CRISPR screen in regulatory T cells reveals modulators of Foxp3.

Regulatory T (Treg) cells are required to control immune responses and maintain homeostasis, but are a significant barrier to antitumour immunity1. Conversely, Treg instability, characterized by loss of the master transcription factor Foxp3 and acquisition of proinflammatory properties2, can promote autoimmunity and/or facilitate more effective tumour immunity3,4. A comprehensive understanding of the pathways that regulate Foxp3 could lead to more effective Treg therapies for autoimmune disease and cancer. The availability of new functional genetic tools has enabled the possibility of systematic dissection of the gene regulatory programs that modulate Foxp3 expression. Here we developed a CRISPR-based pooled screening platform for phenotypes in primary mouse Treg cells and applied this technology to perform a targeted loss-of-function screen of around 500 nuclear factors to identify gene regulatory programs that promote or disrupt Foxp3 expression. We identified several modulators of Foxp3 expression, including ubiquitin-specific peptidase 22 (Usp22) and ring finger protein 20 (Rnf20). Usp22, a member of the deubiquitination module of the SAGA chromatin-modifying complex, was revealed to be a positive regulator that stabilized Foxp3 expression; whereas the screen suggested that Rnf20, an E3 ubiquitin ligase, can serve as a negative regulator of Foxp3. Treg-specific ablation of Usp22 in mice reduced Foxp3 protein levels and caused defects in their suppressive function that led to spontaneous autoimmunity but protected against tumour growth in multiple cancer models. Foxp3 destabilization in Usp22-deficient Treg cells could be rescued by ablation of Rnf20, revealing a reciprocal ubiquitin switch in Treg cells. These results reveal previously unknown modulators of Foxp3 and demonstrate a screening method that can be broadly applied to discover new targets for Treg immunotherapies for cancer and autoimmune disease.

Atypical characteristic changes of surface morphology and structural covariance network in developmental dyslexia.

BACKGROUND: Developmental dyslexia (DD) is a neurodevelopmental disorder that is characterized by difficulties with all aspects of information acquisition in the written word, including slow and inaccurate word recognition. The neural basis behind DD has not been fully elucidated. METHOD: The study included 22 typically developing (TD) children, 16 children with isolated spelling disorder (SpD), and 20 children with DD. The cortical thickness, folding index, and mean curvature of Broca's area, including the triangular part of the left inferior frontal gyrus (IFGtriang) and the opercular part of the left inferior frontal gyrus, were assessed to explore the differences of surface morphology among the TD, SpD, and DD groups. Furthermore, the structural covariance network (SCN) of the triangular part of the left inferior frontal gyrus was analyzed to explore the changes of structural connectivity in the SpD and DD groups. RESULTS: The DD group showed higher curvature and cortical folding of the left IFGtriang than the TD group and SpD group. In addition, compared with the TD group and the SpD group, the structural connectivity between the left IFGtriang and the left middle-frontal gyrus and the right mid-orbital frontal gyrus was increased in the DD group, and the structural connectivity between the left IFGtriang and the right precuneus and anterior cingulate was decreased in the DD group. CONCLUSION: DD had atypical structural connectivity in brain regions related to visual attention, memory and which might impact the information input and integration needed for reading and spelling.

Alterations in CX3CL1 Levels and Its Role in Viral Pathogenesis.

CX3CL1, also named fractalkine or neurotactin, is the only known member of the CX3C chemokine family that can chemoattract several immune cells. CX3CL1 exists in both membrane-anchored and soluble forms, with each mediating distinct biological activities. CX3CL1 signals are transmitted through its unique receptor, CX3CR1, primarily expressed in the microglia of the central nervous system (CNS). In the CNS, CX3CL1 acts as a regulator of microglia activation in response to brain disorders or inflammation. Recently, there has been a growing interest in the role of CX3CL1 in regulating cell adhesion, chemotaxis, and host immune response in viral infection. Here, we provide a comprehensive review of the changes and function of CX3CL1 in various viral infections, such as human immunodeficiency virus (HIV), SARS-CoV-2, influenza virus, and cytomegalovirus (CMV) infection, to highlight the emerging roles of CX3CL1 in viral infection and associated diseases.

