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Technologically critical rare-earth elements are notoriously difficult to separate, owing to their subtle differences in ionic radius and coordination number1–3. The natural lanthanide-binding protein lanmodulin (LanM)4,5 is a sustainable alternative to conventional solvent-extraction-based separation6. Here we characterize a new LanM, from Hansschlegelia quercus (Hans-LanM), with an oligomeric state sensitive to rare-earth ionic radius, the lanthanum(III)-induced dimer being >100-fold tighter than the dysprosium(III)-induced dimer. X-ray crystal structures illustrate how picometre-scale differences in radius between lanthanum(III) and dysprosium(III) are propagated to Hans-LanM’s quaternary structure through a carboxylate shift that rearranges a second-sphere hydrogen-bonding network. Comparison to the prototypal LanM from Methylorubrum extorquens reveals distinct metal coordination strategies, rationalizing Hans-LanM’s greater selectivity within the rare-earth elements. Finally, structure-guided mutagenesis of a key residue at the Hans-LanM dimer interface modulates dimerization in solution and enables single-stage, column-based separation of a neodymium(III)/dysprosium(III) mixture to >98% individual element purities. This work showcases the natural diversity of selective lanthanide recognition motifs, and it reveals rare-earth-sensitive dimerization as a biological principle by which to tune the performance of biomolecule-based separation processes.

SummaryThe objective of this study was to evaluate the safety and tolerability of DS-1205c, an oral AXL-receptor inhibitor, in combination with osimertinib in metastatic or unresectable EFGR-mutant non-small cell lung cancer (NSCLC) patients who developed disease progression during EGFR tyrosine kinase inhibitor (TKI) treatment. An open-label, non-randomized phase 1 study was conducted in Taiwan, in which 13 patients received DS-1205c monotherapy at a dosage of 200, 400, 800, or 1200 mg twice daily for 7 days, followed by combination treatment with DS-1205c (same doses) plus osimertinib 80 mg once daily in 21-day cycles. Treatment continued until disease progression or other discontinuation criteria were met. At least one treatment-emergent adverse event (TEAE) was reported in all 13 patients treated with DS-1205c plus osimertinib; with ≥ 1 grade 3 TEAE in 6 patients (one of whom also had a grade 4 increased lipase level), and 6 patients having ≥ 1 serious TEAE. Eight patients experienced ≥ 1 treatment-related AE (TRAE). The most common (2 cases each) were anemia, diarrhea, fatigue, increased AST, increased ALT, increased blood creatinine phosphokinase, and increased lipase. All TRAEs were non-serious, with the exception of an overdose of osimertinib in 1 patient. No deaths were reported. Two-thirds of patients achieved stable disease (one-third for > 100 days), but none achieved a complete or partial response. No association between AXL positivity in tumor tissue and clinical efficacy was observed. DS-1205c was well-tolerated with no new safety signals in patients with advanced EGFR-mutant NSCLC when administered in combination with the EFGR TKI osimertinib. ClinicalTrials.gov; NCT03255083.

Objective: Aberrant driving behavior (ADB) decreases road safety and is particularly relevant for urban bus drivers, who are required to drive daily shifts of considerable duration. Although numerous frameworks based on human physiological features have been applied to predict ADB, the research remains at an early stage. This study used heart rate variability (HRV) parameters to establish ADB occurrence prediction models with various machine learning approaches. Methods: Twelve Taiwanese urban bus drivers were recruited for four consecutive days of naturalistic driving data collection (from their routine routes) between March and April 2020; driving behaviors and physiological signals were obtained from provided devices. Weather and traffic congestion information was determined from public data, while sleep quality and professional driving experience were self-reported. To develop the ADB prediction model, several machine learning models—logistic regression, random forest, naive Bayes, support vector machine, and gated recurrent unit (GRU)—were trained and 10-fold cross-validated by using the testing data. Results: Most drivers with ADB reported deficient sleep quality (≤80%), with significantly higher mean scores on the Karolinska Sleepiness Scale and driver behavior questionnaire subcategory of lapses and errors than drivers without ADB. Next, HRV indices significantly differed between the measurement of a pre-ADB event and a baseline. The accuracy of the GRU models ranged from 78.84% ± 1.49% to 89.57% ± 1.31%. Conclusion: Drivers with ADB tend to have inadequate sleep quality, which may increase their fatigue levels and impair driving performance. The established time-series models can be considered for ADB occurrence prediction among urban bus drivers.

The honeybee plays an extremely important role in ecosystem stability and diversity and in the production of bee pollinated crops. Honey bees and other pollinators are under threat from the combined effects of nutritional stress, parasitism, pesticides, and climate change that impact the timing, duration, and variability of seasonal events. To understand how parasitism and seasonality influence honey bee colonies separately and interactively, we developed a non-autonomous nonlinear honeybee-parasite interaction differential equation model that incorporates seasonality into the egg-laying rate of the queen. Our theoretical results show that parasitism negatively impacts the honey bee population either by decreasing colony size or destabilizing population dynamics through supercritical or subcritical Hopf-bifurcations depending on conditions. Our bifurcation analysis and simulations suggest that seasonality alone may have positive or negative impacts on the survival of honey bee colonies. More specifically, our study indicates that (1) the timing of the maximum egg-laying rate seems to determine when seasonality has positive or negative impacts; and (2) when the period of seasonality is large it can lead to the colony collapsing. Our study further suggests that the synergistic influences of parasitism and seasonality can lead to complicated dynamics that may positively and negatively impact the honey bee colony's survival. Our work partially uncovers the intrinsic effects of climate change and parasites, which potentially provide essential insights into how best to maintain or improve a honey bee colony's health.

