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Abstract Oral squamous cell carcinoma (OSCC) biomarker studies rarely employ multi-omic biomarker strategies and pertinent clinicopathologic characteristics to predict mortality. In this study we determine for the first time a combined epigenetic, gene expression, and histology signature that differentiates between patients with different tobacco use history (heavy tobacco use with ≥10 pack years vs. no tobacco use). Using The Cancer Genome Atlas (TCGA) cohort (n = 257) and an internal cohort (n = 40), we identify 3 epigenetic markers (GPR15, GNG12, GDNF) and 13 expression markers (IGHA2, SCG5, RPL3L, NTRK1, CD96, BMP6, TFPI2, EFEMP2, RYR3, DMTN, GPD2, BAALC, and FMO3), which are dysregulated in OSCC patients who were never smokers vs. those who have a ≥ 10 pack year history. While mortality risk prediction based on smoking status and clinicopathologic covariates alone is inaccurate (c-statistic = 0.57), the combined epigenetic/expression and histologic signature has a c-statistic = 0.9409 in predicting 5-year mortality in OSCC patients.

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a chronic inflammatory disease. Exosomes were involved in different inflammatory diseases, but their roles in CRSwNP were poorly explored. Method: We collected serum samples from 8 CRSwNP patients and 8 healthy controls (HC) and isolated their exosomes. MiRNA sequencing was performed for the exosome samples and differentially expressed miRNAs were identified. The top 3 differentially expressed exosomal miRNAs were confirmed in 2 validation cohorts, and their diagnostic values, predictive values for eosinophilic endotype, and recurrence were evaluated. Results: Distinctive serum exosomal miRNA profiles were observed between CRSwNP and HC groups. Reverse transcription-polymerase chain reaction results in the first validation cohort revealed that serum exosomal miR-141-3p levels were increased, and miR-18a-5p and miR-3679-5p levels were decreased in the CRSwNP group compared to the HC group. These 3 miRNAs were further validated in the second validation cohort, and the results showed that miR-141-3p levels were elevated and miR-3679-5p levels were reduced in the serum exosomes in the eosinophilic CRSwNP group in comparison with the non-eosinophilic CRSwNP group. Receiver operating characteristic (ROC) curves highlighted that exosomal miR-141-3p and miR-3679-5p exhibited promising values for predicting the eosinophilic endotype. The patients in the second cohort were followed up for 2 years, and categorized into recurrence and non-recurrence groups. The serum exosomal miR-141-3p levels were increased and miR-3679-5p levels were reduced in the recurrence group in comparison with the non-recurrence group. ROC curves and Kaplan-Meier survival analysis revealed significant associations between the levels of exosomal miR-141-3p and miR-3679-5p and the risk of postoperative recurrence. Conclusions: This study identified unique miRNA expression patterns in serum exosomes of CRSwNP patients. Circulating exosomal miR-141-3p and miR-3679-5p emerged as novel biomarkers for diagnosing CRSwNP, predicting the eosinophilic endotype, and forecasting postoperative recurrence.

BackgroundIn patients underwent fractional flow reserve (FFR) assessment, a noteworthy proportion of adverse events occur in vessels in which FFR has not been measured. However, the effect of these non-target vessel-related events on the evaluation of FFR-related benefits remains unknown.Methods and resultsIn this retrospective study, vessels subjected to FFR measurement were grouped as FFR-based approach and non-compliance with FFR based on whether they received FFR-based treatment. Using inverse probability of treatment weighting (IPTW) to account for potential confounding, we investigated the association between compliance with FFR and 5-year target vessel failure (TVF) non-target vessel failure (NTVF) and vessel-oriented composite endpoints (VOCEs). Of the 1,119 vessels, 201 did not receive FFR-based treatment. After IPTW adjustment, a significantly lower hazard of TVF was observed in the FFR-based approach group (HR: 0.56; 95% CI: 0.34–0.92). While, the intergroup difference in hazard of NTVF (HR: 1.02; 95% CI: 0.45–2.31) and VOCEs (HR: 0.69; 95% CI: 0.45–1.05) were nonsignificant.ConclusionsIn patients with CAD subjected to FFR, the FFR-based treatment yields a sustained clinical benefit in terms of the risks of target vessel-related events. The dilution of non-target vessel-related events renders the difference favoring the FFR-based approach nonsignificant.

Objectives To determine the dysregulated signaling pathways of head and neck squamous cell carcinoma associated with circulating tumor cells (CTCs) via single-cell molecular characterization. Introduction Head and neck squamous cell carcinoma (HNSCC) has a significant global burden and is a disease with poor survival. Despite trials exploring new treatment modalities to improve disease control rates, the 5 year survival rate remains low at only 60%. Most cancer malignancies are reported to progress to a fatal phase due to the metastatic activity derived from treatment-resistant cancer cells, regarded as one of the most significant obstacles to develope effective cancer treatment options. However, the molecular profiles of cancer cells have not been thoroughly studied. Methods Here, we examined in-situ HNSCC tumors and pairwisely followed up with the downstream circulating tumor cells (CTCs)-based on the surrogate biomarkers to detect metastasis that is established in other cancers – not yet being fully adopted in HNSCC treatment algorithms. Results Specifically, we revealed metastatic HNSCC patients have complex CTCs that could be defined through gene expression and mutational gene profiling derived from completed single-cell RNASeq (scRNASeq) that served to confirm molecular pathways inherent in these CTCs. To enhance the reliability of our findings, we cross-validated those molecular profiles with results from previously published studies. Conclusion Thus, we identified 5 dysregulated signaling pathways in CTCs to derive HNSCC biomarker panels for screening HNSCC in situ tumors.

Introduction: High-altitude polycythemia (HAPC) is a common chronic high-altitude disease characterized by significantly increased erythrocyte, hemoglobin (Hb), and hematocrit values and decreased arterial oxygen saturation. The mechanisms underlying HAPC development are unclear; we aimed to investigate this in an HAPC rat model.Methods: Twelve Sprague–Dawley rats were divided into control and HAPC groups. The HAPC group was exposed to hypobaric hypoxia. This HAPC model was assessed using routine blood tests and blood gas analyses. Bone marrow, peripheral blood reticulocytes (RETs), and peripheral blood erythrocyte apoptosis were measured using flow cytometry. Erythrocyte osmotic fragility (EOF) tests were conducted. Abnormal erythrocytes were counted using electron microscopy. Plasma-free hemoglobin, 5′-nucleotidase (CD73), adenosine, erythrocyte cytosolic adenosine, sphingosine-1-phosphate (S1P), and 2,3-bisphosphoglycerate (BPG) levels were measured using enzyme-linked immunosorbent assays. Erythrocyte metabolic pathway-related protein [adenosine A2B receptor (ADORA2B), erythrocyte equilibrative nucleoside transporter 1 (eENT1), sphingosine kinase 1 (SPHK1), phospho-SPHK1, bisphosphoglycerate mutase (BPGM), and glyceraldehyde 3-phosphate dehydrogenase (GAPDH)] levels were assessed by Western blotting.Results: The HAPC rat model was successfully established (Hb > 210 g/L). Indices of bone marrow and peripheral blood RET proportions were significantly higher in the HAPC than the control group (p = 0.04 and p < 0.001, respectively). The proportion of peripheral blood erythrocytes in early apoptosis was significantly lower in the HAPC than the control group (p < 0.001). Vesicular erythrocyte and acanthocyte proportions were significantly higher in the HAPC than the control group (p < 0.001 and p = 0.019, respectively). The EOF tests revealed that 50% erythrocyte hemolysis occurred at 4.0–4.5 and 4.5–5.0 g/L NaCl in the control and HAPC groups, respectively. Plasma-free hemoglobin, CD73, adenosine, erythrocyte cytosolic adenosine, S1P, and 2,3-BPG levels and ADORA2B, eENT1, phospho-SPHK1, S1P, BPGM, and GAPDH erythrocyte expression levels (all p ≤ 0.02) were significantly higher in the HAPC than the control group.Conclusion: In model rats, an HAPC-related erythrocyte increase was associated with enhanced bone marrow hematopoietic function and reduced erythrocyte apoptosis, whereas numerous abnormal erythrocytes, increased EOF, and reduced hemolysis resistance were associated with erythrocyte metabolism. CD73/adenosine/S1P/2,3-BPG and eENT1/adenosine/BPGM/2,3-BPG metabolic pathways in erythrocytes were activated in HAPC rats, facilitating oxygen release. These findings further reveal the intrinsic HAPC mechanism and forms a basis for future development of preventive and therapeutic strategies for HAPC.

