Search

A well-designed spray system, which is located near the source of high-temperature smoke, can improve the capture efficiency of traditional local exhaust ventilation (LEV). However, there is currently no comprehensive evaluation index that clearly reflects the performance of spray-local exhaust ventilation (SLEV), making it challenging to optimize the spray arrangement. The two-phase flow fields in the SLEV and LEV were compared to evaluate the impact of spray on smoke control. The effects of spray arrangement parameters, such as spray position, spacing, initial droplet size, and angle, on the performance of the SLEV system were further evaluated using current evaluation indicators. Based on this, we developed a comprehensive evaluation model for SLEV using the AHP-entropy combination weighting method. The results revealed that the decrease in smoke control with an increase in rolling speed is primarily caused by a reduction in spray control in the central region of the smoke. When the spray flow rate is 0.0028 kg/s and the velocity is 30 m/s, the primary factor that improves ventilation performance is the downward drag force exerted by the spray on smoke, rather than the cooling effect. The comprehensive model was developed using weights of 0.45, 0.34, and 0.21 for the three evaluation indicators: capture efficiency, high-quality concentration field ratio, and spatial droplet size. The model showed good reliability based on the results of the smoke concentration analysis. The results of this study are expected to guide the design, implementation, and evaluation of SLEV systems.

Abstract Spurred by the simultaneous need for data privacy protection and data sharing, federated learning (FL) has been proposed. However, it still poses a risk of privacy leakage in it. This paper, an improved Differential Privacy (DP) algorithm to protect the federated learning model. Additionally, the Fast Fourier Transform (FFT) is used in the computation of the privacy budget $$\epsilon_{total}$$ , to minimize the impact of limited arithmetic resources and numerous users on the effectiveness of training model. Moreover, instead of direct analyses of the privacy budget $$\epsilon$$ through various methods, Privacy Loss Distribution (PLD) and privacy curves are adopted, while the number of artificial assignments hyperparameters is reduced, and the grid parameters delineated for FFT use are improved. The improved algorithm tightens parameter bounds and minimizes human factors’ influence with minimal efficiency impact. It decreases the errors caused by truncation and discreteness of PLDs while expanding the discreteness interval to reduce the calculation workload. Furthermore, an improved activation function using a temper sigmoid with only one parameter $$\tau\:$$ , smooths the accuracy curve and mitigates drastically fluctuating scenarios during model training. Finally, simulation results on real datasets show that our improved DP algorithm, which accounts for long trailing, facilitates a better balance between privacy and utility in federated learning models.

Abstract Genetic epilepsy with febrile seizures plus (GEFS+) is a genetic epilepsy syndrome characterized by a marked hereditary tendency inherited as an autosomal dominant trait. Patients with GEFS+ may develop typical febrile seizures (FS), while generalized tonic–clonic seizures (GTCSs) with fever commonly occur between 3 months and 6 years of age, which is generally followed by febrile seizure plus (FS+), with or without absence seizures, focal seizures, or GTCSs. GEFS+ exhibits significant genetic heterogeneity, with polymerase chain reaction, exon sequencing, and single nucleotide polymorphism analyses all showing that the occurrence of GEFS+ is mainly related to mutations in the gamma-aminobutyric acid type A receptor gamma 2 subunit (GABRG2) gene. The most common mutations in GABRG2 are separated in large autosomal dominant families, but their pathogenesis remains unclear. The predominant types of GABRG2 mutations include missense (c.983A → T, c.245G → A, p.Met199Val), nonsense (R136*, Q390*, W429*), frameshift (c.1329delC, p.Val462fs*33, p.Pro59fs*12), point (P83S), and splice site (IVS6+2T → G) mutations. All of these mutations types can reduce the function of ion channels on the cell membrane; however, the degree and mechanism underlying these dysfunctions are different and could be linked to the main mechanism of epilepsy. The γ2 subunit plays a special role in receptor trafficking and is closely related to its structural specificity. This review focused on investigating the relationship between GEFS+ and GABRG2 mutation types in recent years, discussing novel aspects deemed to be great significance for clinically accurate diagnosis, anti-epileptic treatment strategies, and new drug development.