In this paper, we propose a damage identification method based on minimum mean square error estimation for a wind tunnel flexible plate condition monitoring system. Critical structural members of important equipment are large in size, and the measurement systems used to monitor their condition are often complex. The proposed damage identification method is based on the minimum mean squared error estimator and the generalized likelihood ratio test. It introduced activation function to generate the standard deviation of the data, which can then simulate the sensor output. A single sensor damage only affects a single dimension of the output data matrix of the measurement system. However, structural damage affects the output of multiple sensors. The damage identification method proposed in this paper can not only distinguish the sensor damage from the structure damage, but also locate the damaged sensor or structure damage location. This method can identify the measurement system output anomalies caused by structural damage and locate the approximate location of the damage. It can be applied to damage identification of important structural members such as flexible wind tunnel plates. The damage identification method proposed in this paper is of great significance for damage identification and localization of key components and sensor systems.

We provide results of a deterministic approximation for non-Markovian stochastic processes modeling finite populations of individuals who recurrently play symmetric finite games and imitate each other according to payoffs. We show that a system of delay differential equations can be obtained as the deterministic approximation of such a non-Markovian process. We also show that if the initial states of stochastic process and the corresponding deterministic model are close enough, then the trajectory of stochastic process stays close to that of the deterministic model up to any given finite time horizon with a probability exponentially approaching one as the population size increases. We use this result to obtain that the lower bound of the population size on the absorption time of the non-Markovian process is exponentially increasing. Additionally, we obtain the replicator equations with distributed and discrete delay terms as examples and analyze how the memory of individuals can affect the evolution of cooperation in a two-player symmetric Snow-drift game. We investigate the stability of the evolutionary stable state of the game when agents have the memory of past population states, and implications of these results are given for the stochastic model., 23 pages, 2 figures one of which includes 4 subfigures

Obstructive sleep apnea (OSA) with a low arousal threshold (low-ArTH) phenotype can cause minor respiratory events that exacerbate sleep fragmentation. Although anthropometric features may affect the risk of low-ArTH OSA, the associations and underlying mechanisms require further investigation. This study investigated the relationships of body fat and water distribution with polysomnography parameters by using data from a sleep center database. The derived data were classified as those for low-ArTH in accordance with criteria that considered oximetry and the frequency and type fraction of respiratory events and analyzed using mean comparison and regression approaches. The low-ArTH group members (n = 1850) were significantly older and had a higher visceral fat level, body fat percentage, trunk-to-limb fat ratio, and extracellular-to-intracellular (E–I) water ratio compared with the non-OSA group members (n = 368). Significant associations of body fat percentage (odds ratio [OR]: 1.58, 95% confident interval [CI]: 1.08 to 2.3, p < 0.05), trunk-to-limb fat ratio (OR: 1.22, 95% CI: 1.04 to 1.43, p < 0.05), and E–I water ratio (OR: 1.32, 95% CI: 1.08 to 1.62, p < 0.01) with the risk of low-ArTH OSA were noted after adjustments for sex, age, and body mass index. These observations suggest that increased truncal adiposity and extracellular water are associated with a higher risk of low-ArTH OSA.

Long-term exposure to air pollution can lead to cardiovascular disease, metabolic syndrome, and chronic respiratory disease. However, from a lifetime perspective, the critical period of air pollution exposure in terms of health risk is unknown. This study aimed to evaluate the impact of air pollution exposure at different life stages. The study participants were recruited from community centers in Northern Taiwan between October 2018 and April 2021. Their annual averages for fine particulate matter (PM2.5) exposure were derived from a national visibility database. Lifetime PM2.5 exposures were determined using residential address information and were separated into three stages (40 years). We employed exponentially weighted moving averages, applying different weights to the aforementioned life stages to simulate various weighting distribution patterns. Regression models were implemented to examine associations between weighting distributions and disease risk. We applied a random forest model to compare the relative importance of the three exposure life stages. We also compared model performance by evaluating the accuracy and F1 scores (the harmonic mean of precision and recall) of late-stage (>40 years) and lifetime exposure models. Models with 89% weighting on late-stage exposure showed significant associations between PM2.5 exposure and metabolic syndrome, hypertension, diabetes, and cardiovascular disease, but not gout or osteoarthritis. Lifetime exposure models showed higher precision, accuracy, and F1 scores for metabolic syndrome, hypertension, diabetes, and cardiovascular disease, whereas late-stage models showed lower performance metrics for these outcomes. We conclude that exposure to high-level PM2.5 after 40 years of age may increase the risk of metabolic syndrome, hypertension, diabetes, and cardiovascular disease. However, models considering lifetime exposure showed higher precision, accuracy, and F1 scores and lower equal error rates than models incorporating only late-stage exposures. Future studies regarding long-term air pollution modelling are required considering lifelong exposure pattern.

Peer reviewed: True, Obstructive sleep apnea (OSA) is a risk factor for neurodegenerative diseases. This study determined whether continuous positive airway pressure (CPAP), which can alleviate OSA symptoms, can reduce neurochemical biomarker levels. Thirty patients with OSA and normal cognitive function were recruited and divided into the control (n = 10) and CPAP (n = 20) groups. Next, we examined their in-lab sleep data (polysomnography and CPAP titration), sleep-related questionnaire outcomes, and neurochemical biomarker levels at baseline and the 3-month follow-up. The paired t-test and Wilcoxon signed-rank test were used to examine changes. Analysis of covariance (ANCOVA) was performed to increase the robustness of outcomes. The Epworth Sleepiness Scale and Pittsburgh Sleep Quality Index scores were significantly decreased in the CPAP group. The mean levels of total tau (T-Tau), amyloid-beta-42 (Aβ42), and the product of the two (Aβ42 × T-Tau) increased considerably in the control group (ΔT-Tau: 2.31 pg/mL; ΔAβ42: 0.58 pg/mL; ΔAβ42 × T-Tau: 48.73 pg2/mL2), whereas the mean levels of T-Tau and the product of T-Tau and Aβ42 decreased considerably in the CPAP group (ΔT-Tau: -2.22 pg/mL; ΔAβ42 × T-Tau: -44.35 pg2/mL2). The results of ANCOVA with adjustment for age, sex, body mass index, baseline measurements, and apnea-hypopnea index demonstrated significant differences in neurochemical biomarker levels between the CPAP and control groups. The findings indicate that CPAP may reduce neurochemical biomarker levels by alleviating OSA symptoms.