High-altitude polycythemia (HAPC) can occur in individuals who are intolerant to high-altitude hypoxia. In patients with HAPC, erythrocytosis is often accompanied by a decrease in platelet count. Chronic hypoxia can increase the incidence of arteriovenous thrombosis and the risk of bleeding during antithrombotic treatment due to thrombocytopenia; therefore, understanding the cause of thrombocytopenia can reduce the risk of treatment-related bleeding. In this study, we examined platelet production and apoptosis to understand the cause of thrombocytopenia in patients with HAPC. The classification of myeloid-derived megakaryocytes (MKs) in HAPC patients was mainly granular MKs rather than mature MKs, suggesting impaired differentiation and maturation. However, the total number of MKs and newly generated reticulated platelets in the peripheral blood increased, indicating sufficient platelet generation in HAPC thrombocytopenia. Increased platelet apoptosis may be one of the causes of thrombocytopenia. Platelet activation and GP1bα pathway activation induced by thrombin and von Willebrand factor can lead to platelet apoptosis. Platelet production was not reduced in patients with HAPC, whereas platelet apoptosis was associated with thrombocytopenia. These findings provide a rationale for considering the bleeding risk in HAPC patient while treating thrombotic diseases.

Oral squamous cell carcinoma (OSCC) presents significant treatment challenges due to its poor survival and intense pain at the primary cancer site. Cancer pain is debilitating, contributes to diminished quality of life, and causes opioid tolerance. The stimulator of interferon genes (STING) agonism has been investigated as an anti-cancer strategy. We have developed STINGel, an extended-release formulation that prolongs the availability of STING agonists, which has demonstrated an enhanced anti-tumor effect in OSCC compared to STING agonist injection. This study investigates the impact of intra-tumoral STINGel on OSCC-induced pain using two separate OSCC models and nociceptive behavioral assays. Intra-tumoral STINGel significantly reduced mechanical allodynia in the orofacial cancer model and alleviated thermal and mechanical hyperalgesia in the hind paw model. To determine the cellular signaling cascade contributing to the antinociceptive effect, we performed an in-depth analysis of immune cell populations via single-cell RNA-seq. We demonstrated an increase in M1-like macrophages and N1-like neutrophils after STINGel treatment. The identified regulatory pathways controlled immune response activation, myeloid cell differentiation, and cytoplasmic translation. Functional pathway analysis demonstrated the suppression of translation at neuron synapses and the negative regulation of neuron projection development in M2-like macrophages after STINGel treatment. Importantly, STINGel treatment upregulated TGF-β pathway signaling between various cell populations and peripheral nervous system (PNS) macrophages and enhanced TGF-β signaling within the PNS itself. Overall, this study sheds light on the mechanisms underlying STINGel-mediated antinociception and anti-tumorigenic impact.

Abstract Background Liver plays an important role in maintaining glucose homeostasis. We aimed to examine the associations of liver enzymes and hepatic steatosis index (HSI, a reliable biomarker for non-alcoholic fatty liver disease) in early pregnancy with subsequent GDM risk, as well as the potential mediation effects of lipid metabolites on the association between HSI and GDM. Methods In a birth cohort, liver enzymes were measured in early pregnancy (6-15 gestational weeks, mean 10) among 6,860 Chinese women. Multivariable logistic regression was performed to examine the association between liver biomarkers and risk of GDM. Pearson partial correlation and least absolute shrinkage and selection operator (LASSO) regression were conducted to identify lipid metabolites that were significantly associated with HSI in a subset of 948 women. Mediation analyses were performed to estimate the mediating roles of lipid metabolites on the association of HSI with GDM. Results Liver enzymes and HSI were associated with higher risks of GDM after adjustment for potential confounders, with ORs ranging from 1.42 to 2.24 for extreme-quartile comparisons (false discovery rate-adjusted P-trend ≤0.005). On the natural log scale, each SD increment of alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, alkaline phosphatase, and HSI was associated with a 1.15-fold (95% CI: 1.05, 1.26), 1.10-fold (1.01, 1.20), 1.21-fold (1.10, 1.32), 1.15-fold (1.04, 1.27), and 1.33-fold (1.18, 1.51) increased risk of GDM, respectively. Pearson partial correlation and LASSO regression identified 15 specific lipid metabolites in relation to HSI. Up to 52.6% of the association between HSI and GDM risk was attributed to the indirect effect of the HSI-related lipid score composed of lipid metabolites predominantly from phospholipids (e.g., lysophosphatidylcholine and ceramides) and triacylglycerol. Conclusions Elevated liver enzymes and HSI in early pregnancy, even within a normal range, were associated with higher risks of GDM among Chinese pregnant women. The association of HSI with GDM was largely mediated by altered lipid metabolism.

The loss of contact inhibition is a key step during carcinogenesis. The Hippo–Yes-associated protein (Hippo/YAP) pathway is an important regulator of cell growth in a cell density–dependent manner. However, how Hippo signaling senses cell density in this context remains elusive. Here, we report that high cell density induced the phosphorylation of spectrin α chain, nonerythrocytic 1 (SPTAN1), a plasma membrane–stabilizing protein, to recruit NUMB endocytic adaptor protein isoforms 1 and 2 (NUMB1/2), which further sequestered microtubule affinity–regulating kinases (MARKs) in the plasma membrane and rendered them inaccessible for phosphorylation and inhibition of the Hippo kinases sterile 20–like kinases MST1 and MST2 (MST1/2). WW45 interaction with MST1/2 was thereby enhanced, resulting in the activation of Hippo signaling to block YAP activity for cell contact inhibition. Importantly, low cell density led to SPTAN1 dephosphorylation and NUMB cytoplasmic location, along with MST1/2 inhibition and, consequently, YAP activation. Moreover, double KO of NUMB and WW45 in the liver led to appreciable organ enlargement and rapid tumorigenesis. Interestingly, NUMB isoforms 3 and 4, which have a truncated phosphotyrosine-binding (PTB) domain and are thus unable to interact with phosphorylated SPTAN1 and activate MST1/2, were selectively upregulated in liver cancer, which correlated with YAP activation. We have thus revealed a SPTAN1/NUMB1/2 axis that acts as a cell density sensor to restrain cell growth and oncogenesis by coupling external cell-cell contact signals to intracellular Hippo signaling.

BackgroundTo determine the diagnostic performance of a novel computational fluid dynamics (CFD)-based algorithm for in situ CT-FFR in patients with ischemia-induced coronary artery stenosis. Additionally, we investigated whether the diagnostic accuracy of CT-FFR differs significantly across the spectrum of disease and analyzed the influencing factors that contribute to misdiagnosis.MethodsCoronary computed tomography angiography (CCTA), invasive coronary angiography (ICA), and FFR were performed on 324 vessels from 301 patients from six clinical medical centers. Local investigators used CCTA and ICA to conduct assessments of stenosis, and CT-FFR calculations were performed in the core laboratory. For CCTA and ICA, CT-FFR ≤ 0.8 and a stenosis diameter ≥ 50% were identified as lesion-specific ischemia. Univariate logistic regression models were used to assess the effect of features on discordant lesions (false negative and false positive) in different CT-FFR categories. The diagnostic performance of CT-FFR was analyzed using an invasive FFR ≤ 0.8 as the gold standard.ResultsThe Youden index indicated an optimal threshold of 0.80 for CT-FFR to identify functionally ischemic lesions. On a per-patient basis, the diagnostic sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) for CT-FFR were 96% (91%–98%), 92% (87%–96%), 94% (90%–96%), 91% (85%–95%), and 96% (92%–99%), respectively. The diagnostic efficacy of CT-FFR was higher than that of CCTA without the influence of calcification. Closer to the cut point, there was less certainty, with the agreement between the invasive FFR and the CT-FFR being at its lowest in the CT-FFR range of 0.7–0.8. In all lesions, luminal stenosis ≥ 50% significantly affected the risk of reduced false negatives (FN) and false positives (FP) results by CT-FFR, irrespective of the association with calcified plaque.ConclusionsIn summary, CT-FFR based on the new parameter-optimized CFD model has a better diagnostic performance than CTA for lesion-specific ischemia. The presence of calcified plaque has no significant effect on the diagnostic performance of CT-FFR and is independent of the degree of calcification. Given the range of applicability of our software, its use at a CT-FFR of 0.7–0.8 requires caution and must be considered in the context of multiple factors.

