Decoding the genetic landscape of juvenile dermatomyositis: insights from phosphorylation-associated single nucleotide polymorphisms.

Genome-wide association studies (GWASs) have identified genetic susceptibility loci associated with juvenile dermatomyositis (JDM). Single nucleotide polymorphisms related to phosphorylation (phosSNPs) are critical nonsynonymous mutations exerting substantial influence on gene expression regulation. The aim of this study was to identify JDM susceptibility genes in the GWAS loci by the use of phosSNPs. We explored quantitative trait loci (QTLs) among the phosSNPs associated with JDM using data from eQTL (bulk tissues and single-cell) and pQTL studies. For gene expression and protein levels significantly influenced by JDM-associated phosSNPs, we assessed their associations with JDM through MR analyses. Additionally, we conducted differential expression gene analyses, incorporating single-cell transcriptomic profiling of 6 JDM cases and 11 juvenile controls (99,396 cells). We identified 31 phosSNPs situated in the 6p21 locus that were associated with JDM. Half of these phosSNPs showed effects on gene expression in various cells and circulating protein levels. In MR analyses, we established associations between the expression levels of pivotal JDM-associated genes, including MICB, C4A, HLA-DRB1, HLA-DRB5, and PSMB9, in skin, muscle, or blood cells and circulating levels of C4A, with JDM. Utilizing single-cell eQTL data, we identified a total of 276 association signals across 14 distinct immune cell types for 28 phosSNPs. Further insights were gained through single-cell differential expression analysis, revealing differential expression of PSMB9, HLA-A, HLA-B, HLA-C, HLA-DPB1, HLA-DQA1, HLA-DQB1, and HLA-DRB1 in immune cells. The present study pinpointed phosSNPs within susceptibility genes for JDM and unraveled the intricate relationships among these SNPs, gene expression levels, and JDM.

Application of Cotton Swab-Ag Composite as Flexible Surface-Enhanced Raman Scattering Substrate for DMMP Detection.

It is both important and required to quickly and accurately detect chemical warfare agents, such as the highly toxic nerve agent sarin. Surface-enhanced Raman scattering (SERS) has received considerable attention due to its rapid results, high sensitivity, non-destructive data acquisition, and unique spectroscopic fingerprint. In this work, we successfully prepared SERS cotton swabs (CSs) for the detection of the sarin simulant agent dimethyl methyl phosphonate (DMMP) by anchoring N1-(3-trimethoxysilylpropyl) diethylenetriamine (ATS)/silver nanoparticle (AgNP) nanocomposites on CSs using ATS as the stabilizer and coupling agent. Simultaneously, the binding mode and reaction mechanics between the AgNP, ATS, and CS were confirmed by XPS. The modified CSs exhibited good uniformity, stability, and adsorption capability for SERS measurements, enabling the adsorption and detection of DMMP residue from an irregular surface via a simple swabbing process, with a detection limit of 1 g/L. The relative standard deviations (RSDs) of RSD710 = 5.6% had high reproducibility. In this research, the fabrication method could easily be extended to other cellulose compounds, such as natural fibers and paper. Furthermore, the versatile SERS CSs can be used for the on-site detection of DMMP, particularly in civil and defense applications, to guarantee food security and the health of the population.

Stroke propensity in the Th3+/ mouse model of ß-thalassemia intermedia.

ß-thalassemia is associated with multiple hematological and cerebrovascular symptoms linked to a hypercoagulable state that has not been fully replicated in animal models for the development of stroke treatments. Herein we compared the physiological properties and responses to transient cerebral hypoxia-ischemia (tHI) between six-month-old wildtype and heterozygous Th3/+ mice, a model of non-transfusion-dependent ß-thalassemia intermedia (ß-TI). We found that Th3/+ mice developed microcytic anemia, splenomegaly, higher platelet counts, and increased platelet-erythrocyte plus erythrocyte-leukocyte aggregates. Furthermore, Th3/+ mice showed diminished cerebrovascular reactivity (CVR) and cortical oxygen saturation under repetitive hypercapnic challenges. When subjected to a sub-threshold tHI insult, platelets and leukocytes in Th3/+ mice adhered to the cerebrovascular wall or formed aggregates, while their counterparts flew through smoothly in wildtype mice. Subsequently, Th3/+ mice showed increased fibrin deposition around cerebral blood vessels and larger infarction than wildtype mice, especially in female Th3/+ mice. Collectively these results showed that Th3/+ mice mimic key clinical features and a propensity to thromboembolism in ß-TI patients. The hypercoagulable state in Th3/+ mice is likely caused by multiple hematological and CVR anomalies that are similar, but are not identical to those in the mouse model of sickle cell anemia. As such, we suggest that Th3/+ mice are a useful model to study the pathological mechanisms and prophylactic stroke treatments in thalassemia patients.

