Understanding YTHDF2-mediated mRNA degradation by m6A-BERT-Deg.

N6-methyladenosine (m6A) is the most abundant mRNA modification within mammalian cells, holding pivotal significance in the regulation of mRNA stability, translation and splicing. Furthermore, it plays a critical role in the regulation of RNA degradation by primarily recruiting the YTHDF2 reader protein. However, the selective regulation of mRNA decay of the m6A-methylated mRNA through YTHDF2 binding is poorly understood. To improve our understanding, we developed m6A-BERT-Deg, a BERT model adapted for predicting YTHDF2-mediated degradation of m6A-methylated mRNAs. We meticulously assembled a high-quality training dataset by integrating multiple data sources for the HeLa cell line. To overcome the limitation of small training samples, we employed a pre-training-fine-tuning strategy by first performing a self-supervised pre-training of the model on 427 760 unlabeled m6A site sequences. The test results demonstrated the importance of this pre-training strategy in enabling m6A-BERT-Deg to outperform other benchmark models. We further conducted a comprehensive model interpretation and revealed a surprising finding that the presence of co-factors in proximity to m6A sites may disrupt YTHDF2-mediated mRNA degradation, subsequently enhancing mRNA stability. We also extended our analyses to the HEK293 cell line, shedding light on the context-dependent YTHDF2-mediated mRNA degradation.

Understanding YTHDF2-mediated mRNA Degradation By m6A-BERT-Deg.

N6-methyladenosine (m6A) is the most abundant mRNA modification within mammalian cells, holding pivotal significance in the regulation of mRNA stability, translation, and splicing. Furthermore, it plays a critical role in the regulation of RNA degradation by primarily recruiting the YTHDF2 reader protein. However, the selective regulation of mRNA decay of the m6A-methylated mRNA through YTHDF2 binding is poorly understood. To improve our understanding, we developed m6A-BERT-Deg, a BERT model adapted for predicting YTHDF2-mediated degradation of m6A-methylated mRNAs. We meticulously assembled a high-quality training dataset by integrating multiple data sources for the HeLa cell line. To overcome the limitation of small training samples, we employed a pre-training-fine-tuning strategy by first performing a self-supervised pre-training of the model on 427,760 unlabeled m6A site sequences. The test results demonstrated the importance of this pre-training strategy in enabling m6A-BERT-Deg to outperform other benchmark models. We further conducted a comprehensive model interpretation and revealed a surprising finding that the presence of co-factors in proximity to m6A sites may disrupt YTHDF2-mediated mRNA degradation, subsequently enhancing mRNA stability. We also extended our analyses to the HEK293 cell line, shedding light on the context-dependent YTHDF2-mediated mRNA degradation.

The Role of TGF-β1/Smads Signaling Pathway in Anti-myocardial Fibrosis Effect of SIRT1 and Related Mechanism / 华中科技大学学报(医学版)

Objective To observe the effect of sirtuin 1(SIRT1)on rat myocardial fibrosis induced by pressure overload and the proliferation of cardiac fibroblasts induced by angiotensin Ⅱ(Ang Ⅱ),and to explore the molecular mechanisms.Methods The pressure overload-induced myocardial fibrosis was established by abdominal aorta constriction(AAC)procedure in vi-vo.After treatment with SIRT1 activator,the myocardial interstitial fibrosis and the collagen volume fraction were evaluated by Masson's trichrome staining.The protein expressions of TGF-β1/Smads were determined by immunohistochemical analy-sis.After in vitro intervention of Ang Ⅱ or Ang Ⅱ with SIRT1 activator,the fibroblasts proliferation was detected by MTT as-say.The mRNA and protein expressions of collagen Ⅰ/Ⅲ(Col1α1/3α1),SIRT1 and TGF-β1/Smads in myocardial tissue and fi-broblasts were evaluated by qRT-PCR and Western blotting.Results Compared with the sham operation group,myocardial in-terstitial fibrosis was significantly observed in the pressure overload model group,myocardial collagen volume fraction was in-creased,expressions of Col1α1/3α1 and TGF-β1/Smads were significantly increased,and SIRT1 expression was decreased.After the intervention of SRT1720,SIRT1 activator could improve the myocardial interstitial fibrosis induced by pressure overload,downregulate the expressions of Col1α1/3α1 and TGF-β1/Smads,and upregulate the expression of SIRT1.Meanwhile,correla-tion analysis showed that the protein expression of SIRT1 was negatively correlated with the expression of TGF-β1.In addition,SRT1720 also inhibited Ang Ⅱ-induced fibroblast proliferation and increased expression of Col1α1/3α1 and TGF-β1.Conclusion Activation of SIRT1 inhibits pressure overload-induced myocardial fibrosis and Ang Ⅱ-induced fibroblasts proliferation via regu-lation of the TGF-β1/Smads signaling pathway.