Abstract Background Trametes gibbosa, which is a white-rot fungus of the Polyporaceae family found in the cold temperate zone, causes spongy white rot on wood. Laccase can oxidize benzene homologs and is one of the important oxidases for white rot fungi to degrade wood. However, the pathway of laccase synthesis in white rot fungi is unknown. Results The peak value of laccase activity reached 135.75 U/min/L on the 9th day. For laccase activity and RNA-seq data, gene expression was segmented into 24 modules. Turquoise and blue modules had greater associations with laccase activity (positively 0.94 and negatively -0.86, respectively). For biology function, these genes were concentrated on the cell cycle, citrate cycle, nicotinate, and nicotinamide metabolism, succinate dehydrogenase activity, flavin adenine dinucleotide binding, and oxidoreductase activity which are highly related to the laccase synthetic pathway. Among them, gene_8826 (MW199767), gene_7458 (MW199766), gene_61 (MW199765), gene_1741 (MH257605), and gene_11087 (MK805159) were identified as central genes. Conclusion Laccase activity steadily increased in wood degradation. Laccase oxidation consumes oxygen to produce hydrogen ions and water during the degradation of wood. Some of the hydrogen ions produced can be combined by Flavin adenine dinucleotide (FAD) to form reduced Flavin dinucleotide (FADH2), which can be transmitted. Also, the fungus was starved of oxygen throughout fermentation, and the NADH and FADH2 are unable to transfer hydrogen under hypoxia, resulting in the inability of NAD and FAD to regenerate and inhibit the tricarboxylic acid cycle of cells. These key hub genes related to laccase activity play important roles in the molecular mechanisms of laccase synthesis for exploring industrial excellent strains.

This paper presents an active flow control of ship airwake over the deck to improve the safety of helicopter shipboard operations in various angles of wind over deck (WOD). Firstly, an integrated flight dynamics method coupled with ship airwake was developed to analyze the effect of ship airwake on the helicopter at various angles of WOD. Then, an active flow control strategy in various angles of WOD was investigated with the analysis of airwake distribution and the impact on helicopter trim flight. Finally, the effects of active blowing on airwake distribution, flight control inputs, control margins, and helicopter attitudes in trim were analyzed. The results indicate that the variation of the angles of WOD has a significant impact on flight controls and helicopter attitudes for helicopter hovering relative to ship motion. The nonuniformity of ship airwake can be effectively alleviated by applying active flow control. The variations of flight control inputs and helicopter attitude angles at trim states are reduced, which increases the control margins and contributes to enhancing the safety of helicopter shipboard operations.

Stem cell based transplants effectively regenerate tissues; however, limitations such as immune rejection and teratoma formation prevent their application. Extracellular vesicles (EVs)-mediated acellular tissue regeneration is a promising alternative to stem cell based transplants. Although neural EGFL-like 1 (Nell1) is known to contribute to the osteogenic differentiation of bone marrow stem cells (BMSCs), it remains unknown whether EVs are involved in this process. Here, we present that EVs derived from Nell1-modified BMSCs (Nell1/EVs) have a stronger ability to promote BMSC osteogenesis owing to miR-25–5p downregulation. MiR-25–5p inhibits osteogenesis by targeting Smad2 and suppressing the SMAD and extracellular signal-related kinase 1 and 2 (ERK1/2) pathway activation. In addition, we demonstrate that the 3D-Nell1/EV-hydrogel system is beneficial for bone regeneration in vivo, probably stemming from a slow, continuous release and high concentration of EVs in the bone defect area. Thus, our results have shown the potential of Nell1/EVs as a novel acellular bone regeneration strategy. Mechanistically, the identification of miR-25-5p-SMAD2 signaling axis expands the knowledge of Nell1/EVs induced osteogenesis.

Abstract Background The management of sub-totally resected sporadic vestibular schwannoma (VS) may include observation, re-resection or irradiation. Identifying the optimal choice can be difficult due to the disease’s variable progression rate. We aimed to define an immune signature and associated transcriptomic fingerprint characteristic of rapidly-progressing VS to elucidate the underpinnings of rapidly progressing VS and identify a prognostic model for determining rate of progression. Methods We used multiplex immunofluorescence to characterize the immune microenvironment in 17 patients with sporadic VS treated with subtotal surgical resection alone. Transcriptomic analysis revealed differentially-expressed genes and dysregulated pathways when comparing rapidly-progressing VS to slowly or non-progressing VS. Results Rapidly progressing VS was distinctly enriched in CD4+, CD8+, CD20+, and CD68+ immune cells. RNA data indicated the upregulation of anti-viral innate immune response and T-cell senescence. K − Top Scoring Pair analysis identified 6 pairs of immunosenescence-related genes (CD38-KDR, CD22-STAT5A, APCS-CXCR6, MADCAM1-MPL, IL6-NFATC3, and CXCL2-TLR6) that had high sensitivity (100%) and specificity (78%) for identifying rapid VS progression. Conclusion Rapid progression of residual vestibular schwannoma following subtotal surgical resection has an underlying immune etiology that may be virally originating; and despite an abundant adaptive immune response, T-cell immunosenescence may be associated with rapid progression of VS. These findings provide a rationale for clinical trials evaluating immunotherapy in patients with rapidly progressing VS.

Abstract Objective To examine the association of early-pregnancy serum C-peptide with incident gestational diabetes mellitus (GDM) and the predictive ability of maternal C-peptide for GDM. Methods A nested case–control study of 332 GDM cases and 664 controls was established based on the Tongji-Shuangliu Birth Cohort. The GDM cases and controls were matched at 1:2 on maternal age (± 3 years) and gestational age (± 4 weeks). Multivariable conditional logistic regression was applied to assess the association of C-peptide with risk of GDM. Partial Spearman’s correlation coefficients were estimated for the correlations between C-peptide and multiple metabolic biomarkers. C-statistics were calculated to assess the predictive ability of early-pregnancy C-peptide for GDM. Results Of 996 pregnant women, median maternal age was 28.0 years old and median gestational age was 11.0 weeks. After adjustment for potential confounders, the odds ratio of GDM comparing the extreme quartiles of C-peptide was 2.28 (95% confidence interval, 1.43, 3.62; P for trend

Abstract Pine wilt disease (PWD) is a worldwide forest disease caused by pine wood nematode (PWN). In this article, we investigated the composition, organization, correlation, and function of the endophytic microbial community in Pinus massoniana field with and without PWN. Samples were taken from branches, upper, middle, and lower trunks, as well as soil, from both healthy and infected trees. The results showed that the fungal diversity of healthy pines is around 1.1 times that of infected pines, while the bacterial diversity is about 0.75 times that of infected pines at the OTUs level. An increase of the abundance of pathogenic fungus such as Saitozyma, Graphilbum, Diplodia, Candida, Pseudoxanthomonas, Dyella and Pantoea was witnessed in infected pines according to the result of LEfSe. Furthermore, Ophiostoma and saprophytic fungus such as Entomocorticium, ganoderma, tomentella, entomocorticium were exclusively prominent in infected pines, which were substantially and highly connected with other species (p

Pain associated with head and neck cancer (HNC) is difficult to manage and reduces quality of life. It has been increasingly recognized that HNC patients exhibit a wide range of pain symptoms. Here we developed an orofacial pain assessment questionnaire and conducted a pilot study to improve pain phenotyping in HNC patients at the diagnosis. The questionnaire captures the following pain characteristics: pain intensity, location, quality, duration, and frequency; the impact of pain on daily activities; changes in smell and food sensitivities. Twenty-five HNC patients completed the questionnaire. 88% patients reported pain at the site of tumor; 36% reported multiple pain sites. All patients with pain reported at least one neuropathic pain (NP) descriptor, 54.5% reported at least two NP descriptors. The most common descriptors were “burning” and “pins and needles”. Most patients reported increased pain to sour or hot/spicy food/drinks, and to food with coarse/hard textures. Patients exhibited impaired oral function, especially chewing, talking, mouth/jaw opening, and eating. Tumor progression has a significant impact on pain. Nodal metastasis is linked to pain at multiple body sites. Patients with advanced tumor staging experience greater pain at the primary tumor site, when exposed to hot or spicy food/drinks or food with hard/coarse texture, or when eating or chewing. We conclude that HNC patients experience a wide range of pain symptoms with altered mechanical, chemical, and temperature sensation. Improved phenotyping and stratification of pain in HNC patients will help address the underlying etiology, which may enable personalized therapeutic approaches in the future.

