Single-cell analyses reveal evolution mimicry during the specification of breast cancer subtype.

Background: The stem or progenitor antecedents confer developmental plasticity and unique cell identities to cancer cells via genetic and epigenetic programs. A comprehensive characterization and mapping of the cell-of-origin of breast cancer using novel technologies to unveil novel subtype-specific therapeutic targets is still absent. Methods: We integrated 195,144 high-quality cells from normal breast tissues and 406,501 high-quality cells from primary breast cancer samples to create a large-scale single-cell atlas of human normal and cancerous breasts. Potential heterogeneous origin of malignant cells was explored by contrasting cancer cells against reference normal epithelial cells. Multi-omics analyses and both in vitro and in vivo experiments were performed to screen and validate potential subtype-specific treatment targets. Novel biomarkers of identified immune and stromal cell subpopulations were validated by immunohistochemistry in our cohort. Results: Tumor stratification based on cancer cell-of-origin patterns correlated with clinical outcomes, genomic aberrations and diverse microenvironment constitutions. We found that the luminal progenitor (LP) subtype was robustly associated with poor prognosis, genomic instability and dysfunctional immune microenvironment. However, the LP subtype patients were sensitive to neoadjuvant chemotherapy (NAC), PARP inhibitors (PARPi) and immunotherapy. The LP subtype-specific target PLK1 was investigated by both in vitro and in vivo experiments. Besides, large-scale single-cell profiling of breast cancer inspired us to identify a range of clinically relevant immune and stromal cell subpopulations, including subsets of innate lymphoid cells (ILCs), macrophages and endothelial cells. Conclusion: The present single-cell study revealed the cellular repertoire and cell-of-origin patterns of breast cancer. Combining single-cell and bulk transcriptome data, we elucidated the evolution mimicry from normal to malignant subtypes and expounded the LP subtype with vital clinical implications. Novel immune and stromal cell subpopulations of breast cancer identified in our study could be potential therapeutic targets. Taken together, Our findings lay the foundation for the precise prognostic and therapeutic stratification of breast cancer.

The association between urbanization and depression in the elderly: A network analysis from the complexity science perspective.

IMPORTANCE: The global increase in urbanization has coincided with a rise in depression prevalence. However, the effect of urbanization on depression remains controversial, especially for the elderly. OBJECTIVE: To clarify how urbanization impacts depression in the elderly from a network perspective. DESIGN, SETTING, AND PARTICIPANTS: This sectional cohort study used data from China Health and Retirement Longitudinal Study (CHARLS). MAIN OUTCOMES AND MEASURES: The occurrence of depressive symptoms in urban and rural elderly residents. Network metrics of depressive symptoms. RESULTS: Of the 13,993 participants, lower incidence of depressive symptoms was observed in urban (26.3 %, 95 % CI, 24.7 %-27.8 %) than in rural (40.4 %, 95 % CI, 39.5 %-41.3 %, P < 0.0001) residents. However, higher incidence of depressive symptoms was observed in urban (26.3 %, 95 % CI, 25.2 %-28.4 %) than in rural (17.5 %, 95 % CI, 16.1 %-18.9 %, P < 0.0001) residents in a subset of 2898 pairs of participants after PSM. No difference in the network structure and metrics between urban and rural residents before (M = 0.071, p = 0.054, S = 0.037, p = 0.80) and after (M = 0.085, p = 0.133, S = 0.086, p = 0.47) PSM was detected. The networks structure revealed that negative affect was strongly connected to somatic symptoms and that the two anhedonic symptoms were also strongly connected. CONCLUSIONS: The current study indicated the homogeneity of the ultimate nature of depression between rural and urban residents from the network perspective, supporting the viewpoint that urbanization might not impose influence on depression. Further researches delving deeper into the complexity of the issue may provide new insights into our understanding of depression in an urban environment among the elderly.

Research on the "shape-performance-control" integrated digital twin system for boom-type roadheaders.

