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Abstract Killer cell lectin-like receptor G1 (KLRG1) is an immune checkpoint receptor expressed predominantly in NK and T-cell subsets that downregulates the activation and proliferation of immune cells and participates in cell-mediated immune responses. Accumulating evidence has demonstrated the importance of KLRG1 as a noteworthy disease marker and therapeutic target that can influence disease onset, progression, and prognosis. Blocking KLRG1 has been shown to effectively mitigate the effects of downregulation in various mouse tumor models, including solid tumors and hematologic malignancies. However, KLRG1 inhibitors have not yet been approved for human use, and the understanding of KLRG1 expression and its mechanism of action in various diseases remains incomplete. In this review, we explore alterations in the distribution, structure, and signaling pathways of KLRG1 in immune cells and summarize its expression patterns and roles in the development and progression of autoimmune diseases, infectious diseases, and cancers. Additionally, we discuss the potential applications of KLRG1 as a tool for tumor immunotherapy.

Severe pneumonia (SP) is a prevalent respiratory ailment characterized by high mortality and poor prognosis. Current scoring systems for pneumonia are not only time-consuming but also exhibit limitations in early SP prediction. To address this gap, this study aimed to develop a machine-learning model using inflammatory markers from peripheral blood for early prediction of SP. A total of 204 pneumonia patients from seven medical centers were studied, with 143 (68 SP cases) in the training cohort and 61 (32 SP cases) in the test cohort. Clinical characteristics and laboratory test results were collected at diagnosis. Various models including Logistic Regression, Random Forest, Naïve Bayes, XGBoost, Support Vector Machine, and Decision Tree were built and evaluated. Seven predictors—age, sex, WBC count, T-lymphocyte count, NLR, CRP, TNF-α, IL-4/IFN-γ ratio, IL-6/IL-10 ratio—were selected through LASSO regression and clinical insight. The XGBoost model, exhibiting best performance, achieved an AUC of 0.901 (95 % CI: 0.827 to 0.985) in the test cohort, with an accuracy of 0.803, sensitivity of 0.844, specificity of 0.759, and F1_score of 0.818. Indeed, SHAP analysis emphasized the significance of elevated WBC counts, older age, and elevated CRP as the top predictors. The use of inflammatory biomarkers in this concise predictive model shows significant potential for the rapid assessment of SP risk, thereby facilitating timely preventive interventions.

As a commonly used traditional Chinese medicine formula for treating rheumatoid arthritis (RA), Sishen Decoction (SSD) has anti-inflammatory, analgesic and swelling relief effects. However, at present, the pharmacodynamic basis of SSD and its mechanism of treating RA have not been clarified, and further research is needed. Analyzing the pharmacological basis of SSD was the aim of our study and further elucidate its therapeutic mechanism and potential targets for treating RA. LC‒MS was used to identify the high content and characteristic chemical components of SSD. On this basis, a network of pharmacological analysis was established between the chemical structure and RA. According to the predicted possible pathways and targets, in vivo pharmacodynamic experiments and related pathway analysis were conducted. Finally, the possible targets and mechanisms of SSD in treating RA were analyzed. Identified 78 compounds from SSD by LC-MS, including 23 flavonoids, 19 phenolic acids, 9 monoterpenoids and 26 other compounds. Network pharmacological analysis based on pharmacodynamic substances revealed that the most likely interaction pathway between SSD and RA was the PI3K/AKT/mTOR pathway. Foot swelling and inflammatory factors (IL-6, IL-10, IL-18, TGF, TNF-α, VEGF) in model mice were shown to be significantly improved in vivo. WB and qPCR experiments proved that SSD could significantly regulate the pathway of PI3K/AKT/mTOR. The interaction between SSD and AKT target was further analyzed by multispectroscopy. This study revealed that SSD alleviates RA by regulating the pathway of PI3K/AKT/mTOR and preliminarily revealed the pharmacodynamic mechanism of SSD for the first time.

Reading acquisition is a prolonged learning process relying on language development starting in utero. Behavioral longitudinal studies reveal prospective associations between infant language abilities and preschool/kindergarten phonological development that relates to subsequent reading performance. While recent pediatric neuroimaging work has begun to characterize the neural network underlying language development in infants, how this neural network scaffolds long-term language and reading acquisition remains unknown. We addressed this question in a 7-year longitudinal study from infancy to school-age. Seventy-six infants completed resting-state fMRI scanning, and underwent standardized language assessments in kindergarten. Of this larger cohort, forty-one were further assessed on their emergent word reading abilities after receiving formal reading instructions. Hierarchical clustering analyses identified a modular infant language network in which functional connectivity (FC) of the inferior frontal module prospectively correlated with kindergarten-age phonological skills and emergent word reading abilities. These correlations were obtained when controlling for infant age at scan, nonverbal IQ and parental education. Furthermore, kindergarten-age phonological skills mediated the relationship between infant FC and school-age reading abilities, implying a critical mid-way milestone for long-term reading development from infancy. Overall, our findings illuminate the neurobiological mechanisms by which infant language capacities could scaffold long-term reading acquisition.

The silent information regulator sirtuin 1 (SIRT1) protein is an NAD+-dependent class-III lysine deacetylase that serves as an important post-transcriptional modifier targeting lysine acetylation sites to mediate deacetylation modifications of histones and non-histone proteins. SIRT1 has been reported to be involved in several physiological or pathological processes such as aging, inflammation, immune responses, oxidative stress and allergic diseases. In this review, we summarized the regulatory roles of SIRT1 during allergic disorder progression. Furthermore, we highlight the therapeutic effects of targeting SIRT1 in allergic diseases.

Abstract Background Metabolic dysfunction-associated fatty liver disease (MAFLD) has been proposed as a new term for diagnosing fatty liver disease, which is considered to be a multi-systemic disease with multiple extrahepatic manifestations, including sarcopenia. The link between sarcopenia and MAFLD remains uncertain, especially among young and middle-aged adults. Thus, we examined the relationship between MAFLD and sarcopenia in young and middle-aged individuals in this study. Methods A total of 2214 individuals with laboratory tests, dual-energy X-ray absorptiometry and ultrasound transient elastography from NHANES 2017–2018 were selected for this study. MAFLD was diagnosed as fatty liver disease with any one of the situations: overweight/obesity, diabetes mellitus, presence of metabolic dysregulation. Sarcopenia was defined by appendicular lean mass adjusted for body mass index (BMI). Multivariable logistic regression and restricted cubic spline (RCS) model were applied to explore the relationship between MAFLD and sarcopenia, and the mediation analyses were also conducted. Moreover, subgroup analyses stratified by BMI and lifestyles were done. Results The prevalence of MAFLD was 47.85%, and nearly 8.05% of participants had sarcopenia. The prevalence of sarcopenia was higher in participants with MAFLD (12.75%; 95% CI 10.18–15.31%) than in the non-MAFLD (3.73%; 95% CI 2.16–5.31%). MAFLD was significantly positively associated with sarcopenia after adjustments [OR = 2.87 (95% CI: 1.62–5.09)]. Moreover, significant positive associations were observed between liver fibrosis and sarcopenia prevalence in MAFLD patients (OR = 2.16; 95% CI 1.13–4.15). The RCS curve revealed that MAFLD was linearly associated with sarcopenia. The relationship between the MAFLD and sarcopenia were mediated by C-reactive protein (mediation proportion: 15.9%) and high-density lipoprotein cholesterol (mediation proportion: 18.9%). Subgroup analyses confirmed the association between MAFLD and sarcopenia differed in different lifestyle groups. Conclusions Both MAFLD prevalence and severity was significantly associated with sarcopenia. Thus, clinicians should advise comorbidity screening and lifestyle changes to young and middle-aged patients.