Hypoxic pulmonary hypertension (HPH) is a complicated vascular disorder characterized by diverse mechanisms that lead to elevated blood pressure in pulmonary circulation. Recent evidence indicates that HPH is not simply a pathological syndrome but is instead a complex lesion of cellular metabolism, inflammation, and proliferation driven by the reprogramming of gene expression patterns. One of the key mechanisms underlying HPH is hypoxia, which drives immune/inflammation to mediate complex vascular homeostasis that collaboratively controls vascular remodeling in the lungs. This is caused by the prolonged infiltration of immune cells and an increase in several pro-inflammatory factors, which ultimately leads to immune dysregulation. Hypoxia has been associated with metabolic reprogramming, immunological dysregulation, and adverse pulmonary vascular remodeling in preclinical studies. Many animal models have been developed to mimic HPH; however, many of them do not accurately represent the human disease state and may not be suitable for testing new therapeutic strategies. The scientific understanding of HPH is rapidly evolving, and recent efforts have focused on understanding the complex interplay among hypoxia, inflammation, and cellular metabolism in the development of this disease. Through continued research and the development of more sophisticated animal models, it is hoped that we will be able to gain a deeper understanding of the underlying mechanisms of HPH and implement more effective therapies for this debilitating disease.

Abstract Though gut microbiome disturbance may be involved in the etiology of gestational diabetes mellitus (GDM), data on the gut microbiome's dynamic change during pregnancy and associations with gestational glucose metabolism are still inadequate. In this prospective study comprising 120 pairs of GDM patients and matched pregnant controls, a decrease in the diversity of gut microbial species and changes in the microbial community composition with advancing gestation are found in controls, while no such trends are observed in GDM patients. Multivariable analysis identifies 10 GDM‐related species (e.g., Alistipes putredinis), and the integrated associations of these species with glycemic traits are modified by habitual intake of fiber‐rich plant foods. In addition, the microbial metabolic potentials related to fiber fermentation (e.g., mannan degradation pathways) and their key enzymes consistently emerge as associated with both GDM status and glycemic traits. Microbial features especially those involved in fiber fermentation, provide an incremental predictive value in a prediction model with established risk factors of GDM. These data suggest that the gut microbiome remodeling with advancing gestation is different in GDM patients compared with controls, and dietary fiber fermentation contributes to the influence of gut microbiome on gestational glycemic regulation.

Oral cancer pain remains a significant public health concern. Despite the development of improved treatments, pain continues to be a debilitating clinical feature of the disease, leading to reduced oral mobility and diminished quality of life. Opioids are the gold standard treatment for moderate-to-severe oral cancer pain; however, chronic opioid administration leads to hyperalgesia, tolerance, and dependence. The aim of this review is to present accumulating evidence that epidermal growth factor receptor (EGFR) signaling, often dysregulated in cancer, is also an emerging signaling pathway critically involved in pain and opioid tolerance. We presented preclinical and clinical data to demonstrate how repurposing EGFR inhibitors typically used for cancer treatment could be an effective pharmacological strategy to treat oral cancer pain and to prevent or delay the development of opioid tolerance. We also propose that EGFR interaction with the µ-opioid receptor and glutamate N-methyl-D-aspartate receptor could be two novel downstream mechanisms contributing to pain and morphine tolerance. Most data presented here support that repurposing EGFR inhibitors as non-opioid analgesics in oral cancer pain is promising and warrants further research.

Abstract Background The sensitive and accurate diagnosis of nosocomial meningitis and ventriculitis is still a critical problem. This study was designed to explore the diagnostic value of cerebrospinal fluid heparin-binding protein (HBP) in nosocomial meningitis and ventriculitis in comparison with procalcitonin and lactate. Methods In this observational study, 323 suspected patients were enrolled, of which 42 participants were excluded because they could not be accurately grouped, 131 subjects who were eventually diagnosed with nosocomial meningitis or ventriculitis and 150 patients in whom infection was ultimately ruled out were included in the final analysis. The main results are expressed as medians (interquartile ranges). The Chi-squared test was used to compare the baseline characteristics. The Mann–Whitney U-test was used for group and subgroup analyses. The area under the receiver operating characteristic curve was calculated to describe the diagnostic accuracy of the biomarkers. Spearman's partial correlation was used to analyze associations between the biomarkers. Statistical significance was set when p value 0.05). Higher concentrations of HBP were present in patients with positive microbiological findings (p

IntroductionAlcohol is the main legal drug in the world, and excessive consumption of alcohol seriously damages the morphological structure and function of various organs. The insufficiency of an essential enzyme in ethanol metabolism, aldehyde dehydrogenase-2 (ALDH2), will aggravate the alcohol-induced brain injury. The effect of ALDH2 after chronic alcohol exposure on global lipid profiling of the brain remains unclear.MethodsIn this study, ALDH2*2 knock-in mice were fed the Lieber-DeCarli liquid diet containing ethanol for 8 weeks. Blood alcohol and acetaldehyde levels were examined, and the mice were tested through novel object recognition and the Y-maze test to evaluate cognitive impairment toward the end of the study. The lipidome profiling of cerebral cortex samples was investigated using a lipidomics method based on ultra-high performance liquid tandem chromatography quadrupole time of flight mass spectrometry (UHPLC-QTOFMS).Results and DiscussionCompared with similarly treated wild-type (WT) mice, ALDH2*2 mice exhibited poor cognitive performance, though the result did not achieve statistical significance. The lipidomics results indicated that 74 differential lipid species were selected in WT mice, of which 57 species were up-regulated, and 17 were down-regulated. Moreover, 99 differential lipids were identified in ALDH2*2 mice, of which 73 were up-regulated, and 26 were down-regulated. For ALDH2*2 mice, the number of changed significantly glycerophospholipids (GPs) subtypes was lower than that of WT mice. Interestingly, compared with WT mice, a lower proportion of polyunsaturated fatty acids (PUFAs) was found in ALDH2*2 mice. Collectively, the results provide clear evidence for a lipidomic signature of marked changes in the cerebral cortex of ALDH2*2 mice after chronic alcohol exposure.Highlights• The cerebral cortex of heterozygous ALDH2*2 mice showed more significant changes in lipidome profiles after chronic alcohol exposure than wild-type mice.• Most lipids were significantly up-regulated in both groups of mice, whereas the increase in TAG was restricted to WT mice.• For ALDH2*2 mice, GPs substances changed significantly, and SHexCer and SM subclasses in sphingolipids also deserved attention.

