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Rambutan (Nephelium lappaceum L.) (Sapinadeae) fruit, a nutritional staple in Hawaii, exhibits desiccation and physiological browning soon after harvest, and methods to prolong shelf life may be commercially advantageous. In this study, freshly harvested fruit were treated with pectin coatings with or without trans-cinnamaldehyde (TCIN) and stored at 10 °C or 20 °C (room temperature) to evaluate postharvest quality attributes. Control fruit were treated with deionized water only. To find the best formulation of the coatings, three concentrations of TCIN were incorporated into a pectin solution to get 0.05% TCIN, 0.1% TCIN, and 0.2% TCIN coatings. At 0, 2, 4, and 6 days postharvest, fruit stored at 20 °C were evaluated for weight loss, firmness, pericarp browning, sugar, acid, and taste. The results showed that the 0.1% TCIN coating exhibited significantly lower weight loss than both control and the 0.2% TCIN coating through the entire storage time at 20 °C. The 0.1% TCIN coating–treated fruit were significantly firmer than control after 4 days of storage at 20 °C. The 0.1% TCIN coating also significantly reduced the pericarp browning over the control. Therefore, we selected 0.1% TCIN coating for fruit storage at 10 °C for up to 15 days. At 10 °C, the control fruit showed significantly higher pericarp browning than all TCIN-containing coated fruit. The 0.1% TCIN-treated fruit showed a significantly higher overall quality value than control fruit. The results indicate that the 0.1% TCIN coating may extend the commercial shelf life of rambutans and other perishable fruits. By extending shelf life, this coating can reduce postharvest losses and facilitate expanded fruit exports in Hawaii.

Apriona swainsoni is a vital forest pest prevalent in China. The larvae of A. swainsoni live solely in the branches of trees and rely entirely on the xylem for nutrition. However, there is still a lack of in-depth research on the gut microbiota’s use of almost nitrogen-free wood components to provide bio-organic macromolecular components needed for their growth. Thus, in this study, the metagenome, metaproteome, and metabolome of the A. swainsoni larvae in four gut segments (foregut; midgut; anterior hindgut; posterior hindgut) were analyzed by the multi-omics combined technology, to explore the metabolic utilization mechanism of the corresponding gut microbiota of A. swainsoni. Firstly, we found that the metagenome of different gut segments was not significantly different in general, but there were different combinations of dominant bacteria and genes in different gut segments, and the metaproteome and metabolome of four gut segments were significantly different in general. Secondly, the multi-omics results showed that there were significant gradient differences in the contents of cellulose and hemicellulose in different segments of A. swainsoni, and the expression of corresponding metabolic proteins was the highest in the midgut, suggesting the metabolic characteristics of these lignocellulose components in A. swainsoni gut segments. Finally, we found that the C/N ratio of woody food was significantly lower than that of frass, and metagenomic results showed that nitrogen fixation genes mainly existed in the foregut and two hindgut segments. The expression of the key nitrogen fixing gene nifH occurred in two hindgut parts, indicating the feature of nitrogen fixation of A. swainsoni. In conclusion, our results provide direct evidence that the larvae of A. swainsoni can adapt to the relatively harsh niche conditions through the highly organized gut microbiome in four gut segments, and may play a major role in their growth.

IntroductionEither exposure to secondhand smoke (SHS) or frailty has been linked to adverse health outcomes in nonsmoking adults. However, their relationship is rarely studied. The purpose of this study is to examine the association between serum cotinine level and frailty status among non-smoking older adults.MethodThe study population consisted of 2,703 older adults aged ≥60 from the National Health and Nutrition Examination Survey 2011–2014. Non-smokers were included based on (1) a serum cotinine level ≤ 10 ng/mL and 2) a response of “no” to the question, “Do you currently smoke?” Frailty status was measured based on the Fried Phenotype and had three groups- robust, pre-frailty, and frailty. Multinomial logistic regression models were constructed to examine the association between serum cotinine level quartile and frailty status, controlling for age, sex, race/ethnicity, education, depressive symptoms, alcohol use, and systolic blood pressure.ResultsAbout half of the participants (median age 70.0 years, range 64–78) were female (53.6%), non-Hispanic White (48.3%), and completed some college and above (50.1%). Multinomial logistic regression with a reference group being those in the 1st quantile (the lowest) of serum cotinine level showed that participants in the 4th quartile (the highest) of serum cotinine level had increased odds of pre-frailty vs. robust (OR 1.522, 95% confidence interval [CI] 1.060, 2.185, P = 0.023) as well as increased odds of frailty vs. robust (OR 2.349, 95% CI 1.081, 5.107, P = 0.031).ConclusionsHigher serum cotinine level is associated with increased risk of pre-frailty and frailty versus robust in non-smoking older adults. Prevention and reduction of SHS in older adults may help protect them from developing pre-frailty or frailty.

Background: Head and neck squamous cell carcinoma (HNSCC) is a malignant tumor with a very high mortality rate, and a large number of studies have confirmed the correlation between inflammation and malignant tumors and the involvement of inflammation-related regulators in the progression of HNSCC. However, a prognostic model for HNSCC based on genes involved in inflammatory factors has not been established.Methods: First, we downloaded transcriptome data and clinical information from patients with head and neck squamous cell carcinoma from TCGA and GEO (GSE41613) for data analysis, model construction, and differential gene expression analysis, respectively. Genes associated with inflammatory factors were screened from published papers and intersected with differentially expressed genes to identify differentially expressed inflammatory factor-related genes. Subgroups were then typed according to differentially expressed inflammatory factor-related genes. Univariate, LASSO and multivariate Cox regression algorithms were subsequently applied to identify prognostic genes associated with inflammatory factors and to construct prognostic prediction models. The predictive performance of the model was evaluated by Kaplan-Meier survival analysis and receiver operating characteristic curve (ROC). Subsequently, we analyzed differences in immune composition between patients in the high and low risk groups by immune infiltration. The correlation between model genes and drug sensitivity (GSDC and CTRP) was also analyzed based on the GSCALite database. Finally, we examined the expression of prognostic genes in pathological tissues, verifying that these genes can be used to predict prognosis.Results: Using univariate, LASSO, and multivariate cox regression analyses, we developed a prognostic risk model for HNSCC based on 13 genes associated with inflammatory factors (ITGA5, OLR1, CCL5, CXCL8, IL1A, SLC7A2, SCN1B, RGS16, TNFRSF9, PDE4B, NPFFR2, OSM, ROS1). Overall survival (OS) of HNSCC patients in the low-risk group was significantly better than that in the high-risk group in both the training and validation sets. By clustering, we identified three molecular subtypes of HNSCC carcinoma (C1, C2, and C3), with C1 subtype having significantly better OS than C2 and C3 subtypes. ROC analysis suggests that our model has precise predictive power for patients with HNSCC. Enrichment analysis showed that the high-risk and low-risk groups showed strong immune function differences. CIBERSORT immune infiltration score showed that 25 related and differentially expressed inflammatory factor genes were all associated with immune function. As the risk score increases, specific immune function activation decreases in tumor tissue, which is associated with poor prognosis. We also screened for susceptibility between the high-risk and low-risk groups and showed that patients in the high-risk group were more sensitive to talazoparib-1259, camptothecin-1003, vincristine-1818, Azd5991-1720, Teniposide-1809, and Nutlin-3a (-) −1047.Finally, we examined the expression of OLR1, SCN1B, and PDE4B genes in HNSCC pathological tissues and validated that these genes could be used to predict the prognosis of HNSCC.Conclusion: In this experiment, we propose a prognostic model for HNSCC based on inflammation-related factors. It is a non-invasive genomic characterization prediction method that has shown satisfactory and effective performance in predicting patient survival outcomes and treatment response. More interdisciplinary areas combining medicine and electronics will be explored in the future.

Microorganisms play as fundamental contributors to maintain hosts’ fitness, which can be shaped by external environment. Moreover, symbiotic microbiome also varied within species (e.g., between sexes and developmental stages). However, we still need more studies to quantify whether the intraspecific variation patterns of symbiotic microbes can be modified with the change of environment. The Chinese giant salamander (CGS; Andrias davidianus) is a Critically Endangered species. Despite quantitative captive bred individuals were released to rebuild wild populations, the effectiveness is limited. More importantly, no studies have revealed the adaptation of released CGSs to the complex field conditions. In the present study, we explored whether reintroduction can reshape the intraspecific variations of symbiotic microbiota in captive bred CGSs using high-throughput amplicon sequencing of the16S rRNA gene. We found no significant difference of symbiotic microbiome in captive bred males and females, but released males and females differed significantly in skin microbiome. Juveniles had higher diversity of microbial symbiont than adults in hatchery, but lower diversity in field. Moreover, dominant bacterial taxa differed between juveniles and adults in both hatchery and field. Importantly, this symbiotic microbiome variations within species can be modified (alpha and beta diversity, and community composition) when captive bred individuals were released to the field. Overall, we observed a lower alpha diversity and higher relative abundance of Chryseobacterium, Plesiomonas, and Acinetobacter in the bacterial community of captive bred individuals. Instead, higher alpha diversity of symbiotic microbiota and higher relative abundance of S24-7 and Lactobacillus was detected in released individuals. These modifications may associate with the change of living environment, as well as the specific behavior within CGSs (e.g., movement patterns and foraging activities). Future studies can incorporate other approaches (e.g., blood physiology) to better evaluate the growth and health of reintroduced CGSs.

