Synthesis and real-time characterization of self-healing, injectable, fast-gelling hydrogels based on alginate multi-reducing end polysaccharides (MREPs).

Polysaccharide-based hydrogels are promising for many biomedical applications including drug delivery, wound healing, and tissue engineering. We illustrate herein self-healing, injectable, fast-gelling hydrogels prepared from multi-reducing end polysaccharides, recently introduced by the Edgar group. Simple condensation of reducing ends from multi-reducing end alginate (M-Alg) with amines from polyethylene imine (PEI) in water affords a dynamic, hydrophilic polysaccharide network. Trace amounts of acetic acid can accelerate the gelation time from hours to seconds. The fast-gelation behavior is driven by rapid Schiff base formation and strong ionic interactions induced by acetic acid. A cantilever rheometer enables real-time monitoring of changes in viscoelastic properties during hydrogel formation. The reversible nature of these crosslinks (imine bonds, ionic interactions) provides a hydrogel with low toxicity in cell studies as well as self-healing and injectable properties. Therefore, the self-healing, injectable, and fast-gelling M-Alg/PEI hydrogel holds substantial promise for biomedical, agricultural, controlled release, and other applications.

Reductive amination of oxidized hydroxypropyl cellulose with ω-aminoalkanoic acids as an efficient route to zwitterionic derivatives.

Zwitterionic polymers, with their equal amounts of cationic and anionic functional groups, have found widespread utility including as non-fouling coatings, hydrogel materials, stabilizers, antifreeze materials, and drug carriers. Polysaccharide-derived zwitterionic polymers are attractive because of their sustainable origin, potential for lower toxicity, and possible biodegradability, but previous methods for synthesis of zwitterionic polysaccharide derivatives have been limited in terms of flexibility and attainable degree of substitution (DS) of charged entities. We report herein successful design and synthesis of zwitterionic polysaccharide derivatives, in this case based on cellulose, by reductive amination of oxidized 2-hydroxypropyl cellulose (Ox-HPC) with ω-aminoalkanoic acids. Reductive amination products could be readily obtained with DS(cation) (= DS(anion)) up to 1.6. Adduct hydrophilic/hydrophobic balance (amphiphilicity) can be influenced by selecting the appropriate chain length of the ω-aminoalkanoic acid. This strategy is shown to produce a range of amphiphilic, water-soluble, moderately high glass transition temperature (Tg) polysaccharide derivatives in just a couple of efficient steps from commercially available building blocks. The adducts were evaluated as crystallization inhibitors. They are strong inhibitors of crystallization even for the challenging, poorly soluble, fast-crystallizing prostate cancer drug enzalutamide, as supported by surface tension and Flory-Huggins interaction parameter results.

Correlating Young's Modulus with High Thermal Conductivity in Organic Conjugated Small Molecules.

Attaining elevated thermal conductivity in organic materials stands as a coveted objective, particularly within electronic packaging, thermal interface materials, and organic matrix heat exchangers. These applications have reignited interest in researching thermally conductive organic materials. The understanding of thermal transport mechanisms in these organic materials is currently constrained. This study concentrates on N, N'-dioctyl-3,4,9,10-perylenedicarboximide (PTCDI-C8), an organic conjugated crystal. A correlation between elevated thermal conductivity and augmented Young's modulus is substantiated through meticulous experimentation. Achievement via employing the physical vapor transport method, capitalizing on the robust C═C covalent linkages running through the organic matrix chain, bolstered by π-π stacking and noncovalent affiliations that intertwine the chains. The coexistence of these dynamic interactions, alongside the perpendicular alignment of PTCDI-C8 molecules, is confirmed through structural analysis. PTCDI-C8 thin film exhibits an out-of-plane thermal conductivity of 3.1 ± 0.1 W m-1 K-1, as determined by time-domain thermoreflectance. This outpaces conventional organic materials by an order of magnitude. Nanoindentation tests and molecular dynamics simulations elucidate how molecular orientation and intermolecular forces within PTCDI-C8 molecules drive the film's high Young's modulus, contributing to its elevated thermal conductivity. This study's progress offers theoretical guidance for designing high thermal conductivity organic materials, expanding their applications and performance potential.