Background Despite the success of immune checkpoint inhibitor (ICI)-based combination therapies in hepatocellular carcinoma (HCC), its effectiveness remains confined to a subset of patients. The development of reliable, predictive markers is important for accurate patient stratification and further mechanistic understanding of therapy response.Methods We comprehensively analyzed paired single-cell RNA transcriptome and T-cell repertoire profiles from 14 HCC ascites samples, collected from 7 patients before and after treatment with the combination of sintilimab (anti-PD-1) and bevacizumab (anti-VEGF).Results We identify a widespread convergence on interferon (IFN) signaling across various immune cell lineages in treatment-responsive patients with HCC, indicating a common transcriptional state transition in the immune microenvironment linked to immunotherapy response in HCC. Strong IFN signaling marks CD8+ T cells with larger clonal expansion and enhanced cytotoxicity, macrophages toward M1-like polarization and strong T-cell recruitment ability, dendritic cells with increased antigen presentation capacity, as well as highly cytotoxic natural killer cells and activated B cells. By translating our finding to cohorts of patients with HCC, we demonstrate the specificity of IFN-signaling in the prognosis of patients with HCC and its ability to predict immunotherapy response.Conclusions This study provides a unique single-cell resource with clonal and longitudinal resolution during ICI therapy and reveals IFN signaling as a biomarker of immunotherapy response in HCC, suggesting a beneficial effect by combining IFN inducers with ICIs for patients with HCC.

Abstract Interferon gamma (IFNγ) is a critical cytokine known for its diverse roles in immune regulation, inflammation, and tumor surveillance. However, while IFNγ levels were elevated in sera of most newly diagnosed acute myeloid leukemia (AML) patients, its complex interplay in AML remains insufficiently understood. We aim to characterize these complex interactions through comprehensive bulk and single-cell approaches in bone marrow of newly diagnosed AML patients. We identify monocytic AML as having a unique microenvironment characterized by IFNγ producing T and NK cells, high IFNγ signaling, and immunosuppressive features. IFNγ signaling score strongly correlates with venetoclax resistance in primary AML patient cells. Additionally, IFNγ treatment of primary AML patient cells increased venetoclax resistance. Lastly, a parsimonious 47-gene IFNγ score demonstrates robust prognostic value. In summary, our findings suggest that inhibiting IFNγ is a potential treatment strategy to overcoming venetoclax resistance and immune evasion in AML patients.

Abstract The incentive mechanism of federated learning has been a hot topic, but little research has been done on the compensation of privacy loss. To this end, this study uses the Local SGD federal learning framework and gives a theoretical analysis under the use of differential privacy protection. Based on the analysis, a multi‐attribute reverse auction model is proposed to be used for user selection as well as payment calculation for participation in federal learning. The model uses a mixture of economic and non‐economic attributes in making choices for users and is transformed into an optimisation equation to solve the user choice problem. In addition, a post‐auction negotiation model that uses the Rubinstein bargaining model as well as optimisation equations to describe the negotiation process and theoretically demonstrate the improvement of social welfare is proposed. In the experimental part, the authors find that their algorithm improves both the model accuracy and the F1‐score values relative to the comparison algorithms to varying degrees.

Abstract Federated learning is a widely used distributed learning approach in recent years, however, despite model training from collecting data become to gathering parameters, privacy violations may occur when publishing and sharing models. A dynamic approach is proposed to add Gaussian noise more effectively and apply differential privacy to federal deep learning. Concretely, it is abandoning the traditional way of equally distributing the privacy budget ϵ and adjusting the privacy budget to accommodate gradient descent federation learning dynamically, where the parameters depend on computation derived to avoid the impact on the algorithm that hyperparameters are created manually. It also incorporates adaptive threshold cropping to control the sensitivity, and finally, moments accountant is used to counting the ϵ consumed on the privacy‐preserving, and learning is stopped only if the ϵtotal by clients setting is reached, this allows the privacy budget to be adequately explored for model training. The experimental results on real datasets show that the method training has almost the same effect as the model learning of non‐privacy, which is significantly better than the differential privacy method used by TensorFlow.

