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Alternative splicing (AS) plays a crucial role in the hallmarks of cancer and can open new avenues for targeted therapies. However, the aberrant AS events and the metastatic cascade in papillary thyroid carcinoma (PTC) remain largely unclear. Here, we identify the splicing factor, quaking protein (QKI), which was significantly downregulated in PTC and correlated with poor survival outcomes in patients with PTC. Functional studies indicated that low expression of QKI promoted the PTC cell growth and metastasis in vitro and in vivo. Mechanistically, low QKI induced exon 14 retention of extended synaptotagmin 2 (E-Syt2) and produced a long isoform transcript (termed E-Syt2L) that acted as an important oncogenic factor of PTC metastasis. Notably, overexpression of long non-coding RNA eosinophil granule ontogeny transcript (EGOT) physically binds to QKI and suppressed its activity by inhibiting ubiquitin specific peptidase 25 (USP25) mediated deubiquitination and subsequent degradation of QKI. Collectively, these data demonstrate the novel mechanistic links between the splicing factor QKI and splicing event in PTC metastasis and support the potential utility of targeting splicing events as a therapeutic strategy for PTC., Competing Interests: Declaration of competing interest The authors declared no competing interests. All authors have seen and approved the manuscript and consent publication., (Copyright © 2024. Published by Elsevier B.V.)

Background: The biological activity and pharmacological effects of rare ginsenosides have been proven to be superior to those of the major ginsenosides, but they are rarely found in ginseng., Methods: Ginsenoside Rb1 was chemically transformed with the involvement of methanol molecules by a synthesized heterogeneous catalyst 12-HPW@MeSi, which was obtained by the immobilization of 12-phosphotungstic acid on a mesoporous silica framework. High-performance liquid chromatography coupled with mass spectrometry was used to identify the transformation products., Results: A total of 18 transformation products were obtained and identified. Methanol was found to be involved in the formation of 8 products formed by the addition of methanol molecules to the C-24 (25), C-20 (21) or C-20 (22) double bonds of the aglycone. The transformation pathways of ginsenoside Rb1 involved deglycosylation, addition, elimination, cycloaddition, and epimerization reactions. These pathways could be elucidated in terms of the stability of the generated carbenium ion. In addition, 12-HPW@MeSi was able to maintain a 60.5% conversion rate of Rb1 after 5 cycles., Conclusion: Tandem and high-resolution mass spectrometry analysis allowed rapid and accurate identification of the transformation products through the characteristic fragment ions and neutral loss. Rare ginsenosides with methoxyl groups grafted at the C-25 and C-20 positions were obtained for the first time by chemical transformation using the composite catalyst 12-HPW@MeSi, which also enabled cyclic heterogeneous transformation and facile centrifugal separation of ginsenosides. This work provides an efficient and recyclable strategy for the preparation of rare ginsenosides with the involvement of organic molecules., Competing Interests: 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., (© 2024 The Korean Society of Ginseng. Publishing services by Elsevier B.V.)

Acteoside is a bioactive phenylethanoid glycoside widely distributed throughout the plant kingdom. Because of its two catechol moieties, acteoside displays a variety of beneficial activities. The biosynthetic pathway of acteoside has been largely elucidated, but the assembly logic of two catechol moieties in acteoside remains unclear. Here, we identified a novel polyphenol oxidase OfPPO2 from Osmanthus fragrans, which could hydroxylate various monophenolic substrates, including tyrosine, tyrosol, tyramine, 4-hydroxyphenylacetaldehyde, salidroside, and osmanthuside A, leading to the formation of corresponding catechol-containing intermediates for acteoside biosynthesis. OfPPO2 could also convert osmanthuside B into acteoside, creating catechol moieties directly via post-modification of the acteoside skeleton. The reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis and subcellular localization assay further support the involvement of OfPPO2 in acteoside biosynthesis in planta. These findings suggest that the biosynthesis of acteoside in O. fragrans may follow "parallel routes" rather than the conventionally considered linear route. In support of this hypothesis, the glycosyltransferase OfUGT and the acyltransferase OfAT could direct the flux of diphenolic intermediates generated by OfPPO2 into acteoside. Significantly, OfPPO2 and its orthologs constitute a functionally conserved enzyme family that evolved independently from other known biosynthetic enzymes of acteoside, implying that the substrate promiscuity of this PPO family may offer acteoside-producing plants alternative ways to synthesize acteoside. Overall, this work expands our understanding of parallel pathways plants may employ to efficiently synthesize acteoside, a strategy that may contribute to plants' adaptation to environmental challenges., (© 2024 Society for Experimental Biology and John Wiley & Sons Ltd.)

Motivation is a key factor in engagement, achievement, and career choices in science, technology, engineering, and mathematics (STEM). While existing research has focused on student motivation toward math in formal school programs, new work is needed that focuses on motivation for those involved in informal STEM programs. Specifically, the role of math mindset and perceived inclusivity of informal STEM sites (to those of varying gender and ethnic backgrounds) on longitudinal trajectories of adolescents' math motivation has not been explored. This study investigates longitudinal changes in math expectancy, interest, and utility values and the effects of math fixed mindset, math growth mindset, and perceptions of the inclusivity of informal STEM learning sites on these changes for adolescents participating in STEM programs at these informal sites in the United Kingdom and the United States (n = 249, M T1age  = 15.2, SD = 1.59). Three latent growth curve models were tested. The data suggest that math expectancy, interest, and utility values declined over three years. Growth mindset positively predicted changes in utility, while fixed mindset negatively predicted changes in utility. Inclusivity positively influenced the initial levels of utility. Girls reported lower initial expectancy than boys. Age influenced both the initial levels and rate of change for expectancy. Older adolescents had lower levels of expectancy compared to their younger counterparts; however, they had a less steep decline in expectancy over three years. These findings suggest that designing inclusive learning environments and promoting growth mindset may encourage math motivation., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Hemophagocytic lymphohistiocytosis (HLH) is an immune dysfunction characterized by an exaggerated and pathological inflammatory response, potentially leading to systemic inflammatory reactions and multiple-organ failure, including renal involvement. HLH can be classified as primary or secondary, with primary HLH associated with genetic mutations affecting cell degranulation capacity, and secondary HLH often linked to infections, tumors, and autoimmune diseases. The pathogenesis of HLH is not fully understood, but primary HLH is typically driven by genetic defects, whereas secondary HLH involves the activation of CD8+ T cells and macrophages, leading to the release of inflammatory cytokines and systemic inflammatory response syndrome (SIRS). The clinical presentation of HLH includes non-specific manifestations, making it challenging to differentiate from severe sepsis, particularly secondary HLH due to infections. Shared features include prolonged fever, hepatosplenomegaly, hematopenia, hepatic dysfunction, hypertriglyceridemia, and hypofibrinogenemia, along with histiocytosis and hemophagocytosis. However, distinctive markers like dual hemocytopenia, hypertriglyceridemia, hypofibrinogenemia, and elevated sCD25 levels may aid in differentiating HLH from sepsis. Indeed, no singular biomarker effectively distinguishes between hemophagocytic lymphohistiocytosis and infection. However, research on combined biomarkers provides insights into the differential diagnosis. Renal impairment is frequently encountered in both HLH and sepsis. It can result from a systemic inflammatory response triggered by an influx of inflammatory mediators, from direct damage caused by these factors, or as a consequence of the primary disease process. For instance, macrophage infiltration of the kidney can lead to structural damage affecting various renal components, precipitating disease. Presently, tubular necrosis remains the predominant form of renal involvement in HLH-associated acute kidney injury (HLH-AKI). However, histopathological changes may also encompass interstitial inflammation, glomerular abnormalities, microscopic lesions, and thrombotic microangiopathy. Treatment approaches for HLH and sepsis diverge significantly. HLH is primarily managed with repeated chemotherapy to eliminate immune-activating stimuli and suppress hypercellularity. The treatment approach for sepsis primarily focuses on anti-infective therapy and intensive symptomatic supportive care. Renal function significantly influences clinical decision-making, particularly regarding the selection of chemotherapy and antibiotic dosages, which can profoundly impact patient prognosis. Conversely, renal function recovery is a complex process influenced by factors such as disease severity, timely diagnosis, and the intensity of treatment. A crucial aspect in managing HLH-AKI is the timely diagnosis, which plays a pivotal role in reversing renal impairment and creating a therapeutic window for intervention, may have opportunity to improve patient prognosis. Understanding the clinical characteristics, underlying causes, biomarkers, immunopathogenesis, and treatment options for hemophagocytic lymphohistiocytosis associated with acute kidney injury (HLH-AKI) is crucial for improving patient prognosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhao, Guan, Lin, Qiu, Zhao and Duan.)