Brain metastases are not rare in patients with renal cell carcinoma. However, there have been few reports of isolated brain metastases. In patients with localized renal masses, urologists tend to evaluate only the chest and abdomen region. We report the case of a 65-year-old patient who presented with sudden left-sided weakness. He underwent brain surgery after a mass was found on brain imaging. Histopathology analysis revealed a single brain metastasis that occurred 15 months after robot-assisted laparoscopic radical nephrectomy for renal cell carcinoma. Although the patient had been evaluated for localized kidney cancer in preoperative staging, he had not complained of any neurological symptoms before or after radical nephrectomy. Therefore, we had not perceived a need for brain evaluation at that time. This report is intended to draw attention to the need for further evaluation in patients with large renal masses, as well as patients with moderate to high recurrence risk scores.

The development of synthetic biological circuits that maintain functionality over application relevant timescales remains a significant challenge. Here, we employed synthetic overlapping sequences in which one gene is encoded or “entangled” entirely within an alternative reading frame of another gene. In this design, the toxin-encodingrelEwas entangled withinilvA, which encodes threonine deaminase, an enzyme essential for isoleucine biosynthesis. A functional entanglement construct was obtained upon modification of the ribosome binding site of the internalrelEgene. Using this optimized design, we found that the selection pressure to maintain functional IlvA stabilized the production of burdensome RelE for over 130 generations, which compares favorably with the most stable kill-switch circuits developed to date. This stabilizing effect was achieved through a complete alteration of the mutational landscape such that mutations inactivating the entangled genes were disfavored. Instead, the majority of lineages accumulated mutations within the regulatory region ofilvA. By reducing baselinerelEexpression, these more ‘benign’ mutations lowered circuit burden, which suppressed the accumulation ofrelEinactivating mutations, thereby prolonging kill-switch function. Overall, this work demonstrates the utility of sequence entanglement paired with an adaptive laboratory evolution campaign to increase the evolutionary stability of burdensome synthetic circuits.

BackgroundChronic obstructive pulmonary disease (COPD) has high global health concerns, and previous research proposed various indicators to predict mortality, such as the distance-saturation product (DSP), derived from the 6-min walk test (6MWT), and the low-attenuation area percentage (LAA%) in pulmonary computed tomographic images. However, the feasibility of using these indicators to evaluate the stability of COPD still remains to be investigated. Associations of the DSP and LAA% with other COPD-related clinical parameters are also unknown. This study, thus, aimed to explore these associations.MethodsThis retrospective study enrolled 111 patients with COPD from northern Taiwan. Individuals’ data we collected included results of a pulmonary function test (PFT), 6MWT, life quality survey [i.e., the modified Medical Research Council (mMRC) scale and COPD assessment test (CAT)], history of acute exacerbation of COPD (AECOPD), and LAA%. Next, the DSP was derived by the distance walked and the lowest oxygen saturation recorded during the 6MWT. In addition, the DSP and clinical phenotype grouping based on clinically significant outcomes by previous study approaches were employed for further investigation (i.e., DSP of 290 m%, LAA% of 20%, and AECOPD frequency of ≥1). Mean comparisons and linear and logistic regression models were utilized to explore associations among the assessed variables.ResultsThe low-DSP group (ConclusionA lower value of the DSP was related to a greater worsening of symptoms, more-frequent exacerbations, poorer pulmonary function, and more-severe emphysema (higher LAA%). These readily determined parameters, including the DSP and LAA%, can serve as indicators for assessing the COPD clinical course and may can serve as a guide to corresponding treatments.

The objective of this study was the quantitative evaluation and comparison of the responses of the Hybrid III 5th percentile female (HIII-05F) and the 5th percentile female Test Device for Human Occupant Restraint (THOR-05F) anthropomorphic test devices (ATDs) subjected to abdominal loading conditions. The HIII-05F and THOR-05F were subjected to 3 different abdominal loading conditions: fixed-back belt pull (low compression), fixed-back belt pull (high compression), and free-back rigid bar impact at 6 m/s. The stroke of the impact was controlled to represent injurious and noninjurious loading conditions as observed in the experiments with postmortem human subjects (PMHS). Quantitative comparisons were made between the ATD abdominal force and compression responses and biofidelity corridors obtained from matched-pair PMHS tests under identical loading conditions, using the most recent version of the NHTSA Biofidelity Ranking System (BRS). The overall THOR-05F BRS scores across all tests (BRS score = 1.84) indicated good biofidelity. For the belt loading test conditions, the average BRS scores for both THOR-05F (BRS scores = 1.45 and 1.34) and HIII-05F (BRS scores = 1.42 and 1.01) showed good biofidelity. For the rigid bar loading condition, the THOR-05F (BRS score = 2.74) showed better biofidelity compared to HIII-05F (BRS score = 10.63), with the HIII-05F exhibiting poor performance in this condition. The average pressures recorded by the abdomen pressure twin sensors (APTS) in the current study ranged from 45 to 130 kPa, increasing proportionally with higher stroke and loading rate. Overall, the THOR-05F BRS scores were better than the HIII-05F BRS scores, which suggests improved biofidelity of the THOR-05F abdomen. The abdominal insert in the HIII-05F did not provide enough room for compression, leading to higher stiffness and occupant motion as observed in the rigid bar tests. Because of practical challenges in measuring abdomen deflection in a soft ATD abdomen component, use of APTS in THOR-05F provides the ability to measure the restraint loading to the abdomen and assess the risk of abdominal injury. With good BRS scores observed in this study for THOR-05F, pressure and other measurements included in the THOR-05F may be used to develop abdominal injury risk functions in the future.