The interfaces between the electrode and solid‐state electrolyte play a decisive role in the performance of all‐solid‐state batteries. For example, the formation of the interphase between cathode and solid‐state electrolyte can affect interfacial impedance and thus the rate capability. Herein, the thermal stability at the solid–solid interface between LiMn2O4 cathode and garnet electrolyte LLZTO via combined in situ techniques is studied, including in situ X‐Ray diffraction, in situ transmission electron microscopy, and in situ Raman. The dynamic process of interfacial reaction at different scales is elucidated. Starting from 300 °C, Mn ions from LiMn2O4 would migrate into the solid‐state electrolyte, accompanied with the formation of LiMn3O4 interphase. As the temperature increases to 500 °C, the LiMn3O4 interphase transforms to MnO structure which hinders Li‐ion transportation and therefore increases the interfacial impedance. Although both LiMn2O4 and LLZTO could withstand continuous heating, their interface is inherently thermally unstable at relatively low temperature, which requires special attention during thermal treatment for practical fabrication. Findings provide mechanistic insights into the interfacial reaction which serves as a guidance for the design and manufacturing of all‐solid‐state batteries.

Background Acute myeloid leukemia (AML) is associated with a dismal prognosis. Immune checkpoint blockade (ICB) to induce antitumor activity in AML patients has yielded mixed results. Despite the pivotal role of B cells in antitumor immunity, a comprehensive assessment of B lymphocytes within AML’s immunological microenvironment along with their interaction with ICB remains rather constrained.Methods We performed an extensive analysis that involved paired single-cell RNA and B-cell receptor (BCR) sequencing on 52 bone marrow aspirate samples. These samples included 6 from healthy bone marrow donors (normal), 24 from newly diagnosed AML patients (NewlyDx), and 22 from 8 relapsed or refractory AML patients (RelRef), who underwent assessment both before and after azacitidine/nivolumab treatment.Results We delineated nine distinct subtypes of B cell lineage in the bone marrow. AML patients exhibited reduced nascent B cell subgroups but increased differentiated B cells compared with healthy controls. The limited diversity of BCR profiles and extensive somatic hypermutation indicated antigen-driven affinity maturation within the tumor microenvironment of RelRef patients. We established a strong connection between the activation or stress status of naïve and memory B cells, as indicated by AP-1 activity, and their differentiation state. Remarkably, atypical memory B cells functioned as specialized antigen-presenting cells closely interacting with AML malignant cells, correlating with AML stemness and worse clinical outcomes. In the AML microenvironment, plasma cells demonstrated advanced differentiation and heightened activity. Notably, the clinical response to ICB was associated with B cell clonal expansion and plasma cell function.Conclusions Our findings establish a comprehensive framework for profiling the phenotypic diversity of the B cell lineage in AML patients, while also assessing the implications of immunotherapy. This will serve as a valuable guide for future inquiries into AML treatment strategies.

Greenhouse tomato production is a growing business worldwide, and it is strongly promoted by bumblebee pollination. Although there are over 250 bumblebee species worldwide, very few species have been reared successfully for greenhouse tomato pollination. Those successfully managed species, especially Bombus terrestris, are shipped around the world for commercial use. However, managed bumblebees are known to escape greenhouse facilities, have established local populations, spread disease to local bumblebees, and are blamed for the declines of some indigenous bee species. An alternative to shipping exotic bumblebees around the world is to develop local species for greenhouse pollination. Such an approach has the dual benefits of creating a new industry of insect rearing while reducing threats to local bee communities. In this study, we successfully reared Bombus haemorrhoidalis, which is the most common bumblebee species in Northern Pakistan, in a laboratory and compared its effectiveness as a tomato pollinator with that of commercial B. terrestris in a greenhouse. We found that the effectiveness of B. haemorrhoidalis in tomato pollination in a greenhouse is very similar to that of B. terrestris when it comes to the fruit size, number of seeds, and fruit weight. Our study provides an example of how to rear a native bumblebee species to pollinate local crops, which is a method that could potentially substitute the importation of non-ingenious bumblebees.

