ABSTRACT
Previous studies in small samples have identified inconsistent cortical abnormalities in major depressive disorder (MDD). Despite genetic influences on MDD and the brain, it is unclear how genetic risk for MDD is translated into spatially patterned cortical vulnerability. Here, we initially examined voxel-wise differences in cortical function and structure using the largest multi-modal MRI data from 1660 MDD patients and 1341 controls. Combined with the Allen Human Brain Atlas, we then adopted transcription-neuroimaging spatial correlation and the newly developed ensemble-based gene category enrichment analysis to identify gene categories with expression related to cortical changes in MDD. Results showed that patients had relatively circumscribed impairments in local functional properties and broadly distributed disruptions in global functional connectivity, consistently characterized by hyper-function in associative areas and hypo-function in primary regions. Moreover, the local functional alterations were correlated with genes enriched for biological functions related to MDD in general (e.g., endoplasmic reticulum stress, mitogen-activated protein kinase, histone acetylation, and DNA methylation); and the global functional connectivity changes were associated with not only MDD-general, but also brain-relevant genes (e.g., neuron, synapse, axon, glial cell, and neurotransmitters). Our findings may provide important insights into the transcriptomic signatures of regional cortical vulnerability to MDD.
Subject(s)
Depressive Disorder, Major , Transcriptome , Humans , Depressive Disorder, Major/genetics , Depressive Disorder, Major/physiopathology , Female , Male , Adult , Cerebral Cortex/physiopathology , Cerebral Cortex/diagnostic imaging , Cerebral Cortex/metabolism , Middle Aged , Magnetic Resonance Imaging , Gene Expression ProfilingABSTRACT
OBJECTIVES: The performance of the new Respiratory Pathogen panel (fluorescent probe melting curve, FPMC) for the qualitative detection of 12 organisms (chlamydia pneumoniae, mycoplasma pneumoniae, adenovirus, influenza A virus, influenza B virus, parainfluenza virus, rhinovirus, etc.) was assessed. METHODS: Prospectively collected nasopharyngeal swab (NPS) and sputum specimens (n = 635) were detected by using the FPMC panel, with the Sanger sequencing method as the comparative method. RESULTS: The overall percent concordance between the FPMC analysis method and the Sanger sequencing method was 100% and 99.66% for NPS and sputum specimens, respectively. The FPMC testified an overall positive percent concordance of 100% for both NPS and sputum specimens. The FPMC analysis method also testified an overall negative percent concordance of 100% and 99.38% for NPS and sputum specimens, respectively. CONCLUSIONS: The FPMC analysis method is a stable and accurate assay for rapid, comprehensive detecting for respiratory pathogens.
Subject(s)
Molecular Diagnostic Techniques , Nasopharynx , Respiratory Tract Infections , Sputum , Humans , Sputum/microbiology , Sputum/virology , Nasopharynx/virology , Nasopharynx/microbiology , Respiratory Tract Infections/virology , Respiratory Tract Infections/diagnosis , Respiratory Tract Infections/microbiology , Molecular Diagnostic Techniques/methods , Viruses/isolation & purification , Viruses/genetics , Viruses/classification , Adult , Prospective Studies , Middle Aged , Adolescent , Female , Young Adult , Child , Male , Aged , Child, Preschool , Infant , Specimen Handling/methods , Sensitivity and Specificity , Aged, 80 and overABSTRACT
In industrial process monitoring, it is always a challenging and practical problem to analyze the causes of the system fault by isolating true fault variables from vast amounts of process data. However, the phenomenon of smearing effect occurs by using the traditional contribution analysis-based isolation methods since the defined isolation indices of different variables affect each other. In this paper, a new fault isolation method is proposed based on local outlier factor and improved k-nearest neighbor rule aiming to improve the isolation accuracy. Firstly, the nearest neighbors of each sample are obtained along the direction of a specific variable. Based on the nearest neighbors, the outlier-degree value of the variable is calculated and regarded as the contribution of the variable. Then, the contribution of the variable in all samples are obtained in the same way, among which the maximum one is selected as the isolation threshold value of this variable. During the online monitoring, the contribution of the variable in the newly collected sample is calculated in real time. Once the contribution is greater than the threshold, the variable is judged to be the dominant factor causing the system fault. Two cases on numerical example and Tennessee Eastman process are conducted to evaluate the effectiveness of the proposed method.