HTNV infection induces activation and deficiency of CD8+MAIT cells in HFRS patients.

Hantaan virus (HTNV) infection causes an epidemic of hemorrhagic fever with renal syndrome (HFRS) mainly in Asia. Mucosal-associated invariant T (MAIT) cells are innate-like T lymphocytes known to play an important role in innate host defense during virus infection. However, their roles and phenotypes during HTNV infection have not yet been explored. We characterized CD8+MAIT cells from HFRS patients based on scRNA-seq data combined with flow cytometry data. We showed that HTNV infection caused the loss and activation of CD8+MAIT cells in the peripheral blood, which were correlated with disease severity. The production of granzyme B and IFN-γ from CD8+MAIT cells and the limitation of HTNV replication in endothelia cells indicated the anti-viral property of CD8+MAIT cells. In addition, in vitro infection of MAIT cells by HTNV or HTNV-exposed monocytes showed that the activation of MAIT cells was IL-18 mediated. In conclusion, this study identified, for the first time, gene expression profiles of MAIT cells, provided underlying molecular mechanisms for activation of MAIT cells during HTNV infection, and suggested a potential anti-viral role of MAIT cells in HFRS.

Local characteristics of molecular epidemiolgy of Acinetobacter baumannii in Jilin province (northeast China).

A. Baumannii is an opportunistic nosocomial pathogen which has severe antibiotic resistance. However, the epidemiology is less clearly understood in Jilin province and China. Thus, 89 A. baumannii isolates from a single hospital in Jilin province between 2013-2017 were performed by MLST. In order to better understanding of the epidemiology of Jilin isolates, Chinese strains originated from other domestic regions and worldwide isolates in MLST database were analyzed by silico phylogenetic tools together. A total of 22 STs in Jilin were identified, and 10 STs were found to be novel. The top three predominant sequence types are ST195 (n = 34, 38.2%), ST208 (n = 14, 15.7%) and ST540 (n = 13, 14.6%). ST369 is predicted to be group founder and ST195, ST540 are subgroup founders of the majority STs in Jilin Province. Some newly discovered singletons showed close relationship with strains from other countries, which suggest that nation-cross transmission is one of important origin of Jilin strains. The majority of Jilin STs showed clonality and close relationship with the majorities from other regions of China. But occupation of individual STs in Jilin were different from that of other domestic regions. The aggregation trend and genetic relationship proved that predominant Jilin STs continue to mutate during transmission. Drug resistance facilitated transmission of Jilin A.baumannii isolates because more than 94% of isolates are resistant to at least one carbapenem and the STs with strong resistance to carbapenems usually has more isolates. In conclusion, high diversity and different occupation of STs, and occupation of novel STs proved that epidemiology of A. baumannii in Jilin has special regional characteristics, and drug resistance facilitated transmission of domestic strains and foreign strains.

Adiponectin's globular domain inhibits T cell activation by interacting with LAIR-1.

Adiponectin (APN) is the most abundant adipokine in human plasma, and has insulin-sensitizing effect. Recent studies have reported that APN plays both anti- and pro-inflammatory roles under different circumstances. However, there is a lack of convincing evidence that decipher APN's anti-inflammatory role through the known receptors and their downstream signaling pathways. In this study, we evaluated a new molecular mechanism underlying APN's anti-inflammatory roles. Our results revealed that the globular domain of adiponectin (gAdp) interacted with the inhibitory leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1). In vitro experiments showed that gAdp inhibited activation of the T cells via the LAIR-1, through a process that also involved downstream SHP-2. These findings indicate that LAIR-1 is a novel APN receptor, affirming APN's anti-inflammatory effect. In summary, we have identified a novel mechanism of peripheral immunoregulatory processes that provides baseline information for further studies on gAdp's role and its contribution to inflammation.

Design and synthesis of HLA-A*02-restricted Hantaan virus multiple-antigenic peptide for CD8+ T cells.