Abstract Background Shoulder function complications are common after treatment for breast cancer. Quite a few survivors still report a limited shoulder range of motion, even though the free range-of-motion upper limb exercise is helpful to restore shoulder function. Mirror therapy (MT) is a classical and effective rehabilitation technique to recover motor and sensory function for the limbs; in addition, studies have reported that MT has an influence on patients with shoulder functional dysfunction including increasing shoulder range of motion, improving shoulder function scores, and decreasing pain scores. Here, we describe a protocol of a randomized controlled trial to explore if free range-of-motion upper limb exercise based on MT has efficacy on shoulder function in survivors after surgery of breast cancer. Methods/design This is a prospective, single-blind, two-arm randomized controlled trial. An estimated 70 participants will be randomly allocated to (1) the MT group or (2) the control group. The participants in the control group receive free range-of-motion upper limb exercise, and participants in the MT group will engage in free range-of-motion upper limb exercise based on MT. The intervention will start on the first day after surgery and be completed at 8 weeks after surgery. The primary outcome in this protocol is shoulder range of motion (ROM), while the Constant-Murley Score (CMS); Disability of the Arm, Shoulder, and Hand Questionnaire (DASH); Tampa Scale of Kinesiophobia (13-item TSK); visual analog scale (VAS); grip strength; arm circumference; and lymphedema are the secondary outcomes. Assessment will be conducted before allocation (baseline) and at 2 weeks, 4 weeks, and 8 weeks after surgery. Discussion Based on the results that MT has an influence on shoulder function immediately after intervention in patients without nerve injury, this randomized controlled trial is to observe the efficacy of MT on shoulder function after a long-term intervention in breast cancer survivors. We look forward to the innovation of this study for both breast cancer rehabilitation and MT. Trial registration Chinese Clinical Trial Registry ( ChiCTR ) ChiCTR2000033080. Registered on 19 May 2020

Abstract Background Schizophrenia is a polygenic disease; however, the specific risk genetic variants of schizophrenia are still largely unknown. Single nucleotide polymorphism (SNP) is important genetic factor for the susceptibility of schizophrenia. Investigating individual candidate gene contributing to disease risk remains important. Methods In a case-control study, five SNPs located in 6p21.3-p23.1 including rs2021722 in human leukocyte antigen (HLA) locus and rs107822, rs383711, rs439205 and rs421446 within the upstream of microRNA-219a-1 were genotyped in 454 schizophrenia patients and 445 healthy controls to investigate the possible association between the loci and schizophrenia in a Han Chinese population. Results Our results showed significant associations between the rs2021722 and schizophrenia in allele (A vs. G: adjusted OR = 1.661, 95%CI = 1.196–2.308), co-dominant (AG vs. GG: OR = 1.760, 95%CI = 1.234–2.510) and dominant genetic model (AG + AA vs. GG: OR = 1.756, 95%CI = 1.237–2.492), respectively. Haplotype analysis showed that TGGT and CAAC were protective factor for schizophrenia compared with TAAC haplotype (OR = 0.324, 95% CI = 0.157–0.672; OR = 0.423, 95% CI = 0.199–0.900). Conclusions These findings indicate that rs2021722 in HLA locus might be involved in pathogenesis of schizophrenia and that genotypes AG and allele A of the locus are risk factors for schizophrenia in the Han Chinese population, confirming the association between immune system and schizophrenia.

Abstract Study design A retrospective cohort study. Objective To investigate the radiological and clinical outcomes of patients with or without pedicle-screw rod fixation (PSRF) in OLIF surgery. Methods Between June 2017 and December 2019, 66 consecutive patients who underwent OLIF surgery at two centers were divided into stand-alone and combined groups according to whether or not PSRF was used. Imaging and clinical data were collected preoperatively, postoperatively, 3 and 6 months postoperatively, and at the last follow-up. Related coefficient and multiple linear regression analysis was used to detect the influencing factors of cage subsidence (CS). Results There was a lower baseline BMD in the combined group (p = 0.005). The combined group showed superior VAS score at 3 months postoperatively, although there was no difference in long-term VAS and ODI scores between the two groups. The foraminal height (FH) of the two groups was comparable at preoperatively, postoperatively, and 3 months postoperatively, but the combined group showed better maintenance of FH at 6 months postoperatively (p = 0.049) and last follow-up (p = 0.019). The total CS (tCS) of the combined group was lower than that of the stand-alone group during the whole follow-up period (all p ≤ 0.001). Multiple linear regression suggested that lower BMD was the risk factor for main CS, and PSRF could significantly reduce the BMD threshold for severe CS (−4.77 vs −1.38). Conclusions OLIF combined with PSRF can effectively avoid foraminal height loss and prevent severe CS, which may be more suitable for patients with osteoporosis or osteopenia and improve clinical outcomes.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a new type of oral hypoglycaemic agent with good cardiovascular protective effects. There are several lines of clinical evidence suggest that SGLT2i can significantly reduce the risks of heart failure, cardiovascular death, and delay the progression of chronic kidney disease. In addition, recent basic and clinical studies have also reported that SGLT2i also has good anti-arrhythmic effects. However, the exact mechanism is poorly understood. The aim of this review is to summarize recent clinical findings, studies of laboratory animals, and related study about this aspect of the antiarrhythmic effects of SGLT2i, to further explore its underlying mechanisms, safety, and prospects for clinical applications of it.

BackgroundThe underlying biological mechanisms for neurological symptoms following a traumatic brain injury (TBI) remain poorly understood. This study investigated the associations between serum inflammatory biomarkers and neurological symptoms in the chronic phase following moderate to severe TBI.MethodsThe serum interleukin [IL]-1β, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, and the tumor necrosis factor [TNF]-α in 72 TBI patients 6 months to 2 years post injury were measured. Neurological symptoms including depression, chronic headache, sleep disturbance, irritability, anxiety, and global neurological disability was assessed. The associations between the biomarkers and the neurological symptoms were assessed using correlation and regression analysis.ResultsIt was found that the most common post-injury symptom was sleep disturbance (84.7%), followed by chronic headaches (59.7%), irritability (55.6%), and depression (54.2%). TNF-α was a protective factor for chronic headache (OR = 0.473, 95% CI = 0.235–0.952). IL-6 was positively associated with sleep disturbance (r = 0.274, p = 0.021), while IL-5 and IL-12p70 were negatively associated with the degree of global neurological disability (r = −0.325, p = 0.006; r = −0.319, p = 0.007).ConclusionThis study provides preliminary evidence for the association between chronic inflammation with neurological symptoms following a TBI, which suggests that anti-inflammatory could be a potential target for post-TBI neurological rehabilitation. Further research with larger sample sizes and more related biomarkers are still needed, however, to elucidate the inflammatory mechanisms for this association.

ABSTRACT Carbapenem-resistant Gram-negative bacteria (CRGNB)-related health care-associated ventriculitis and meningitis (HCAVM) is dangerous. We aimed to report the antimicrobial resistance of the pathogens, treatment, and outcome. All cases with CRGNB-related HCAVM in2012–2020 were recruited. Antimicrobial agents were classified as active, untested, or inactive using antimicrobial susceptibility tests. The treatment stage was classified as empirical or targeted according to the report of pathogens. The treatment effect was classified as ineffective or effective according to HCAVM-related parameters. Overall, 92 cases were recruited. For most antimicrobial agents, the resistance rate was higher than 70.0%. The polymyxin resistance rate was the lowest at 11.6%. The chloramphenicol, trimethoprim-sulfamethoxazole, amikacin, levofloxacin, and tetracycline resistance rates were relatively low, ranging from 21.1% to 64.1%. The meropenem resistance rate was 81.9%. There was no significant trend for any antimicrobial agent tested. Meropenem was the most common antimicrobial agent used in empirical treatment; trimethoprim-sulfamethoxazole and polymyxin were the most used active antimicrobial agents, and meropenem/sulbactam and polymyxin were the most used untested antimicrobial agents in targeted treatment. In total, 42 (45.7%) cases received ineffective treatments. The ineffective treatment rate of cases that received active antimicrobial agents was lower than that of cases that received untested antimicrobial agents and cases that received inactive antimicrobial agents (29.3% [12/41] versus 46.2% [18/39] versus 100.0% [12/12], P < 0.001). Antimicrobial resistance was prevalent but without increasing trends. Active antimicrobial agents are necessary. Additionally, untested antimicrobial agents, including meropenem/sulbactam and polymyxin, might be optional. Inactive antimicrobial agents must be replaced. IMPORTANCE Carbapenem-resistant Gram-negative bacteria-related health care-associated ventriculitis and meningitis is a clinical threat because of the poor outcome and challenges in treatment. We reached several conclusions: (i) the antimicrobial resistance of pathogens is severe, and some antimicrobial agents represented by polymyxin are optional according to the antimicrobial susceptibility tests; (ii) in the background that the portion of carbapenems resistance in Gram-negative bacteria is increasing, there is no increasing trend for the antimicrobial resistance of carbapenem-resistant Gram-negative bacteria in the 9-year study; (iii) meropenem is the main antimicrobial agent in treatment, and trimethoprim-sulfamethoxazole, tigecycline, polymyxin, and meropenem/sulbactam are commonly used in the targeted treatment; (iv) the treatment effect was poor and affected by the treatment: timely active antimicrobial agents should be given. And untested antimicrobial agents represented by polymyxin and meropenem/sulbactam might be optional. Inactive antimicrobial agents must be replaced.

