Computational phenotyping of aberrant belief updating in individuals with schizotypal traits and schizophrenia.

BACKGROUND: Psychotic experiences are thought to emerge from various interrelated patterns of disrupted belief updating, such as overestimating the reliability of sensory information and misjudging task volatility. Yet, these substrates have never been jointly addressed under one computational framework and it is not clear to what degree they reflect trait-like computational patterns. METHODS: We introduced a novel hierarchical Bayesian model that describes how individuals simultaneously update their beliefs about the task volatility and noise in observation. We applied this model to data from a modified Predictive inference task in a test-retest study with healthy volunteers (N=45, 4 sessions) and examined the relationship between model parameters and schizotypal traits in a larger online sample (N = 437) and in a cohort of patients with schizophrenia (N = 100). RESULTS: The interclass correlations were moderate to high for model parameters and excellent for averaged belief trajectories and precision-weighted learning rates estimated through hierarchical Bayesian inference. We found that uncertainty about the task volatility was related to schizotypal traits and to positive symptoms in patients, when learning to gain rewards. In contrast, negative symptoms in patients were associated with more rigid beliefs about observational noise, when learning to avoid losses. CONCLUSION: These findings suggest that individuals with schizotypal traits across the psychosis continuum are less likely to learn or utilize higher-order statistical regularities of the environment and showcase the potential of clinically relevant computational phenotypes for differentiating symptom groups in a transdiagnostic manner.

Efficacy of topical application of corticosteroids in the remineralization of dental pulp tissue. A systematic review of the literature.

OBJECTIVES: The aim of this systematic review was to demonstrate the efficacy of topical application of corticosteroids in remineralization of dental pulp tissues to preserve their vitality and function. DATA, SOURCES AND STUDY SELECTION: An electronic search was performed using MEDLINE by PubMed, EMBASE, Web of Science (WOS), and Scopus databases. The inclusion criteria were in vitro studies that employed dental pulp tissue obtained from extracted healthy permanent human teeth and were subjected to topical administration of corticosteroids and evaluated tissue remineralization by performing any mineralization assay. A total of 11 studies were selected for inclusion. PRISMA guidelines were followed, and the methodological quality and risk of bias of the included studies were evaluated using the RoBDEMAT guidelines. Also, tables were designed for data extraction, including tissue mineralization and osteogenic differentiation as primary and secondary outcomes, respectively. CONCLUSIONS: Alizarin Red S (ARS) has been able to demonstrate a possible mineralizing power of corticosteroids, applied at an adequate dose. The up-regulation of Alkaline phosphatase (ALP), osteocalcin (OCN), osteopontin (OSP), sialophosphoprotein (DSPP), runt-related transcription factor 2 (RUNX2), collagen type 1 alpha 1(COL1α1) and dentin matrix protein 1 (DMP-1) induced the osteogenic/odontogenic differentiation of dental pulp stem cells (DPSCs). CLINICAL SIGNIFICANCE: Deep carious lesions treatment is still challenging in restorative dentistry. Some treatments have been focused on dental pulp tissue remineralization to maintain the function and vitality. After corticosteroids topical application, mineral deposition and osteogenic differentiation have been detected.

Relaxin-2 promotes osteoblastic differentiation mediated by epidermal growth factor and epidermal growth factor receptor signaling.

Loss of osteogenic differentiation potential of osteoblasts has been associated with the pathogenesis of osteoporosis. Thus, stimulation of osteoblastic differentiation is a therapeutic strategy for osteoporosis. Relaxin-2 is a peptide hormone with potent biological functions. However, the effects of Relaxin-2 in osteoblastic differentiation and osteoporosis have not been reported before. Here, we report a novel physiological role of Relaxin-2 in promoting osteoblastic differentiation and mineralization of MC3T3-E1 cells. Our results indicate that exposure to Relaxin-2 upregulated the expression, and elevated the activity of alkaline phosphatase (ALP) when MC3T3-E1 cells were cultured in osteogenic differentiation medium (OM). Additionally, Relaxin-2 upregulated the mRNA levels of osteocalcin (ocn), osteopontin (opn), and collagen type I alpha 1 (Col1a1). The alizarin red S staining assay revealed that Relaxin-2 promoted the mineralization of MC3T3-E1 cells. We also found that Relaxin-2 increased the expression of Runx-2 as well as the epidermal growth factor (EGF) and epidermal growth factor receptor (EGFR). Importantly, silencing of EGF abolished the effects of Relaxin-2 in osteoblastic differentiation and related gene expression. These findings suggest that Relaxin-2 stimulates osteogenic differentiation through activating EGF/EGFR signaling.

