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Abstract Kluyveromyces marxianus is a food‐safe yeast with great potential for producing heterologous proteins. Improving the yield in K. marxianus remains a challenge and incorporating large‐scale functional modules poses a technical obstacle in engineering. To address these issues, linear and circular yeast artificial chromosomes of K. marxianus (KmYACs) were constructed and loaded with disulfide bond formation modules from Pichia pastoris or K. marxianus. These modules contained up to seven genes with a maximum size of 15 kb. KmYACs carried telomeres either from K. marxianus or Tetrahymena. KmYACs were transferred successfully into K. marxianus and stably propagated without affecting the normal growth of the host, regardless of the type of telomeres and configurations of KmYACs. KmYACs increased the overall expression levels of disulfide bond formation genes and significantly enhanced the yield of various heterologous proteins. In high‐density fermentation, the use of KmYACs resulted in a glucoamylase yield of 16.8 g/l, the highest reported level to date in K. marxianus. Transcriptomic and metabolomic analysis of cells containing KmYACs suggested increased flavin adenine dinucleotide biosynthesis, enhanced flux entering the tricarboxylic acid cycle, and a preferred demand for lysine and arginine as features of cells overexpressing heterologous proteins. Consistently, supplementing lysine or arginine further improved the yield. Therefore, KmYAC provides a powerful platform for manipulating large modules with enormous potential for industrial applications and fundamental research. Transferring the disulfide bond formation module via YACs proves to be an efficient strategy for improving the yield of heterologous proteins, and this strategy may be applied to optimize other microbial cell factories.

Abstract Immune checkpoint inhibitor (ICI) rechallenge in non‐small cell lung cancer (NSCLC) is a promising therapeutic strategy. The situation for ICI rechallenge can be divided into three categories: adverse events (AEs); resistance to ICIs, and rechallenge becomes compulsive because of tumor relapse while the patients had completed a 2 year course of immunotherapy. However, these categories are still controversial and should be explored further. Through voting at the 6th Straits Summit Forum on Lung Cancer, in this study we summarize the consensus of 147 experts in ICI rechallenges. A total of 97.74% experts agreed to rechallenge; 48.87% experts rechallenge with the original drug, and the others rechallenge with a different drug; 40.3% agreed to rechallenge directly after progression; 88.06% experts agreed to ICI rechallenge with a combination regimen; and factors such as previous performance status score, PD‐1 expression, and age should also be considered. Understanding the the clinical studies in ICI rechallenge could bring us one step closer to understanding the consensus. In patients with advanced NSCLC who have suffered recurrent or distant metastasis after immunotherapy, the option of rechallenge with ICIs is a promising treatment option.

Abstract Immune checkpoint inhibitors (PD‐1/PD‐L1 and CTLA‐4 blockade) have revolutionized the treatment landscape in non‐small cell lung cancer (NSCLC). Secondary resistance to immunotherapy (IO), which poses a substantial challenge in clinical settings, occurs in several initial responders. Currently, new treatment approaches have been extensively evaluated in investigational studies for these patients to tackle this difficult problem; however, the lack of consistency in clinical definition, uniform criteria for enrollment in clinical trials, and interpretation of results remain significant hurdles to progress. Thus, our expert panel comprehensively synthesized data from current studies to propose a practical clinical definition of secondary resistance to immunotherapy in NSCLC in metastatic and neoadjuvant settings. In addition to patients who received IO alone (including IO‐IO combinations), we also generated a definition for patients treated with chemotherapy plus IO. This consensus aimed to provide guidance for clinical trial design and facilitate future discussions with investigators. It should be noted that additional updates in this consensus are required when new data is available.

Abstract The coronavirus disease 2019 (COVID‐19) has developed into a global health crisis. Pulmonary fibrosis, as one of the complications of SARS‐CoV‐2 infection, deserves attention. As COVID‐19 is a new clinical entity that is constantly evolving, and many aspects of disease are remain unknown. The datasets of COVID‐19 and idiopathic pulmonary fibrosis were obtained from the Gene Expression Omnibus. The hub genes were screened out using the Random Forest (RF) algorithm depending on the severity of patients with COVID‐19. A risk prediction model was developed to assess the prognosis of patients infected with SARS‐CoV‐2, which was evaluated by another dataset. Six genes (named NELL2, GPR183, S100A8, ALPL, CD177, and IL1R2) may be associated with the development of PF in patients with severe SARS‐CoV‐2 infection. S100A8 is thought to be an important target gene that is closely associated with COVID‐19 and pulmonary fibrosis. Construction of a neural network model was successfully predicted the prognosis of patients with COVID‐19. With the increasing availability of COVID‐19 datasets, bioinformatic methods can provide possible predictive targets for the diagnosis, treatment, and prognosis of the disease and show intervention directions for the development of clinical drugs and vaccines.

