Background and Purpose
Heparanase is the only confirmed endoglycosidase that cleaves heparan sulfate (HS), a ubiquitous glycosaminoglycan with various essential roles in multiple pathological ...processes. Thus, the development of heparanase inhibitors has become an attractive strategy for drug discovery, especially in tumour therapy, in which HS mimetics are the most promising compounds. The various biological effects of heparanase also suggest a role for HS mimetics in many non‐cancer indications, such as type 1 diabetes. However, the potential benefits of HS mimetics in obesity‐related type 2 diabetes have not been elucidated.
Experimental Approach
In this study, we investigated muparfostat (PI‐88), a developed HS mimetic currently enrolled in Phase III clinical trials, in obese mouse models and in vitro cultured murine hepatocytes.
Key Results
Daily administration of muparfostat for 4 weeks caused hyperlipidaemia and aggravated hepatic steatosis in obese mice models, but not in lean animals. In cultured hepatocytes, muparfostat did not alter lipid accumulation. Acute tests suggested that muparfostat binds to lipoprotein lipase in competition with HS on vascular endothelial cell surfaces, thereby reducing the degradation of circulating triglycerides by lipoprotein lipase and subsequent uptake of fatty acids into vascular endothelial cells and causing hyperlipidaemia. This hyperlipidaemia aggravates hepatic steatosis and causes liver injury in muparfostat‐treated obese mice.
Conclusions and Implications
The binding activity of HS mimetics to lipoprotein lipase should be investigated as an additional pharmacological effect during heparanase inhibitor drug discovery. This study also provides novel evidence for an increased risk of drug‐induced liver injury in obese individuals.
Although upregulated expression of local IgD has been reported in patients with chronic rhinosinusitis (CRS), its function is unclear.
We sought to explore the expression and function of soluble IgD ...in patients with CRS, particularly CRS with nasal polyps.
IgD levels in sinonasal mucosa were analyzed by using RT-PCR and ELISA. Numbers and phenotypes of IgD+ cells were studied by means of immunohistochemistry, immunofluorescence, and flow cytometry. HMC-1 cells, a human mast cell line, and mast cells purified from eosinophilic polyps were cultured alone or with naive B cells purified from peripheral blood. The antigen specificity of nasal IgD was investigated by using ELISA.
The mRNA expression of immunoglobulin heavy constant delta gene, numbers of IgD+ cells, and protein levels of secretory IgD in sinonasal mucosa were increased in patients with CRS with or without nasal polyps compared with control subjects. Numbers of IgD+ plasmablasts were increased in both eosinophilic and noneosinophilic polyps, whereas numbers of IgD+ mast cells were only increased in eosinophilic polyps. Cross-linking IgD induced serum preincubated HMC-1 cells and polyp mast cells to produce B-cell activating factor, IL-21, IL-4, and IL-13 and to promote IgM, IgG, IgA, and IgE production from B cells. In eosinophilic polyps expression of those B cell–stimulating factors in mast cells and close contact between mast cells and B cells were found. Moreover, positive correlations of total IgD levels with total IgE levels and eosinophilia and upregulation of specific IgD against house dust mites were discovered in eosinophilic polyps.
IgD-activated mast cells can facilitate IgE production and eosinophilic inflammation in patients with CRS with nasal polyps.
Oral submucous fibrosis (OSF) stands as a progressive oral ailment, designated as a potentially malignant disorder. OSF has gained widespread recognition as a significant precursor to malignant ...transformation. In the pursuit of dependable, straightforward, and non-invasive diagnostic measures for the early detection of oral malignant progression, research has delved into potential diagnostic biomarkers of OSF. This comprehensive review delves into current investigations that explore the correlation between various biomarkers and OSF. The molecular biomarkers of OSF are categorized based on cytology and sampling methods. Moreover, this review encompasses pertinent studies detailing how these biomarkers are acquired and processed. Within this scope, we scrutinize four potential biomarkers that hold the promise of facilitating the development of diagnostic tools for detecting early-stage OSF.