The boom-type roadheader plays a crucial role in coal mining. However, conducting the real-time monitoring of the mechanical performance and comprehensive adaptive cutting in the dynamic cutting process are challenging. To address these issues, a digital twin system that integrates the elements of "shape, performance, and control" for roadheaders is presented in this paper. The system comprises three components: physical space, service space, and twin space. The service space forms the core of the entire system. Within this space, twin models and control models are created using numerical simulation, artificial intelligence and multi-source data fusion technology. These models serve the purpose of predicting the roadheader's mechanical performance and controlling the swing speed of the cutting arm. The physical space is built using technologies such as robot kinematics, electrical systems, hydraulic transmission, and other relevant techniques. This approach facilitates the transmission of multi-sensor data to twin models. The control model then manages the roadheader's function based on the output signals from the control model. The twin space is constructed utilizing physical rendering engines, databases, and 3D modelling tools. This space visualizes and stores the movement, performance, and control parameters of the roadheader. The results demonstrate that the average absolute error between the measured data from the test's three position strain gauges and the predicted data from the twin system is 10.38 MPa. Furthermore, the twin system achieves an average update interval of 0.34 s, allowing real-time stress monitoring of the structural components of the roadheader and preventing damage caused by overload. The proposed control model enables adaptive adjustment of the swing speed of the cutting arm in approximately 0.3 s. This improvement significantly enhances the adaptive cutting capabilities of roadheaders when dealing with complex coal and rock formations.

Astragaloside IV Mitigated Diabetic Nephropathy by Restructuring Intestinal Microflora and Ferroptosis.

SCOPE: To investigate the underlying mechanism of Astragaloside IV (AS-IV) in ameliorating diabetic nephropathy (DN) by regulating intestinal microbiota ecology and intestinal mucosal barrier. METHODS AND RESULTS: Genetically db/db mice are used to establish DN mouse model to monitor the therapeutic effects of AS-IV and fecal microbiota transplantation (FMT) against DN. Supplementation with AS-IV dramatically attenuates several clinical indicators of DN in db/db mice. In addition, AS-IV markedly improves intestinal barrier function, modifies intestinal permeability, and reduces inflammation. Moreover, AS-IV treatment remarkably improves intestinal dysbiosis in db/db mice, characterized by an elevated abundance of Akkermansia, Ligilactobacillus, and Lactobacillus, indicating the fundamental role of the microbiome in DN progression. Furthermore, FMT derived from AS-IV-treated db/db mice is potentially efficient in antagonizing renal dysfunction, rebalancing gut microbiota, and improving intestinal permeability in recipient db/db mice. AS-IV-enriched Akkermansia muciniphila dramatically alleviates DN and intestinal mucosal barrier dysfunction in db/db mice. Intriguingly, AS-IV intervention dramatically diminishes ferroptosis in the kidney and colon tissues. CONCLUSION : Intestinal microbiome alterations and ferroptosis modulation by AS-IV may play instrumental roles in this mechanism, providing compelling evidence for the role of the gut-renal axis in DN.

Ionic-resolution protoacoustic microscopy: A feasibility study.

Visualizing micro- and nano-scale biological entities requires high-resolution imaging and is conventionally achieved via optical microscopic techniques. Optical diffraction limits their resolution to ∼200 nm. This limit can be overcome by using ions with ∼1 MeV energy. Such ions penetrate through several micrometers in tissues, and their much shorter de Broglie wavelengths indicate that these ion beams can be focused to much shorter scales and hence can potentially facilitate higher resolution as compared to the optical techniques. Proton microscopy with ∼1 MeV protons has been shown to have reasonable inherent contrast between sub-cellular organelles. However, being a transmission-based modality, it is unsuitable for in vivo studies and cannot facilitate three-dimensional imaging from a single raster scan. Here, we propose proton-induced acoustic microscopy (PrAM), a technique based on pulsed proton irradiation and proton-induced acoustic signal collection. This technique is capable of label-free, super-resolution, 3D imaging with a single raster scan. Converting radiation energy into ultrasound enables PrAM with reflection mode detection, making it suitable for in vivo imaging and probing deeper than proton scanning transmission ion microscopy (STIM). Using a proton STIM image of HeLa cells, a coupled Monte Carlo+k-wave simulations-based feasibility study has been performed to demonstrate the capabilities of PrAM. We demonstrate that sub-50 nm lateral (depending upon the beam size and energy) and sub-micron axial resolution (based on acoustic detection bandwidth and proton beam pulse width) can be obtained using the proposed modality. By enabling visualization of biological phenomena at cellular and subcellular levels, this high-resolution microscopic technique enhances understanding of intricate cellular processes.

