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Nan Tang,1 Mengyue Pei,2 Huihui Liu,3 Jingru Chen,1 Youting Wang,1 Lei Xie,4 Junping Hu,3,5 Jing Wang,6 Yuan Gao1 1Department of Nursing, 1st Medical Centre of PLA General Hospital, Beijing, People’s Republic of China; 2School of Medicine, Henan Kaifeng College of Science Technology and Communication, Kaifei, Henan Province, People’s Republic of China; 3School of Nursing, Lanzhou University, Lanzhou, Gansu Province, People’s Republic of China; 4Renji Hospital, Shanghai Jiaotong University, Shanghai, People’s Republic of China; 5Department of Reproductive Medicine, The First Hospital of Lanzhou University, Lanzhou, Gansu Province, People’s Republic of China; 6Department of Gynecology, 1th Medical Centre of PLA General Hospital, Beijing, People’s Republic of ChinaCorrespondence: Jing Wang; Yuan Gao, Email wangjing353535@163.com; gaoyuanzd@163.comBackground: The purpose of this study was to explore the relationship between infertility-related stress and dyadic coping with quality of life (QoL) in couples with infertility issues, and verify gender differences and dyadic interactions in the associations between them.Methods: This cross-sectional study included 340 couples who were recruited from the First Affiliated Hospital of Lanzhou University between March 2022 and November 2022. The Fertility Problem Inventory, Dyadic Coping Inventory and FertiQoL were used to measure infertility-related stress, dyadic coping and QoL. The Actor-Partner Interdependence Model was used to analyze the effects of infertility-related stress and dyadic coping on the couple’s own QoL (actor effect) as well as on their partner’s QoL (partner effect).Results: Female patients perceived significantly lower levels of QoL and dyadic coping than those of husbands. There was no statistically significant difference in the infertility-related stress between wives and husbands. Husbands’ infertility-related stress had actor and partner effects on their own and their wives’ QoL, while wives’ infertility-related stress only had an actor effect on their own QoL. Husbands’ dyadic coping had both actor effect and partner effects on their own and their wives’ QoL, meanwhile wives’ dyadic coping had both actor effect and partner effects on their own and their husbands’ QoL.Conclusion: Husbands’ QoL was impacted by their own infertility-related stress, dyadic coping and their wives’ dyadic coping. Whereas wives’ QoL was influenced by infertility-related stress and dyadic coping from both their own and their spouses. Therefore, elevating the level of dyadic coping may contribute to improving QoL for both husbands and wives. Moreover, enhancing the ability to cope with infertility-related stress might be useful for husbands and indirectly contribute to wives’ QoL.Keywords: infertility, couple, infertility-related stress, dyadic coping, QoL

Nan Tang,1,2,&ast; Mengyue Pei,2,3,&ast; Lei Xie,2,4 Xueping Liang,2 Junping Hu,2,5 Yuan Gao1 1Department of Nursing, 1th Medical Centre of PLA General Hospital, Beijing, People’s Republic of China; 2School of Nursing, Lanzhou University, Lanzhou, Gansu, People’s Republic of China; 3Henan Kaifeng College of Science Technology and Communication, Kaifei, Henan, People’s Republic of China; 4Renji Hospital, Shanghai Jiaotong University, Shanghai, People’s Republic of China; 5The First hospital of Lanzhou University, Lanzhou, Gansu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Junping Hu; Yuan Gao, Email hjplandashengzhi@126.com; gaoyuanzd@163.comBackground: This study aims to examine the relationship between anxiety and depression and dyadic coping in infertile couples, exploring gender differences and dyadic interactions in these associations.Methods: A cross-sectional study was conducted involving 288 couples recruited from the First Affiliated Hospital of Lanzhou University between November 2021 and November 2022. The Dyadic Coping Scale, Anxiety Scale, and Depression Scale were utilized to measure dyadic coping, anxiety, and depression, respectively. The Actor-Partner Interdependence Model was used to analyze the actor effect and partner effect.Results: Wives exhibited significantly higher anxiety and depression scores compared to husbands (p< 0.001). No statistically significant difference was found in dyadic coping between wives and husbands. Positive dyadic coping in infertile couples had significant actor effects on anxiety and depression (p< 0.05) and partner effects (p< 0.05). Positive dyadic coping negatively predicted anxiety and depression of oneself and one’s partner. Negative dyadic coping in infertile couples also had significant actor effects on anxiety and depression (p< 0.05) and partner effects (p< 0.05). Negative dyadic coping positively predicted anxiety and depression of oneself and one’s partner.Conclusion: The dyadic coping style of infertile couples has both actor and partner effects on their own and their partner’s anxiety and depression. Anxiety and depression in infertile couples are influenced by their own and their partner’s dyadic coping style, respectively. Therefore, dyadic coping serves as an important indicator for predicting psychological outcomes in these couples.Keywords: infertility couple, dyadic coping, anxiety, depression