A cascade reaction for regioselective construction of pyrazole-containing aliphatic sulfonyl fluorides.

A copper-catalyzed cascade reaction of α-diazocarbonyl compounds with ethenesulfonyl fluoride (ESF) is developed, affording a variety of highly functionalized pyrazolyl aliphatic sulfonyl fluorides in good to excellent yields (66-98%). This transformation features broad substrates, exclusive regioselectivity, high atom economy and operational simplicity, thus providing a straightforward method for the direct construction of pyrazole-containing aliphatic sulfonyl fluorides, which will provide great applicable value in medicinal chemistry and other related disciplines.

Association of Body Mass Index and Abdominal Obesity with the Risk of Airflow Obstruction: National Health and Nutrition Examination Survey (NHANES) 2007-2012.

This study aimed to explore the relationship between body mass index (BMI) and abdominal obesity and the risk of airflow obstruction, based on the data from the 2007-2012 National Health and Nutrition Survey (NHANES). Logistic regression was applied to assess the relationships between BMI or abdominal obesity and the risk of airflow obstruction by the fixed ratio method and the lower limit of normal (LLN) method. We further used the restricted cubic splines with 3 knots located at the 5th, 50th, and 95th percentiles of the distribution to evaluate the dose-response relationship. A total of 12,865 individuals aged 20-80 years old were included. In the fixed ratio method, underweight was positively correlated with the risk of airflow obstruction, and overweight and obesity were negatively correlated with the risk of airflow obstruction. In the LLN method, the results were consistent with the fixed ratio method. Abdominal obesity was positively associated with the risk of airflow obstruction only in the fixed ratio method (OR: 1.41, 95% CI: 1.04-1.90). There was an additive interaction between underweight and smoking on airflow obstruction in both methods. Abdominal obesity and smoking had additive interactions in the LLN method. Dose-response analysis indicated that there was a non-linear trend between BMI and the risk of airflow obstruction (Pfor nonlinearity < 0.01). Our study suggested that underweight and abdominal obesity were associated with the increased risk of airflow obstruction, and overweight and general obesity were associated with the decreased risk of airflow obstruction.

Monocytic Infiltrates Contribute to Autistic-like Behaviors in a Two-Hit Model of Neurodevelopmental Defects.

Growing evidence suggests that early-life interactions among genetic, immune, and environment factors may modulate neurodevelopment and cause psycho-cognitive deficits. Maternal immune activation (MIA) induces autism-like behaviors in offspring, but how it interplays with perinatal brain injury (especially birth asphyxia or hypoxia ischemia [HI]) is unclear. Herein we compared the effects of MIA (injection of poly[I:C] to dam at gestational day 12.5), HI at postnatal day 10, and the combined MIA/HI insult in murine offspring of both sexes. We found that MIA induced autistic-like behaviors without microglial activation but amplified post-HI NFκB signaling, pro-inflammatory responses, and brain injury in offspring. Conversely, HI neither provoked autistic-like behaviors nor concealed them in the MIA offspring. Instead, the dual MIA/HI insult added autistic-like behaviors with diminished synaptic density and reduction of autism-related PSD-95 and Homer-1 in the hippocampus, which were missing in the singular MIA or HI insult. Further, the dual MIA/HI insult enhanced the brain influx of Otx2-positive monocytes that are associated with an increase of perineuronal net-enwrapped parvalbumin neurons. Using CCR2-CreER mice to distinguish monocytes from the resident microglia, we found that the monocytic infiltrates gradually adopted a ramified morphology and expressed the microglial signature genes (Tmem119, P2RY12, and Sall1) in post-MIA/HI brains, with some continuing to express the proinflammatory cytokine TNFα. Finally, genetic or pharmacological obstruction of monocytic influx significantly reduced perineuronal net-enwrapped parvalbumin neurons and autistic-like behaviors in MIA/HI offspring. Together, these results suggest a pathologic role of monocytes in the two-hit (immune plus neonatal HI) model of neurodevelopmental defects.SIGNIFICANCE STATEMENT In autism spectrum disorders (ASDs), prenatal infection or maternal immune activation (MIA) may act as a primer for multiple genetic and environmental factors to impair neurodevelopment. This study examined whether MIA cooperates with neonatal cerebral hypoxia ischemia to promote ASD-like aberrations in mice using a novel two-hit model. It was shown that the combination of MIA and neonatal hypoxia ischemia produces autistic-like behaviors in the offspring, and has synergistic effects in inducing neuroinflammation, monocytic infiltrates, synaptic defects, and perineuronal nets. Furthermore, genetic or pharmacological intervention of the MCP1-CCR2 chemoattractant pathway markedly reduced monocytic infiltrates, perineuronal nets, and autistic-like behaviors. These results suggest reciprocal escalation of immune and neonatal brain injury in a subset of ASD that may benefit from monocyte-targeted treatments.

