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Ting-Ting Chang,1– 3 Jaw-Wen Chen1– 6 1Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan; 2Department and Institute of Pharmacology, National Yang Ming Chiao Tung University, Taipei, Taiwan; 3School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; 4Healthcare and Services Center, Taipei Veterans General Hospital, Taipei, Taiwan; 5Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; 6Cardiovascular Research Center, National Yang Ming Chiao Tung University, Taipei, TaiwanCorrespondence: Jaw-Wen ChenHealthcare and Services Center, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of ChinaTel +886-2-28757730Fax +886-2-28757703Email jwchen@vghtpe.gov.tw; iwchen99@gmail.comPurpose: Modulation of the gut microbiota may lead to changes in pathological conditions. C-C chemokine motif ligand (CCL) 4 was upregulated in diabetes mellitus (DM) and was shown to play a significant role in pancreatic inflammation and glucose metabolism. The detailed in vivo mechanisms have not been well explored. This study aimed to investigate the hypothesis that direct CCL4 inhibition could modify gut microbiota and systemic metabolism in diet-induced DM mice.Methods: C57BL/6 mice fed a high-fat diet (HFD) were used as a diet-induced DM model. CCL4 inhibition was conducted by anti-CCL4 neutralizing monoclonal antibodies. The gut microbiota was analyzed by high-throughput sequencing of the 16S rRNA. Fecal microbiota transplantation (FMT) was used to verify the effect of CCL4 deficiency on gut microbiota and the linkage between CCL4-modulated gut microbiota and HFD-induced DM.Results: CCL4 inhibition stabilized glucose homeostasis, modulated lipid parameter, and decreased inflammatory markers in HFD-induced DM mice. Moreover, CCL4 inhibition reversed HFD-induced gut dysbiosis, evidenced by the decreased abundance of family Muribaculaceae and increased abundance of family Atopobiaceae when CCL4 antibodies were administrated. CCL4 inhibition led to a decrease in circulating trimethylamine N-oxide levels, a proinflammatory metabolite from gut microbiota. Taken together, CCL4 inhibition could modify gut microbiota profiles, suppress proinflammatory metabolites, reduce systemic inflammation, improve insulin resistance, and retard the progression of hyperglycemia in HFD-induced DM. Furthermore, FMT from CCL4 knockout mice rescued the glucose homeostasis in HFD-induced DM mice.Conclusion: Our findings may not only provide a novel rationale to in vivo CCL4-based therapeutic approach in diet-induced DM but also indicate the significance of gut microbiota profile including the family Muribaculaceae and the family Atopobiaceae as a potential modifiable target for systemic metabolism.Keywords: diabetes mellitus, gut microbiota, inflammation, chemokine, trimethylamine N-oxide

Khai-Jing Ng,1,2,* Chih-Wei Tseng,1–4,* Ting-Tsung Chang,5,6 Shinn-Jia Tzeng,7 Yu-Hsi Hsieh,1,2 Tsung-Hsing Hung,1,2 Hsiang-Ting Huang,8 Shu-Fen Wu,9 Kuo-Chih Tseng1,2 1Department of Internal Medicine, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chia-Yi, 2School of Medicine, Tzu Chi University, Hualien, 3Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, 4School of Medicine, National Yang-Ming University, Taipei, 5Department of Internal Medicine, National Cheng Kung University Medical College and Hospital, Tainan, 6Infectious Disease and Signaling Research Center, National Cheng Kung University, Tainan, 7Department of Agronomy, National Chiayi University, Chia-Yi, 8Department of Nursing, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chia-Yi, 9Institute of Molecular Biology, National Chung Cheng University, Chia-Yi, Taiwan *These authors contributed equally to this work Background: The aim of this study was to evaluate the clinically significant predictors of hepatocellular carcinoma (HCC) development among hepatitis C virus (HCV) cirrhotic patients receiving combination therapy.Patients and methods: One hundred and five compensated cirrhosis patients who received pegylated interferon plus ribavirin between January 2005 and December 2011 were enrolled. All the patients were examined with abdominal sonography and liver biochemistry at baseline, end of treatment, and every 3–6 months posttreatment. The occurrence of HCC was evaluated every 3–6 months posttreatment.Results: A total of 105 patients were enrolled (mean age 58.3±10.4 years). The average follow-up time for each patient was 4.38 years (standard deviation 1.73 years; range 1.13–9.27 years). Fifteen (14.3%) patients developed HCC during follow-up period. Thirteen of them had high baseline aspartate aminotransferase to platelet ratio index (APRI) (ie, an APRI >2.0). Multivariate analysis showed that those without sustained virologic response (SVR) (hazard ratio [HR] 5.795; 95% confidence interval [CI] 1.370–24.5; P=0.017) and high APRI (HR 5.548; 95% CI 1.191–25.86; P=0.029) had a significantly higher risk of HCC occurrence. The cumulative incidence of HCC was significantly higher (P=0.009) in patients without SVR (3-year cumulative incidence 21.4%; 95% CI 7.4%–35.5%; 5-year cumulative incidence 31.1%; 95% CI 11.2%–51.1%) compared to those with SVR (3- and 5-year cumulative incidence 6.2%; 95% CI 0%–1.3%). Further, the cumulative incidence of HCC was significantly higher (P=0.006) in patients with high APRI (3-year cumulative incidence 21.8%; 95% CI 8.2%–35.3%; 5-year cumulative incidence 30.5%, 95% CI 11.8%–49.3%) compared to those with low APRI (3- and 5-year cumulative incidence 4.2%, 95% CI 0%–1.0%).Conclusion: In HCV-infected cirrhotic patients who received combination therapy, APRI and SVR are the two major predictors of HCC development. Keywords: aspartate aminotransferase to platelet ratio index, chronic hepatitis C, hepatitis C virus, hepatocellular carcinoma, liver cirrhosis, sustained virologic response