Cytomegalovirus (CMV) can cause infection and critical diseases in hematopoietic stem cell transplantation (HSCT) recipients. This study aimed to explore the cumulative incidence and risk factors for ...CMV infection and disease among HSCT recipients in Taiwan.
This retrospective cohort study using the Taiwan Blood and Marrow Transplantation Registry (TBMTR) included HSCT recipients between 2009 and 2018 in Taiwan. The primary outcome was cumulative incidence of CMV infection or disease at day 100 after HSCT. Secondary outcomes included day 180 cumulative incidence of CMV infection or disease, infection sites, risk factors for CMV infection or disease, survival analysis, and overall survival after CMV infection and disease.
There were 4394 HSCT recipients included in the study (2044 auto-HSCT and 2350 allo-HSCT). The cumulative incidence of CMV infection and disease was significantly higher in allo-HSCT than in auto-HSCT patients at day 100 (53.7% vs. 6.0%, P < 0.0001 and 6.1% vs. 0.9%, P < 0.0001). Use of ATG (HR 1.819, p < 0.0001), recipient CMV serostatus positive (HR 2.631, p < 0.0001) and acute GVHD grades ≥ II (HR 1.563, p < 0.0001) were risk factors for CMV infection, while matched donor (HR 0.856, p = 0.0180) and myeloablative conditioning (MAC) (HR 0.674, p < 0.0001) were protective factors.
The study revealed a significant disparity in terms of the incidence, risk factors, and clinical outcomes of CMV infection and disease between auto and allo-HSCT patients. These findings underscore the importance of considering these factors in the management of HSCT recipients to improve outcomes related to CMV infections.
The contribution of ectopic lymphoid tissues (eLTs) to local immunoglobulin hyperproduction in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) is unclear.
We sought to explore the ...cellular basis, formation mechanisms, and function of eLTs in patients with CRSwNP.
We graded lymphoid aggregations in sinonasal mucosa and histologically studied their structures. The expression of lymphorganogenic factors and molecules required for immunoglobulin production was measured by using real-time PCR, and their localization was analyzed by means of immunohistochemistry and immunofluorescence. The phenotype of follicular helper T cells was analyzed by performing flow cytometry. Immunoglobulin levels were quantified by using the Bio-Plex assay or ImmunoCAP system. Nasal tissue explants were challenged ex vivo with Dermatophagoides pteronyssinus group 1 (Der p 1), and the expression of Iε-Cμ and Iε-Cγ circle transcripts was detected by using seminested PCR.
Increased formation of eLTs with germinal center–like structures was discovered in patients with eosinophilic (20.69%) and noneosinophilic (17.31%) CRSwNP compared with that in patients with chronic rhinosinusitis without nasal polyps (5.66%) and control subjects (3.70%). The presence of eLTs was associated with increased expression of lymphorganogenic and inflammatory chemokines and cytokines, as well as their receptors. The expression of molecules required for immunoglobulin production, generation of follicular helper T cells, and production of IgE in eosinophilic polyps and IgG and IgA in both eosinophilic and noneosinophilic polyps were predominantly upregulated in patients with eLTs. After Der p 1 challenge ex vivo, Iε-Cμ transcript was detected only in eosinophilic polyps with eLTs but not in polyps without eLTs and noneosinophilic polyps.
eLTs might support local immunoglobulin production and therefore significantly contribute to the development of CRSwNP.
Timing macro modeling has been widely employed to enhance the efficiency and accuracy of parallel and hierarchical timing analysis. However, existing studies primarily focused on generating an ...accurate and compact timing macro model for single-corner libraries, making it difficult to adapt these approaches to multi-corner situations. This either incurs substantial engineering effort or results in significant performance degradation. To tackle this challenge, we offer a fresh perspective on the timing macro modeling problem by drawing inspiration from recommendation systems and formulating it as a matrix completion task. We propose a neural collaborative filtering-based framework capable of capturing the convoluted relationships between circuit pins and timing corners. This framework enables the precise identification of timing variant regions across different corners. Additionally, we design several training features and implement various training techniques to enhance precision. Experimental results show that our framework reduces model sizes by more than 10% compared to state-of-the-art single-corner approaches, while maintaining competitive timing accuracy and exhibiting significant runtime improvements. Furthermore, when applied to unseen corners, our framework consistently delivers superior performance, demonstrating its potential for use in off-corner chiplets in a heterogeneous integration system.
