Relationship Between Asymmetry of Transverse Sinus and Difference in Intraocular Pressure.

BACKGROUND AND OBJECTIVE: This study used two-dimensional time-of-flight magnetic resonance venography (2D TOF MRV) to show the shape of the transverse sinus and to determine whether there is a correlation between the asymmetry of the transverse sinus morphology and the intraocular pressure (IOP) of the two eyes. METHODS: In this study, 63 male and 42 female volunteers were included. Those with obvious neurological diseases and eye diseases were excluded. According to the morphology of the transverse sinus scanned with 2D TOF MRV, subjects were divided into five groups. The IOP of the volunteers was measured separately. RESULTS: The difference between group I and group V is statistically significant (Z = 6.78, P < 0.01). Statistically, significant differences also existed among the IOP of each group, including the mean values of both eyes and the difference between the right eye and the left eye. The asymmetry of the transverse sinus maintained a negative correlation with the right IOP (r = 0.51, P < 0.01) and the difference between the right eye and the left eye (r = 0.79, P < 0.01). The asymmetry and the left IOP had no statistical correlation. CONCLUSION: The preliminary conclusion of this study is that if one side of the transverse sinus is thicker, the drainage-related ocular veins are relatively coarser, and the IOP is relatively lower. The 2D TOF MRV examination can be used as an examination to show the shape of the transverse sinus. It is a display method to provide a feasible means of inspection for a reasonable interpretation.

Epigenetic Targeting of Heparan Sulfate 3-O- and 6-O-Sulfation in Breast Cancer Cells: Prospects for Attenuating Prothrombotic Tumor Cell Activities.

The deregulation of cell surface heparan sulfate proteoglycans (HSPGs) is a main issue of cancer cells for increasing their malignancy. In these terms, the sulfation pattern of HS, created by an orchestrated activity of enzymes balancing a site-specific sulfation, is of key importance. These enzymes are often deregulated by epigenetic processes in cancer, e.g., being silenced by DNA hypermethylation. Here, we address this issue in human breast cancer cell lines aiming to target epigenetic processes to reactivate HS sulfation, shifting HS into an antithrombotic phenotype for which 3-O-sulfation is particularly important. Treatment of MCF-7 and MDA-MB-231 cells with nontoxic concentrations of 5-azacytidine (azacytidine) and 5-fluoro-2'-deoxycytidine (FdCyd) as DNMT inhibitors or vorinostat for targeting HDAC increased HS3-O-sulfation remarkably, as confirmed by fluorescence microscopy, by upregulating HS3-O-sulfotransferases, detected by quantitative real-time polymerase chain reaction and Western blot. Flow cytometry and microscopic approaches confirm that upon inhibitor treatment, increased HS3-O-sulfation improves cell binding to antithrombin, leading to an antithrombotic activity. Nevertheless, only azacytidine- and vorinostat-treated cells display anticoagulative properties, represented by attenuated thrombin formation, a lower activation of human platelet aggregation, or ATP release. In contrast, FdCyd additionally upregulated tissue factor expression in both cell lines, overshadowing the anticoagulant effects of HS, leading to an overall prothrombotic phenotype. Our data provide evidence for the first time that targeting epigenetic processes in HS sulfation is a valuable means to foster anticoagulative cell properties for decreasing malignancy and metastatic potency. These data warrant further investigations to fine-tune epigenetic targeting and to search for potential biomarkers attributed to these activities.

FXR contributes to obstructive jaundice-induced vascular hyporeactivity in mesenteric arteries by reconstituting BKCa channels.