Crocetin inhibits choroidal neovascularization in both in vitro and in vivo models.

Choroidal neovascularization (CNV) is the primary pathogenic process underlying wet age-related macular degeneration, leading to severe vision loss. Despite current anti-vascular endothelial growth factor (VEGF) therapies, several limitations persist. Crocetin, a major bioactive constituent of saffron, exhibits multiple pharmacological activities, yet its role and mechanism in CNV remain unclear. Here, we investigated the potential effects of crocetin on CNV using in vitro and in vivo models. In human umbilical vein endothelial cells, crocetin demonstrated inhibition of VEGF-induced cell proliferation, migration, and tube formation in vitro, as assessed by CCK-8 and EdU assays, transwell and scratch assays, and tube formation analysis. Additionally, crocetin suppressed choroidal sprouting in ex vivo experiments. In the human retinal pigment epithelium (RPE) cell line ARPE-19, crocetin attenuated cobalt chloride-induced hypoxic cell injury, as evidenced by CCK-8 assay. As evaluated by quantitative PCR and Western blot assay, it also reduced hypoxia-induced expression of VEGF and hypoxia-inducible factor 1α (HIF-1α), while enhancing zonula occludens-1 expression. In a laser-induced CNV mouse model, intravitreal administration of crocetin significantly reduced CNV size and suppressed elevated expressions of VEGF, HIF-1α, TNFα, IL-1ß, and IL-6. Moreover, crocetin treatment attenuated the elevation of phospho-S6 in laser-induced CNV and hypoxia-induced RPE cells, suggesting its potential anti-angiogenic effects through antagonizing the mechanistic target of rapamycin complex 1 (mTORC1) signaling. Our findings indicate that crocetin may hold promise as an effective drug for the prevention and treatment of CNV.

A predictive model for disease severity among COVID-19 elderly patients based on IgG subtypes and machine learning.

Objective: Due to the increased likelihood of progression of severe pneumonia, the mortality rate of the elderly infected with coronavirus disease 2019 (COVID-19) is high. However, there is a lack of models based on immunoglobulin G (IgG) subtypes to forecast the severity of COVID-19 in elderly individuals. The objective of this study was to create and verify a new algorithm for distinguishing elderly individuals with severe COVID-19. Methods: In this study, laboratory data were gathered from 103 individuals who had confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection using a retrospective analysis. These individuals were split into training (80%) and testing cohort (20%) by using random allocation. Furthermore, 22 COVID-19 elderly patients from the other two centers were divided into an external validation cohort. Differential indicators were analyzed through univariate analysis, and variable selection was performed using least absolute shrinkage and selection operator (LASSO) regression. The severity of elderly patients with COVID-19 was predicted using a combination of five machine learning algorithms. Area under the curve (AUC) was utilized to evaluate the performance of these models. Calibration curves, decision curves analysis (DCA), and Shapley additive explanations (SHAP) plots were utilized to interpret and evaluate the model. Results: The logistic regression model was chosen as the best machine learning model with four principal variables that could predict the probability of COVID-19 severity. In the training cohort, the model achieved an AUC of 0.889, while in the testing cohort, it obtained an AUC of 0.824. The calibration curve demonstrated excellent consistency between actual and predicted probabilities. According to the DCA curve, it was evident that the model provided significant clinical advantages. Moreover, the model performed effectively in an external validation group (AUC=0.74). Conclusion: The present study developed a model that can distinguish between severe and non-severe patients of COVID-19 in the elderly, which might assist clinical doctors in evaluating the severity of COVID-19 and reducing the bad outcomes of elderly patients.

Organic Conjugated Small Molecules with High Thermal Conductivity as an Effective Coupling Layer for Heat Transfer.