Supplemental material, sj-docx-1-dhj-10.1177_20552076231152751 for Screening the risk of obstructive sleep apnea by utilizing supervised learning techniques based on anthropometric features and snoring events by Cheng-Yu Tsai, Wen-Te Liu, Wen-Hua Hsu, Arnab Majumdar, Marc Stettler, Kang-Yun Lee, Wun-Hao Cheng, Dean Wu, Hsin-Chien Lee, Yi-Chun Kuan, Cheng-Jung Wu and Yi-Chih Lin, Shu-Chuan Ho in Digital Health

In 2020, 17% of all crash fatalities were individuals aged 65 years or older. Crash data also revealed that for older occupants, thoracic related injuries are among the leading causes of fatality. Historically, the majority of near-side impact postmortem human subjects (PMHS) studies used a generic load wall to capture external loads that were applied to PMHS. While these data were helpful in documenting biofidelity, they did not represent a realistic response an occupant would undergo in a near-side crash. The objective of this research was to test small, elderly female PMHS in a repeatable, realistic near-side impact crash scenario to investigate current injury criteria as they relate to this vulnerable population. Ten small, elderly PMHS were subjected to a realistic near-side impact loading condition. The PMHS were targeted to be elderly females age 60+, approximately 5th percentile in height and weight, with osteopenic areal bone mineral density. Each subject was seated on a mass-production seat, equipped with a side airbag and standard three-point restraint with a pretensioner. Other boundary conditions included an intruding driver’s side door. PMHS instrumentation included strain gages on ribs 3-10 bilaterally to identify fracture timing. Two chestbands were used to measure chest deflection, one at the level of the axilla and one at the level of the xiphoid process. Injuries observed included rib fractures, particularly on the struck side, and in multiple cases a flail chest was observed. Eight of ten subjects resulted in AIS3+ thoracic injuries, despite previously tested ATDs predicting less than a 10% chance of AIS3+ injury. Subjects crossed the threshold for AIS3 injury in the range of only 1% − 9% chest compression. Additionally, mechanisms of injury varied, as some injuries were incurred by door interactions while others came during airbag interactions. This research points to two areas of concern that likely require further analysis: (1) the appropriateness of potentially oversimplified PMHS testing to establish injury thresholds and define injury criteria for complicated crash scenarios; (2) the importance of identifying the precise timing of injuries to better understand the effect of current passive restraint systems.

Introduction This study, for the first time to our knowledge, evaluated the efficacy of ropeginterferon alfa-2b, a long-acting pegylated interferon (IFN)-alfa, in the treatment of COVID-19. Methods We retrospectively evaluated ropeginterferon alfa-2b administered subcutaneously at a single dose of 250 µg for the treatment of mild and moderate COVID-19. Primary outcome was to compare the overall negative conversion time from the confirmed, last positive SARS-CoV-2 RT-PCR to the first RT-PCR negative conversion between patients receiving ropeginterferon alfa-2b plus standard of care (SOC) and those receiving SOC alone. Results Thirty-five patients with mild COVID-19 and 37 patients with moderate disease were included. Of them, 19 patients received SOC plus ropeginterferon alfa-2b and 53 patients received SOC alone. All patients with moderate disease in the ropeginterferon alfa-2b group showed RT-PCR negative conversion within 8 days, while a significant portion of patients in the SOC alone group failed to do so. For patients with moderate disease and age ≤ 65 years old, the ropeginterferon alfa-2b group had statistically significant shorter median RT-PCR conversion time than the SOC alone group (7 vs. 11.5 days, p

Introduction Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib are approved for advanced non–small-cell lung cancer (NSCLC) with ALK rearrangement. However, the mechanisms of resistance remain largely unclear. Methods This prospective multicenter study analyzed cell-free DNA (cfDNA) and/or cancer tissues of patients with NSCLC after progression on ALK TKI(s), using targeted next-generation sequencing. Patients’ clinicopathologic characteristics and treatment outcomes were analyzed. Results Overall, 88 patients were enrolled; 31 cancer tissues and 90 cfDNA samples were analyzed. Five (16%) ALK mutations (L1196M × 2, I1171T, D1203N, G1269A/F1174L) and 3 possible bypass mutations (NRAS G12V, EGFR R108K, PIK3CA E545K) were found in 32 crizotinib-resistant cancers. Four (22%) ALK mutations (G1128A, G1202R, G1269A, I1171T/E1210K) and 3 possible bypass mutations (KIT D820E, MET E1012∗, EGFR P265_C291del) were found in 18 ceritinib-resistant cancers. Four (17%) ALK mutations (G1202R × 2, W1295C, G1202R/L1196M) and 1 possible bypass mutation (EGFR P753S) were found in 24 alectinib-resistant cancers. Two (11%) ALK mutations (G1202R/G1269A × 2) and 2 possible bypass mutations (BRAF V600E, MET D1246N) were found in 18 lorlatinib-resistant cancers. In patients with simultaneous paired tissue and cfDNA samples (n = 20), mutations were identified in 9 (45%) and 6 (30%) cases, respectively; the concordance rate was 45%. Conclusions The mechanisms of ALK TKI resistance were heterogeneous; ALK mutations were found in less than one-third of patients. Compound ALK mutations, which may confer lorlatinib resistance, may occur in crizotinib, ceritinib, and alectinib-resistant lung cancers.