ABSTRACT
Clinical evidence indicates a close association between muscle dysfunction and bone loss; however, the underlying mechanisms remain unclear. Here, we report that muscle dysfunction-related bone loss in humans with limb-girdle muscular dystrophy is associated with decreased expression of folliculin-interacting protein 1 (FNIP1) in muscle tissue. Supporting this finding, murine gain- and loss-of-function genetic models demonstrated that muscle-specific ablation of FNIP1 caused decreased bone mass, increased osteoclastic activity, and mechanical impairment that could be rescued by myofiber-specific expression of FNIP1. Myofiber-specific FNIP1 deficiency stimulated expression of nuclear translocation of transcription factor EB, thereby activating transcription of insulin-like growth factor 2 (Igf2) at a conserved promoter-binding site and subsequent IGF2 secretion. Muscle-derived IGF2 stimulated osteoclastogenesis through IGF2 receptor signaling. AAV9-mediated overexpression of IGF2 was sufficient to decrease bone volume and impair bone mechanical properties in mice. Further, we found that serum IGF2 concentration was negatively correlated with bone health in humans in the context of osteoporosis. Our findings elucidate a muscle-bone cross-talk mechanism bridging the gap between muscle dysfunction and bone loss. This cross-talk represents a potential target to treat musculoskeletal diseases and osteoporosis.
Subject(s)
Bone and Bones , Insulin-Like Growth Factor II , Animals , Female , Humans , Male , Mice , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism , Bone and Bones/metabolism , Insulin-Like Growth Factor II/metabolism , Muscle, Skeletal/metabolism , Muscles/metabolism , Osteoclasts/metabolism , Osteogenesis , Signal TransductionABSTRACT
Obtaining information about cellular interactions is fundamental to the elucidation of physiological and pathological processes. Proximity labeling technologies have been widely used to report cellular interactions in situ; however, the reliance on addition of tag molecules typically restricts their application to regions where tags can readily diffuse, while the application in, for example, solid tissues, is susceptible. Here, we propose an "in-situ-tag-generation mechanism" and develop the GalTag technology based on galactose oxidase (GAO) for recording cellular interactions within three-dimensional biological solid regions. GAO mounted on bait cells can in situ generate bio-orthogonal aldehyde tags as interaction reporters on prey cells. Using GalTag, we monitored the dynamics of cellular interactions and assessed the targeting ability of engineered cells. In particular, we recorded, for the first time, the footprints of Bacillus Calmette-Guérin (BCG) invasion into the bladder tissue of living mice, providing a valuable perspective to elucidate the anti-tumor mechanism of BCG.