Transcriptomic Analysis Reveals the Heterogeneous Role of Conducting Films Upon Electrical Stimulation.

Central nervous system (CNS) injuries and neurodegenerative diseases have markedly poor prognoses and can result in permanent dysfunction due to the general inability of CNS neurons to regenerate. Differentiation of transplanted stem cells has emerged as a therapeutic avenue to regenerate tissue architecture in damaged areas. Electrical stimulation is a promising approach for directing the differentiation outcomes and pattern of outgrowth of transplanted stem cells, however traditional inorganic bio-electrodes can induce adverse effects such as inflammation. This study demonstrates the implementation of two organic thin films, a polymer/reduced graphene oxide nanocomposite (P(rGO)) and PEDOT:PSS, that have favorable properties for implementation as conductive materials for electrical stimulation, as well as an inorganic indium tin oxide (ITO) conductive film. Transcriptomic analysis reveals that electrical stimulation improves neuronal differentiation of SH-SY5Y cells on all three films, with the greatest effect for P(rGO). Unique material- and electrical stimuli-mediated effects are observed, associated with differentiation, cell-substrate adhesion, and translation. The work demonstrates that P(rGO) and PEDOT:PSS are highly promising organic materials for the development of biocompatible, conductive scaffolds that will enhance electrically-aided stem cell therapeutics for CNS injuries and neurodegenerative diseases.

CB1 Promotes Osteogenic Differentiation Potential of Periodontal Ligament Stem Cells by Enhancing Mitochondrial Transfer of Bone Marrow Mesenchymal Stem Cells.

OBJECTIVE: To reveal the role and mechanism of cannabinoid receptor 1 (CB1) and mitochondria in promoting osteogenic differentiation of periodontal ligament stem cells (PDLSCs) in the inflammatory microenvironment. METHODS: Bidirectional mitochondrial transfer was performed in bone mesenchymal stem cells (BMSCs) and PDLSCs. Laser confocal microscopy and quantitative flow cytometry were used to observe the mitochondrial transfer and quantitative mitochondrial transfer efficiency. Realtime reverse transcription polymerase chain reaction (RT-PCR) was employed to detect gene expression. Alkaline phosphatase (ALP) activity, alizarin red staining (ARS) and quantitative calcium ion analysis were used to evaluate the degree of osteogenic differentiation of PDLSCs. RESULTS: Bidirectional mitochondrial transfer was observed between BMSCs and PDLSCs. The indirect co-culture system could simulate intercellular mitochondrial transfer. Compared with the conditioned medium (CM) for BMSCs, that for HA-CB1 BMSCs could significantly enhance the mineralisation ability of PDLSCs. The mineralisation ability of PDLSCs could not be enhanced after removing the mitochondria in CM for HA-CB1 BMSCs. The expression level of HO-1, PGC-1α, NRF-1, ND1 and HK2 was significantly increased in HA-CB1 BMSCs. CONCLUSION: CM for HA-CB1 BMSCs could significantly enhance the damaged osteogenic differentiation ability of PDLSCs in the inflammatory microenvironment, and the mitochondria of CM played an important role. CB1 was related to the activation of the HO-1/PGC-1α/NRF-1 mitochondrial biogenesis pathway, and significantly increased the mitochondrial content in BMSCs.

Idiopathic Inflammatory Myopathies-associated Interstitial Lung Disease in Adults.