Philadelphia chromosome-positive (Ph + ) leukemia is a fatal hematological malignancy. Although standard treatments with tyrosine kinase inhibitors (TKIs) have achieved remarkable success in prolonging patient survival, intolerance, relapse, and TKI resistance remain serious issues for patients with Ph + leukemia. Here, we report a new leukemogenic process in which RAPSYN and BCR-ABL co-occur in Ph + leukemia, and RAPSYN mediates the neddylation of BCR-ABL. Consequently, neddylated BCR-ABL enhances the stability by competing its c-CBL-mediated degradation. Furthermore, SRC phosphorylates RAPSYN to activate its NEDD8 E3 ligase activity, promoting BCR-ABL stabilization and disease progression. Moreover, in contrast to in vivo ineffectiveness of PROTAC-based degraders, depletion of RAPSYN expression, or its ligase activity decreased BCR-ABL stability and, in turn, inhibited tumor formation and growth. Collectively, these findings represent an alternative to tyrosine kinase activity for the oncoprotein and leukemogenic cells and generate a rationale of targeting RAPSYN-mediated BCR-ABL neddylation for the treatment of Ph + leukemia., Competing Interests: MZ, BD, XL, YZ, SW, YY, YC listed as an inventor on Chinese patent 202210107464.7 (patent protection filed for by China Pharmaceutical University on RAPSYN), CQ, YQ, ZL, QL No competing interests declared, (© 2023, Zhao, Dai, Li et al.)

Selenium-rich tea polysaccharides (Se-TPS) were extracted via high hydrostatic pressure technology with a pressure of 400 MPa (200-500 MPa) for 10 min (3-20 min) at a material-to-solvent ratio of 1:40 (1:20-1:50). Subsequently, Se-TPS1-4 were isolated and purified, with Se-TPS3-4 as the main components. A spectral analysis proved that Se, which has antioxidant activity, existed. An in vitro study found that among Se-TPS, Se-TPS3-4 attenuated the release of β-hexosaminidase, histamine, and interleukin (IL)-4. Furthermore, in vivo experiments revealed that treatment with Se-TPS downregulated IL-4 levels and upregulated TGF-β and interferon-γ levels to improve imbalanced Th1/Th2 immunity in tropomyosin-sensitized mice. Moreover, Se-TPS promoted Lactobacillus and norank_f_Muribaculaceaek growth and upregulated metabolites such as genipin and coniferyl alcohol. Overall, these results showed the strong anti-allergy potential of Se-TPS by regulating mast cell-mediated allergic inflammatory responses and microbiota regulation, highlighting the potential of Se-TPS as a novel therapeutic agent to regulate allergy-associated metabolic disorders., Competing Interests: Declaration of competing interest The authors declared that there is no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background and Aims: The role of beta2-microglobulin (β2-MG) in predicting acute kidney injury (AKI) in hemophagocytic lymphohistiocytosis patients has been poorly studied. This study aimed to analyze the clinical characteristics of hemophagocytic lymphohistiocytosis patients and identify risk factors that predict AKI development., Methods: This retrospective observational cohort study conducted at a single-center involved 938 patients diagnosed with hemophagocytic lymphohistiocytosis, who were divided into AKI  group and non-AKI group. Patient data were collected and analyzed using univariate and multivariate binary logistic regression to identify potiential risk factors associated with AKI occurrence.   RESULTS: Among the enrolled patients, 486 were male (51.9%), the median age was 37 years (interquartile range, 28.0, 52.0), 58.4% experienced AKI. Mechanical ventilation (8.0% vs. 0.8%) and vasopressor support (21.7% vs. 4.1%) occurred at significantly higher rates in the AKI group compared to the non-AKI group, with significantly higher in-hospital mortality (5.5% vs. 1.3%) and 28-day mortality (12.8% vs. 5.4%). When β2-MG was used as a continuous variable, multifactorial analysis showed that β2-MG, transplantation, and vasopressor support were independently associated with risk for the development of AKI., Conclusions: The incidence of morbidity and mortality in patients with hemophagocytic lymphohistiocytosis complicated by AKI remains high. Monitoring levels of β2-MG may provide clinicians with timely indicators of changes in renal function,  facilitating adjustments to treatment strategies., (© 2024. The Author(s).)

Background & Aims: Although the presence of tertiary lymphoid structures (TLS) correlates with positive responses to immunotherapy in many solid malignancies, the mechanism by which TLS enhances antitumor immunity is not well understood. The present study aimed to investigate the underlying cross talk circuits between B cells and tissue-resident memory T (Trm) cells within the TLS and to understand their role in the context of immunotherapy., Methods: Immunostaining and H&E staining of TLS and chemokine (C-X-C motif) ligand 13 (CXCL13) + cluster of differentiation (CD)103 + CD8 + Trm cells were performed on tumor sections from patients with gastric cancer (GC). The mechanism of communication between B cells and CXCL13 + CD103 + CD8 + Trm cells was determined in vitro and in vivo. The effect of CXCL13 + CD103 + CD8 + Trm cells in suppressing tumor growth was evaluated through anti-programmed cell death protein (PD)-1 therapy., Results: The presence of TLS and CXCL13 + CD103 + CD8 + Trm cells in tumor tissues favored a superior response to anti-PD-1 therapy in patients with GC. Additionally, our research identified that activated B cells enhanced CXCL13 and granzyme B secretion by CD103 + CD8 + Trm cells. Mechanistically, B cells facilitated the glycolysis of CD103 + CD8 + Trm cells through the lymphotoxin-α/tumor necrosis factor receptor 2 (TNFR2) axis, and the mechanistic target of rapamycin signaling pathway played a critical role in CD103 + CD8 + Trm cells glycolysis during this process. Moreover, the presence of TLS and CXCL13 + CD103 + CD8 + Trm cells correlated with potent responsiveness to anti-PD-1 therapy in a TNFR2-dependent manner., Conclusions: This study further reveals a crucial role for cellular communication between TLS-associated B cell and CXCL13 + CD103 + CD8 + Trm cells in antitumor immunity, providing valuable insights into the potential use of the lymphotoxin-α/TNFR2 axis within CXCL13 + CD103 + CD8 + Trm cells for advancing immunotherapy strategies in GC., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The vasculature of the central nervous system is a 3D lattice composed of laminar vascular beds interconnected by penetrating vessels. The mechanisms controlling 3D lattice network formation remain largely unknown. Combining viral labeling, genetic marking, and single-cell profiling in the mouse retina, we discovered a perivascular neuronal subset, annotated as Fam19a4/Nts-positive retinal ganglion cells (Fam19a4/Nts-RGCs), directly contacting the vasculature with perisomatic endfeet. Developmental ablation of Fam19a4/Nts-RGCs led to disoriented growth of penetrating vessels near the ganglion cell layer (GCL), leading to a disorganized 3D vascular lattice. We identified enriched PIEZO2 expression in Fam19a4/Nts-RGCs. Piezo2 loss from all retinal neurons or Fam19a4/Nts-RGCs abolished the direct neurovascular contacts and phenocopied the Fam19a4/Nts-RGC ablation deficits. The defective vascular structure led to reduced capillary perfusion and sensitized the retina to ischemic insults. Furthermore, we uncovered a Piezo2-dependent perivascular granule cell subset for cerebellar vascular patterning, indicating neuronal Piezo2-dependent 3D vascular patterning in the brain., Competing Interests: Declaration of interests J.Z. and X.Y. are employees of Genentech/Roche. J.K. is listed as an inventor on Boehringer Ingelheim’s patent (AAV-BR1, #10696717)., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The biotransformation of ginsenosides using microorganisms represents a promising and ecofriendly approach for the production of rare ginsenosides. The present study reports on the biotransformation of ginsenoside Rb1 using the fungus Irpex lacteus , resulting in the production of ginsenoside Rd and seven rare ginsenosides with novel structures. Employing high-performance liquid chromatography coupled with high-resolution tandem mass spectrometry, the identities of the transformation products were rapidly determined. Two sets of isomers with molecular weights of 980.56 and 962.55 were discovered among the seven rare ginsenosides, which were generated through the isomerization of the olefin chain in the protopanaxadiol (PPD)-type ginsenoside skeleton. Each isomer exhibited characteristic fragment ions and neutral loss patterns in their tandem mass spectra, providing evidence of their unique structures. Time-course experiments demonstrated that the transformation reaction reached equilibrium after 14 days, with Rb1 initially generating Rd and compound 5 , followed by the formation of other rare ginsenosides. The biotransformation process catalyzed by I. lacteus was found to involve not only the typical deglycosylation reaction at the C-20 position but also hydroxylation at the C-22 and C-23 positions, as well as hydrogenation, transfer, and cyclization of the double bond at the C-24(25) position. These enzymatic capabilities extend to the structural modification of other PPD-type ginsenosides such as Rc and Rd, revealing the potential of I. lacteus for the production of a wider range of rare ginsenosides. The transformation activities observed in I. lacteus are unprecedented among fungal biotransformations of ginsenosides. This study highlights the application of a medicinal fungi-based biotransformation strategy for the generation of rare ginsenosides with enhanced structural diversity, thereby expanding the variety of bioactive compounds derived from ginseng., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Past research has shown that growth mindset and motivational beliefs have an important role in math and science career interest in adolescence. Drawing on situated expectancy-value theory (SEVT), this study extends these findings by investigating the role of parental motivational beliefs (e.g., expectancy beliefs, utility values) and parent growth mindset in math on adolescent career interest in math-intensive fields (e.g., mathematics, computer science, statistics, and engineering; MCSE) through adolescent motivational beliefs in math. Structural equation modeling was used to test the hypothesized model using data from 290 adolescents (201 girls, 69.3%; Mage = 15.20), who participate in informal STEM (science, technology, engineering, mathematics) youth programs, and their parents (162 parents, 87.7% female) in the United Kingdom and the United States. As hypothesized, adolescent expectancy beliefs, utility values, and growth mindset in math had a significant direct effect on MCSE career interest. Further, there was a significant indirect effect of parental expectancy beliefs in math on MCSE career interest through adolescents' expectancy beliefs. Similarly, there was a significant indirect effect from parental utility values in math to MCSE career interest through adolescents' utility values. The findings suggest that parents' math motivational beliefs play a critical role in adolescent math motivational beliefs and their career interest in math-intensive fields., Competing Interests: We have no conflicts of interest to disclose., (Copyright: © 2024 Ozturk et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Ochratoxin A (OTA) contamination in grape juice has attracted widespread concern as OTA can lead to kidney disease and cause adverse neurological effects. An effective method to remove OTA is to make use of highly adsorbent materials that are able to remove the toxic contaminant. Recently, inactivated Lactobacillus plantarum- based biosorbents have shown to be an efficient, cost-effective and environmentally friendly bioremediation method in removing toxic pollutants such as OTA. We used five chemical thiol-modification methods to improve the adsorption efficiency of OTA in grape juice. The esterification of Lactobacillus plantarum (L-Es) significantly increased the sulfhydryl contents (-SH) by 251.33 μmol/g and >90% of OTA was removed. However, the inactivated microbial adsorbent was difficult to separate after adsorption and therefore, the prepared L-Es were embedded into the cellulose nanocrystals (L-Es@CNCs). Moreover, L-Es@CNCs significantly increased the adsorption rate of OTA in grape juice samples by 88.28% with negligible effects on juice quality due to the properties of easy re-use and excellent biodegradability. This showcases its potential application for OTA removal in the grape juice industry., Competing Interests: Authors declare that there are no conflicts of interest., (© 2024 The Authors.)