Association of triglyceride glucose-body mass index and hemoglobin glycation index with heart failure prevalence in hypertensive populations: a study across different glucose metabolism status.

BACKGROUND: The Triglyceride glucose-body mass index (TyG-BMI) and hemoglobin glycation index (HGI) are well-established surrogate markers for insulin resistance. Nevertheless, the extent to which these markers offer additive predictive value for heart failure (HF) prevalence in hypertensive populations, and their predictive utility across various diabetic statuses, remains to be clarified. Consequently, this study aimed to explore the independent and synergistic effects of TyG-BMI and HGI on HF risk among individuals with different diabetic statuses. METHODS: Data from the study population (n = 9847) were obtained from the National Health and Nutrition Examination Survey (NHANES). Multivariable logistic regression models were employed to estimate odds ratios (ORs) and 95% confidence intervals (CIs) to assess the combined associations between TyG-BMI and HGI and the prevalence of HF across various diabetic statuses. RESULTS: In the total population, compared to the reference group (low TyG-BMI and low HGI), the OR (95% CI) for HF prevalence was 1.30 (1.04, 1.64) for the combination of low TyG-BMI and high HGI, 2.40 (1.76, 3.29) for high TyG-BMI and low HGI, and 3.47 (2.41, 4.99) for high TyG-BMI and high HGI. Interestingly, among normoglycemic individuals, higher TyG-BMI and HGI did not significantly increase the prevalence of HF. Conversely, in the prediabetic population, the OR (95%CI) for HF prevalence was 2.42 (1.69, 3.48) for the combination of high TyG-BMI and low HGI, and 4.30 (2.45, 7.54) for high TyG-BMI and high HGI. Similarly, in the diabetic population, the OR (95%CI) for HF prevalence was 2.22 (1.43, 3.45) for low TyG-BMI and high HGI, 4.04 (2.43, 6.73) for high TyG-BMI and low HGI, and 4.13 (2.25, 7.59) for high TyG-BMI and high HGI, compared to low TyG-BMI and low HGI. CONCLUSION: This study reveals that elevated TyG-BMI and HGI levels exert a synergistic impact on the prevalence of HF in hypertensive adults, especially in those with prediabetes and diabetes. Additionally, the presence of prediabetes and diabetes may amplify the detrimental combined effect of TyG-BMI and HGI on HF prevalence.

Proton-FLASH: effects of ultra-high dose rate irradiation on an in-vivo mouse ear model.

FLASH-radiotherapy may provide significant sparing of healthy tissue through ultra-high dose rates in protons, electrons, and x-rays while maintaining the tumor control. Key factors for the FLASH effect might be oxygen depletion, the immune system, and the irradiated blood volume, but none could be fully confirmed yet. Therefore, further investigations are necessary. We investigated the protective (tissue sparing) effect of FLASH in proton treatment using an in-vivo mouse ear model. The right ears of Balb/c mice were irradiated with 20 MeV protons at the ion microprobe SNAKE in Garching near Munich by using three dose rates (Conv = 0.06 Gy/s, Flash9 = 9.3 Gy/s and Flash930 = 930 Gy/s) at a total dose of 23 Gy or 33 Gy. The ear thickness, desquamation, and erythema combined in an inflammation score were measured for 180 days. The cytokines TGF-ß1, TNF-α, IL1α, and IL1ß were analyzed in the blood sampled in the first 4 weeks and at termination day. No differences in inflammation reactions were visible in the 23 Gy group for the different dose rates. In the 33 Gy group, the ear swelling and the inflammation score for Flash9 was reduced by (57 ± 12) % and (67 ± 17) % and for Flash930 by (40 ± 13) % and (50 ± 17) % compared to the Conv dose rate. No changes in the cytokines in the blood could be measured. However, an estimation of the irradiated blood volume demonstrates, that 100-times more blood is irradiated when using Conv compared to using Flash9 or Flash930. This indicates that blood might play a role in the underlying mechanisms in the protective effect of FLASH.