Wan Chen,1,&ast; Mingyu Pei,1,&ast; Chunxia Chen,2,&ast; Bo Wang,1,&ast; Lei Shi,1,&ast; Guozheng Qiu,1 Wenlong Duan,1 Shengxin Chen,1 Qiao Wei,1 Xi Zeng,1 Huifeng Pang,1 Yanlin Wei,1 Ruihua Wu,1 Ruikai Zhu,1 Qingwei Ji,3 Liwen Lyu1 1Department of Emergency, the People’s Hospital of Guangxi Zhuang Autonomous Region& Research Center of Cardiovascular Disease, Guang Xi Academy of Medical Sciences, Nanning, People’s Republic of China; 2Department of Pharmacy, the People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, People’s Republic of China; 3Department of Cardiovascular Medicine, The People’s Hospital of Guang Xi Zhuang Autonomous Region& Research Center of Cardiovascular Disease, Guangxi Academy of Medical Sciences Nanning, Nanning, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Liwen Lyu, Department of Emergency, The People’s Hospital of Guangxi Zhuang Autonomous Region, Research Center of Cardiovascular Disease, Guangxi Academy of Medical Sciences, Nanning, 530021, People’s Republic of China, Email iculvliwen@163.com Qingwei Ji, Department of Cardiology, The People’s Hospital of Guangxi Zhuang Autonomous Region, Research Center of Cardiovascular Disease, Guangxi Academy of Medical Sciences Nanning, Nanning, 530021, People’s Republic of China, Email gxqyyjzk@163.comObjective: The incidence of cardiogenic shock cases treated with veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support has been on the rise. Acute kidney injury (AKI) is a significant complication of cardiogenic shock and a frequent serious complication in patients requiring ECMO-supported therapy. AKI is strongly associated with unfavorable patient prognosis. However, there is a paucity of data on the influence of AKI on the prognosis of patients with acute myocardial infarction complicated by cardiogenic shock (AMI-CS) who are receiving ECMO support, particularly with regard to long-term outcomes.Methods: This retrospective observational study included 103 patients in the People’s Hospital of Guangxi Zhuang Autonomous Region from January 2017 and June 2022. AKI was defined according to Kidney Disease Improving Global Outcome (KDIGO) criteria. Cox regression and logistic regression were used to identify risk factors.Results: In this study, the incidence of AKI was 63.11%, with AKI stage 1, 2, and 3 accounting for 21.36%, 12.62%, and 29.13%, respectively. Patients with severe AKI had significantly higher in-hospital mortality (43.33% vs 27.40%, P < 0.001), 30-day mortality (60.00% vs 31.51%, P = 0.001), and 1-year mortality (63.67% vs 34.25%, P< 0.001) than those without severe AKI. Furthermore, severe AKI significantly increased the risk of one-year mortality (HR 10.816, CI 3.118– 37.512, P< 0.001). Baseline serum creatinine, baseline platelet, and active cardiopulmonary resuscitation were independent predictors of one-year mortality. In addition, baseline white blood cell count, baseline aspartate aminotransferase, baseline alanine aminotransferase (ALT), baseline serum creatinine, preoperative lactate, and postoperative mean arterial pressure were independent risk factors of severe AKI during hospitalization.Conclusion: In patients with AMI-CS receiving ECMO support, AKI is highly prevalent. Development of severe AKI significantly increased the risk of one-year mortality.Keywords: acute kidney injury, extracorporeal membrane oxygenation, prognosis, risk factors