Preparation methods,advantages,and disadvantages of cartilage scaffold materials / 中国组织工程研究

BACKGROUND:Scaffold materials serve as platforms that provide space and structure,playing a crucial role in the regeneration of cartilage tissue.Scholars from around the world are exploring different approaches to fabricate more ideal scaffold materials. OBJECTIVE:To review the design principles and preparation methods of cartilage scaffolds,and to further explore the advantages and limitations of various preparation methods. METHODS:Literature searches were conducted on the databases of CNKI,WanFang Data,PubMed,and FMRS from 1998 to 2023.The search terms were"cartilage repair,cartilage tissue engineering,cartilage scaffold materials,preparation"in Chinese and English.A total of 57 articles were ultimately reviewed. RESULTS AND CONCLUSION:(1)The articular cartilage has a unique structure and limited self-repair capacity after injury.Even if self-repair occurs,the newly formed cartilage is typically fibrocartilage,which is far inferior to normal articular cartilage in terms of structure and mechanical properties.It is difficult to maintain normal function and often leads to degenerative changes.Currently,the design and fabrication of scaffold materials for cartilage repair need to consider the following aspects:biocompatibility and biodegradability,suitable pore structure and porosity,appropriate mechanical properties,and bioactivity.(2)Research on the preparation of cartilage scaffolds has made significant progress,continuously introducing new preparation methods and optimization strategies.These methods have their advantages and disadvantages,providing more possibilities for customized preparation and functional design of cartilage scaffolds according to specific requirements.

Establishment and validation of bioactivity measurement method for recombinant human midkine / 药学学报

To establish and optimize a method for the detection of recombinant human midkine (rhMK) activity and verify its methodology, cell counting kit-8 (cck-8) method was used to measure the proliferation activity of rat knee chondrocytes. The specificity, accuracy, precision, linearity and robustness of the method were also verified in this study. The established method was proven to have good specificity because the buffer of rhMK and recombinant human interleukin-1 receptor antagonist have no obvious active effect; the recoveries of the samples with relative activities of 50%, 75%, 100%, 125%, 150% were in the range of 80.0% to 124.0% by statistical analysis, the relative standard deviations (RSD) of relative potency were all within 20%, the linear correlation coefficient, R2 ≥ 0.98, suggesting that the accuracy, precision and linearity of the method were good; the robustness correlation coefficient, R2 ≥ 0.92 and the ratio of maximum to minimum of sigmoidal dose-response were no less than 1.5, indicating that robustness of the methods was good. In conclusion, a bioactivity measurement method for rhMK was established and fully validated in this study and it provides a reliable method for the bioactivity analysis of rhMK routine samples during the development. This study was approved by the Animal Care and Use Committee of Shanghai Model Organisms Center, Inc. (approval number: 2019-0008-06).

Relationship of parental anger expression and symptoms in children with oppositional defiant disorder / 中国心理卫生杂志

Objective:This study is to investigate the relationship of parental anger expression and symptoms in children with oppositional defiant disorder(ODD).Methods:Forty-six children with ODD and 46 age-gender-matched normal children participated.The Diagnostic and Statistical Manual of Mental Disorders,Fifth Edition(DSM-5),guided the diagnoses.Parental anger expression and children's anger management were assessed using the State-Trait Anger Expression Inventory-2 and Children Emotion Management Scales.Results:ODD symptoms were directly predicted by maternal anger index(AI)(β=0.13,P＜0.05)and anger expression-out(AX-O)(β=0.25,P＜0.05).Children's anger cope(AC)played a mediating function to maternal AI through ODD symptoms,occupying 13％of the total effect;their AC and anger dysregulation(AD)played a mediating function to maternal AX-Othrough ODD symptoms,accounting for 29％and 18％of the total effect,respectively.Conclusion:It sug-gests that anger cope and anger dysregulation in children with oppositional defiant disordermay may play a media-ting role between maternal anger expression and oppositional defiant disorder symptoms.