A human-specific insertion promotes cell proliferation and migration by enhancing TBC1D8B expression.

Human-specific insertions play important roles in human phenotypes and diseases. Here we reported a 446-bp insertion (Insert-446) in intron 11 of the TBC1D8B gene, located on chromosome X, and traced its origin to a portion of intron 6 of the EBF1 gene on chromosome 5. Interestingly, Insert-446 was present in the human Neanderthal and Denisovans genomes, and was fixed in humans after human-chimpanzee divergence. We have demonstrated that Insert-446 acts as an enhancer through binding transcript factors that promotes a higher expression of human TBC1D8B gene as compared with orthologs in macaques. In addition, over-expression TBC1D8B promoted cell proliferation and migration through "a dual finger" catalytic mechanism (Arg538 and Gln573) in the TBC domain in vitro and knockdown of TBC1D8B attenuated tumorigenesis in vivo. Knockout of Insert-446 prevented cell proliferation and migration in cancer and normal cells. Our results reveal that the human-specific Insert-446 promotes cell proliferation and migration by upregulating the expression of TBC1D8B gene. These findings provide a significant insight into the effects of human-specific insertions on evolution.

Opportunities and challenges in the application of single-cell and spatial transcriptomics in plants.

Single-cell and spatial transcriptomics have diverted researchers' attention from the multicellular level to the single-cell level and spatial information. Single-cell transcriptomes provide insights into the transcriptome at the single-cell level, whereas spatial transcriptomes help preserve spatial information. Although these two omics technologies are helpful and mature, further research is needed to ensure their widespread applicability in plant studies. Reviewing recent research on plant single-cell or spatial transcriptomics, we compared the different experimental methods used in various plants. The limitations and challenges are clear for both single-cell and spatial transcriptomic analyses, such as the lack of applicability, spatial information, or high resolution. Subsequently, we put forth further applications, such as cross-species analysis of roots at the single-cell level and the idea that single-cell transcriptome analysis needs to be combined with other omics analyses to achieve superiority over individual omics analyses. Overall, the results of this review suggest that combining single-cell transcriptomics, spatial transcriptomics, and spatial element distribution can provide a promising research direction, particularly for plant research.

Genomic alterations affecting tumor-infiltrating lymphocytes and PD-L1 expression patterns in triple-negative breast cancer.

BACKGROUND: Tumor-infiltrating lymphocytes (TILs) and programmed cell death 1 ligand 1 (PD-L1) remain imperfect in predicting clinical outcomes of triple-negative breast cancer because outcomes do not always correlate with the expression of these biomarkers. Genomic and transcriptomic alterations that may contribute to the expression of these biomarkers remain incompletely uncovered. METHODS: We evaluated PD-L1 immunohistochemistry scores (SP142 and 28-8 assays) and TILs in our triple-negative breast cancer multiomics dataset and 2 immunotherapy clinical trial cohorts. Then, we analyzed genomic and transcriptomic alterations correlated with TILs, PD-L1 expression, and patient outcomes. RESULTS: Despite TILs serving as a decent predictor for triple-negative breast cancer clinical outcomes, exceptions remained. Our study revealed that several genomic alterations were correlated with unexpected events. In particular, PD-L1 expression may cause a paradoxical relationship between TILs and prognosis in certain patients. Consequently, we classified triple-negative breast cancers into 4 groups based on PD-L1 and TIL levels. The TIL-negative PD-L1-positive and TIL-positive PD-L1-negative groups were not typical "hot" tumors; both were associated with worse prognoses and lower immunotherapy efficacy than TIL-positive PD-L1-positive tumors. Copy number variation of PD-L1 and oncogenic signaling activation were correlated with PD-L1 expression in the TIL-negative PD-L1-positive group, whereas GSK3B-induced degradation may cause undetectable PD-L1 expression in the TIL-positive PD-L1-negative group. These factors have the potential to affect the predictive function of both PD-L1 and TILs. CONCLUSIONS: Several genomic and transcriptomic alterations may cause paradoxical effects among TILs, PD-L1 expression, and prognosis in triple-negative breast cancer. Investigating and targeting these factors will advance precision immunotherapy for patients with this disease.