Yao Wang,* Xun Li,* Qian Chen, Fangzhou Jiao, Chunxia Shi, Maohua Pei, Luwen Wang, Zuojiong Gong Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zuojiong Gong; Luwen WangDepartment of Infectious Diseases, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan, 430060, People’s Republic of ChinaEmail zjgong@163.com; wangluw8253@163.comBackground: The glycolysis pathway of M1 macrophages is a key factor affecting the inflammatory response. The aim of this article is to investigate the role of histone deacetylase 6 (HDAC6) in the M1 macrophage glycolysis pathway during acute liver failure (ALF).Methodology: Targeted metabolomics for quantitative analysis of energy metabolites technology was used to detect the characteristics of energy metabolism for 8 ALF patients and 8 normal volunteers. The ALF mice model was intervened with HDAC6 inhibitor ACY-1215. iTRAQ/TMT quantitative proteomics was used to detect protein expression in livers in different mice groups. The liver function, energy metabolites, M1 macrophages, cytokines, and pathological structure, DDX3X, NLRP3 and DNMT1 in liver tissue were detected. The changes of the above molecules were verified in cell groups.Results: ALF patients and mice have significant energy metabolism disorders, accompanied by activation of M1 macrophages. After the intervention of ACY-1215, the activated M1 macrophages and cytokines levels in the mouse liver were reduced. The levels of IDH1, MDH1, and ATP were significantly increased. The expression of DDX3X increased, while the expression of NLRP3 and DNMT1 decreased. ACY-1215 could reduce the model cell apoptosis level and inflammatory response, and improve energy metabolism. It could also promote the expression of DDX3X, and inhibit the expression of NLRP3 and DNMT1.Conclusion: ACY-1215 could inhibit the activation of M1 macrophages by improving the glycolytic pathway through regulating DNMT1 and DDX3X/NLRP3 signals to alleviate ALF.Keywords: HDAC6, M1 macrophage, metabolic reprogramming, acute liver failure

Ying Dong,1 Jing Gao,1 Mengyue Pei,2 Xiaoli Wang,2 Chuangnian Zhang,2 Yingjie Du,1 Yanjun Jiang1 1School of Chemical Engineering and Technology, Hebei University of Technology, Tianjin 300130, People’s Republic of China; 2Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, People’s Republic of ChinaCorrespondence: Jing Gao; Xiaoli Wang Tel +86-22-60204945; +86-22-87890151Email jgao@hebut.edu.cn; wangxl@bme.pumc.edu.cnBackground: Nanocarriers could deliver significantly higher amounts of antigen to antigen-presenting cells (APCs), which have great potential to stimulate humoral and cellular response in cancer immunotherapy. Thereafter, silica solid nanosphere (SiO2) was prepared, and a model antigen (ovalbumin, OVA) was covalently conjugated on the surface of SiO2 to form nanovaccine (OVA@SiO2). And the application of OVA@SiO2 for cancer immunotherapy was evaluated.Materials and Methods: SiO2 solid nanosphere was prepared by the Stöber method, then successively aminated by aminopropyltriethoxysilane and activated with glutaraldehyde. OVA was covalently conjugated on the surface of activated SiO2 to obtain nanovaccine (OVA@SiO2). Dynamic light scattering, scanning electron microscope, and transmission electron microscope were conducted to identify the size distribution, zeta potential and morphology of OVA@SiO2. The OVA loading capacity was investigated by varying glutaraldehyde concentration. The biocompatibility of OVA@SiO2 to DC2.4 and RAW246.7 cells was evaluated by a Cell Counting Kit-8 assay. The uptake of OVA@SiO2 by DC2.4 and its internalization pathway were evaluated in the absence or presence of different inhibitors. The activation and maturation of bone marrow-derived DC cells by OVA@SiO2 were also investigated. Finally, the in vivo transport of OVA@SiO2 and its toxicity to organs were appraised.Results: All results indicated the successful covalent conjugation of OVA on the surface of SiO2. The as-prepared OVA@SiO2 possessed high antigen loading capacity, which had good biocompatibility to APCs and major organs. Besides, OVA@SiO2 facilitated antigen uptake by DC2.4 cells and its cytosolic release. Noteworthily, OVA@SiO2 significantly promoted the maturation of dendritic cells and up-regulation of cytokine secretion by co-administration of adjuvant CpG-ODN.Conclusion: The as-prepared SiO2 shows promising potential for use as an antigen delivery carrier.Keywords: antigen delivery, silica solid sphere, nanovaccine, cancer immunotherapy