Limited research has explored the longitudinal pathway to youth career interests via identity and efficacy together. This study examined the longitudinal associations between science efficacy, STEM (science, technology, engineering and math) identity, and scientist career interest among girls who are historically considered as an underrepresented group among scientists. The sample included 308 girls (M age  = 15.22, SD age  = 1.66; 42.8% White) from six STEM youth programs, each at a different informal science learning site within the U.K. and the U.S. Longitudinal structural equation modelling demonstrated that science efficacy consistently predicted STEM identity and scientist career interest, and similarly, STEM identity consistently predicted science efficacy over a two-year period. Scientist career interest at 12 months predicted science efficacy at 24 months. The coefficients of efficacy predicting STEM identity and scientist career interest were significantly larger compared to STEM identity and scientist career interest in predicting science efficacy from 12 months to 24 months. Further mediation analysis supported a significant pathway from STEM identity at 3 months to scientist career interest at 24 months via 12-month science efficacy. The findings highlight that science efficacy and STEM identity for girls relate to their scientist career interest and these longitudinal associations are reciprocal. This study suggests that science efficacy and STEM identity mutually influence each other, and enhancing science efficacy and STEM identity is key to promoting adolescents' interest in being a scientist., (© 2023. Crown.)

Introduction: Cuproptosis is a novel form of cell death regulated by protein lipoylation and implicated in mitochondrial metabolism. However, further research is needed to explore the influence of the cuproptosis-related gene γ-glutamylcysteine synthetase (GCSH) on the prognosis of endometrial cancer (EC), the tumor immune microenvironment, and therapeutic response., Methods: The differential expression of GCSH between EC and normal tissues was analyzed using multiple public databases. Additionally, cancer and adjacent tissues were prospectively collected from 17 EC patients, and immunohistochemical analysis was performed to further investigate GCSH expression differences. The relationship between GCSH and the prognosis and clinicopathological characteristics of EC patients was evaluated, and a nomogram was constructed to predict patient survival based on GCSH expression. Subsequently, Gene set variation analysis was used to explore the potential biological functions of GCSH in EC. The impact of GCSH on the tumor microenvironment (TME) was estimated. Finally, the effect of GCSH on the response to immunotherapy and chemotherapeutic drugs in EC was investigated., Results: The expression of GCSH was significantly upregulated in EC. High GCSH expression was associated with poor prognosis in EC patients. Enrichment analysis revealed an association between high GCSH and immune suppression. Furthermore, high GCSH was found to be associated with a non-inflamed TME, leading to decreased infiltration levels of immune cells. Lastly, it was observed that patients with high GCSH exhibited insensitivity to both immunotherapy and chemotherapeutic drugs., Conclusion: This study revealed the role of GCSH in TME, response to therapy, and clinical prognosis in EC, which provided novel insights for the therapeutic application in EC., (© 2023 S. Karger AG, Basel.)

Rare ginsenosides with major pharmacological effects are barely present in natural ginseng and are required to be obtained by transformation. In the current study, ginsenoside Rb1 was chemically transformed with the involvement of ethanol molecules to prepare rare ginsenosides using the synthesized heterogeneous catalyst 12-HPW@MeSi. A total of 16 transformation products were obtained and identified using high-performance liquid chromatography coupled with multistage tandem mass spectrometry and high-resolution mass spectrometry. Ethanol molecules were involved in the production of 6 transformation products by adding to the C-20(21), C-20(22), or C-24(25) double bonds on the aglycone to produce ethoxyl groups at the C-25 and C-20 positions. Transformation pathways of ginsenoside Rb1 are summarized, which involve deglycosylation, elimination, cycloaddition, epimerization, and addition reactions. In addition, 12-HPW@MeSi was recyclable through a simple centrifugation, maintaining an 85.1% conversion rate of Rb1 after 3 cycles. This work opens up an efficient and recycled process for the preparation of rare ginsenosides with the involvement of organic molecules., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Background & Aims: Although the presence of tertiary lymphoid structures (TLS) correlates with positive responses to immunotherapy in many solid malignancies, the mechanism by which TLS enhances anti-tumor immunity is not well understood. The present study aimed to investigate the underlying cross-talk circuits between B cells and tissue-resident memory T (Trm) cells within the TLS and to understand their role in the context of immunotherapy., Methods: Immunostaining and hematoxylin and eosin staining of TLS and CXCL13 + CD103 + CD8 + Trm cells were performed on tumor sections from patients with gastric cancer (GC). The mechanism of communication between B cells and CXCL13 + CD103 + CD8 + Trm cells was determined both in vitro and in vivo. The effect of CXCL13 + CD103 + CD8 + Trm cells in suppressing tumor growth was evaluated through anti-PD-1 therapy., Results: The presence of TLS and CXCL13 + CD103 + CD8 + Trm cells in tumor tissues favored a superior response to anti-PD-1 therapy in GC patients. Additionally, our research identified that activated B cells enhanced CXCL13 and granzyme B secretion by CD103 + CD8 + Trm cells. Mechanistically, B cells facilitated the glycolysis of CD103 + CD8 + Trm cells through the Lymphotoxin Alpha (LTα)/Tumor necrosis factor receptor 2 (TNFR2) axis, and the mTOR signaling pathway played a critical role in CD103 + CD8 + Trm cells glycolysis during this process. Moreover, the presence of TLS and CXCL13 + CD103 + CD8 + Trm cells correlated with potent responsiveness to anti-PD-1 therapy in a TNFR2 dependent manner., Conclusions: This study further reveals a crucial role for cellular communication between TLS-associated B cell and CXCL13 + CD103 + CD8 + Trm cells in anti-tumor immunity, providing valuable insights into the potential utilization of the LTα/TNFR2 axis within CXCL13 + CD103 + CD8 + Trm cells for advancing immunotherapy strategies in GC., (Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objectives: Self-compassion is the ability to be kind to oneself in adversity. This multidimensional construct is typically assessed by the Self-Compassion Scale (SCS). In Chinese samples, there have been inconsistent psychometric findings that impede cross-cultural research. This study aimed to explore the factor structure of the Chinese version (SCS-C)., Methods: Two samples of young Chinese adults were recruited (Sample 1, N = 465, 141 men, Mean age [ M age ] = 20.26; Sample 2, N = 392, 71 men; M age = 18.97). Confirmatory factor analyses and exploratory structural equation modeling (ESEM) were used to examine previously reported four- and six-factor structures of SCS-C., Results: Although ESEM supported the six-factor structure when a problematic item was omitted, we found stronger evidence for a novel four-factor structure of the SCS-C revealed with self-kindness, common humanity, mindfulness, and uncompassionate self-responding. This suggests that Chinese individuals have a different understanding of the negative components of the original self-compassion definition, which was based on the United States and other mostly Western samples. Omega coefficients of the bifactor models suggested that using the SCS total score in Chinese samples is inappropriate. However, high factor determinacy and construct replicability indicated that the general factor of SCS-C could be used in a structural equation modeling context for both four-factor and six-factor structures., Conclusions: When using the existing SCS-C in path models, researchers should use a latent variable approach and establish the measurement construct rather than sum scores of the scale or subscales without checking the factor structure in future empirical studies. Also, the SCS-C needs to be revised, and we proposed directions forward for future research.