Psoriasis is a chronic inflammatory skin disease characterized by skin infiltration of immune cells and abnormal epidermal thickening. The initial pathogenesis has not been fully elucidated. Non-coding RNAs (ncRNAs), which include long ncRNAs (lncRNAs) and circular RNAs (circRNAs), comprise the majority of genome transcripts and are important influencers of gene transcription and post-transcription modulations. Emerging roles of ncRNAs in psoriasis were identified recently. This review summarizes the existing studies of psoriasis-related lncRNAs and circRNAs. A considerable proportion of the studied lncRNAs and circRNAs regulate keratinocyte mobility, such as keratinocyte proliferation and differentiation. Some lncRNAs and circRNAs are tightly related to keratinocyte inflammation reactions. Other reports demonstrated that they are also implicated in modulating immune cell differentiation, proliferation, and activation. This review might illuminate future psoriasis research and highlight that lncRNAs and circRNAs might act as therapeutic targets.

Abstract T-lymphocytes are prevalent in the tumor microenvironment of follicular lymphoma (FL). However, the phenotype of T-cells may vary, and the prevalence of certain T-cell subsets may influence tumor biology and patient survival. We therefore analyzed a cohort of 82 FL patients using CyTOF to determine whether specific T-cell phenotypes were associated with distinct tumor microenvironments and patient outcome. We identified four immune subgroups with differing T-cell phenotypes and the prevalence of certain T-cell subsets was associated with patient survival. Patients with increased T cells with early differentiation stage tended to have a significantly better survival than patients with increased T-cells of late differentiation stage. Specifically, CD57+ TFH cells, with a late-stage differentiation phenotype, were significantly more abundant in FL patients who had early disease progression and therefore correlated with an inferior survival. Single cell analysis (CITE-seq) revealed that CD57+ TFH cells exhibited a substantially different transcriptome from CD57− TFH cells with upregulation of inflammatory pathways, evidence of immune exhaustion and susceptibility to apoptosis. Taken together, our results show that different tumor microenvironments among FL patients are associated with variable T-cell phenotypes and an increased prevalence of CD57+ TFH cells is associated with poor patient survival.

Abstract Most existing Siamese Network trackers rely on a predefined anchor box to predict object position. However, they require complicated hyperparameter settings. The authors directly forecast the object boundary by using the fully convolutional network as the head of the tracking network to solve this issue and simplify the application. The end‐to‐end design avoids the setting of hyperparameters and candidate boxes. The authors also discovered that the validation loss decreased less than the training loss throughout Siamese training. The authors changed the normalisation layer from batch normalisation to group normalisation to solve this issue. It solved the problem that the loss function is difficult to decrease and increased training efficiency. Test experiments on the tracking dataset, including VOT2019 and GOT10k, show that the authors’ network outperforms DaSiamRPN and SiamFC regarding precision under the same network size and runs at 24 FPS on an AMD 4800 CPU. It also runs at 306 FPS on a 3090 GPU.

Facial palsy would lead to a series of physical and mental problems, as facial function plays an important role in various aspects of daily life. However, the current strategies for evaluating facial function relied heavily on raters and the results varied from the experience of raters. Thus, an objective and accurate facial evaluation system is always claimed. In this study, a customized automatical facial evaluation system (AFES) was proposed, which might have the potential to be employed as an adjunctive and efficient assessing method in clinic. In order to investigate the feasibility of AFES, ninety-two participants with facial palsy were recruited and received scale-based subjective manual evaluation (including mHBGS and mSFGS) and objective automatical evaluation of AFES (including aHBGS, aSFGS and indicators of facial regional features) at enrollment and after two weeks. The correlations between the results of the two methods were analyzed and the participants were stratified according to the severity of facial function for further analyses. Strong positive correlations between manual and automatical HBGS and SFGS were observed and higher correlations were reported in the participants with normal-mild and moderate facial palsy. Significant improvements in clinical scales and indicator of eye synkinesis were found in forty-two participants in two weeks. Furthermore, some of the indicators were correlated with scale scores (I4, I7) and one of them presented a significant change between the baseline evaluation and follow-up evaluation (I7). According to the results, AFES could be considered as a viable method to perform objective and reliable evaluation for patients with facial palsy and provide clarified results for prognosis.

The clinical success of immune checkpoint inhibitors (ICIs) has initiated a new era in the treatment of metastatic cancer. Unfortunately, the overall response rate of ICIs in pretreated metastatic breast cancer (BC) is generally less than 20% due to many challenges, including low immunogenicity and immunosuppressive tumour microenvironment (ITM). Herein, we synthesized nanoliposomes that codelivered diclofenac (DC) and Mn (5,10,15,20-tetrakis (4-chlorophenyl) porphyrin) Cl (PMnCl) (denoted MD@Lip) to overcome these challenges. DC could block lactate transporters (monocarboxylate transporters 1 and 4) on the cancer cell membrane, thus reducing the concentration of lactate, which acts as a critical regulator of the ITM. Meanwhile, PMnCl-induced sonodynamic therapy (SDT) could induce apoptotic and/or necrotic tumour cell death. Importantly, SDT could induce immunogenic cell death (ICD) during the tumour cell debris generation, which changed the state of tumour cells from nonimmunogenic to immunogenic. Thus, MD@Lip was verified to activate T cells, inactivate regulatory T cells and regulate the levels of immune cytokines, ultimately inhibiting primary and distant tumours by improving the antitumour effect of anti-PD1-based immunotherapy.

Hypercalcaemia associated with malignancy is a complication of advanced tumors. Lactic acidosis is also an extremely rare paraneoplastic syndrome of malignancy, and the presence of both usually indicates an extremely poor prognosis for the tumour. Diffuse large B-cell lymphoma is the most common type of non-Hodgkin's lymphoma and is also a common aggressive lymphoma. It is extremely rare for patients with diffuse large B-cell lymphoma to develop both hypercalcaemia and severe lactic acidosis. In this article, we report a case of CD5 positive diffuse large B-cell lymphoma with hypercalcaemic crisis and persistent lactic acidosis, in which calcium was rapidly reduced to normal after rehydration, diuresis, calcitonin and zoledronate, and continuous renal replacement therapy (CRRT). After correction of acidosis with sodium bicarbonate, diuresis, vitamin B1 and CRRT, the patient's lactate remained at a high level. The aim of this article is to analyse the experience of the combination of hypercalcaemia and intractable lactic acidosis, which should be considered as a serious electrolyte disorder possibly associated with abnormal metabolism of malignant tumors, and to identify and treat the primary lesion as early as possible.

A significant distinction between the COVID-19 pandemic and previous pandemics is the significant role of social media platforms in shaping public adherence to non-pharmaceutical interventions and vaccine acceptance. However, with the recurrence of the epidemic, the conflict between epidemic prevention and production recovery has become increasingly prominent on social media. To help design effective communication strategies to guide public opinion, we propose a susceptible-forwarding-immune pseudo-environment (SFI-PE) dynamic model for understanding the environment with direct and indirect propagation behaviors. Then, we introduce a system with external interventions for direct and indirect propagation behaviors, termed the macro-controlled SFI-PE (M-SFI-PE) model. Based on the numerical analyses that were performed using actual data from the Chinese Sina microblogging platform, the data fitting results prove our models' effectiveness. The research grasps the law of the new information propagation paradigm, and our work bridges the gap between reality and theory in information interventions.