Subject(s)
Galactose Oxidase , Animals , Mice , Galactose Oxidase/metabolism , Galactose Oxidase/chemistry , Humans , Cell CommunicationABSTRACT
BACKGROUND: There are various therapeutic methods for treating stage IA (T1N0M0) non-small cell lung cancer (NSCLC), but no studies have systematically assessed multiple treatments to determine the most effective therapy. METHODS: Stage IA NSCLC patient data collected between 2004 and 2018 were gathered from the Surveillance, Epidemiology, and End Results (SEER) database. Treatment modalities included observation, chemotherapy alone (CA), radiation alone (RA), radiation+chemotherapy (RC), surgery alone (SA), surgery+chemotherapy (SC), surgery+radiation (SR) and surgery+radiation+chemotherapy (SRC). Comparisons were made of overall survival (OS) and lung cancer-specific survival (LCSS) among patients based on different therapeutic methods by survival analysis. RESULTS: Ultimately, 89147 patients with stage IA NSCLC between 2004 and 2018 were enrolled in this study. The order of multiple treatment modalities based on the hazard ratio (HR) for OS for the entire cohort revealed the following results: SA (HR: 0.20), SC (HR: 0.25), SR (HR: 0.42), SRC (HR: 0.46), RA (HR: 0.56), RC (HR: 0.72), CA (HR: 0.91) (P<0.001), and observation (HR: Ref). The SA group had the best OS and LCSS, and similar results were found in most subgroup analyses (all P<0.001). The order of surgical modalities based on the HR for OS for the entire cohort revealed the following results: lobectomy (HR: 0.32), segmentectomy (HR: 0.41), wedge resection (HR: 0.52) and local tumor destruction (HR: Ref). Lobectomy had the best effects on OS and LCSS, and similar results were found in all subgroup analyses (all P<0.001). CONCLUSION: SA appeared to be the optimal treatment modality for patients with stage IA NSCLC, and lobectomy was associated with the best prognosis. There may be some indication and selection bias in our study, and the results of this study should be confirmed in a prospective study.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Neoplasm Staging , SEER Program , Humans , Carcinoma, Non-Small-Cell Lung/therapy , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Non-Small-Cell Lung/mortality , Lung Neoplasms/therapy , Lung Neoplasms/pathology , Lung Neoplasms/mortality , Female , Male , Aged , Middle Aged , Combined Modality Therapy , Adult , Aged, 80 and over , Survival AnalysisABSTRACT
Background: Epidemiological evidence has confirmed that periodontitis is an essential and independent risk factor of chronic obstructive pulmonary disease (COPD). Porphyromonas gingivalis, a major pathogen implicated in periodontitis, may make a vital contribution to COPD progression. However, the specific effects and molecular mechanism of the link between P. gingivalis and COPD are not clear. Methods and Results: A COPD rat model was constructed by smoke exposure combined intratracheal instillation of E. coli-LPS, then P. gingivalis was introduced into the oral cavity of COPD rats. This research observed that lower lung function, more severe alveolar damage and inflammation occurred in COPD rats with P. gingivalis group. Meanwhile, P. gingivalis/gingipains could colonize the lung tissues and be enriched in bronchoalveolar lavage fluid (BALF) of COPD rats with P. gingivalis group, along with alterations in lung microbiota. Proteomic analysis suggested that Hsp90α/MLKL-meditated necroptosis pathway was up-regulated in P. gingivalis-induced COPD aggravation, the detection of Hsp90α and MLKL in serum and lung tissue verified that Hsp90α/MLKL was up-regulated. Conclusion: These results indicate that P. gingivalis could emigrate into the lungs, alter lung microbiota and lead to aggravation of COPD, which Hsp90α/MLKL might participate in.
ABSTRACT
OBJECTIVES: This study aims to explore the incidence of, and risk factors for medical adhesive-related skin injury (MARSI) at peripherally inserted central venous catheter (PICC) sites in patients with cancer. DESIGN: A prospective observational cohort study was conducted at a tertiary hospital in Shenzhen, China. SETTING: This was a single-centre study conducted in a tertiary hospital in Shenzhen, China. PARTICIPANTS: A total of 340 patients with cancer and PICC placement from January 2022 to June 2023 were selected using a convenience sampling method. METHODS: Factors potentially associated with PICC-related MARSI (PICC-MARSI) were recorded, including patient demographics, and catheter placement and maintenance. Patients were divided into MARSI and non-MARSI groups. Univariate analysis was performed to screen for associated variables, and logistic regression analysis was used to identify independent risk factors for PICC-MARSI. RESULTS: Of all 340 patients enrolled, 33 (9.7%) developed PICC-MARSI, including skin tear (8, 24.2%), tension injury (5, 15.2%), irritant contact dermatitis (10, 30.3%), allergic dermatitis (7, 21.2%) and maceration (3, 9.1%). Multivariable analysis showed that age (OR=1.058, p=0.001, 95% CI 1.023-1.094), wet skin (OR=4.873, p=0.003, 95% CI 1.728-13.742), dry skin (OR=6.247, p<0.0001, 95% CI 2.239-17.431), oedema (OR=3.302, p=0.008, 95% CI 1.365-7.985), allergy history (OR=6.044, p=0.001, 95% CI 2.040-17.906), dressing type (OR=3.827, p=0.003, 95% CI 1.595-9.185), body mass index (BMI) <18.5 (OR=4.271, p=0.015, 95% CI 1.327-13.742) and BMI 25-30 (OR=2.946, p=0.027, 95% CI 1.131-7.678) were independent risk factors for PICC-MARSI. CONCLUSIONS: Proper catheter maintenance and appropriate dressing selection are crucial for the prevention of this condition.
