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Abstract Background Cancer is a major cause of death, and its early identification and intervention have potential for clinical actionability and benefits for human health. The studies using whole‐genome sequencing (WGS) and large samples analysis of cancer‐related genes have been rarely done. Methods We performed WGS to explore germline mutations in coding and non‐coding areas of cancer‐related genes and non‐coding driver genes and regulatory areas. Structural variants (SVs) was also analyzed. We used several tools and a subgrouping method to analyze the variants in 1491 healthy participants. Moreover, 275 cancer‐related genes sequencing was carried out in 125 cancer patients. Results The incidence of familial cancer in the Taiwanese general population is 8.79% (131/1491). Cancer carrier rate of cancer‐related genes is about 7.04% (105/1491) for pathogenic/likely pathogenic variants (P/LP) on ClinVar database only, and 28.24% (421/1491) for P/LP and loss of function variants. The carrier frequencies of cancer‐related genes P/LP on ClinVar database were as follows: 8.40% (11/131), 7.11% (28/394), and 6.83% (66/966) in FC, 1MC, and nMC, respectively. The SVs and non‐coding driver gene variants are uncommon. There are 1.54% (23/1491) of actionable cancer genes in American College of Medical Genetics and Genomics (ACMG), and the germline mutation rate of 275 cancer‐related genes is 7.2% (9/125) in cancer patients including 4.0% (5/125) of actionable cancer genes in ACMG. After analyzing the frequencies of P/LP variants on GJB2 and SLC25A13 genes, we suggest that these two genes may not be cancer‐related genes and need be re‐evaluated. Conclusions WGS analysis can completely detect germline mutations in cancer carriers. This study use subgrouping approach for samples provides a strategy to study whether a gene or variant is a cancer‐related gene or variant in the future studies.

Positional fluctuation and covariance during protein dynamics are key observables for understanding the molecular origin of biological functions. A frequently employed potential energy function for describing protein structural variation at the coarse-gained level is elastic network model (ENM). A long-standing issue in biomolecular simulation is thus the parametrization of ENM spring constants from the components of positional covariance matrix (PCM). Based on sensitivity analysis of PCM, the direct-coupling statistics of each spring, which is a specific combination of position fluctuation and covariance, is found to exhibit prominent signal of parameter dependence. This finding provides the basis for devising the objective function and the scheme of running through the effective one-dimensional optimization of every spring by self-consistent iteration. Formal derivation of the positional covariance statistical learning (PCSL) method also motivates the necessary data regularization for stable calculations. Robust convergence of PCSL is achieved in taking an all-atom molecular dynamics trajectory or an ensemble of homologous structures as input data. The PCSL framework can also be generalized with mixed objective functions to capture specific property such as the residue flexibility profile. Such physical chemistry-based statistical learning thus provides a useful platform for integrating the mechanical information encoded in various experimental or computational data.

Abstract Objective This paper aims to explore the diagnostic value of enhanced magnetic resonance imaging (MRI) combined with a carcinoembryonic antigen (CEA) and carbohydrate antigen in terms of the liver metastasis of colorectal cancer. Methods A total of 167 colorectal cancer patients with liver metastasis and 167 colorectal cancer patients without liver metastasis were selected as the subjects. An automatic electrochemiluminescence analyser was then used to detect the tumour markers CEA, CA19-9, CA125 and CA72-4. The consistency between the MRI examination and clinical pathological examination was also analysed, and the sensitivity, specificity and positive and negative predictive values of various combined detection methods were compared. Results The abnormal rates of CEA, CA19-9, CA125 and CA72-4 in the two groups were statistically significant (P < 0.05), while the results of the enhanced MRI and clinicopathological examination for liver metastasis in patients with colon cancer were largely consistent (Kappa coefficient = 0.788, P < 0.000). However, the two methods were inconsistent. The false positive rate of the enhanced MRI examination was 15.3%, while the false negative rate was 6.0%. The specificity (94.61%), positive predictive value (92.68%) and positive likelihood ratio (12.67%) were the highest for the MRI combined with serial CEA, while the sensitivity (98.80%) and negative predictive value (97.22%) were the highest with the MRI combined with parallel CEA, and this combination returned the lowest negative likelihood ratio (0.03). Conclusion The combination of MRI and CEA excludes non-metastatic patients and identifies colorectal liver metastasis cancer patients. Overall, it has a higher diagnostic value.