Brain-targeted hypoxia-inducible factor stabilization reduces neonatal hypoxic-ischemic brain injury.

Hypoxia-inducible factor-1α (HIF1α) is a major regulator of cellular adaptation to hypoxia and oxidative stress, and recent advances of prolyl-4-hydroxylase (P4H) inhibitors have produced powerful tools to stabilize HIF1α for clinical applications. However, whether HIF1α provokes or resists neonatal hypoxic-ischemic (HI) brain injury has not been established in previous studies. We hypothesize that systemic and brain-targeted HIF1α stabilization may have divergent effects. To test this notion, herein we compared the effects of GSK360A, a potent P4H inhibitor, in in-vitro oxygen-glucose deprivation (OGD) and in in-vivo neonatal HI via intracerebroventricular (ICV), intraperitoneal (IP), and intranasal (IN) drug-application routes. We found that GSK360A increased the erythropoietin (EPO), heme oxygenase-1 (HO1) and glucose transporter 1 (Glut1) transcripts, all HIF1α target-genes, and promoted the survival of neurons and oligodendrocytes after OGD. Neonatal HI insult stabilized HIF1α in the ipsilateral hemisphere for up to 24 h, and either ICV or IN delivery of GSK360A after HI increased the HIF1α target-gene transcripts and decreased brain damage. In contrast, IP-injection of GSK360A failed to reduce HI brain damage, but elevated the risk of mortality at high doses, which may relate to an increase of the kidney and plasma EPO, leukocytosis, and abundant vascular endothelial growth factor (VEGF) mRNAs in the brain. These results suggest that brain-targeted HIF1α-stabilization is a potential treatment of neonatal HI brain injury, while systemic P4H-inhibition may provoke unwanted adverse effects.

Metabolic syndrome and its relation to dietary patterns among a selected urbanised and semi-urbanised Tibetan population in transition from nomadic to settled living environment.

OBJECTIVE: To explore the scope of metabolic syndrome (MetS) and its relationship to the major dietary patterns among an urbanised and semi-urbanised Tibetan population in transition from nomadic to settled settings. DESIGN: Cross-sectional. SETTING: Community-based. PARTICIPANTS: Urbanised and semi-urbanised Tibetan adults (n 920, aged 18-90 years), who have moved from nomadic to settled living environments, answered questionnaires on food consumption frequency and lifestyle characteristics through structured face-to-face interviews and completed anthropometric measurement and metabolic biomarker tests. RESULTS: MetS prevalence was 30·1 % in males and 32·1 % in females. Low HDL-cholesterol and central obesity were the leading metabolic abnormalities (86·3 and 55·8 %, respectively). Three major dietary patterns - urban, western and pastoral - were identified. Beef/mutton was an important food group for all three identified dietary patterns. In addition, the urban dietary pattern was characterised by frequent consumption of vegetables, tubers/roots and refined carbohydrates; the western pattern was characterised by sweetened drinks, snacks and desserts; and the pastoral pattern featured tsamba (roasted Tibetan barley), Tibetan cheese, butter tea/milk tea and whole-fat dairy foods. Individuals in the highest quintile of urban dietary pattern scores were found to be at a higher risk of developing MetS (OR 2·43, 95 % CI 1·41, 4·18) and central obesity (OR 1·91, 95 % CI 1·16, 3·14) after controlling for potential confounders. CONCLUSIONS: MetS was common among urbanised and semi-urbanised Tibetan adult population in transition. The urban dietary pattern, in particular, was a risk factor for MetS. To prevent MetS, nutrition interventions need to be tailored to address the variety of local diet patterns to promote healthy eating.