Abstract Objective To describe a novel method of medial fixation of titanium mesh with a right‐angled screwdriver for orbital floor and maxillary reconstruction and to compare the reconstruction outcome of orbital floor reconstruction with modified and traditional methods. Methods The data of 23 patients who underwent maxillectomy and orbital floor defect reconstruction by individualized titanium mesh in Peking University School and Hospital of Stomatology between 2018 and 2021 were retrospectively reviewed. While eight patients received modified orbital floor reconstruction with titanium mesh and angled screwdriver (group A), 15 patients received traditional orbital floor reconstruction (group B). The contact area with buccal flap for titanium mesh in groups A and B was calculated. Titanium mesh deformation, fracture or exposure was recorded. Postoperative ophthalmic function and success of esthetic restoration were assessed. Results Mean follow‐up was for 15.7 months (range, 9–22 months). The contact area with buccal flap for the modified titanium mesh in group A (13.11 ± 1.41 cm2) was significantly less than that of the traditional titanium mesh in group B (21.83 ± 1.23 cm2; p .05). No specific complications were reported. Conclusion We propose a novel method of zygomatic medial fixation of titanium mesh with a right‐angled screwdriver for orbital floor and maxillary reconstruction, which has the potential to prevent the postoperative exposure of titanium mesh. Level of Evidence Level III (Retrospective comparative study).

Abstract Soil microorganisms play vital roles in regulating multiple ecosystem functions. Recent studies have revealed that the rare microbial taxa (with extremely low relative abundances, which are still largely ignored) are also crucial in maintaining the health and biodiversity of the soil and may respond differently to environmental pressure. However, little is known about the soil community structures of abundant and rare taxa and their assembly processes in different soil layers on the Qinghai‐Tibet Plateau (QTP). The present study investigated the community structure and assembly processes of soil abundant and rare microbial taxa on the northeastern edge of the QTP. Soil microbial abundance was defined by abundant taxa, whereas rare taxa contributed to soil microbial diversity. The results of null model show that the stochastic process ruled the assembly processes of all sub‐communities. Dispersal limitation contributed more to the assembly of abundant microbial taxa in the different soil layers. In contrast, drift played a more critical role in the assembly processes of the rare microbial taxa. In addition, in contrast to previous studies, the abundant taxa played more important roles in co‐occurrence networks, most likely because of the heterogeneity of the soil, the sparsity of amplicon sequencing, the sampling strategy, and the limited samples in the present study. The results of this study improve our understanding of soil microbiome assemblies on the QTP and highlight the role of abundant taxa in sustaining the stability of microbial co‐occurrence networks in different soil layers.

Abstract Multifunctional nanomedicines have been used in atherosclerosis theranostics. Herein, phosphatidylserine‐specific peptide CLIKKPF‐functionalized carbon‐dots nanozymes (pep‐CDs) are reported for specific and efficient noninvasive theranostic of atherosclerosis. Surprisingly, pep‐CDs are discovered to not only inherit the inherent properties of carbon dots (CDs), including deep‐red fluorescence emission, photoacoustic response, and superoxide dismutase‐like antioxidant, and anti‐inflammatory activities but also possess the ability to target recognition on foam cells and target localization on plaques due to the specific interaction of CLIKKPF with phosphatidylserine on the membrane outer surface of foam cells. Furthermore, the target localization effect of pep‐CDs vastly promotes the efficient accumulation of CDs in plaque, thus maximizing AS theranostic of CDs. Interestingly, pep‐CDs could be developed to image plaque for monitoring atherosclerosis pathological progression in real‐time resulting from the different content of foam cells. This work on the one hand proposes a simple and feasible strategy to construct theranostic nanoplatform employing only a single functional unit (i.e., multifunctional CDs) to simplify the fabrication procedure, on the other hand, highlights the advantages of the active target auxiliary mode for atherosclerosis theranostic applications.