Chronic neurodegeneration and acute injuries lead to neuron losses via diverse processes. We compared retinal ganglion cell (RGC) responses between chronic glaucomatous conditions and the acute injury model. Among major RGC subclasses, αRGCs and intrinsically photosensitive RGCs (ipRGCs) preferentially survive glaucomatous conditions, similar to findings in the retina subject to axotomy. Focusing on an αRGC intrinsic factor, Osteopontin (secreted phosphoprotein 1 [Spp1]), we found an ectopic neuronal expression of Osteopontin (Spp1) in other RGCs subject to glaucomatous conditions. This contrasted with the Spp1 downregulation subject to axotomy. αRGC-specific Spp1 elimination led to significant αRGC loss, diminishing their resiliency. Spp1 overexpression led to robust neuroprotection of susceptible RGC subclasses under glaucomatous conditions. In contrast, Spp1 overexpression did not significantly protect RGCs subject to axotomy. Additionally, SPP1 marked adult human RGC subsets with large somata and SPP1 expression in the aqueous humor correlated with glaucoma severity. Our study reveals Spp1's role in mediating neuronal resiliency in glaucoma., Competing Interests: Declaration of interests D.S.W. is a founder of and consultant to Perceive Biotherapeutics., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background and Study Aim: Currently, several limitations exist in the examination of the oviduct. In this study, the usefulness and feasibility of a novel ultrafine dual-modality oviduct endoscopy device for in vivo assessment of the oviduct were evaluated., Methods: Five Japanese white rabbits were selected to undergo oviduct probing using a combination of optical coherence tomography (OCT) and intratubal ultrasonography. The feasibility of the procedure was evaluated through 152 pairs of clear, clinically interpretable images obtained using spiral scanning via the pull-back method. OCT images were compared with the oviduct histopathology sections., Results: Visualization of the oviduct using both OCT and ultrasound revealed a differentiated three-layer tissue; however, ultrasound showed a poorer clarity than OCT. By comparing OCT images with the histological morphology of the oviduct, the inner low-reflective layer of the oviduct corresponds to the mucosal layer, the middle high-reflective layer corresponds to the fibrous muscle layer, and the outer low-reflective layer corresponds to the connective tissue layer. Postoperatively, the general condition of the animals was good., Conclusion: This study demonstrated the feasibility and potential clinical value of the novel ultrafine dual-modality oviduct endoscope. Dual-modality imaging of OCT and intratubal ultrasonography can provide clearer microstructure of the oviduct wall., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2023. Published by Elsevier B.V.)

Bupleurum chinense DC. and Bupleurum scorzonerifolium Willd. have different clinical efficacies, with the former typically used to treat typhoid fever and the latter mainly used to clear liver heat. The differences in their clinical efficacy are closely related to their complex chemical composition, especially the active components. In this study, the saponins and volatile oils in two varieties of Radix Bupleuri grown in different regions were extracted and analyzed using high-performance liquid chromatography (HPLC) and gas chromatography coupled with mass spectrometry (MS), and the absolute contents of five saikosaponins were accurately quantified using an established HPLC-MS method in the multiple reaction monitoring mode. Multivariate statistical analysis was performed to reveal the difference in the active components between the two varieties. The saikosaponin content was significantly affected by variety and growing region, with all five saikosaponins being significantly higher in Bupleurum chinense DC. than in Bupleurum scorzonerifolium Willd. The results of principal component analysis and hierarchical cluster analysis show a clear distinction between the two varieties in terms of both saponins and volatile oils. Twenty-one saponins, including saikosaponin b2 and b1, and fifty-two volatile oils, including 2-tetradecyloxirane and chloromethyl cyanide, were screened and identified as differential compounds contributing to the significant difference between the two varieties. These compounds may also be responsible for the difference in clinical efficacy between Bupleurum chinense DC. and Bupleurum scorzonerifolium Willd. All the results suggest that the accumulation and diversity of active components in Radix Bupleuri are significantly affected by the variety. In contrast to previous reports, this study provides the absolute contents of five saikosaponins in Radix Bupleuri of different varieties and reduces the influence of the growing region on the analytical results by collecting samples from different regions. The results of this study may provide a reference for the identification and quality evaluation of different varieties of Radix Bupleuri.

Purpose: Self-evaluation and interpersonal factors are theoretically and empirically linked to depression in young people. An improved understanding of the multifactorial developmental pathways that explain how these factors predict depression could inform intervention strategies., Methods: Using structural equation modeling, this study explored whether self-evaluation and interpersonal factors were associated with adolescent depressive symptoms in a population-based sample (n = 11,921; Avon Longitudinal Study of Parents and Children, ALSPAC), across four development stages: early and late childhood plus early and middle adolescence from 3 to 17 years old., Results: Early good parenting practices predicted self-esteem, fewer peer difficulties, good friendships and fewer depressive symptoms in late childhood development outcomes. Higher self-esteem and less negative self-concept mediated the effect of early good parenting practice on reduced depressive symptoms in middle adolescence. The hypothesized erosion pathway from depressive symptoms in late childhood via higher levels of negative self-concept in early adolescence to depressive symptoms in middle adolescence was also confirmed. Additionally, peer difficulties played a mediation role in developing depressive symptoms. Contrary to the hypothesis, poor friendships predicted fewer depressive symptoms. The analysis supported a developmental pathway in which good parenting practices in early childhood led to fewer peer difficulties in late childhood and to less negative self-concept in early adolescence, which in turn predicted fewer depressive symptoms in middle adolescence., Conclusion: The social-developmental origin of youth depressive symptoms was supported via the effect of peer relationships in late childhood on self-evaluation in early adolescence., (© 2023. The Author(s).)

Little is known about the factors that influence engagement for adolescents participating in informal youth science programs. This study examined longitudinal reciprocal associations between adolescents' science engagement, interest, and growth mindset. Participants were adolescents (M age  = 15.06, SD = 1.82 years, 66.8% female) from the UK (n = 168) and the US (n = 299). A cross lagged path analysis indicated that participants' science growth mindset at baseline was positively related to interest, and engagement at year 1, and science interest at year 1 was positively related to growth mindset at year 2. Additionally, girls had lower science growth mindsets than boys. This evidence suggests that informal programs may encourage positive STEM trajectories by fostering engagement, growth mindset and interest., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Previous studies have discussed the pregnancy outcomes of diminished ovarian reserve (DOR) patients. However, data on embryonic development potential, neonatal outcomes, and maternal complications of DOR patients still remained unknown. This is the first study to investigate the risk of DOR on pregnancy and perinatal outcomes among women < 38 years., Methods: Retrospective cohort study was conducted. Patients (< 38 years of age) undergoing their first oocyte retrieval cycle were included. Patients were divided into DOR group and non-DOR group. Pregnancy outcomes of fresh cycle and cumulative live birth rate and perinatal outcomes after one oocyte retrieved cycle were compared between DOR and non-DOR group., Result(s): From January 2016 to September 2020, there were 8,179 patients involved: 443 patients in the DOR group and 7,736 patients in the non-DOR group. The incidences of live birth and clinical pregnancy did not differ significantly between patients with or without DOR after fresh cycle transfer, but the cumulative live birth rate was significantly lower in DOR group. Among women who had singleton live births, after binary logistic regression, the rates of maternal complications and neonatal outcomes were comparable in the two groups., Conclusion(s): DOR patients (< 38 years of age) showed similar pregnancy outcomes in the first fresh embryo transfer cycle but a lower chance of live birth after a whole oocyte retrieval cycle to non-DOR patients and DOR is not associated with adverse perinatal outcomes., (© 2023. The Author(s).)