Idiopathic inflammatory myopathies (IIM) are a heterogeneous group of autoimmune diseases characterized by muscle involvement and various extramuscular manifestations. Interstitial lung disease (ILD) is one of the most common extramuscular manifestations of IIM and is associated with significant mortality and morbidity. The clinical phenotypes, treatment responses, and prognosis of IIM-ILD are significantly related to myositis-specific antibody (MSA) profiles, with some racial differences. The features associated with MSA in IIM-ILD could also be relevant to cases of ILD where MSA is present but does not meet the criteria for IIM. The anti-melanoma differentiation-associated gene 5 antibody is highly associated with rapidly progressive ILD (RP-ILD), especially in Asian populations, and with characteristic cutaneous manifestations, such as skin ulcers. Radiologically, ground-glass opacities, consolidations, and nonsegmental linear opacities were more predominant than reticular opacities and honeycombing. While the mortality rate is still around 30%, the prognosis can be improved with early intensive therapy with corticosteroids and multiple immunosuppressants. In contrast, anti-aminoacyl-tRNA synthetase (ARS) antibodies are associated with chronic ILD, although RP-ILD is also common. Patients with anti-ARS antibodies often show lung-predominant presentations, with subtle muscle and skin involvement. Radiologically, reticular opacities, with or without consolidation, are predominant and may progress to honeycombing over time. Combination therapy with corticosteroids and a single immunosuppressant is recommended to prevent relapses, which often lead to a decline in lung function and fatal long-term outcomes. Significant advances in immunology and genetics holds promise for fostering more personalized approaches to managing IIM-ILD.

Prostatic lineage differentiation from human embryonic stem cells through inducible expression of NKX3-1.

BACKGROUND: Understanding the lineage differentiation of human prostate not only is crucial for basic research on human developmental biology but also significantly contributes to the management of prostate-related disorders. Current knowledge mainly relies on studies on rodent models, lacking human-derived alternatives despite clinical samples may provide a snapshot at certain stage. Human embryonic stem cells can generate all the embryonic lineages including the prostate, and indeed a few studies demonstrate such possibility based on co-culture or co-transplantation with urogenital mesenchyme into mouse renal capsule. METHODS: To establish a stepwise protocol to obtain prostatic organoids in vitro from human embryonic stem cells, we apply chemicals and growth factors by mimicking the regulation network of transcription factors and signal transduction pathways, and construct cell lines carrying an inducible NKX3-1 expressing cassette, together with three-dimensional culture system. Unpaired t test was applied for statistical analyses. RESULTS: We first successfully generate the definitive endoderm, hindgut, and urogenital sinus cells. The embryonic stem cell-derived urogenital sinus cells express prostatic key transcription factors AR and FOXA1, but fail to express NKX3-1. Therefore, we construct NKX3-1-inducible cell line by homologous recombination, which is eventually able to yield AR, FOXA1, and NKX3-1 triple-positive urogenital prostatic lineage cells through stepwise differentiation. Finally, combined with 3D culture we successfully derive prostate-like organoids with certain structures and prostatic cell populations. CONCLUSIONS: This study reveals the crucial role of NKX3-1 in prostatic differentiation and offers the inducible NKX3-1 cell line, as well as provides a stepwise differentiation protocol to generate human prostate-like organoids, which should facilitate the studies on prostate development and disease pathogenesis.

Genetic structure and climate niche differentiation among populations of Leopardus geoffroyi.

Geoffroy's cat (Leopardus geoffroyi) is a small-sized felid native to South America. Given the species' distribution covering a wide variety of habitats, and the presence of high levels of anthropization in part of its range, it is possible that genetically differentiated groups exist and that they occupy different climatic niches. We assessed patterns of contemporary genetic diversity and structure in the species across most of its range, characterizing each inferred genetic group based on ecological niche models. We genotyped 11 microsatellites for 142 samples covering most of Geoffroy's cat distribution, and investigated patterns of genetic structure and diversity, applying spatial and nonspatial Bayesian clustering methods and a spatial principal component analysis. We created ecological niche models for each genetic cluster, evaluating whether these clusters occupy different climatic spaces and display differences in the suitability of different values of the climatic variables analyzed. We identified two genetic clusters, one in the north-northeast and the other in the south-southwest of the species' distribution. These clusters showed moderate FST values between them and differences in dispersal/genetic diversity. We found isolation-by-distance patterns globally and within each cluster. We observed lower expected heterozygosity compared with other studies and a north-south gradient in allelic richness. The southern cluster showed lower genetic variability and a more restricted climatic niche suggesting that this group is more vulnerable to the effects of the current context of climate change. Individuals from the southern genetic cluster are under different pressures, likely a product of the particularly dry habitat they occupy. Climatic variables associated with habitat suitability suggest the southern cluster has affinity for the arid and semiarid conditions present in its distribution. Conservation measures should consider the genetic structure observed and differences in climatic spaces to maintain the evolutionary potential of the species.