This paper presents a novel Double-negative (DNG) metamaterial (MM) resonator with a mirror-symmetric configuration, designed to exhibit multiband resonances in the S, C, and X bands. The resonator is fabricated using advanced processing techniques on a Rogers 5880 substrate and features electrodeposited copper. It consists of four equal regions, each containing interconnected split-ring resonators that are connected through a cross-shaped structure to ensure mirror symmetry. The simulation results demonstrate six resonance points at frequencies of 2.45 GHz, 4.27 GHz, 6.86 GHz, 8.98 GHz, 10.69 GHz, and 11.65 GHz. These resonances are characterized by near-zero/negative permeability, negative permittivity, refractive index, and impedance. Furthermore, the cross-polarization effect of incident waves is investigated.Additionally, the potential for tunability of resonance frequencies is explored through a sandwiched configuration of the MM resonator, achieved by modifying the cover of the resonating patch. Moreover, the equivalent circuit model of the proposed MM resonator is in good agreement with practical measurements, validating the simulation results. The new tuning method for MM resonators holds the promise for future sensing applications and wireless communications.

BackgroundIkigai (meaning or purpose in life) is a concept understood by most older adults in Japan. The term has also garnered international attention, with recent academic attempts to map it to concepts in the Western well-being literature. In addition, efforts to use social and home robots to increase well-being have grown; however, they have mostly focused on hedonic well-being (eg, increasing happiness and decreasing loneliness) rather than eudaimonic well-being (eg, fostering meaning or purpose in life). ObjectiveFirst, we explored how Japanese older adults experience ikigai and relate these to concepts in the Western well-being literature. Second, we investigated how a home robot meant to promote ikigai is perceived by older adults. MethodsWe used a mixed methods research design—including 20 interviews with older adults, a survey of 50 older adults, and 10 interviews with family caregivers. For interviews, we asked questions about older adults’ sources of ikigai, happiness, and social support, along with their perception of the robot (QT). For surveys, a number of well-being scales were used, including 2 ikigai scales—ikigai-9 and K-1—and 6 Patient-Reported Outcomes Measurement Information System scales, measuring meaning and purpose, positive affect, satisfaction with participation in social roles, satisfaction with participation in discretionary social activities, companionship, and emotional support. Questions related to the perception and desired adoption of the robot and older adults’ health status were also included. ResultsOur results suggest that health is older adults’ most common source of ikigai. Additionally, although self-rated health correlated moderately with ikigai and other well-being measures, reported physical limitation did not. As opposed to social roles (work and family), we found that ikigai is more strongly related to satisfaction with discretionary social activities (leisure, hobbies, and friends) for older adults. Moreover, we found that older adults’ sources of ikigai included the eudaimonic aspects of vitality, positive relations with others, contribution, accomplishment, purpose, and personal growth, with the first 3 being most common, and the hedonic aspects of positive affect, life satisfaction, and lack of negative affect, with the first 2 being most common. However, the concept of ikigai was most related to eudaimonic well-being, specifically meaning in life, along the dimension of significance. Finally, we found that Japanese older adults have high expectations of a home robot for well-being, mentioning that it should support them in a multitude of ways before they would likely adopt it. However, we report that those with the highest levels of meaning, and satisfaction with their leisure life and friendships, may be most likely to adopt it. ConclusionsWe outline several ways to improve the robot to increase its acceptance, such as improving its voice, adding functional features, and designing it to support multiple aspects of well-being.

Based on Iron cathodes, nitrate could be selectively decomposed into other lower-valence nitrogen compounds, including ammonia, nitrogen gas, nitrite and nitric oxide, but the removal efficiencies of nitrate and total nitrogen (TN), are affected significantly by the synergistic effects of anodes, chloride electrolyte and conductive plastic particles electrodes. In this work, the base material Titanium (Ti) metal plates and plastic particles which surfaces were mainly coated with Ru-Sn oxidizing compounds, were applied as plates anodes and conductive particles electrodes in Three Dimensional Electrode Reactors (TDER). The Ti/RuSn plate anodes showed excellent performance on degrading nitrate, more nitrogen gas (83.84%) and less ammonia (15.51%) was produced, less TN and Iron ion (0.02 mg/L) was left in the wastewater, and less amount of chemical sludge (0.20 g/L) was produced. Furthermore, the removal efficiencies of nitrate and TN were further increased by the surface-modified plastic particles, which were cheap, reusable, corrosion-resistance, easy to obtain as manufactured materials and light to be suspended in waters. The degradation of nitrate and its intermediates was enhanced possibly by the continuous synergistic reactions initiated by hydrogen radicals, which was generated on the countless surficial active Ru-Sn sites of Ti/RuSn metal plate anodes and plastic particles electrodes, among residual nitrogen intermediates, most of ammonia was selectively converted to gaseous nitrogen by hypochlorite from chloride ion reaction.