IRSDT: A Framework for Infrared Small Target Tracking with Enhanced Detection.

Currently, infrared small target detection and tracking under complex backgrounds remains challenging because of the low resolution of infrared images and the lack of shape and texture features in these small targets. This study proposes a framework for infrared vehicle small target detection and tracking, comprising three components: full-image object detection, cropped-image object detection and tracking, and object trajectory prediction. We designed a CNN-based real-time detection model with a high recall rate for the first component to detect potential object regions in the entire image. The KCF algorithm and the designed lightweight CNN-based target detection model, which parallelly lock on the target more precisely in the target potential area, were used in the second component. In the final component, we designed an optimized Kalman filter to estimate the target's trajectory. We validated our method on a public dataset. The results show that the proposed real-time detection and tracking framework for infrared vehicle small targets could steadily track vehicle targets and adapt well in situations such as the temporary disappearance of targets and interference from other vehicles.

Antioxidant Carboxymethyl Chitosan Carbon Dots with Calcium Doping Achieve Ultra-Low Calcium Concentration for Iron-Induced Osteoporosis Treatment by Effectively Enhancing Calcium Bioavailability in Zebrafish.

Iron overloads osteoporosis mainly occurs to postmenopausal women and people requiring repeated blood transfusions. Iron overload increases the activity of osteoclasts and decreases the activity of osteoblasts, leading to the occurrence of osteoporosis. Conventional treatment options include calcium supplements and iron chelators. However, simple calcium supplementation is not effective, and it does not have a good therapeutic effect. Oxidative stress is one of the triggers for osteoporosis. Therefore, the study focuses on the antioxidant aspect of osteoporosis treatment. The present work revealed that antioxidant carboxymethyl chitosan-based carbon dots (AOCDs) can effectively treat iron overload osteoporosis. More interestingly, the functional modification of AOCDs by doping calcium gluconate (AOCDs:Ca) is superior to the use of any single component. AOCDs:Ca have the dual function of antioxidant and calcium supplement. AOCDs:Ca effectively improve the bioavailability of calcium and achieve ultra-low concentration calcium supplement for the treatment of iron-induced osteoporosis in zebrafish.

Nur77 Serves as a Potential Prognostic Biomarker That Correlates with Immune Infiltration and May Act as a Good Target for Prostate adenocarcinoma.

Prostate adenocarcinoma (PRAD) is the most frequent malignancy, and is the second leading cause of death due to cancer in men. Thus, new prognostic biomarkers and drug targets for PRAD are urgently needed. As we know, nuclear receptor Nur77 is important in cancer development and changes in the tumor microenvironment; whereas, the function of Nur77 in PRAD remains to be elucidated. The TCGA database was used to explore the Nur77 expression and its role in the prognosis of PRAD. It was shown that Nur77 was down regulated in PRAD, and low Nur77 expression was correlated with advanced clinical pathologic characteristics (high grade, histological type, age) and poor prognosis. Furthermore, key genes screening was examined by univariate Cox analysis and Kaplan-Meier survival. Additionally, Nur77 was closely related to immune infiltration and some anti-tumor immune functions. The differentially expressed genes (DEGs) were presented by protein-protein interaction (PPI) network analysis. Therefore, the expression level of Nur77 might help predict the survival of PRAD cases, which presents a new insight and a new target for the treatment of PRAD. In vitro experiments verified that natural product malayoside targeting Nur77 exhibited significant therapeutic effects on PRAD and largely induced cell apoptosis by up-regulating the expression of Nur77 and its mitochondrial localization. Taken together, Nur77 is a prognostic biomarker for patients with PRAD, which may refresh the profound understanding of PRAD individualized treatment.