The potent osteo-inductive capacity of bioinspired brown seaweed-derived carbohydrate nanofibrous three-dimensional scaffolds.

This study aimed to investigate the osteo-inductive capacity of a fucoidan polysaccharide network derived from brown algae on human adipose-derived stem cells (HA-MSCs) for bone regeneration. The physiochemical properties of the scaffold including surface morphology, surface chemistry, hydrophilicity, mechanical stiffness, and porosity were thoroughly characterized. Both in vitro and in vivo measurements implied a superior cell viability, proliferation, adhesion, and osteo-inductive performance of obtained scaffolds compared to using specific osteogenic induction medium with increased irregular growth of calcium crystallites, which mimic the structure of natural bones. That scaffold was highly biocompatible and suitable for cell cultures. Various examinations, such as quantification of mineralization, alkaline phosphatase, gene expression, and immunocytochemical staining of pre-osteocyte and bone markers confirmed that HAD-MSCs differentiate into osteoblasts, even without an osteogenic induction medium. This study provides evidence for the positive relationship and synergistic effects between the physical properties of the decellularized seaweed scaffold and the chemical composition of fucoidan in promoting the osteogenic differentiation of HA-MSCs. Altogether, the natural matrices derived from brown seaweed offers a sustainable, cost-effective, non-toxic bioinspired scaffold and holds promise for future clinical applications in orthopedics.

Genetic diversity evaluation of Luculia yunnanensis, a vulnerable species endemic to Yunnan, Southwestern China based on morphological traits and EST-SSR markers.

Luculia yunnanensis is a vulnerable species endemic to Yunnan Province, Southwestern China, which has high ornamental value. Its wild population has not been fully protected and utilized for a long time, which is not conducive to the long-term stable development of this species. Genetic diversity assessment is the basis and prerequisite for the conservation of rare species. In this study, 21 phenotypic traits and 17 highly polymorphic EST-SSR markers were used to analyze the genetic diversity and genetic structure of 164 individuals from six L. yunnanensis populations. The coefficient of variation of 21 phenotypic traits ranged from 11.76% to 52.58% (mean=21.72%), and the coefficient of variation of 18 traits was less than 30%. The average values of Ne, I, Ho and He were 1.710, 0.619, 0.384, and 0.352, respectively. The genetic diversity of LLO (Ho = 0.476 and He = 0.426) and LCM (Ho = 0.424 and He = 0.381) populations in Lushui County was highest. The GDX populations (Ho = 0.335 and He = 0.269) isolated by Gaoligong Mountain had the lowest genetic diversity. The AMOVA results showed that 13.04% of the genetic variation was among populations and 86.96% was within populations. The average phenotypic differentiation coefficient of phenotypic traits among populations was 18.69%. The results of phenotypic and genetic variation analysis were consistent, indicating that the most of variation exists within population. Genetic structure, UPGMA clustering and PCA analysis results showed that the populations of L. yunnanensis had obvious geographical divisions, and the populations distributed in the southern region and distributed in the northern region of the Nujiang River clustered into one group respectively. Combining the results of phenotypic and molecular markers, we recommend that give priority to the protection of LLO, LCM and GDX population, in order to ensure the sustainable utilization of L. yunnanensis germplasm resources.

Construction of a predictive model for gastric cancer neuroaggression and clinical validation analysis: A single-center retrospective study.