The identification of risk factors for future prediabetes in young men remains largely unexamined. This study enrolled 6247 young ethnic Chinese men with normal fasting plasma glucose at the baseline (FPGbase), and used machine learning (Mach-L) methods to predict prediabetes after 5.8 years. The study seeks to achieve the following: 1. Evaluate whether Mach-L outperformed traditional multiple linear regression (MLR). 2. Identify the most important risk factors. The baseline data included demographic, biochemistry, and lifestyle information. Two models were built, where Model 1 included all variables and Model 2 excluded FPGbase, since it had the most profound effect on prediction. Random forest, stochastic gradient boosting, eXtreme gradient boosting, and elastic net were used, and the model performance was compared using different error metrics. All the Mach-L errors were smaller than those for MLR, thus Mach-L provided the most accurate results. In descending order of importance, the key factors for Model 1 were FPGbase, body fat (BF), creatinine (Cr), thyroid stimulating hormone (TSH), WBC, and age, while those for Model 2 were BF, white blood cell, age, TSH, TG, and LDL-C. We concluded that FPGbase was the most important factor to predict future prediabetes. However, after removing FPGbase, WBC, TSH, BF, HDL-C, and age were the key factors after 5.8 years.

Abstract Background Gastric cancer has a high incidence and mortality rate. Angiogenesis is necessary for tumor infiltration and metastasis and affects patient prognosis. YKL-39 has monocyte chemotactic activity and pro-angiogenic activity in some tumors. In this study, we investigated the relationship between YKL-39 and tumor-associated macrophages and microangiogenesis in gastric cancer to determine its potential as a prognostic biomarker. Materials and methods A total of 119 patients with gastric cancer who had undergone gastrectomy at the 940th Hospital of the Joint Security Force between 2014 and 2018 were included in this study. We assayed the protein expression of YKL-39, CD68, and CD34 by immunohistochemistry in tissues of 119 patients with gastric cancer, as well as the intracellular expression of YKL-39 and CD68 by immunofluorescence. Data were analyzed with SPSS Statistics 25.0 to explore the impact of expression of YKL-39, CD68, and CD34 in gastric cancer patients and the relationship among them. Results Our results show that YKL-39 was expressed in both the nucleus and cytoplasm of gastric cancer cells and tumor mesenchyme. YKL-39 protein expression was associated with the depth of tumor infiltration, lymph node metastasis, and TNM stage; CD68 protein expression was associated with lymph node metastasis and TNM stage; CD34 protein expression was not associated with clinicopathological characteristics. Expression of YKL-39 was positively correlated with CD68 and CD34 (p

Background: Accumulating evidence suggests that postmenopausal osteoporosis (PMOP) is a common chronic systemic metabolic bone disease, but its specific molecular pathogenesis remains unclear. This study aimed to identify novel genetic diagnostic markers for PMOP.Methods: In this paper, we combined three GEO datasets to identify differentially expressed genes (DEGs) and performed functional enrichment analysis of PMOP-related differential genes. Key genes were analyzed using two machine learning algorithms, namely, LASSO and the Gaussian mixture model, and candidate biomarkers were found after taking the intersection. After further ceRNA network construction, methylation analysis, and immune infiltration analysis, ACACB and WWP1 were finally selected as diagnostic markers. Twenty-four clinical samples were collected, and the expression levels of biomarkers in PMOP were detected by qPCR.Results: We identified 34 differential genes in PMOP. DEG enrichment was mainly related to amino acid synthesis, inflammatory response, and apoptosis. The ceRNA network construction found that XIST—hsa-miR-15a-5p/hsa-miR-15b-5p/hsa-miR-497-5p and hsa-miR-195-5p—WWP1/ACACB may be RNA regulatory pathways regulating PMOP disease progression. ACACB and WWP1 were identified as diagnostic genes for PMOP, and validated in datasets and clinical sample experiments. In addition, these two genes were also significantly associated with immune cells, such as T, B, and NK cells.Conclusion: Overall, we identified two vital diagnostic genes responsible for PMOP. The results may help provide potential immunotherapeutic targets for PMOP.