Clinical observation of free composite tissue flap transplantation in repairing head skin defect with artificial dural exposure infection / 中国医师杂志

Objective:To explore the effect of free transplantation of composite tissue flap from the anterior lateral aspect of the femur in repairing head skin defects with artificial dural exposure infection.Methods:A retrospective study was conducted on 13 patients admitted to the First Affiliated Hospital of Air Force Military Medical University from April 2018 to August 2020 with craniotomy complications, including craniotomy skin and soft tissue defects combined with artificial dural exposure and infection. After preoperative anti infection treatment, the neurosurgery department participated in debridement and removed the artificial dura mater as much as possible during the operation. A composite tissue flap carrying the fascia lata was designed for the anterior lateral aspect of the thigh, and the flap artery and vein were anastomosed with the superficial temporal artery and superficial temporal vein/middle temporal vein respectively. The defect of the dura mater was repaired with the fascia lata with blood supply. The flap was used to seal the wound, and the donor site was directly sutured or transplanted with autologous medium thick skin graft. The postoperative blood supply and survival of the flap, the presence of cerebrospinal fluid leakage, and the healing of the donor site were observed; The observation of dural integrity and postoperative effects of skull reconstruction using cranial magnetic resonance imaging was followed up.Results:Among the 13 patients in this group, 11 patients had their artificial dura mater completely removed, while 2 patients were not completely removed due to severe adhesion. Among them, 1 patient had a residual area of 0.8 cm×1 cm, and the other had 3 residual areas, with a maximum area of 0.5 cm×0.7 cm; All transplanted skin flaps survived, with 12 cases achieving primary healing and 1 case of partial wound rupture after suture removal, which healed after conservative dressing change; All patients had no cerebrospinal fluid leakage; There was one case of partial necrosis of the graft in the donor site, which healed after supplementing the graft; Thirteen patients underwent cranial magnetic resonance imaging at 3-6 months postoperatively, all of which showed intact dura mater; Among them, 8 patients have completed skull reconstruction surgery, and all of them have healed well after reconstruction, with a good appearance of the surgical area.Conclusions:For wounds with head skin defects and exposed artificial dura mater infection, free transplantation of the anterior lateral composite tissue flap carrying the fascia lata can effectively cover the wound and repair the dura mater defect, achieve good function and appearance, and create favorable conditions for later skull reconstruction.

Interpretation on Consensus on drug-induced liver injury by CIOMS Working Group:liver injury attributed to herbal and dietary supplements / 中国中药杂志

With the increase in the medical level, the improvement of adverse drug reaction(ADR) monitoring systems, and the enhancement of public awareness of safe medication, drug safety incidents have been frequently reported. Drug-induced liver injury(DILI), especially liver injury attributed to herbal and dietary supplements(HDS), has globally attracted high attention, bringing great threats and severe challenges to the people for drug safety management such as clinical medication and medical supervision. Consensus on drug-induced liver injury had been published by the Council for International Organizations of Medical Sciences(CIOMS) in 2020. In this consensus, liver injury attributed to HDS was included in a special chapter for the first time. The hot topics, including the definition of HDS-induced liver injury, epidemiological history, potential risk factors, collection of related risk signals, causality assessment, risk prevention, control and management were discussed from a global perspective. Based on the previous works, some experts from China were invited by CIOMS to undertake the compilation of this chapter. Meanwhile, a new causality assessment in DILI based on the integrated evidence chain(iEC) method was widely recognized by experts in China and abroad, and was recommended by this consensus. This paper briefly introduced the main contents, background, and characteristics of the Consensus on drug-induced liver injury. Significantly, a brief interpretation was illustrated to analyze the special highlights of Chapter 8, "Liver injury attributed to HDS", so as to provide practical references for the medical staff and the researchers who worked on either Chinese or Western medicine in China.