Abstract The control of unmanned aerial vehicle quadrotor is challenging because of non‐linearities, coupling and disturbance. Here, a novel control method which includes reinforcement learning (RL) component and robust component is proposed. In this method, the RL component only relies on collected data instead of modelling to handle coupling and disturbance from aerodynamics and model. To ensure safety during training and improve training speed, the robust component is used to reduce the disturbance .The stability of the system with our controller is proven by Lyapunov method. The results of the simulation exhibit advanced performance of our controller.

Abstract Malnutrition is a state of altered body composition and body cell mass due to inadequate intake or utilization of energy or nutrients, leading to physical and mental dysfunction and impaired clinical outcomes. As one of the most common geriatric syndromes, malnutrition in the elderly is a significant risk factor for poor clinical outcomes, causing a massive burden on medical resources and society. The risk factors for malnutrition in the elderly are diverse and include demographics, chronic diseases, and psychosocial factors. Presently, recommendations for the prevention and intervention of malnutrition in the elderly are not clear or consistent in China. This consensus is based on the latest global evidence and multiregional clinical experience in China, which aims to standardize the prevention and intervention of malnutrition in the elderly in China and improve the efficacy of clinical practice and the prognosis of elderly patients.

Abstract Extensive research have been devoted to the exploration of multifunctional theranostic agents for cancer, but the poor tumor specificity and unsatisfactory treatment efficacy are some of the critical obstacles for their clinical translations. Herein, ferrocene‐carbon dot‐crosslinked nanoparticles (Fc‐CD NPs) were designed and fabricated for achieving highly specific and photothermal‐augmented chemodynamic therapy (CDT). The Fc‐CD NPs were found not only to inherit the immanent fluorescence, photoacoustic, and photothermal properties of carbon dots (CDs), but also be endowed with CDT that could occur selectively in tumor microenvironment (TME) due to the presence of Fc for triggering Fenton reaction. Moreover, the enlarged particle size of Fc‐CD NPs facilitated their effective accumulation at tumor sites, thus realizing great improvement for antitumor treatment outcomes. Once docking at tumor and being exposed to 660 nm laser irradiation, significantly amplified CDT effect of Fc‐CD NPs was observed due to heat‐accelerating generation of reactive oxygen species (ROS). More interestingly, since the produced ROS could in turn alleviate the thermal‐resistance of photothermal therapy (PTT), the therapeutic efficiency of integrated PTT and CDT was synergized to the maximum extent. This study on the one hand provides a facile approach to fabricate CDs‐based multifunctional theranostic nanoplatform with enhanced tumor accumulation and specificity, on the other hand emphasizes the merits of synergizing mutually beneficial therapeutic modalities for more efficient cancer therapy.

Background Heart failure with recovered ejection fraction (HFrecEF) has been a newly recognized entity since 2020. However, the concept has primarily focused on left ventricular ejection fraction improvement, with less focus on the recovery of the left atrium. In this study, we investigated changes in left atrial (LA) echocardiographic indices in HFrecEF. Methods and Results An inpatient cohort with heart failure with reduced ejection fraction (HFrEF) was identified retrospectively and followed up prospectively in a single tertiary hospital. The enrolled patients were classified into HFrecEF and persistent HFrEF groups. Alternations in LA parameters by echocardiography were calculated. The primary outcome was a composite of cardiovascular death or heart failure rehospitalization. A total of 699 patients were included (HFrecEF: n=228; persistent HFrEF: n=471). Compared with persistent HFrEF, the HFrecEF group had greater reductions in LA diameter, LA transverse diameter, LA superior–inferior diameter, LA volume, and LA volume index but not in LA sphericity index. Cox regression analysis showed that the HFrecEF group experienced lower risks of prespecified end points than the persistent HFrEF group after adjusting for confounders. Additionally, 136 (59.6%) and 62 (13.0%) patients showed LA reverse remodeling (LARR) for the HFrecEF and persistent HFrEF groups, respectively. Among the HFrecEF subgroup, patients with LARR had better prognosis compared with those without LARR. Multivariate logistic analysis demonstrated that age and coronary heart disease were 2 independent negative predictors for LARR. Conclusions In HFrecEF, both left ventricular systolic function and LA structure remodeling were improved. Patients with HFrecEF with LARR had improved clinical outcomes, indicating that the evaluation of LA size provides a useful biomarker for risk stratification of heart failure.