Over the past few decades, there has been a noticeable surge in the market of plant-based meat analogs (PBMA). Such popularity stems from their environmentally friendly production procedures as well as their positive health effects. In order to meet the market demand, it is necessary to look for plant protein processing techniques that can help them match the quality of conventional meat protein from the aspects of sensory, quality and functionality. Bean proteins are ideal options for PBMA with their easy accessibility, high nutrient-density and reasonable price. However, the high polyunsaturated lipids content of beans inevitably leads to the unpleasant beany flavor of soy protein products, which severely affects the promotion of soy protein-based PBMA. In order to solve this issue, various methods including bleaching, enzyme and fermentation etc. are developed. Among these, fermentation is widely investigated due to its high efficiency, less harm to the protein matrix, targeted performance and low budget. In addition, proper utilization of microbiome during the fermentation process not only reduces the unpleasant beany flavors, but also enhances the aroma profile of the final product. In this review, we provide a thorough and succinct overview of the mechanism underlying the formation and elimination of beany flavor with associated fermentation process. The pros and cons of typical fermentation technologies for removing beany flavors are discussed in alongside with their application scenarios. Additionally, the variations among different methods are compared in terms of the strains, fermentation condition, target functionality, matrix for application, sensory perception etc.

IntroductionPseudomonas aeruginosa is a major nosocomial pathogen that frequently causes ventilator-associated pneumonia in specific populations. Sodium houttuyfonate (SH) has shown mild antibacterial activity against P. aeruginosa in vitro, but the mechanism of potent antimicrobial activity of SH against P. aeruginosa infection in vivo remains unclear.MethodsHere, using the mouse pneumonia model induced by P. aeruginosa nasal drip to explore the therapeutic effects of SH.ResultsWe found that SH exhibits dose-dependent therapeutic effects of reducing P. aeruginosa burden and systemic inflammation in pneumonia mice. SH ameliorates inflammatory gene expression and production of inflammatory proteins, such as interleukin-6 (IL-6), nuclear factor kappa-B (NF-κB) and toll-like receptor 4 (TLR4), associated with the TLR4/NF-κB pathway in mice with P. aeruginosa pneumonia. Furthermore, we analyzed the intestinal flora of mice and found that compared with the model group, the abundance and diversity of beneficial bacterial flora of SH treatment groups increased significantly, suggesting that SH can improve the intestinal flora disorder caused by inflammation. In addition, SH improves alpha and beta diversity index and reduces species abundance differences of intestinal flora in pneumonia mice.DiscussionTaken together, our presented results indicate that SH may effectively alleviate the acute pulmonary infection induced by P. aeruginosa by reducing the disturbance of regulating immunity and intestinal flora in mice.

Study region: Mixed- and tall-grass prairies in the southern Great Plains, USA Study focus: Estimates of evapotranspiration (ET) are widely available from remote sensing and commonly used for water management. However, this approach is limited by prolonged satellite revisit periods and prominent algorithm-induced bias. We compared ET estimates from MODIS (Moderate Resolution Imaging Spectroradiometer) products and those based on the biophysically-based Soil and Water Assessment Tool (SWAT) to measurements using the eddy covariance (EC) technique for a subhumid, tall-grass prairie site near Stillwater, Oklahoma (OK) and a semiarid, mixed-grass prairie site near Clinton, OK in the southern Great Plains, USA. New hydrological insights for the region: SWAT and MODIS produced ET estimates closer to EC measurements for the tall-grass prairie (calibration site) than for the mixed-grass prairie (validation site), with a better performance from SWAT. For the tall-grass prairie, the R2 values were relatively high and comparable (0.77 and 0.87), and the biases were relatively small (−0.40% and 5.04%) for the SWAT and MODIS comparisons to EC. SWAT performed much better than MODIS for the mixed-grass prairie with R2 values of 0.68 vs. 0.13 and bias of − 1.87% vs. − 45.71%, respectively. The SWAT simulation also reproduced better estimates of aboveground net primary productivity than the MODIS products. This study suggests that site-specific SWAT simulations can produce better ET estimates than MODIS products, especially in the water-limited mixed-grass prairie.

Particulate matter (PM) produced by moving vehicles causes the deterioration of urban air quality and seriously endangers the health of residents. By considering PM10 as discrete phase and adopting dynamic mesh updating technology, a mathematical model of PM10 dispersion in three-dimensional ideal street canyon is established to evaluate the contribution of vehicle-induced turbulence to the dispersion of PM10. The dynamic spatial distribution characteristics of PM10 are analyzed when the average vehicle speed is 60 km/h, 50 km/h and 40 km/h. PM10 diffuses outwards in the form of alternating turbulent vortices on both sides, and its diffusion law is mainly affected by vehicle-induced turbulence. After a quarter of total moving time, the peak concentration of PM10 on the horizontal monitoring line drops to 0.3%, 14.4% and 10.7%, respectively, and the peak concentration of PM10 on the vertical monitoring line drops to 0.03%, 9.6% and 4.3%, respectively. For car drivers, they need to maintain a following distance of more than 3.5 m. For roadside pedestrians, they only need to walk on the sidewalk as required. This paper studies the diffusion of PM10 under different moving conditions from microscopic perspective, and provides a theoretical basis for urban development of traffic emission control measures.

Volume-to-point (VP) problem is a classic prototype of heat conduction optimization and benefits important applications such as electronic devices thermal management. However, many studies employ various optimization principles without verifying their applicability; some other studies rashly apply a single principle on different cases but ignore influences of various objectives and boundary conditions. Here, a novel optimization principle for VP problems is derived by applying adjoint analysis, where the minimization of average temperature is considered as an example. The derived optimization principle reads the optimal thermal conductivity distribution maximizes the synergy between temperature gradient and adjoint temperature gradient fields. Relations among the proposed principle and three common ones are clarified rigorously, and reasons of why the latter cannot give optimal results are revealed. A one- and a two-dimensional cases are numerically optimized to validate the proposed principle, and results show that it gives the lowest average temperature as expected. For instance, the average temperature after optimization by using the proposed principle can be lower than that obtained from entropy generation minimization by around 25 and 10 K in the one- and two-dimensional cases studied, respectively. The presented derivation also applies to other objectives for obtaining corresponding optimization principle, showing its flexibility.

T cell receptor (TCR) repertoire as a biomarker for predicting immunotherapy efficiency has been widely studied. However, its dynamics during radiotherapy combined with PD-1 blockade is little known. Using paired tumor and blood samples from the phase Ib clinical study (NCT03222440), we investigate the time-spatial TCR repertoire in esophageal squamous cell carcinoma (ESCC) patients treated with first-line definitive radiotherapy concurrently with anti-PD-1 antibody camrelizumab, and also evaluate the association between TCR repertoire and clinical outcomes. TCR sequencing was performed on tumor biopsies (n = 34, 15 pairs) and peripheral CD8+ T cells (n = 36, 18 pairs) collected at baseline and during treatment (after 40 Gy radiation and 2 rounds of camrelizumab). Whole exome sequencing was applied to estimate genomic mutations and tumor mutation burden. We show that the intratumoral TCR repertoire at baseline was correlated with tumor microenvironment and presented heterogeneity inter-individually. T-cell clones inflowed mutually between tumors and peripheral blood under combination treatment, resulting in an elevation of intratumoral TCR diversity. The peripheral CD8+ TCR diversity at baseline, increased tumor-peripheral Morisita-Horn overlap during treatment, and expansion of persistent intratumoral T-cell clones during treatment predicted improved survival. While it is unclear whether radiation contributed to the TCR changes versus PD-1 therapy alone, our results firstly reveal radiotherapy combined with PD-1 blockade greatly promoted time-spatial alteration of TCR repertoire between tumor and peripheral blood, which demonstrate the peripheral CD8+ TCR diversity at baseline and dynamic alteration of intratumoral TCRs acted as potential effective biomarkers of radiotherapy combined with immunotherapy in ESCC.