OBJECTIVE: Vascular hyporeactivity increases with the incidence of obstructive jaundice (OJ). Evidence suggests that OJ activates the farnesoid X receptor (FXR) as well as the large-conductance Ca2+-activated K+ (BKCa or MaxiK) channel. This study was designed to explore the role of the FXR in vascular hyporesponsiveness induced by cholestasis. METHODS: The OJ model rats were constructed by bile duct ligation (BDL) and treated with an FXR agonist or antagonist. Vasoconstriction of the mesenteric arteries (MAs) was assessed in vitro. Whole-cell patch clamp recordings were used to investigate BKCa channel function. Real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot were used to detect mRNA and protein levels. RESULTS: A significant increase in vascular tone and responsiveness to norepinephrine (NE) was observed after the MaxiK channel blocker (IbTX) was administered. This effect was pronounced in BDL animals and can be mimicked by the FXR agonist GW4064 and inhibited by the FXR antagonist Z-guggulsterone (Z-Gu). GW4064 has a similar effect as cholestasis in promoting MaxiK currents in isolated arterial smooth muscle cells (ASMCs), while Z-Gu blunted this effect. The mRNA and protein expression of FXR and MaxiK-ß1, but not MaxiK-α, were significantly increased in the BDL group in comparison to the sham. Furthermore, activation or inhibition of FXR promoted or inhibited the mRNA and protein expression of the MaxiK-ß1 subunit, respectively. CONCLUSION: Activation of FXR enhances the capability of the MaxiK channel to regulate vascular tone and leads to vascular hyporesponsiveness in the MAs of BDL rats, which may be mediated by the nonparallel upregulation of MaxiK-α and MaxiK-ß1 subunit expression.

Neuromuscular conditions in post-stroke ankle-foot dysfunction reflected by surface electromyography.

BACKGROUND: Rating scales and linear indices of surface electromyography (sEMG) cannot quantify all neuromuscular conditions associated with ankle-foot dysfunction in hemiplegic patients. This study aimed to reveal potential neuromuscular conditions of ankle-foot dysfunction in hemiplegic patients by nonlinear network indices of sEMG. METHODS: Fourteen male patients with hemiplegia and 10 age- and sex-matched healthy male adults were recruited and tested in static standing position. The characteristics of the root mean square (RMS), median frequency (MF), and three nonlinear indices, the clustering coefficient (C), the average shortest path length (L), and the degree centrality (DC), of eight groups of muscles in bilateral calves were observed. RESULTS: Compared to those of the control group, the RMS of the medial gastrocnemius (MG), flexor digitorum longus (FDL), and extensor digitorum longus (EDL) on the affected side were significantly lower (P < 0.05), and the RMS of the tibial anterior (TA) and EDL on the unaffected side were significantly higher (P < 0.05). The MF of the EDL on the affected side was significantly higher than that on the control side (P < 0.05). The C of the unaffected side was significantly higher than that of the control group, whereas the L was lower (P < 0.05). Compared to those of the control group, the DC of the TA, EDL, and soleus (SOL) on the unaffected sides were higher (P < 0.05), and the DC of the MG on the affected sides was lower (P < 0.05). CONCLUSION: The change trends and clinical significance of these three network indices, including C, L, and DC, are not in line with those of the traditional linear indices, the RMS and the MF. The C and L may reflect the degree of synchronous activation of muscles during a certain motor task. The DC might be able to quantitatively assess the degree of muscle involvement and reflect the degree of involvement of a single muscle. Linear and nonlinear indices may reveal more neuromuscular conditions in hemiplegic ankle-foot dysfunction from different aspects. TRIAL REGISTRATION: ChiCTR2100055090.

Avoiding the Kinetic Inertness of Chromium Ions Using a Coordination Substitution Strategy for the Rapid Synthesis of Chromium-Based Metal-Organic Frameworks.

Chromium-based metal-organic frameworks (Cr-MOFs) are very attractive in a wide range of applications due to their robustness and high porosity. However, the kinetic inertness of chromium ions results in the synthesis of Cr-MOFs often taking prolonged reaction times, which limit their industrial applications. Herein, we report a novel synthesis strategy based on coordination substitution, which overcomes the kinetic inertness of chromium ions and can synthesize Cr-MOFs in a shorter time. The versatility of this strategy has been demonstrated by producing several known Cr-MOFs, such as TYUT-96Cr, MIL-100Cr, MIL-101Cr, and MIL-53Cr. PXRD, SEM, TEM, 77 K N2 adsorption, and TGA have proved that the Cr-MOFs synthesized using this new strategy have good crystallinity, high porosity, and excellent thermal stability. The synthesis mechanism was investigated using theoretical calculations.

Heparan sulfate-dependent phase separation of CCL5 and its chemotactic activity.