ObjectivesObstructive sleep apnea (OSA) may increase the risk of Alzheimer's disease (AD). However, potential associations among sleep-disordered breathing, hypoxia, and OSA-induced arousal responses should be investigated. This study determined differences in sleep parameters and investigated the relationship between such parameters and the risk of AD.MethodsPatients with suspected OSA were recruited and underwent in-lab polysomnography (PSG). Subsequently, blood samples were collected from participants. Patients' plasma levels of total tau (T-Tau) and amyloid beta-peptide 42 (Aβ42) were measured using an ultrasensitive immunomagnetic reduction assay. Next, the participants were categorized into low- and high-risk groups on the basis of the computed product (Aβ42 × T-Tau, the cutoff for AD risk). PSG parameters were analyzed and compared.ResultsWe included 36 patients in this study, of whom 18 and 18 were assigned to the low- and high-risk groups, respectively. The average apnea–hypopnea index (AHI), apnea, hypopnea index [during rapid eye movement (REM) and non-REM (NREM) sleep], and oxygen desaturation index (≥3%, ODI-3%) values of the high-risk group were significantly higher than those of the low-risk group. Similarly, the mean arousal index and respiratory arousal index (R-ArI) of the high-risk group were significantly higher than those of the low-risk group. Sleep-disordered breathing indices, oxygen desaturation, and arousal responses were significantly associated with an increased risk of AD. Positive associations were observed among the AHI, ODI-3%, R-ArI, and computed product.ConclusionsRecurrent sleep-disordered breathing, intermittent hypoxia, and arousal responses, including those occurring during the NREM stage, were associated with AD risk. However, a longitudinal study should be conducted to investigate the causal relationships among these factors.

BackgroundThe interactions between tumor cells and the host immune system play a crucial role in lung cancer progression and resistance to treatment. The alterations of EGFR signaling have the potential to produce an ineffective tumor-associated immune microenvironment by upregulating a series of immune suppressors, including inhibitory immune checkpoints, immunosuppressive cells, and cytokines. Elevated Heparin-binding EGF-like growth factor (HB-EGF) expression, one EGFR ligand correlated with higher histology grading, worse patient prognosis, and lower overall survival rate, acts as a chemotactic factor. However, the role of heparin-binding epidermal growth factor-like growth factor (HB-EGF) in the accumulation of immune cells in the tumor microenvironment remains unclear.MethodsThe clinical association of HB-EGF expression in lung cancer was examined using the Gene Expression Omnibus (GEO) repository. HB-EGF expression in different cell types was determined using single-cell RNA sequencing (scRNA-seq) dataset. The correlation between HB-EGF expression and cancer-immune infiltrated cells was investigated by performing TIMER and ClueGo pathways analysis from TCGA database. The chemotaxis of HB-EGF and macrophage infiltration was investigated using migration and immunohistochemical staining.ResultsThe high HB-EGF expression was significantly correlated with poor overall survival in patients with lung adenocarcinoma (LUAD) but not lung squamous cell carcinoma (LUSC). Moreover, HB-EGF expression was correlated with the infiltration of monocytes, macrophages, neutrophils, and dendritic cells in LUAD but not in LUSC. Analysis of scRNA-seq data revealed high HB-EGF expression in lung cancer cells and myeloid cells. Results from the pathway analysis and cell-based experiment indicated that elevated HB-EGF expression was associated with the presence of macrophage and lung cancer cell migration. HB-EGF was highly expressed in tumors and correlated with M2 macrophage infiltration in LUAD.ConclusionsHB-EGF is a potential prognostic marker and therapeutic target for lung cancer progression, particularly in LUAD.

BACKGROUND Obstructive sleep apnea (OSA) is sleep-disordered breathing and is typically diagnosed by polysomnography (PSG). However, PSG is time-consuming and has some clinical limitations. OBJECTIVE This study thus aimed to establish machine learning models to screen for the risk of having moderate-to-severe and severe OSA based on easily acquired features (e.g., symptoms or risk factors of OSA). METHODS This retrospective study collected data on 3629 patients from Taiwan, who had undergone PSG for symptoms of OSA. Their baseline characteristics, anthropometric measures, and PSG data were obtained. The number of snoring events of PSG was further derived, and correlations among the collected variables were investigated. Next, this study utilized six common supervised machine learning techniques to establish OSA risk screening models, including random forest (RF), XGBoost, k-nearest neighbors, support vector machine, logistic regression, and naïve Bayes. First, data were independently separated into a training and validation dataset (80%) and a test dataset (20%). The approach which had the highest accuracy in the training and validation phase was employed to perform the classification for the test dataset. Moreover, the feature importance of employed models was determined by calculating the Shapley value of every factor, which represented the impact on OSA risk screening. RESULTS RF models manifested the highest accuracy and area under the receiver operating characteristic curve (AUC) in the training and validation phase in screening for both OSA severities (over 70% of accuracy and over 80% of AUC). Hence, we employed the RF to perform the classification of the independent test dataset, and results showed 79.32% accuracy for moderate-to-severe OSA and 74.37% accuracy for severe OSA. Next, snoring events and the visceral fat level were the most and second-most essential features of screening for OSA risk. CONCLUSIONS Snoring events and the visceral fat level were essential features of screening for OSA risk. Based on these easily assessed variables, this study established models that can be considered to apply for screening OSA risk in populations with similar craniofacial features.