Objective: The aim of this study was to describe the cumulative live birth rates (CLBRs) of young women with or without low prognosis according to the POSEIDON criteria after IVF/ICSI cycles and to investigate whether the diagnosis of low prognosis increases the risk of abnormal birth outcomes., Design: Retrospective study., Setting: A single reproductive medicine center., Population: From January 2016 to October 2020, there were 17,893 patients (<35 years) involved. After screening, 4,105 women were included in POSEIDON group 1, 1,375 women were included in POSEIDON group 3, and 11,876 women were defined as non-POSEIDON., Interventions: Baseline serum AMH level was measured on the D2-D3 of menstrual cycle before IVF/ICSI treatment., Main Outcome Measures: Cumulative live birth rate (CLBR), birth outcomes., Results: After four stimulation cycles, the CLBRs in POSEIDON group 1, POSEIDON group 3, and non-POSEIDON group reached 67.9% (95% CI, 66.5%-69.3%), 51.9% (95% CI, 49.2%-54.5%), and 79.6% (95% CI, 78.9%-80.3%), respectively. There was no difference in gestational age, preterm delivery, cesarean delivery, and low birth weight infants between the three groups, but macrosomia was significantly higher in non-POSEIDON group, after adjusting for maternal age and BMI., Conclusions: The POSEIDON group shows lower CLBRs than the non-POSEIDON group in young women, while the risk of abnormal birth outcomes in the POSEIDON group will not increase., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Yan, Li, Jin, Zhao, Chen, Hu, Chu, Guo and Jin.)

Little research has examined the associations between perceived inclusivity within informal science learning sites, youth program belonging and perceptions of program career preparation. This study explored relations between these factors at three timepoints (T1 = start of program, T2 = 3 months and T3 = 12 months after start). Participants were a diverse sample of 209 adolescents participating in STEM youth programs within informal science learning sites situated in the United States and United Kingdom (70% females: M age  = 15.27, SD age  = 1.60), with 53.1% British and 64.1% non-White. Path analysis revealed that only perceptions of inclusivity for own social identity group (i.e., gender, ethnicity) at T1 were associated with T2 STEM youth program belonging. There was a significant indirect effect of T1 perceptions of inclusivity for one's own social identity groups on T3 perceptions of program career preparation via T2 program belonging. This study highlights that, over time, perceptions of inclusivity around youth's own social identity groups (i.e., gender and ethnicity/culture) are related to a sense of youth program belonging, which in turn is later associated with perceptions of program career preparation., (© 2022. Crown.)

This study aimed to assess the feasibility of high hydrostatic pressure (HHP) treatment to obtain high quality juice, and prepared functional apple juice using fermentation technology. The physicochemical properties of HHP (10 min) pasteurized and pasteurized (85 °C, 15 min) apple juices were compared during fermentation. Moreover, the survival of Lactobacillus plantarum after fermentation under simulated gastrointestinal conditions was evaluated. Results showed that HHP-treated apple juice had better properties than that of pasteurized in terms of color difference, total phenol content, and antioxidant activity. After fermentation, about 2.00 log CFU/mL increase in viability of cells was observed and there was around 0.8 reduction in pH value, and the antioxidant capacities were also significantly improved. Additionally, the content of caffeic acid, ferulic acid, and chlorogenic acid significantly increased after 24 h of fermentation. The survival of Lactobacillus plantarum in simulated gastric fluid reached 97.37% after fermentation. Overall, HHP treatment is expected to be a substitute technology to pasteurization in order to obtain higher quality fermented fruit juice. This study could also be helpful for exploitation of fermented juice.

Cu-Ni-Sn alloys have been widely used in the aerospace industry, the electronics industry, and other fields due to their excellent electrical and thermal conductivity, high strength, corrosion and wear resistance, etc., which make Cu-15Ni-8Sn alloys the perfect alternative to Cu-Be alloys. This paper begins with how Cu-Ni-Sn alloys are prepared. Then, the microstructural features, especially the precipitation order of each phase, are described. In addition, the influence of alloying elements, such as Si, Ti, and Nb, on its microstructure and properties is discussed. Finally, the effects of plastic deformation and heat treatment on Cu-Ni-Sn alloys are discussed. This review is able to provide insight into the development of novel Cu-Ni-Sn alloys with a high performance.

Prcis: Anterior chamber depth (ACD) change after pupillary dilation is correlated with lens vault (LV) and anterior chamber width (ACW), as observed by swept-source optical coherence tomography (SS-OCT) at both horizontal and vertical scans in patients with primary angle closure suspect and cataract., Purpose: The purpose of this study is to evaluate the association between ACD and other anterior chamber parameters after pharmacological dilation in patients with primary angle closure suspect and cataract., Patients and Methods: SS-OCT was performed for 78 patients at baseline and 1 hour after pharmacological dilation. Measurements were taken at 8 evenly spaced axes at 250, 500, and 750 μm from the scleral spur. Pearson correlation coefficient (ρ) was used to evaluate the relationship between averaged ACD change and other SS-OCT parameters. Multivariable regression analyses were performed to determine the parameters that predict ACD change., Results: Across all 14 dimension and angle parameters, 12 parameters at the 270-degree axis and 10 parameters at the 0-degree axis yielded significant correlations with ACD change (ρ=0.24-0.55, P <0.05). Angle parameters were most significantly correlated to ACD change 750 µm from the scleral spur. The prediction model for ACD change after pharmacological dilation at 0 degree included decreased LV, wider ACW, and increased trabecular iris space area (all P ≤0.001). The prediction model for ACD change at 270 degrees included: decreased LV, wider ACW, larger change in anterior chamber volume, larger baseline anterior chamber volume, and smaller baseline angle opening distance (all P ≤0.03)., Conclusions: LV and ACW, as measured in both vertical and horizontal scans, were found to be determinants of the ACD change after pharmacological pupillary dilation. Examination of these parameters may help identify patients at higher risk of developing angle-closure disease., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: This work aimed to study the compounds, targets, and pathways of turmeric and corn silk for gout and to explore the mechanism of "the same disease with different treatments" based on network pharmacology and molecular docking., Methods: We used the TCMSP, PubChem, and SEA databases to screen the compounds and targets of turmeric and corn silk, gout-related proteins through TTD, Drugbank, DisGeNET, GeneCards, OMIM, and PharmGkb, and used Cytoscape to construct a "compound-target-disease" network. Then, we constructed a protein-protein interaction network (PPI) and used Metascape to perform GO and KEGG analysis. Finally, molecular docking (SYBYL) was used to verify the degree of binding between key targets and compounds., Results: We found bisacumol, campesterol, and stigmasterol to be the main turmeric compounds that exerted a marked effect on gout treatment by targeting protein processing in the endoplasmic reticulum through the HSPA1B, HSP90AB1, and STUB1 proteins. The main corn silk compound, Mandenol, treated gout by targeting the Hippo signaling pathway through the CTNNB1, YWHAG, and YWHAZ proteins., Conclusion: Turmeric and corn silk can treat the same disease, gout, through different pathways and targets. The scientific connotation of "same disease with different treatments" can be preliminarily clarified by analyzing targets and pathways., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Haoyu Zhang et al.)

The quality of Radix Bupleuri is greatly affected by its growing environment. In this study, Radix Bupleuri samples that were harvested from seven different regions across northwest China were examined by high-performance liquid chromatography (HPLC) and gas chromatography (GC) coupled with mass spectrometry (MS) to reveal significant differences in quality contributed by the cultivation region. An HPLC-MS method was firstly established and used in the multiple reaction monitoring mode for the quantitative analysis of five saikosaponins in Radix Bupleuri so as to evaluate the difference in the absolute content of saikosaponins attributable to the cultivation region. The effect on the components of Radix Bupleuri was further investigated based on the profiles of the representative saponins and volatile compounds, which were extracted from the Radix Bupleuri samples and analyzed by HPLC-MS and GC-MS. Multivariate statistical analysis was employed to differentiate the Radix Bupleuri samples cultivated in different regions and to discover the differential compositions. The developed quantitative method was validated to be accurate, stable, sensitive, and repeatable for the determination of five saikosaponins. Further statistical tests revealed that the collected Radix Bupleuri samples were distinctly different from each other in terms of both saponins and volatile compounds, based on the provinces where they were grown. In addition, twenty-eight saponins and fifty-eight volatile compounds were identified as the differentially accumulated compositions that contributed to the discrimination of the Radix Bupleuri samples. The Radix Bupleuri samples grown in Shouyang county showed the highest content of saikosaponins. All of the results indicated that the cultivation region significantly affected the accumulation and diversity of the main chemical components of Radix Bupleuri. The findings of this research provide insights into the effect of the cultivation region on the quality of Radix Bupleuri and the differentiation of Radix Bupleuri cultivated in different regions based on the use of HPLC-MS and GC-MS combined with multivariate statistical analysis.