Secreted chemokines form concentration gradients in target tissues to control migratory directions and patterns of immune cells in response to inflammatory stimulation; however, how the gradients are formed is much debated. Heparan sulfate (HS) binds to chemokines and modulates their activities. In this study, we investigated the roles of HS in the gradient formation and chemoattractant activity of CCL5 that is known to bind to HS. CCL5 and heparin underwent liquid-liquid phase separation and formed gradient, which was confirmed using CCL5 immobilized on heparin-beads. The biological implication of HS in CCL5 gradient formation was established in CHO-K1 (wild-type) and CHO-677 (lacking HS) cells by Transwell assay. The effect of HS on CCL5 chemoattractant activity was further proved by Transwell assay of human peripheral blood cells. Finally, peritoneal injection of the chemokines into mice showed reduced recruitment of inflammatory cells either by mutant CCL5 (lacking heparin-binding sequence) or by addition of heparin to wild-type CCL5. Our experimental data propose that co-phase separation of CCL5 with HS establishes a specific chemokine concentration gradient to trigger directional cell migration. The results warrant further investigation on other heparin-binding chemokines and allows for a more elaborate insight into disease process and new treatment strategies.

Comparison of Tumor Non-specific and PD-L1 Specific Imaging by Near-Infrared Fluorescence/Cerenkov Luminescence Dual-Modality In-situ Imaging.

Background: Labeled antibodies are excellent imaging agents in oncology to non-invasively visualize cancer-related antigens expression levels. However, tumor tracer uptake (TTU) of specific antibodies in-vivo may be inferior to non-specific IgG in some cases. Objectives: To explore factors affecting labeled antibody visualization by PD-L1 specific and non-specific imaging of nude mouse tumors. Methods: TTU was observed in RKO model on Cerenkov luminescence (CL) and near-infrared fluorescence (NIRF) imaging of radionuclide 131I or NIRF dyes labeled Atezolizumab and IgG. A mixture of NIRF dyes labeled Atezolizumab and 131I-labeled IgG was injected, and TTU was observed in the RKO and HCT8 model by NIRF/CL dual-modality in-situ imaging. TTU were observed by 131I-labeled Atezolizumab and IgG in-vitro distribution. Results: Labeled IgG concentrated more in tumors than Atezolizumab. NIRF/CL imaging in 24 to 168 h showed that TTU gradually decreased over time, which decreased more slowly on CL imaging compared to NIRF imaging. The distribution data in-vitro showed that TTU of 131I-labeled IgG was higher than that of 131I-labeled Atezolizumab at any time point. Conclusion: Non-specific IgG may not be suitable as a control for Atezolizumab in comparing tumor PD-L1 expression in nude mice via labeled antibody optical imaging under certain circumstances.

Inducing Intermolecular Oxygen Coupling by Introducing S and FeOOH on Co(OH)2 Nanoneedle Arrays for Industrial Water Oxidation.

The design of electrocatalysts for oxygen evolution reaction (OER) remains a limitation of industrial hydrogen production by electrolysis of water. Excellent and stable OER catalysts can be developed by activating lattice oxygen and changing the reaction path. Herein, S and FeOOH on the Co(OH)2 nanoneedle arrays are introduced to construct a heterostructure (S-FeOOH/Co(OH)2/NF) as a proof of concept. Theoretical calculations and experimental suggest that the Co-O-Fe motif formed at the heterogeneous interface with the introduction of FeOOH, inducing electron transfer from Co to Fe, enhancing Co─O covalency and reducing intramolecular charge transfer energy, thereby stimulating direct intramolecular lattice oxygen coupling. Doping of S in FeOOH further accelerates electron transfer, improves lattice oxygen activity, and prevents dissolution of FeOOH. Consequently, the overpotential of S-FeOOH/Co(OH)2/NF is only 199 mV at 10 mA cm-2, and coupled with the Pt/C electrode can be up to 1 A cm-2 under 1.79 V and remain stable for over 120 h in an anion exchange membrane water electrolyzer (AEMWE). This work proposes a strategy for the design of efficient and stable electrocatalysts for industrial water electrolysis and promotes the commercialization of AEMWE.

Advancing the treatment of low carbon-to-nitrogen ratio municipal wastewater using a novel microaerobic sludge bed approach: Insights into enhanced performance and functional microbial community.