BACKGROUND: This study investigated the construction and clinical validation of a predictive model for neuroaggression in patients with gastric cancer. Gastric cancer is one of the most common malignant tumors in the world, and neuroinvasion is the key factor affecting the prognosis of patients. However, there is a lack of systematic analysis on the construction and clinical application of its prediction model. This study adopted a single-center retrospective study method, collected a large amount of clinical data, and applied statistics and machine learning technology to build and verify an effective prediction model for neuroaggression, with a view to providing scientific basis for clinical treatment decisions and improving the treatment effect and survival rate of patients with gastric cancer. AIM: To investigate the value of a model based on clinical data, spectral computed tomography (CT) parameters and image omics characteristics for the preoperative prediction of nerve invasion in patients with gastric cancer. METHODS: A retrospective analysis was performed on 80 gastric cancer patients who underwent preoperative energy spectrum CT at our hospital between January 2022 and August 2023, these patients were divided into a positive group and a negative group according to their pathological results. Clinicopathological data were collected, the energy spectrum parameters of primary gastric cancer lesions were measured, and single factor analysis was performed. A total of 214 image omics features were extracted from two-phase mixed energy images, and the features were screened by single factor analysis and a support vector machine. The variables with statistically significant differences were included in logistic regression analysis to construct a prediction model, and the performance of the model was evaluated using the subject working characteristic curve. RESULTS: There were statistically significant differences in sex, carbohydrate antigen 199 expression, tumor thickness, Lauren classification and Borrmann classification between the two groups (all P < 0.05). Among the energy spectrum parameters, there were statistically significant differences in the single energy values (CT60-CT110 keV) at the arterial stage between the two groups (all P < 0.05) and statistically significant differences in CT values, iodide group values, standardized iodide group values and single energy values except CT80 keV at the portal vein stage between the two groups (all P < 0.05). The support vector machine model with the largest area under the curve was selected by image omics analysis, and its area under the curve, sensitivity, specificity, accuracy, P value and parameters were 0.843, 0.923, 0.714, 0.925, < 0.001, and c:g 2.64:10.56, respectively. Finally, based on the logistic regression algorithm, a clinical model, an energy spectrum CT model, an imaging model, a clinical + energy spectrum model, a clinical + imaging model, an energy spectrum + imaging model, and a clinical + energy spectrum + imaging model were established, among which the clinical + energy spectrum + imaging model had the best efficacy in diagnosing gastric cancer nerve invasion. The area under the curve, optimal threshold, Youden index, sensitivity and specificity were 0.927 (95%CI: 0.850-1.000), 0.879, 0.778, 0.778, and 1.000, respectively. CONCLUSION: The combined model based on clinical features, spectral CT parameters and imaging data has good value for the preoperative prediction of gastric cancer neuroinvasion.

DNA Methyltransferase Inhibition by RG108 Improves Stemness and Multipotential Differentiation of Human Adipose Tissue-derived Stem Cells.

Background: DNA methylation plays important roles in regulating various biological processes, including self-renewal, differentiation and regenerative capacity of stem cells. Previous studies have demonstrated that lineage-specific differentiation of mesenchymal stem cells can be promoted using nontoxic chromatin-modifying drugs. Objectives: Here we evaluated the impact of RG108, a known DNA methyltransferase inhibitor, on the expression of pluripotency genes in human adipose tissue-derived stem cells (hADSCs) and their proliferation and differentiation. Materials and Methods: Human ADSCs were isolated by collagenase treatment and characterized. Then, ADSCs were treated with 5 µM RG108 for four days. The control and RG108-treated cells were analyzed for the cell cycle progression, apoptosis and the expression of pluripotency genes. Also, ADSCs were cultured in adipogenic and osteogenic differentiation media for three weeks and were assessed by Oil Red O and Alizarin Red S staining and qPCR analysis. Results: We showed that RG108 treatment increased proliferation of hADSCs and upregulated the expression of pluripotency-related genes. Additionally, RG108 had a positive impact on the differentiation capability of ADSCs. This was evident through elevated levels of Oil Red O staining in the RG108 treatment group. Also, qPCR analysis showed the upregulation of some adipogenic and osteogenic markers by RG108. Conclusion: These findings indicate that pretreatment with RG108 improves the differentiation potential of ADSCs, probably making these cells more beneficial for cell therapy applications.