Asthma management and asthma control level in children / 中国当代儿科杂志

OBJECTIVES@#To investigate the influencing factors for asthma management and asthma control level in children.@*METHODS@#A total of 202 children with a confirmed diagnosis of asthma were enrolled. The questionnaire of asthma control level and family management was used to investigate the influencing factors for asthma control level and the indicators of family management. The awareness of childhood asthma and its management was analyzed among the parents, as well as the influence on asthma control level in children, and the association between them was analyzed.@*RESULTS@#Compared with the non-complete control group, the complete control group had significantly longer course of asthma and treatment time (P<0.05). The proportions of asthma attacks ≥3 times and aerosol treatment for asthma attacks >3 times in one year in the complete control group were significantly lower than those in the non-complete control group (P<0.05). The complete control group had a significantly lower proportion of children with frequent respiratory infection, wheezing during respiratory infection, or a family history of allergic diseases (P<0.05). The parents in the complete control group had significantly stronger awareness of short-term escalation to asthma medication after respiratory infection and significantly enhanced management of maintenance medication (P<0.05). Compared with the complete control group, the non-complete control group had a significantly higher proportion of children with abnormal pulmonary function at the initial stage (P<0.05). The level of asthma control in children was associated with short-term escalation to asthma medication during respiratory infection and initial lung function (P<0.05).@*CONCLUSIONS@#The level of asthma control in children is closely associated with the severity of asthma and the comprehensive management of childhood asthma. Early treatment and family management, especially escalation to asthma medication during the early stage of respiratory infection, are of great importance in asthma control. Citation:Chinese Journal of Contemporary Pediatrics, 2023, 25(1): 73-79.

Effect of miR-96-5p targeting IRS1 on apoptosis of PC12 cells induced by aluminum maltol / 中华劳动卫生职业病杂志

Objective: To investigate the effect and mechanism of miR-96-5p on apoptosis of PC12 cells induced by maltol aluminum. Methods: In January 2021, PC12 cells at logarithmic growth phase were divided into blank control group and low, medium and high dose group. Cells in each group were treated with 0, 100, 200 and 400 μmol/L maltol aluminum for 24 hours respectively. Cells were collected and cell apoptosis rates were detected by flow cytometry, miR-96-5p and insulin receptor substrate 1 (IRS1) mRNA expressions were detected by qRT-PCR, and the protein expression levels of cysteine protease 3 (Caspase3) 、activated cysteine protease 3 (Cleaved-caspase3) 、IRS1、phosphorylated protein kinase B (p-AKT) and phosphorylated glucose synthesis kinase 3β (p-GSK3β) were detected by western blotting. The target binding relationship between miR-96-5p and IRS1 was detected by double luciferase reporter gene experiment. The miR-96-5p inhibitor cells and negative control cells were constructed after transfecting PC12 cells with miR-96-5p inhibitor for 24 hours. The cells were divided into blank control group, negative control group, aluminum exposure group, aluminum exposure+negative control group, aluminum exposure+miR-96-5p inhibition group, and miR-96-5p inhibition group. After transfecting PC12 cells with miR-96-5p inhibition and IRS1 siRNA for 24 h, the cells were divided into aluminum exposure+miR-96-5p inhibition+negative control group and aluminum exposure+miR-96-5p inhibition+IRS1 inhibition group. The control group was cultured in complete culture medium, and cells in the aluminum exposure group were treated with 200 μmol/L maltol aluminum for 24 hours. Cells in each group were collected and the apoptosis rate, miR-96-5p and IRS1 mRNA expression levels, as well as protein expression levels of Caspase3, Cleaved-caspase3, IRS1, p-AKT, and p-GSK3β were measured. Results: After 24 hours of exposure, compared with blank control group and low-dose group, the apoptosis rates, relative expressions of Caspase3 and Cleaved-caspase3 proteins, and relative expressions of miR-96-5p in the medium and high-dose groups of PC12 cells were significantly increased, while the relative expression levels of IRS1 mRNA, IRS1, p-AKT and p-GSK3β proteins were significantly decreased (P<0.05). Targetscan prediction and double luciferase report experiment both proved that IRS1 was a direct target gene of miR-96-5p. In the transfection experiment, compared with the aluminum exposure group, the apoptosis rate, the relative expressions of Caspase3 and Cleaved-caspase3 proteins, the relative expression of miR-96-5p in the aluminum exposure+miR-96-5p inhibition group were significantly decreased, while the relative expression levels of IRS1 mRNA and IRS1, p-AKT and p-GSK3β proteins were significantly increased (P<0.05). In the IRS1 low expression experiment, compared with the aluminum exposure+miR-96-5p inhibition+negative control group, the apoptosis rate, the relative expressions of Caspase3 and Cleaved-caspase3 proteins in the aluminum exposure+miR-96-5p inhibition+IRS1 inhibition group were significantly increased, while the relative expression levels of IRS1 mRNA and IRS1, p-AKT and p-GSK3β proteins were significantly decreased (P<0.05) . Conclusion: The increased expression of miR-96-5p and the targeted inhibition of IRS1 may be one of the mechanisms of apoptosis of PC12 cells induced by maltol aluminum exposure.