BackgroundThe Human Cell Differentiation Molecules (HCDM) organizes Human Leukocyte Differentiation Antigen (HLDA) workshops to test and name clusters of antibodies that react with a specific antigen. These cluster of differentiation (CD) markers have provided the scientific community with validated antibody clones, consistent naming of targets and reproducible identification of leukocyte subsets. Still, quantitative CD marker expression profiles and benchmarking of reagents at the single-cell level are currently lacking.ObjectiveTo develop a flow cytometric procedure for quantitative expression profiling of surface antigens on blood leukocyte subsets that is standardized across multiple research laboratories.MethodsA high content framework to evaluate the titration and reactivity of Phycoerythrin (PE)-conjugated monoclonal antibodies (mAbs) was created. Two flow cytometry panels were designed: an innate cell tube for granulocytes, dendritic cells, monocytes, NK cells and innate lymphoid cells (12-color) and an adaptive lymphocyte tube for naive and memory B and T cells, including TCRγδ+, regulatory-T and follicular helper T cells (11-color). The potential of these 2 panels was demonstrated via expression profiling of selected CD markers detected by PE-conjugated antibodies and evaluated using 561 nm excitation.ResultsUsing automated data annotation and dried backbone reagents, we reached a robust workflow amenable to processing hundreds of measurements in each experiment in a 96-well plate format. The immunophenotyping panels enabled discrimination of 27 leukocyte subsets and quantitative detection of the expression of PE-conjugated CD markers of interest that could quantify protein expression above 400 units of antibody binding capacity. Expression profiling of 4 selected CD markers (CD11b, CD31, CD38, CD40) showed high reproducibility across centers, as well as the capacity to benchmark unique clones directed toward the same CD3 antigen.ConclusionWe optimized a procedure for quantitative expression profiling of surface antigens on blood leukocyte subsets. The workflow, bioinformatics pipeline and optimized flow panels enable the following: 1) mapping the expression patterns of HLDA-approved mAb clones to CD markers; 2) benchmarking new antibody clones to established CD markers; 3) defining new clusters of differentiation in future HLDA workshops.

Background: Patients with predominantly antibody deficiency (PAD) suffer from severe and recurrent infections that require lifelong immunoglobulin replacement and prophylactic antibiotic treatment. Disease incidence is estimated to be 1:25,000 worldwide, and up to 68% of patients develop non-infectious complications (NIC) including autoimmunity, which are difficult to treat, causing high morbidity, and early mortality. Currently, the etiology of NIC is unknown, and there are no diagnostic and prognostic markers to identify patients at risk.Objectives: To identify immune cell markers that associate with NIC in PAD patients.Methods: We developed a standardized 11-color flow cytometry panel that was utilized for in-depth analysis of B and T cells in 62 adult PAD patients and 59 age-matched controls.Results: Nine males had mutations in Bruton's tyrosine kinase (BTK) and were defined as having X-linked agammaglobulinemia. The remaining 53 patients were not genetically defined and were clinically diagnosed with agammaglobulinemia (n = 1), common variable immunodeficiency (CVID) (n = 32), hypogammaglobulinemia (n = 13), IgG subclass deficiency (n = 1), and specific polysaccharide antibody deficiency (n = 6). Of the 53, 30 (57%) had one or more NICs, 24 patients had reduced B-cell numbers, and 17 had reduced T-cell numbers. Both PAD–NIC and PAD+NIC groups had significantly reduced Ig class-switched memory B cells and naive CD4 and CD8 T-cell numbers. Naive and IgM memory B cells, Treg, Th17, and Tfh17 cells were specifically reduced in the PAD+NIC group. CD21lo B cells and Tfh cells were increased in frequencies, but not in absolute numbers in PAD+NIC.Conclusion: The previously reported increased frequencies of CD21lo B cells and Tfh cells are the indirect result of reduced naive B-cell and T-cell numbers. Hence, correct interpretation of immunophenotyping of immunodeficiencies is critically dependent on absolute cell counts. Finally, the defects in naive B- and T-cell numbers suggest a mild combined immunodeficiency in PAD patients with NIC. Together with the reductions in Th17, Treg, and Tfh17 numbers, these key differences could be utilized as biomarkers to support definitive diagnosis and to predict for disease progression.

Quantification of T-cell receptor excision circles (TRECs) has impacted on human T-cell research, but interpretations on T-cell replication have been limited due to the lack of a genomic coding joint. We here overcome this limitation with multiplex TRG rearrangement quantification (detecting ~0.98 alleles per TCRαβ+ T cell) and the HSB-2 cell line with a retrovirally introduced TREC construct. We uncovered 10 cell divisions in effector memory T-cell subsets. Furthermore, we show that TREC dilution with age in healthy adults results mainly from increased T cell replication history. This proliferation was significantly increased in patients with predominantly antibody deficiency. Finally, Guthrie cards of neonates with Down syndrome have fewer T and B cells than controls, with similar T-cell and slightly higher B-cell replication. Thus, combined analysis of TRG coding joints and TREC signal joints can be utilized to quantify in vivo T-cell replication, and has direct applications for research into aging, immunodeficiency, and newborn screening.