Vaping is an increasing health threat in the US and worldwide. The damaging impact of vaping on the human distal lung has been highlighted by the recent epidemic of electronic cigarette or vaping use-associated lung injury (EVALI). The pathogenesis of EVALI remains incompletely understood, due to a paucity of models that recapitulate the structural and functional complexity of the human distal lung and the still poorly defined culprit exposures to vaping products and respiratory viral infections. Our aim was to establish the feasibility of using single cell RNA-sequencing (scRNA-seq) technology in human precision-cut lung slices (PCLS) as a more physiologically relevant model to better understand how vaping regulates the antiviral and pro-inflammatory response to influenza A virus infection. Normal healthy donor PCLS were treated with vaping extract and influenza A viruses for scRNA-seq analysis. Vaping extract augmented host antiviral and pro-inflammatory responses in structural cells such as lung epithelial cells and fibroblasts, as well as in immune cells such as macrophages and monocytes. Our findings suggest that human distal lung slice model is useful to study the heterogeneous responses of immune and structural cells under EVALI conditions, such as vaping and respiratory viral infection.

IntroductionDeployment related asthma-like symptoms including distal airway obstruction have been described in U.S. military personnel who served in Iraq and Afghanistan. The mechanisms responsible for the development of distal airway obstruction in deployers exposed to desert particulate matter (PM) is not well understood. We sought to determine if respiratory exposure to PM from Afghanistan (PMa) increases human distal airway hyperresponsiveness (AHR) with or without exposures to IL-13, a type 2 cytokine. We further tested whether mitochondrial dysfunction, such as ATP signaling and oxidative stress, may contribute to PMa- mediated AHR.MethodsPrecision-cut lung slices from donors without a history of lung disease, tobacco smoking, or vaping were pre-treated with IL-13 for 24 h. This was followed by exposure to PMa or PM from California (PMc, control for PMa) for up to 72 h. The role of hydrogen peroxide and ATP in AHR was assessed using the antioxidant enzyme catalase or an ATP receptor P2Y13 antagonist MRS2211. AHR in response to methacholine challenges as well as cytokine IL-8 production were measured.ResultsPMa alone, but not PMc alone, trended to increase AHR. Importantly, the combination of PMa and IL-13 significantly amplified AHR compared to control or PMc+IL-13. PMa alone and in combination with IL-13 increased IL-8 as compared to the control. PMa increased H2O2 and ATP. MRS211 and catalase reduced AHR in PCLS exposed to both PMa and IL-13.DiscussionOur data suggests that PMa in a type 2 inflammation-high lung increased AHR in part through oxidative stress and ATP signaling.

Abstract Immunoproteasomes (IP) serve as an important modulator of immune responses to pathogens and other pathological factors. LMP7/β5i, one of the IP subunits, plays a critical role in autoimmune diseases by downregulating inflammation. Rhinovirus (RV) infection is a major risk factor in the exacerbations of respiratory inflammatory diseases, but whether LMP7 regulates RV-mediated inflammation in the lung particularly in the airway epithelium, the first line of defense against RV infection, remains unclear. In this study, we determined whether airway epithelial LMP7 promotes the resolution of RV-mediated lung inflammation. Inducible airway epithelial-specific LMP7-deficient (conditional knockout, CKO) mice were generated to reveal the in vivo anti-inflammatory and antiviral functions of LMP7. By using LMP7-deficient primary human airway epithelial cells generated by CRISPR-Cas9, we confirmed that airway epithelial LMP7 decreased pro-inflammatory cytokines and viral load during RV infection. Additionally, airway epithelial LMP7 enhanced the expression of a negative immune regulator A20/TNFAIP3 during viral infection that may contribute to the anti-inflammatory function of LMP7. We also discovered that induction of LMP7 by a low dose of polyinosinic:polycytidylic acid (PI:C) reduced RV-mediated inflammation in our CKO mice infected with RV. Our findings suggest that airway epithelial LMP7 has anti-inflammatory and antiviral functions that is critical to the resolution of RV-mediated lung inflammation. Induction of airway epithelial LMP7 may open a novel avenue for therapeutic intervention against RV infection.