Shoulder arthroscopic treatment of avulsion fracture of humeral greater tuberosity with double-row suture bridge / 中华创伤骨科杂志

Objective:To evaluate the shoulder arthroscopic treatment of avulsion fracture of humeral greater tuberosity with double-row suture bridge.Methods:Retrospectively analyzed were the 13 avulsion fractures of humeral greater tuberosity which had been treated by shoulder arthroscopic double-row suture bridge at Bone and Joint Department, Guangzhou Liwan District Orthopedic Hospital from March, 2018 to March, 2020. There were 6 males and 7 females, with an average ages of 52.3 years (from 35 to 69 years). According to the Mutch classification, all the fractures of humeral greater tuberosity were attributed to the avulsion type. Of them, 3 were simple avulsion fractures of humeral greater tuberosity and 10 were complicated with shoulder anterior dislocation which was reduced manually before operation. There were 3 obsolete avulsion fractures of humeral greater tuberosity. Regular clinic and X-ray follow-ups were carried out. At the final follow-up, the pain, range of motion (ROM) and stability of the shoulder joint were assessed using visual analogue scale (VAS), American shoulder elbow scores (ASES), and Korean shoulder scores (KSS).Results:All the patients were followed up for an average of 12.3 months (from 10 to 16 months) postoperatively. No infection or shoulder instability was observed. At the final follow-up, the abduction and elevation averaged 164.6° (from 135° to 180°), the lateral external rotation 62.7° (from 40° to 80°), the internal rotation touch back test T10 level (from L2 to T6), the VAS 0.65 (from 0 to 2.5), the ASES 90.5 (from 78 to 100), and the KSS 91.5 (from 84 to 100).Conclusion:Shoulder arthroscopic treatment of avulsion fracture of humeral greater tuberosity with double-row suture bridge is minimally invasive and allows for repair of combined injury, leading to quick postoperative recovery.

Effects and mechnism of abnormal stress promoting MIF,COX2 and PGE2 in the progression of temporomandibular joint osteoarthritis / 解放军医学杂志

Objective To investigate the effects and mechnism of abnormal stress promoting macrophage mobility inhibitory factor(MIF),cyclooxygenase 2(COX2)and prostaglandin E2(PGE2)in the progression of temporomandibular joint osteoarthritis(TMJOA).Methods From January 2020 to December 2021,TMJOA and temporomandibular joint internal derangement(TMJID)patients(30 cases in each group,we divided the TMJOA into group TMJ Ⅰ,Ⅱ,Ⅲ according to the stage)who were admitted to TMJOA special clinic of the First Affiliated Hospital of Xinjiang Medical University and accompanied by abnormal occlusion were collected.The pain score of the occlusal state of the patients was evaluated by visual analogue scale.The expression levels of MIF,COX2 and PGE2 in synovial fluid were detected by ELISA.We used the unilateral anterior crossbite for TMJOA(UAC)rats model(the grouped into:UAC-4 weeks,UAC-8 weeks and UAC-12 weeks group),and control group at the same time(grouped into:Ctrl-4 weeks,Ctrl-8 weeks and Ctrl-12 weeks group),each group had 6 rats.The expression levels of MIF,COX2 and PGE2 in serum and synovial fluid of rats were detected by ELISA.The expression levels of IL-1β,IL-18,MIF,COX2 and PTGER2 in temporomandibular joint of rats were detected by Western blotting.The fluid flow shear stress(FFSS)model of fibroblast-like synovial cells(FLSs)was established,and the mRNA and protein expression levels of above indexes were detected by RT-PCR and Western blotting.Results Visual analogue scale evaluation showed that the pain score of TMJOA Ⅰ and Ⅱ group was significantly higher than that of TMJID(P<0.001).ELISA results showed that the expression levels of MIF,COX2 and PGE2 in synovial fluid in TMJOA group were higher than those in TMJID group(P<0.05),and the expression levels were the highest in TMJOA Ⅱ group.Compared with control group,the expressions of MIF,COX2 and PGE2 in serum and synovial fluid at UAC-4 weeks,8 weeks and 12 weeks were slightly higher,and significantly higher at UAC-8 weeks in rat TMJOA model(P<0.05).In addition,the expression trend of protein levels in temporomandibular joint tissues was similar,which showed higher expression levels of IL-1β,IL-18,MIF,COX2 and PTGER2(P<0.05).In the cell model where FFSS interfered with FLSs,with the increase of FFSS,cell with deformation,incomplete cell membrane and reduced number.Compared with control group,the expression levels of IL-1β,IL-18,MIF,COX2 and PGE2(PTGER2)of FLSs were increased in 1,3,5 and 10 dyn/cm2 intervention groups(P<0.05).Conclusion MIF,COX2 and PGE2 were highly expressed in temporomandibular joint synovial fluid of TMJOA patients with malocclusion.And these three factors were also highly expressed in serum and synovial fluid of UAC rats.The abnormal fluid shear stress promotes the secretion of MIF,COX2 and PGE2 by FLSs to participate in joint microenvironment inflammation and accelerate disease progression.