Objective: To produce valerenic acid (VA) in Saccharomyces cerevisiae by engineering a heterologous synthetic pathway., Result: Valerena-4,7(11)-diene synthase (VDS) derived from Valeriana officinalis (valerian) was expressed in S. cerevisiae to generate valerena-4,7(11)-diene as the precursor of VA. By overexpressing the key genes of the mevalonate pathway ERG8, ERG12 and ERG19, and integrating 4 copies of MBP (maltose-binding protein)-VDS-ERG20 gene expression caskets into the genome, the production of valerena-4,7(11)-diene was improved to 75 mg/L. On this basis, the cytochrome P450 monooxygenase LsGAO2 derived from Lactuca sativa was expressed to oxidize valerena-4,7(11)-diene to produce VA, and the most effective VA production strain was used for fermentation. The yield of VA reached 2.8 mg/L in the flask and 6.8 mg/L in a 5-L bioreactor fed glucose., Conclusions: An S. cerevisiae strain was constructed and optimized to produce VA, but the valerena-4,7(11)-diene oxidation by LsGAO2 is still the rate-limiting step for VA synthesis that needs to be further optimized in future studies., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Glaucoma is a heterogeneous group of progressive optic neurodegenerative. Although most patients with primary open angle glaucoma (POAG) are stable for many years, certain subgroups of POAG patients could progress over time even with treatment. This study is to identify aqueous humor (AH) biomarkers that may be associated with disease progression in POAG patients. Gene differential expression study of prospectively collected AH from patients with stable or progressive POAG. Metagenomic deep sequencing (MDS) was performed on the aqueous fluid of 20 patients with stable POAG and 20 patients with progressive POAG. Differential gene expression analysis was performed to identify host transcriptome signatures. A total of 21 transcripts were differentially expressed between groups. Differential transcripts identified by MDS. Twenty transcripts were up-regulated and 1 transcript was down-regulated in progressive POAG patients compared to stable patients. Of those, 11 transcripts were eye-related, and 5 transcripts were related to glaucomatous phenotypes (Fibronectin type III domain containing 3B (FNDC3B), Clusterin (CLU), Proprotein convertase subtilisin/kexin type 6 (PCSK6), Cadherin EGF LAG seven-pass G-type receptor 1 (Celsr1), and Rho guanine nucleotide exchange factor 4 (ARHGEF4)). Biomarkers associated with POAG progression can be identified from aqueous fluid. Identification of the biomarkers may improve glaucoma surveillance for progressive POAG., (Published by Elsevier Ltd.)

With the evolution of society, an increasing number of people have realized the importance of sports on human health. However, participation in sports is a double-edged sword as improperly exercising can lead to injury. Many athletes and patients with sports injuries choose traditional Chinese medicine (TCM) when modern medicine fails to relieve their musculoskeletal symptoms. TCM is a splendid legacy of Chinese civilization whose therapies are effective, economical, and convenient, with some administration by trained patients at home. This review analyzes the literature on the application of acupuncture, moxibustion, massage, and cupping in sports injuries to provide novel ideas for the application of TCM in sports medicine., Competing Interests: All the authors declare that they do not have any conflicts of interest., (Copyright © 2022 Haoyu Zhang et al.)

Background: Glioma is the most common primary malignant tumor in the central nervous system. Myeloid differentiation protein 2 (MD2) acts as a coreceptor of toll-like receptor 4 (TLR4) to mediate innate immune response. However, the actual roles of MD2 in the regulation of progression and immune cell infiltration in gliomas remain largely unclear. This study aims to explore whether MD2 could be an independent prognostic factor through the mediation of immune cell infiltration in gliomas., Methods: The mRNA expression and DNA methylation differential analyses of MD2 were performed using CGGA, TCGA and Rembrandt databases and survival analyses were performed using Kaplan-Meier plotter. Univariate and multivariate Cox regression was applied to analyze the prognostic value of MD2 and nomograms were constructed to evaluate the clinical value of MD2. Then, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were utilized to analyze MD2-related signal pathways. Furthermore, correlations between MD2 and immune cell infiltration were calculated by TIMER and CIBERSOPT. The correlation between MD2 expression and the infiltrations of macrophages and neutrophils was experimentally verified by the knockdown of MD2 expression using small interfering RNA (siRNA) in glioma cells., Results: We found that MD2 was overexpressed and associated with a poor prognosis in gliomas. Meanwhile, higher expression of MD2 could be a result of lower DNA methylation of MD2 gene in gliomas. In addition, univariate and multivariate Cox regression analysis indicated that MD2 could be an independent prognostic factor for gliomas. Further functional enrichment analysis revealed that the functions of MD2 were closely related to immune responses. Moreover, the expression level of MD2 was strongly correlated with the infiltration and polarization of pro-tumor phenotype of tumor-associated macrophages and tumor-associated neutrophils in gliomas., Conclusions: These findings have provided strong evidence that MD2 could be served as a valuable immune-related biomarker to diagnose and predict the progression of gliomas., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhao, Li, Chen and Wang.)

Introduction: The main aim of this article was to study the retinal peripapillary and macular vascular structures in eyes with primary angle-closure suspects (PACS) using optical coherence tomography angiography (OCTA)., Methods: In this cross-sectional study, control and PACS subjects were recruited from a community screening. Only one eye per subject was used for analysis. All participants underwent a questionnaire survey, physical and ophthalmic examinations, ocular biometry measurements, and OCTA. We compared basic demographics and vessel structure parameters between control and PACS eyes. Univariate and multivariate linear regression analyses were performed to investigate factors associated with vascular parameters in both groups., Results: Data from 254 subjects including 155 PACS and 99 controls were analyzed. In the peripapillary region, PACS eyes showed similar retina nerve fiber layer (RNFL) and vessel densities (VDs) including and excluding large vessels compared to control eyes. Compared to control eyes, all macular OCTA parameters showed significant differences in PACS eyes, including decreased superficial VD (p = 0.006) and deep VD (p = 0.004), larger fovea avascular zone (FAZ) area (p = 0.006), and longer FAZ perimeter (p = 0.004). Gender (p = 0.039), age (p < 0.001), and Garway-Heath superior hemisphere RNFL (p < 0.001) were risk factors influencing optic disc VD excluding large vessels. Axial length was the major factor affecting macula superficial and deep VDs (p = 0.004 and 0.001 respectively), while PACS was an independent factor associated with larger FAZ perimeter (p = 0.046)., Conclusion: While PACS and control eyes have comparable RNFL and vascular structure around the optic nerve head, macular vascular structures are significantly different., (© 2021 The Author(s). Published by S. Karger AG, Basel.)

Purpose : To evaluate the inter- and intra-observer reliability of anterior chamber (AC) angle measurements obtained by swept-source optical coherence tomography (SS-OCT). Methods: Forty-eight consecutive patients diagnosed with primary angle closure suspect (PACS) were included. Three masked observers at different training levels (one glaucoma specialist, one ophthalmology resident, and one pre-medical college student) measured 192 SS-OCT images of the PACS patients. One observer (the glaucoma specialist) repeated measurements 1 week later. SS-OCT parameters included: Anterior segment volume, including corneal, AC, and iris volume; anterior segment dimensions, including AC depth and width (ACD, ACW), and lens vault (LV); and angle parameters, including angle opening distance (AOD), angle recess area (ARA), trabecular iris space area (TISA), and the trabecular iris angle (TIA). Intraclass correlation coefficients (ICCs) were used to measure reliability. Results: For inter-observer reproducibility, ICCs of corneal, AC, and iris volumes were 0.952 to 0.998. ICCs of ACD at all axes were above 0.989. ICCs of ACW and LV were smallest in the 90°-270° axis (0.751 and 0.768) but not significantly different from other axes. ARA, TISA, and TIA at all angles had significantly smallest ICCs 250 µm from the scleral spur compared with 500 µm and 750 µm. The ICCs comparing observers with different training levels had similar ranges and followed similar trends. For intra-observer repeatability, the smallest ICC was 0.843. Decreasing AC depth correlated with increased inter-observer reproducibility. Conclusions: We found excellent intra-observer repeatability for all SS-OCT parameters. Angle measurements have more variation among the observers when taken 250 µm from the scleral spur. Shallow AC might lead to more variability for angle parameters. Non-expert observers may be recruited for high-quality image grading with standard training.