Background: Alveolar epithelial cell injury is a key factor in the occurrence and development of pulmonary acute respiratory distress syndrome (ARDSp). Yet the gene expression profile of alveolar epithelial cells of patients with ARDSp remains unclear. Methods: We analyzed single nuclear RNA sequencing (snRNA-Seq) data from autopsy lung tissues of both ARDSp patients and healthy donors. Sequence data for type 2 alveolar epithelizal cells (AT2) were extracted by the Seurat package. Differentially expressed genes (DEGs) in AT2 were identified by the criteria |log2FC| ≥ 0.25 and P

Summary: Despite extensive research, the specific factor associated with SARS-CoV-2 infection that mediates the life-threatening inflammatory cytokine response in patients with severe COVID-19 remains unidentified. Herein we demonstrate that the virus-encoded Open Reading Frame 8 (ORF8) protein is abundantly secreted as a glycoprotein in vitro and in symptomatic patients with COVID-19. ORF8 specifically binds to the NOD-like receptor family pyrin domain-containing 3 (NLRP3) in CD14+ monocytes to induce inflammasomal cytokine/chemokine responses including IL1β, IL8, and CCL2. Levels of ORF8 protein in the blood correlate with severity and disease-specific mortality in patients with acute SARS-CoV-2 infection. Furthermore, the ORF8-induced inflammasome response was readily inhibited by the NLRP3 inhibitor MCC950 in vitro. Our study identifies a dominant cause of pathogenesis, its underlying mechanism, and a potential new treatment strategy for severe COVID-19.

Natural products are widely used for treating mitochondrial dysfunction-related diseases and cancers. Curcumin, a well-known natural product, can be potentially used to treat cancer. Human salt-induced kinase 3 (SIK3) is one of the target proteins for curcumin. However, the interactions between curcumin and human SIK3 have not yet been investigated in detail. In this study, we studied the binding models for the interactions between curcumin and human SIK3 using computational tools such as homology modeling, molecular docking, molecular dynamics simulations, and binding free energy calculations. The open activity loop conformation of SIK3 with the ketoenol form of curcumin was the optimal binding model. The I72, V80, A93, Y144, A145, and L195 residues played a key role for curcumin binding with human SIK3. The interactions between curcumin and human SIK3 were also investigated using the kinase assay. Moreover, curcumin exhibited an IC50 (half-maximal inhibitory concentration) value of 131 nM, and it showed significant antiproliferative activities of 9.62 ± 0.33 µM and 72.37 ± 0.37 µM against the MCF-7 and MDA-MB-23 cell lines, respectively. This study provides detailed information on the binding of curcumin with human SIK3 and may facilitate the design of novel salt-inducible kinases inhibitors.

232Th/233U fuel cycle is an alternate candidate for future nuclear energy. Neutron-induced fission cross section of 232Th is one of the important nuclear data if using thorium as the fuel in the future. 232Th(n, f) cross sections from 1 to 300 MeV were measured at China Spallation Neutron Source (CSNS) Back-streaming neutron facility (Back-n) relative to 235U(n, f) and n-p scattering. A fast ionization chamber for fission cross section measurement (FIXM) and a proton recoil telescope (PRT) were used to perform the measurement. The neutron energy in this measurement reaches up to 300 MeV which is supposed to be the highest among the current Experimental Nuclear Reaction Data (EXFOR) library. It stands as the only experimental data in the region of 200-300 MeV in EXFOR as well. The experimental and evaluated data of 232Th(n, f) cross section above 60 MeV are scarce, the measurement data of this work will be valuable references for future evaluation in high energy. For the data below 60 MeV, most of our data are more consistent with ENDF/B-VIII.0, excepting in the region of 1-2 MeV where our data are more in favor of CENDL-3.2.

Seahorses are valuable species for their use in traditional Chinese medicine, as well as for the aquarium trade as ornamentals and curiosities. To balance market demand and reduce pressure on wild populations, many countries have undertaken commercial seahorse cultivation. Skeletal development plays a crucial role in fish fry culture, affecting external morphology, feeding, and movement. This study investigated the ontogeny allometry, timing, and progression of skeletal development in H. abdominalis from DAB (day after birth) 1 to DAB 100 under mass-scale captive breeding conditions in north China. The results of this study revealed the growth rate was significantly increased between DAB 30 and DAB 54. Allometry analysis revealed that in the early stage, the head, trunk, and tail demonstrated almost isometric growth. However, in the later stage, the head and trunk exhibited negative isometric growth, whereas the tail displayed positive isometric growth. Skeletal staining results showed that newborn seahorses do not have ossified bones until DAB 11 (SL 28.14 ± 2.94 mm). Ossification was primarily observed in the jaw region and the tubular nasal structure of the cranium, which indicated the importance of the early development of feeding organs. The initial formation of ossified vertebral columns was observed at DAB 13 (SL 26.48 ± 0.63 mm), with the complete ossification of all vertebrae occurring by DAB 45 (SL 54.87 ± 4.70 mm). Furthermore, the cranium, rings, and plates were all fully ossified by DAB 30. Ossification of the fins began at DAB 23 (SL 31.27 ± 4.05 mm). However, neither of them were fully ossified by DAB 100. The pelvic fin and the complete structure of the caudal fin were not observed, possibly because of caudal fin ray structure degeneration within the pouch. In addition, no skeletal deformities were observed in all the tested samples. The results of this study provide valuable information on the developmental biology of H. abdominalis, enriching our understanding of their growth and offering insights for optimizing fish fry breeding technologies.

Abstract Objective As one of the most common primary headaches in clinical practice, migraine affects the learning ability and life quality of college students worldwide, posing a heavy burden on individuals and society. This study aims to investigate the incidence of migraine among Chinese medical college students and to explore its characteristics and typical triggers. Method From July 2019 to July 2020, North Sichuan Medical College in Sichuan province, China preliminarily screened migraine cases using ID-Migraine through cluster sampling. College students with positive ID-Migraine results would be included in this study if they were further diagnosed with migraine by neurologists based on ICHD-3. After the ethical review, patients’ personal and headache information would be collected, and the frequency, severity, onset time, and related triggers of migraine would be measured. Results The preliminary screening covered 8783 college students. The overall prevalence rate of migraine is 6.57%, 5.90% in men and 6.77% in women. The prevalence rate of migraine is higher for students in the first and second grades (8.01%, 8.05%), and students with a family history of migraine are more likely to suffer from migraine (OR = 1.509, 95% CI 1.060–2.148, P = 0.022

Abstract Circular RNAs (circRNAs) are a type of recently discovered noncoding RNA. They exert their biological functions by competitively binding to microRNAs (miRNAs) as miRNA sponges, promoting gene transcription and participating in the regulation of selective splicing, interacting with proteins and being translated into proteins. Exosomes are derived from intracavitary vesicles (ILVs), which are formed by the inward budding of multivesicular bodies (MVBs), and exosome release plays a pivotal role in intercellular communication. Accumulating evidence indicates that circRNAs in exosomes are associated with solid tumor invasion and metastasis. Additionally, emerging studies in the last 1 ~ 2 years have revealed that exosomal circRNA also have effect on hematological malignancies. In this review, we outline the properties and biological functions of circRNAs and exosomes. In particular, we summarize in detail the mechanism and roles of exosomal circRNAs and highlight their application as novel biomarkers in malignant tumors.