As the features of electronics are miniaturized, the need for interfacial thermal coupling layers to enhance their thermal transfer efficiency and improve device performance becomes critical. Organic conjugated small molecules possess a unique combination of periodic crystal structures and conjugated units with π electrons, resulting in notable thermal conductivities and molecular structure orientation that facilitates directed heat transfer. Nevertheless, there is a noticeable gap in literatures regarding the thermal properties of organic conjugated small molecules and their potential applications in nanoscale thermal management. Herein, we report the fabrication of high-quality thin films of organic conjugated small molecules. The result reveals that the 2D organic conjugated small molecule thin films exhibit a high cross-plane thermal conductivity of 3.2 W/m K. The increased thermal conductivity is attributed to the well-organized lattice structure and existence of π-electrons induced by conjugated systems. The studied conjugated small molecules engage in π-π stacking interactions with carbon materials and efficiently exchange energy with electrons in metals, promoting rapid interfacial heat transfer. These molecules act as coupling layers, significantly enhancing thermal transfer efficiency between graphite-based thermal pads and copper heat sinks. This pioneering research represents the inaugural investigation of the thermal performance of conjugated organic small molecules. These findings highlight the potential of conjugated small molecules as thermal coupling layers, offering tunable combinations of desirable properties.

Creating Biomimetic Central-Radial Skeletons with Efficient Mass Adsorption and Transport.

Porous skeletons play a crucial role in various applications. Their fundamental significance stems from their remarkable surface area and capacity to enhance mass adsorption and transport. Freeze-casting is a commonly utilized methodology for the production of porous skeletons featuring vertically aligned channels. Nevertheless, the resultant single-oriented skeleton displays anisotropic mass transfer characteristics and suboptimal mechanical properties. Our investigation was motivated by the intricate microstructures observed in botanical organisms, leading us to devise an advanced freeze-casting methodology. A novel central-radial skeleton with significantly enhanced capabilities has been successfully engineered. The central-radial architecture demonstrates superior refinement and uniformity in its pore structure, featuring an axial mass transfer axis and meticulously arranged radial channels. This microstructure endows the porous skeleton with a higher compression resilience, superior adsorption rate, and structural maintenance capacity. Through a rigorous examination of the thermal conductivity of skeleton-filled composites coupled with comprehensive COMSOL simulations, the exceptional characteristics of this unique structural arrangement have been definitively ascertained. Furthermore, the efficacy of implementing this skeleton in chip cooling and photothermal conversion has been convincingly substantiated. Our pioneering method of microstructure preparation, employing freeze-casting, holds immense potential in expanding its applicability and inspiring innovative concepts for the advancement of novel structures.

High expression of IL6 and decrease in immune cells in COVID-19 patients combined with myocardial injury.

Purpose: Myocardial injury, as a serious complication of coronavirus disease-2019 (COVID-19), increases the occurrence of adverse outcomes. Identification of key regulatory molecules of myocardial injury may help formulate corresponding treatment strategies and improve the prognosis of COVID-19 patients. Methods: Gene Set Enrichment Analysis (GSEA) was conducted to identify co-regulatory pathways. Differentially expressed genes (DEGs) in GSE150392 and GSE169241 were screened and an intersection analysis with key genes of the co-regulatory pathway was conducted. A protein-protein interaction (PPI) network was constructed to screen for key regulatory genes. Preliminarily screened genes were verified using other datasets to identify genes with consistent expression. Based on the hierarchical cluster, we divided the patients from GSE177477 into high- and low-risk groups and compared the proportion of immune cells. A total of 267 COVID-19 patients from the Zhejiang Provincial Hospital of Chinese Medicine from December 26, 2022, to January 11, 2023, were enrolled to verify the bioinformatics results. Univariate and multivariate analyses were performed to analyze the risk factors for myocardial injury. According to high-sensitivity troponin (hsTnI) levels, patients with COVID-19 were divided into high- and low-sensitivity groups, and interleukin 6 (IL6) expression and lymphocyte subsets were compared. Patients were also divided into high and low groups according to the IL6 expression, and hsTnI levels were compared. Results: Interleukin signaling pathway and GPCR ligand binding were shown to be co-regulatory pathways in myocardial injury associated with COVID-19. According to the hierarchical cluster analysis of seven genes (IL6, NFKBIA, CSF1, CXCL1, IL1R1, SOCS3, and CASP1), patients with myocardial injury could be distinguished from those without myocardial injury. Age, IL6 levels, and hospital stay may be factors influencing myocardial injury caused by COVID-19. Compared with COVID-19 patients without myocardial injury, the levels of IL6 in patients with myocardial injury increased, while the number of CD4+ T cells, CD8+ T cells, B cells, and NK cells decreased (P<0.05). The hsTnI levels in COVID-19 patients with high IL6 levels were higher than those in patients with low IL6 (P<0.05). Conclusions: The COVID-19 patients with myocardial injury had elevated IL6 expression and decreased lymphocyte counts. IL6 may participate in myocardial injury through the interleukin signaling pathway.