Subject(s)
Central Venous Catheters , Deafness , Lacerations , Neoplasms , Humans , Prospective Studies , Central Venous Catheters/adverse effects , China/epidemiologyABSTRACT
BACKGROUND: Methods for predicting the outcome of lung adenocarcinoma (LUAD) in the clinic are limited. Anoikis is an important route to programmed cell death in LUAD, and the prognostic value of a model constructed with anoikis-related lncRNAs (ARlncRNAs) in LUAD is unclear. METHODS: Transcriptome and basic information for LUAD patients was obtained from the Cancer Genome Atlas. Coexpression and Cox regression analyses were utilized to identify prognostically significant ARlncRNAs and construct a prognostic signature. Furthermore, the signature was combined with clinical characteristics to create a nomogram. Finally, we performed principal component, enrichment, tumor mutation burden (TMB), tumor microenvironment (TME) and drug sensitivity analyses to evaluate the basic research and clinical merit of the signature. RESULTS: The prognostic signature developed with eleven ARlncRNAs can accurately predict that high-risk group patients have a worse prognosis, as proven by the receiver operating characteristic (ROC) curve (AUC: 0.718). Independent prognostic analyses indicated that the risk score is a significant independent prognostic element for LUAD (P<0.001). In the high-risk group, enrichment analysis demonstrated that glucose metabolism and DNA replication were the main enrichment pathways. TMB analysis indicated that the high-risk group had a high TMB (P<0.05). Drug sensitivity analyses can recognize drugs that are sensitive to different risk groups. Finally, 11 ARlncRNAs of this signature were verified by RT-qPCR analysis. CONCLUSIONS: A novel prognostic signature developed with 11 ARlncRNAs can accurately predict the OS of LUAD patients and offer clinical guidance value for immunotherapy and chemotherapy treatment.
Subject(s)
Adenocarcinoma , Lung Neoplasms , RNA, Long Noncoding , Humans , Anoikis/genetics , Prognosis , RNA, Long Noncoding/genetics , Lung , Lung Neoplasms/genetics , Tumor Microenvironment/geneticsABSTRACT
Stress and illness connection is complex and involves multiple physiological systems. Panax ginsengs, reputed for their broad-spectrum "cure-all" effect, are widely prescribed to treat stress and related illnesses. However, the identity of ginseng's "cure-all" medicinal compounds that relieve stress remains unresolved. Here, we identify ginsentides as the principal bioactives that coordinate multiple systems to restore homeostasis in response to stress. Ginsentides are disulfide-rich, cell-penetrating and proteolytic-stable microproteins. Using affinity-enrichment mass spectrometry target identification together with in vitro, ex vivo and in vivo validations, we show that highly purified or synthetic ginsentides promote vasorelaxation by producing nitric oxide through endothelial cells via intracellular PI3K/Akt signaling pathway, alleviate α1-adrenergic receptor overactivity by reversing phenylephrine-induced constriction of aorta, decrease monocyte adhesion to endothelial cells via CD166/ESAM/CD40 and inhibit P2Y12 receptors to reduce platelet aggregation. Orally administered ginsentides were effective in animal models to reduce ADP-induced platelet aggregation, to prevent collagen and adrenaline-induced pulmonary thrombosis as well as anti-stress behavior of tail suspension and forced swimming tests in mice. Together, these results strongly suggest that ginsentides are the principal panacea compounds of ginsengs because of their ability to target multiple extra- and intra-cellular proteins to reverse stress-induced damages.