Chih-Wei Tseng,1,2 Ting-Tsung Chang,3,4 Shinn-Jia Tzeng,5 Yu-Hsi Hsieh,1,2 Tsung-Hsing Hung,1,2 Hsiang-Ting Huang,6 Shu-Fen Wu,7 Kuo-Chih Tseng1,2 1Department of Internal Medicine, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chia-Yi, 2School of Medicine, Tzuchi University, Hualien, 3Department of Internal Medicine, National Cheng Kung University Medical College and Hospital, 4Infectious Disease and Signaling Research Center, National Cheng Kung University, Tainan, 5Department of Agronomy, National Chiayi University, 6Department of Nursing, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, 7Institute of Molecular Biology, National Chung Cheng University, Chia-Yi, Taiwan Objective: We studied the effect of sustained virologic response (SVR) after treatment with pegylated-interferon (PEG-IFN) plus ribavirin on the development of liver cirrhosis in elderly patients with chronic hepatitis C (CHC). Patients and methods: This retrospective study enrolled 145 elderly CHC patients (aged ≥65 years) who were treatment-naïve and were treated with PEG-IFN plus ribavirin for 6 months between January 2005 and December 2011. Abdominal sonography was performed and liver biochemistry was studied at baseline, at the end of treatment, and every 3–6 months thereafter. The development of liver cirrhosis and related complications was evaluated at the follow-ups. The aspartate aminotransferase-to-platelet ratio index was used as a noninvasive maker for fibrosis. Results: The mean patient age was 69.1±3.3 years, and the average follow-up time was 5.5 years (standard deviation: 2.5 years, range: 1.1–12.3 years). Ninety-five patients (65.5%) achieved SVR, and 26 (17.9%) discontinued treatment. Twenty-seven patients (18.6%) developed liver cirrhosis after treatment. Patients without SVR had significantly greater risk of liver cirrhosis than those with SVR (hazard ratio [HR]: 3.39, 95% confidence interval [CI]: 1.312–8.761, P=0.012). The difference in 3-year cumulative incidence of liver cirrhosis was 24.8% greater for patients without SVR (35.2%, 95% CI: 13.0–57.5, P=0.012) compared with those with SVR (10.4%, 95% CI: 3.1–17.7). There was a trend of a higher baseline aspartate aminotransferase-to-platelet ratio index score in patients who progressed to liver cirrhosis compared with those who did not progress (2.1±1.2 vs 1.6±1.3, P=0.055), but the difference failed to reach significance by Cox regression (adjusted HR: 1.285, 95% CI: 0.921–1.791, P=0.14). Conclusion: An SVR following PEG-IFN combination treatment can reduce the risk of liver cirrhosis in elderly CHC patients. Keywords: hepatitis C, sustained virologic response, pegylated interferon, ribavirin, liver cirrhosis

Zygomycosis is a rare invasive opportunistic fungal infection that occurs in the setting of hematologic malignancies, chemotherapy-induced neutropenia, and immunosuppressive therapies. We report the first case of disseminated appendiceal zygomycosis due to

The T cell response to the 65-kD mycobacterial heat-shock protein (Bhsp65) has been implicated in the pathogenesis of autoimmune arthritis. Adjuvant arthritis (AA) induced in the Lewis rat (RT-1(l)) by injection of Mycobacterium tuberculosis serves as an experimental model for human rheumatoid arthritis (RA). However, the immunological basis of regulation of acute AA, or of susceptibility/resistance to AA is not known. We have defined the specificity of the proliferative T cell responses to Bhsp65 during the course of AA in the Lewis rat. During the early phase of the disease (6-9 d after onset of AA), Lewis rats raised T cell responses to many determinants within Bhsp65, spread throughout the molecule. Importantly, in the late phase of the disease (8-10 wk after onset of AA), there was evidence for diversification of the T cell responses toward Bhsp65 carboxy-terminal determinants (BCTD) (namely, 417-431, 441-455, 465-479, 513-527, and 521-535). Moreover, arthritic rats in the late phase of AA also raised vigorous T cell responses to those carboxy-terminal determinants within self(rat) hsp65 (Rhsp65) that correspond in position to the above BCTD. These results suggest that the observed diversification is possibly triggered in vivo by induction of self(Rhsp65)-reactive T cells. Interestingly, another strain of rat, the Wistar Kyoto (WKY/NHsd) rat (RT-1(l)), with the same major histocompatibility complex class II molecules as the Lewis rat, was found to be resistant to AA. In WKY rats, vigorous responses to the BCTD, to which the Lewis rat responded only in the late phase of AA, were observed very early, 10 d after injection of M. tuberculosis, Strikingly, pretreatment with the peptides comprising the set of BCTD, but not its amino-terminal determinants, provided significant protection to naive Lewis rats from subsequent induction of AA. Thus, T cell responses to the BCTD are involved in regulating inflammatory arthritis in the Lewis rat and in conferring resistance to AA in the WKY rat. These results have important implications in understanding the pathogenesis of RA and in devising new immunotherapeutic strategies for this disease.