Analysis of long noncoding RNAs in the aqueous humor of wet age-related macular degeneration.

Wet age-related macular degeneration (wAMD) is the main cause of irreversible blindness in the elderly, and its pathogenesis is still not fully understood. Long non-coding RNAs (lncRNAs) participated in the pathogenesis of a number of neovascular diseases, but their role in wAMD is less known. In order to reveal the potential role of lncRNAs in wAMD, we used high-throughput sequencing to assess lncRNAs and mRNAs expression profile in the aqueous humor of patients with wAMD and of patients with age-related cataract as control. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed to identify the potential biological functions and signaling pathways of RNA. A coding-non-coding gene co-expression (CNC) network was constructed to identify the interaction of lncRNAs and mRNAs. Quantitative PCR was used to validate the expression of selected lncRNAs. We identified 1071 differentially expressed lncRNAs and 3658 differentially expressed mRNAs in patients with wAMD compared to controls. GO and KEGG analyses suggested that differentially expressed lncRNAs-coexpressed mRNAs were mainly enriched in Rab GTPase binding, GTPase activation, RAS signaling pathway and autophagy. The top 100 differentially expressed genes were selected to build the CNC network, which could be connected by 416 edges. LncRNAs are differentially expressed in the aqueous humor of patients with wAMD and they are involved in several pathogenetic pathways. These dysregulated lncRNAs and their target genes could represent promising therapeutic targets in wAMD.

Synthesis and Characterization of Multi-Reducing-End Polysaccharides.

Site-specific modification is a great challenge for polysaccharide scientists. Chemo- and regioselective modification of polysaccharide chains can provide many useful natural-based materials and help us illuminate fundamental structure-property relationships of polysaccharide derivatives. The hemiacetal reducing end of a polysaccharide is in equilibrium with its ring-opened aldehyde form, making it the most uniquely reactive site on the polysaccharide molecule, ideal for regioselective decoration such as imine formation. However, all natural polysaccharides, whether they are branched or not, have only one reducing end per chain, which means that only one aldehyde-reactive substituent can be added. We introduce a new approach to selective functionalization of polysaccharides as an entrée to useful materials, appending multiple reducing ends to each polysaccharide molecule. Herein, we reduce the approach to practice using amide formation. Amine groups on monosaccharides such as glucosamine or galactosamine can react with carboxyl groups of polysaccharides, whether natural uronic acids like alginates, or derivatives with carboxyl-containing substituents such as carboxymethyl cellulose (CMC) or carboxymethyl dextran (CMD). Amide formation is assisted using the coupling agent 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM). By linking the C2 amines of monosaccharides to polysaccharides in this way, a new class of polysaccharide derivatives possessing many reducing ends can be obtained. We refer to this class of derivatives as multi-reducing-end polysaccharides (MREPs). This new family of derivatives creates the potential for designing polysaccharide-based materials with many potential applications, including in hydrogels, block copolymers, prodrugs, and as reactive intermediates for other derivatives.

Cuproptosis-related gene FDX1 as a prognostic biomarker for kidney renal clear cell carcinoma correlates with immune checkpoints and immune cell infiltration.