Abstract The growth and tolerance of Kluyveromyces marxianus at high temperatures decreased significantly in the synthetic medium (SM), which is commonly used in industrial fermentations. After 100 days of adaptive laboratory evolution, a strain named KM234 exhibited excellent tolerance at a high temperature, without loss of its growth ability at a moderate temperature. Transcriptomic analysis revealed that the KM234 strain decreased the expression of the ammonium (NH4+) transporter gene MEP3 and increased the synthesis of the amino acid carbon backbone, which may contribute greatly to the high‐temperature growth phenotype. High NH4+ content in SM significantly increased the reactive oxygen species (ROS) production at high temperatures and thus caused toxicity to yeast cells. Replacing NH4+ with organic nitrogen sources or increasing the concentration of potassium ions (K+) in the medium restored the growth of the wild‐type K. marxianus at a high temperature in SM. We also showed that the NH4+ toxicity mitigated by K+ might closely depend on the KIN1 gene. Our results provide a practical solution to industrial fermentation under high‐temperature conditions.

Abstract An effective feature representation can boost recognition tasks in the sketch domain. Due to an abstract and diverse structure of the sketch relatively with a natural image, it is complex to generate a discriminative features representation for sketch recognition. Accordingly, this article presents a novel scheme for sketch recognition. It generates a discriminative features representation as a result of integrating asymmetry essential information from deep features. This information is kept as an original feature‐vector space for making a final decision. Specifically, five different well‐known pre‐trained deep convolutional neural networks (DCNNs), namely, AlexNet, VGGNet‐19, Inception V3, Xception, and InceptionResNetV2 are fine‐tuned and utilised for feature extraction. First, the high‐level deep layers of the networks were used to get multi‐features hierarchy from sketch images. Second, an entropy‐based neighbourhood component analysis was employed to optimise the fusion of features in order of rank from multiple different layers of various deep networks. Finally, the ranked features vector space was fed into the support vector machine (SVM) classifier for sketch classification outcomes. The performance of the proposed scheme is evaluated on two different sketch datasets such as TU‐Berlin and Sketchy for classification and retrieval tasks. Experimental outcomes demonstrate that the proposed scheme brings substantial improvement over human recognition accuracy and other state‐of‐the‐art algorithms.

A clear understanding of nanoconfined gas flow behavior in shale gas reservoirs is beneficial for its efficient development. Nanopores in the shale gas reservoirs are characterized by complex surface chemistry and composition, as well as affinity, while their impact on methane flow has not been investigated comprehensively before. In light of current research status, this article proposes a simple yet robust theoretical model, incorporating bulk-gas flow flux and surface diffusion of adsorption gas. In particular, wettability effect, indicating the influences of the shifted critical properties and adsorption thickness, is captured as well. In this article, gas physical attributes, such as gas compressibility factor and gas viscosity, are modified under the nanoconfinement effect and wettability effect, and also the variation of effective pore size, induced by surface wettability, is considered. Notably, wettability effect in this article is described by using a macroscopic form, surface contact angle, facilitating the model applicability. In addition, both the bulk-gas flow model and surface-diffusion model, developed in this research, are able to achieve excellent agreements compared with the existed documents, clarifying the reliability of the proposed model. Meanwhile, key role of wettability effect on nanoconfined gas flow behavior, especially for surface diffusion of adsorption gas, is demonstrated. Results show that (a) the gas flux in small nanopores may exceed that in large nanopores, due to the predominant role of surface diffusion, while pore size is less than 10 nm; (b) the absence of real gas effect will lead to inaccurate characterization of nanoconfined gas flow capacity, and the magnitude can reach 7% for pore size of 5 nm and will enlarge with further pore size shrinkage; (c) wettability effect governs the total gas flux when pore size is less than 10 nm, while its impact will be greatly mitigated when pore size is greater than 50 nm. This article provides a comprehensive investigation to shed light on surface wettability on gas flow behavior through nanopores.

Damage caused by climate catastrophes is severe, especially for the 1-in-100-year events. This study is aimed at assessing the frequency and spatiotemporal regularity of extreme weather events. Based on the selected Gumbel copula function, a joint trivariate distribution of weather events is established. In this study, different univariate return periods and return periods of the joint trivariate distribution are calculated separately. Second, the Moran index is used to determine whether there is a spatial correlation between weather events. In this paper, the spatial and temporal patterns of weather events are determined based on a geographically weighted regression model. The suggestion of adding Bayesian information to the model measurements to improve the model accuracy is presented. Finally, a wavelet neural network model is constructed to predict the probability of extreme weather events throughout the Americas.