Brown root rot disease (BRRD) is a highly destructive tree disease. Early diagnosis of BRRD has been challenging because the first symptoms and signs are often observed after extensive tissue colonization. Existing molecular detection methods, all based on the internal transcribed spacer (ITS) region, were developed without testing against global Phellinus noxius isolates, other wood-decay fungi, or host plant tissues. This study aimed to develop SYBR Green real-time quantitative PCR (qPCR) assays for P. noxius . The primer pair Pn_ITS_F/Pn_ITS_R targets the ITS, and the primer pair Pn_NLR_F/Pn_NLR_R targets a P. noxius -unique group of homologous genes identified through a comparative genomics analysis. The homologous genes belong to the nucleotide-binding-oligomerization-domain-like receptor (NLR) superfamily. The new primer pairs and a previous primer pair G1F/G1R were optimized for qPCR conditions and tested for specificity using 61 global P. noxius isolates, 5 other Phellinus species, and 22 non- Phellinus wood-decay fungal species. Although all three primer pairs could detect as little as 100 fg (approximately 2.99 copies) of P. noxius genomic DNA, G1F/G1R had the highest specificity and Pn_NLR_F/Pn_NLR_R had the highest efficiency. To avoid false positives, the cutoff quantification cycle values were determined as 34 for G1F/G1R, 29 for Pn_ITS_F/Pn_ITS_R, and 32 for Pn_NLR_F/Pn_NLR_R. We further validated these qPCR assays using Ficus benjamina seedlings artificially inoculated with P. noxius , six tree species naturally infected by P. noxius , rhizosphere soil, and bulk soil. The newly developed qPCR assays provide sensitive detection and quantification of P. noxius , which is useful for long-term monitoring of BRRD status., Competing Interests: The author(s) declare no conflict of interest.

The plasticizer di(2-ethylhexyl) phthalate (DEHP) is a widespread environmental pollutant due to its extensive use. While circadian rhythms are inherent in most living organisms, the detrimental effects of DEHP on circadian rhythm and the underlying mechanisms remain largely unknown. This study investigated the influence of early developmental exposure to DEHP on circadian rhythm and explored the possible relationship between circadian disruption and DEHP metabolism in the model organism Caenorhabditis elegans. We observed that DEHP disrupted circadian rhythm in a dose-dependent fashion. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis revealed that DEHP-induced circadian disruption accompanies with altered proportions of DEHP metabolites in C. elegans. RNA sequencing data demonstrated that DEHP-induced circadian rhythm disruption caused differential gene expression. Moreover, DEHP-induced circadian disruption coincided with attenuated inductions of DEHP-induced cytochrome P450 genes, cyp-35A2, cyp-35A3, and cyp-35A4. Notably, cyp-35A2 mRNA exhibited circadian rhythm with entrainment, but DEHP exposure disrupted this rhythm. Our findings suggest that DEHP exposure disrupts circadian rhythm, which is associated with changes in DEHP metabolites and cytochrome P450 gene expression in C. elegans. Given the ubiquitous nature of DEHP pollution and the prevalence of circadian rhythms in living organisms, this study implies a potential negative impact of DEHP on circadian rhythm and DEHP metabolism in organisms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Inflammation is one of exacerbating factors of diabetic kidney disease (DKD). Upregulated CXCL5 is found in clinical and experimental diabetes studies. This study aimed to investigate the impact and mechanism of CXCL5 on DKD. DKD patients with different levels of urine albumin-to-creatinine ratio were enrolled. Lepr db/db mice and CXCL5-knockout diabetic mice were used as mouse models for DKD. Human renal tubular epithelial cells were used for in vitro experiments. Circulating CXCL5 were increased in DKD patients compared to the non-DKD subjects. CXCL5 inhibition through CXCL5-neutralizing antibodies or genetic knockout improved kidney function and ameliorated tubular injury and renal fibrosis. In high-glucose-stimulated tubular epithelial cells, administration of CXCL5-neutralizing antibodies or siRNA resulted in reduced phospho-JNK/c-JUN/p65 and the downstream inflammatory, fibrotic, and apoptotic protein expressions. Administration of CXCR2 and JNK inhibitors impeded the CXCL5-induced tubular epithelial cell damages. In conclusion, these findings indicated that anti-CXCL5 strategies may be potential treatments for DKD., Competing Interests: Declaration of competing interest The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2024. Published by Elsevier Inc.)