Objective To explore the recruitment and retention strategy of blood donors by investigating the age composition of blood donors in some areas of China, so as to promote blood donation and enhance clinical blood supply. Methods Through the working platform of Practice Comparison Working Group of China’s Mainland Blood Collection and Supply Institutions, the average age and age composition of blood donors from 22 blood centers were collected, and statistical analysis was conducted after eliminating invalid data. Results The median average age of blood donors during the survey year was 30.02.The median age in 2.89% of the blood centers was lower than 25. The average age of different genders was statistically significant only in 2018(P

Despite the critical breakthrough achieved by immune checkpoint blockade (ICB) therapies in the clinic, the antitumor effect is seriously restricted by the immunosuppressive tumor microenvironment (ITM). A variety of strategies to alleviate the ITM have been investigated. Direct regulation of lactate metabolism in the tumor microenvironment (TME) holds promise for ITM modulation. Herein, we fabricated a glutathione-responsive PEGylated hollow mesoporous organosilicon (HMOP), with monocarboxylate transporter 1/4 inhibitor (diclofenac, DC) and lactate oxidase (LOX) loaded in/onto the HMOP (denoted as DC-HMOP-LOX). DC-HMOP-LOX could spontaneously be biodegraded in the TME due to the disulfide bonds, and then DC/LOX could be released to exhaust intra/extracellular lactate. DC-HMOP-LOX hindered the transmission of lactate effectively and oxidized lactate directly. Therefore, DC-HMOP-LOX collaboratively depleted lactate in the TME, which induced an immunocompetent TME by activating immune-promoting cells (dendritic cell, T cells, natural killer cells, and M1-macrophage), inactivating immunosuppressive cells (M2-macrophage and bone marrow-derived suppressor cells), and regulating the levels of immune cytokines (IFN-γ, TNF-α, IL-10, and IL-12). The immunocompetent TME ultimately strengthened the antitumor effect of anti-PD1-based immunotherapy.

Hyphantria cunea (Drury) is a globally important forest pest. We found that the Serratia marcescens Bizio strain SM1 had insecticidal activity against H. cunea, but the transcriptomic response of H. cunea to SM1 were not clear. Therefore, we performed full-length sequencing of the transcriptomes of H. cunea larvae infected with SM1 and the control group. A total of 1,183 differentially expressed genes (DEGs) were identified by comparing the group infected with SM1 and the control group, including 554 downregulated genes and 629 upregulated genes. We found many downregulated genes in metabolic pathways. Furthermore, some of these downregulated genes were involved in cellular immunity, melanization, and detoxification enzymes, which showed that SM1 weakened H. cunea immunity. In addition, genes in the juvenile hormone synthesis pathway were upregulated, which was detrimental to the survival of H. cunea. This research analyzed the transcriptomic response of H. cunea to SM1 by high-throughput full-length transcriptome sequencing. The results provide useful information to explore the relationship between S. marcescens and H. cunea, and theoretical support for the application of S. marcescens and the control of H. cunea in the future.

Using fiber and cement to modify waste slurry and apply it to roads is an effective way to recycle waste slurry. A new type of road material, fiber–cement-modified waste slurry (FRCS), was prepared in this study. The static and dynamic characteristics of the cement soil were studied using an unconfined compressive strength test and dynamic triaxial test. The results show that the optimum fiber content of FRCS is 0.75%. In the unconfined compressive strength test, under this fiber content, the unconfined compressive strength (UCS) of the FRCS is the largest, and the elastic modulus and modulus strength ratio are both the smallest, indicating that the tensile properties of the cement slurry have been enhanced. In the dynamic triaxial test, the hysteretic curve of the FRCS tends to be stable with the increase in the number of cycles, the dynamic elastic modulus of the FRCS decreases first and then increases with the increase in the dosage, while the damping ratio becomes stable after a rapid decline, and the fiber incorporation increases the cumulative strain of the soil–cement under low-stress cycles, indicating that the ductility of the FRCS is improved. In addition, a cumulative strain prediction model of the FRCS is established in this paper, which can provide a reference for the resource application of waste slurry in road engineering.

ObjectiveVertigo is very common in children, but the specific diagnosis and characteristics are not clear. The main objective of this study was to analyze the characteristics of caloric test (CT) and video head impulse test (vHIT) in vestibular migraine of childhood (VMC), probable vestibular migraine of childhood (PVMC), and recurrent vertigo of childhood (RVC), which can provide a reference value for their clinical diagnosis.MethodsWe selected VMC, PVMC and RVC patients under 18 years of age from the outpatient Department of Otolaryngology–Head and Neck Surgery between May 2021 and August 2022. All patients underwent vestibular function examinations, including eye movement recording CT and vHIT. CT results depended on whether both canal paresis and directional preponderance were under normal limits, and vHIT results depended on the gain values of vestibulo-ocular reflex. The results of both tests were analyzed according to the disease type.ResultsAmong the 81 pediatric vertigo patients aged 5–17 years, 44 were females and 37 were males. According to the type of vertigo, 29 patients (25.80%) were diagnosed with VMC, 11 (13.58%) with PVMC, and 41 (50.62%) with RVC. The abnormal rates of the CT in VMC, PVMC, and RVC patients were 24.14%, 36.36%, and 17.07%, respectively. There was no significant difference in the abnormal rates among the three groups (P > 0.05). None of the patients showed abnormal vHIT results (all abnormal rates 0.00%). The abnormal CT rates were significantly higher than those of abnormal vHIT rates (P < 0.05).ConclusionsVMC, PVMC, and RVC are more likely to be diagnosed by symptoms, as neither CT nor vHIT are specific to any conditions. Due to different clinical presentations of vertigo in pediatric patients, it is critical to further clarify the diagnosis with medical history and clinical characteristics.

BackgroundLeukemia caused by occupational risk is a problem that needs more attention and remains to be solved urgently, especially for acute lymphoid leukemia (ALL), acute myeloid leukemia (AML), and chronic lymphoid leukemia (CLL). However, there is a paucity of literature on this issue. We aimed to assess the global burden and trends of leukemia attributable to occupational risk from 1990 to 2019.MethodsThis observational trend study was based on the Global Burden of Disease (GBD) 2019 database, the global deaths, and disability-adjusted life years (DALYs), which were calculated to quantify the changing trend of leukemia attributable to occupational risk, were analyzed by age, year, geographical location, and socio-demographic index (SDI), and the corresponding estimated annual percentage change (EAPC) values were calculated.ResultsGlobal age-standardized DALYs and death rates of leukemia attributable to occupational risk presented significantly decline trends with EAPC [−0.38% (95% CI: −0.58 to −0.18%) for DALYs and −0.30% (95% CI: −0.45 to −0.146%) for death]. However, it was significantly increased in people aged 65–69 years [0.42% (95% CI: 0.30–0.55%) for DALYs and 0.38% (95% CI: 0.26–0.51%) for death]. At the same time, the age-standardized DALYs and death rates of ALL, AML, and CLL were presented a significantly increased trend with EAPCs [0.78% (95% CI: 0.65–0.91%), 0.87% (95% CI: 0.81–0.93%), and 0.66% (95% CI: 0.51–0.81%) for DALYs, respectively, and 0.75% (95% CI: 0.68–0.82%), 0.96% (95% CI: 0.91–1.01%), and 0.55% (95% CI: 0.43–0.68%) for death], respectively. The ALL, AML, and CLL were shown an upward trend in almost all age groups.ConclusionWe observed a substantial reduction in leukemia due to occupational risks between 1990 and 2019. However, the people aged 65–69 years and burdens of ALL, AML, and CLL had a significantly increased trend in almost all age groups. Thus, there remains an urgent need to accelerate efforts to reduce leukemia attributable to occupational risk-related death burden in this population and specific causes.