BACKGROUND: Hantaan virus (HTNV) can cause hemorrhagic fever with renal syndrome (HFRS) in humans with severe morbidity and high mortality. Although inactivated HFRS vaccines are given annually for prevention in populations, China still has the highest number of HFRS cases and deaths worldwide. Consequently, vaccination for HFRS requires the development of novel, more effective vaccines. Epitope peptide vaccines have been developed rapidly in recent years and are considered a novel approach for the prevention of infection. Specifically, the multiple antigenic peptide (MAP) design with preferable immunogenicity can arouse a satisfactory immune response for vaccination. However, there are few reports on the design and evaluation of MAP for HTNV. METHODS: Three HLA-A*02-restricted 9-mer cytotoxic T lymphocyte (CTL) epitopes on HTNV glycoprotein and one HLA-A*02-restricted 9-mer CTL epitope on the HTNV nucleocapsid, which have been proven to be immunoprotective in our previous study, were selected for the design of HTNV MAP. A four-branched HTNV MAP was evaluated by the IFN-γ-secreting enzyme-linked immunospot assay and proliferation induction capacity of CD8+ T cells and compared with the single HTNV CTL epitope in 17 HLA-A*02+ patients with HFRS. The Mann-Whitney U test was used for comparison of parameters between different subject groups. RESULTS: The macromolecular HTNV MAP was designed with a polylysine core and four radially branched single CTL epitope chains. Importantly, HTNV MAP could stimulate CD8+ T cell secretion of IFN-γ in HLA-A*02+ patients with HFRS. The frequency of IFN-γ-secreting CD8+ T cells in the MAP stimulation group was significantly higher than that in the single HTNV CTL epitope stimulation groups (P < 0.005). Meanwhile, the activity of IFN-γ-secreting CD8+ T cells in the HTNV MAP group was also higher than that of the single CTL epitope groups (P < 0.05). Moreover, there was a much stronger ability of HTNV MAP to stimulate CD8+ T cell proliferation compared with that of a single HTNV CTL epitope. CONCLUSIONS: The designed HTNV MAP could induce CTL responses ex vivo and may be considered a candidate for the design and development of novel HTNV peptide vaccines.

Protective CD8+ T-cell response against Hantaan virus infection induced by immunization with designed linear multi-epitope peptides in HLA-A2.1/Kb transgenic mice.

BACKGROUND: An effective vaccine that prevents disease caused by hantaviruses is a global public health priority, but up to now, no vaccine has been approved for worldwide use. Therefore, novel vaccines with high prophylaxis efficacy are urgently needed. METHODS: Herein, we designed and synthesized Hantaan virus (HTNV) linear multi-epitope peptide consisting of HLA-A*02-restricted HTNV cytotoxic T cell (CTL) epitope and pan HLA-DR-binding epitope (PADRE), and evaluated the immunogenicity, as well as effectiveness, of multi-epitope peptides in HLA-A2.1/Kb transgenic mice with interferon (IFN)-γ enzyme-linked immunospot assay, cytotoxic mediator detection, proliferation assay and HTNV-challenge test. RESULTS: The results showed that a much higher frequency of specific IFN-γ-secreting CTLs, high levels of granzyme B production, and a strong proliferation capacity of specific CTLs were observed in splenocytes of mice immunized with multi-epitope peptide than in those of a single CTL epitope. Moreover, pre-immunization of multi-epitope peptide could reduce the levels of HTNV RNA loads in the liver, spleen and kidneys of mice, indicating that specific CTL responses induced by multi-epitope peptide could reduce HTNV RNA loads in vivo. CONCLUSIONS: This study may provide an important foundation for the development of novel peptide vaccines for HTNV prophylaxis.

The endoplasmic reticulum-resident E3 ubiquitin ligase Hrd1 controls a critical checkpoint in B cell development in mice.