Abstract Burkholderia pseudomallei is a Gram-negative intracellular bacterium that causes melioidosis, a life-threatening disease. The interaction of B. pseudomallei with its host is complicated, and cellular response to B. pseudomallei infection is still largely unknown. In this study, we aimed to determine host-cell responses to B. pseudomallei at the proteomics level. We performed proteomic profiling of B. pseudomallei HNBP001-infected mouse macrophage RAW264.7 cells to characterize the cellular response dynamics during infection. Western blot analysis was utilized for the validation of changes in protein expression. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted using the clusterProfiler R package. Compared with the negative control (NC) group, 811 common proteins varied over time, with a cut-off level of two fold change and an adjusted P-value less than 0.05. The bioinformatics analysis revealed that the proteins significantly changed in the B. pseudomallei HNBP001 infection group (Bp group) were enriched in glycometabolism pathways, including glycolysis, fructose and mannose metabolism, pentose phosphate pathway, galactose metabolism, and carbon metabolism. Western blot analysis verified three selected proteins involved in glycometabolism pathways, namely PGM1, PKM, and PGK1 were increase over time post the infection. Furthermore, in vitro functional analysis revealed an increased glucose uptake and decreased ATP production and O-GlcNAcylation in the Bp group compared with control group, suggesting that B. pseudomallei HNBP001 infection induces changes in glycometabolism in RAW264.7 cells. These results indicate that glycometabolism pathways change in RAW264.7 cells post B. pseudomallei HNBP001 infection, providing important insights into the intimate interaction between B. pseudomallei and macrophages.

Chromatin regulators (CRs) regulate the gene transcription process through combinatorial patterns, which currently remain obscure for pan-cancer. This study identified the interaction of CRs and constructed CR-CR interaction networks across five tumor cell lines. The global interaction analysis revealed that CRs tend to function in synergistically. In addition, common and specific CRs in interaction networks were identified, and the epigenetic processes of these CRs in regulating gene transcription were analyzed. Common CRs have conserved binding sites but cooperate with different partners in multiple tumor cell lines. They also participate in gene transcription regulation, through mediation of different histone modifications (HMs). Specific CRs, ATF2 and PRDM10 were found to distinguish liver cancer samples with different prognosis. PRDM10 participates in gene transcription regulation, by exertion of influence on the DNA methylation level of liver cancer. Through analysis of the edges in the CR-CR interaction networks, it was found EP300-TAF1 has genome-wide distinct signaling patterns, which exhibit different effects on downstream targets. This analysis provides novel insights for the understanding of synergistic mechanism of CRs function, as controllers of gene transcription across cancer types.

Abstract Mutations in the GABRG2 gene encoding the γ-aminobutyric acid (GABA) A receptor gamma 2 subunit are associated with genetic epilepsy with febrile seizures plus, febrile seizures plus, febrile seizures, and other symptoms of epilepsy. However, the mechanisms underlying Gabrg2-mediated febrile seizures are poorly understood. Here, we used the Cre/loxP system to generate conditional knockout (CKO) mice with deficient Gabrg2 in the hippocampus and neocortex. Heterozygous CKO mice (Gabrg2 fl/wt Cre + ) exhibited temperature-dependent myoclonic jerks, generalised tonic-clonic seizures, increased anxiety-like symptoms, and a predisposition to induce seizures. Cortical electroencephalography showed the hyperexcitability in response to temperature elevation in Gabrg2 fl/wt Cre + mice, but not in wild-type mice. Gabrg2 fl/wt Cre + mice exhibited spontaneous seizures and susceptibility to temperature-induced seizures. Loss of neurons were observed in cortical layers V–VI and hippocampus of Gabrg2 fl/wt Cre + mice. Furthermore, the latency of temperature- or pentylenetetrazol-induced seizures were significantly decreased in Gabrg2 fl/wt Cre + mice compared with wild-type mice. In summary, Gabrg2 fl/wt Cre + mice with Gabrg2 deletion in the neocortex and hippocampus reproduce many features of febrile seizures and therefore provide a novel model to further understand this syndrome at the cellular and molecular level.