Cancer metastasis leading to the dysfunction of invaded organs is the main cause of the reduced survival rates in lung cancer patients. However, the molecular mechanism for lung cancer metastasis remains unclear. Recently, the increased activity of inflammasome appeared to correlate with the metastatic progression and immunosuppressive ability of various cancer types. Our results showed that the mRNA levels of absence in melanoma 2 (AIM2), one of the inflammasome members, are extensively upregulated in primary tumors compared with normal tissues derived from the TCGA lung adenocarcinoma (LUAD) database. Moreover, Kaplan-Meier analysis demonstrated that a higher mRNA level of AIM2 refers to a poor prognosis in LUAD patients. Particularly, AIM2 upregulation is closely correlated with smoking history and the absence of EGFR/KRAS/ALK mutations in LUAD. We further showed that the endogenous mRNA levels of AIM2 are causally associated with the metastatic potentials of the tested LUAD cell lines. AIM2 knockdown suppressed but overexpression promoted the migration ability and lung colony-forming ability of tested LUAD cells. In addition, we found that AIM2 upregulation is closely associated with an increased level of immune checkpoint gene set, as well as programmed cell death-ligand 1 (PD-L1) transcript, in TCGA LUAD samples. AIM2 knockdown predominantly repressed but overexpression enhanced PD-L1 expression via altering the activity of PD-L1 transcriptional regulators NF-κB/STAT1 in LUAD cells. Our results not only provide a possible mechanism underlying the AIM2-promoted metastatic progression and immune evasion of LUAD but also offer a new strategy for combating metastatic/immunosuppressive LUAD via targeting AIM2 activity.

Background Exposure to air pollution exerts direct effects on respiratory organs; however, molecular alterations underlying air pollution-induced pulmonary injury remain unclear. In this study, we investigated the effect of air pollution on the lung tissues of Sprague-Dawley rats with whole-body exposure to traffic-related PM1 (particulate matter Results Rats in the 6-month PM1-exposed group exhibited a significant decline in lung function, as determined by decreased FEF25–75% and FEV20/FVC; however, histological analysis revealed earlier lung damage, as evidenced by increased congestion and macrophage infiltration in 3-month PM1-exposed rat lungs. The lung tissue proteomics analysis identified 2673 proteins that highlighted the differential dysregulation of proteins involved in oxidative stress, cellular metabolism, calcium signalling, inflammatory responses, and actin dynamics under exposures to PM1 and gaseous pollutants. The presence of PM1 specifically enhanced oxidative stress and inflammatory reactions under subchronic exposure to traffic-related PM1 and suppressed glucose metabolism and actin cytoskeleton signalling. These factors might lead to repair failure and thus to lung function decline after chronic exposure to traffic-related PM1. A detailed pathogenic mechanism was proposed to depict temporal and dynamic molecular regulations associated with PM1- and gaseous pollutants-induced lung injury. Conclusion This study explored several potential molecular features associated with early lung damage in response to traffic-related air pollution, which might be used to screen individuals more susceptible to air pollution.

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality in chronic lung disease patients throughout the world. Mesenchymal stem cells (MSCs) have been shown to regulate immunomodulatory, anti-inflammatory, and regenerative responses. However, the effects of human-umbilical-cord-derived mesenchymal stem cells (hUC-MSCs) on the lung pathophysiology of COPD remain unclear. We aimed to investigate the role of hUC-MSCs in emphysema severity and Yes-associated protein (Yap) phosphorylation (p-Yap) in a porcine-pancreatic-elastase (PPE)-induced emphysema model. We observed that the emphysema percentages (normalized to the total lung volume) measured by chest computed tomography (CT) and exercise oxygen desaturation were significantly reduced by hUC-MSCs at 107 cells/kg body weight (BW) via intravenous administration in emphysematous mice (p < 0.05). Consistently, the emphysema index, as assessed by the mean linear intercept (MLI), significantly decreased with hUC-MSC administration at 3 × 106 and 107 cells/kg BW (p < 0.05). Changes in the lymphocytes, monocytes, and splenic cluster of differentiation 4-positive (CD4+) lymphocytes by PPE were significantly reversed by hUC-MSC administration in emphysematous mice (p < 0.05). An increasing neutrophil/lymphocyte ratio was reduced by hUC-MSCs at 3 × 106 and 107 cells/kg BW (p < 0.05). The higher levels of tumor necrosis factor (TNF)-α, keratinocyte chemoattractant (KC), and lactate dehydrogenase (LDH) in bronchoalveolar lavage fluid (BALF) were significantly decreased by hUC-MSC administration (p < 0.05). A decreasing p-Yap/Yap ratio in type II alveolar epithelial cells (AECII) of mice with PPE-induced emphysema was significantly increased by hUC-MSCs (p < 0.05). In conclusion, the administration of hUC-MSCs improved multiple pathophysiological features of mice with PPE-induced emphysema. The effectiveness of the treatment of pulmonary emphysema with hUC-MSCs provides an essential and significant foundation for future clinical studies of MSCs in COPD patients.

Background Some evidences have shown the association between air pollution exposure and the development of interstitial lung diseases. However, the effect of air pollution on the progression of restrictive ventilatory impairment and diffusion capacity reduction is unknown. This study aimed to evaluate the effects of long-term exposure to ambient air pollution on the change rates of total lung capacity, residual volume, and diffusion capacity among the elderly. Methods From 2016 to 2018, single-breath helium dilution with the diffusion capacity of carbon monoxide was performed once per year on 543 elderly individuals. Monthly concentrations of ambient fine particulate matters (PM2.5) and nitric dioxide (NO2) at the individual residential address were estimated using a hybrid Kriging/Land-use regression model. Linear mixed models were used to evaluate the association between long-term (12 months) exposure to air pollution and lung function with adjustment for potential covariates, including basic characteristics, indoor air pollution (second-hand smoke, cooking fume, and incense burning), physician diagnosed diseases (asthma and chronic airway diseases), dusty job history, and short-term (lag one month) air pollution exposure. Results An interquartile range (5.37 ppb) increase in long-term exposure to NO2 was associated with an additional rate of decline in total lung volume (− 1.8% per year, 95% CI: − 2.8 to − 0.9%), residual volume (− 3.3% per year, 95% CI: − 5.0 to − 1.6%), ratio of residual volume to total lung volume (− 1.6% per year, 95% CI: − 2.6 to − 0.5%), and diffusion capacity (− 1.1% per year, 95% CI: − 2.0 to − 0.2%). There is no effect on the transfer factor (ratio of diffusion capacity to alveolar volume). The effect of NO2 remained robust after adjustment for PM2.5 exposure. Conclusions Long-term exposure to ambient NO2 is associated with an accelerated decline in static lung volume and diffusion capacity in the elderly. NO2 related air pollution may be a risk factor for restrictive lung disorders.