Abstract The Aurignacian is one of the first cultural-technological traditions commonly associated with the expansion of Homo sapiens in Europe. Early Homo sapiens demographics across the continent are therefore typically inferred using the distribution of Aurignacian assemblages. Western Romania has been used as a tie-point to connect the well-researched lithic assemblages from the eastern Mediterranean and Western Europe through its early Homo sapiens fossils. However, Romania’s archeological record remains underexplored thereby hindering our ability to directly connect better understood regions through time and space. Here we report on excavations from the open-air Middle/Upper Paleolithic site of Româneș ti-Dumbrăvița I in southwestern Romania. Three stratified Paleolithic assemblages were extensively excavated within a 1-m-thick eolian-deposited sequence. Spatial, geochemical, raw material, techno-typological, and use-wear analysis of the site reveal patterns of artifact configuration, resource exploitation, fire history, knapping objectives, and functionality. Taken together, Românești-Dumbrăvița I is the first well-contextualized archeological site in close spatiotemporal proximity to many early, well-preserved human fossils and in East-Central Europe.

Respiratory influenza A virus (IAV) infection continues to pose significant challenges in healthcare of human diseases including asthma. IAV infection in mice was shown to increase IL-33, a key cytokine in driving airway inflammation in asthma, but how IL-33 is regulated during viral infection remains unclear. We previously found that a genetic mutation in Toll-interacting protein (Tollip) was linked to less airway epithelial Tollip expression, increased neutrophil chemokines, and lower lung function in asthma patients. As Tollip is involved in maintaining mitochondrial function, and mitochondrial stress may contribute to extracellular ATP release and IL-33 secretion, we hypothesized that Tollip downregulates IL-33 secretion via inhibiting ATP release during IAV infection. Wild-type and Tollip knockout (KO) mice were infected with IAV and treated with either an ATP converter apyrase or an IL-33 decoy receptor soluble ST2 (sST2). KO mice significantly lost more body weight and had increased extracellular ATP, IL-33 release, and neutrophilic inflammation. Apyrase treatment reduced extracellular ATP levels, IL-33 release, and neutrophilic inflammation in Tollip KO mice. Excessive lung neutrophilic inflammation in IAV-infected Tollip KO mice was reduced by sST2, which was coupled with less IL-33 release. Our data suggest that Tollip inhibits IAV infection, potentially by inhibiting extracellular ATP release and reducing IL-33 activation and lung inflammation. In addition, sST2 may serve as a potential therapeutic approach to mitigate respiratory viral infection in human subjects with Tollip deficiency.

The exercise of quantifying the energy consumption data assembled through household surveys, either by the recall-based approach or the meter-based approach, remains a challenging task, especially in rural areas of developing countries. In this article, we propose a device-based bottom-up accounting method for estimating household energy consumption. This method provides microlevel disaggregated estimates at the intensive margin and documents other difficult-to-measure energy consumption such as biomass at the extensive margin. Even though measurement errors of the household survey might still exist, the structured questionnaire of daily routine behavior questions should greatly alleviate the problem. The new method supplements the existing household energy statistical system, improves its flexibility, and is particularly applicable in developing countries and/or rural areas. We apply the method to a Chinese rural household survey and discuss its differences and similarities with the conventional methods.

Abstracts: This work analyzed the electromagnetic field (EM) anomalies recorded by the electric field detector (EFD) and the search coil magnetometer (SCM) onboard the China Seismo-Electromagnetic Satellite (CSES) during the two earthquakes (EQ), which are the Yangbi Ms6.4 EQ on May 21 (China Standard Time, CST) and the Madoi Ms7.4 EQ on May 22 (CST), 2021. These two EQs successively occurred in West China. The prevailing frequency band excluding the interferences from the satellite platform was chosen to extract convincible seismic-related EM disturbances. Two criteria were put forward to obtain reliable precursors using the Kp and Dst index and the variation rate of Dst per hour to eliminate the tinier spatial perturbations. We found that the seismic-related EM disturbances mainly appeared 1–10 days before the two earthquakes within the spatial extension of 1000 ​km above the epicenters.