Humoral immunity involves multiple checkpoints that occur in B cell development, maturation, and activation. The pre-B-cell receptor (pre-BCR) is expressed following the productive recombination of the immunoglobulin heavy-chain gene, and sSignalsing through the pre-BCR are required for the differentiation of pre-B cells into immature B cells. However, the molecular mechanisms controlling the pre-BCR expression and signaling strength remain undefined. Herein, we probed the role of the endoplasmic reticulum-associated, stress-activated E3 ubiquitin ligase HMG-CoA reductase degradation 1 (Hrd1) in B cell differentiation. Using mice with a specific Hrd1 deletion in pro-B cells and subsequent B cell developmental stages, we showed that the E3 ubiquitin ligase Hrd1 governs a critical checkpoint during B cell development. We observed that Hrd1 is required for degradation of the pre-BCR complex during the early stage of B cell development. As a consequence, loss of Hrd1 in the B cell lineage resulted in increased pre-BCR expression levels and a developmental defect in the transition from large to small pre-B cells. This defect, in turn, resulted in reduced fewer mature B cells in bone marrow and peripheral lymphoid organs. Our results revealed a novel critical role of Hrd1 in controlling a critical checkpoint in B cell-mediated immunity and suggest that Hrd1 may functioning as an E3 ubiquitin ligase of the pre-BCR complex.

Endoplasmic reticulum-resident E3 ubiquitin ligase Hrd1 controls B-cell immunity through degradation of the death receptor CD95/Fas.

Humoral immunity involves multiple checkpoints during B-cell development, maturation, and activation. The cell death receptor CD95/Fas-mediated apoptosis plays a critical role in eliminating the unwanted activation of B cells by self-reactive antigens and in maintaining B-cell homeostasis through activation-induced B-cell death (AICD). The molecular mechanisms controlling AICD remain largely undefined. Herein, we show that the E3 ubiquitin ligase Hrd1 protected B cells from activation-induced cell death by degrading the death receptor Fas. Hrd1-null B cells exhibited high Fas expression during activation and rapidly underwent Fas-mediated apoptosis, which could be largely inhibited by FasL neutralization. Fas mutation in Hrd1 KO mice abrogated the increase in B-cell AICD. We identified Hrd1 as the first E3 ubiquitin ligase of the death receptor Fas and Hrd1-mediated Fas destruction as a molecular mechanism in regulating B-cell immunity.

Hantaan virus infection induces both Th1 and ThGranzyme B+ cell immune responses that associated with viral control and clinical outcome in humans.

Hantaviruses infection causing severe emerging diseases with high mortality rates in humans has become public health concern globally. The potential roles of CD4(+)T cells in viral control have been extensively studied. However, the contribution of CD4(+)T cells to the host response against Hantaan virus (HTNV) infection remains unclear. Here, based on the T-cell epitopes mapped on HTNV glycoprotein, we studied the effects and characteristics of CD4(+)T-cell responses in determining the outcome of hemorrhagic fever with renal syndrome. A total of 79 novel 15-mer T-cell epitopes on the HTNV glycoprotein were identified, among which 20 peptides were dominant target epitopes. Importantly, we showed the presence of both effective Th1 responses with polyfunctional cytokine secretion and ThGranzyme B(+) cell responses with cytotoxic mediators production against HTNV infection. The HTNV glycoprotein-specific CD4(+)T-cell responses inversely correlated with the plasma HTNV RNA load in patients. Individuals with milder disease outcomes showed broader epitopes targeted and stronger CD4(+)T-cell responses against HTNV glycoproteins compared with more severe patients. The CD4(+)T cells characterized by broader antigenic repertoire, stronger polyfunctional responses, better expansion capacity and highly differentiated effector memory phenotype(CD27-CD28-CCR7-CD45RA-CD127(hi)) would elicit greater defense against HTNV infection and lead to much milder outcome of the disease. The host defense mediated by CD4(+)T cells may through the inducing antiviral condition of the host cells and cytotoxic effect of ThGranzyme B+ cells. Thus, these findings highlight the efforts of CD4(+)T-cell immunity to HTNV control and provide crucial information to better understand the immune defense against HTNV infection.

CD8low CD100- T Cells Identify a Novel CD8 T Cell Subset Associated with Viral Control during Human Hantaan Virus Infection.