Corneal epithelial remodeling following stromal lenticule addition keratoplasty combined with corneal collagen cross-linking for the treatment of keratoconus / 国际眼科杂志(Guoji Yanke Zazhi)

AIM: To observe the epithelial remodeling of femtosecond laser-assisted stromal lenticule addition keratoplasty combined with corneal collagen cross-linking(SLAK-CXL)in patients with progressive keratoconus, investigate the remodeling rules of corneal epithelial and influencing factors, and provide clinical data for further refractive correction.METHODS: Retrospective and observational study. A total of 28 keratoconus patients(29 eyes)who received SLAK-CXL from September 2020 to October 2021 were included. Preoperative and postoperative visual acuity, intraocular pressure(IOP), diopter, keratometry and corneal epithelial thickness(CET)were recorded. The trend of CET change was observed. The factors affecting CET were analyzed according to the thickness and depth of the lenticule.RESULTS: Flattest meridian keratometry(Kf)and steepest meridian keratometry(Ks)at 1mo postoperatively were significantly larger than those preoperatively(P&#x003C;0.05). The thinnest corneal thickness(TCT)at 1, 2, 6mo and 1a postoperatively were significantly larger than preoperative(P&#x003C;0.05). The CET changed with time, with the central CET showing a larger variation tendency. The CET of superior, superior nasal, nasal, superior temporal in paracentral area were thinned, the CET of superior, temporal, superior temporal in midperipheral area were thinned, while the CET of superior nasal was thickened in peripheral area at 1, 2, 6mo and 1a postoperatively. The variation of CET was not correlated with the thickness or depth of lenticule at 1a postoperatively(P&#x003E;0.05).CONCLUSIONS: It is firstly found that the corneal morphology has changed after SLAK-CXL. CET decreases and then increases and then decreases again. At 1a postoperatively, the CET of the central and paracentral areas is thinner, while the CET of the midperipheral and peripheral areas is thicker. The degree of epithelial remodeling is not correlated with lenticule thickness or depth.

A Brief Discussion on the in Vitro Diagnostic Reagent Inspection Practice of Self-examination Management Regulations for Medical Device Registration / 中国医疗器械杂志

On October 21, 2021, the National Medical Products Administration issued and implemented the Self-examination Management Regulations for Medical Device Registration. The regulations clarify the specific requirements of the registration applicants in the process of self-examination, and put forward detailed requirements from the aspects of self-examination ability, self-examination report, declaration materials and responsibility requirements, so as to ensure the orderly development of the self-examination of medical device registration. Based on the actual verification work of in vitro diagnostic reagent, this study briefly discussed the understanding of the relevant contents of the regulations, aiming to provide some reference for enterprises and related supervision departments that have the requirement of registered self-examination.

Transformer for Gene Expression Modeling (T-GEM): An Interpretable Deep Learning Model for Gene Expression-Based Phenotype Predictions.

Deep learning has been applied in precision oncology to address a variety of gene expression-based phenotype predictions. However, gene expression data's unique characteristics challenge the computer vision-inspired design of popular Deep Learning (DL) models such as Convolutional Neural Network (CNN) and ask for the need to develop interpretable DL models tailored for transcriptomics study. To address the current challenges in developing an interpretable DL model for modeling gene expression data, we propose a novel interpretable deep learning architecture called T-GEM, or Transformer for Gene Expression Modeling. We provided the detailed T-GEM model for modeling gene-gene interactions and demonstrated its utility for gene expression-based predictions of cancer-related phenotypes, including cancer type prediction and immune cell type classification. We carefully analyzed the learning mechanism of T-GEM and showed that the first layer has broader attention while higher layers focus more on phenotype-related genes. We also showed that T-GEM's self-attention could capture important biological functions associated with the predicted phenotypes. We further devised a method to extract the regulatory network that T-GEM learns by exploiting the attributions of self-attention weights for classifications and showed that the network hub genes were likely markers for the predicted phenotypes.

