &lt; 0.05) groups. No difference was observed after 7 and 14 days of induction. Despite this, on day 14, histological analysis of cicatricial tissue from the animals treated with isoorientin showed reduced epidermal thickness (p &lt; 0.001) and increased collagen deposition (p &lt; 0.001). These effects were accompanied by decreased myeloperoxidase activity and interleukin-1β concentration on the third day of induction, without alteration in TNF-α and interleukin-6. Conclusions: The treatment with isoorientin promoted better tissue repair in excisional wounds in mice, which may be linked to the modulation of the early inflammatory response.

Plasma neurofilament heavy chain is a prognostic biomarker for the development of severe epilepsy after experimental traumatic brain injury.

This study was undertaken to test whether the postinjury plasma concentration of phosphorylated neurofilament heavy chain (pNF-H), a marker of axonal injury, is a prognostic biomarker for the development of posttraumatic epilepsy. Tail vein plasma was sampled 48 h after traumatic brain injury (TBI) from 143 rats (10 naïve, 21 controls, 112 with lateral fluid percussion injury) to quantify pNF-H by enzyme-linked immunosorbent assay. During the 6th postinjury month, rats underwent 30 days of continuous video-electroencephalographic monitoring to detect unprovoked seizures and evaluate epilepsy severity. Somatomotor (composite neuroscore) and spatial memory (Morris water maze) testing and quantitative T2 magnetic resonance imaging were performed to assess comorbidities and lesion severity. Of the 112 TBI rats, 25% (28/112) developed epilepsy (TBI+) and 75% (84/112) did not (TBI-). Plasma pNF-H concentrations were higher in TBI+ rats than in TBI- rats (p < .05). Receiver operating characteristic curve analysis indicated that plasma pNF-H concentration distinguished TBI+ rats from TBI- rats (area under the curve [AUC] = .647, p < .05). Differentiation was stronger when comparing TBI+ rats exhibiting severe epilepsy (≥3 seizures/month) with all other TBI rats (AUC = .732, p < .01). Plasma pNF-H concentration on day 2 (D2) distinguished TBI+ rats with seizure clusters from other TBI rats (AUC = .732, p < .05). Higher plasma pNF-H concentration on D2 after TBI correlated with lower neuroscores on D2 (p < .001), D6 (p < .001), and D14 (p < .01). Higher pNF-H concentration on D2 correlated with greater T2 signal abnormality volume on D2 (p < .001) and D7 (p < .01) and larger cortical lesion area on D182 (p < .01). Plasma pNF-H concentration on D2 did not correlate with Morris water maze performance on D37-D39. Plasma pNF-H is a promising clinically translatable prognostic biomarker for the development of posttraumatic epilepsy with frequent seizures or seizure clusters.

Selective and multi-scale fusion Mamba for medical image segmentation

Given the high variability in the morphology and size of lesion areas in medical images, accurate medical image segmentation requires both precise positioning of global contours and careful processing of local boundaries. This emphasizes the importance of fusing multi-scale local and global features. However, existing CNN and Transformer-based models are often limited by high parameter counts and complex calculations, making it difficult to efficiently integrate these features. To address this challenge, we proposed two innovative optimization architectures: Selective Fusion Mamba (SF-Mamba) and Multi-Scale Fusion Mamba (MF-Mamba). SF-Mamba can flexibly and dynamically adjust the fusion strategy of local and global features according to the characteristics of the lesions, effectively handling segmentation tasks with variable morphology. MF-Mamba enhances the model’s segmentation ability for lesions of different sizes by capturing global information across scales. Based on these two structures, we constructed a lightweight SMM-UNet model, which not only significantly reduces the computational burden (with only 0.038M parameters) but also demonstrates excellent generalization ability and can efficiently adapt to various types of medical images. Extensive tests on the ISIC2017, ISIC2018, and BUSI public datasets show that SMM-UNet achieves excellent segmentation performance with an extremely low parameter cost.

ASGR1 Deficiency Inhibits Atherosclerosis in Western Diet-Fed ApoE-/- Mice by Regulating Lipoprotein Metabolism and Promoting Cholesterol Efflux.