Microaerobic sludge bed systems could align with low-energy, reasonable carbon-nitrogen (C/N) ratio, and synchronous removal objectives during wastewater treatment. However, its ability to treat municipal wastewater (MW) with varying low C/N ratio, low NH4+ concentration, along with managing sludge bulking and loss are still unclear. Against this backdrop, this study investigated the performance of an Upflow Microaerobic Sludge Bed Reactor (UMSR) treating MW characterized by varying low C/N ratios and low NH4+ concentrations. The study also thoroughly examined associated sludge bulking and loss, pollutant removal efficiencies, sludge settleability, microbial community structures, functional gene variations, and metabolic pathways. Findings revealed that the effluent NH4+-N concentration gradually decreased to 0 mg/L with a decrease in the C/N ratio, whereas the effluent COD was unaffected by the influent, maintaining a concentration below 50 mg/L. Notably, TN removal efficiency reached 90% when C/N ratio was 3. The decrease in the C/N ratio (C/N ratio was 1) increased microbial community diversity, with abundances of AOB, AnAOB, aerobic denitrifying bacteria, and anaerobic digestion bacteria reaching 8.34%, 0.96%, 5.07%, and 9.01%, respectively. Microorganisms' metabolic pathways significantly shifted, showing increased carbohydrate and cofactor/vitamin metabolism and decreased amino acid metabolism and xenobiotic biodegradation. This study not only provides a solution for the effluent of different pre-capture carbon processes but also demonstrates the UMSR's capability in managing low C/N ratio municipal wastewater and emphasizes the critical role of microbial community adjustments and functional gene variations in enhancing nitrogen removal efficiency.

Prognostic and immunological significance of metastasis-associated protein 3 in patients with thymic epithelial tumors.

BACKGROUND: Immune checkpoint inhibitors have shown promising anticancer activity and have recently been proposed as a therapy for thymic epithelial tumors (TETs); however, this treatment is only effective for a subgroup of TET patients. Thus, this study aims to identify the potential genes implicated in the regulation of cancer immunity in TETs. METHODS: The TETs RNA-seq and clinical data were obtained from The Cancer Genome Atlas (TCGA) database. The clinical significance of the tumor microenvironment (TME) in TETs was evaluated. Weighted gene coexpression network analysis (WGCNA) was used to identify the immune response-related hub genes. The expression of metastasis-associated protein 3 (MTA3) in TETs was investigated in public datasets and a patient cohort. Kaplan‒Meier curves were generated to analyze the prognostic value of various factors. The Tumor Immune Estimation Resource (TIMER2.0) was used to estimate the relevance of MTA3 to immune cell infiltration. Gene set enrichment analysis (GSEA) and pathway enrichment analysis were applied to explore the MTA3-related pathways. RESULTS: The TME was found to be clinically significant in TETs. Moreover, MTA3 was identified as a key gene associated with the immune score, and lower MTA3 expression was linked to poor TME and reduced cytotoxic activity in TETs. Furthermore, MTA3 was found to be deregulated in TETs, predictive of poor prognosis. MTA3 was also significantly associated with the infiltration levels of various immune cell types and highly correlated with their corresponding markers. Notably, MTA3 was positively associated with various immune response pathways. CONCLUSION: MTA3 is clinically significant in TETs and correlated with immune cell infiltration. Thus, MTA3 might be a biomarker for predicting the prognosis and immune status of TET patients.

Single­cell RNA­seq necroptosis­related genes predict the prognosis of breast cancer and affect the differentiation of CD4+ T cells in tumor immune microenvironment.

Breast cancer (BC) is one of the most prevalent types of malignancy and a major cause of cancer-related death. The purpose of the present study was to identify prognostic models of necroptosis-related genes (NRGs) in BC at the single-cell RNA-sequencing level and reveal the role of NRGs in tumour immune microenvironment (TIME). A risk model was constructed based on Cox regression and LASSO methods. Next, high-scoring cell populations were searched through AUCell scores, and cell subtypes were then analyzed by pseudotime analysis. Finally, the expression level of the model genes was verified by reverse transcription-quantitative (RT-qPCR). A new prognostic model was constructed and validated based on five NRGs (BCL2, BIRC3, AIFM1, IFNG and VDAC1), which could effectively predict the prognosis of patients with BC. NRGs were found to be highly active in CD4+ T cells and differentially expressed in their developmental trajectories. Finally, the RT-qPCR results showed that most of the model genes were significantly overexpressed in MDA-MB-231 and MCF-7 cells (P<0.05). In conclusion, an NRG signature with excellent predictive properties in prognosis and TIME was successfully established. Moreover, NRGs were involved in the differentiation and development of CD4+ T cells in TIME. These findings provide potential therapeutic strategies for BC.