Dermal white adipose tissue may participate in the wound-healing process. Obesity-mediated chronic low-grade inflammation impairs wound healing by suppressing vascularity. Given that FABP4 is upregulated in the skin tissue of animals with obesity, this study aimed to investigate the effects of FABP4 inhibition on wound healing in mice with high-fat diet-induced metabolic dysfunction in vivo. The interaction between adipocyte-derived FABP4 and vascular endothelial cell function was also investigated. In mice with high-fat diet-induced metabolic dysfunction, FABP4 inhibition increased angiogenesis and facilitated wound healing with reduced wound inflammation. FABP4 inhibition not only attenuated systemic inflammation, decreased body weight, and reduced insulin resistance but also improved the sizes of adipocytes and hypoxic conditions in dermal white adipose tissue. In vitro hypoxia was used to induce adipocyte inflammation, and the supernatants from hypoxia-stimulated adipocytes impaired the function and angiogenetic capability of human dermal microvascular endothelial cells (HDMECs). Both of them were improved by FABP4 inhibition. Altogether, FABP4 inhibition reduced systemic and adipocyte inflammation, improved vascular endothelial cell function, and facilitated wound healing in metabolic dysfunctions. Given the complex involvement of wound healing, future studies may be required to validate FABP4 as a potential therapeutic target for wound repair in metabolic dysfunctions., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Diabetic vascular disease is a major complication of diabetes mellitus (DM). Chemokine C-C motif ligand 7 (CCL7) attracts macrophages and monocytes, amplifying inflammatory processes in the vasculature. We hypothesized a causal role for CCL7 in diabetic vasculopathy. CCL7 concentrations were higher in the plasma of patients with type 2 DM, as well as in supernatants from their endothelial progenitor cells (EPCs). High-glucose stimulation increased the secretion of CCL7 from human dermal microvascular endothelial cells (HDMECs) through the c-Fos and c-Jun signaling pathways. CCL7 inhibition using knockdown or neutralization antibody treatment reversed the high glucose-induced impaired tube formation and migration abilities of EPCs, human aortic endothelial cells, human coronary artery endothelial cells, and HDMECs. Administration of recombinant human CCL7 protein impaired tube formation and migration abilities by down-regulating the AKT-endothelial nitric oxide synthase and AKT/nuclear factor erythroid 2-related factor 2/heme oxygenase-1/vascular endothelial growth factor/stromal cell-derived factor-1 pathways and by up-regulating ERK/phosphorylated p65/interleukin-1β/interleukin-6/tumor necrosis factor-α pathways through CC chemokine receptor 3 in endothelial cells. Ccl7 knockout in streptozotocin-treated mice showed improved neovasculogenesis in ischemic limbs and accelerated wound repair, with increased circulating EPCs and capillary density. CCL7 antibody treatment in db/db mice and high-fat diet-induced hyperglycemia mice showed improved neovasculogenesis in ischemic limbs and wound areas, accompanied by up-regulation of angiogenic proteins and down-regulation of inflammatory proteins. Endothelial cell-specific Ccl7 -knockout mice showed ameliorated diabetic vasculopathy in streptozotocin-induced DM. This study highlights the potential of CCL7 as a therapeutic target for diabetic vasculopathy.

Introduction: Febrile neutropenia is a common complication in patients undergoing chemotherapy for hematologic malignancies and is associated with significant morbidity and mortality. Primary granulocyte colony-stimulating factor (G-CSF) prophylaxis is consistently associated with a notable reduction in the risk of febrile neutropenia. However, the use of G-CSF in patients who are already neutropenic from chemotherapy remains controversial. Studies have shown that 12.9 % of cancer patients incorporate traditional Chinese medicine (TCM) to alleviate chemotherapy side effects in Taiwan; thereby providing an alternative management strategy for febrile neutropenia in cancer patients., Case Presentation: This is an 18-year-old female with newly diagnosed precursor T-lymphoblastic lymphoma. After chemotherapy, the patient developed febrile neutropenia. Despite the use of antibiotics and G-CSF, the febrile neutropenia persisted for two months. Approximately ten days after the initiation of traditional Chinese medicine decoction with the strategy of tonifying the spleen and stomach, clearing yin fire, and uplifting yang, her absolute neutrophil count (ANC) had gradually increased. Additionally, after two weeks of treatment, her fever subsided. The patient continued with chemotherapy and was discharged in stable condition., Discussion: Antibiotic use aligns with the TCM perspective of an "attack" approach. Conversely, our TCM decoction was designed to raise the ANC by tonifying the spleen and stomach, clearing Yin Fire, and uplifting Yang. Li Dongyuan, one of the four great masters of the Jin Yuan Dynasty, created the formula: Bupiwei Shengyang Sanhuo Decoction that is notable in this regard. The herbs in our decoction have shown hematopoietic and myelosuppression-alleviating effect. For many patients who do not respond adequately to G-CSF alone, integrative treatments involving both TCM and Western medicine can offer additional therapeutic benefits by increasing blood cell counts., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Treating older patients with acute appendicitis with multiple underlying diseases is a challenging situation in the clinical setting. Throughout the history of East Asian medicine, many texts have noted the use of herbal decoctions to successfully treat symptoms associated with appendicitis, thereby providing an alternative management strategy for treating frail patients with acute appendicitis., Case Presentation: This report presents the case of a 93-year-old male diagnosed with acute appendicitis with appendicolith who was unsuitable for surgical intervention due to poor lung condition and prolonged prothrombin time caused by Apixaban. By receiving complementary therapy consisting of traditional Chinese medicine (TCM) and antibiotics, he recovered successfully., Discussion: In the early stage of acute appendicitis, infection control and gastrointestinal mobility are the most important factors to consider. Scientific research has demonstrated that many herbs used in TCM formulas possess anti-inflammatory, anti-oxidative and immune attenuation effects. For many patients who are unsuitable for surgical intervention due to unfavorable conditions, such as the prolonged prothrombin time presented in this case, complementary treatment with TCM offers adjuvant therapeutical effects associated with infection control, and improvement of the gastrointestinal environment and function of elderly patients., (Copyright © 2024. Published by Elsevier Inc.)