Association of Body Mass Index with Risk of Chronic Obstructive Pulmonary Disease: A Systematic Review and Meta-Analysis.

The association between body mass index (BMI) and chronic obstructive pulmonary disease (COPD) remains controversial. Therefore, a meta-analysis was conducted to further evaluate the relationship. A comprehensive literature search was performed in PubMed, Web of Science, EMBASE, China National Knowledge Infrastructure (CNKI), and Wanfang databases to identify eligible articles until July 15, 2020. Random effect model (REM) was used to compute the pooled results with 95% confidence intervals (CIs). We conducted meta-regression and subgroup analysis to explore potential sources of heterogeneity. Publication bias was evaluated by funnel plots and Egger's test. Thirty articles with 1,578,449 participants were included in the meta-analysis. The pooled OR of COPD was 1.96 (95% CI: 1.78-2.17) for the underweight group, 0.80 (95% CI: 0.73-0.87) for overweight group, and 0.86 (95% CI: 0.73-1.02) for obesity group. After further excluding 5 studies of high between-study heterogeneity in sensitivity analysis, the pooled OR of COPD was 0.77 (95% CI: 0.68-0.86) for the obesity group. This meta-analysis indicated that BMI was associated with COPD. Specifically, underweight might increase the risk of COPD; overweight and obesity might reduce the risk of COPD.

Macrophage migration inhibitory factor is critical for dengue NS1-induced endothelial glycocalyx degradation and hyperpermeability.

Vascular leakage is one of the salient characteristics of severe dengue. Nonstructural protein 1 (NS1) of dengue virus (DENV) can stimulate endothelial cells to secrete endothelial hyperpermeability factor, macrophage migration inhibitory factor (MIF), and the glycocalyx degradation factor heparanase 1 (HPA-1). However, it is unclear whether MIF is directly involved in NS1-induced glycocalyx degradation. In this study, we observed that among NS1, MIF and glycocalyx degradation-related molecules, the HPA-1, metalloproteinase 9 (MMP-9) and syndecan 1 (CD138) serum levels were all increased in dengue patients, and only NS1 and MIF showed a positive correlation with the CD138 level in severe patients. To further characterize and clarify the relationship between MIF and CD138, we used recombinant NS1 to stimulate human cells in vitro and challenge mice in vivo. Our tabulated results suggested that NS1 stimulation could induce human endothelial cells to secrete HPA-1 and immune cells to secrete MMP-9, resulting in endothelial glycocalyx degradation and hyperpermeability. Moreover, HPA-1, MMP-9, and CD138 secretion after NS1 stimulation was blocked by MIF inhibitors or antibodies both in vitro and in mice. Taken together, these results suggest that MIF directly engages in dengue NS1-induced glycocalyx degradation and that targeting MIF may represent a possible therapeutic approach for preventing dengue-induced vascular leakage.

Major dietary patterns and their relationship to obesity among urbanized adult Tibetan pastoralists.