UNLABELLED: Hantaan virus (HTNV) infection can cause a severe lethal hemorrhagic fever with renal syndrome (HFRS) in humans. CD8(+) T cells play a critical role in combating HTNV infections. However, the contributions of different CD8(+) T cell subsets to the immune response against viral infection are poorly understood. Here, we identified a novel subset of CD8(+) T cells characterized by the CD8(low) CD100(-) phenotype in HFRS patients. The CD8(low) CD100(-) subset accounted for a median of 14.3% of the total CD8(+) T cells in early phase of HFRS, and this percentage subsequently declined in the late phase of infection, whereas this subset was absent in healthy controls. Furthermore, the CD8(low) CD100(-) cells were associated with high activation and expressed high levels of cytolytic effector molecules and exhibited a distinct expression profile of effector CD8(+) T cells (CCR7(+/-) CD45RA(-) CD127(high) CD27(int) CD28(low) CD62L(-)). When stimulated with specific HTNV nucleocapsid protein-derived peptide pools, most responding CD8(+) cells (gamma interferon [IFN-γ] positive and/or tumor necrosis factor alpha [TNF-α] positive) were CD8(low) CD100(-) cells. The frequency of CD8(low) CD100(-) cells among HTNV-specific CD8(+) T cells was higher in milder cases than in more severe cases. Importantly, the proportion of the CD8(low) CD100(-) subset among CD8(+) T cells in early phase of HFRS was negatively correlated with the HTNV viral load, suggesting that CD8(low) CD100(-) cells may be associated with viral clearance. The contraction of the CD8(low) CD100(-) subset in late phase of infection may be related to the consistently high expression levels of PD-1. These results may provide new insights into our understanding of CD8(+) T cell-mediated protective immunity as well as immune homeostasis after HTNV infection in humans. IMPORTANCE: CD8(+) T cells play important roles in the antiviral immune response. We found that the proportion of CD8(low) CD100(-) cells among CD8(+) T cells from HFRS patients was negatively correlated with the HTNV viral load, and the frequency of CD8(low) CD100(-) cells among virus-specific CD8(+) T cells was higher in milder HFRS cases than in more severe cases. These results imply a beneficial role for the CD8(low) CD100(-) cell subset in viral control during human HTNV infection.

Enzymatic hydrolysis of oleuropein from Olea europea (olive) leaf extract and antioxidant activities.

Oleuropein (OE), the main polyphenol in olive leaf extract, is likely to decompose into hydroxytyrosol (HT) and elenolic acid under the action of light, acid, base, high temperature. In the enzymatic process, the content of OE in olive leaf extract and enzyme are key factors that affect the yield of HT. A selective enzyme was screened from among 10 enzymes with a high OE degradation rate. A single factor (pH, temperature, time, enzyme quantity) optimization process and a Box-Behnken design were studied for the enzymatic hydrolysis of 81.04% OE olive leaf extract. Additionally, enzymatic hydrolysis results with different substrates (38.6% and 81.04% OE) were compared and the DPPH antioxidant properties were also evaluated. The result showed that the performance of hydrolysis treatments was best using hemicellulase as a bio-catalyst, and the high purity of OE in olive extract was beneficial to biotransform OE into HT. The optimal enzymatic conditions for achieving a maximal yield of HT content obtained by the regression were as follows: pH 5, temperature 55 °C and enzyme quantity 55 mg. The experimental result was 11.31% ± 0.15%, and the degradation rate of OE was 98.54%. From the present investigation of the antioxidant activity determined by the DPPH method, the phenol content and radical scavenging effect were both decreased after enzymatic hydrolysis by hemicellulase. However, a high antioxidant activity of the ethyl acetate extract enzymatic hydrolysate (IC50 = 41.82 µg/mL) was demonstated. The results presented in this work suggested that hemicellulase has promising and attractive properties for industrial production of HT, and indicated that HT might be a valuable biological component for use in pharmaceutical products and functional foods.

Hantaan virus infection induces CXCL10 expression through TLR3, RIG-I, and MDA-5 pathways correlated with the disease severity.