Integrin α2 is an early marker for osteoclast differentiation that contributes to key steps in osteoclastogenesis.

Introduction: Osteoclasts determine bone tissue turnover. Their increased activity causes osteoporosis, their dysfunction osteopetrosis. Methods and Results: Murine monocytic ER-Hoxb8 cells differentiate into OCs upon treatment with M-CSF and RANKL and upregulate the collagen-binding integrin α2ß1 distinctly earlier than other OC markers, such as the OC-associated receptor, OSCAR. Integrin α2ß1 promotes OC differentiation at multiple levels by stimulating differentiation-relevant genes, by regulating cell matrix adhesion and the formation of adhesion-promoting protrusions, and by the upregulation of proteins involved in precursor cell fusion. The two key factors in osteoclastogenesis, RANK and NFATc1, were essentially unaffected after knocking out the ITGA2 gene encoding integrin α2 subunit. However, compared to integrin α2ß1 expressing ER-Hoxb8 cells, ITGA2-deficient cells adhered differently with more branched filopodia and significantly longer tunneling nanotubes. Despite the higher number of fusion-relevant TNTs, they form fewer syncytia. They also resorb less hydroxyapatite, because integrin α2ß1 regulates expression of lacuna proteins necessary for bone matrix resorption. The impaired syncytia formation of ITGA2-deficient OC precursor cells also correlated with reduced gene activation of fusion-supporting DC-STAMP and with an almost abolished transcription of tetraspanin CD9. CD9 only partially colocalized with integrin α2ß1 in TNTs and filopodia of integrin α2ß1-expressing OC precursors. Discussion: Our findings define integrin α2ß1 as an early marker of OC differentiation.

Enzymatic activity of fibroblast activation protein-α is essential for TGF-ß1-induced fibroblastic differentiation of human periodontal ligament cells.

Human periodontal ligament cells (hPDLCs) contain multipotent postnatal stem cells that can differentiate into PDL fibroblasts, osteoblasts, and cementoblasts. Interaction between the extracellular environment and stem cells is an important factor for differentiation into other progenitor cells. To identify cell surface molecules that induce PDL fibroblastic differentiation, we developed a series of monoclonal antibodies against membrane/ECM molecules. One of these antibodies, an anti-PDL25 antibody, recognizes approximately a 100 kDa protein, and this antigenic molecule accumulates in the periodontal ligament region of tooth roots. By mass spectrometric analysis, we found that the antigenic molecule recognized by the anti-PDL25 antibody is fibroblast activation protein α (FAPα). The expression level of FAPα/PDL25 increased in TGF-ß1-induced PDL fibroblasts, and this protein was localized in the cell boundaries and elongated processes of the fibroblastic cells. Ectopic expression of FAPα induced fibroblastic differentiation. In contrast, expression of representative markers for PDL differentiation was decreased by knock down and antibody blocking of FAPα/PDL25. Inhibition of dipeptidyl peptidase activity by a potent FAPα inhibitor dramatically inhibited PDL fibroblastic marker expression but did not affect in cell proliferation and migration.

Integrated multi-omics analysis identifies features that predict human pluripotent stem cell-derived progenitor differentiation to cardiomyocytes.

Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) are advancing cardiovascular development and disease modeling, drug testing, and regenerative therapies. However, hPSC-CM production is hindered by significant variability in the differentiation process. Establishment of early quality markers to monitor lineage progression and predict terminal differentiation outcomes would address this robustness and reproducibility roadblock in hPSC-CM production. An integrated transcriptomic and epigenomic analysis assesses how attributes of the cardiac progenitor cell (CPC) affect CM differentiation outcome. Resulting analysis identifies predictive markers of CPCs that give rise to high purity CM batches, including TTN, TRIM55, DGKI, MEF2C, MAB21L2, MYL7, LDB3, SLC7A11, MAB21L2, and CALD1. Predictive models developed from these genes provide high accuracy in determining terminal CM purities at the CPC stage. Further, insights into mechanisms of batch failure and dominant non-CM cell types generated in failed batches are elucidated. Namely EMT, MAPK, and WNT signaling emerge as significant drivers of batch divergence, giving rise to off-target populations of fibroblasts/mural cells, skeletal myocytes, epicardial cells, and a non-CPC SLC7A11+ subpopulation. This study demonstrates how integrated multi-omic analysis of progenitor cells can identify quality attributes of that progenitor and predict differentiation outcomes, thereby improving differentiation protocols and increasing process robustness.