BACKGROUND AND OBJECTIVES: This study investigated major dietary patterns and their relationship to obesity among urbanized Tibetan pastoralists. METHODS AND STUDY DESIGN: Using a cross-sectional design, this study assessed 782 urbanized Tibetan pastoralists aged 18-84 y. A food frequency questionnaire and anthropometric measurements were conducted in 2018. Principal component analysis was used to identify dietary patterns. Logistic regression was applied to compare the risks for overweight (BMI >=24 kg/m2), obesity (BMI >=28 kg/m2), and central obesity (waist circumference >=80 cm for women and >=85 cm for men) across quintiles of dietary pattern scores after controlling for gender, age, education, medical insurance, smoking status, alcohol consumption and physical activity. RESULTS: This study identified three major dietary patterns: an urban pattern characterized by high intake of vegetables, tubers/roots, and refined carbohydrates; a western pattern characterized by sugary drinks, snacks, and desserts; and a pastoral pattern characterized by tsamba (roasted Tibetan barley), Tibetan cheese, and buttered/milk tea. Subjects in the highest quintile of urban pattern scores were more likely to be overweight (OR=2.58, 95% CI 1.48-4.49) (p-for-trend=0.001), obese (2.94, 1.57-5.49) (p-for-trend=0.001), and centrally obese (1.94, 1.12-3.36) (p-for-trend=0.019) compared to those in the lowest quintile with confounders controlled. The western dietary pattern was positively associated with overweight (p-for-trend=0.037). No clear association was observed for the pastoral dietary pattern. CONCLUSIONS: Urban and western dietary patterns independently predict the likelihood of being overweight. Improved nutrition education may contribute to healthier eating behaviors, thus reducing or preventing obesity.

Dengue virus non-structural protein 1: a pathogenic factor, therapeutic target, and vaccine candidate.

Dengue virus (DENV) infection is the most common mosquito-transmitted viral infection. DENV infection can cause mild dengue fever or severe dengue hemorrhagic fever (DHF)/dengue shock syndrome (DSS). Hemorrhage and vascular leakage are two characteristic symptoms of DHF/DSS. However, due to the limited understanding of dengue pathogenesis, no satisfactory therapies to treat nor vaccine to prevent dengue infection are available, and the mortality of DHF/DSS is still high. DENV nonstructural protein 1 (NS1), which can be secreted in patients' sera, has been used as an early diagnostic marker for dengue infection for many years. However, the roles of NS1 in dengue-induced vascular leakage were described only recently. In this article, the pathogenic roles of DENV NS1 in hemorrhage and vascular leakage are reviewed, and the possibility of using NS1 as a therapeutic target and vaccine candidate is discussed.

Cdk12 Regulates Neurogenesis and Late-Arising Neuronal Migration in the Developing Cerebral Cortex.

DNA damage response (DDR) pathways are critical for ensuring that replication stress and various types of DNA lesion do not perturb production of neural cells during development. Cdk12 maintains genomic stability by regulating expression of DDR genes. Mutant mice in which Cdk12 is conditionally deleted in neural progenitor cells (NPCs) die after birth and exhibit microcephaly with a thinner cortical plate and an aberrant corpus callosum. We show that NPCs of mutant mice accumulate at G2 and M phase, and have lower expression of DDR genes, more DNA double-strand breaks and increased apoptosis. In addition to there being fewer neurons, there is misalignment of layers IV-II neurons and the presence of abnormal axonal tracts of these neurons, suggesting that Cdk12 is also required for the migration of late-arising cortical neurons. Using in utero electroporation, we demonstrate that the migrating mutant cells remain within the intermediate zone and fail to adopt a bipolar morphology. Overexpression of Cdk5 brings about a partially restoration of the neurons reaching layers IV-II in the mutant mice. Thus, Cdk12 is crucial to the repair of DNA damage during the proliferation of NPCs and is also central to the proper migration of late-arising neurons.

Designed Macrocyclic Peptides as Nanomolar Amyloid Inhibitors Based on Minimal Recognition Elements.

Amyloid self-assembly is linked to the pathogenesis of Alzheimer's disease (AD) and type 2 diabetes (T2D), but so far, no anti-amyloid compound has reached the clinic. Macrocyclic peptides belong to the most attractive drug candidates. Herein we present macrocyclic peptides (MCIPs) designed using minimal IAPP-derived recognition elements as a novel class of nanomolar amyloid inhibitors of both Aß40(42) and IAPP or Aß40(42) alone and show that chirality controls inhibitor selectivity. Sequence optimization led to the discovery of an Aß40(42)-selective MCIP exhibiting high proteolytic stability in human plasma and human blood-brain barrier (BBB) crossing ability in a cell model, two highly desirable properties for anti-amyloid AD drugs. Owing to their favorable properties, MCIPs should serve as leads for macrocyclic peptide-based anti-amyloid drugs and scaffolds for the design of small-molecule peptidomimetics for targeting amyloidogenesis in AD or in both AD and T2D.