Using data samples collected with the BESIII detector at the BEPCII collider at center-of-mass energies ranging from 3.80 to 4.95 GeV, corresponding to an integrated luminosity of 20  fb^{-1}, a measurement of Born cross sections for the e^{+}e^{-}→D^{0}D[over ¯]^{0} and D^{+}D^{-} processes is presented with unprecedented precision. Many clear peaks in the line shape of e^{+}e^{-}→D^{0}D[over ¯]^{0} and D^{+}D^{-} around the mass range of G(3900), ψ(4040), ψ(4160), Y(4260), and ψ(4415), etc., are foreseen. These results offer crucial experimental insights into the nature of hadron production in the open-charm region.

Acute kidney injury (AKI), if not well controlled, may progress to chronic kidney disease (CKD). Diosgenin is a natural phytosteroid sapogenin from plants. This study aimed to investigate the mechanistic effects of diosgenin on AKI and AKI related development of CKD. The mouse model of ischemia/reperfusion (I/R)-induced AKI was used, and its progressive changes were followed. Human renal proximal tubular epithelial cells were used, and hypoxia stimulation was applied to mimic the in vivo I/R. Diosgenin, given after renal injury, preserved kidney function, as evidenced by a reduction in serum levels of BUN, creatinine, and UACR in both acute and chronic phases of AKI. Diosgenin alleviated I/R-induced tubular injury and prevented macrophage infiltration and renal fibrosis in AKI mice. Furthermore, diosgenin also mitigated the development of CKD from AKI with reduced renal expression of inflammatory, fibrotic, and epithelial-mesenchymal transition markers. In human renal tubular epithelial cells, diosgenin downregulated the hypoxia-induced oxidative stress and cellular damages that were dependent on the NOX4/p65 signaling pathways. Taken together, diosgenin treatment reduced I/R-induced AKI and ameliorated the progression to CKD from AKI probably by modifying the NOX4/p65 signaling pathways.

The relevance of aberrant serum IgG N-glycosylation in liver fibrosis has been identified; however, its causal effect remains unclear. Because hepatic stellate cells (HSCs) contribute substantially to liver fibrosis, we investigated whether and through which mechanisms IgG N-glycosylation affects the fibrogenic properties of HSCs. Analysis of serum IgG 1 N-glycome from 151 patients with chronic hepatitis B or liver cirrhosis revealed a positive correlation between Ishak fibrosis grading and IgG 1 with agalactosyl N-glycoforms on the crystallizable fragment (Fc). Fc gamma receptor (FcγR) IIIa was observed in cultured human HSCs and HSCs in human liver tissues, and levels of FcγRIIIa in HSCs correlated with the severity of liver fibrosis. Additionally, agalactosyl IgG treatment caused HSCs to have a fibroblast-like morphology, enhanced migration and invasion capabilities, and enhanced expression of the FcγRIIIa downstream tyrosine-protein kinase SYK. Furthermore, agalactosyl IgG treatment increased fibrogenic factors in HSCs, including transforming growth factor (TGF)-β1, total collagen, platelet-derived growth factor subunit B and its receptors, pro-collagen I-α1, α-smooth muscle actin, and matrix metalloproteinase 9. These effects were more pronounced in HSCs that stably expressed FCGR3A and were reduced in FCGR3A knockout cells. Agalactosyl IgG and TGF-β1 each increased FCGR3A in HSCs. Furthermore, serum TGF-β1 concentrations in patients were positively correlated with agalactosyl IgG 1 levels and liver fibrosis severity, indicating a positive feedback loop involving agalactosyl IgG, HSC-FcγRIIIa, and TGF-β1. In conclusion, agalactosyl IgG promotes fibrogenic characteristics in HSCs through FcγRIIIa. © 2024 The Pathological Society of Great Britain and Ireland., (© 2024 The Pathological Society of Great Britain and Ireland.)

The development and refinement of functional brain circuits crucial to human cognition is a continuous process that spans from childhood to adulthood. Research increasingly focuses on mapping these evolving configurations, with the aim to identify markers for functional impairments and atypical development. Among human cognitive systems, nonsymbolic magnitude representations serve as a foundational building block for future success in mathematical learning and achievement for individuals. Using task-based frontoparietal (FPN) and salience network (SN) features during nonsymbolic magnitude processing alongside machine learning algorithms, we developed a framework to construct brain age prediction models for participants aged 7-30. Our study revealed differential developmental profiles in the synchronization within and between FPN and SN networks. Specifically, we observed a linear increase in FPN connectivity, concomitant with a decline in SN connectivity across the age span. A nonlinear U-shaped trajectory in the connectivity between the FPN and SN was discerned, revealing reduced FPN-SN synchronization among adolescents compared to both pediatric and adult cohorts. Leveraging the Gradient Boosting machine learning algorithm and nested fivefold stratified cross-validation with independent training datasets, we demonstrated that functional connectivity measures of the FPN and SN nodes predict chronological age, with a correlation coefficient of .727 and a mean absolute error of 2.944 between actual and predicted ages. Notably, connectivity within the FPN emerged as the most contributing feature for age prediction. Critically, a more matured brain age estimate is associated with better arithmetic performance. Our findings shed light on the intricate developmental changes occurring in the neural networks supporting magnitude representations. We emphasize brain age estimation as a potent tool for understanding cognitive development and its relationship to mathematical abilities across the critical developmental period of youth. PRACTITIONER POINTS: This study investigated the prolonged changes in the brain's architecture across childhood, adolescence, and adulthood, with a focus on task-state frontoparietal and salience networks. Distinct developmental pathways were identified: frontoparietal synchronization strengthens consistently throughout development, while salience network connectivity diminishes with age. Furthermore, adolescents show a unique dip in connectivity between these networks. Leveraging advanced machine learning methods, we accurately predicted individuals' ages based on these brain circuits, with a more mature estimated brain age correlating with better math skills., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