Biomarker-enhanced cardiovascular risk prediction in patients with cancer: a prospective cohort study.

BACKGROUND: Continuously improving cancer-specific survival puts a growing proportion of cancer patients at risk of major adverse cardiovascular events (MACE), but tailored tools for cardiovascular risk prediction remain unavailable. OBJECTIVES: To assess a broad panel of cardiovascular biomarkers and risk factors for the prediction of MACE and cardiovascular death in cancer patients. METHODS: In total, 2192 patients with newly diagnosed or recurrent cancer were followed prospectively for the occurrence of 2-year MACE and 5-year cardiovascular death. Univariable and multivariable risk models were fit to assess independent associations of cardiovascular risk factors and biomarkers with adverse outcomes, and a risk score was developed. RESULTS: Traditional cardiovascular risk factors and selected cancer types were linked to higher MACE risk. While levels of Lp(a), CRP, and GDF-15 did not associate with MACE, levels of ICAM-1, P-/E-/L-selectins, and NT-proBNP were independently linked to 2-year MACE risk. A clinical risk score was derived, assigning +1 point for male sex, smoking, and age of ≥60 years and +2 points for atherosclerotic disease, yielding a bootstrapped C-statistic of 0.76 (95% CI: 0.71-0.81) for the prediction of 2-year MACE. Implementation of biomarker data conferred improved performance (0.83, 95% CI: 0.78-0.88), with a simplified model showing similar performance (0.80, 95% CI: 0.74-0.86). The biomarker-enhanced and simplified prediction models achieved a C-statistic of 0.82 (95% CI: 0.71-0.93) and 0.74 (95% CI: 0.64-0.83) for the prediction of 5-year cardiovascular death. CONCLUSION: Biomarker-enhanced risk prediction strategies allow the identification of cancer patients at high risk of MACE and cardiovascular death. While external validation studies are ongoing, this first-of-its-kind risk score may provide the basis for personalized cardiovascular risk assessment across cancer entities.

Exploration of Genetic Variation and Population Structure in Bergenia ciliata for its Conservation Implications.

Bergenia ciliata (Haw.) Sternb. is a perennial medicinal herb distributed in Indian Himalayan Region (IHR). A total of eight populations of B. ciliata were collected from diverse locales of IHR, and 17 EST-SSR markers were used in this study. The present study revealed moderate genetic diversity at the locus level with the mean number of alleles (Na = 7.823), mean number effective of alleles (Ne = 3.375), mean expected heterozygosity (He = 0.570), and mean Shannon's diversity index (I = 1.264). The MSR (He = 0.543, I = 1.067) and DRJ populations (He = 0.309, I = 0.519) revealed the highest and lowest genetic diversity at the population level, respectively. AMOVA analysis showed that 81.76% of genetic variation was within populations, 10.55% was among populations, and 7.69% was among the regions. In addition, a moderate to high level of differentiation was found among the populations (FST = 0.182), which could be indicative of low to moderate gene flow (Nm = 0.669) in the B. ciliata populations. UPGMA and PCoA analysis revealed that eight populations could be differentiated into two groups, while the structure analysis of the 96 individuals differentiated into three groups. The Mantel test showed a positive relationship between genetic and geographical distance. The findings of this study will provide the development of conservation and germplasm management strategies for this valuable medicinal species.

Fractional differentiation based image enhancement for automatic detection of malignant melanoma.