Heterozygous STAT1 gain-of-function (GOF) mutations form the most common genetic cause of chronic mucocutaneous candidiasis (CMC). In such patients, increased STAT1 function leads to impaired STAT3-dependent activation of IL-17A and IL-17F in T cells, thereby causing impaired Th17 responses to Candida. In spite of the critical role of STAT3 in IL-21 signaling in B cells, nearly all STAT1 GOF patients have normal or high serum IgG. We here present a 44 year-old male with childhood onset of CMC and antibody deficiency since early adulthood. Sequence analysis of STAT1 revealed a heterozygous missense mutation in the coiled-coil domain (p.D168E), which resulted in increased STAT1 phosphorylation of B-cells activated with IFNα and IFNγ. IL-21 induced STAT3 phosphorylation and nuclear localization were normal, but resulted in impaired upregulation of IL2Rα. This newly identified B-cell intrinsic impairment of STAT3 function could underlie the progressive development of hypogammaglobulinemia. Considering the high risk of bronchiectasis and irreversible organ damage, this case illustrates the need for monitoring of IgG levels and/or function in adult patients with STAT1 GOF mutations.

Patients with X-linked agammaglobulinemia (XLA) have failure of B-cell development with lack of immunoglobulin (Ig) production. While immunoglobulin replacement therapy (IgRT) is beneficial, XLA patients remain at risk for infections, structural lung damage, and rarely, neoplasia. Allogeneic stem cell transplantation (alloSCT) may offer a potential cure, but is associated with significant life-threatening complications. Here, we present a 25-year old XLA patient who developed pre-B acute lymphocytic leukemia (ALL) with somatic TP53 mutation, and treatment for this high-risk malignancy involved full myeloablative conditioning and a HLA-matched sibling alloSCT. Full donor chimerism was achieved for CD3+ and CD3- cell fractions. The patient remains in morphological and flow cytometric remission 14 months post-transplant, with late-onset oral GvHD requiring low dose prednisolone and cyclosporin. Following IgRT discontinuation at 4 months post-transplantation, humoral immunity was established within 14 months as reflected by normal numbers of total B cells, memory B cells, serum IgG, IgM, and IgA, and production of specific IgG responses to Prevenar-13 vaccination. This is only the second reported case of an XLA patient with pre-B-ALL, and the most detailed report of engraftment following alloSCT in XLA. Together with the two previous XLA cases treated with alloSCT, our report provides evidence for the potential for successful humoral reconstitution with alloSCT in patients with B-cell intrinsic antibody deficiency. These observations may be relevant given IgRT, while beneficial, remains an imperfect solution to long-term infectious complications.

Age-related macular degeneration (AMD) is a leading cause of visual impairment in aging populations in industrialized countries. Here we investigated whether the genotype of vascular endothelial growth factor A (VEGFA) gene is associated with response to anti-VEGF therapy. 223 eyes with neovascular AMD were treated with intravitreal anti-VEGF therapy. Responders were defined as patients who had an improvement in best corrected visual acuity (BCVA) of at least 5 letters or one line on the EDTRS visual acuity chart along with resolution of intraretinal or subretinal fluid over 12 months. Patients who did not meet the definition of responders were classified as poor-responders. The vision of responders (n = 148) improved while the vision of poor-responders (n = 75) worsened (P

Abstract Background Immunosurveillance is pivotal in the effectiveness of anticancer therapies and tumor control. The ineffectiveness of cisplatin in activating the immunosurveillance is attributed to its lack of adjuvanticity resulting from its inability to stimulate endoplasmic reticulum stress. Dihydroartemisinin demonstrates the anti-tumor effects through various mechanisms, including the activation of the endoplasmic reticulum stress. This study aimed to develop a novel strategy to enhance the immunogenicity of dying tumor cells by combining cisplatin with dihydroartemisinin, thereby triggering effective anti-tumor immunosurveillance and improving the efficacy of cisplatin in clinical practice. Methods Lewis lung carcinoma (LLC) and CT26 colon cancer cell lines and subcutaneous tumor models were used in this study. The importance of immunosurveillance was validated in both immunocompetent and immunodeficient mouse models. The ability of dihydroartemisinin and cisplatin therapy to induce immunogenic cell death and tumor growth control in vivo was validated by prophylactic tumor vaccination and therapeutic tumor models. The underlying mechanism was elucidated through the pharmaceutical or genetic intervention of the PERK/eIF2α pathway in vitro and in vivo. Results Dihydroartemisinin enhanced the generation of reactive oxygen species in cisplatin-treated LLC and CT26 cancer cells. The combination treatment of dihydroartemisinin with cisplatin promoted cell death and ensured an optimal release of damage-associated molecular patterns from dying cancer cells, promoting the phagocytosis of dendritic cells. In the tumor vaccination model, we confirmed that dihydroartemisinin plus cisplatin treatment induced immunogenic cell death. Utilizing immunocompetent and immunodeficient mouse models, we further demonstrated that the combination treatment suppressed the tumor growth of CT26 colon cancer and LLC lung cancer, leading to an improved prognosis through the restoration of cytotoxic T lymphocyte responses and reinstatement of anti-cancer immunosurveillance in vivo. Mechanistically, dihydroartemisinin restored the immunogenicity of cisplatin by activating the adjuvanticity of damage-associated molecular patterns, such as calreticulin exposure, through the PERK/eIF2α pathway. Additionally, the inhibition of eIF2α phosphorylation attenuated the anti-tumor efficiency of C + D in vivo. Conclusions We highlighted that dihydroartemisinin acts as an immunogenic cell death rescuer for cisplatin, activating anticancer immunosurveillance in a PERK/eIF2α-dependent manner and offering a strategy to enhance the anti-tumor efficacy of cisplatin in clinical practice.