The genome of Methylocystis sp. strain SB2, which was previously isolated from a spring bog in southeast Michigan, was sequenced using long-read sequencing technology. This new sequencing and assembly effort yielded a complete assembly of the genome in a single contig.

Social insects are ecologically and evolutionarily most successful organisms on earth, which can achieve robust collective behaviors through local interactions among group members. Colony migration has been considered as a leading example of collective decision-making in social insects. In this paper, a piecewise colony migration system with recruitment switching is proposed to explore underlying mechanisms and synergistic effects of colony size and quorum on the outcomes of collective decision. The completed dynamical analysis for the non-smooth system (including the dynamics on subsystems, switching surface, and full system) is performed, and the sufficient conditions significantly related to colony size for the stability of equilibria are provided. The theoretical results suggest that large colonies are more likely to emigrate to a new site. More interesting findings include but not limit to: (a) the system may exhibit oscillation when the colony size is below a critical level; (b) the system may also exhibit a bistable state, and colonies migrate to a new site or the old nest depending on their initial sizes of recruiters. Bifurcation analysis shows that the variations of colony size and quorum threshold greatly impact the dynamics. The results suggest that it is important to distinguish two populations of recruiters in modeling. This work may provide important insights on how simple and local interactions achieve the collective migrating activity in social insects.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a public health emergency. The most common symptoms of COVID-19 are fever, cough, and fatigue. While most patients with COVID-19 present with mild illness, some patients develop pneumonia, an important risk factor for mortality, at early stage of viral infection, putting these patients at increased risk of death. So far, little has been known about differences in the T cell repertoires between COVID-19 patients with and without pneumonia during SARS-CoV-2 infection. Herein, we aimed to investigate T cell receptor (TCR) repertoire profiles and patient-specific SARS-CoV-2-associated TCR clusters between COVID-19 patients with mild disease (no sign of pneumonia) and pneumonia. The TCR sequencing was conducted to characterize the peripheral TCR repertoire profile and diversity. The TCR clustering and CDR3 annotation were exploited to further discover groups of patient-specific TCR clonotypes with potential SARS-CoV-2 antigen specificities. Our study indicated a slight decrease in the TCR repertoire diversity and a skewed CDR3 length usage in patients with pneumonia compared to those with mild disease. The SARS-CoV-2-associated TCR clusters enriched in patients with mild disease exhibited significantly higher TCR generation probabilities and most of which were highly shared among patients, compared with those from pneumonia patients. Importantly, using similarity network-based clustering followed by the sequence conservation analysis, we found different patterns of CDR3 sequence motifs between mild disease- and pneumonia-specific SARS-CoV-2-associated public TCR clusters. Our results showed that characteristics of overall TCR repertoire and SARS-CoV-2-associated TCR clusters/clonotypes were divergent between COVID-19 patients with mild disease and patients with pneumonia. These findings provide important insights into the correlation between the TCR repertoire and disease severity in COVID-19 patients. Supplementary Information The online version contains supplementary material available at 10.1007/s10875-021-01045-z.

The recent outbreak of coronavirus disease 2019 (COVID-19) by SARS-CoV-2 has led to uptodate 24.3 M cases and 0.8 M deaths. It is thus in urgent need to rationalize potential therapeutic targets against the progression of diseases. An effective, feasible way is to use the pre-existing ΔORF6 mutant of SARS-CoV as a surrogate for SARS-CoV-2, since both lack the moiety responsible for interferon antagonistic effects. By analyzing temporal profiles of upregulated genes in ΔORF6-infected Calu-3 cells, we prioritized 55 genes and 238 ligands to reposition currently available medications for COVID-19 therapy. Eight of them are already in clinical trials. Of particular importance is the emergence of immune checkpoint inhibitors targeting PD-L1 that have not been used in COVID-19 treatment. We also pinpointed 16 drug groups from the Anatomical Therapeutic Chemical classification system, with the potential to mitigate symptoms of SARS-CoV-2 infection and thus to be repositioned for COVID-19 therapy., Highlights • Rationalization of useful therapeutic targets against the COVID-19 is of urgent need. • Transcriptomic perturbation profiles of SARS-CoV ΔORF6 mutant revealing 55 genes and 238 ligands to reposition to COVID-19. • Immune checkpoint inhibitors targeting PD-L1 shows potential for COVID-19 treatment. • 16 Anatomical Therapeutic Chemical classes were valuable for further investigation to treat COVID-19.

This paper proposes a method of curve interpolation based on the parameters of arc length that is used to interpolate the stress field of the wind tunnel flexible plate. The quotient of the arc length from the starting point to the interpolation point divided by the total arc length is the parameter corresponding to this point. The researchers calculated the optimum combination of parameters with the help of the particle swarm optimization algorithm. The optimization computation aims to find the combination of parameters corresponding to the shortest arc length of the interpolation curve. The simulated strain data of the flexible plate are collected by researchers to verify the performance of the algorithm. The experimental results show that the error of this method is small and that the increase in the error in the computation of the higher-order interpolation is not significant. This paper introduces fiber Bragg grating to the multipoint strain measurement of a wind tunnel flexible plate. The authors interpolated the stress measured from FBGs by the interpolation method proposed in this paper. Then, the stress distribution law and the maximum stress point of the flexible plate were found. The maximum one-dimensional stress is −193.21 MPa, and the position is 623.55 mm and 149.5 mm.