Background: Kidney renal clear cell carcinoma (KIRC) is not sensitive to radiotherapy and chemotherapy, and only some KIRC patients can benefit from immunotherapy and targeted therapy. Cuproptosis is a new mechanism of cell death, which is closely related to tumor progression, prognosis and immunity. The identification of prognostic markers related to cuproptosis in KIRC may provide targets for treatment and improve the prognosis of KIRC patients. Methods: Ten cuproptosis-related genes were analyzed for differential expression in KIRC-TCGA and a prognostic model was constructed. Nomogram diagnostic model was used to screen independent prognostic molecules. The screened molecules were verified in multiple datasets (GSE36895 and GSE53757), and in KIRC tumor tissues by RT-PCR and immunohistochemistry (IHC). Clinical correlation of cuproptosis-related independent prognostic molecules was analyzed. According to the molecular expression, the two groups were divided into high and low expression groups, and the differences of immune checkpoint and tumor infiltrating lymphocytes (TILs) between the two groups were compared by EPIC algorithm. The potential Immune checkpoint blocking (ICB) response of high and low expression groups was predicted by the "TIDE" algorithm. Results: FDX1 and DLAT were protective factors, while CDKN2A was a risk factor. FDX1 was an independent prognostic molecule by Nomogram, and low expressed in tumor tissues compared with adjacent tissues (p < 0.05). FDX1 was positively correlated with CD274, HAVCR2, PDCD1LG2, and negatively correlated with CTLA4, LAG3, and PDCD1. The TIDE score of low-FDX1 group was higher than that of high-FDX1 group. The abundance of CD4+ T cells, CD8+ T cells and Endothelial cells in FDX1-low group was lower than that in FDX1-high group (p < 0.05). Conclusion: FDX1, as a key cuproptosis-related gene, was also an independent prognostic molecule of KIRC. FDX1 might become an interesting biomarker and potential therapeutic target for KIRC.

Oxidized hydroxypropyl cellulose/carboxymethyl chitosan hydrogels permit pH-responsive, targeted drug release.

Polysaccharide-based Schiff base hydrogels have promise for drug delivery, tissue engineering, and many other applications due to their reversible imine bond crosslinks. We describe herein pH-responsive, injectable, and self-healing hydrogels prepared by reacting oxidized hydroxypropyl cellulose (Ox-HPC) with carboxymethyl chitosan (CMCS). Simple combination of ketones from Ox-HPC side chains with amines from CMCS in water provides a dynamic, hydrophilic polysaccharide network. The reversible nature of these imine bonds in the presence of water provides a hydrogel with injectable and self-healing properties. Phenylalanine as a model amine-containing drug was linked by imine bonds to Ox-HPC within the hydrogel. Phenylalanine release was faster at the pH of the extracellular space around tumors (6.8) than in normal tissues (7.4), a surprising degree of pH sensitivity. Therefore, Ox-HPC/CMCS hydrogels show promise as drug carriers that may selectively target even slightly lower pH environments like the extracellular milieu around cancer cells.

T lymphocyte subsets and PD-1 expression on lymphocytes in peripheral blood of patients with non-small cell lung cancer.

The incidence rate and mortality rate of lung cancer (LC) are very high. This study aimed to analyze the T lymphocyte subsets and programmed death-1 (PD-1) expression on lymphocytes in the peripheral blood of non-small cell lung cancer (NSCLC) patients and explore whether there were changes in cellular immunity in NSCLC. Peripheral blood samples were collected from newly diagnosed NSCLC patients and healthy individuals. The T lymphocyte subsets and PD-1 expression were evaluated using flow cytometry. Single-sample gene set enrichment analysis (ssGSEA) was performed to explore the correlations of PD-1 expression with infiltration patterns for tumor-infiltrating T immune cells. By flow cytometry, two populations of lymphocytes in NSCLC patients were observed. Apart from a population of normal volume lymphocytes (Lym1), the other population had larger volume and more particles (Lym2). Compared with the healthy group, the proportion of CD4+ T cells and PD-1 expression on Lym1 was higher, and that of CD8+ T cells was lower in the NSCLC group. In the NSCLC group, the proportions of CD3+ T cells, CD8+ T cells, CD4+CD8+ T (DPT) cells, and PD-1 expression were higher on Lym2 than those on Lym1 (P < .05). ssGSEA showed that tumor infiltrating immune T cells were positively correlated with PD-1 expression. The PD-1 expression on lymphocytes increased in recurrent patients who treated with PD-1 inhibitor. Lym2 may be tumor-infiltrating lymphocytes (TILs) which upregulated PD-1 expression in NSCLC. PD-1 expression on lymphocytes may be used as a recurrence indicator for NSCLC patients treated with PD-1 inhibitors.