Circular RNAs (circRNAs) are important transcriptional regulators of genome expression that participate in the pathogenesis of human diseases. Mechanistically, circRNAs, as competitive endogenous RNAs (ceRNAs), can sponge microRNAs (miRNAs) with miRNA response elements. A previous study identified that hsa_circ_0089172 (circNUP214) is abnormally expressed in Hashimoto’s thyroiditis. However, the role of circNUP214 in rheumatoid arthritis (RA) remains unclear. In total, 28 RA patients and 28 healthy controls were enrolled in this study. We found that circNUP214 is an abundant and stable circRNA in RA patients that can potentially differentiate RA patients from healthy subjects. Additionally, the elevated levels of IL-23R positively correlated with circNUP214 expression. The knockdown of circNUP214 resulted in the reduction of IL-23R at both transcriptional and translational levels in human CD4+ T cells. The proportion of circulating Th17 cells and the transcript levels of IL-17A were increased in RA patients and were both positively correlated with IL-23R expression. Moreover, positive correlations between the transcript levels of circNUP214 and the percentage of Th17 cells and the transcript levels of IL-17A were observed in RA patients. The downregulation of circNUP214 decreased the proportion of Th17 cells and the transcript levels of IL-17A in vitro. Furthermore, circNUP214 functioned as a ceRNA for miR-125a-3p in RA patients. Taken together, our results indicate that elevated levels of circNUP214 contribute to the Th17 cell response in RA patients.

Abstract This study took shear wave elastography (SWE) technology to measure the shear wave velocity (SWV) of peripheral nerve in healthy population, which represents the stiffness of the peripheral nerves, and research whether these parameters (location, age, sex, body mass index (BMI), the thickness and cross-sectional area(CSA) of the nerve) would affect the stiffness of the peripheral nerves. 105 healthy volunteers were enrolled in this study. We recorded the genders and ages of these volunteers, measured height and weight, calculated BMI, measured nerve thickness and CSA using high-frequency ultrasound (HFUS), and then, we measured and compared the SWV of the right median nerve at the middle of the forearm and at the proximal entrance of the carpal tunnel. The SWV of the median nerve of the left side was measured to explore whether there exist differences of SWV in bilateral median nerve. Additionally, we also measured the SWV of the right tibial nerve at the ankle canal to test whether there is any difference in shear wave velocity between different peripheral nerves. This study found that there existed significant differences of SWV between different sites in one nerve and between different peripheral nerves. No significant difference was found in SWV between bilateral median nerves. Additionally, the SWV of peripheral nerves was associated with gender, while not associated with age or BMI. The mean SWV of the studied male volunteers in median nerve were significantly higher than those of female (p

Data acquisition and treatment are key issues for any Deep Learning (DL) technique, especially in computer vision tasks. A big effort must be done for the creation of labeled datasets, due to the time this task requires and its complexity in cases where different sensors must be used. This is the case of radar imaging applications, where radar data are difficult to analyze and must be labeled manually. In this paper, a semi-automatic framework to generate labels for range Doppler maps (radar images) is proposed. This technique is based on a sensor fusion approach with radar and camera sensors. The proposed scheme operates in two steps: The first step is the environment features extraction, in which the radar data is preprocessed and filtered to remove ghost targets and detect clusters, and camera data are used to extract the information of the targets. In the second step, a rule-based system that considers the extracted features fuses the information to generate labels for the radar data. By using the proposed framework, the experimentation performed suggests that the time required to label the data is reduced as well as the possibility of human error during the labeling task. Our results show that the proposed technique can improve the final model accuracy with regards the traditional labeling method, carried out by human experts.

Background CD8+ T-lymphocyte subsets defined by killer lectin-like receptor G1 (KLRG1) and CD127 expression have been reported to have an important role in infection, but their role in the setting of lymphoid malignancies, specifically follicular lymphoma (FL), has not been studied.Methods To characterize the phenotype of KLRG1/CD127-defined CD8+ subsets, surface and intracellular markers were measured by flow cytometry and Cytometry by time of flight (CyTOF), and the transcriptional profile of these cells was determined by CITE-Seq (Cellular Indexing of Transcriptomes and Epitopes by Sequencing). The functional capacity of each subset was determined, as was their impact on overall survival (OS) and event-free survival (EFS) of patients with FL.Results We found that intratumoral CD8+ cells in FL are skewed toward effector cell subsets, particularly KLRG+CD127- and KLRG1-CD127- cells over memory cell subsets, such as KLRG1-CD127+ and KLRG1+CD127+ cells. While effector subsets exhibited increased capacity to produce cytokines/granules when compared with memory subsets, their proliferative capacity and viability were found to be substantially inferior. Clinically, a skewed distribution of intratumoral CD8+ T cells favoring effector subtypes was associated with an inferior outcome in patients with FL. Increased numbers of CD127+KLRG1- and CD127+KLRG1+ were significantly associated with a favorable OS and EFS, while CD127-KLRG1- correlated with a poor EFS and OS in patients with FL. Furthermore, we demonstrated that interleukin (IL)-15 promotes CD127-KLRG1+ cell development in the presence of dendritic cells via a phosphoinositide 3-kinase (PI3K)-dependent mechanism, and treatment of CD8+ T cells with a PI3K inhibitor downregulated the transcription factors responsible for CD127-KLRG1+ differentiation.Conclusions Taken together, these results reveal not only a biological and prognostic role for KLRG1/CD127-defined CD8+ subsets in FL but also a potential role for PI3K inhibitors to manipulate the differentiation of CD8+ T cells, thereby promoting a more effective antitumor immune response.

Oxidative phosphorylation (OXPHOS) is an emerging target in cancer therapy. However, the prognostic signature of OXPHOS in colorectal adenocarcinoma (COAD) remains non-existent. We comprehensively investigated the expression pattern of OXPHOS-related genes (ORGs) in COAD from public databases. Based on four ORGs, an OXPHOS-related prognostic signature was established in which COAD patients were assigned different risk scores and classified into two different risk groups. It was observed that the low-risk group had a better prognosis but lower immune activities including immune cells and immune-related function in the tumor microenvironment. Combining with relevant clinical features, a nomogram for clinical application was also established. Receiver operating characteristic (ROC) and calibration curves were constructed to demonstrate the predictive ability of this risk signature. Moreover, a higher risk score was significantly positively correlated with higher tumor mutation burden (TMB) and generally higher gene expression of immune checkpoint, N6-methyladenosine (m6A) RNA methylation regulators and mismatch repair (MMR) related proteins. The results also indicated that the high-risk group was more sensitive to immunotherapy and certain chemotherapy drugs. In conclusion, OXPHOS-related prognostic signature can be utilized to better understand the roles of ORGs and offer new perspectives for clinical prognosis and personalized treatment.