ABSTRACT
In lobectomy of patients with lung cancer, the principle of operation is to cut off the pulmonary vein first, but it is often not taken seriously in clinical practice. We conducted this research to compare the impact of different sequences of pulmonary vessel ligation on the long-term survival of patients. This cohort study included 1239 patients treated surgically with video-assisted thoracoscopic lobectomy from January 2015 to December 2019 at The Second Affiliated Hospital of Nanchang University. Survival and perioperative indicators were compared between a Vein-first group (VF) and an artery-first group. After matching, 364 patients were included in each group for analysis. VF was associated with better overall survival (hazard ratio: 1.96 [1.4~2.74], P < .0001) and disease-free survival (hazard ratio: 1.65 [1.22~2.24], P = .0011). Meanwhile, the survival advantage of VF was achieved in almost all subgroups, particularly in the pathological tumor node metastasis stage I-II group and squamous cell carcinoma group. We obtained no significant differences in perioperative indications (operation time, hospital stay, etc) between VF and artery-first group. With better overall survival and disease-free survival, especially for pathological stage I-II squamous cell carcinoma, vein-first ligation should be strictly observed in lobectomy for patients with non-small cell lung cancer.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Carcinoma, Squamous Cell , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/pathology , Lung Neoplasms/pathology , Cohort Studies , Thoracic Surgery, Video-Assisted/adverse effects , Pneumonectomy/adverse effects , Carcinoma, Squamous Cell/surgery , Retrospective StudiesABSTRACT
Rumination is closely linked to the onset and maintenance of major depressive disorder (MDD). Prior neuroimaging studies have identified the association between self-reported rumination trait and the functional coupling among a network of brain regions using resting-state functional magnetic resonance imaging (MRI). However, little is known about the underlying neural circuitry mechanism during active rumination in MDD. Degree centrality (DC) is a simple metric to denote network integration, which is critical for higher-order psychological processes such as rumination. During an MRI scan, individuals with MDD (N = 45) and healthy controls (HC, N = 46) completed a rumination state task. We examined the interaction effect between the group (MDD vs. HC) and condition (rumination vs. distraction) on vertex-wise DC. We further characterized the identified brain region's functional involvement with Neurosynth and BrainMap. Network-wise seed-based functional connectivity (FC) analysis was also conducted for the identified region of interest. Finally, exploratory correlation analysis was conducted between the identified region of interest's network FCs and self-reported in-scanner affect levels. We found that a left superior frontal gyrus (SFG) region, generally overlapped with the frontal eye field, showed a significant interaction effect. Further analysis revealed its involvement with executive functions. FCs between this region, the frontoparietal, and the dorsal attention network (DAN) also showed significant interaction effects. Furthermore, its FC to DAN during distraction showed a marginally significant negative association with in-scanner affect level at the baseline. Our results implicated an essential role of the left SFG in the rumination's underlying neural circuitry mechanism in MDD and provided novel evidence for the conceptualization of rumination in terms of impaired executive control.