Cryptococcus gattii Infection as the Major Clinical Manifestation in Patients with Autoantibodies Against Granulocyte-Macrophage Colony-Stimulating Factor.

PURPOSE: Anti-granulocyte-macrophage colony-stimulating factor autoantibodies (anti-GM-CSF Abs) are a predisposing factor for pulmonary alveolar proteinosis (PAP) and Cryptococcus gattii cryptococcosis. This study aimed to investigate clinical manifestations in anti-GM-CSF Ab-positive patients with C. gattii cryptococcosis and analyze the properties of anti-GM-CSF Abs derived from these patients and patients with PAP. METHODS: Thirty-nine patients diagnosed with cryptococcosis (caused by C. neoformans or C. gattii) and 6 with PAP were enrolled in the present study. Clinical information was obtained from medical records. Blood samples were collected for analysis of autoantibody properties. We also explored the National Health Insurance Research Database (NHIRD) of Taiwan to investigate the epidemiology of cryptococcosis and PAP. RESULTS: High titers of neutralizing anti-GM-CSF Abs were identified in 15 patients with cryptococcosis (15/39, 38.5%). Most anti-GM-CSF Ab-positive cryptococcosis cases had central nervous system (CNS) involvement (14/15, 93.3%). Eleven out of 14 (78.6%) anti-GM-CSF Ab-positive CNS cryptococcosis patients were confirmed to be infected with C. gattii, and PAP did not occur synchronously or metachronously in a single patient from our cohort. Exploration of an association between HLA and anti-GM-CSF Ab positivity or differential properties of autoantibodies from cryptococcosis patients and PAP yielded no significant results. CONCLUSION: Anti-GM-CSF Abs can cause two diseases, C. gattii cryptococcosis and PAP, which seldom occur in the same subject. Current biological evidence regarding the properties of anti-GM-CSF Abs cannot provide clues regarding decisive mechanisms. Further analysis, including more extensive cohort studies and investigations into detailed properties, is mandatory to better understand the pathogenesis of anti-GM-CSF Abs.

Pathogenic autoantibodies to IFN-γ act through the impedance of receptor assembly and Fc-mediated response.

Anti-interferon (IFN)-γ autoantibodies (AIGAs) are a pathogenic factor in late-onset immunodeficiency with disseminated mycobacterial and other opportunistic infections. AIGAs block IFN-γ function, but their effects on IFN-γ signaling are unknown. Using a single-cell capture method, we isolated 19 IFN-γ-reactive monoclonal antibodies (mAbs) from patients with AIGAs. All displayed high-affinity (KD < 10-9 M) binding to IFN-γ, but only eight neutralized IFN-γ-STAT1 signaling and HLA-DR expression. Signal blockade and binding affinity were correlated and attributed to somatic hypermutations. Cross-competition assays identified three nonoverlapping binding sites (I-III) for AIGAs on IFN-γ. We found that site I mAb neutralized IFN-γ by blocking its binding to IFN-γR1. Site II and III mAbs bound the receptor-bound IFN-γ on the cell surface, abolishing IFN-γR1-IFN-γR2 heterodimerization and preventing downstream signaling. Site III mAbs mediated antibody-dependent cellular cytotoxicity, probably through antibody-IFN-γ complexes on cells. Pathogenic AIGAs underlie mycobacterial infections by the dual blockade of IFN-γ signaling and by eliminating IFN-γ-responsive cells.

A broad and potent neutralization epitope in SARS-related coronaviruses

Many neutralizing antibodies (nAbs) elicited to ancestral SARS-CoV-2 through natural infection and vaccination generally have reduced effectiveness to SARS-CoV-2 variants. Here we show therapeutic antibody ADG20 is able to neutralize all SARS-CoV-2 variants of concern (VOCs) including Omicron (B.1.1.529) as well as other SARS-related coronaviruses. We delineate the structural basis of this relatively escape-resistant epitope that extends from one end of the receptor binding site (RBS) into the highly conserved CR3022 site. ADG20 can then benefit from high potency through direct competition with ACE2 in the more variable RBS and interaction with the more highly conserved CR3022 site. Importantly, antibodies that are able to target this site generally neutralize all VOCs, albeit with reduced potency against Omicron. Thus, this highly conserved and vulnerable site can be exploited for design of universal vaccines and therapeutic antibodies.