The past decades have witnessed the flourishing of non-Hermitian physics in non-conservative systems, leading to unprecedented phenomena of unidirectional invisibility, enhanced sensitivity and more recently the novel topological features such as bulk Fermi arcs. Among them, growing efforts have been invested to an intriguing phenomenon, known as the non-Hermitian skin effect (NHSE). Here, we review the recent progress in this emerging field. By starting from the one-dimensional (1D) case, the fundamental concepts of NHSE, its minimal model, the physical meanings and consequences are elaborated in details. In particular, we discuss the NHSE enriched by lattice symmetries, which gives rise to unique non-Hermitian topological properties with revised bulk-boundary correspondence (BBC) and new definitions of topological invariants. Then we extend the discussions to two and higher dimensions, where dimensional surprises enable even more versatile NH.SE phenomena. Extensions of NHSE assisted with extra degrees of freedom such as long-range coupling, pseudospins, magnetism, non-linearity and crystal defects are also reviewed. This is followed by the contemporary experimental progress for NHSE. Finally, we provide the outlooks to possible future directions and developments.

Hyperbolic metasurfaces with unique dispersion properties can manipulate light–matter interactions according to the demands. However, due to their inherent physical properties, topological transitions (flat bands) exist only in the orthogonal directions, which greatly limit their application. Here, we unveil rich dispersion engineering and topological transitions in hyperbolic metasurfaces. Based on the effective medium theory, the rotation matrix is introduced into the dispersion relation to explain the distorted energy band diagrams, iso-frequency contours and higher-order multi-dipoles of the novel twisted metasurfaces, thereby forming multi-directional topological transitions and surface plasmon polariton propagation. Furthermore, we develop an integrated model to realize new dual-channel negative refraction and nondiffraction negative refraction. The phenomena observed in the experiments match well with the simulations, which proves that the designed metasurfaces make new types of negative refraction possible and will help to overcome the diffraction limit. The hyperbolic metasurfaces presented here exhibit exceptional capabilities for designing microscopes with a super lens at the molecular level, concealment of military aircraft, invisibility cloaks and other photonic devices with higher transmission efficiency.

In order to solve the problem of false terrains caused by environmental interferences and tunneling effect in the conventional multi-beam seafloor terrain detection, this paper proposed a seafloor topography detection method based on fast two-dimensional (2D) Censored Mean Level Detector-statistics Constant False Alarm Rate (CMLD-CFAR) method. The proposed method uses s cross-sliding window. The target occlusion phenomenon that occurs in multi-target environments can be eliminated by censoring some of the large cells of the reference cells, while the remaining reference cells are used to calculate the local threshold. The conventional 2D CMLD-CFAR methods need to estimate the background clutter power level for every pixel, thus increasing the computational burden significantly. In order to overcome this limitation, the proposed method uses a fast algorithm to select the Regions of Interest (ROI) based on a global threshold, while the rest pixels are distinguished as clutter directly. The proposed method is verified by experiments with real multi-beam data. The results show that the proposed method can effectively solve the problem of false terrain in a multi-beam terrain survey and achieve a high detection accuracy.

Abstract Background The identification of biomarkers to select patients with metastatic renal cell carcinoma (mRCC) most likely to respond to combination immunotherapy (IO) is needed. We sought to investigate an association of the baseline neutrophil-to-eosinophil ratio (NER) with outcomes to nivolumab plus ipilimumab for patients with mRCC. Methods We performed a retrospective review of patients with clear cell mRCC treated with nivolumab plus ipilimumab from Vanderbilt-Ingram Cancer Center and Duke Cancer Institute. Patients with prior receipt of immunotherapy and those without available baseline complete blood count with differential were excluded. Patients were divided into groups by the median baseline NER and analyzed for overall survival (OS), progression free survival (PFS), and objective response rate (ORR). Patients were also divided by median baseline neutrophil-to-lymphocyte ratio (NLR) and analyzed for clinical outcome. Further analyses of patients above/below the median NER and NLR were performed in subgroups of IMDC intermediate/poor risk, IMDC favorable risk, and treatment naïve patients. Results A total of 110 patients were included: median age was 61 years and 75% were treatment naïve. The median NER (mNER) at baseline was 26.4. The ORR was 40% for patients with mNER (OR 2.39, p = 0.04). The median PFS for patients with mNER (HR 0.50, p mNER (HR 0.31, p mNLR group. Conclusions A lower baseline NER was associated with improved clinical outcomes (PFS, OS, and ORR) in patients with mRCC treated with nivolumab plus ipilimumab, and prospective validation of the baseline NER as a predictive biomarker for response to immunotherapy-based combinations in mRCC is warranted.

Abstract The global coronavirus disease 2019 (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a positive-sense RNA virus. How the host immune system senses and responds to SARS-CoV-2 infection remain largely unresolved. Here, we report that SARS-CoV-2 infection activates the innate immune response through the cytosolic DNA sensing cGAS-STING pathway. SARS-CoV-2 infection induces the cellular level of 2′3′-cGAMP associated with STING activation. cGAS recognizes chromatin DNA shuttled from the nucleus as a result of cell-to-cell fusion upon SARS-CoV-2 infection. We further demonstrate that the expression of spike protein from SARS-CoV-2 and ACE2 from host cells is sufficient to trigger cytoplasmic chromatin upon cell fusion. Furthermore, cytoplasmic chromatin-cGAS-STING pathway, but not MAVS-mediated viral RNA sensing pathway, contributes to interferon and pro-inflammatory gene expression upon cell fusion. Finally, we show that cGAS is required for host antiviral responses against SARS-CoV-2, and a STING-activating compound potently inhibits viral replication. Together, our study reported a previously unappreciated mechanism by which the host innate immune system responds to SARS-CoV-2 infection, mediated by cytoplasmic chromatin from the infected cells. Targeting the cytoplasmic chromatin-cGAS-STING pathway may offer novel therapeutic opportunities in treating COVID-19. In addition, these findings extend our knowledge in host defense against viral infection by showing that host cells’ self-nucleic acids can be employed as a “danger signal” to alarm the immune system.

Abstract Background Non-alcoholic fatty liver disease (NAFLD) is characterized by ectopic accumulation of triglycerides in the liver. Emerging evidence has demonstrated that lipophagy regulates lipid mobilization and energy homeostasis in the liver. Sirtuin 3 (SIRT3), a mitochondrial NAD+-dependent deacetylase, modulates the activities of several substrates involving in autophagy and energy metabolism. Honokiol (HK) is a natural lignan from the plants of Magnolia genus that exhibits potent liver protective property. Methods AML12 was challenged with 500 μM palmitic acid and 250 μM oleic acid mixture solution to induce lipotoxicity. C57BL/6J mice were fed with a choline-deficient high fat diet (CDHFD) to generate liver steatosis. The expression of autophagy-related and AMP-activated protein kinase (AMPK) pathway proteins was evaluated by Western blotting and immunofluorescence staining. Intracellular lipid accumulation was validated by Nile red staining. Molecular docking analysis was performed on AutoDock 4.2. Results HK (5 and 10 μM) was found to attenuate lipid accumulation through promoting SIRT3-AMPK-mediated autophagy, mainly on lipid droplets. HK had hydrophobic interaction with amino acid residues (PHE294, GLU323 and VAL324) and NAD+. Moreover, HK improved mitochondrial function to enhance lipolysis, through decreasing the acetylated long-chain acyl-CoA dehydrogenase level. In CDHFD-fed mice, HK (2.5 and 10 mg/Kg) treatment obviously prevented lipid accumulation in the liver. And co-treatment of the AMPK inhibitor, Compound C, almost abolished the above changes. Conclusions These results suggest that HK could ameliorate lipotoxicity in hepatocytes by activating SIRT3-AMPK-lipophagy axis, which might be a potential therapeutic agent against NAFLD.

Abstract The no‐reference image quality assessment (NR‐IQA) method can evaluate the distortions in an image without the reference image. However, due to the diversity of the image contents and distortion types, it is hard for the existing NR‐IQA algorithms to obtain competitive performance on both synthetically and authentically distorted images. To address the problem, a multiscale feature representation‐based NR‐IQA method that performs well for both synthetic and authentic distortions is proposed. This model consists of two parts: The feature extraction part and the feature fusion part. First, part of the Res2Net‐50 network is chosen as the feature extraction part due to its high ability in increasing the range of receptive fields. Then, the feature fusion part consisting of a novel residual block and two fully connected layers is designed to fuse the extracted features and realize the quality score mapping. After a series of stepwise optimization experiments, the most competitive network architecture consisting of the feature extraction part and the feature fusion part is obtained. Comprehensive experiments on the LIVE, TID2013, CSIQ, KADID‐10k, KonIQ‐10K, and LIVE challenge databases demonstrate that the proposed method can work powerfully on both the synthetic and authentic distortions and also has a strong generalization ability.