Subject(s)
Depressive Disorder, Major , Humans , Brain/diagnostic imaging , Prefrontal Cortex , Executive Function , Frontal Lobe , Magnetic Resonance Imaging , Brain MappingABSTRACT
BACKGROUND: Precisely forecasting the prognosis of esophageal squamous cell carcinoma (ESCC) patients is a formidable challenge. Cuproptosis has been implicated in ESCC pathogenesis; however, the prognostic value of cuproptosis-associated long noncoding RNAs (CuRLs) in ESCC is unclear. METHODS: Transcriptomic and clinical data related to ESCC were sourced from The Cancer Genome Atlas (TCGA). Using coexpression and Cox regression analysis to identify prognostically significant CuRLs, a prognostic signature was created. Nomogram models were established by incorporating the risk score and clinical characteristics. Tumor Immune Dysfunction and Rejection (TIDE) scores were derived by conducting an immune landscape analysis and evaluating the tumor mutational burden (TMB). Drug sensitivity analysis was performed to explore the underlying molecular mechanisms and guide clinical dosing. RESULTS: Our risk score based on 5 CuRLs accurately predicted poorer prognosis in high-risk ESCC patients across almost all subgroups. The nomogram that included the risk score provided more precise prognostic predictions. Immune pathways, such as the B-cell receptor signaling pathway, were enriched in the datasets from high-risk patients. High TMB in high-risk patients indicated a relatively poor prognosis. High-risk patients with lower TIDE scores were found to benefit more from immunotherapy. High-risk patients exhibited greater responsiveness to Nilotinib, BI-2536, P22077, Zoledronate, and Fulvestrant, as revealed by drug sensitivity analysis. Real-time PCR validation demonstrated significant differential expression of four CuRLs between ESCC and normal cell lines. CONCLUSIONS: The above risk score and nomogram can accurately predict prognosis in ESCC patients and provide guidance for chemotherapy and immunotherapy.
Subject(s)
Esophageal Neoplasms , Esophageal Squamous Cell Carcinoma , RNA, Long Noncoding , Humans , Prognosis , Esophageal Squamous Cell Carcinoma/genetics , RNA, Long Noncoding/genetics , Esophageal Neoplasms/genetics , Nomograms , ApoptosisABSTRACT
A growing number of studies have found that the lymph node ratio (LNR) is an important indicator of prognosis in non-small-cell lung cancer (NSCLC). Impact analysis for LNR was performed for survival in patients undergoing surgery for stage III NSCLC compared to the surveillance, epidemiology and end results databank. Clinicopathological variables, such as cancer-specific survival (CSS), were taken from the surveillance epidemiology and end result databank of stage III NSCLC patients who underwent surgery, and the LNR threshold stratification of NSCLC patients was computed by X-tile. CSS was assessed by the Kaplan-Meier method with CSS-independent risk factors calculated by multivariate Cox regression analysis. In total, 7011 lung cancer patients were included. Multifactorial analysis showed that LNR and positive node category had predictive value for stage III NSCLC. In patients with stage IIIA NSCLC, Kaplan-Meier analysis demonstrated that patients with T1-2N2 stage had clearly superior CSS than those with T3-4N1 stage (Pâ <â .001), which conflicted with the results from the assessment of primary tumor, lymph nodes, and metastasis/N stage. The cutoff values for LNR were 0.31 and 0.59. Kaplan-Meier analysis demonstrated that the CSS was substantially better in patients with LNR-low than in those with LNR-medium or LNR-high (Pâ <â .001), which was also proven by multivariate competing risk regression. Subgroup analysis suggested that the survival advantage of a lower LNR was achieved in all subgroups (sex, race, etc). In stage III NSCLC, the LNR is a valuable factor for assessing prognosis, in which a higher LNR indicates a worse prognosis.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/pathology , Prognosis , Lung Neoplasms/pathology , Lymph Node Ratio , Retrospective Studies , Neoplasm Staging , Lymphatic Metastasis/pathology , Lymph Nodes/pathologyABSTRACT
The present study aimed to investigate clinical phenotype and genotype characteristics of a male child with SATB2-associated syndrome (SAS) and analyzed the relationship between these characteristics and the possible underlying genetic mechanism. His clinical phenotype was analyzed. Using a high-throughput sequencing platform, his DNA samples were subjected to medical exome sequencing, screened for suspected variant loci and analyzed for chromosomal copy number variations. The suspected pathogenic loci were verified by Sanger sequencing. He presented with phenotypic anomalies of delayed growth, delayed speech and mental development, facial dysmorphism showing the typical manifestation of SAS and motor retardation symptoms. Gene sequencing result analyses revealed a de novo heterozygous repeat insertion shift mutation in the SATB2 gene (NM_015265.3) c.771dupT (p.Met258Tyrfs*46), resulting in a frameshift mutation from methionine to tyrosine at the amino acid site 258 and a truncated protein with 46 amino acids missing. The parents showed no mutation at this locus. This mutation was identified as the nosogenesis of this syndrome in children. To the best of the authors' knowledge, this is the first report on this mutation. The clinical manifestations and gene variation characteristics of 39 previously reported SAS cases were analyzed together with this case. The findings of the present study suggested severely impaired language development, facial dysmorphism and varying degrees of delayed intellectual development as the characteristic clinical manifestations of SAS.