Aging is a natural process associated with chronic inflammation in the development of vascular dysfunction. We hypothesized that chemokine C-C motif ligands 4 (CCL4) might play a vital role in aging-related vascular dysfunction. Circulating CCL4 was up-regulated in elderly subjects and in aged animals. CCL4 inhibition reduced generation of reactive oxygen species (ROS), attenuated inflammation, and restored cell functions in endothelial progenitor cells from elderly subjects and in aged human aortic endothelial cells. CCL4 promoted cell aging, with impaired cell functioning, by activating ROS production and inflammation. CCL4 knockout mice and therapeutic administration of anti-CCL4 neutralizing antibodies exhibited vascular and dermal anti-aging effects, with improved wound healing, via the down-regulation of inflammatory proteins and the activation of angiogenic proteins. Altogether, our findings suggested that CCL4 may contribute to aging-related vascular dysfunction via activating oxidative stress and endothelial inflammation. CCL4 may be a potential therapeutic target for vascular protections during aging., (© 2024. The Author(s).)

Background: Local translation at synapses is important for rapidly remodeling the synaptic proteome to sustain long-term plasticity and memory. While the regulatory mechanisms underlying memory-associated local translation have been widely elucidated in the postsynaptic/dendritic region, there is no direct evidence for which RNA-binding protein (RBP) in axons controls target-specific mRNA translation to promote long-term potentiation (LTP) and memory. We previously reported that translation controlled by cytoplasmic polyadenylation element binding protein 2 (CPEB2) is important for postsynaptic plasticity and memory. Here, we investigated whether CPEB2 regulates axonal translation to support presynaptic plasticity., Methods: Behavioral and electrophysiological assessments were conducted in mice with pan neuron/glia- or glutamatergic neuron-specific knockout of CPEB2. Hippocampal Schaffer collateral (SC)-CA1 and temporoammonic (TA)-CA1 pathways were electro-recorded to monitor synaptic transmission and LTP evoked by 4 trains of high-frequency stimulation. RNA immunoprecipitation, coupled with bioinformatics analysis, were used to unveil CPEB2-binding axonal RNA candidates associated with learning, which were further validated by Western blotting and luciferase reporter assays. Adeno-associated viruses expressing Cre recombinase were stereotaxically delivered to the pre- or post-synaptic region of the TA circuit to ablate Cpeb2 for further electrophysiological investigation. Biochemically isolated synaptosomes and axotomized neurons cultured on a microfluidic platform were applied to measure axonal protein synthesis and FM4-64FX-loaded synaptic vesicles., Results: Electrophysiological analysis of hippocampal CA1 neurons detected abnormal excitability and vesicle release probability in CPEB2-depleted SC and TA afferents, so we cross-compared the CPEB2-immunoprecipitated transcriptome with a learning-induced axonal translatome in the adult cortex to identify axonal targets possibly regulated by CPEB2. We validated that Slc17a6, encoding vesicular glutamate transporter 2 (VGLUT2), is translationally upregulated by CPEB2. Conditional knockout of CPEB2 in VGLUT2-expressing glutamatergic neurons impaired consolidation of hippocampus-dependent memory in mice. Presynaptic-specific ablation of Cpeb2 in VGLUT2-dominated TA afferents was sufficient to attenuate protein synthesis-dependent LTP. Moreover, blocking activity-induced axonal Slc17a6 translation by CPEB2 deficiency or cycloheximide diminished the releasable pool of VGLUT2-containing synaptic vesicles., Conclusions: We identified 272 CPEB2-binding transcripts with altered axonal translation post-learning and established a causal link between CPEB2-driven axonal synthesis of VGLUT2 and presynaptic translation-dependent LTP. These findings extend our understanding of memory-related translational control mechanisms in the presynaptic compartment., (© 2024. The Author(s).)

Background/aims: Oral EDP-514 is a potent core protein inhibitor of hepatitis B virus (HBV) replication, which produced a >4-log viral load reduction in HBV-infected chimeric mice with human liver cells. This study evaluated the safety, pharmacokinetics, and antiviral activity of three doses of EDP-514 in treatment-naive viremic patients with HBeAgpositive or -negative chronic HBV infection., Methods: Patients with HBsAg detectable at screening and at least 6 months previously were eligible. HBeAg-positive and -negative patients had a serum/plasma HBV DNA level ≥20,000 and ≥2,000 IU/mL, respectively. Twenty-five patients were randomized to EDP-514 200 (n=6), 400 (n=6) or 800 mg (n=7) or placebo (n=6) once daily for 28 days., Results: A dose-related increase in EDP-514 exposure (AUClast and Cmax) was observed across doses. At Day 28, mean reductions in HBV DNA were -2.9, -3.3, -3.5 and -0.2 log10 IU/mL with EDP-514 200 mg, 400 mg, 800 mg, and placebo groups, respectively. The corresponding mean change from baseline for HBV RNA levels was -2.9, -2.4, -2.0, and -0.02 log10 U/mL. No virologic failures were observed. No clinically meaningful changes from baseline were observed for HBsAg, HBeAg or HBcrAg. Nine patients reported treatment emergent adverse events of mild or moderate severity with no discontinuations, serious AEs or deaths., Conclusion: In treatment-naïve viremic patients, oral EDP-514 was generally safe and well-tolerated, displayed PK profile supportive of once-daily dosing, and markedly reduced HBV DNA and HBV RNA.