Background: First-line durvalumab plus etoposide with either cisplatin or carboplatin (platinum–etoposide) showed a significant improvement in overall survival versus platinum–etoposide alone in patients with extensive-stage small-cell lung cancer (ES-SCLC) in the CASPIAN study. Here we report updated results, including the primary analysis for overall survival with durvalumab plus tremelimumab plus platinum–etoposide versus platinum–etoposide alone. Methods: CASPIAN is an ongoing, open-label, sponsor-blind, randomised, controlled phase 3 trial at 209 cancer treatment centres in 23 countries worldwide. Eligible patients were aged 18 years or older (20 years in Japan) and had treatment-naive, histologically or cytologically documented ES-SCLC, with a WHO performance status of 0 or 1. Patients were randomly assigned (1:1:1) in blocks of six, stratified by planned platinum, using an interactive voice-response or web-response system to receive intravenous durvalumab plus tremelimumab plus platinum–etoposide, durvalumab plus platinum–etoposide, or platinum–etoposide alone. In all groups, patients received etoposide 80–100 mg/m2 on days 1–3 of each cycle with investigator's choice of either carboplatin area under the curve 5–6 mg/mL/min or cisplatin 75–80 mg/m2 on day 1 of each cycle. Patients in the platinum–etoposide group received up to six cycles of platinum–etoposide every 3 weeks and optional prophylactic cranial irradiation (investigator's discretion). Patients in the immunotherapy groups received four cycles of platinum–etoposide plus durvalumab 1500 mg with or without tremelimumab 75 mg every 3 weeks followed by maintenance durvalumab 1500 mg every 4 weeks. The two primary endpoints were overall survival for durvalumab plus platinum–etoposide versus platinum–etoposide and for durvalumab plus tremelimumab plus platinum–etoposide versus platinum–etoposide in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This study is registered at ClinicalTrials.gov, NCT03043872. Findings: Between March 27, 2017, and May 29, 2018, 972 patients were screened and 805 were randomly assigned (268 to durvalumab plus tremelimumab plus platinum–etoposide, 268 to durvalumab plus platinum–etoposide, and 269 to platinum–etoposide). As of Jan 27, 2020, the median follow-up was 25·1 months (IQR 22·3–27·9). Durvalumab plus tremelimumab plus platinum–etoposide was not associated with a significant improvement in overall survival versus platinum–etoposide (hazard ratio [HR] 0·82 [95% CI 0·68–1·00]; p=0·045); median overall survival was 10·4 months (95% CI 9·6–12·0) versus 10·5 months (9·3–11·2). Durvalumab plus platinum–etoposide showed sustained improvement in overall survival versus platinum–etoposide (HR 0·75 [95% CI 0·62–0·91]; nominal p=0·0032); median overall survival was 12·9 months (95% CI 11·3–14·7) versus 10·5 months (9·3–11·2). The most common any-cause grade 3 or worse adverse events were neutropenia (85 [32%] of 266 patients in the durvalumab plus tremelimumab plus platinum–etoposide group, 64 [24%] of 265 patients in the durvalumab plus platinum–etoposide group, and 88 [33%] of 266 patients in the platinum–etoposide group) and anaemia (34 [13%], 24 [9%], and 48 [18%]). Any-cause serious adverse events were reported in 121 (45%) patients in the durvalumab plus tremelimumab plus platinum–etoposide group, 85 (32%) in the durvalumab plus platinum–etoposide group, and 97 (36%) in the platinum–etoposide group. Treatment-related deaths occurred in 12 (5%) patients in the durvalumab plus tremelimumab plus platinum–etoposide group (death, febrile neutropenia, and pulmonary embolism [n=2 each]; enterocolitis, general physical health deterioration and multiple organ dysfunction syndrome, pneumonia, pneumonitis and hepatitis, respiratory failure, and sudden death [n=1 each]), six (2%) patients in the durvalumab plus platinum–etoposide group (cardiac arrest, dehydration, hepatotoxicity, interstitial lung disease, pancytopenia, and sepsis [n=1 each]), and two (1%) in the platinum–etoposide group (pancytopenia and thrombocytopenia [n=1 each]). Interpretation: First-line durvalumab plus platinum–etoposide showed sustained overall survival improvement versus platinum–etoposide but the addition of tremelimumab to durvalumab plus platinum–etoposide did not significantly improve outcomes versus platinum–etoposide. These results support the use of durvalumab plus platinum–etoposide as a new standard of care for the first-line treatment of ES-SCLC. Funding: AstraZeneca.

In this paper, we propose a new method for multiattribute decision making (MADM) using probability density functions and the transformed decision matrix (TDMx) of the decision matrix (DMx) offered by the decision maker (DM) in interval-valued intuitionistic fuzzy (IVIF) environments. First, it gets the TDMx of the DMx given by the DM. Then, it computes the average value of the interval-valued intuitionistic fuzzy values (IVIFVs) appearing at each column of the TDMx. Then, it calculates the variance of each IVIFV in the TDMx. Then, it computes the standard deviation (SD) of the IVIFVs appearing at each column of the TDMx. Then, based on the obtained TDMx, the obtained average value of the IVIFVs appearing at each column of the TDMx, and the obtained SD of the IVIFVs appearing at each column of the TDMx, it gets the z-score DMx. Then, each attribute’s IVIF weight is transformed into a crisp weight between zero and one. Finally, each alternative’s weighted score is calculated using the z-score DMx and each attribute’s transformed crisp weight. The larger the weighted score of an alternative, the better the preference order (PO) of the alternative. It can overcome the shortcomings of the existing MADM methods.