Hantaan virus (HTNV) is a major agent causing hemorrhagic fever with renal syndrome (HFRS). Although the pathogenesis of HFRS is unclear, some reports have suggested that the abundant production of proinflammatory cytokines and uncontrolled inflammatory responses may contribute to the development of HFRS. CXCL10 is one of these cytokines and is found to be involved in the pathogenesis of many virus infectious diseases. However, the role of CXCL10 in the pathogenesis of HFRS and the molecular regulation mechanism of CXCL10 in HTNV infection remain unknown. In this study, we report that CXCL10 expresses highly in the HFRS patients' sera and the elevated CXCL10 is positively correlated with the severity of HFRS. We find that HTNV, a single-strand RNA virus, can act as a double-strand RNA to activate the TLR3, RIG-I, and MDA-5 signaling pathways. Through the downstream transcription factors of these pathways, NF-κB and IRF7, which bind directly to the CXCL10's promoter, the expression of CXCL10 is increased. Our results may help to better understand the role of CXCL10 in the development of HFRS and may provide some novel insights into the immune response of HTNV infection.

[DNA barcoding research and its application on medicinal plants of Bletilla H. G. Reichenbach].

To identify adulterants from medicinal plants of Bletilla H. G. Reichenbach, the suitable candidate DNA barcoding of Bletilla was evaluated. In this study, the internal transcribed spacer (ITS) of nuclear ribosomal DNA, the LFY homologous gene intron 2 and chloroplast ycfl gene were amplified and sequenced from forty-one samples. The intra-specific and inter-specific divergences of Bletilla were calculated, and the identification efficiency was assessed using Barcoding Gap, NJ tree by K2P distance and BLAST1 method. The result showed the intra-specific divergence of nrDNA ITS and ycJfl (0.022-0.106 and 0.017-0.106) were obviously higher than the inter-specific divergence (0-0.012 and 0-0.015), and four species of Bletilla were also accurately distinguished in NJ trees. Whereas, there was no Barcoding Gap on LFY homologous gene intron 2, thus it cannot effectively identify species of Bletilla. Using NJ tree of nrDNA ITS and ycfl gene, powdery medicine and the adulterants of Bletilla were successfully unidentified. In conclusion, nrDNA ITS and ycfl can be used as a potential DNA barcoding to identify the medicinal plants in Bletilla and its adulterants. There were only three basic differences on nrDNA ITS between "Jujing baiji" and Bletilla striata of Lu'an in Anhui province, and two basic differences in ycfl. Based on morphological and molecular data, "Jujing baiji" could be recognized as the species of Bletilla striata.

The lifespan-extending effects of Nymphaea hybrid root extract in the nematode Caenorhabditis elegans.

Nymphaea hybrid, a water lily from the Nymphaeaceae family, has been found to exhibit some in vivo beneficial effects. In the present study we investigated the lifespan-extending effects of Nymphaea hybrid root extract in the nematode Caenorhabditis elegans. We found that Nymphaea hybrid root extract significantly extended the lifespan of C.elegans and improved its locomotion during aging. Moreover, Nymphaea hybrid root extract increased the resistance of C.elegans to both heat stress and oxidative stress. We found that the ability of Nymphaea hybrid root extract to increase lifespan was independent of its antimicrobial effects and was probably associated with its effects on the reproduction of C.elegans. In addition, the lifespan-extending effects of Nymphaea hybrid root extract were found to be dependent on the insulin/IGF signaling pathway. We also found that total flavones of Nymphaea hybrid could increase survival of C.elegans in both normal and adverse conditions, indicating that total flavones comprise the major fractions with lifespan-extending effects. Therefore, Nymphaea hybrid root extract has lifespan-extending effects in C.elegans and could be developed as a functional food.

Hantaan virus RNA load in patients having hemorrhagic fever with renal syndrome: correlation with disease severity.

To investigate the role of viral load in the pathogenesis of hemorrhagic fever with renal syndrome, the Hantaan virus RNA load in plasma from 101 patients was quantified, and the relationships between viral load and disease course, severity, and level of specific humoral immunity were analyzed. The viral load, detectable in 79 patients, ranged from 3.43 to 7.33 log10 copies/mL of plasma. In the early stage of disease, patients in severe/critical group were found to have higher viral loads than those in the mild/moderate group (5.90 vs 5.03 log10 copies/mL; P = .001), suggesting an association between Hantaan virus load and disease severity.