Association between green tea intake and risk of gastric cancer: a systematic review and dose-response meta-analysis of observational studies.

OBJECTIVE: To examine and quantify the potential dose-response relationship between green tea intake and the risk of gastric cancer. DESIGN: We searched PubMed, EMBASE, Web of Science, CBM, CNKI and VIP up to December 2015 without language restrictions. SETTING: A systematic review and dose-response meta-analysis of observational studies. SUBJECTS: Five cohort studies and eight case-control studies. RESULTS: Compared with the lowest level of green tea intake, the pooled relative risk (95 % CI) of gastric cancer was 1·05 (0·90, 1·21, I 2=20·3 %) for the cohort studies and the pooled OR (95 % CI) was 0·84 (0·74, 0·95, I 2=48·3 %) for the case-control studies. The pooled relative risk of gastric cancer was 0·79 (0·63, 0·97, I 2=63·8 %) for intake of 6 cups green tea/d, 0·59 (0·42, 0·82, I 2=1·0 %) for 25 years of green tea intake and 7·60 (1·67, 34·60, I 2=86·5 %) for drinking very hot green tea. CONCLUSIONS: Drinking green tea has a certain preventive effect on reducing the risk of gastric cancer, particularly for long-term and high-dose consumption. Drinking too high-temperature green tea may increase the risk of gastric cancer, but it is still unclear whether high-temperature green tea is a risk factor for gastric cancer. Further studies should be performed to obtain more detailed results, including other gastric cancer risk factors such as smoking and alcohol consumption and the dose of the effective components in green tea, to provide more reliable evidence-based medical references for the relationship between green tea and gastric cancer.

Pathogenic roles of macrophage migration inhibitory factor during dengue virus infection.

Dengue virus (DENV) infection is the most common cause of viral hemorrhagic fever, which can lead to life-threatening dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). Hemorrhage and plasma leakage are two major hallmarks of DHF/DSS. Because the mechanisms causing these pathogenic changes are unclear, there is no effective therapy against DHF/DSS. In this review, we focus on the possible pathogenic effects of a pleiotropic cytokine, macrophage migration inhibitory factor (MIF), on the pathogenesis of DENV infection. MIF is a critical mediator of the host immune response and inflammation, and there is a correlation between the serum levels of MIF and disease severity in dengue patients. Furthermore, MIF knock-out mice exhibit less severe clinical disease and lethality. However, the role of MIF in the pathogenesis of DHF/DSS is not limited to immune cell recruitment. Recent evidence indicates that DENV infection induced MIF production and may contribute to vascular hyperpermeability and viral replication during DENV infection. The expression of both adhesion and coagulation molecules on MIF-stimulated monocytes and endothelial cells is also increased, which may contribute to inflammatory and anticoagulatory states during DHF/DSS. Therefore, blocking MIF production or its function may provide a solution for the treatment and prevention of DHF/DSS.

Effects of high pressure processing on structural changes, aggregation, and binding mechanisms of ß-Lactoglobulin with typical polyphenols.

The binding capacity of ß-Lactoglobulin (BLG) is crucial for delivering polyphenols, influenced by structural changes. High pressure processing (HPP) has the potential to modify BLG's structure and aggregation, but its specific impact on BLG-polyphenol interactions is uncertain. This study used circular dichroism spectroscopy and molecular dynamics simulations to reveal HPP-induced structural changes in BLG, supported by particle size analysis indicating aggregation. Seven structurally diverse polyphenols (quercetin-QR, hesperetin-HSP, dihydromyricetin-DHM, gallic acid-GA, (-)-epicatechin-EC, resveratrol-RES, and secoisolariciresinol diglucoside-SDG) were investigated to comprehensively analyze their binding patterns using fluorescence spectroscopy and molecular docking. HPP reduced BLG's ordered structure and increased its aggregation. Binding affinities peaked at 400 MPa for DHM, QR, HSP, GA, and RES, while SDG and EC exhibited maximum affinities at atmospheric pressure and 600 MPa, respectively. Elevated pressures enhanced BLG-polyphenol interactions, particularly at residues 44GLU and 160CYS, with van der Waals forces dominating the binding free energy.