Broadly neutralizing anti-S2 antibodies protect against all three human betacoronaviruses that cause severe disease

Pan-betacoronavirus neutralizing antibodies may hold the key to developing broadly protective vaccines against coronaviruses that cause severe disease, for anticipating novel pandemic-causing viruses, and to respond more effectively to SARS-CoV-2 variants. The emergence of the Omicron variant of SARS-CoV-2 has illustrated the limitations of solely targeting the receptor binding domain (RBD) of the envelope Spike (S)-protein. Here, we isolated a large panel of broadly neutralizing antibodies (bnAbs) from SARS-CoV-2 recovered-vaccinated donors that target a conserved S2 region in the fusion machinery on betacoronavirus spikes. Select bnAbs show broad in vivo protection against all three pathogenic betacoronaviruses, SARS-CoV-1, SARS-CoV-2 and MERS-CoV, that have spilled over into humans in the past 20 years to cause severe disease. The bnAbs provide new opportunities for antibody-based interventions and key insights for developing pan-betacoronavirus vaccines.

Diagnostic value of serum TIM-3 in patients with liver cancer / 国际肿瘤学杂志

Objective:To analyze the changes of T cell immunoglobulin- and mucin-domain-containing molecule-3 (TIM-3) in serum of patients with liver cancer and its diagnostic value.Methods:From March 2021 to May 2021, 37 patients with viral hepatitis type B (hepatitis B group) , 44 patients with liver cirrhosis (liver cirrhosis group) and 27 patients with liver cancer (liver cancer group) were selected in the Second Affiliated Hospital of Air Force Medical University, and 35 healthy subjects who underwent physical examination during the same period were selected as the healthy control group. The serum alpha fetoprotein (AFP) , liver function indexes and TIM-3 levels were detected, and the differences among groups were analyzed. The correlations between TIM-3 and AFP and liver function indexes were analyzed by Spearman correlation. Receiver operating characteristic (ROC) curve was used to analyze the diagnostic value of TIM-3 in liver cancer.Results:There was a statistically significant difference in AFP among the hepatitis B group, liver cirrhosis group and liver cancer group ( χ2=11.75, P=0.003) . There were statistically significant differences in total bilirubin ( χ2=22.85, P<0.001) , direct bilirubin ( χ2=25.90, P<0.001) , indirect bilirubin ( χ2=19.92, P<0.001) , alanine aminotransferase ( χ2=36.64, P<0.001) , aspertate aminotransferase ( χ2=26.26, P<0.001) , aspertate aminotransferase/alanine aminotransferase ( χ2=34.67, P<0.001) and total bile acid ( χ2=13.10, P<0.001) among the hepatitis B group, liver cirrhosis group and liver cancer group. The serum levels of TIM-3 in the healthy control group, hepatitis B group, liver cirrhosis group and liver cancer group were 11.1 (4.2, 14.4) ng/ml, 12.7 (4.3, 23.9) ng/ml, 11.4 (3.4, 17.0) ng/ml and 15.7 (10.5, 21.2) ng/ml, with a statistically significant difference ( χ2=11.85, P=0.008) . There were statistically significant differences between the liver cancer group and healthy control group and liver cirrhosis group (both P<0.05) . Spearman correlation analysis showed that TIM-3 had no correlation with AFP in the four groups ( r=0.05, P=0.791; r=0.18, P=0.497; r=0.03, P=0.883; r=0.24, P=0.396) . There were correlations between serum TIM-3 and total protein in the healthy control group ( r=0.36, P=0.036) , serum TIM-3 and globulin in the hepatitis B group ( r=0.35, P=0.034) , and serum TIM-3 and total bile acid in the liver cancer group ( r=0.46, P=0.017) . ROC curve analysis showed that the sensitivity of serum TIM-3 for the diagnosis of liver cancer was 48.10%, and the specificity was 91.43%, when taking healthy subjects as the control group. The sensitivity of serum TIM-3 for the diagnosis of liver cancer was 96.30%, and the specificity was 41.77%, when taking healthy subjects and liver cirrhosis patients as the control group. The sensitivity of serum TIM-3 for the diagnosis of liver cancer was 96.30%, and the specificity was 40.52%, when taking healthy subjects, hepatitis B patients and liver cirrhosis patients as the control group. Conclusion:The serum level of TIM-3 in patients with liver cancer is significantly increased, which has certain diagnostic value for liver cancer, and can be used as a diagnostic marker and potential therapeutic target for liver cancer patients.