Topical application of an irreversible small molecule inhibitor of lysyl oxidases ameliorates skin scarring and fibrosis.

Scarring is a lifelong consequence of skin injury, with scar stiffness and poor appearance presenting physical and psychological barriers to a return to normal life. Lysyl oxidases are a family of enzymes that play a critical role in scar formation and maintenance. Lysyl oxidases stabilize the main component of scar tissue, collagen, and drive scar stiffness and appearance. Here we describe the development and characterisation of an irreversible lysyl oxidase inhibitor, PXS-6302. PXS-6302 is ideally suited for skin treatment, readily penetrating the skin when applied as a cream and abolishing lysyl oxidase activity. In murine models of injury and fibrosis, topical application reduces collagen deposition and cross-linking. Topical application of PXS-6302 after injury also significantly improves scar appearance without reducing tissue strength in porcine injury models. PXS-6302 therefore represents a promising therapeutic to ameliorate scar formation, with potentially broader applications in other fibrotic diseases.

Structural and functional retinal changes in patients with type 2 diabetes without diabetic retinopathy.

OBJECTIVE: The characteristics of the early changes in preclinical diabetic retinopathy (DR) are poorly known. This study aimed to analyse the changes in the structure and function of the fundus in diabetic patients without diabetic retinopathy (NDR). METHODS: This prospective study enrolled patients with type 2 diabetes and healthy controls from April to December 2020. Retinal sensitivity was measured by microperimetry. The peripapillary retinal nerve fibre layer (p-RNFL) thickness, macular retinal thickness, and retinal volume were measured by optical coherence tomography (OCT). The vessel density (VD) and perfusion density (PD) of the peripapillary area, as well as the foveal avascular zone (FAZ) area, FAZ perimeter, and FAZ circularity, were measured by optical coherence tomographic angiography (OCTA). RESULTS: A total of 71 cases (100 eyes) were enrolled in the study, including 34 cases (51 eyes) in the NDR group and 37 cases (49 eyes) in the control group. The mean retinal sensitivity was lower in the NDR group than in the control group for all sectors (all p < .001). Compared with controls, the NDR group showed thinner p-RNFL in the T sector (76.24 ± 14.29 vs. 85.47 ± 19.66 µm, p = .035). The NDR group had a thinner retina in the N2 sector (304.55 ± 16.07 vs. 312.02 ± 12.30 µm, p = .010). The PD of DCP was lower in the N2 sector in the NDR group (44.92 ± 11.77 vs. 50.27 ± 6.37%, p = .044). The VD was higher in the NDR group in RPCP-S/N/I, and the PD was higher in the RPCP-S/N (all p < .05). The frequencies of perifoveal capillary drop-out, notched or punched out borders of the superficial FAZ, and loss of smooth contour were all higher in the NDR group (all p < .05). CONCLUSION: The structure (p-RNFL thickness, VD, and PD) and function (retinal sensitivity) display some changes in diabetic patients even if they had not been found to have DR.Key messagesDecreased retinal sensitivity was observed in diabetic patients before the onset of diabetic retinopathy.Compared with the control group, we found the changes in vessel density or perfusion density in a certain area, whether in SCP, DCP, or RPCP in the NDR group.Before the onset of diabetic retinopathy, the structure and function of the retina in diabetic patients had changed.

Pan-Lysyl Oxidase Inhibitor PXS-5505 Ameliorates Multiple-Organ Fibrosis by Inhibiting Collagen Crosslinks in Rodent Models of Systemic Sclerosis.