Role of protein Post-translational modifications in enterovirus infection.

Enteroviruses (EVs) are the main cause of a number of neurological diseases. Growing evidence has revealed that successful infection with enteroviruses is highly dependent on the host machinery, therefore, host proteins play a pivotal role in viral infections. Both host and viral proteins can undergo post-translational modification (PTM) which can regulate protein activity, stability, solubility and interactions with other proteins; thereby influencing various biological processes, including cell metabolism, metabolic, signaling pathways, cell death, and cancer development. During viral infection, both host and viral proteins regulate the viral life cycle through various PTMs and different mechanisms, including the regulation of host cell entry, viral protein synthesis, genome replication, and the antiviral immune response. Therefore, protein PTMs play important roles in EV infections. Here, we review the role of various host- and virus-associated PTMs during enterovirus infection.

Predicting Regional Recurrence and Prognosis in Stereotactic Body Radiation Therapy-Treated Clinical Stage I Non-small Cell Lung Cancer Using a Radiomics Model Constructed With Surgical Data.

PURPOSE: Risk stratification of regional recurrence (RR) is clinically important in the design of adjuvant treatment and surveillance strategies in patients with clinical stage I non-small cell lung cancer (NSCLC) treated with stereotactic body radiation therapy (SBRT). This study aimed to develop a radiomics model predicting occult lymph node metastasis (OLNM) using surgical data and apply it to the prediction of RR in SBRT-treated early-stage NSCLC patients. METHODS AND MATERIALS: Patients with clinical stage I NSCLC who underwent curative surgery with systematic lymph node dissection from January 2013 to December 2018 (the training cohort) and from January 2019 to December 2020 (the validation cohort) were included. A preoperative computed tomography-based radiomics model, a clinical feature model, and a fusion model predicting OLNM were constructed. The performance of the 3 models was quantified and compared in the training and validation cohorts. Subsequently, the radiomics model was used to predict RR in a cohort of consecutive SBRT-treated early-stage NSCLC patients from 2 academic medical centers. RESULTS: A total of 769 patients were included. Eight computed tomography features were identified in the radiomics model, achieving areas under the curves of 0.85 (95% CI, 0.81-0.89) and 0.83 (95% CI, 0.80-0.88) in the training and validation cohorts, respectively. Nevertheless, adding clinical features did not improve the performance of the radiomics model. With a median follow-up of 40.0 (95% CI, 35.2-44.8) months, 32 of the 213 patients in the SBRT cohort developed RR and those in the high-risk group based on the radiomics model had a higher cumulative incidence of RR (P < .001) and shorter regional recurrence-free survival (P = .02), progression-free survival (P = .004) and overall survival (P = .006) than those in the low-risk group. CONCLUSIONS: The radiomics model based on pathologically confirmed data effectively identified patients with OLNM, which may be useful in the risk stratification among SBRT-treated patients with clinical stage I NSCLC.

Receptor transfer between immune cells by autoantibody-enhanced, CD32-driven trogocytosis is hijacked by HIV-1 to infect resting CD4 T cells.

Immune cell phenotyping frequently detects lineage-unrelated receptors. Here, we report that surface receptors can be transferred from primary macrophages to CD4 T cells and identify the Fcγ receptor CD32 as driver and cargo of this trogocytotic transfer. Filamentous CD32+ nanoprotrusions deposit distinct plasma membrane patches onto target T cells. Transferred receptors confer cell migration and adhesion properties, and macrophage-derived membrane patches render resting CD4 T cells susceptible to infection by serving as hotspots for HIV-1 binding. Antibodies that recognize T cell epitopes enhance CD32-mediated trogocytosis. Such autoreactive anti-HIV-1 envelope antibodies can be found in the blood of HIV-1 patients and, consistently, the percentage of CD32+ CD4 T cells is increased in their blood. This CD32-mediated, antigen-independent cell communication mode transiently expands the receptor repertoire and functionality of immune cells. HIV-1 hijacks this mechanism by triggering the generation of trogocytosis-promoting autoantibodies to gain access to immune cells critical to its persistence.