Backgrounds. The prevalence of diabetes has increased with the increase of obesity, and finding indicators to predict diabetes risk has become an urgent need. The purpose of this study is to compare the correlation between four anthropometric indices and the prevalence of diabetes. Methods. A total of 4052 participants aged 40 years and above were selected in Dehui City, Jilin Province, using a multistage stratified whole group sampling method. Face-to-face interviews and physical examinations were conducted. Multivariate logistic analysis was used. The values of BMI, waist circumference (WC), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR) were divided into quartiles (Q1:

Time-varying output formation control problems for high-order time-invariant swarm systems are studied with nonlinear uncertainties and directed network topology in this paper. A robust controller which consists of a nominal controller and a robust compensator is applied to achieve formation control. The nominal controller based on the output feedback is designed to achieve desired time-varying formation properties for the nominal system. And the robust compensator based on the robust signal compensator technology is constructed to restrain nonlinear uncertainties. The time-varying formation problem is transformed into the stability problem. And the formation errors can be arbitrarily small with expected convergence rate. Numerical examples are provided to illustrate the effectiveness of the proposed strategy.

The explosion pressure and minimum explosible concentration (MEC) properties of metal sulfide ore dust clouds are valuable for the prevention and control of metal sulfide ore dust explosions. In this study, a 20 L explosion sphere vessel was used to investigate the effect of sulfur content, particle size, and concentration on the explosion pressure and minimum explosible concentration of metal sulfide ore dust clouds. Four samples with different sulfur contents were selected (30%–40%, 20%–30%, 10%–20%, and 0%–10%). Before and after the explosion, samples were tested by X-ray diffraction. The results indicate that the metal sulfide ore dust is explosive dust with St1 grade explosion pressure. With an increase in concentration, the maximum explosion pressure increased at first and then decreased. With an increase in sulfide content, the explosion pressure of metal sulfide ore dust increased, while the minimum explosible concentration decreased. As particle size decreased, the MEC also decreased. The sulfur content, particle size, and concentration of metal sulfide ore dust were the main factors affecting the explosion hazard.

In order to respond to the variable state of traffic network in time, a distributed dynamic traffic assignment strategy is proposed which can improve the intelligent traffic management. The proposed dynamic assignment method is based on utility theory and is oriented to different levels of induced users. A distributed model based on the marginal utility is developed which combines the advantages of both decentralized paradigm and traveler preference, so as to provide efficient and robust dynamic traffic assignment solutions under uncertain network conditions. Then, the solution algorithm including subroute update and subroute calculation is proposed. To testify the effectiveness of the proposed model in optimizing traffic network operation and minimizing traveler’s cost on different induced levels, a sequence numerical experiment is conducted. In the experiment, there are two test environments: one is in different network load conditions and the other is in different deployment coverage of local agents. The numerical results show that the proposed model not only can improve the running efficiency of road network but also can significantly decrease the average travel time.

This paper is devoted to reconsider the one-loop oblique corrections arising from the scalar superpartners in the MSSM, that is, the squarks, the sleptons, and the scalars in Higgs sector. We explicitly present the complete one-loop forms of self-energy corrections to the gauge bosons of SM electroweak gauge groups, as well as their descendants the S , T , and U parameters, which can be directly applied to constrain the parameter space of the MSSM. Our results about one-loop self energies are found to agree with Drees et al. (1992) and Pierce et al. (1997). Nevertheless, the S , T , and U parameters are not in agreement with Dobado et al. (1999).

The kinematics analysis method of a novel 3-DOF wind tunnel mechanism based on cable-driven parallel mechanism is provided. Rodrigues' parameters are applied to express the transformation matrix of the wire-driven mechanism in the paper. The analytical forward kinematics model is described as three quadratic equations using three Rodridgues' parameters based on the fundamental theory of parallel mechanism. Elimination method is used to remove two of the variables, so that an eighth-order polynomial with one variable is derived. From the equation, the eight sets of Rodridgues' parameters and corresponding Euler angles for the forward kinematical problem can be obtained. In the end, numerical example of both forward and inverse kinematics is included to demonstrate the presented forward-kinematics solution method. The numerical results show that the method for the position analysis of this mechanism is effective.