Atherosclerosis is the most common cause of cardiovascular diseases. Clinical studies indicate that loss-of-function ASGR1 (asialoglycoprotein receptor 1) is significantly associated with lower plasma cholesterol levels and reduces cardiovascular disease risk. However, the effect of ASGR1 on atherosclerosis remains incompletely understood; whether inhibition of ASGR1 causes liver injury remains controversial. Here, we comprehensively investigated the effects and the underlying molecular mechanisms of ASGR1 deficiency and overexpression on atherosclerosis and liver injury in mice. We engineered Asgr1 knockout mice (Asgr1-/-), Asgr1 and ApoE double-knockout mice (Asgr1-/-ApoE-/-), and ASGR1-overexpressing mice on an ApoE-/- background and then fed them different diets to assess the role of ASGR1 in atherosclerosis and liver injury. After being fed a Western diet for 12 weeks, Asgr1-/-ApoE-/- mice exhibited significantly decreased atherosclerotic lesion areas in the aorta and aortic root sections, reduced plasma VLDL (very-low-density lipoprotein) cholesterol and LDL (low-density lipoprotein) cholesterol levels, decreased VLDL production, and increased fecal cholesterol contents. Conversely, ASGR1 overexpression in ApoE-/- mice increased atherosclerotic lesions in the aorta and aortic root sections, augmented plasma VLDL cholesterol and LDL cholesterol levels and VLDL production, and decreased fecal cholesterol contents. Mechanistically, ASGR1 deficiency reduced VLDL production by inhibiting the expression of MTTP (microsomal triglyceride transfer protein) and ANGPTL3 (angiopoietin-like protein 3)/ANGPTL8 (angiopoietin-like protein 8) but increasing LPL (lipoprotein lipase) activity, increased LDL uptake by increasing LDLR (LDL receptor) expression, and promoted cholesterol efflux through increasing expression of LXRα (liver X receptor-α), ABCA1 (ATP-binding cassette subfamily A member 1), ABCG5 (ATP-binding cassette subfamily G member 5), and CYP7A1 (cytochrome P450 family 7 subfamily A member 1). These underlying alterations were confirmed in ASGR1-overexpressing ApoE-/- mice. In addition, ASGR1 deficiency exacerbated liver injury in Western diet-induced Asgr1-/-ApoE-/- mice and high-fat diet-induced but not normal laboratory diet-induced and high-fat and high-cholesterol diet-induced Asgr1-/- mice, while its overexpression mitigated liver injury in Western diet-induced ASGR1-overexpressing ApoE-/- mice. Inhibition of ASGR1 inhibits atherosclerosis in Western diet-fed ApoE-/- mice, suggesting that inhibiting ASGR1 may serve as a novel therapeutic strategy to treat atherosclerosis and cardiovascular diseases.

Neuroprotective agents ineffective in mitigating autonomic dysreflexia following experimental spinal cord injury

Background and objectivesLoss of supraspinal cardiovascular control and secondary damage following spinal cord injury (SCI) lead to cardiovascular dysfunction, where autonomic dysreflexia (AD), triggered by stimuli below the injury, can cause uncontrolled blood pressure (BP) surges, posing severe health risks such as stroke and seizures. While anti-inflammatory neuroprotective agents have been studied for motor recovery, their impact on cardiovascular function remains under investigated. The objective was to assess the efficacy of four clinically approved neuroprotective agents in promoting cardiovascular recovery following SCI. MethodsMale Wistar rats received contusion at the third thoracic spinal segment (T3). Fluoxetine, Glyburide, Valproic acid, and Indomethacin were first administered at 1 h or 6 h post-SCI, and every 12 h for two weeks thereafter. Four weeks following SCI, hemodynamics were measured at rest and during colorectal distension. Locomotor function was assessed prior to SCI and weekly for four weeks after SCI, using the Basso-Beattie-Bresnahan (BBB) locomotor scale. Quantitative comparisons of lesion area were performed. ResultsContrary to the published literature, Indomethacin and Valproic acid resulted in high morbidity and mortality rates 60 % and 40 % respectively) within 2–3 days of administration. Fluoxetine, and Glyburide were well-tolerated. There were no differences in change in systolic BP with colorectal distension compared to control i.e., all experimental groups experienced severe episodes of AD [F(6, 67) = 0.94, p = 0.47]. There was no significant difference in BBB scores in any experimental group compared to control [F(18, 252) = 0.3, p = 0.99]. No between-group differences were observed in tissue sparing at the lesion epicentre [F(6, 422) = 6.98, p = 0.29]. DiscussionDespite promising beneficial effect reported in previous studies, none of the drugs demonstrated improvement in cardiovascular or motor function. Indomethacin and Valproic acid exhibited unexpected high mortality at doses deemed safe in the literature. This emphasizes the necessity for reproducibility studies in pre-clinical research and underscores the importance of publishing null findings to guide future investigations.