Systemic sclerosis (SSc) is characterised by progressive multiple organ fibrosis leading to morbidity and mortality. Lysyl oxidases play a vital role in the cross-linking of collagens and subsequent build-up of fibrosis in the extracellular matrix. As such, their inhibition provides a novel treatment paradigm for SSc. A novel small molecule pan-lysyl oxidase inhibitor, PXS-5505, currently in clinical development for myelofibrosis treatment was evaluated using in vivo rodent models resembling the fibrotic conditions in SSc. Both lysyl oxidase and lysyl oxidase-like 2 (LOXL2) expression were elevated in the skin and lung of SSc patients. The oral application of PXS-5505 inhibited lysyl oxidase activity in the skin and LOXL2 activity in the lung. PXS-5505 exhibited anti-fibrotic effects in the SSc skin mouse model, reducing dermal thickness and α-smooth muscle actin. Similarly, in the bleomycin-induced mouse lung model, PXS-5505 reduced pulmonary fibrosis toward normal levels, mediated by its ability to normalise collagen/elastin crosslink formation. PXS-5505 also reduced fibrotic extent in models of the ischaemia-reperfusion heart, the unilateral ureteral obstruction kidney, and the CCl4-induced fibrotic liver. PXS-5505 consistently demonstrates potent anti-fibrotic efficacy in multiple models of organ fibrosis relevant to the pathogenesis of SSc, suggesting that it may be efficacious as a novel approach for treating SSc.

Optimization of Effective Thermal Conductivity of Thermal Interface Materials Based on the Genetic Algorithm-Driven Random Thermal Network Model.

Polymer-based thermal interface materials (TIMs) are indispensable for reducing the thermal contact resistance of high-power electronic devices. Owing to the low thermal conductivity of polymers, adding multiscale dispersed particles with high thermal conductivity is a common approach to enhance the effective thermal conductivity. However, optimizing multiscale particle matching, including particle size distribution and volume fraction, for improving the effective thermal conductivity has not been achieved. In this study, three kinds of filler-loaded samples were prepared, and the effective thermal conductivity and average particle size of the samples were tested. The finite element model (FEM) and the random thermal network model (RTNM) were applied to predict the effective thermal conductivity of TIMs. Compared with the FEM, the RTNM achieves higher accuracy with an error less than 5% and higher computational efficiency in predicting the effective thermal conductivity of TIMs. Combining the abovementioned advantages, we designed a set of procedures for an RTNM driven by the genetic algorithm (GA). The procedure can find multiscale particle-matching ways to achieve the maximum effective thermal conductivity under a given filler load. The results show that the samples with 40 vol %, 50 vol %, and 60 vol % filler loading have similar particle size distribution and volume fractions when the effective thermal conductivity reaches the highest. It should be emphasized that the optimized effective thermal conductivity can be improved obviously with the increase in the volume fraction of the filler loading. The high efficiency and accuracy of the procedure show great potential for the future design of high-efficiency TIMs.

A New Index AGR-PLR Score (APS) for Patients with Esophageal Squamous Cell Carcinoma Undergoing Radical Esophagectomy.

PURPOSE: Biomarkers of the systemic inflammatory response and nutritional-related indicators have been used to assess the host anti-tumor immune response and predict prognosis in esophageal squamous cell carcinoma (ESCC). However, a new indicator system combining platelet-to-lymphocyte ratio (PLR) and albumin-globulin ratio (AGR), AGR-PLR score (APS), has not yet been evaluated for the prognosis prediction among ESCC patients. METHODS: A retrospective analysis was performed, including 633 patients with ESCC, comprising 450 in the training cohort and 183 in the validation cohort. RESULTS: In this study, we found that the overall survival time among patients with an APS of 2 was significantly shorter than that among patients with an APS of 1, and the survival time of patients with an APS of 1 was significantly shorter than that of patients with an APS of 0. Multivariate analysis showed that the APS was an independent prognostic factor for patients with ESCC. The APS demonstrated better prognostic accuracy and effectiveness for ESCC patients than either PLR or AGR alone. In addition, a new prediction nomogram was established according to tumor grade, APS, and tumor, node, metastasis (TNM) stage. Compared with the traditional 8th version of TNM staging system, this nomogram demonstrated improved sensitivity and specificity for the prediction of 3- and 5-year survival. CONCLUSION: APS is a novel independent prognostic indicator for the radical resection of ESCC and a potential biomarker for monitoring the therapeutic response.