Recent improvements in artificial intelligence and computer vision make it possible to automatically detect abnormalities in medical images. Skin lesions are one broad class of them. There are types of lesions that cause skin cancer, again with several types. Melanoma is one of the deadliest types of skin cancer. Its early diagnosis is at utmost importance. The treatments are greatly aided with artificial intelligence by the quick and precise diagnosis of these conditions. The identification and delineation of boundaries inside skin lesions have shown promise when using the basic image processing approaches for edge detection. Further enhancements regarding edge detections are possible. In this paper, the use of fractional differentiation for improved edge detection is explored on the application of skin lesion detection. A framework based on fractional differential filters for edge detection in skin lesion images is proposed that can improve automatic detection rate of malignant melanoma. The derived images are used to enhance the input images. Obtained images then undergo a classification process based on deep learning. A well-studied dataset of HAM10000 is used in the experiments. The system achieves 81.04% accuracy with EfficientNet model using the proposed fractional derivative based enhancements whereas accuracies are around 77.94% when using original images. In almost all the experiments, the enhanced images improved the accuracy. The results show that the proposed method improves the recognition performance.

Development of electrospun electroactive polyurethane membranes for bone repairing.

To fabricate electroactive fibrous membranes and provide simulated bioelectric micro-environment for bone regeneration mimicking nature periosteum, a series of electroactive polyurethanes (PUAT) were synthesized using amino-capped aniline trimers (AT) and lysine derivatives as chain extenders. These PUAT were fabricated into fibrous membranes as guided bone tissue regeneration membranes (GBRMs) via electrospinning. The ultraviolet-visible (UV-vis) absorption spectroscopy and cyclic voltammetry (CV) of PUAT copolymers showed that the electroactive PUAT fibrous membranes had good electroactivity. Besides, the introduction of AT significantly improved the hydrophobicity and thermal stability of PUAT fibrous membranes and decreased the degradation rate of PUAT fibers in vitro. With the increasing content of AT incorporated into copolymers, the tensile strength and Young's modulus of PUAT fibrous membranes increased from 4 MPa (PUAT0) to 15 MPa (PUAT10) and from 2.1 MPa (PUAT0) to 18 MPa (PUAT10), respectively. The cell morphology and proliferation of rat mesenchymal stem cells (rMSCs) on PUAT fibers indicated that the incorporation of AT enhanced the cell attachment and proliferation. Moreover, the expression levels of OCN, CD31, and VEGF secreted by rMSCs on PUAT fibers increased with the increasing content of AT. In conclusion, an electroactive polyurethane fibrous membrane mimicking natural periosteum was prepared via electrospinning and showed good potential application in guiding bone tissue regeneration.

Osteogenic potency of dental stem cell-composite scaffolds in an animal cleft palate model.

Objective: To evaluate the osteogenic potency of stem cells isolated from human exfoliated deciduous teeth (SHED) in polycaprolactone with gelatin surface modification (PCL-GE) and poly (lactic-co-glycolic acid)-bioactive glass composite (PLGA-bioactive glass (BG)) scaffolds after implantation in a rat cleft model. Methods: Cleft palate-like lesions were induced in Sprague-Dawley rats by extracting the right maxillary first molars and drilling the intact alveolar bone. Rats were then divided into five groups: Control, PCL-GE, PCL-GE-SHED, PLGA-BG, and PLGA-BG-SHED, and received corresponding composite scaffolds with/without SHED at the extraction site. Tissue samples were collected at 2, 3, and 6 months post-implantation (4 rats per group). Gross and histological analyses were conducted to assess osteoid or bone formation. Immunohistochemistry for osteocalcin and human mitochondria was performed to evaluate bone components and human stem cell viability in the tissue. Results: Bone tissue formation was observed in the PCL-GE and PLGA-BG groups compared to the control, where no bone formation occurred. PLGA-BG scaffolds demonstrated greater bone regeneration potential than PCL-GE over 2-6 months. Additionally, scaffolds with SHED accelerated bone formation compared to scaffolds alone. Osteocalcin expression was detected in all rats, and positive immunoreactivity for human mitochondria was observed in the regenerated bone tissue with PCL-GE-SHED and PLGA-BG-SHED. Conclusion: PCL-GE and PLGA-BG composite scaffolds effectively repaired and regenerated bone tissue in rat cleft palate defects. Moreover, scaffolds supplemented with SHED exhibited enhanced osteogenic potency. Clinical significance: PCL-GE and PLGA-BG scaffolds, augmented with SHED, emerge as promising biomaterial candidates for addressing cleft repair and advancing bone tissue engineering endeavors.