Hypertension is one of the most reported cardiovascular and cerebrovascular diseases with significantly high morbidity and mortality rates. This condition threatens the very existence of human beings. Numerous studies conducted earlier revealed the good therapeutic effect of isorhynchophylline on hypertension since the former regulates the metabolic disorders in neurotransmitters. However, the mechanism behind this action is yet to be deciphered. The current study followed the targeted metabolomics method to investigate the changes in the neurotransmitter level in the hippocampus of spontaneously hypertensive rats (SHRs) after the rats were treated with isorhynchophylline. The authors predicted the metabolic pathways involved in extensively modified neurotransmitters. Further, the expressions of metabolism-key enzymes in mRNA and protein levels were also determined. When treated with isorhynchophylline, it induced notably varying metabolomic profiles of the hippocampus in SHRs. Isorhynchophylline perturbed a total of seven extensively modified neurotransmitters as well as the primarily related pathways such as tyrosine and glutamate metabolism. An increase in the key metabolic enzymes such as DDC, MAO, COMT, TH, and DβH was observed in the SHR group, whereas their levels decreased after treatment with isorhynchophylline. The expression of GAD67 established cross-current validity. So, isorhynchophylline has been proved to have potential therapeutic value to treat hypertension via tyrosine and glutamate metabolism in the hippocampus. Further, the current study also opened new ventures to further investigate the working mechanism of isorhynchophylline in hypertension.

Abstract Sonodynamic therapy (SDT), presenting spatial and temporal control of ROS generation triggered by ultrasound field, has attracted considerable attention in tumor treatment. However, its therapeutic efficacy is severely hindered by the intrinsic hypoxia of solid tumor and the lack of smart design in material band structure. Here in study, fine α-Fe2O3 nanoparticles armored with Pt nanocrystals (α-Fe2O3@Pt) was investigated as an alternative SDT agent with ingenious bandgap and structural design. The Schottky barrier, due to its unique heterostructure, suppresses the recombination of sono-induced electrons and holes, enabling superior ROS generation. More importantly, the composite nanoparticles may effectively trigger a reoxygenation phenomenon to supply sufficient content of oxygen, favoring the ROS induction under the hypoxic condition and its extra role played for ultrasound imaging. In consequence, α-Fe2O3@Pt appears to enable effective tumor inhibition with imaging guidance, both in vitro and in vivo. This study has therefore demonstrated a highly potential platform for ultrasound-driven tumor theranostic, which may spark a series of further explorations in therapeutic systems with more rational material design. Graphical Abstract

Abstract Background Improving oral anticancer agent (OAA) initiation and adherence is the important quality‐of‐care issues, particularly since one fourth of anticancer agents being developed will be administered orally. Our objective was to identify provider‐ and patient‐level characteristics associated with OAA initiation and adherence among individuals with metastatic renal cell carcinoma (mRCC). Methods We used state cancer registry data linked to multi‐payer claims data to identify patients with mRCC diagnosed in 2004–2015. Provider data were obtained from North Carolina Health Professions Data System and the National Plan & Provider Enumeration System. We estimated risk ratios (RRs) and corresponding 95% confidence limits (CLs) using modified Poisson regression to evaluate factors associated with OAA initiation and adherence. Results Among the 207 (out of 687) patients who initiated an OAA following mRCC diagnosis and survived 90 days, median proportion of days covered was 0.91. Patients with a modal provider specializing in hematology/medical oncology were much more likely to initiate OAAs than those seen by other specialties. Additionally, patients with a female provider were more likely to initiate OAAs than those with a male provider. Compared to patients treated by providers practicing in both urban and rural areas, patients with providers practicing solely in urban areas were more likely to initiate OAAs, after controlling for patient‐level factors (RR = 1.37; 95% CL: 1.09–1.73). Medicare patients were less likely to be adherent than those with private insurance (RR = 0.61; 95% CL: 0.42–0.87). Conclusions Our results suggest that provider‐ and patient‐level factors influence OAA initiation in patients with mRCC but only insurance type was associated with adherence.

Abstract Necroptosis is a form of regulated necrotic cell death that promotes inflammation. In cells undergoing necroptosis, activated RIPK1 kinase mediates the formation of RIPK1/RIPK3/MLKL complex to promote MLKL oligomerization and execution of necroptosis. RIPK1 kinase activity also promotes cell-autonomous activation of proinflammatory cytokine production in necroptosis. However, the signaling pathways downstream of RIPK1 kinase in necroptosis and how RIPK1 kinase activation controls inflammatory response induced by necroptosis are still largely unknown. Here, we quantitatively measured the temporal dynamics of over 7000 confident phosphorylation-sites during necroptosis using mass spectrometry. Our study defined a RIPK1-dependent phosphorylation pattern in late necroptosis that is associated with a proinflammatory component marked by p-S473 TRIM28. We show that the activation of p38 MAPK mediated by oligomerized MLKL promotes the phosphorylation of S473 TRIM28, which in turn mediates inflammation during late necroptosis. Taken together, our study illustrates a mechanism by which p38 MAPK may be activated by oligomerized MLKL to promote inflammation in necroptosis.

Abstract Background This study aimed to probe and verify aberrantly methylated and expressed genes in hepatoblastoma and to analyze their interactions with tumor immune microenvironment. Methods Aberrantly methylated and expressed genes were obtained by comprehensively analyzing gene expression and DNA methylation profiles from GSE81928, GSE75271 and GSE78732 datasets. Their biological functions were predicted by the STRING and Metascape databases. CIBERSORT was utilized for inferring the compositions of tumor-infiltrating immune cells (TIICs) in each sample. Correlation between hub genes and immune cells was then analyzed. Hub genes were validated in hepatoblastoma tissues via western blot or immunohistochemistry. After transfection with sh-NOTUM, migration and invasion of HuH-6 and HepG2 cells were investigated. The nude mouse tumorigenesis model was constructed. Results Totally, 83 aberrantly methylated and expressed genes were determined in hepatoblastoma, which were mainly involved in metabolic and cancer-related pathways. Moreover, their expression was liver-specific. 13 hub genes were screened, which were closely related to immune cells in hepatoblastoma tissues. Among them, it was confirmed that AXIN2, LAMB1 and NOTUM were up-regulated and SERPINC1 was down-regulated in hepatoblastoma than normal tissues. NOTUM knockdown distinctly weakened migration and invasion of HuH-6 and HepG2 cells and tumor growth in vivo. Conclusions This study identified aberrantly methylated and expressed signatures that were in relation to immune microenvironment in hepatoblastoma. Targeting NOTUM hub gene could suppress migration and invasion of hepatoblastoma cells. Thus, these aberrantly methylated and expressed genes might act as therapeutic agents in hepatoblastoma therapy.

Objective(s): This study aimed to evaluate the effects and the underlying mechanisms of tertiary butylhydroquinone (TBHQ) on diabetic liver steatosis and cell survival. Materials and Methods: We performed streptozocin injection and used a high-sugar-high-fat diet for mice to develop an animal model of type 2 diabetes mellitus (T2DM). Bodyweight, blood glucose levels, and content of insulin were measured on all of the mice. The liver tissues were observed by hematoxylin-eosin staining. Protein levels of the liver were measured by Western blot analysis in mice. Primary hepatocytes were induced by hypochlorous acid (HClO) and insulin to form insulin resistance (IR). Primary hepatocyte apoptosis was observed by Hoechst staining. The PI3K/AKT signaling pathway and β-arrestin-2 factor were evaluated by Western blot assay. Results: TBHQ reduced the blood glucose level and content of insulin in serum, increased body weight, and effectively alleviated liver steatosis in diabetic mice. TBHQ significantly up-regulated the expression of p-PI3K, p-AKT, GLUT4, GSK3β, and β-arrestin-2 in the liver of diabetic mice. Cell experiments confirmed that TBHQ increased the survival ability of primary hepatocytes, and TBHQ improved the expression of p-PI3K, p-AKT, GLUT4, and GSK3β by activating β-arrestin-2 in primary hepatocytes. Conclusion: TBHQ could alleviate liver steatosis and increase cell survival, and the mechanism is due in part to β-arrestin-2 activation.

As an important part of the space-integrated-ground information network, the satellite communication system has become a research hotspot.The system modeling language (SysML), which is the most popular digital design language, was adopted to analyzing requirements, decomposing functions and synthesizing designs of the satellite communication system.The verifi cation result indicated that the architecture and the service process of the satellite communication system designed in this paper is of robustness to some degree.By used SysML in the digital design of satellite communication system, this research supported the key technologies’ design and verifi cation in the satellite communication system.