A multicenter, randomized, double-blind, duloxetine-controlled, non-inferiority trial of desvenlafaxine succinate extended-release in patients with major depressive disorder.

BACKGROUND: Desvenlafaxine and duloxetine are selective serotonin and norepinephrine reuptake inhibitors. Their efficacy has not been directly compared using statistical hypotheses. This study evaluated the non-inferiority of desvenlafaxine extended-release (XL) to duloxetine in patients with major depressive disorder (MDD). METHODS: In this study, 420 adult patients with moderate-to-severe MDD were enrolled and randomly assigned (1:1) to receive 50 mg (once daily [QD]) of desvenlafaxine XL (n = 212) or 60 mg QD of duloxetine (n = 208). The primary endpoint was evaluated using a non-inferiority comparison based on the change from baseline to 8 weeks in the 17-item Hamilton Depression Rating Scale (HAMD17) total score. Secondary endpoints and safety were evaluated. RESULTS: Least-squares mean change in HAM-D17 total score from baseline to 8 weeks was -15.3 (95% confidence interval [CI]: -17.73, -12.89) in the desvenlafaxine XL group and - 15.9 (95% CI, -18.44, -13.39) in the duloxetine group. The least-squares mean difference was 0.6 (95% CI: -0.48, 1.69), and the upper boundary of 95% CI was less than the non-inferiority margin (2.2). No significant between-treatment differences were found in most secondary efficacy endpoints. The incidence of the most common treatment-emergent adverse events (TEAEs) was lower for desvenlafaxine XL than for duloxetine for nausea (27.2% versus 48.8%) and dizziness (18.0% versus 28.8%). LIMITATIONS: A short-term non-inferiority study without a placebo arm. CONCLUSIONS: This study demonstrated that desvenlafaxine XL 50 mg QD was non-inferior to duloxetine 60 mg QD in efficacy in patients with MDD. Desvenlafaxine had a lower incidence of TEAEs than duloxetine did.

Immunity orchestrates a bridge in gut-brain axis of neurodegenerative diseases.

Neurodegenerative diseases, in particular for Alzheimer's disease (AD), Parkinson's disease (PD) and Multiple sclerosis (MS), are a category of diseases with progressive loss of neuronal structure or function (encompassing neuronal death) leading to neuronal dysfunction, whereas the underlying pathogenesis remains to be clarified. As the microbiological ecosystem of the intestinal microbiome serves as the second genome of the human body, it is strongly implicated as an essential element in the initiation and/or progression of neurodegenerative diseases. Nevertheless, the precise underlying principles of how the intestinal microflora impact on neurodegenerative diseases via gut-brain axis by modulating the immune function are still poorly characterized. Consequently, an overview of initiating the development of neurodegenerative diseases and the contribution of intestinal microflora on immune function is discussed in this review.

Lead Exposure Causes Spinal Curvature during Embryonic Development in Zebrafish.

Lead (Pb) is an important raw material for modern industrial production, they enter the aquatic environment in several ways and cause serious harm to aquatic ecosystems. Lead ions (Pb2+) are highly toxic and can accumulate continuously in organisms. In addition to causing biological deaths, it can also cause neurological damage in vertebrates. Our experiment found that Pb2+ caused decreased survival, delayed hatching, decreased frequency of voluntary movements at 24 hpf, increased heart rate at 48 hpf and increased malformation rate in zebrafish embryos. Among them, the morphology of spinal malformations varied, with 0.4 mg/L Pb2+ causing a dorsal bending of the spine of 72 hpf zebrafish and a ventral bending in 120 hpf zebrafish. It was detected that spinal malformations were mainly caused by Pb2+-induced endoplasmic reticulum stress and apoptosis. The genetic changes in somatic segment development which disrupted developmental polarity as well as osteogenesis, resulting in uneven myotomal development. In contrast, calcium ions can rescue the series of responses induced by lead exposure and reduce the occurrence of spinal curvature. This article proposes new findings of lead pollution toxicity in zebrafish.