The naturally occurring bile acid lithocholic acid (LCA) has been a crucial core structure for many non-sugar-containing sialyltranferase (ST) inhibitors documented in literature. With the aim of elucidating the impact of the terminal carboxyl acid substituent of LCA on its ST inhibition, in this present study, we report the (bio)isosteric replacement-based design and synthesis of sulfonate and sulfate analogues of LCA. Among these compounds, the sulfate analogue SPP-002 was found to selectively inhibit N-glycan sialylation by at least an order of magnitude, indicating a substantial improvement in both potency and selectivity when compared to the unmodified parent bile acid. Molecular docking analysis supported the stronger binding of the synthetic analogue in the enzyme active site. Treatment with SPP-002 also hampered the migration, adhesion, and invasion of MDA-MB-231 cells in vitro by suppressing the expression of signaling proteins involved in the cancer metastasis-associated integrin/FAK/paxillin pathway. In totality, these findings offer not only a novel structural scaffold but also valuable insights for the future development of more potent and selective ST inhibitors with potential therapeutic effects against tumor cancer metastasis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Urinary albumin-creatinine ratio (UACR) and estimated glomerular filtration rates (eGFR) help predict worsening diabetic kidney disease (DKD) but have their limitations. Soluble tumor necrosis factor receptor type 1 (sTNFR1) is a biomarker of DKD. The predictive abilities of sTNFR1 and UACR plus eGFR have not been compared., Methods: This prospective cohort study included patients with type 2 diabetes (T2D) to identify the risk factors of worsening DKD. Renal events were defined as > 30 % loss in eGFR based on consecutive tests after 6 months. The associations of sTNFR1, UACR, and eGFR levels and the risks of renal events were tested using a Cox regression model and the area under the curve (AUC) was compared between sTNFR1 levels and UACR plus eGFR using receiver-operating characteristic (ROC) analysis. The accuracy of stratification was evaluated using Kaplan-Meier analysis., Results: Levels of sTNFR1 and UACR were associated with risks of > 30 % decline in eGFR after adjusting for relevant factors. The association between sTNFR1 levels and renal outcomes was independent of UACR and eGFR at baseline. The AUC of sTNFR1 level was comparable with that of combined UACR and eGFR (0.73 vs. 0.71, respectively, p = 0.72) and the results persisted for quartile groups of sTNFR1 and risk categories of Kidney Disease: Improving Global Outcomes (KDIGO) (0.70 vs. 0.71, respectively, p = 0.84). Both stratifications by sTNFR1 levels and KDIGO were accurate., Conclusion: sTNFR1 could be an alternative marker for identifying patients with diabetes at risk of declining renal function., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Both the clinical and mechanistic impacts of endocan were not well elucidated especially in coronary artery disease (CAD)., Objective: This study aimed to investigate the prognostic and potential pathological role of endocan for cardiovascular (CV) events in stable CAD patients., Methods: A total of 1,071 stable CAD patients with previous percutaneous coronary intervention (PCI) were enrolled prospectively in a nationwide Biosignature study. Another cohort of 76 CAD patients with or without PCI were enrolled for validation. Baseline biomarkers including endocan level was measured and total CV events especially hard CV events (including CV mortality, non-fatal myocardial infection and stroke) during follow-up were identified. Circulating endothelial progenitor cells (EPCs) as an in vivo biological contributor to vascular repairment from CAD patients were used for the in vitro functional study., Results: After 24 months, there were 42 patients (3.92%) with hard CV events and 207 (19.3%) with total CV events in the study group. The incidence of both events was increased with the tertiles of baseline endocan level (hard events: 1.7%,3.4%, and 6.7% in 1st,2nd, and 3rd tertile respectively, p = 0.002; total events: 13.8%vs.16.2%vs.28.0%, p < 0.0001). Multivariate regression analysis revealed the independent association of endocan level with total and hard CV events. These findings were validated in another cohort with a 5-year follow-up. Furthermore, in vitro inhibition of endocan improved cell migration and tube formation capacities, and reduced cell adhesiveness of EPCs from CAD patients., Conclusions: Endocan might be a novel prognostic indicator, mechanistic mediator, and potential therapeutic target for clinical CAD., (© 2024. The Author(s).)