BACKGROUND The current technical specification, or standard method, to obtain the precision control level of a certain test item is to send the standard sample and a certain number of actual samples, with a known concentration level, to specific laboratories for comparison testing. OBJECTIVES To provide a more effective, representative and universal precision control evaluation standard. METHODS 871 actual soil samples with different concentration gradients, types (34 kinds) and geographical representation from 31 provinces (autonomous regions and municipalities) were selected and distributed blind to 76 different laboratories. Each sample was subjected to indoor and inter-laboratory parallel comparison tests by 2 to 4 different laboratories. Two standard methods, flame atomic absorption spectrometry (AAS) and wavelength dispersive X-ray fluorescence spectrometry (WD-XRF), which are commonly used in soil ecological environment monitoring in China, were selected. RESULTS When the concentration of Zn is less than 50mg/kg, it is proposed to control RD ≤ 15% in laboratory and RD' ≤ 20% inter laboratories for the open code test samples and standard samples, while RD ≤ 20% in laboratory and RD' ≤ 30% inter laboratories for the blind test samples. In the case of the concentration of Zn is 50-90mg/kg, it is proposed to control RD ≤ 10% in laboratory and RD' ≤ 20% inter laboratories for the open code test samples and standard samples, while RD ≤ 15% in laboratory and RD' ≤ 25% inter laboratories for the blind test samples. When the concentration of Zn is higher than 90mg/kg, it is proposed to control RD ≤ 10% in laboratory and RD' ≤ 15% inter laboratories for the open code test samples and standard samples, while RD ≤ 10% in laboratory and RD' ≤ 20% inter laboratories for the blind test samples. CONCLUSIONS There is no significant difference in the precision control results under AAS and XRF analysis methods. Different soil types may affect the precision control level. The main reason is that different matrix compositions of different soil types lead to different levels of digestion or compaction. Therefore, in actual monitoring work, it is also necessary to consider the difference in requirements of analysis and test conditions for different types of soil and the comparability of test results.

Abiraterone acetate (AA) has been proven effective for metastatic castration-resistant prostate cancer (mCRPC), and it has been proposed that adaptive AA may reduce toxicity and prolong time to progression, when compared to continuous AA. We developed a simple quantitative model of prostate-specific antigen (PSA) dynamics to evaluate prostate cancer (PCa) stem cell enrichment as a plausible driver of AA treatment resistance. The model incorporated PCa stem cells, non-stem PCa cells and PSA dynamics during adaptive therapy. A leave-one-out analysis was used to calibrate and validate the model against longitudinal PSA data from 16 mCRPC patients receiving adaptive AA in a pilot clinical study. Early PSA treatment response dynamics were used to predict patient response to subsequent treatment. We extended the model to incorporate metastatic burden and also investigated the survival benefit of adding concurrent chemotherapy for patients predicted to become resistant. Model simulations demonstrated PCa stem cell self-renewal as a plausible driver of resistance to adaptive therapy. Evolutionary dynamics from individual treatment cycles combined with metastatic burden measurements predicted patient response with 81% accuracy (specificity=92%, sensitivity=50%). In those patients predicted to progress, simulations of the addition of concurrent chemotherapy suggest a benefit between 1% and 11% reduction in probability of progression when compared to adaptive AA alone. This study developed the first mCRPC patient-specific mathematical model to use early PSA treatment response dynamics to predict subsequent responses to adaptive AA, demonstrating the putative value of integrating mathematical modeling into clinical decision making.

COVID-19 pandemic caused by SARS-CoV-2 infection severely threatens global health and economic development. No effective antiviral drug is currently available to treat COVID-19 and any other human coronavirus infections. We report herein that a macrolide antibiotic, carrimycin, potently inhibited the cytopathic effects (CPE) and reduced the levels of viral protein and RNA in multiple cell types infected by human coronavirus 229E, OC43, and SARS-CoV-2. Time-of-addition and pseudotype virus infection studies indicated that carrimycin inhibited one or multiple post-entry replication events of human coronavirus infection. In support of this notion, metabolic labelling studies showed that carrimycin significantly inhibited the synthesis of viral RNA. Our studies thus strongly suggest that carrimycin is an antiviral agent against a broad-spectrum of human coronaviruses and its therapeutic efficacy to COVID-19 is currently under clinical investigation.

Abstract Immunotherapies such as immune checkpoint blockade (ICB) and adoptive cell therapy (ACT) have revolutionized cancer treatment, especially in patients whose disease was otherwise considered incurable. However, primary and secondary resistance to single agent immunotherapy often results in treatment failure, and only a minority of patients experience long-term benefits. This review article will discuss the relationship between cancer immune response and mechanisms of resistance to immunotherapy. It will also provide a comprehensive review on the latest clinical status of combination therapies (e.g., immunotherapy with chemotherapy, radiation therapy and targeted therapy), and discuss combination therapies approved by the US Food and Drug Administration. It will provide an overview of therapies targeting cytokines and other soluble immunoregulatory factors, ACT, virotherapy, innate immune modifiers and cancer vaccines, as well as combination therapies that exploit alternative immune targets and other therapeutic modalities. Finally, this review will include the stimulating insights from the 2020 China Immuno-Oncology Workshop co-organized by the Chinese American Hematologist and Oncologist Network (CAHON), the China National Medical Product Administration (NMPA) and Tsinghua University School of Medicine.

Abstract Background The optimal sequence of pulmonary vessel interruption during lung cancer resection remains controversial. This review aimed to elucidate the association of vein-first versus artery-first ligation and survival of the patients. Methods We searched PubMed, Web of Science, Scopus, Embase, Cochrane Library and Google Scholar from their inception to September 2021 for published articles that compared vein-first (the pulmonary vein was interrupted first) and artery-first procedure (the pulmonary artery was ligated first) during lung cancer surgery. Results Finally, a total of 13 full articles were obtained. First, 7 studies with survival information were included for meta-analyses. As compared with the artery-first ligation, vein-first approach did not decrease the risk of local recurrence (risk ratio [RR] 0.92 in favour of vein-first; 95% confidence interval [CI] 0.61–1.39, p = 0.68) or distant metastasis (RR 0.92; 95% CI 0.30–2.85, p = 0.89); but it was associated with better disease-free survival (RR 0.52; 95% CI 0.37–0.73, p

The existing researches have concluded that the number of gravity heat pipes, insertion depth and angle, filling rate, working fluid will affect the distribution of the internal temperature field of coal pile. However, there are few researches on the optimal arrangement of gravity heat pipes in coal pile. In order to solve the above problems, based on the gravity heat pipe heat transfer theoretical model, the heat source is equivalent to a sphere, and the effect of gravity heat pipe arrangement on the high temperature point of coal pile is analyzed by a combination of numerical simulation and experiment, and the optimal arrangement of gravity heat pipe is derived. The numerical simulation results based on Comsol software show that the depth of gravity heat pipe insertion has greater effect on the temperature of the high-temperature heat source point inside coal pile than the inclination angle of gravity heat pipe insertion. Under the same angle, the greater the gravity heat pipe arrangement depth is, the better. This means that the closer to the heat source, the better. Under the same depth, when the gravity heat pipe arrangement angle is 60, 90, 45 and 30°, the cooling range decreases in order. When the insertion depth of gravity heat pipe is 60 cm and the insertion angle is 60°, the highest cooling range reaches 61.2 ℃, and the coal pile has the best cooling effect. The experimental results based on the coal storage pile heat transfer test bench show that the optimal arrangement of gravity heat pipes is consistent with the simulation results, and the overall trend of the cooling rate is similar to the simulation results. With the increase of the inclination angle, the cooling rate of heat pipe decreases first and then increases, and the cooling rate reaches the maximum when the inclination angle of heat pipe insertion reaches 60°.

The oviduct consists of three parts: the infundibulum (In), ampulla (Am), and isthmus (Is). These have the same histological structure, but different physiological functions. In this study, transcriptomics was used to analyze mRNA in these three parts of yak oviduct. The results showed that there were 325 up-regulated genes and 282 down-regulated genes in the infundibulum and ampulla. Moreover, there were 234 up-regulated genes and 776 down-regulated genes in the isthmus and ampulla, as well as 873 up-regulated genes and 297 down-regulated genes in the infundibulum and isthmus. The expression of C3 in the infundibulum was significantly higher than that in the ampulla and isthmus. The expression of FAU in the isthmus was significantly lower than that in the ampulla and infundibulum, and the expression of EEF1A1 in the ampulla was significantly higher than that in the ampulla and infundibulum. When the infundibulum was compared with the ampulla and isthmus, it was found that the up-regulated genes were enriched in the lysosome, phagosome, staphylococcus aureus infection, and leishmaniasis pathway. When the isthmus was compared with the ampulla and infundibulum, the up-regulated genes were present in the apoptosis pathway, oxidative phosphorylation, and viral myocarditis pathway. When the isthmus was compared with the infundibulum and ampulla, the down-regulated pathways were protein processing in the endoplasmic reticulum and the endocytosis. The Epstein–Barr virus infection pathway was up-regulated according to a comparison of the isthmus and infundibulum and was down-regulated based on a comparison of the isthmus and ampulla. Transcriptional misregulation in the Middle East pathway was up-regulated based on a comparison of the isthmus and ampulla and was down-regulated based on a comparison of the isthmus and infundibulum. ERBB2, JUP, CTNND1, and KRT7 were defined as the hub genes of the yak oviduct. The results of this study provide sufficient omics data for yak fertilization, which is also of great significance to altitude medicine.