Overview of the current procedures in synthesis of heparin saccharides.

Natural heparin, a glycosaminoglycan consisting of repeating hexuronic acid and glucosamine linked by 1 â†’ 4 glycosidic bonds, is the most widely used anticoagulant. To subvert the dependence on animal sourced heparin, alternative methods to produce heparin saccharides, i.e., either heterogenous sugar chains similar to natural heparin, or structurally defined oligosaccharides, are becoming hot subjects. Although the success by chemical synthesis of the pentasaccharide, fondaparinux, encourages to proceed through a chemical approach generating homogenous product, synthesizing larger oligos is still cumbersome and beyond reach so far. Alternatively, the chemoenzymatic pathway exhibited exquisite stereoselectivity of glycosylation and regioselectivity of modification, with the advantage to skip the tedious protection steps unavoidable in chemical synthesis. However, to a scale of drug production needed today is still not in sight. In comparison, a procedure of de novo biosynthesis in an organism could be an ultimate goal. The main purpose of this review is to summarize the current available/developing strategies and techniques, which is expected to provide a comprehensive picture for production of heparin saccharides to replenish or eventually to replace the animal derived products. In chemical and chemoenzymatic approaches, the methodologies are discussed according to the synthesis procedures: building block preparation, chain elongation, and backbone modification.

Effect of the Number of Methyl Groups in DMOF on N2O Adsorption and N2O/N2 Separation.

Nitrous oxide (N2O), as the third largest greenhouse gas in the world, also has great applications in industry, so the purification of N2O from N2 in industrial tail gas is a crucial process for achieving environmental protection and giving full play to its economic value. Based on the polarity difference of N2O and N2, N2O adsorption was researched on DMOF series materials with different polarities and methyl numbers of the ligand. N2O adsorption at 0.1 bar is enhanced, attributed to an increase of the methyl group densities at the benzenedicarboxylate linker. Grand canonical Monte Carlo simulations demonstrate the key role of methyl groups within the pore surface in the preferential N2O affinity. Methyl groups preferentially bind to N2O and thus enhanced low (partial) pressure N2O adsorption and N2O/N2 separation. The result shows that DMOF-TM has the highest N2O adsorption capacity (19.6 cm3/g) and N2O/N2 selectivity (23.2) at 0.1 bar. Breakthrough experiments show that, with an increase of the methyl number, the coadsorption time and retention time also increase, and DMOF-TM has the best N2O/N2 separation performance.

Phase Separation Enhanced PROTAC for Highly Efficient Protein Degradation.

Biomacromolecular condensates formed via phase separation establish compartments for the enrichment of specific compositions, which is also used as a biological tool to enhance molecule condensation, thereby increasing the efficiency of biological processes. Proteolysis-targeting chimeras (PROTACs) have been developed as powerful tools for targeted protein degradation in cells, offering a promising approach for therapies for different diseases. Herein, we introduce an intrinsically disordered region in the PROTAC (denoted PSETAC), which led to the formation of droplets of target proteins in the cells and increased degradation efficiency compared with PROTAC without phase separation. Further, using a nucleus targeting intrinsically disordered domain, the PSETAC was able to target and degrade nuclear-located proteins. Finally, we demonstrated intracellular delivery of PSETAC using lipid nanoparticle-encapsulated mRNA (mRNA-LNP) for the degradation of the endogenous target protein. This study established the PSETAC mRNA-LNP method as a potentially translatable, safe therapeutic strategy for the development of clinical applications based on PROTAC.

Utilization Potential of Aerated Concrete Block Powder and Coffee Grounds Ash in Green-Growing Concrete.