The molecular events that modulate the progression of monoclonal gammopathy of undetermined significance of the immunoglobulin M class (IgM-MGUS) to Waldenstrom Macroglobulinemia (WM) are mostly unknown. We implemented comparative proteomics and metabolomics analyses on patient serum samples to identify differentially expressed molecules crucial to the progression from IgM-MGUS to WM. Our data identified altered lipid metabolism as a discriminating factor between MGUS, WM, and matched normal controls. Levels of many fatty acids, including polyunsaturated fatty acids and dicarboxylic acids, were significantly downregulated in WM sera when compared to MGUS. These reductions were associated with diminished 15-LOX and PPAR protein expression and increased 5-LOX and GPX4 expression in WM versus MGUS patients’ samples. Furthermore, WM serum samples showed increased lipid peroxidation compared to MGUS. Treatment with IL-6 or TNFα, upstream regulators of differentially expressed proteins between MGUS and WM, increased lipid absorption and lipid peroxidation in WM cell lines. Knock-down of 15-LOX expression increased WM cell survival, an effect accompanied by increased 5-LOX and GPX4 expression. In summary, our data show that reduced fatty acid and lipid metabolite levels in the serum of the WM patients are associated with increased lipid peroxidation and that downregulation of 15-LOX increases the survival of WM cells. These data are highly significant in identifying the biomarkers of disease progression and designing targeted therapeutic intervention.

Abstract Background Colorectal signet ring cell carcinoma (SRCC) is a rare histological subtype of colorectal adenocarcinoma with high metastatic frequency compared to non‐SRCC colorectal cancer (NOS). The aim of this study was to analyze prognostic factors of colorectal SRCC with different metastatic sites and evaluate impacts of various therapies for metastatic colorectal SRCC. Methods Patients with NOS and SRCC were from the Surveillance, Epidemiology, and End Results (SEER) database during 2010‐2014. χ2 tests were used to compare data significance. Kaplan‐Meier and COX models were used to analyze the differences in the survival. Propensity‐matched analyses were used to adjust numerical differences. Results Among the 173 460 patients, 1932 (1.11%) patients had colorectal SRCC. In univariate analysis, older age, male sex, and peritoneum metastasis were associated with higher mortality risk. The peritoneum was both the site with the highest metastatic frequency and the site with the worst prognosis in SRCC. In the COX regression model, peritoneum‐metastatic SRCC patients receiving chemotherapy had better survival than patients treated with surgery. Conclusions Our study analyzed the unique metastatic pattern of colorectal SRCC toward different sites and found that compared to surgery, chemotherapy was associated with better survival for colorectal SRCC patients with distant metastasis, which provided insights for future SRCC patient treatment.

Abstract Background Circular RNAs (circRNAs) represent a class of widespread and variety endogenous RNAs that may regulate gene expression. Thousands of mammalian circRNAs harbor miRNA response elements (MREs), suggesting a potential role as competitive endogenous RNAs (ceRNAs). Recent studies have demonstrated that ciRS-7 (circular CDR1 antisense), which acts as a powerful miR-7 sponge, contains more than 70 putative binding sites for miR-7 and may inhibit its target genes. The aim of this preliminary study was to investigate the expression of ciRS-7 in patients with rheumatoid arthritis (RA) as well as the correlation between ciRS-7 and the target genes of miR-7. Methods Eighteen patients with RA and 14 healthy controls were enrolled in the current study. The relative expression of ciRS-7, miR-7, miR-671 and mTOR in peripheral blood mononuclear cells (PBMCs) from these samples were detected by real-time PCR. Results We found that ciRS-7 was significantly increased in RA patients and could potentially differentiate the RA patients from healthy controls. Additionally, the expression of mTOR, one of the miR-7 target genes, had positive and negative relationships with ciRS-7 and miR-7 expression, respectively. Notably, the relative expression of miR-671, which mediated the regulation of circular CDR1 antisense homeostasis, was significantly decreased in RA patients. Conlusion Downregulated miR-671 may influence the level of ciRS-7 in RA patients. Enhanced ciRS-7 could inhibit the function of miR-7 and further relieve the inhibitory effect of miR-7 on mTOR.

This paper studied an atomic layer etching (ALE) technique with a surface treatment function for InAlN/GaN heterostructures with AlN spacer layers. Various parameters were attempted, and 30 s O2 + 15 W BCl3 was chosen as the optimal recipe. The optimal ALE approach exhibited satisfactory etching results, with regard to the etch-stop effect, compared with other techniques. The atomic force microscopy (AFM) results showed an etching per cycle (EPC) value of 0.15 nm/cycle, with a 0.996 fit coefficient and root mean square (RMS) surface roughness of around 0.61 nm (0.71 nm for as-grown sample), which was the lowest in comparison with digital etching (0.69 nm), Cl2/BCl3 continuous etching (0.91 nm) and BCl3 continuous etching (0.89 nm). X-ray photoelectron spectroscopy (XPS) and scanning transmission electron microscopy with energy dispersive X-ray spectroscopy measurements (STEM/EDS) verified the indium clustered phenomena at the bottom apex of V-pit defects in the epi structure of InAlN/GaN high electron mobility transistors (HEMTs) for the first time, in addition to the surface morphology optimization for the ALE under-etching technique used in this work. The resistor hall effect (Hall) and AFM measurements demonstrated that after 4 or 5 ALE cycles, the two-dimensional electron gas (2-DEG) density and RMS roughness were improved by 15% and 11.4%, respectively, while the sheet resistance (Rsh) was reduced by 6.7%, suggesting a good surface treatment function. These findings were important for realizing high-performance InAlN/GaN HEMTs.

Scene parsing is a very challenging work for complex and diverse scenes. In this study, the authors address the problem of semantic segmentation of indoor scenes for red, green, blue‐depth (RGB‐D) images. Most existing works use only the colour or photometric information for this problem. Here, they present an approach to fusing feature maps between colour network branch and depth network branch to integrate the photometric information and geometric information, which improves the semantic segmentation performance. They propose a novel convolutional neural network that uses ResNet as a baseline network. Their proposed network adopts a spatial pyramid pooling module to make full use of different sub‐region representations. Their proposed network also adopts multiple feature maps fusion modules to integrate texture and structure information between the colour branch and depth branch. Moreover, their proposed network has multiple auxiliary loss branches together with the main loss function to prevent the gradient of frontal layers disappear and accelerate the training phase of the fusion part. Comprehensive experimental evaluations show that their proposed network ‘ResFusion’ improves the performance greatly over the baseline network and has achieved competitive performance compared with other state‐of‐the‐art methods on the challenging SUN RGB‐D benchmark.

Signaling lymphocytic activation molecule (SLAM) and SLAM-associated protein (SAP) play important role in inflammatory and autoimmune diseases. Our study is aimed at detecting the expression of SLAM and SAP in patients with Graves’ disease (GD) and analyzing the effect of SLAM/SAP on circulating blood CD4+CXCR5+Foxp3+ follicular regulatory T (Tfr) cells. The level of SAP in CD4+CXCR5+ T cells and the level of SLAM on CD19+ B cells were significantly increased in the patients with GD, but no significant difference in the level of SLAM on CD4+CXCR5+ T cells was observed between the patients with GD and the healthy controls. A decrease in the percentage of Foxp3+ cells in CD4+CXCR5+ T cells was observed following anti-SLAM treatment, but the percentages of IFN-γ+ cells, IL-4+ cells, and IL-17+ cells showed no obvious differences. The proportion of circulating Tfr cells was decreased in the patients with GD, and the proportion of circulating Tfr cells had a negative correlation with the level of SAP in CD4+CXCR5+ T cells and the levels of autoantibodies in the serum of the patients with GD. Our results suggested that the SLAM/SAP signaling pathway is involved in the decrease of circulating Tfr cells in Graves’ disease.