Chun-Yan Zhang, Yu-Shen Yang, Meng-Qin Pei, Xin-Li Chen, Wei-can Chen, He-Fan He Department of Anesthesiology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, People’s Republic of ChinaCorrespondence: He-Fan He, Department of Anesthesiology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, People’s Republic of China, Tel +86 15860905262, Email 15860905262@163.comAbstract: Postoperative cognitive dysfunction (POCD) is a neurological complication associated with surgery and anesthesia that is commonly observed in older patients, and it can significantly affect patient prognosis and survival. Therefore, predicting and preventing POCD is important. Regional cerebral oxygen saturation (rSO2) reflects cerebral perfusion and oxygenation, and decreased intraoperative cerebral oxygen saturation has been reported to increase the risk of POCD. In this review, we elucidated the important relationship between the decline in rSO2 and risk of POCD in older patients. We also emphasized the importance of monitoring rSO2 during surgery to predict and prevent adverse perioperative cognitive outcomes. The findings reveal that incorporating intraoperative rSO2 monitoring into clinical practice has potential benefits, such as protecting cognitive function, reducing perioperative adverse outcomes, and ultimately improving the overall quality of life of older adults.Keywords: anesthesia, surgery, prognosis, perioperative adverse outcome, cognitive function

RBD-specific Bmem were detected in all donors after first and second doses, with significantly higher numbers (1.7-fold) post-dose 2 (Figure 1F, Figure S1A-D). The second COVID-19 mRNA vaccine dose enhances the capacity of Spike-specific memory B cells to bind Omicron BA.2 (A) Participants were sampled pre-BNT162b2 vaccination, 3 weeks post-dose 1, and 4 weeks post-dose 2 with a median of 23 days (range: 21-39 days) between doses. [Extracted from the article]

Ovalbumin (OVA) is the primary allergenic protein, associated with T helper 2 (Th2)-mediated allergy reactions. Here, we studied OVA’s conformational structure, digestibility, and allergenic potency upon galactomannan (Man) conjugation along with transglutaminase-catalyzed crosslinking (TG-Man/OVA) and tyrosinase/caffeic acid-catalyzed crosslinking (Tyr-Man/OVA). Enzymatic glycosylation altered OVA’s conformation and enhanced the gastrointestinal digestibility. Stimulation of bone marrow-derived dendritic cells (BMDCs) with enzymatically glycosylated OVA reduced the expression of CD40, CD80, CD86 and MHC class II molecules. Furthermore, glycosylated OVA increased IL-10 production while suppressing proinflammatory cytokine production in BMDCs. In an OVA-induced mouse asthma model, TG-Man/OVA and Tyr-Man/OVA upregulated IFN-γ and IL-10 expression and downregulated IL-4, IL-5, and IL-13 in lungs. Crosslinked OVA diminished infiltrated cells in bronchoalveolar lavage fluid and lung and attenuated eosinophilic airway inflammation. These findings offer valuable insights into the development of a novel product with improved hypoallergenic and immunomodulatory properties and hold promise in attenuating allergic diseases.