The purpose of this research is to investigate the utilization potential of recycled powder made from spent coffee grounds (SCGs) and aerated concrete blocks (ACBs) in green-growing concrete. The green-growing concrete is prepared using ACB powder and SCG ash as raw materials instead of 5%, 15%, and 25% and 5%, 10%, and 15% cement, respectively. Then, the two raw materials are compounded with the optimal content. The compressive strength and alkalinity of green-growing concrete at 7d and 28d and the frost resistance after 25 freeze-thaw cycles at 28d are studied. The results showed that the optimum content of ACB powder and SCG ash was 5%. Replacing 5% cement with recycled powder could improve the strength of concrete. The alkalinity of concrete containing ACB powder gradually increased, while the alkalinity of concrete containing SCG ash gradually decreased. The alkalinity of ACB-SCG powder was lower than that of ACB powder but slightly higher than that of SCG ash. The frost resistance of concrete containing ACB powder decreased gradually, and the frost resistance of concrete containing SCG ash increased first and then decreased greatly. The frost resistance of ACB-SCG powder could neutralize that of ACB powder and SCG ash.

Cobalt telluride regulated by nickel for efficient electrooxidation of 5-hydroxymethylfurfural.

Replacing the anodic oxygen evolution reaction (OER) in water splitting with 5-hydroxymethylfurfural oxidation reaction (HMFOR) can not only reduce the energy required for hydrogen production but also yield the valuable chemical 2,5-furandicarboxylic acid (FDCA). Co-based catalysts are known to be efficient for HMFOR, with high-valent Co being recognized as the main active component. However, efficiently promoting the oxidation of Co2+ to produce high-valent reactive species remains a challenge. In this study, Ni-doped CoTe (CoNiTe) nanorods were prepared as efficient catalysts for HMFOR, achieving a high HMFOR current density of 65.3 mA cm-2 at 1.50 V. Even after undergoing five successive electrolysis processes, the Faradaic efficiency (FE) remained at approximately 90.7 %, showing robust electrochemical durability. Mechanistic studies indicated that Ni doping changes the electronic configuration of Co, enhancing its charge transfer rate and facilitating the oxidation of Co2+ to high-valent CoO2 species. This work reveals the effect of Ni doping on the reconfiguration of the active phase during HMFOR.

Shifting the Oxygen-Evolution Reaction Pathway via Cation Engineering to Activate Lattice Oxygen in Metal-Organic Frameworks.

Metal-organic frameworks (MOFs) as promising electrocatalysts have been widely studied, but their performance is limited by conductivity and coordinating saturation. This study proposes a cationic (V) modification strategy and evaluates its effect on the electrocatalytic performance of CoFe-MOF nanosheet arrays. The optimal V-CoFe-MOF/NF electrocatalyst exhibits excellent oxygen-evolution reaction (OER)/hydrogen-evolution reaction (HER) performance (231 mV at 100 mA cm-2/86 mV at 10 mA cm-2) in alkaline conditions, with its OER durability exceeding 400 h without evident degradation. Furthermore, as a bifunctional electrocatalyst for water splitting, a small cell voltage is achieved (1.60 V at 10 mA cm-2). The practicability of the catalyst is further evaluated by membrane electrode assembly (MEA), showing outstanding activity (1.53 V at 10 mA cm-2) and long-term stability (at 300 mA cm-2). Moreover, our results reveal the apparent reconstruction properties of V-CoFe-MOF/NF in alkaline electrolytes, where the partially dissolved V promotes the formation of more active ß-MOOH. The mechanism study shows the OER mechanism shifts to a lattice oxygen oxidation mechanism (LOM) after V doping, which directly avoids complex multistep adsorption mechanism and reduces reaction energy. This study provides a cation mediated strategy for designing efficient electrocatalysts.

Inhibitors of dermatan sulfate epimerase 1 decreased accumulation of glycosaminoglycans in mucopolysaccharidosis type I fibroblasts.