Abstract An increasing number of studies show that listeners often have difficulty hearing in situations with background noise, despite normal tuning curves in quiet. One potential source of this difficulty could be sensorineural changes in the auditory periphery (the ear). Signal in noise detection deficits also arise in animals raised with developmental conductive hearing loss (CHL), a manipulation that induces acoustic attenuation to model how sound deprivation changes the central auditory system. This model attributes perceptual deficits to central changes by assuming that CHL does not affect sensorineural elements in the periphery that could raise masked thresholds. However, because of efferent feedback, altering the auditory system could affect cochlear elements. Indeed, recent studies show that adult-onset CHL can cause cochlear synapse loss, potentially calling into question the assumption of an intact periphery in early-onset CHL. To resolve this issue, we tested the long-term peripheral effects of CHL via developmental bilateral malleus displacement. Using forward masking tuning curves, we compared peripheral tuning in animals raised with CHL vs age-matched controls. Using compound action potential measurements from the round window, we assessed inner hair cell synapse integrity. Results indicate that developmental CHL can cause minor synaptopathy. However, developmental CHL does not appreciably alter peripheral frequency tuning.

Abstract Oral cancer is very painful and impairs a patient’s ability to eat, talk, and drink. Mediators secreted from oral cancer can excite and sensitize sensory neurons inducing pain. Cancer mediators can also activate Schwann cells, the peripheral glia that regulates neuronal function and repair. The contribution of Schwann cells to oral cancer pain is unclear. We hypothesize that the oral cancer mediator TNFα activates Schwann cells, which further promotes cancer progression and pain. We demonstrate that TNFα is overexpressed in human oral cancer tissues and correlates with increased self-reported pain in patients. Antagonizing TNFα reduces oral cancer proliferation, cytokine production, and nociception in mice with oral cancer. Oral cancer or TNFα alone increases Schwann cell activation (measured by Schwann cell proliferation, migration, and activation markers), which can be inhibited by neutralizing TNFα. Cancer- or TNFα-activated Schwann cells release pro-nociceptive mediators such as TNFα and nerve growth factor (NGF). Activated Schwann cells induce nociceptive behaviors in mice, which is alleviated by blocking TNFα. Our study suggests that TNFα promotes cancer proliferation, progression, and nociception at least partially by activating Schwann cells. Inhibiting TNFα or Schwann cell activation might serve as therapeutic approaches for the treatment of oral cancer and associated pain.

Glutathione S-transferases (GSTs) are a class of enzymes with detoxification function. GSTs can be used for the degradation of toxic aromatic compounds, such as dyes. In order to promote their application and cost-effective dye degradation and to understand their structure and function more deeply, we cloned and expressed a gst2 gene from Trametes gibbosa—a white rot fungus. T.gibbosa gst2 has a 672-bp open reading frame (ORF) and encodes 223 amino acids. The recombinant Tg-gst2 in Escherichia coli has a molecular weight of 25.59 k. Real-time polymerase chain reaction and high throughput sequencing technique were used to verify Tg-gst2 gene response to congo red dye. GST activity enhanced with congo red treatment. The tertiary structure of Tg-GST2 was predicted using homology modeling, and we found that it belongs to Ure2pA family of GST, which is a specific family of fungi. Active sites contained catalytic tri-linked groups, such as Gly15-Pro16-Asn17. Oxidized glutathione binding residues are Gln 44, Arg 57, Ile 58, Glu 73, Ser 74, Ser 111, Arg 137 and Trp 174. Molecular docking predicted that the binding effect of Tg-GST2 with oxidized glutathione and congo red was strong. This study has great significance in the research and application GST of Ure2pA family in dye decolorization and detoxification. Supplemental data for this article is available online at https://doi.org/10.1080/13102818.2021.1997157 .

Short tandem repeats on the Y chromosome (Y-STRs), characterized by paternal inheritance, are valuable in forensic practice. Notably, the potential application of Y-STRs in pedigrees should be drawn upon, especially in China’s surname-concentrated natural villages. The study focused on 50 Y-STRs, including 13 rapidly mutating (RM) Y-STRs that largely constitute the current Y-STR commercial kits, and determined the differences in these Y-STRs between branches in a large pedigree and the discriminatory power of these haplotypes in different units for male relatives. As indicated in the results, 14 inconsistencies were observed at 9 Y-STRs between 10 father-son pairs. In addition, these 50 Y-STR haplotypes discriminated 10 out of 47 father-son pairs, 106 of 148 cousin pairs, 70 of 119 uncle-nephew pairs, 17 of 39 brother pairs, and 14 out of 33 grandfather-grandson pairs in a large pedigree. The RM Y-STR set is able to differentiate close male relatives in a large pedigree.

ABSTRACT Coagulase-negative staphylococci (CoNS) are the main pathogens in health care-associated ventriculitis and meningitis (HCAVM). This study aimed to assess antimicrobial susceptibility. Moreover, the treatment and clinical outcome were described. All neurosurgical adults admitted to one of the largest neurosurgical centers in China with clinically significant CoNS isolated from cerebrospinal fluid cultures in 2012 to 2020 were recruited. One episode was defined as one patient with one bacterial strain. Interpretive categories were applied according to the MICs. The clinical outcomes were dichotomized into poor (Glasgow Outcome Scale 1 to 3) and acceptable (Glasgow Outcome Scale 4 to 5). In total, 534 episodes involving 519 patients and 16 bacteria were analyzed. Over the 9 years, eight antimicrobial agents were used in antimicrobial susceptibility tests, including six in over 80% of CoNS. The range of resistance rates was 0.8% to 84.6%. The vancomycin resistance rate was the lowest, whereas the penicillin resistance rate was the highest. The linezolid (a vancomycin replacement) resistance rate was 3.1%. The rate of oxacillin resistance, representing methicillin-resistant staphylococci, was 70.2%. There were no significant trends of antimicrobial susceptibility over the 9 years for any agents analyzed. However, there were some apparent changes. Notably, vancomycin-resistant CoNS appeared in recent years, while linezolid-resistant CoNS appeared early and disappeared in recent years. Vancomycin (or norvancomycin), the most common treatment agent, was used in 528 (98.9%) episodes. Finally, 527 (98.7%) episodes had acceptable outcomes. It will be safe to use vancomycin to treat CoNS-related HCAVM in the immediate future, although continuous monitoring will be needed. IMPORTANCE Coagulase-negative staphylococci are the main pathogens in health care-associated ventriculitis and meningitis. There are three conclusions from the results of this study. First, according to antimicrobial susceptibility, the rates of resistance to primary antimicrobial agents are high and those to high-level agents, including vancomycin, are low. Second, the trends of resistance rates are acceptable, especially for high-level agents, although long-term and continuous monitoring is necessary. Finally, the clinical outcomes of neurosurgical adults with coagulase-negative staphylococci-related health care-associated ventriculitis and meningitis are acceptable after treatment with vancomycin. Therefore, according to the antimicrobial susceptibility and clinical practice, vancomycin will be safe to treat coagulase-negative staphylococci-related health care-associated ventriculitis and meningitis.