Background. Long noncoding RNAs (lncRNAs) represent an important novel class of noncoding RNA molecule greater than 200 nucleotides that play a key role in the regulation of autoimmune diseases. Previous studies have demonstrated that MAFTRR (MAF transcriptional regulator RNA) regulated Th1 cells differentiation by inhibiting the expression of MAF in activated CD4+ T cells. However, the effect of MAFTRR on the pathogenesis of Hashimoto’s thyroiditis (HT) remains unclear. This research was aimed at investigating the expression of MAFTRR in Hashimoto’s thyroiditis (HT) as well as the correlation between MAFTRR and Th1 cells. Methods. Thirty-eight HT patients and thirty-eight healthy controls were enrolled in the study. The proportion of Th1 cells and CD8+IFN-γ+ T cells in peripheral blood mononuclear cells (PBMCs) from these specimens was determined by flow cytometric analysis. The transcript levels of MAFTRR, MAF, and IFNG in PBMCs and thyroid glands were detected by quantitative real-time PCR. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the potential value of MAFTRR in the HT patients. Results. We found that the proportion of circulating Th1 cells and the transcript levels of IFNG were increased in peripheral blood of the HT patients. The transcript levels of MAFTRR were significantly increased in the HT patients and positively correlated with the percentage of Th1 cells and serum levels of antithyroglobulin antibody and antithyroperoxidase antibody. The transcript levels of MAF, a transcription factor that inhibits Th1 cells activity and IFN-γ production, were attenuated in PBMCs from the HT patients. The transcript levels of IFNG had positive and inverse correlations with MAFTRR and MAF expression in PBMCs from the HT patients, respectively. Additionally, a significantly positive correlation between upregulated MAFTRR expression and augmented IFNG expression was revealed in thyroid tissues from the HT patients. ROC curve suggested that MAFTRR could potentially differentiate the HT patients from healthy controls. Conclusion. MAFTRR is significantly augmented in the HT patients and may contribute to the pathogenic role of the Th1 cells response in HT.

The results of recent studies have shown that granulocytic-myeloid derived suppressor cells (G-MDSCs) can secrete exosomes that transport various biologically active molecules with regulatory effects on immune cells. However, their roles in autoimmune diseases such as rheumatoid arthritis remain to be further elucidated. In the present study, we investigated the influence of exosomes from G-MDSCs on the humoral immune response in murine collagen-induced arthritis (CIA). G-MDSCs exosomes-treated mice showed lower arthritis index values and decreased inflammatory cell infiltration. Treatment with G-MDSCs exosomes promoted splenic B cells to secrete IL-10 both in vivo and in vitro. In addition, a decrease in the proportion of plasma cells and follicular helper T cells was observed in drainage lymph nodes from G-MDSCs exosomes-treated mice. Moreover, lower serum levels of IgG were detected in G-MDSCs exosomes-treated mice, indicating an alteration of the humoral environment. Mechanistic studies showed that exosomal prostaglandin E2 (PGE2) produced by G-MDSCs upregulated the phosphorylation levels of GSK-3β and CREB, which play a key role in the production of IL-10+ B cells. Taken together, our findings demonstrated that G-MDSC exosomal PGE2 attenuates CIA in mice by promoting the generation of IL-10+ Breg cells.

Collaborative reasoning for knowledge-based visual question answering is challenging but vital and efficient in understanding the features of the images and questions. While previous methods jointly fuse all kinds of features by attention mechanism or use handcrafted rules to generate a layout for performing compositional reasoning, which lacks the process of visual reasoning and introduces a large number of parameters for predicting the correct answer. For conducting visual reasoning on all kinds of image–question pairs, in this paper, we propose a novel reasoning model of a question-guided tree structure with a knowledge base (QGTSKB) for addressing these problems. In addition, our model consists of four neural module networks: the attention model that locates attended regions based on the image features and question embeddings by attention mechanism, the gated reasoning model that forgets and updates the fused features, the fusion reasoning model that mines high-level semantics of the attended visual features and knowledge base and knowledge-based fact model that makes up for the lack of visual and textual information with external knowledge. Therefore, our model performs visual analysis and reasoning based on tree structures, knowledge base and four neural module networks. Experimental results show that our model achieves superior performance over existing methods on the VQA v2.0 and CLVER dataset, and visual reasoning experiments prove the interpretability of the model.

Metabolic reprogramming is a hallmark of cancer cells. In Waldenstrom Macroglobulinemia (WM), the infiltration of IgM-secreting lymphoplamacytic cells into the bone marrow (BM) could shift the homeostasis of proteins and metabolites towards a permissive niche for tumor growth. Here, we investigated whether alerted metabolic pathways contribute to the pathobiology of WM and whether the cytokine composition of the BM promotes such changes.Metabolomics analysis on WM patients and normal donors’ serum samples revealed a total of 75 metabolites that were significantly altered between two groups. While these metabolites belonged to amino acids, glucose, glutathione and lipid metabolism pathways, the highest number of the differentially expressed metabolites belonged to glutathione metabolism. Proteomics analysis and immunohistochemical staining both confirmed the increased protein levels mediating glutathione metabolism, including GCLC, MT1X, QPCT and GPX3. Moreover, treatment with IL-6 and IL-21, cytokines that induce WM cell proliferation and IgM secretion, increased gene expression of the amino acid transporters mediating glutathione metabolism, including ASCT2, SLC7A11 and 4F2HC, indicating that cytokines in the WM BM could modulate glutathione metabolism. Glutathione synthesis inhibition using Buthionine sulphoximine (BSO) significantly reduced WM cells proliferation in vitro, accompanied with decreased NFκB-p65 and MAPK-p38 phosphorylation. Moreover, BSO treatment significantly reduced the tumor growth rate in a WM xenograft model, further highlighting the role of glutathione metabolism in promoting tumor growth and proliferation.In summary, our data highlight a central role for glutathione metabolism in WM pathobiology and indicate that intervening with the metabolic processes could be a potential therapy for WM patients.

MicroRNAs (miRNAs) have emerged as key regulators of cellular processes by suppressing target mRNAs at the posttranscriptional level. However, little is known regarding the expression of miRNAs in peripheral blood mononuclear cells (PBMCs) from Hashimoto's thyroiditis (HT) patients. Therefore, 38 HT patients and 36 healthy volunteers were enrolled in this study to identify HT-mediated changes in miRNA expression. Over 1,000 dysregulated miRNAs and their biological functions in the HT patients were identified. Among them, miR-125a-5p expression was upregulated and inversely correlated with low levels of MAF, a transcription factor that inhibits Th1 cells activity and the production of IFN-γ. Luciferase assay results demonstrated that MAF is a direct target gene of miR-125a-5p. Moreover, the proportion of circulating Th1 cells and the transcript levels of IFN-γ were increased in the HT patients. MiR-125a-5p expression positively correlated with the proportion of circulating Th1 cells and the serum concentrations of anti-thyroperoxidase antibodies in the HT patients. Interestingly, knockdown of miR-125a-5p in CD4+ T cells resulted in an elevated level of MAF but decreased the proportion of Th1 cells and the transcript level of IFN-γ in vitro. Furthermore, upregulated miR-125a-5p and IFN-γ transcript levels and downregulated MAF expression were detected in thyroid tissues from HT patients. Receiver operating characteristic (ROC) curves suggested that miR-125a-5p has a crucial role in the HT. Our results demonstrate that the elevated levels of miR-125a-5p contribute to the Th1 cells response in the HT patients and may be involved in the pathogenesis of HT.