Genetic deficiency of alpha-L-iduronidase causes mucopolysaccharidosis type I (MPS-I) disease, due to accumulation of glycosaminoglycans (GAGs) including chondroitin/dermatan sulfate (CS/DS) and heparan sulfate (HS) in cells. Currently, patients are treated by infusion of recombinant iduronidase or by hematopoietic stem cell transplantation. An alternative approach is to reduce the L-iduronidase substrate, through limiting the biosynthesis of iduronic acid. Our earlier study demonstrated that ebselen attenuated GAGs accumulation in MPS-I cells, through inhibiting iduronic acid producing enzymes. However, ebselen has multiple pharmacological effects, which prevents its application for MPS-I. Thus, we continued the study by looking for novel inhibitors of dermatan sulfate epimerase 1 (DS-epi1), the main responsible enzyme for production of iduronic acid in CS/DS chains. Based on virtual screening of chemicals towards chondroitinase AC, we constructed a library with 1,064 compounds that were tested for DS-epi1 inhibition. Seventeen compounds were identified to be able to inhibit 27%-86% of DS-epi1 activity at 10 µM. Two compounds were selected for further investigation based on the structure properties. The results show that both inhibitors had a comparable level in inhibition of DS-epi1while they had negligible effect on HS epimerase. The two inhibitors were able to reduce iduronic acid biosynthesis in CS/DS and GAG accumulation in WT and MPS-I fibroblasts. Docking of the inhibitors into DS-epi1 structure shows high affinity binding of both compounds to the active site. The collected data indicate that these hit compounds may be further elaborated to a potential lead drug used for attenuation of GAGs accumulation in MPS-I patients.

Antiviral Activities of Heparan Sulfate Mimetic RAFT Polymers Against Mosquito-borne Viruses.

Mosquito-borne viruses are a major worldwide health problem associated with high morbidity and mortality rates and significant impacts on national healthcare budgets. The development of antiviral drugs for both the treatment and prophylaxis of these diseases is thus of considerable importance. To address the need for therapeutics with antiviral activity, a library of heparan sulfate mimetic polymers was screened against dengue virus (DENV), Yellow fever virus (YFV), Zika virus (ZIKV), and Ross River virus (RRV). The polymers were prepared by RAFT polymerization of various acidic monomers with a target MW of 20 kDa (average Mn ∼ 27 kDa by GPC). Among the polymers, poly(SS), a homopolymer of sodium styrenesulfonate, was identified as a broad spectrum antiviral with activity against all the tested viruses and particularly potent inhibition of YFV (IC50 = 310 pM). Our results further uncovered that poly(SS) exhibited a robust inhibition of ZIKV infection in both mosquito and human cell lines, which points out the potential functions of poly(SS) in preventing mosquito-borne viruses associated diseases by blocking viral transmission in their mosquito vectors and mitigating viral infection in patients.

Comprehensive pan-cancer analysis: essential role of ABCB family genes in cancer.

Background: The adenosine triphosphate-binding-cassette (ABC) transporter orchestrates the transmembrane transport of diverse substrates with the aid of ATP as an energy source. ABC transporter constitutes a widespread superfamily of transporters prominently present on the cellular membrane of organisms. Advancements in understanding have unveiled additional roles beyond mere intracellular or extracellular transport functions for the ABC protein family, encompassing involvement in DNA repair, protein translation, and gene expression regulation. Yet its role in tumors is still unknown. Methods: This study drew support from multiple databases, including Gene Expression Omnibus (GEO), European Genome-phenome Archive (EGA), The Cancer Genome Atlas (TCGA), and employed multidimensional bioinformatics analyses, incorporating online databases and the R-project. Through a comprehensive analysis, we seek to discern transcriptional-level disparities among genes and their consequential impacts on prognosis, tumor microenvironment (TME), stemness score, immune subtypes, clinical characteristics, and drug sensitivity across human cancers. Results: ABC transporter subfamily B (ABCB) family genes exhibited heightened expression across diverse tumors, demonstrating a significant correlation with overall prognosis in pan-cancer contexts. Notably, gene expression levels manifested substantial associations with TME, stemness score, immune subtypes, clinical characteristics, and drug sensitivity in specific cancers, including kidney renal papillary cell carcinoma (KIRP), liver hepatocellular carcinoma (LIHC), and pancreatic adenocarcinoma (PAAD). Within this subset, transporter associated with antigen processing 1 (TAP1), TAP2, and ABCB6 emerged as noteworthy oncogenes. Conclusions: The outcomes of this study contribute to a comprehensive understanding of the implications of ABCB family genes in tumor progression, offering insights into potential therapeutic targets for cancer. Notably, the identification of ABCB6 as a significant oncogene suggests promising avenues for targeted therapies in KIRP, LIHC, and PAAD.