Long non-coding RNAs (lncRNAs) have been widely recognized as important regulators in myocardial infarction (MI) and other heart diseases. Our study aimed to investigate the mechanism and biological function of an unknown lncRNA zinc finger protein 561 antisense RNA 1 (ZNF561-AS1) in MI. After confirming the MI model was successful, we applied reverse transcription quantitative polymerase chain reaction and Western blot (WB) and found that the expression of NLR family pyrin domain containing 3 (NLRP3), interleukin (IL)-1β, and IL-18 was substantially increased in infarct and border zones of MI mice heart at 24 h and 72 h compared with that in sham-operated models. Moreover, we found that NLRP3 expression was promoted in hypoxia human cardiomyocytes (HCMs). Through cell function assays including CCK-8, 5-Ethynyl-2’-deoxyuridine (EdU), flow cytometry, and TdT-mediated dUTP Nick-End Labeling (TUNEL), supported by WB analysis, we verified that silencing of NLRP3 facilitated proliferation but impeded apoptosis of hypoxia-induced myocardial cell. Moreover, Ago2-RIP and RNA pull-down assays displayed that NLRP3 could combine with miR-223-3p. Luciferase reporter assays further confirmed that NLRP3 was directly targeted by miR-223-3p. Simultaneously, we found that miR-223-3p was the downstream gene of ZNF561-AS1. In addition, we conducted a series of rescue experiments to affirm that ZNF561-AS1 regulated cell proliferation and apoptosis in MI through miR-223-3p/NLRP3 axis.

Due to the rapid development of modern communication technology and the substantial improvement of the processing capacity of communication equipment, it has become a challenging and meaningful research direction to realize the covert transmission of information by ensuring the low probability of detection (LPD) performance of the communication signals. The disadvantage of traditional fixed-parameter signal in LPD gradually appears. The paper proposes a time-varying chaotic multitone communication method to accomplish the LPD for the eavesdroppers. The method gets rid of the conventional LPD communication method whose performance improvement is exchanged at the expense of its reliability loss or sacrificing more resources. Based on the original chaotic multitone (CMT) communication method, the time-varying parameter is introduced to improve the randomness of the waveform and thus reduce the detection probability of eavesdroppers to the single tones in the multitone group (MTG). Meanwhile, to improve spectrum efficiency and reduce system complexity, the corresponding communication system model is designed based on orthogonal frequency division multiplexing (OFDM) technology. After given the corresponding detection and demodulation scheme based on the diversity and combination, the influence of time-varying parameters on the reliability for the cooperative receiver is analyzed. The LPD contribution of this method is evaluated by analyzing the detection probability of the eavesdropper. The experimental results show that the proposed method not only maintains the original reliability but also reduces the detection probability of eavesdroppers under the constant false alarm probability detection scheme.

An accumulating body of research indicates that long-noncoding RNAs (lncRNAs) regulate the target genes and act as competitive endogenous RNAs (ceRNAs) playing an indispensable role in lung adenocarcinoma (LUAD). LUAD is frequently accompanied by the feature of chromosomal instability (CIN); however, CIN-related ceRNAs have not been investigated yet. We systematically analyzed and integrated CIN-related dysregulated ceRNAs characteristics in LUAD samples for the first time. In TCGA LUAD cohort, CIN in tumor samples was significantly higher than that in those of adjacent, and patients with high CIN risk tended to have worse clinical outcomes. We constructed a double-weighted CIN-related dysregulated ceRNA network, in which edge weight and node weight represented the disorder extent of ceRNA and the correlation of RNA expression level and prognosis, respectively. After module mining and analysis, a potential prognostic biomarker composed of 12 RNAs (8 mRNAs and 4 lncRNAs) named CIN-related dysregulated ceRNAs (CRDC) was obtained. The CRDC risk score had a positive relation with clinical stage and CIN, and patients with high CRDC risk scores exhibited poor prognosis. Moreover, CRDC tended to be an independent risk factor with high robustness to overcome the effect of multicollinearity among other explanatory variables for disease-specific survival (DSS) in TCGA and two GEO cohorts. The result of functional analysis indicated that CRDC was involved in multiple cancer progresses, especially immune-related pathways. The patients with lower CRDC risk had higher B cell, T cell CD4+, T cell CD8+, neutrophil, macrophage, and myeloid dendritic cell infiltration than the patients with higher CRDC risk. Meanwhile, patients with lower CRDC risk could get more benefits from immunological therapy. The results suggested that the CRDC could be a potential prognostic biomarker and an immunotherapy predictor for lung adenocarcinoma.