Background: Lung adenocarcinoma (LUAD) is the most common subtype of non-small-cell lung cancer (NSCLC). The aim of our study was to determine prognostic risk factors and establish a novel nomogram for lung adenocarcinoma patients. Methods: This retrospective cohort study is based on the Surveillance, Epidemiology, and End Results (SEER) database and the Chinese multicenter lung cancer database. We selected 22,368 eligible LUAD patients diagnosed between 2010 and 2015 from the SEER database and screened them based on the inclusion and exclusion criteria. Subsequently, the patients were randomly divided into the training cohort (n = 15,657) and the testing cohort (n = 6711), with a ratio of 7:3. Meanwhile, 736 eligible LUAD patients from the Chinese multicenter lung cancer database diagnosed between 2011 and 2021 were considered as the validation cohort. Results: We established a nomogram based on each independent prognostic factor analysis for 1-, 3-, and 5-year overall survival (OS) . For the training cohort, the area under the curves (AUCs) for predicting the 1-, 3-, and 5-year OS were 0.806, 0.856, and 0.886. For the testing cohort, AUCs for predicting the 1-, 3-, and 5-year OS were 0.804, 0.849, and 0.873. For the validation cohort, AUCs for predicting the 1-, 3-, and 5-year OS were 0.86, 0.874, and 0.861. The calibration curves were observed to be closer to the ideal 45° dotted line with regard to 1-, 3-, and 5-year OS in the training cohort, the testing cohort, and the validation cohort. The decision curve analysis (DCA) plots indicated that the established nomogram had greater net benefits in comparison with the Tumor-Node-Metastasis (TNM) staging system for predicting 1-, 3-, and 5-year OS of lung adenocarcinoma patients. The Kaplan–Meier curves indicated that patients’ survival in the low-risk group was better than that in the high-risk group ( P

Mutation detecting is a routine work for sequencing data analysis and the trading of existing tools often involves the combinations of signals on a set of overlapped sequencing reads. However, the subclonal mutations, which are reported to contribute to tumor recurrence and metastasis, are sometimes eliminated by existing signals. When the clonal proportion decreases, signals often present ambiguous, while complicated interactions among signals break the IID assumption for most of the machine learning models. Although the mutation callers could lower the thresholds, false positives are significantly introduced. The main aim here was to detect the subclonal mutations with high specificity from the scenario of ambiguous sample purities or clonal proportions. We proposed a novel machine learning approach for filtering false positive calls to accurately detect mutations with wide spectrum subclonal proportion. We have carried out a series of experiments on both simulated and real datasets, and compared to several state-of-art approaches, including freebayes, MuTect2, Sentieon and SiNVICT. The results demonstrated that the proposed method adapts well to different diluted sequencing signals and can significantly reduce the false positive when detecting subclonal mutations. The codes have been uploaded at https://github.com/TrinaZ/TL-fpFilter for academic usage only.

ObjectiveThe systematic immune status of cancer patients undergoing immunotherapy is little known. We prospectively identified the function and differentiation traits of peripheral CD8+ T cells based on our phase 1b clinical trial (NCT03222440) of radiotherapy combined with camrelizumab in patients with locally advanced esophageal squamous cell carcinoma (ESCC) and compared it with concurrent chemoradiotherapy (CCRT).Methods19 and 18 patients were included in the cohort of radiotherapy plus camrelizumab and cohort of CCRT treatment. By using flow cytometry, we evaluated the expression levels of PD-1, Eomes, T-bet and IFN-γ (function), CD38 and HLA-DR (activation), and differentiation subsets classified according to the expression levels of CD45RA and CD62L in peripheral CD8+ T cells before and during treatment.ResultsEffective binding of anti-PD-1 antibody camrelizumab with PD-1 on CD8+ T cells was detected during treatment. Both two treatments elevated the expression levels of activation molecules CD38 and HLA-DR on CD8+ T cells. PD-1+CD8+ T cells had more activation features than PD-1-CD8+ T cells in two groups and the treatments did not alter these differences. The two treatments activated both PD-1+ and PD-1- CD8+ T cells. PD-1+CD8+ T cells had less Naïve and TEMRA but more Tcm and Tem than PD-1-CD8+ T cells in two groups and both two treatments changed the ratio of memory T cells in PD-1+ and PD-1- cells. RT plus camrelizumab treatment reduced Naïve T cells and TEMRA subsets both in PD-1+ and PD-1- CD8+ T cells while elevated Tcm subset in PD-1+CD8+ T cells and Tem subset in PD-1-CD8+ T cells. CCRT elevated Tcm subset and reduced TEMRA subset in PD-1-CD8+ T cells while did not change any subset in PD-1+CD8+ T cells. Furthermore, patients undergoing radiotherapy plus immunotherapy were found to obtain better prognosis than those receiving CCRT.ConclusionsThis study identified the dynamic changes of systematic immune status of patients undergoing treatment. The two treatments had similar activation effects on peripheral CD8+ T cells with different PD-1 properties but had different effects on their differentiation status. These results provided potential clues to the reasons underlying the difference in prognosis of the two treatments.

Over the past 2 decades, researches in artificial neural networks (ANNs) and deep learning have flourished and enabled the applications of artificial intelligence (AI) in image recognition, natural language processing, medical image analysis, molecular and material science, autopilot and so on. As the application scenarios for AI become more complex, massive perceptual data need to be processed in real-time. Thus, the traditional electronic integrated chips for executing the calculation of ANNs and deep learning algorithms are faced with higher requirements for computation speed and energy consumption. However, due to the unsustainability of Moore’s Law and the failure of the Dennard’s scaling rules, the growth of computing power of the traditional electronic integrated chips based on electronic transistors and von Neumann architecture could difficultly match the rapid growth of data volume. Enabled by silicon-based optoelectronics, analog optical computing can support sub-nanosecond delay and ∼fJ energy consumption efficiency, and provide an alternative method to further greatly improve computing resources and to accelerate deep learning tasks. In Chapter 1, the challenges of electronic computing technologies are briefly explained, and potential solutions including analog optical computing are introduced. Then, separated by four photonic platforms, including coherent integration platform, incoherent integration platform, space-propagation optical platform, and optical fiber platform, the recent important research progresses in analog optical computing are outlined in Chapter 2. Then, the nonlinearity and training algorithm for analog optical computing are summarized and discussed in Chapter 3. In Chapter 4, the prospects and challenges of analog optical computing are pointed out.

The combined disease burden of diabetes mellitus (DM) and Alzheimer's disease (AD) is increasing, and the two diseases share some common pathological changes. However, the pharmacotherapeutic approach to this clinical complexity is limited to symptomatic rather than disease-arresting, with the possible exception of metformin. Whether nutritional intervention might extend or synergize with these effects of metformin is of interest. In particular, dietary patterns with an emphasis on dietary diversity shown to affect cognitive function are of growing interest in a range of food cultural settings. This paper presents the association between diabetes and AD. In addition, the cross-cultural nutritional intervention programs with the potential to mitigate both insulin resistance (IR) and hyperglycemia, together with cognitive impairment are also reviewed. Both dietary patterns and nutritional supplementation showed the effects of improving glycemic control and reducing cognitive decline in diabetes associated with AD, but the intervention specificity remained controversial. Multi-nutrient supplements combined with diverse diets may have preventive and therapeutic potential for DM combined with AD, at least as related to the B vitamin group and folate-dependent homocysteine (Hcy). The nutritional intervention has promise in the prevention and management of DM and AD comorbidities, and more clinical studies would be of nutritional scientific merit.