Long noncoding RNAs (lncRNAs) have been increasingly recognized as key immune molecules that participate in the pathogenesis of autoimmune diseases. Previous studies have demonstrated that the lncRNA Ifng-AS1, a key scaffold that contributes to the transcription of IFN-γ, depends on T-bet for active transcription in Th1 cells. However, the effect of its human ortholog, IFNG-AS1, on the pathogenesis of rheumatoid arthritis (RA) remains unclear. In this study, we found that the transcript level of lncRNA IFNG-AS1 was increased in the peripheral blood of RA patients. IFNG, as a target gene of IFNG-AS1, was overexpressed and positively correlated with the transcript level of IFNG-AS1 in the RA patients. Our data also showed that the transcript level of T-bet was upregulated and positively correlated with IFNG-AS1 expression. T-bet regulated the transcription of IFNG-AS1 in human CD4+ T cells in vitro. Furthermore, strong positive correlations were observed between the increased transcript level of IFNG-AS1 and the serum level of rheumatoid factor, the erythrocyte sedimentation rate, and the C-reactive protein in RA patients, and patients positive for anticyclic citrullinated peptide antibodies had increased levels of IFNG-AS1. Finally, receiver operating characteristic (ROC) curve analysis suggested that IFNG-AS1 might be a potential biomarker of RA. Taken together, our findings indicated that IFNG-AS1, guided by T-bet, is augmented in the peripheral blood of RA patients and may play a critical role in the pathogenesis of RA by regulating the expression of IFNG.

Metformin, an oral medicine broadly used for the treatment of type 2 diabetes, has been found to significantly improve tumor incidence and survival in large-scale clinical analysis. In recent years, the antitumor effect and mechanism of metformin have received much attention. Myeloid-derived suppressor cells (MDSCs), a major immunosuppressive cell type that accumulates in tumor-bearing hosts, can inhibit T cells and promote tumor immune escape. The mechanism by which metformin exerts its anti-tumor effect by regulating MDSCs remains unclear. Here, we found that metformin could inhibit the accumulation and suppressive capacity of G-MDSCs, delay tumor progression and elicit Th1 and CTL responses in murine colon cancer CT-26 cell-transplanted mice. In additionally, metformin could enhance the phosphorylation of AMPK, reduce STAT3 phosphorylation levels, and down-regulate the inhibitory function of G-MDSCs in vitro. These results suggest that metformin may be a potential clinical benefit for antitumor immunotherapy in tumor-bearing mice.

Abstract T cells secrete bioactive extracellular vesicles (EVs), but the potential biological effects of CD4+ T cell EVs are not clear. The main purpose of this study is to investigate the effects of CD4+ T cell–derived EVs on B cell responses and examine their role in antigen‐mediated humoral immune responses. In this study, CD4+ T cell EVs are purified from activated CD4+ T cells in vitro. After immunization with the Hepatitis B surface antigen (HBsAg) vaccine, CD4+ T cell EVs‐treated mice show stronger humoral immune responses, which is indicated by a greater Hepatitis B surface antibody (HBsAb) level in serum and a greater proportion of plasma cells in bone marrow. In addition, it is found that EVs released from activated CD4+ T cells play an important role in B cell responses in vitro, which significantly promote B cell activation, proliferation, and antibody production. Interestingly, antigen‐specific CD4+ T cell EVs are found to be more efficient than control EVs in enhancing B cell responses. Furthermore, it is shown that CD40 ligand (CD40L) is involved in CD4+ T cell EVs‐mediated B cell responses. Overall, the results have demonstrated that CD4+ T cell EVs enhance B cell responses and serve as a novel immunomodulator to promote antigen‐specific humoral immune responses.

In this paper, we provide external image features and use the internal attention mechanism to solve the VQA problem given a dataset of textual questions and related images. Most previous models for VQA use a pair of images and questions as input. In addition, the model adopts a question-oriented attention mechanism to extract the features of the entire image and then perform feature fusion. However, the shortcoming of these models is that they cannot effectively eliminate the irrelevant features of the image. In addition, the problem-oriented attention mechanism lacks in the mining of image features, which will bring in redundant image features. In this paper, we propose a VQA model based on adversarial learning and bidirectional attention. We exploit external image features that are not related to the question to form an adversarial mechanism to boost the accuracy of the model. Target detection is performed on the image—that is, the image-oriented attention mechanism. The bidirectional attention mechanism is conducive to promoting model attention and eliminating interference. Experimental results are evaluated on benchmark datasets, and our model performs better than other models based on attention methods. In addition, the qualitative results show the attention maps on the images and leads to predicting correct answers.

Abstract Cancer stem cells play a critical role in colorectal cancer (CRC) progression. Myeloid‐derived suppressor cells (MDSCs) promote tumor progression through multiple mechanisms in CRC. The roles of MDSCs in CRC cell stemness are unclear. MDSC‐derived exosomes are proposed to act as intercellular messengers. Herein, it is reported that granulocytic MDSCs (G‐MDSCs) promote CRC cell stemness and progression in mice through exosomes. It is found that S100A9, is highly expressed in G‐MDSC‐derived exosomes, and its blockade suppresses CRC cell stemness and the susceptibility of mice to AOM/DSS‐induced colitis‐associated colon cancer. Hypoxia induces G‐MDSCs to secrete more exosomes in a hypoxia‐inducible factor 1α (HIF‐1α)‐dependent manner, and respiratory hyperoxia can reduce CRC cells stemness through the inhibition of GM‐Exo production. Study‐based CRC patients also show that human MDSCs enhance CRC cell stemness and growth via exosomal S100A9, and plasma exosomal S100A9 level in CRC patients is markedly higher than that in healthy subjects. Thus, this study suggests that G‐MDSCs promote CRC cell stemness and growth through exosomal S100A9. Moreover, respiratory hyperoxia may be a beneficial strategy to reduce CRC cells stemness through the inhibition of GM‐Exo production. MDSCs exosomal S100A9 may be a marker for predicting the development of CRC.

Circular RNAs (circRNAs) are covalently linked single-stranded RNAs, compared to linear counterparts that are relatively abundant, conserved, stable, and specific. Previously, most studies have revealed that circRNAs function in gene expression processes and participate in the pathogenesis of cancers, cardiovascular diseases, and neurological diseases. With advances in biotechnology, more biological functions of circRNAs have been found in several signaling pathways that are related to tumorigenesis, immunity, and metabolism. Recently, many circRNAs have been reported to be expressed abnormally and play important roles in the progression of autoimmune diseases. Thus, circRNAs may not only serve as potential biomarkers but also act as immune regulators and offer potential opportunities for therapy. This review briefly introduces the properties as well as the functions of circRNAs in different stages of gene expression. In addition, this article summarizes the available knowledge about abnormally expressed circRNAs in different autoimmune diseases and discusses their potential roles in these diseases, which helps us understand their regulatory mechanisms and provides future research perspectives.

Abstract Long non-coding RNAs (lncRNAs) have been attracting immense research interests. The relevance of lncRNAs in biological and physiological as well as in pathological processes has increased along with the understanding of their various regulatory mechanisms. Abundant studies have indicated that lncRNAs are involved in the differentiation, proliferation, activation, and initiation of apoptosis in different cell types. However, most studies about the regulating biology of lncRNAs are currently focused on cancer cells. This review is focused on the widely unexplored role of lncRNAs in the cell fate of myeloid cells. In this review, we summarize recent studies that have confirmed lncRNAs to be essential in the development of myeloid cells under normal and pathological conditions.