We report the measurement of the inclusive cross sections for e^{+}e^{-}→nOCH (where nOCH denotes non-open charm hadrons) with improved precision at center-of-mass (c.m.) energies from 3.645 to 3.871 GeV. We observe three resonances: R(3760), R(3780), and R(3810) with significances of 8.1σ, 13.7σ, and 8.8σ, respectively. The R(3810) state is observed for the first time, while the R(3760) and R(3780) states are observed for the first time in the nOCH cross sections. Two sets of resonance parameters describe the energy-dependent line shape of the cross sections well. In set I [set II], the R(3810) state has mass (3805.7±1.1±2.7) [(3805.7±1.1±2.7)]  MeV/c^{2}, total width (11.6±2.9±1.9) [(11.5±2.8±1.9)]  MeV, and an electronic width multiplied by the nOCH decay branching fraction of (10.9±3.8±2.5) [(11.0±3.4±2.5)]  eV. In addition, we measure the branching fractions B[R(3760)→nOCH]=(25.2±16.1±30.4)%[(6.4±4.8±7.7)%] and B[R(3780)→nOCH]=(12.3±6.6±8.3)%[(10.4±4.8±7.0)%] for the first time. The R(3760) state can be interpreted as an open-charm (OC) molecular state, but containing a simple four-quark state component. The R(3810) state can be interpreted as a hadrocharmonium state.

We present measurements of the Born cross sections for the processes e^{+}e^{-}→ωχ&#95;{c1} and ωχ&#95;{c2} at center-of-mass energies sqrt[s] from 4.308 to 4.951 GeV. The measurements are performed with data samples corresponding to an integrated luminosity of 11.0  fb^{-1} collected with the BESIII detector operating at the Beijing Electron Positron Collider storage ring. Assuming the e^{+}e^{-}→ωχ&#95;{c2} signals come from a single resonance, the mass and width are determined to be M=(4413.6±9.0±0.8)  MeV/c^{2} and Γ=(110.5±15.0±2.9)  MeV, respectively, which is consistent with the parameters of the well-established resonance ψ(4415). In addition, we also use one single resonance to describe the e^{+}e^{-}→ωχ&#95;{c1} line shape and determine the mass and width to be M=(4544.2±18.7±1.7)  MeV/c^{2} and Γ=(116.1±33.5±1.7)  MeV, respectively. The structure of this line shape, observed for the first time, requires further understanding.

We perform a study of the χ&#95;{c1}(3872) line shape using the data samples of e^{+}e^{-}→γχ&#95;{c1}(3872), χ&#95;{c1}(3872)→D^{0}D[over ¯]^{0}π^{0}, and π^{+}π^{-}J/ψ collected with the BESIII detector. The effects of the coupled channels and the off-shell D^{*0} are included in the parametrization of the line shape. The line shape mass parameter is obtained to be M&#95;{X}=(3871.63±0.13&#95;{-0.05}^{+0.06})  MeV. Two poles are found on the first and second Riemann sheets corresponding to the D^{*0}D[over ¯]^{0} branch cut. The pole location on the first sheet is much closer to the D^{*0}D[over ¯]^{0} threshold than the other, and is determined to be 7.04±0.15&#95;{-0.08}^{+0.07}  MeV above the D^{0}D[over ¯]^{0}π^{0} threshold with an imaginary part -0.19±0.08&#95;{-0.19}^{+0.14}  MeV.

Sialyltransferase-catalyzed membrane protein and lipid glycosylation plays a vital role as one of the most abundant post-translational modifications and diversification reactions in eukaryotes. However, aberrant sialylation has been associated with cancer malignancy and metastasis. Sialyltransferases thus represent emerging targets for the development of small molecule cancer drugs. Herein, we report the inhibitory effects of a recently discovered lithocholic acid derivative FCW393 on sialyltransferase catalytic activity, integrin sialyation, cancer-associated signal transduction, MDA-MB-231 and B16F10 cell migration and invasion, and in in vivo studies, on tumor growth, metastasis, and angiogenesis. FCW393 showed effective and selective inhibition of the sialyltransferases ST6GAL1 (IC 50 = 7.8 μM) and ST3GAL3 (IC 50 = 9.45 μM) relative to ST3GAL1 (IC 50 > 400 μM) and ST8SIA4 (IC 50 > 100 μM). FCW393 reduced integrin sialylation in breast cancer and melanoma cells dose-dependently and downregulated proteins associated with the integrin-regulated FAK/paxillin and GEF/Rho/ROCK pathways, and with the VEGF-regulated Akt/NFκB/HIF-1α pathway. FCW393 inhibited cell migration (IC 50 = 2.6 μM) and invasion in in vitro experiments, and in in vivo studies of tumor-bearing mice, FCW393 reduced tumor size, angiogenesis, and metastatic potential. Based on its demonstrated selectivity, cell permeability, relatively low cytotoxicity (IC 50 = 55 μM), and high efficacy, FCW393 shows promising potential as a small molecule experimental tool compound and a lead for further development of a novel cancer therapeutic.

Using a sample of (10087±44)×10^{6}  J/ψ events, which is about 45 times larger than that was previously analyzed, a further investigation on the J/ψ→γ3(π^{+}π^{-}) decay is performed. A significant distortion at 1.84  GeV/c^{2} in the line shape of the 3(π^{+}π^{-}) invariant mass spectrum is observed for the first time, which could be resolved by two overlapping resonant structures, X(1840) and X(1880). The new state X(1880) is observed with a statistical significance larger than 10σ. The mass and width of X(1880) are determined to be 1882.1±1.7±0.7  MeV/c^{2} and 30.7±5.5±2.4  MeV, respectively, which indicates the existence of a pp[over ¯] bound state.