Job burnout is one of the most widespread mental problems in today’s society and seriously affects the mental health and combat effectiveness of soldiers and officers. Herein, the effect of burnout on individual attention is studied from the perspective of neuroelectrophysiology. A total of 1,155 army soldiers and officers were included in this investigation and completed the Job Burnout Scale for Military Personnel. A total of 42 soldiers and officers were randomly selected from those with and without burnout to participate in an event-related potential (ERP) study using a visual oddball task. The characteristics of visual P3a and P3b at Fz, FCz, Cz, CPz, and Pz were recorded and analyzed by repeated-measures analysis of variance (ANOVA). P < 0.05 was the criterion for a significant difference. The total average score on the Job Burnout Scale for Military Personnel among the participants was 0.74 ± 0.46, and the detection rate of job burnout was 29.85%. In the Oddball task, the average number of target stimuli counted in the burnout group was lower than that in the control group, but no significant difference was found. For P3a, the Fz, FCz, Cz, CPz, and Pz amplitudes in the burnout group were significantly lower than those in the control group. The average amplitude of P3a evoked in the central parietal area was larger than that in the prefrontal area. For P3b, the amplitudes of the five electrodes in the burnout group were significantly lower than those in the control group. The average amplitude of P3b evoked in the parietal region was larger than those in the prefrontal and central parietal regions. A certain degree of job burnout is evident in army soldiers and officers. The voluntary attention and involuntary attention of individuals with burnout are both affected to some extent, as reflected by the lower amplitudes of P3a and P3b. The results suggest that P3a and P3b can be used as indicators to monitor cognitive neural function in soldiers and officers with burnout and can also be used as references for evaluating the effects of cognitive training and screening methods. In this study, ERP was used to research the attention ability of soldiers and officers with job burnout, and related issues were discussed from the aspects of the burnout results, behavioral results, ERP results, compensation effect of cognitive resources, application in the military field, limitations, and prospects.

BackgroundBenign paroxysmal positional vertigo (BPPV) is the most common cause of peripheral vestibular vertigo. Although BPPV is benign, its underlying mechanisms are complicated, and patients diagnosed with BPPV are significantly affected by it in their daily lives. Hence, this study's purpose was to investigate global trends and frontiers in the field of BPPV.MethodsWe searched the research literature published from 2002 to 2021 on BPPV using two databases from the Web of Science Core Collection, and we conducted a bibliometric and visualization analysis. Bibliometric tools were used to perform co-authorship, co-citation, and co-occurrence analyses of countries or regions, institutions, authors, journals, keywords, and references.ResultsIn all, 1,419 publications from 4,594 authors, 1,542 institutions, and 65 countries or regions with 71 subject categories were included in the study. The number of articles increased gradually from 2002 to 2021. Seoul National University, the University of Munich, and Osaka University were among the leading institutions with the most publications, while United States of America, South Korea, and China were the leading countries. JS Kim was the most prolific author, Otology & Neurotology was the most prolific journal, and Otorhinolaryngology was the most published subject category. The five most frequently occurring keywords were BPPV, vertigo, dizziness, nystagmus, and management and the top research hot spots were osteoporosis and vitamin D.ConclusionThis study systematically analyzed trends in global scientific research on BPPV. The academic understanding of BPPV has improved significantly over the last two decades, with osteoporosis and vitamin D the two main research hot spots in the field of BPPV in recent years. These findings provide direction for current research to grasp the trends and research frontiers of current research.

Frequent outbreaks of agricultural pests can reduce crop production severely and restrict agricultural production. Therefore, automatic monitoring and precise recognition of crop pests have a high practical value in the process of agricultural planting. In recent years, pest recognition and detection have been rapidly improved with the development of deep learning-based methods. Although certain progress has been made in the research on pest detection and identification technology based on deep learning, there are still many problems in the production application in a field environment. This work presents a pest detector for multi-category dense and tiny pests named the Pest-YOLO. First, the idea of focal loss is introduced into the loss function using weight distribution to improve the attention of hard samples. In this way, the problems of hard samples arose from the uneven distribution of pest populations in a dataset and low discrimination features of small pests are relieved. Next, a non-Intersection over Union bounding box selection and suppression algorithm, the confluence strategy, is used. The confluence strategy can eliminate the errors and omissions of pest detection caused by occlusion, adhesion and unlabeling among tiny dense pest individuals to the greatest extent. The proposed Pest-YOLO model is verified on a large-scale pest image dataset, the Pest24, which includes more than 20k images with over 190k pests labeled by agricultural experts and categorized into 24 classes. Experimental results show that the Pest-YOLO can obtain 69.59% for mAP and 77.71% for mRecall on the 24-class pest dataset, which is 5.32% and 28.12% higher than the benchmark model YOLOv4. Meanwhile, our proposed model is superior to other several state-of-the-art methods, including the SSD, RetinaNet, Faster RCNN, YOLOv3, YOLOv4, YOLOv5s, YOLOv5m, YOLOX, DETR, TOOD, YOLOv3-W, and AF-RCNN detectors. The code of the proposed algorithm is available at: https://github.com/chr-secrect/Pest-YOLO.

Background Immunotherapy combinations including ipilimumab and nivolumab are now the standard of care for untreated metastatic renal cell carcinoma (mRCC). Biomarkers of response are lacking to predict patients who will have a favorable or unfavorable response to immunotherapy. This study aimed to use the OmniSeq transcriptome-based platform to develop biomarkers of response to immunotherapy.Methods Two cohorts of patients were retrospectively collected. These included an investigational cohort of patients with mRCC treated with immune checkpoint inhibitor therapy from five institutions, and a subsequent validation cohort of patients with mRCC treated with combination ipilimumab and nivolumab from two institutions (Duke Cancer Institute and Cleveland Clinic Taussig Cancer Center). Tissue-based RNA sequencing was performed using the OmniSeq Immune Report Card on banked specimens to identify gene signatures and immune checkpoints associated with differential clinical outcomes. A 5-gene expression panel was developed based on the investigational cohort and was subsequently evaluated in the validation cohort. Clinical outcomes including progression-free survival (PFS) and overall survival (OS) were extracted by retrospective chart review. Objective response rate (ORR) was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1.Results The initial investigation cohort identified 86 patients with mRCC who received nivolumab (80%, 69/86), ipilimumab/nivolumab (14%, 12/86), or pembrolizumab (6%, 5/86). A gene expression score was created using the top five genes found in responders versus non-responders (FOXP3, CCR4, KLRK1, ITK, TIGIT). The ORR in patients with high gene expression (GEhigh) on the 5-gene panel was 29% (14/48), compared with low gene expression (GElow) 3% (1/38, χ2 p=0.001). The validation cohort was comprised of 62 patients who received ipilimumab/nivolumab. There was no difference between GEhigh and GElow in terms of ORR (44% vs 38.5%), PFS (HR 1.5, 95% CI 0.58 to 3.89), or OS (HR 0.96, 95% CI 0.51 to 1.83). Similarly, no differences in ORR, PFS or OS were observed when patients were stratified by tumor mutational burden (high=top 20%), PD-L1 (programmed death-ligand 1) expression by immunohistochemistry or RNA expression, or CTLA-4 (cytotoxic T-lymphocytes-associated protein 4) RNA expression. The International Metastatic RCC Database Consortium (IMDC) risk score was prognostic for OS but not PFS.Conclusion A 5-gene panel that was associated with improved ORR in a predominantly nivolumab monotherapy population of patients with mRCC was not predictive for radiographic response, PFS, or OS among patients with mRCC treated with ipilimumab and nivolumab.

AimWe investigated the relationship between the sarcopenia-indicating Ishii test scores and pneumonia risk in stable schizophrenia patients.MethodsThis prospective investigation involves schizophrenic inpatients from two mental health centers in western China. Patient baseline information was gathered over 1 month from September 1 to 30 in 2020. All pneumonia-related patient information, including diagnosis and treatment, was acquired over 1 year between October 2020 and October 2021. Patients with schizophrenia were screened for sarcopenia utilizing a threshold value established by Ishii et al. Using regression analysis, the link between Ishii test scores and pneumonia risk in schizophrenia patients was investigated.ResultThis study recruited 232 males and 107 females with schizophrenia over the age of 50 and older. During a 1-year follow-up period, four patients (3 males and 1 female) acquired pneumonia within 1 week of relapse in schizophrenia; therefore, these patients were excluded from the study. Finally, data were collected for 335 patients. The pneumonia incidences were 29.3% in males and 14.2% in females. Our analysis confirmed that compared to the male schizophrenia patients with Ishii test scores < 105 (non-sarcopenia), those with Ishii test scores ≥ 105 (sarcopenia) exhibited an elevated pneumonia risk (OR = 2.739, 95%CI: 1.406–5.333). Following confounders adjustment, Ishii test scores ≥ 105 remained a risk factor for pneumonia (OR = 2.064, 95%CI: 1.029–4.143). Among females with schizophrenia, the Ishii test scores were not associated with pneumonia risk.ConclusionIn conclusion, our results demonstrated that the Ishii test scores ≥ 105 were strongly associated with pneumonia risk in stable schizophrenic male patients.