Background. Functional nasal endoscopic surgery (FESS) is an effective treatment approach for chronic rhinosinusitis with nasal polyps (CRSwNP) patients, but some patients still suffer from postoperative recurrence. This study is aimed at investigating the expression of multiple cytokines in CRSwNP and revealing their relationships with postoperative recurrence. Methods. A total of 72 patients with CRSwNP, including 36 primary and 36 recurrent patients, were enrolled. Serum samples were obtained, 30 cytokine levels were measured by multiplex analysis, and the association between cytokine levels and recurrence was assessed. The most potential cytokines were further validated in another independent cohort with 60 primary and 60 recurrent CRSwNP patients. Results. The results of multiple cytokine profiling exhibited that the levels of eotaxin, G-CSF, IFN-α, IL-13, IL-17A, IL-5, MCP-1, and RANTES were vastly changed in the recurrent group in comparison with the primary group. Receiver-operating characteristic (ROC) curves highlighted that serum levels of eotaxin, IL-17A, and RANTES were strongly predictive of postoperative recurrence (area under the curve AUC>0.7, P

Objective. Clopidogrel is widely used for preventing ischemic complications related to cardiovascular diseases. However, many patients experience clopidogrel resistance (CR). The polymorphisms of CYP2C19 have been implicated in CR, but CYP2C19 polymorphism considerably varies with both ethnic group and geographical location. This study aimed to investigate the association between CYP2C19 polymorphisms and clopidogrel resistance (CR) in patients with coronary heart disease and ischemic stroke among Han and Tibetan populations in Qinghai Province, China. Methods. From June 2019 to January 2020, patients who were diagnosed with coronary heart disease or cerebral infarction in internal medicine of Qinghai Provincial People’s Hospital and had taken dual antiplatelet drugs were included in this study. Blood was collected and routine items were completed. Whole exome sequencing was performed for CYP2C19 genetic polymorphisms of CYP2C19∗2 (rs4244285), CYP2C19∗3 (rs4986893), and CYP2C19∗17 (rs12248560). Results. A total of 91 patients with coronary heart disease or cerebral infarction (67 Han people (65.99 ± 12.25 years old) and 24 Tibetan (63.6324 Tib years old)) including 52 cases with CR and 39 cases with non-CR were enrolled in this study. For the Han population, the differences in age, glycosylated hemoglobin, activated partial thromboplastin time (APTT), gender, aspirin resistance, and diabetes were significant between the CR and non-CR groups. For the Tibetan population, the two groups showed no significant difference in all indicators. There was no significant difference between CR and non-CR groups for all genotypes (CYP2C19 ∗2, ∗3, and ∗17) in either Han or Tibetan populations. For the Han populations, age, APTT, and aspirin resistance were significantly correlated with CR. Conclusion. The present study indicated that CYP2C19∗2, CYP2C19∗3, and CYP2C19∗17 alleles were not correlated with CR for both Han and Tibetan populations in Qinghai Province, while age, APTT, and aspirin resistance were independent risk factors of CR in this region.

BackgroundTo examine the prospective association between higher blood pressure (BP) and risk of type 2 diabetes mellitus (T2DM) in middle-aged and elderly Chinese adults.MethodsA total of 9,642 middle-aged and elderly Chinese adults (≥45 years old; 47.30% men) without diabetes from the China Health and Retirement Longitudinal Study were included for analyses. Participants were categorized into three groups: normal BP, prehypertension, and hypertension, according to the 2010 Chinese Guidelines for the Management of Hypertension. The incidence of T2DM was determined by self-reported physician diagnosis during two follow-up surveys conducted in 2013 to 2014 and 2015 to 2016.ResultsDuring the 4-year follow-up, 429 participants (4.45%) developed T2DM, including 3.51% of the men and 5.29% of the women. The incidence rates of T2DM were 2.57%, 3.75%, and 6.71% in the normal BP, prehypertension, and hypertension groups, respectively. After adjustment for age, sex, education level, residence, smoking status, alcohol consumption, body mass index, waist circumference, and dyslipidemia, both prehypertension (odds ratio [OR], 1.32; 95% confidence interval [CI], 0.98 to 1.77) and hypertension (OR, 2.02; 95% CI, 1.54 to 2.64) were associated with increased risk of T2DM, compared to those with a normal BP. The ORs associated with T2DM were 1.08 (95% CI, 1.03 to 1.13) for an increase of 10 mm Hg in systolic BP and 1.06 (95% CI, 1.01 to 1.10) for an increase of 5 mm Hg in diastolic BP.ConclusionHigher BP is a risk factor for T2DM in middle-aged and elderly Chines. It may be a potential target for diabetes prevention.

Drug-facilitated sexual assault (DFSA) is a sexual act in which the victim is unable to give or rescind consent due to alcohol or drug intoxication, which involved the abuse of benzodiazepines around the world. Conventional techniques used for the analysis of benzodiazepines have the limitation of short detection time window due to the rapid metabolism of these drugs in body. This study aimed to investigate the characteristic changes of metabolites in the blood of rats after ingesting diazepam/clonazepam through a gas chromatography-mass spectrometry-based metabolomics method, allowing the indirect reveal of the rats ingested diazepam/clonazepam. First, we found that diazepam and clonazepam in the blood of rats could not be detected by liquid chromatography-tandem mass spectrometry after 48 h of ingestion. Then, orthogonal partial least squares discrimination analysis regression models were, respectively, constructed to determine whether the rats ingested diazepam/clonazepam after 48 h. The results showed that 5 metabolites were found to be associated with diazepam exposure, and 7 metabolites were found to be associated with clonazepam exposure, which may be characterization for the evaluation of digestion of diazepam and clonazepam in rat.

Symmetry brings beauty, while asymmetry is the general law of nature. This paper reports a novel parallel-type asymmetric memristive diode-bridge (AMDB) emulator, which is implemented by an unbalance diode-bridge linked with a RC filter. Following the voltage constraints of the unbalance diode-bridge, the mathematical model of the parallel-type AMDB emulator is established. Thereafter, the asymmetric property of the hysteresis loops is demonstrated by the numerical simulations and confirmed by the hardware experiments. Furthermore, by importing the parallel-type AMDB emulator into the classical Chua’s circuit, a novel memristive Chua’s circuit is proposed, so that the asymmetric double-scroll chaotic attractor, asymmetric coexisting single-scroll chaotic attractors, and asymmetric coexisting limit cycles can be revealed herein. The parallel-type AMDB emulator enriches the types of memristor emulators and it can mimic the asymmetric property of the physical memristor device.

Due to the continuous improvement in packaging technique widely used for illicit drug trafficking, body packers involved in criminal activities are rarely arrested or died of chemical intoxication. A fatal case of a young body packer was presented with packages of morphine served as analgesics for clinical activities or raw material for opioids, which was seldom reported for body packing in contrast to the main illegal substances such as cocaine, heroin, and methamphetamine. A literature review regarding deaths from morphine poisoning was conducted to summarize data to support medico-legal practice. Our study provides a possible insight into the packages’ leakage or rupture of illegal substances occasionally discovered during forensic autopsy. Based on the unusual case compared with previous data, raising awareness of the drug traffic pathways of road routes would be useful for identifying possible unrecognized cases of body packing.

Nowadays, the abuse of illegal drugs has been an increasingly grim problem in the world. Excitation–emission matrix fluorescence combined with parallel factor analysis was used to make a quantitative analysis of the simulated amphetamine-type illegal drugs. Satisfactory results were achieved for simultaneous determination of methamphetamine (MAM) and 3, 4-methylenedioxymethamphetamine (MDMA) in the presence of adulterants. The average recoveries were (99.8 ± 0.6)% and (101.6 ± 5.7)% for MAM and MDMA, respectively. Figures of merit including root-mean-square error of calibration and prediction, sensitivity and selectivity were investigated to evaluate the performance of the proposed method. The limits of detection were 0.054 and 0.002 1 μg/mL for MAM and MDMA, respectively.