Soyasapogenol B is an oleanane-type pentacyclic triterpene that has various applications in food and healthcare and has a higher biological activity than soyasaponin. Saccharomyces cerevisiae is a potential platform for terpenoid production with mature genetic tools for metabolic pathway manipulation. In this study, we developed a biosynthesis method to produce soyasapogenol B. First, we expressed β-amyrin synthase derived from Glycyrrhiza glabra in S. cerevisiae to generate β-amyrin, as the precursor of soyasapogenol B. Several different types of promoters were then used to regulate the expression of key genes in the mevalonate pathway (MVA), and this subsequently increased the yield of β-amyrin to 17.6 mg/L, 25-fold more than that produced in the original strain L01 (0.68 mg/L). Then, using the β-amyrin-producing strain, we expressed soyasapogenol B synthases from Medicago truncatula (CYP93E2 and CYP72A61V2) and from G. glabra (CYP93E3 and CYP72A566). Soyasapogenol B yields were then optimized by using soyasapogenol B synthases and cytochrome P450 reductase from G. glabra. The most effective soyasapogenol B production strain was used for fermentation, and the yield of soyasapogenol B reached 2.9 mg/L in flask and 8.36 mg/L in a 5-L bioreactor with fed glucose and ethanol. This study demonstrated the heterologous synthesis of soyasapogenol B in S. cerevisiae using the combined expression of CYP93E3 and CYP72A566 in the synthesis pathway, which significantly increased the production of soyasapogenol B and provides a reference method for the biosynthesis of other triterpenes., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Hawthorn berry has been proved hypoglycemic effect due to the presence of some α-glucosidase inhibitors. Herein, screening and identifying of α-glucosidase inhibitors from hawthorn berry were conducted, and the results showed polyphenols mainly containing quercetin (74.58%) and hyperioside (9.58%) were responsible for its bioactivity. In order to enhance the hypoglycemic effect, the combined glucose-lowering complex (DEH) consisting of hawthorn polyphenols, D-chiro-inositol (DCI), and epigallocatechin gallate (EGCG) was prepared, where three ingredients exerted the synergistic hypoglycemic effect to enhance glucose consumption and glycogen levels and inhibit hepatic gluconeogenesis in IR-HepG2 cells. In STZ/HFD-induced mice, DEH effectively improved insulin resistance, reduced fasting blood glucose (FBG) and hepatic gluconeogenesis, and increased hepatic glycogen synthesis and storage via down-regulation of PI3K/Akt/FOXO1-mediated PEPCK and G6Pase and up-regulation of PI3K/Akt/GSK3-mediated GS activation in the liver. In summary, these findings indicate that DEH is a potential novel strategy for the treatment of type 2 diabetes. PRACTICAL APPLICATIONS: Glucose-lowering complex (DEH) with superior hypoglycemic effect, can effectively improve the insulin resistance, reduce the fasting blood glucose, hepatic gluconeogenesis and increase the hepatic glycogen synthesis and storage in mice, which represents a potential novel strategy for the treatment of type 2 diabetes., (© 2021 Wiley Periodicals LLC.)

Diabetic retinopathy (DR) is the leading cause of acquired blindness in middle-aged people. The complex pathology of DR is difficult to dissect, given the convoluted cytoarchitecture of the retina. Here, we performed single-cell RNA sequencing (scRNA-seq) of retina from a model of type 2 diabetes, induced in leptin receptor-deficient ( db/db ) and control db/m mice, with the aim of elucidating the factors mediating the pathogenesis of DR. We identified 11 cell types and determined cell-type-specific expression of DR-associated loci via genome-wide association study (GWAS)-based enrichment analysis. DR also impacted cell-type-specific genes and altered cell-cell communication. Based on the scRNA-seq results, retinaldehyde-binding protein 1 (RLBP1) was investigated as a promising therapeutic target for DR. Retinal RLBP1 expression was decreased in diabetes, and its overexpression in Müller glia mitigated DR-associated neurovascular degeneration. These data provide a detailed analysis of the retina under diabetic and normal conditions, revealing new insights into pathogenic factors that may be targeted to treat DR and related dysfunctions., (© 2021 by the American Diabetes Association.)

Bumblebees are a diverse group of globally important pollinators in natural ecosystems and for agricultural food production. With both eusocial and solitary life-cycle phases, and some social parasite species, they are especially interesting models to understand social evolution, behavior, and ecology. Reports of many species in decline point to pathogen transmission, habitat loss, pesticide usage, and global climate change, as interconnected causes. These threats to bumblebee diversity make our reliance on a handful of well-studied species for agricultural pollination particularly precarious. To broadly sample bumblebee genomic and phenotypic diversity, we de novo sequenced and assembled the genomes of 17 species, representing all 15 subgenera, producing the first genus-wide quantification of genetic and genomic variation potentially underlying key ecological and behavioral traits. The species phylogeny resolves subgenera relationships, whereas incomplete lineage sorting likely drives high levels of gene tree discordance. Five chromosome-level assemblies show a stable 18-chromosome karyotype, with major rearrangements creating 25 chromosomes in social parasites. Differential transposable element activity drives changes in genome sizes, with putative domestications of repetitive sequences influencing gene coding and regulatory potential. Dynamically evolving gene families and signatures of positive selection point to genus-wide variation in processes linked to foraging, diet and metabolism, immunity and detoxification, as well as adaptations for life at high altitudes. Our study reveals how bumblebee genes and genomes have evolved across the Bombus phylogeny and identifies variations potentially linked to key ecological and behavioral traits of these important pollinators., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

Purpose: To evaluate the safety of pupillary dilation in primary angle-closure suspects (PACS) with concurrent visually significant cataract (VSC), to identify risk factors associated with elevated intraocular pressure (IOP), and to describe changes in anterior segment anatomy after pupillary dilation., Design: Prospective study., Participants: Patients with PACS and VSC and no prior laser or intraocular surgery were recruited. Visually significant cataract was defined as best-corrected visual acuity ≤ 20/40 due to cataract., Methods: Subjects' eyes were dilated with 0.5% tropicamide and 0.5% phenylephrine hydrochloride. A standardized eye examination, biometry, and swept-source OCT (SS-OCT) were performed before dilation. Intraocular pressure and SS-OCT were repeated 1, 4, and 6 hours postdilation (PDH1, PDH4, and PDH6, respectively). All parameters were compared between time points before and after dilation using paired t test. Linear regression models were used to determine the risk factors associated with postdilation IOP changes., Main Outcome Measures: Change in IOP and SS-OCT parameters from baseline., Results: Seventy-eight eyes from 78 patients were included, with 78, 66, and 12 patients completing the study at PDH1, PDH4, and PDH6, respectively. Mean IOP increased from 14.8 ± 2.6 mmHg at baseline to 15.5 ± 3.5 mmHg at PDH1 (P = 0.03) and decreased to 14.9 ± 3.1 mmHg at PDH4 (P = 0.09). Four patients (5.13%) and 3 patients (3.85%) had an increase in IOP ≥ 5 mmHg at PDH1 and PDH4, respectively. Two patients (2.56%) and 1 patient (1.28%) had an increase in IOP ≥ 8 mmHg at PDH1 and PDH4, respectively. None developed acute primary angle-closure during the observation period. Almost all anterior chamber parameters showed a significant increase after dilation at PDH1 and PDH4, except lens vault and iris volume, which decreased at PDH1 and PDH4 from baseline. Increase in anterior chamber depth was negatively associated with the level of IOP elevation after dilation (P < 0.01)., Conclusions: Dilation of patients' eyes with PACS and VSC in this cohort appears to have a low risk for IOP spike. This may be associated with relaxation of the ciliary muscle leading to posterior displacement of the lens-iris diaphragm and deepening of the anterior chamber., (Published by Elsevier Inc.)