Background Histone deacetylase (HDAC), a kind of protease that regulates gene expression by modifying protein acetylation levels, is usually aberrantly activated in tumors. The approved pan-HDAC inhibitors (HDACi) have exhibited clinical benefits for hematopoietic malignancies. Recently, HDACis have emerged as enhancers of antitumor immunity. However, the effect of HDACs on the tumor immune microenvironment of lung adenocarcinoma (LUAD) and the underlying mechanism is largely unknown.Methods C57BL/6J and BALB/c nude mice with subcutaneous tumors were used for in vivo therapeutic effects and mechanistic investigations. Flow cytometry was used to measure the toxicity and exhaustion of human CD8+T cells after co-culturing with tumor cells and to determine the immunophenotype of tumor-infiltrating CD8+T cells. A series of experimental techniques, including RNA sequencing, quantitative PCR, western blot, ELISA, mass spectrometry, co-immunoprecipitation, chromatin immunoprecipitation and immunohistochemistry, were used to explore the underlying molecular mechanism.Results The pan-HDACi vorinostat (SAHA) promoted CD8+T cell infiltration and effector function in LUAD through suppressing FGL1, a newly identified major ligand of LAG-3. Mechanistically, SAHA inhibited the activity of HDAC1, an essential deacetylase of JAK1. This increased the acetylation level of JAK1 at lysine 1109, thus promoting its proteasomal degradation and subsequently reducing STAT3-driven FGL1 transcription. The combination regimen of SAHA and anti-LAG-3 therapy was further explored in an immunocompetent LUAD mouse model. Compared with those receiving control or single agent treatments, mice receiving combination therapy exhibited a lower tumor burden and superior CD8+T-cell-killing activity.Conclusions Our results revealed a novel mechanism by which the HDACi SAHA potentiates CD8+T-cell-mediated antitumor activity through the HDAC1/JAK1/FGL1 axis, providing a rationale for the combined use of HDACis and immunotherapy.

Abstract Gastric cancer (GC) is a common malignant tumor worldwide, especially in East Asia, with high incidence and mortality rate. Epigenetic modifications have been reported to participate in the progression of gastric cancer, among which m6A is the most abundant and important chemical modification in RNAs. Fat mass and obesity-associated protein (FTO) is the first identified RNA demethylase but little is known about its role in gastric cancer. In our study, data from TCGA and clinical samples showed that FTO was highly expressed in gastric cancer tissues. Kaplan–Meier plotter suggested that patients with the high level of FTO had a poor prognosis. In vitro and in vivo experiments confirmed the role of FTO in promoting gastric cancer cell proliferation. Mechanistically, we found that FTO bound to circFAM192A at the specific site and removed the m6A modification in circFAM192A, protecting it from degradation. CircFAM192A subsequently interacted with the leucine transporter solute carrier family 7 member 5 (SLC7A5) and enhancing its stability. As a result, an increased amount of SLC7A5 was on the membrane, which facilitated leucine uptake and activated the mTOR signaling pathway. Therefore, our study demonstrated that FTO promoted gastric cancer proliferation through the circFAM192A/SLC7A5 axis in the m6A-dependent manner. Our study shed new light on the role of FTO in gastric cancer progression.

Abstract Many Gram-negative pathogens employ the type III secretion system (T3SS) to deliver effector proteins into host cells, thereby modulating host cellular processes and suppressing host immunity to facilitate pathogenesis and colonization. In this study, we developed a straightforward, rapid, and quantitative method for detecting T3SS-mediated translocation of Pseudomonas syringae effectors using a self-assembling split Nano luciferase (Nluc)-based reporter system. It was demonstrated that this system can detect effector secretion in vitro with an exceptionally high signal-to-noise ratio and sensitivity, attributed to the strong affinity between the split domains of Nluc and the intense luminescence generated by functional Nluc. During natural infections, effectors fused to a small C-terminal fragment of Nluc were successfully translocated into plant cells and retained their virulence functions. Furthermore, upon infection of plants expressing the N-terminal fragment of Nluc with these P. syringae strains, functional Nluc proteins were spontaneously assembled and produced bright luminescence, demonstrating that this system enables the straightforward and rapid assessment of P. syringae T3SS-mediated effector translocation during natural infections. In conclusion, the self-assembling split Nluc-based reporting system developed in this study is suitable for efficient in vitro and in planta detection of effectors secreted via T3SS.

Abstract HER2/ERBB2 evaluation is necessary for treatment decision-making in breast cancer (BC), however current methods have limitations and considerable variability exists. DNA copy number (CN) evaluation by droplet digital PCR (ddPCR) has complementary advantages for HER2/ERBB2 diagnostics. In this study, we developed a single-reaction multiplex ddPCR assay for determination of ERBB2 CN in reference to two control regions, CEP17 and a copy-number-stable region of chr. 2p13.1, validated CN estimations to clinical in situ hybridization (ISH) HER2 status, and investigated the association of ERBB2 CN with clinical outcomes. 909 primary BC tissues were evaluated and the area under the curve for concordance to HER2 status was 0.93 and 0.96 for ERBB2 CN using either CEP17 or 2p13.1 as reference, respectively. The accuracy of ddPCR ERBB2 CN was 93.7% and 94.1% in the training and validation groups, respectively. Positive and negative predictive value for the classic HER2 amplification and non-amplification groups was 97.2% and 94.8%, respectively. An identified biological “ultrahigh” ERBB2 ddPCR CN group had significantly worse survival within patients treated with adjuvant trastuzumab for both recurrence-free survival (hazard ratio, HR: 3.3; 95% CI 1.1–9.6; p = 0.031, multivariable Cox regression) and overall survival (HR: 3.6; 95% CI 1.1–12.6; p = 0.041). For validation using RNA-seq data as a surrogate, in a population-based SCAN-B cohort (NCT02306096) of 682 consecutive patients receiving adjuvant trastuzumab, the ultrahigh-ERBB2 mRNA group had significantly worse survival. Multiplex ddPCR is useful for ERBB2 CN estimation and ultrahigh ERBB2 may be a predictive factor for decreased long-term survival after trastuzumab treatment.