ABSTRACT
How do personal networks evolve as individuals age? To what degree do social disadvantage and contextual factors matter for network dynamics in later life? This paper answers these two questions based on egocentric network data of older adults over a ten-year period. Specifically, I use longitudinal and nationally representative data on 1,168 older adults from the National Social Life, Health, and Aging Project. I use between-within models to separate the within- and between-individual effects of sociodemographic characteristics and contextual factors on three aspects of social connectedness in later life: network size, frequency of contact, and proportion of kin. Patterns of network change vary among people of different races and ethnicities as well as educational levels. Black and Hispanic respondents have a significantly smaller network size and a higher average frequency of contact with confidants. Moreover, Hispanic respondents have a higher proportion of kin in the network, compared to White respondents. Similarly, older adults with less education have a smaller network size, higher frequency of contact and higher proportion of kin in their confidant networks compared to those who attended college. Older adults who have better mental health are more likely to have a higher frequency of contact and higher proportion of kin. When an older adult starts to work for pay, their frequency of contact with confidants tends to increase. Older adults living in neighborhoods with stronger social ties are more likely to have a larger network size, higher frequency of contact, and lower proportion of kin in their confidant network. The above results show that disadvantaged backgrounds and contextual factors are associated with certain less favorable network characteristics, which helps to explain the concentration of social disadvantage on certain populations.
ABSTRACT
Hot tearing is the most common and serious casting defect that restricts the light weight and integration of magnesium alloy components. In the present study, trace Ca (0-1.0 wt.%) was added to improve the resistance of AZ91 alloy to hot tearing. The hot tearing susceptivity (HTS) of alloys was experimentally measured by a constraint rod casting method. The results indicate that the HTS presents a ν-shaped tendency with the increase in Ca content, and reaches its minimum value in AZ91-0.1Ca alloy. Ca is well dissolved into α-Mg matrix and Mg17Al12 phase at an addition not exceeding 0.1 wt.%. The solid-solution behavior of Ca increases eutectic content and its corresponding liquid film thickness, improves the strength of dendrites at high temperature, and thereby promotes the hot tearing resistance of the alloy. Al2Ca phases appear and aggregate at dendrite boundaries with further increases in Ca above 0.1 wt.%. The coarsened Al2Ca phase hinders the feeding channel and causes stress concentration during the solidification shrinkage, thereby deteriorating the hot tearing resistance of the alloy. These findings were further verified by fracture morphology observations and microscopic strain analysis near the fracture surface based on kernel average misorientation (KAM).