Integrated regeneration of periodontal tissues remains a challenge in current clinical applications. Due to the tunable physical characteristics and the precise control of the scaffold microarchitecture, three-dimensionally (3D) printed gelatin methacryloyl (GelMA)-based scaffold has emerged as a promising strategy for periodontal tissue regeneration. However, the optimization of the printing biomaterial links the formulation and the relationship between the composition and structures of the printed scaffolds and their comprehensive properties (e.g. mechanical strength, degradation, and biological behaviors) remains unclear. Here, in this work, a novel mesoporous bioactive glass (BG)/GelMA biomimetic scaffold with a large pore size (∼300 μm) was developed by extrusion-based 3D printing. Our results showed that the incorporation of mesoporous bioactive glass nanoparticles (BG NPs) significantly improved shape fidelity, surface roughness, and bioactivity of 3D-printed macroporous GelMA scaffolds, resulting in the enhanced effects on cell attachment and promoting osteogenic/cementogenic differentiation in human periodontal ligament cells. The excellent maintenance of the macropore structure, the visibly improved cells spreading, the release of bioactive ions (Si4+, Ca2+), the upregulation of gene expressions of osteogenesis and cementogensis, and the increase in alkaline phosphatase (ALP) activity and calcium nodules suggested that BG NPs could endow GelMA-based scaffolds with excellent structural stability and the ability to promote osteogenic/cementogenic differentiation. Our findings demonstrated the great potential of the newly formulated biomaterial inks and biomimetic BG/GelMA scaffolds for being used in periodontal tissue regeneration and provide important insights into the understanding of cell–scaffold interaction in promoting the regeneration of functional periodontal tissues.

BackgroundAlcohol dependence (AD) is a complex addictive disorder with a high relapse rate. Previous studies have shown that both repetitive transcranial magnetic stimulation (rTMS) and cognitive behavioral therapy (CBT) may be effective for AD, and we aim to explore more effective treatment options to reduce relapse rates for AD.Materials and methodsA total of 263 AD patients were recruited. They were divided into six groups according to the location and the type of rTMS: left dorsolateral prefrontal cortex (DLPFC), right DLPFC, sham stimulation, and whether they received CBT treatment: with a fixed schedule (C1) and without a fixed plan (C0). There were included in sham rTMS + C0 group (n = 50), sham rTMS + C1 group (n = 37), right rTMS + C0 group (n = 45), right rTMS + C1 group (n = 42), left rTMS + C0 group (n = 49), left rTMS + C1 group (n = 40). We used obsessive compulsive drinking scale (OCDS), visual analogue scale (VAS), alcohol dependence scale (ADS), montreal cognitive assessment (MoCA), generalized anxiety disorder-7 (GAD-7), patient health questionnaire-9 items (PHQ-9), and Pittsburgh sleep quality index (PSQI) to assess alcohol cravings, alcohol dependence, cognition, anxiety, depression, and sleep quality. They were followed up and evaluated for relapse.ResultsThe sham rTMS + C0 group relapse rate was significantly higher than the right rTMS + C1 group (P = 0.006), the left rTMS + C0 group (P = 0.031), the left rTMS + C1 group (P = 0.043). The right rTMS + C0 group showed significantly higher relapse rate compared to the right rTMS + C1 group (P = 0.046). There was no significant difference in relapse rates between other groups. The repeated-measures ANOVA showed an interaction effect between group and time was significant in the rate of patient health questionnaire-9 items (PHQ-9) scale reduction (P = 0.020). Logistic analysis indicated that smoking and alcohol consumption were independent determinants of relapse (P < 0.05). At 24 weeks of follow-up, Kaplan–Meier survival analysis reveal that there is statistically significant relapse rate between six groups (P = 0.025), left rTMS + C1 group has the best treatment effect for alcohol dependent patients. Cox regression analysis confirmed that current smoking, total cholesterol, and total bilirubin (TBIL) level were risk factors of relapse (P < 0.05).ConclusionThis study is the first to suggest that the combination of rTMS and CBT may be a potentially effective treatment for reducing relapse.

The physical principle of myelin development is obtained from our previous study by explaining Peter’s quadrant mystery: an externally applied negative and positive E-field can promote and inhibit the growth of the inner tongue of the myelin sheath, respectively. In this study, this principle is considered as a fundamental hypothesis, named Hypothesis-E, to explain more phenomena about myelin development systematically. Specifically, the g-ratio and the fate of the Schwann cell’s differentiation are explained in terms of the E-field. Moreover, an experiment is proposed to validate this theory.

BackgroundThe COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global crisis. Although many people recover from COVID-19 infection, they are likely to develop persistent symptoms similar to those of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) after discharge. Those constellations of symptoms persist for months after infection, called Long COVID, which may lead to considerable financial burden and healthcare challenges. However, the mechanisms underlying Long COVID and ME/CFS remain unclear.MethodsWe collected the genes associated with Long COVID and ME/CFS in databases by restricted screening conditions and clinical sample datasets with limited filters. The common genes for Long COVID and ME/CFS were finally obtained by taking the intersection. We performed several advanced bioinformatics analyses based on common genes, including gene ontology and pathway enrichment analyses, protein–protein interaction (PPI) analysis, transcription factor (TF)–gene interaction network analysis, transcription factor–miRNA co-regulatory network analysis, and candidate drug analysis prediction.ResultsWe found nine common genes between Long COVID and ME/CFS and gained a piece of detailed information on their biological functions and signaling pathways through enrichment analysis. Five hub proteins (IL-6, IL-1B, CD8A, TP53, and CXCL8) were collected by the PPI network. The TF–gene and TF–miRNA coregulatory networks were demonstrated by NetworkAnalyst. In the end, 10 potential chemical compounds were predicted.ConclusionThis study revealed common gene interaction networks of Long COVID and ME/CFS and predicted potential therapeutic drugs for clinical practice. Our findings help to identify the potential biological mechanism between Long COVID and ME/CFS. However, more laboratory and multicenter evidence is required to explore greater mechanistic insight before clinical application in the future.

Leukemia inhibitory factor (LIF) is a multipotent cytokine of the IL-6 family which plays a critical role in the maturation and development of oocytes. This study evaluated the influence of LIF on the maturation and development ability of yak oocytes, and the quality of subsequent blastocysts under in vitro culture settings. Different concentrations of LIF (0, 25, 50, and 100 ng/mL) were added during the in vitro culture of oocytes to detect the maturation rate of oocytes, levels of mitochondria, reactive oxygen species (ROS), actin, and apoptosis in oocytes, mRNA transcription levels of apoptosis and antioxidant-related genes in oocytes, and total cell number and apoptosis levels in subsequent blastocysts. The findings revealed that 50 ng/mL LIF could significantly increase the maturation rate (p < 0.01), levels of mitochondria (p < 0.01) and actin (p < 0.01), and mRNA transcription levels of anti-apoptotic and antioxidant-related genes in yak oocytes. Also, 50 ng/mL LIF could significantly lower the generation of ROS (p < 0.01) and apoptosis levels of oocytes (p < 0.01). In addition, blastocysts formed from 50 ng/mL LIF-treated oocytes showed significantly larger total cell numbers (p < 0.01) and lower apoptosis rates (p < 0.01) than the control group. In conclusion, the addition of LIF during the in vitro maturation of yak oocytes improved the quality and the competence of maturation and development in oocytes, as well as the quality of subsequent blastocysts. The result of this study provided some insights into the role and function of LIF in vitro yak oocytes maturation, as well as provided fundamental knowledge for assisted reproductive technologies in the yak.

In the development of oligodendrocytes in the central nervous systems, the inner and outer tongue of the myelin sheath tend to be located within the same quadrant, which was named as Peters quadrant mystery. In this study, we conduct in silico investigations to explore the possible mechanisms underlying the Peters quadrant mystery. A biophysically detailed model of oligodendrocytes was used to simulate the effect of the actional potential-induced electric field across the myelin sheath. Our simulation suggests that the paranodal channel connecting the inner and outer tongue forms a low impedance route, inducing two high-current zones at the area around the inner and outer tongue. When the inner tongue and outer tongue are located within the same quadrant, the interaction of these two high-current-zones will induce a maximum amplitude and a polarity reverse of the voltage upon the inner tongue, resulting in the same quadrant phenomenon. This model indicates that the growth of myelin follows a simple principle: an external negative or positive E-field can promote or inhibit the growth of the inner tongue, respectively.

Detecting SNV at very low read depths helps to reduce sequencing requirements, lowers sequencing costs, and aids in the early screening, diagnosis, and treatment of cancer. However, the accuracy of SNV detection is significantly reduced at read depths below ×34 due to the lack of a sufficient number of read pairs to help filter out false positives. Many recent studies have revealed the potential of mutational signature (MS) in detecting true SNV, understanding the mutational processes that lead to the development of human cancers, and analyzing the endogenous and exogenous causes. Here, we present DETexT, an SNV detection method better suited to low read depths, which classifies false positive variants by combining MS with deep learning algorithms to mine correlation information around bases in individual reads without relying on the support of duplicate read pairs. We have validated the effectiveness of DETexT on simulated and real datasets and conducted comparative experiments. The source code has been uploaded to https://github.com/TrinaZ/extra-lowRD for academic use only.