Background: The SARS-CoV-2 pandemic is an ongoing global health emergency. The aim of our study was to investigate the changes of liver function and its clinical significance in COVID-19 patients., Method: This retrospective, single-centre study was conducted on 115 confirmed cases of COVID-19 in Zhongnan hospital of Wuhan University from 18 January 2020 to 22 February 2020. Liver function and related indexes were analysed to evaluate its relationship with disease progression in COVID-19 patients., Results: Part of the COVID-19 patients presented with varying degrees of abnormality in liver function indexes. However, the levels of ALT, AST, TBIL, GGT and LDH in COVID-19 patients were not significantly different when compared with hospitalised community-acquired pneumonia patients, and the levels of albumin is even significantly higher. The levels of ALT, AST, TBIL, LDH and INR showed statistically significant elevation in severe COVID-19 cases compared with that in mild cases. However, the clinical significance of the elevation is unremarkable. Majority of severe COVID-19 patients showed significantly decreasing in albumin level and continuously decreasing in the progress of illness. Most of the liver function indexes in COVID-19 patients were correlated with CRP and NLR, the markers of inflammation. Logistic regression analysis further identified NLR as the independent risk factor for severe COVID-19, as well as age., Conclusions: Although abnormalities of liver function indexes are common in COVID-19 patients, the impairment of liver function is not a prominent feature of COVID-19, and also may not have serious clinical consequences., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: More than 20% of the world population live in China, which has made significant achievement in human milk research. Part of the data that were published in Chinese were, however, unavailable to non-Chinese speakers. There was also no comprehensive overview of crude protein and amino acid levels in human milk in Chinese population. This systematic review aimed to compile the data on human milk crude protein and amino acid levels in Chinese population., Methods: After searching for and screening original research articles in both English and Chinese, 23 published from 1987 to 2019 were identified (18 in Chinese and 5 in English). The data were pooled into 9 defined lactation stages., Results: Crude protein and amino acids (protein bound plus nonprotein bound) concentrations gradually decreased during the first 60 postpartum days and remained relatively static thereafter. The concentrations and dynamic change of crude protein and amino acids were similar to those in other populations. By contrast, the longitudinal changes in free amino acids (nonprotein bound) were less clear due to the limited data available. Several common weaknesses were identified in these studies., Conclusions: Our study represented the most comprehensive overview on crude protein and amino acid concentrations in human milk in Chinese population, and enhanced the knowledge of protein and amino acid intakes and requirements by Chinese infants.

Objective: To explore the value of lactic acid (Lac), lactate clearance (LCR) and procalcitonin (PCT) in assessing the severity and predicting the prognosis in sepsis., Methods: 18-80-year-old patients with sepsis admitted to the department of critical care medicine of Beijing Friendship Hospital, Capital Medical University from April 2009 to December 2019 were enrolled. The gender, age, basic illness, infection site, organ function, acute physiology and chronic health evaluation II (APACHE II), sequential organ failure assessment (SOFA), Lac and PCT were collected on admission to intensive care unit (ICU), as well as Lac after 24 hours, 24-hour LCR, and 28-day prognosis. The patients were divided into sepsis group and septic shock group according to Sepsis-3 criteria. According to the 28-day prognosis, the septic shock patients were divided into survival group and death group, and the differences of each index between the two groups were compared. Multivariate Logistic regression was used to analyze the risk factors of death in septic shock patients. The receiver operating characteristic (ROC) curve was used to analyze the role of Lac, LCR, PCT, SOFA score and APACHE II score in predicting prognosis of the patients with septic shock., Results: A total of 998 patients with sepsis were enrolled, including 642 males and 356 females; with (59.56±13.22) years old. There were 478 patients with septic shock, among which 180 died and 298 survived during the 28-day observation. (1) Compared with the sepsis group, the age of the sepsis shock group was significantly higher (years old: 60.49±12.31 vs. 58.72±13.97), APACHE II score, SOFA score, Lac, PCT and 24 h Lac increased [APACHE II: 24.57±7.04 vs. 19.37±6.93, SOFA: 7.78±3.31 vs. 4.38±3.42, Lac (mmol/L): 3.00 (1.70, 5.00) vs. 1.40 (1.00, 2.30), PCT (μg/L): 0.05 (0.00, 4.00) vs. 0.00 (0.00, 1.10), 24-hour Lac (mmol/L): 2.60 (1.60, 4.40) vs. 1.40 (1.00, 2.20)], and the 28-day mortality was significantly higher [41.63% (199/478) vs. 19.42% (101/520)], with significant statistic differences (all P < 0.05). (2) Compared with the survival group, APACHE II score, SOFA score, Lac, 24-hour Lac significantly increased in the septic shock death group, and 24-hour LCR decreased [APACHE II: 26.19±6.52 vs. 22.25±6.07, SOFA: 9.07±2.90 vs. 7.50±3.10, Lac (mmol/L): 3.80 (2.50, 5.10) vs. 2.80 (2.00, 3.90), 24-hour Lac (mmol/L): 3.20 (2.20, 5.60) vs. 2.10 (1.60, 3.30), 24-hour LCR: 1.43 (-37.50, 30.77)% vs. 16.67 (0.00, 33.98)%, all P < 0.05]. In assessment of organ function, central venous pressure (CVP) and oxygenation index (PaO 2 /FiO 2 ) were lower in death group [CVP (mmHg; 1 mmHg = 0.133 kPa): 5.00 (2.00, 8.00) vs. 6.00 (2.00, 9.00), PaO 2 /FiO 2 (mmHg): 184.21±84.57 vs. 199.20±86.98], alanine aminotransferase (ALT) and serum creatinine (SCr) increased [ALT (U/L): 376.56±41.43 vs. 104.17±14.10, SCr (μmol/L): 213.53±8.06 vs. 181.91±5.03], with significant statistic differences (all P < 0.05). (3) Multivariate Logistic regression analysis showed that PaO 2 /FiO 2 , SCr, Lac and SOFA were independent risk factors of prognosis in septic shock [PaO 2 /FiO 2 : odds ratio (OR) = 0.997, 95% confidence interval (95%CI) was 0.996-0.999, P = 0.001; SCr: OR = 1.001, 95%CI was 1.000-1.002, P = 0.041; Lac: OR = 0.925, 95%CI was 0.871-0.982, P = 0.011; SOFA: OR = 1.178, 95%CI was 1.110-1.251, P = 0.000]. ROC curve analysis showed that SOFA, SOFA+APACHE II, Lac+24-hour LCR+PCT+SOFA+APACHE II could predict mortality in septic shock patients, and the area under the ROC curve (AUC) was 0.769 (95%CI was 0.740-0.798), 0.787 (95%CI was 0.759-0.815), 0.800 (95%CI was 0.773-0.827), respectively. The joint of the five indicators, Lac, 24-hour LCR, PCT, SOFA and APACHE II has the largest AUC., Conclusions: Lac is an independent risk factor for death in patients with septic shock, however, the prognosis cannot be predicted. Comprehensive analysis of LCR, PCT, SOFA, APACHE II and the clinical organ functions are required for analysis.

Endothelial glycocalyx plays a significant role in the development and progression of diabetic complications. Endomucin (EMCN) is an anti-inflammatory membrane glycoprotein that is mainly expressed in venous and capillary endothelial cells. However, the function of EMCN in diabetic retinopathy (DR) progression is still completely unknown. We first investigated the change of EMCN expression in the retina and human retinal microvascular endothelial cells. We then overexpressed EMCN in the retina with adeno-associated virus and induced DR with streptozotocin (STZ). We analyzed EMCN's effect on the integrity of endothelial glycocalyx under conditions of DR. Furthermore, we investigated EMCN's protective effect against inflammation and blood-retinal barrier (BRB) destruction. We found that EMCN is specifically expressed in retinal endothelial cells and that its levels are decreased during hyperglycemia in vitro and in vivo . Overexpression of EMCN can restore the retinal endothelial glycocalyx of STZ-induced diabetic rats. Furthermore, EMCN overexpression can decrease leukocyte-endothelial adhesion to ameliorate inflammation and stabilize the BRB to inhibit vessel leakage in rats with DR. EMCN may protect patients with diabetes from retinal vascular degeneration by restoring the endothelial glycocalyx. EMCN may thus represent a novel therapeutic strategy for DR because it targets endothelial glycocalyx degradation associated with this disease.-Niu, T., Zhao, M., Jiang, Y., Xing, X., Shi, X., Cheng, L., Jin, H., Liu, K. Endomucin restores depleted endothelial glycocalyx in the retinas of streptozotocin-induced diabetic rats.

Scope: Diabetes endangers health and causes serious economic impediment. The aim of this study is to identify the effects of goat milk consumption on glucose metabolism of rats with high-fat (HF) diet., Methods and Results: Sixty male Sprague Dawley rats are divided into five groups and fed with different diets for 24 weeks: goat-milk-based HF diet (GHF group; goat milk powder+HF diet), cow-milk-based HF diet (CHF group; cow milk powder+HF diet), HF diet, HF diet plus acarbose (HF+A group; acarbose+HF diet), and chow diet (CD group). Fasting glucose in GHF-fed rats are lower than HF-fed rats on weeks 16 and 20. GHF-fed rats display improved insulin sensitivity in oral glucose and insulin tolerance tests. Compared with HF-fed rats, glycated hemoglobin and triglycerides in GHF-fed rats are lower and high-density lipoprotein level is higher. AMP-activated protein kinase activation (AMPK) in the liver and skeletal muscle is higher in GHF rats than HF rats. Phosphoenolpyruvate carboxykinase and glucose 6-phosphatase protein levels in the liver are lower and hexokinase 2 protein level in the skeletal muscle is higher in GHF rats compared with HF rats., Conclusion: Goat milk consumption can ameliorate abnormalities in glucose metabolism, and AMPK pathway in the liver and skeletal muscle plays an important role in the process., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)