ABSTRACT
The frequent mutation of KRAS oncogene in some of the most lethal human cancers has spurred incredible efforts to develop KRAS inhibitors, yet only one covalent inhibitor for the KRASG12C mutant has been approved to date. New venues to interfere with KRAS signaling are desperately needed. Here, we report a "localized oxidation-coupling" strategy to achieve protein-specific glycan editing on living cells for disrupting KRAS signaling. This glycan remodeling method exhibits excellent protein and sugar specificity and is applicable to different donor sugars and cell types. Attachment of mannotriose to the terminal galactose/N-acetyl-D-galactosamine epitopes of integrin αv ß3 , a membrane receptor upstream of KRAS, blocks its binding to galectin-3, suppresses the activation of KRAS and downstream effectors, and mitigates KRAS-driven malignant phenotypes. Our work represents the first successful attempt to interfere with KRAS activity by manipulating membrane receptor glycosylation.
Subject(s)
Lung Neoplasms , Proto-Oncogene Proteins p21(ras) , Humans , Lung Neoplasms/pathology , Mutation , Polysaccharides , Proto-Oncogene Proteins p21(ras)/genetics , Signal TransductionABSTRACT
Multidrug-resistant bacteria caused by the unlimited overuse of antibiotics pose a great challenge to global health. An antibacterial method based on reactive oxygen species (ROS) is one of the effective strategies without inducing bacterial resistance. Owing to the ability of generating ROS, piezocatalytic material-mediated sonodynamic therapy (SDT) has drawn much attention. However, its major challenge is the low ROS generation efficiency in the piezocatalytic process due to the poor charge carrier concentration of piezoelectric materials. Vacancy engineering can regulate the charge density and largely promote ROS generation under ultrasound (US) irradiation. Herein, a US-responsive self-doped barium titanate with controlled oxygen vacancy (Vo) concentrations was successfully synthesized through a facile thermal reduction treatment at different temperatures (i.e., 350, 400, and 450 °C), and the corresponding samples were named as BTO-350, BTO-400, and BTO-450, respectively. Then, the effect of Vo concentrations on ROS generation efficiency during the piezocatalytic process was systematically studied. And BTO-400 was found to possess the highest piezocatalytic activity and excellent sonodynamic antibacterial performance against Escherichia coli and Staphylococcus aureus. Furthermore, its antibacterial mechanism was confirmed that the ROS generated under US could damage bacterial cell membrane and cause considerable leakage of cytoplasmic components and irreversible death of bacteria. Notably, the in vivo results illustrated that the BTO-400 could serve as an effective antibacterial agent and accelerate skin healing via SDT therapy. In all, the Vo defect-modified nano-BaTiO3 has a noticeable potential to induce a rapid and efficient sterilization as well as skin tissue repair by SDT.
Subject(s)
Staphylococcal Infections , Ultrasonic Therapy , Humans , Reactive Oxygen Species/metabolism , Ultrasonic Therapy/methods , Sterilization , Anti-Bacterial Agents/pharmacology , Cell Line, TumorABSTRACT
The tumor microenvironment (TME) has been extensively investigated; however, it is complex and remains unclear, especially in elderly patients. Senescence is a cellular response to a variety of stress signals, which is characterized by stable arrest of the cell cycle and major changes in cell morphology and physiology. To the best of our knowledge, senescence leads to consistent arrest of tumor cells and remodeling of the tumor-immune microenvironment (TIME) by activating a set of pleiotropic cytokines, chemokines, growth factors, and proteinases, which constitute the senescence-associated secretory phenotype (SASP). On the one hand, the SASP promotes antitumor immunity, which enhances treatment efficacy; on the other hand, the SASP increases immunosuppressive cell infiltration, including myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), M2 macrophages, and N2 neutrophils, contributing to TIME suppression. Therefore, a deeper understanding of the regulation of the SASP and components contributing to robust antitumor immunity in elderly individuals with different cancer types and the available therapies is necessary to control tumor cell senescence and provide greater clinical benefits to patients. In this review, we summarize the key biological functions mediated by cytokines and intercellular interactions and significant components of the TME landscape, which influence the immunotherapy response in geriatric oncology. Furthermore, we summarize recent advances in clinical practices targeting TME components and discuss potential senescent TME targets.