The physical properties, packing, morphology, and semiconducting performance of a planar π-conjugated system can be effectively modified by introducing side chains and substituent groups, both of ...which can be complementary to the π framework in changing the intermolecular association, frontier molecular orbital energy, optical band gap, and others. We herein show that installation of end-capped electron-withdrawing groups (EWGs), such as dicyanovinyl (−DCV), 3-ethylrhodanine (−RD), and 2-(3-oxo-indan-1-ylidene)-malononitrile (−INCN), together with siloxane side chains to the backbones of dithienyldiketopyrrolopyrrole (DPPT), such as DPPT-Si-DCV, DPPT-Si-RD, and DPPT-Si-INCN, can greatly improve its solubility, air stability, and film morphology to serve as an n-channel in thin-film transistor fabrication. The EWGs attached to the DPPT core narrowed the optical band gap (E g opt) and changed the highest occupied molecular orbital and the lowest unoccupied molecular orbital energies (E HOMO and E LUMO), making them suitable for n-channel field-effect transistor (FET) applications. The benefits of introducing siloxane side chains to the DPPT core include enhanced solubility, low crystallization barrier, enantiotropic phase behavior, and much improved FET performance. The DPPT-Si-INCN film displayed low-lying HOMO (−5.82 eV) and LUMO (−4.60 eV) energy levels and an optical band gap as low as 1.22 eV, all of which suggest that this derivative can be quite resistant toward aerial oxidation. Thin films of these derivatives were prepared by the solution-shear method. A comparison of the solution-sheared films indicated that the molecular packing motif of DPPT-Si-INCN film was somehow different from that of DPPT-Si-DCV and DPPT-Si-RD, in which the π–π stacking tended to align orthogonally to the shearing direction. This specific π–π stacking alignment could have an impact on the electron mobility (μe) values in transistors based on the solution-sheared films.
In this study, umami-rich seasoning powder was produced from the offcuts of Taiwanese tilapia (
) by cooking concentration and spray drying of granules while yielding an abundance of glutamic acid ...(0.23 mg/100 g), glycine (0.10 mg/100 g), aspartic acid (0.11 mg/100 g), lysine (0.10 mg/100 g), and 11 other aminic acids. It exhibited water content (3.81%), water activity (0.3), powder yields (68.83%), and a good water solubility index (99.89%), while the particle microstructure was a spherical powder. Additionally, it received the highest overall preference score (7.53) in the consumer-type sensory evaluation compared to commercially available seasonings. This study proves that offcuts may be part of the human diet after proper processing and can be widely used to flavor savory food. The producers involved could increase their economic returns while meeting the environmental challenges. The practical contribution could create incremental value for products to critical stakeholders at each point in the tilapia supply chain with an operational guide for transitioning from inefficient to innovative circular practices.
To investigate the dynamic changes in hippocampal metabolism after microwave radiation using liquid chromatography in tandem with mass spectrometry/mass spectrometry (LC–MS/MS) and to identify ...potential biomarkers. Wistar rats were randomly assigned to a sham group and a microwave radiation group. The rats in the microwave radiation group were exposed to 2.856 GHz for 15 min for three times, with 5 min intervals. The rats in the sham group were not exposed. Transmission electron microscope revealed blurring of the synaptic cleft and postsynaptic dense thickening in hippocampal neurons after microwave radiation. Metabolomic analysis revealed 38, 24, and 39 differentially abundant metabolites at 3, 7, and 14 days after radiation, respectively, and the abundance of 9 metabolites, such as argininosuccinic acid, was continuously decreased. After microwave radiation, the abundance of metabolites such as argininosuccinic acid was successively decreased, indicating that these metabolites could be potential biomarkers for hippocampal tissue injury.
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