Abstract High electro-optical conversion efficiency is one of the most distinctive features of semiconductor lasers as compared to other types of lasers. Its further increase remains a significant objective. Further enhancing the efficiency of edge-emitting lasers (EEL), which represent the highest efficiency among semiconductor lasers at present, is challenging. The efficiency of vertical cavity surface emitting lasers (VCSELs) has always been relatively low compared to EEL. This paper, combining modeling with experiments, demonstrates the potential of multi-junction cascaded VCSELs to achieve high efficiency beyond that of EELs, our simulations show, that a 20-junction VCSEL can achieve an efficiency of more than 88% at room temperature. We fabricated VCSEL devices with different numbers of junctions and compared their energy efficiency. 15-junction VCSELs achieved a maximum efficiency of 74% at room temperature under nanosecond driving current, the corresponding differential quantum efficiency exceeds 1100%, being the largest electro-optical conversion efficiency and differential quantum efficiency reported until now for VCSELs.

The adoption of multi-channel strategies by retailers, encompassing both online and offline modalities, has fundamentally transformed consumer shopping behaviors, resulting in a significant increase in mobile shopping. Nonetheless, the long-term success of mobile shopping apps is heavily dependent on consumers’ continuous use. Regrettably, the existing studies on this area remain vague and require further exploration. This study aims to close this gap by examining Malaysian consumers’ continuance intention and continuance use of mobile shopping through the lens of ISSM in the context of mobile shopping apps. We utilised a quantitative approach and successfully collected 369 responses from Klang Valley, using purposive sampling techniques. The predictive hypotheses developed were validated using Partial Least Square – Structural Equation Modelling (PLS-SEM) and were further supplemented with Necessary Condition Analysis (NCA) to determine must-have factors based on necessary logic. The PLS-SEM results confirmed the association between continuance intention and continuance use. The findings revealed that service quality and system quality are associated with satisfaction, but not information quality. Additionally, service quality, system quality, and information quality, together with satisfaction, trust and incentive have a positive significant influence on Malaysians’ mobile shopping app continuance intention. However, the NCA results indicated that system quality is the sole must-have factor that contributes to satisfaction. Meanwhile, service quality, system quality, information quality, satisfaction, trust, and incentive are the must-have predictors for mobile shopping app continuance intention. The study sheds light on previously unexplored aspects namely, continuance intention and continuance use, within the framework of the ISSM in the context of mobile shopping. By doing so, it offers more refined and actionable insights to improve consumer experience and foster sustained engagement with mobile shopping apps. Simultaneously, it contributes to the advancement of knowledge regarding the foundational constructs and their interconnectedness, thereby enhancing theoretical development in this domain.

Direct detection of miRNA is currently limited by the complex amplification and reverse transcription processes of existing methods, leading to low sensitivity and high operational demands. Herein, we developed a CRISPR/Cas13a-mediated photoelectrochemical (PEC) biosensing platform for direct and sensitive detection of miRNA-21. The direct and specific recognition of target miRNA-21 by crRNA-21 eliminates the need for pre-amplification and reverse transcription of miRNA-21, thereby preventing signal distortion and enhancing the sensitivity and precision of target detection. When crRNA-21 binds to miRNA-21, it activates the trans-cleavage activity of CRISPR/Cas13a, leading to the non-specific cleavage of biotin-modified DNA with uracil bases (biotin-rU-DNA). This cleavage prevents the biotin-rU-DNA from being immobilized on the electrode surface. As a result, streptavidin cannot attach to the electrode via specific biotin binding, reducing spatial resistance and causing a positively correlated increase in the photocurrent response. This Cas-PEC biosensor has good analytical capabilities, linear responses between 10 fM and 10 nM, a minimum detection limit of 9 fM, and an excellent recovery rate in the analysis of real human serum samples. This work presented an innovative solution for detecting other biomarkers in bioanalysis and clinical diagnostics.