H2O2/DEM-Promoted Maft Promoter Demethylation Drives Nrf2/ARE Activation in Zebrafish.

The Nrf2/ARE signaling pathway is a cell survival response pathway in response to environmental stresses. The Nrf2/ARE signaling pathway can be activated by stimulating cysteine residues at different positions in the Keap1. However, the epigenetic mechanisms of the Nrf2/ARE pathway under different stimuli are still poorly understood. In this study, we found that both hydrogen peroxide (H2O2) and Diethyl Maleate (DEM) activated the Nrf2/ARE signaling pathway at 120 hpf in zebrafish. H2O2 regulated the demethylation of the maft promoter by inhibiting the expression of methyltransferase. This promotes the mRNA expression of the Nrf2 binding factor maft, thereby promoting the downstream antioxidant genes. The methylation of the Nrf2/ARE signaling pathway was not significantly regulated by DEM. However, under oxidative stress, the methyltransferase inhibitors (decitabine and azacitidine) demethylated the promoter region of maft. It activated the expression of the maft, further improving the Nrf2/ARE signal pathway. At last, antioxidant target genes were activated. It was shown that H2O2 and DEM cooperated with methyltransferase inhibitors, providing an important reference for the treatment of oxidative stress-related diseases and breaking new ground for the study of the mechanism of methyltransferase inhibitors in the process of tumor chemotherapy.

A network analysis of social problem-solving and anxiety/depression in adolescents.

Social problem-solving (SPS) involves the cognitive-behavioral processes through which an individual identifies and copes with everyday problems; it is considered to contribute to anxiety and depression. The Social Problem-Solving Inventory Revised is a popular tool measuring SPS problem orientations and problem-solving styles. Only a negative problem orientation (NPO) is considered strongly related to anxiety and depression. In the present study, we investigated the detailed connections among the five components of SPS and 14 anxiety-depression symptoms and specified the role of NPO and other components in the anxiety-depression network. We employed network analysis, constructed circular and multi-dimensional scaling (MDS) networks, and calculated the network centrality, bridge centrality, and stability of centrality indices. The results were as follows: (1) the MDS network showed a clustering of anxiety and depression symptoms, with NPO and avoidance style components from SPS being close to the anxiety-depression network (demonstrated by large bridge betweenness and bridge closeness); (2) the NPO and positive problem orientation from SPS were most influential on the whole network, though with an opposite effect; (3) strength was the most stable index [correlation stability (CS) coefficient = 0.516] among the centrality indices with case-dropping bootstraps. We also discussed this network from various perspectives and commented on the clinical implications and limitations of this study.

Moderate Dose Irradiation Induces DNA Damage and Impairments of Barrier and Host Defense in Nasal Epithelial Cells in vitro.

Purpose: Radiotherapy (RT) is the mainstay treatment for head and neck cancers. However, chronic and recurrent upper respiratory tract infections and inflammation have been commonly reported in patients post-RT. The underlying mechanisms remain poorly understood. Method and Materials: We used a well-established model of human nasal epithelial cells (hNECs) that forms a pseudostratified layer in the air-liquid interface (ALI) and exposed it to single or repeated moderate dose γ-irradiation (1Gy). We assessed the DNA damage and evaluated the biological properties of hNECs at different time points post-RT. Further, we explored the host immunity alterations in irradiated hNECs with polyinosinic-polycytidylic acid sodium salt (poly [I:C]) and lipopolysaccharides (LPS). Results: IR induced DNA double strand breaks (DSBs) and triggered DNA damage response in hNECs. Repeated IR significantly reduced basal cell proliferation with low expression of p63/KRT5 and Ki67, induced cilia loss and inhibited mucus secretion. In addition, IR decreased ZO-1 expression and caused a significant decline in the transepithelial electrical resistance (TEER). Moreover, hyperreactive response against pathogen invasion and disrupted epithelial host defense can be observed in hNECs exposed to repeated IR. Conclusion: Our study suggests that IR induced prolonged structural and functional impairments of hNECs may contribute to patients post-RT with increased risk of developing chronic and recurrent upper respiratory tract infection and inflammation.