Alterations in hippocampus-centered morphological features and function of the progression from normal cognition to mild cognitive impairment.

Mild cognitive impairment (MCI) is a significant precursor to dementia, highlighting the critical need for early identification of individuals at high risk of MCI to prevent cognitive decline. The study aimed to investigate the changes in brain structure and function before the onset of MCI. This study enrolled 19 older adults with progressive normal cognition (pNC) to MCI and 19 older adults with stable normal cognition (sNC). The gray matter (GM) volume and functional connectivity (FC) were estimated via magnetic resonance imaging during their normal cognition state 3 years prior. Additionally, spatial associations between FC maps and neurochemical profiles were examined using JuSpace. Compared to the sNC group, the pNC group showed decreased volume in the left hippocampus and left amygdala. The significantly positive correlation was observed between the GM volume of the left hippocampus and the MMSE scores after 3 years in pNC group. Besides, it showed that the pNC group had increased FC between the left hippocampus and the anterior-posterior cingulate gyrus, which was significantly correlated with the spatial distribution of dopamine D2 and noradrenaline transporter. Taken together, the study identified the abnormal brain characteristics before the onset of MCI, which might provide insight into clinical research.

[Advances in the role and mechanism of NK cell immune response mediated by NKG2A-HLA-E axis in viral infectious diseases].

Natural killer (NK) cells directly lysis the virus-infected cells through rapidly releasing cytotoxic mediators and cytokines. The balance between inhibitory and activated receptors on the surface of NK cells, as well as the corresponding ligands expressed on target cells are involved in the regulation of the cytotoxic function of NK cells. NKG2A is one of the highly anticipated inhibitory receptors expressed on NK cells, which can inhibit the cytotoxicity of NK cells to autologous normal tissue cells through interacting with the ligand HLA-E. The studies have shown that HLA-E is overexpressed on virus-infected cells and forms a complex with peptides derived from viral proteins. The interaction of HLA-E and NKG2A can regulate the functions of NK cells, participateing the pathogenesis process of virus infectious diseases. This review outlines the characteristics of the molecular interaction between NKG2A and HLA-E, as well as the mechanisms of NKG2A-HLA-E axis in regulating NK cell responses.

Ensemble learning-assisted prediction of prolonged hospital length of stay after spine correction surgery: a multi-center cohort study.

PURPOSE: This research aimed to develop a machine learning model to predict the potential risk of prolonged length of stay in hospital before operation, which can be used to strengthen patient management. METHODS: Patients who underwent posterior spinal deformity surgery (PSDS) from eleven medical institutions in China between 2015 and 2022 were included. Detailed preoperative patient data, including demographics, medical history, comorbidities, preoperative laboratory results, and surgery details, were collected from their electronic medical records. The cohort was randomly divided into a training dataset and a validation dataset with a ratio of 70:30. Based on Boruta algorithm, nine different machine learning algorithms and a stack ensemble model were trained after hyperparameters tuning visualization and evaluated on the area under the receiver operating characteristic curve (AUROC), precision-recall curve, calibration, and decision curve analysis. Visualization of Shapley Additive exPlanations method finally contributed to explaining model prediction. RESULTS: Of the 162 included patients, the K Nearest Neighbors algorithm performed the best in the validation group compared with other machine learning models (yielding an AUROC of 0.8191 and PRAUC of 0.6175). The top five contributing variables were the preoperative hemoglobin, height, body mass index, age, and preoperative white blood cells. A web-based calculator was further developed to improve the predictive model's clinical operability. CONCLUSIONS: Our study established and validated a clinical predictive model for prolonged postoperative hospitalization duration in patients who underwent PSDS, which offered valuable prognostic information for preoperative planning and postoperative care for clinicians. Trial registration ClinicalTrials.gov identifier NCT05867732, retrospectively registered May 22, 2023, https://classic. CLINICALTRIALS: gov/ct2/show/NCT05867732 .