This paper presents a new memristive hypogenetic jerk system with sine memductance. The memristive system owns four line equilibrium sets, from which periodically switched memristor initial boosting behaviors are observed. Numerical simulations of two-dimensional largest Lyapunov exponent plot, bifurcation plots, and phase plots are employed to reveal the boosting evolutions. The results indicate that the memristor initial boosting behaviors display obvious cyclicity. In each cycle, infinite coexisting attractors are founded and their positions switch between the two line equilibrium sets composed of index-2 saddle-foci. Furthermore, the cyclic width can be zoomed in or out by an introduced cyclic width controller. Thus, the periodically switched memristor initial boosting behaviors with the cyclic width controller can be adjusted to obtain the initial value domain with more suitable dynamic range or better controllability, which can set good foundation for the control of extreme multistability. Finally, PSIM (Power Simulation) experiments are performed to verify the numerical results.

The aim of this study was to develop a gas chromatography-mass spectrometry (GC-MS)-based metabolomics method to distinguish different kinds of poisons in the blood. We examined the changes in blood metabolites using GC-MS following administration of four different poisons (paraquat, dichlorvos, aconitine, and sodium nitrite). The data were analyzed with orthogonal partial least squares. Then, total and single differential metabolite profiles were evaluated with support vector machine (SVM) models. The results showed that various metabolites (5-ketone proline, 1,5-anhydrohexitol, lactic acid, glycine 2,2-furoic acid, and 3-hydroxybutyric acid) were differential between the experimental groups and the control groups. The accuracy rates of the SVM models established using total and single differential metabolites were 80% and 100%, respectively. In conclusion, we successfully developed a poison screening method. The established SVM models can distinguish four kinds of poisons and could be used to establish a complete poison metabonomic information database. Furthermore, some of the metabolites could be biomarkers of these poisons. Finally, both the models and potential biomarkers may reduce the time required for poison detection and provide direction for solving cases and auxiliary diagnosis.

MicroRNAs (miRNAs) play important roles in the development of various cancers including lung cancer which is one of the devastating diseases worldwide. How miRNAs function in de novo lung tumorigenesis remains largely unknown. We here developed a CRISPR/Cas9-mediated dual guide RNA (dgRNA) system to knockout miRNAs in genetically engineered mouse model (GEMM). Through bioinformatic analyses of human lung cancer miRNA database, we identified 16 downregulated miRNAs associated with malignant progression and performed individual knockout with dgRNA system in KrasG12D/Trp53L/L (KP) mouse model. Using this in vivo knockout screening, we identified miR-30b and miR-146a, which has been previously reported as tumor suppressors and miR-190b, a new tumor-suppressive miRNA in lung cancer development. Over-expression of miR-190b in KP model as well as human lung cancer cell lines significantly suppressed malignant progression. We further found that miR-190b targeted the Hus1 gene and knockout of Hus1 in KP model dramatically suppressed lung tumorigenesis. Collectively, our study developed an in vivo miRNA knockout platform for functionally screening in GEMM and identified miR-190b as a new tumor suppressor in lung cancer.

Successful osseointegration involves the biological behavior of bone marrow stem cells (BMSCs) on an implant surface; however, the role of BMSC-derived extracellular vesicles (EVs)/exosomes in osseointegration is little known. This study aimed to: (i) explore the interaction force between exosomes (Exo) and cells on a titanium surface; (ii) discuss whether the morphology and biological behavior of BMSCs are affected by exosomes; and (iii) preliminarily investigate the mechanism by which exosomes regulate cells on Ti surface. Exosomes secreted by rat BMSCs were collected by ultracentrifugation and analyzed using transmission electron microscopy and nanoparticle tracking analysis. Confocal fluorescence microscopy, scanning electron microscopy, Cell Counting Kit-8 (CCK-8), quantitative real-time polymerase chain reaction techniques, and alkaline phosphatase bioactivity, Alizarin Red staining, and quantification were used to investigate the exosomes that adhere to the Ti plates under different treatments as well as the morphological change, adhesion, spread, and differentiation of BMSCs. We found that exosomes were efficiently internalized and could regulate cell morphology and promoted the adhesion, spreading, and osteogenic differentiation of BMSCs. These were achieved partly by activating the RhoA/ROCK signaling pathway. Our discovery presents a new insight into the positive regulatory effect of exosomes on the biological behaviors of BMSCs on Ti surface and provides a novel route to modify the surface of a Ti implant.

Optogenetics is emerging as an ideal method for controlling cellular activity. It overcomes some notable shortcomings of conventional methods in the elucidation of neural circuits, promotion of neuroregeneration, prevention of cell death and treatment of neurological disorders, although it is not without its own limitations. In this review, we narratively review the latest research on the improvement and existing challenges of optogenetics, with a particular focus on the field of brain injury, aiming at advancing optogenetics in the study of brain injury and collating the issues that remain. Finally, we review the most current examples of research, applying photostimulation in clinical treatment, and we explore the future prospects of these technologies.

Background The aim of this study was to identify associations between dietary intakes of eggs and cholesterol and all‐cause and heart disease mortality in a US population. Methods and Results Data from the National Health and Nutrition Examination Survey 1999–2014 were used in this study, which included 37 121 participants ≥20 years of age. Dietary information was assessed via 24‐hour dietary recalls at baseline. Mortality status was documented until December 31, 2015. Cox proportional hazards models were used to examine the associations between dietary intakes of eggs and cholesterol and all‐cause and heart disease mortality. During a median follow‐up of 7.8 years, 4991 deaths were documented, including 870 deaths from heart disease. No significant association was observed between additional daily consumption of half an egg and all‐cause mortality (multivariable‐adjusted hazard ratio, 1.04; 95% CI, 0.96–1.13), or heart disease mortality (0.96; 0.80–1.14). Each 50‐mg/day increase of cholesterol intake was inversely associated with all‐cause mortality among participants with daily intake

Heavy alcohol drinking is a major public health problem, causing a large disease, social and economic burden in societies. Subjective response (SR) to alcohol is an intermediate characteristic of heavy drinking. A variety of candidate genes have been reported to be associated with SR to alcohol. In this study, we investigated nine single nucleotide polymorphisms (SNPs) related to SR to alcohol in healthy individuals from five Chinese ethnic groups, the Han, Hui, Tibetan, Mongolian and Uygur populations, and a total of 584 bloodstain samples were collected. The nine SNPs included four SNPs in alcohol-metabolizing genes (ADH1B, ADH1C, ALDH2 and CYP2E1*5B) and five SNPs in genes of neurobiological pathways (GABRA2, OPRM1, CHRNA3, HYKK and SLC6A4). A SNaPshot analysis method was developed to type these SNPs simultaneously, and all samples were typed successfully. Statistical analyses of the allele frequencies indicated that the frequencies of all SNPs, except for ADH1C, showed varying degrees of difference in the five studied ethnic groups. Tibetans showed the highest frequencies of risk alleles for heavy drinking at most loci. The genetic polymorphic differences found in this study revealed the variation in genetic susceptibility to heavy drinking in the studied populations.

This study aimed to investigate the effectiveness of 360-degree panorama-based Virtual Reality (360VR) as a tool to simulate real-world site visit experiences in interior design education. In the first stage of evaluation, the online survey was implemented to ask students about their learning experience of using 360VR. The second stage of 360 VR effectiveness evaluation focused on the objective comparison of students learning outcomes between the 360VR method and the traditional approach. The students' experience survey results indicated that 360VR and virtual walkthrough experiences benefited students' understanding of the site during the design process. Students reflected positive 360 VR experiences on their engagement in learning, special layout, visualization, and educational effectiveness. The result of the student learning outcome evaluation showed no significant difference between 360 VR compared to no site visit. However, there was a significant improvement in students' spatial planning, finish selection, and total scores when using the 360 VR method compared to an on-site visit.

Orofacial pain is a universal predicament, afflicting millions of individuals worldwide. Research on the molecular mechanisms of orofacial pain has predominately focused on the role of neurons underlying nociception. However, aside from neural mechanisms, non-neuronal cells, such as Schwann cells and satellite ganglion cells in the peripheral nervous system, and microglia and astrocytes in the central nervous system, are important players in both peripheral and central processing of pain in the orofacial region. This review highlights recent molecular and cellular findings of the glia involvement and glia–neuron interactions in four common orofacial pain conditions such as headache, dental pulp injury, temporomandibular joint dysfunction/inflammation, and head and neck cancer. We will discuss the remaining questions and future directions on glial involvement in these four orofacial pain conditions.