Background Several systematic reviews have suggested that acupuncture is effective against functional constipation, but it is unknown whether variations in treatment effect across subgroups remain consistent. Our purpose of this study is to explore the heterogeneity of treatment effect of acupuncture on functional constipation across subgroups. Methods We will search eleven English and Chinese electronic databases and three clinical trial registries from inception to December 2021. Randomized controlled trials that evaluate acupuncture compared with sham acupuncture or no treatment for functional constipation will be eligible if they report at least one primary outcome. The primary outcomes will include the change in weekly complete spontaneous bowel movements or spontaneous bowel movements from baseline. Two authors will independently identify the relevant studies, assess the risk of bias using the Cochrane RoB 2 tool and contact the primary researchers of the eligible trials for individual patient data. Individual patient data obtained from the original trial author will be standardized and all trial data will be combined into a single database. Generalized linear mixed effects model will be used to determine possible subgroup effects by adding an interaction term for predefined subgroup and treatment. Systematic review registration International Prospective Register of Systematic Reviews (Number: CRD42020188366).

This study aimed to preliminarily illustrate the cerebral hemodynamic correlates of transcutaneous auricular vagal nerve stimulation (taVNS) in consciousness restoration. Arterial spin labeling (ASL) was adopted with functional magnetic resonance imaging (fMRI) to measure cerebral blood flow (CBF) changes before and after taVNS in 10 qualified patients with disorders of consciousness (DOC). Before taVNS, five patients responded to auditory stimuli (RtAS), and five did not respond to auditory stimuli (nRtAS). The RtAS DOC patients obtained favorable prognoses after the 4-week taVNS treatment, whereas the nRtAS ones did not. Simultaneously, taVNS increased CBF of multiple brain regions in the RtAS DOC patients, but hardly in the nRtAS ones. In conclusion, the preserved auditory function might be the prior key factor of the taVNS responders in DOC patients, and taVNS might alleviate RtAS DOC by activating the salience network, the limbic system, and the interoceptive system.

This paper presents a passive direction finding of a virtual time reversal method based on cross antenna array (CROSS-VTR), which aim is to solve the problem that the number of antenna elements of planar arrays is too large and the layout of circular arrays is complex which requires high hardware design. In order to verify the feasibility and accuracy of the algorithm, the mathematical model of the cross antenna array is first established. The search area of yaw angle and a pitch angle of the CROSS-VTR algorithm is determined according to the basic principle of passive time reversal focusing, and then, the time-reversed signal of each antenna element completes the time delay compensation at each scanning point in the search area. The compensated signals of each antenna element are added up to obtain the signal energy of each scanning point. The value of the yaw angle and pitch angle is obtained by searching the maximum energy among scanning points along the search route of yaw angle and pitch angle, respectively. Finally, the validity of the method is verified and compared with the music algorithm (multiple signal classification) based on the cross antenna array. The results show that the method has good direction finding accuracy at low signal-to-noise ratio.

With the development of communication countermeasure technology, the existing communication mode is exposed to intercept or decipher in the covert transmission of information. Therefore, the development of a new concept and principle covert communication technology with low interception probability and anti-non-cooperative demodulation has drawn increasing attention. In this treatise, we propose a chaotic multi-tone modulation and demodulation technology thus present a method to construct the covert communication system. The technology constructs chaotic multi-tone sets to express the baseband information with the multi-value mapping based on the dynamics principle, which can express the same baseband information with different multi-tone groups. Signal modulation is accomplished by combining frequency hopping and baseband information scrambling technology. Multi-value mapping is adopted to complete chaotic multi-tone modulation. Specifically it has strong information concealment and anti-non-cooperative demodulation characteristics. In order to solve the demodulation problem of the cooperative party, we present a demodulation scheme based on chaotic multi-tone and provide a complete chaotic multi-tone communication system construction scheme. Simulation results verify the performance of the proposed method.

Predicting query cost plays an important role in moving object databases. Accurate predictions help database administrators effectively schedule workloads and achieve optimal resource allocation strategies. There are some works focusing on query cost prediction, but most of them employ analytical methods to obtain an index-based cost prediction model. The accuracy can be seriously challenged as the workload of the database management system becomes more and more complex. Differing from the previous work, this paper proposes a method called CPRQ (Cost Prediction of Range Query) which is based on machine-learning techniques. The proposed method contains four learning models: the polynomial regression model, the decision tree regression model, the random forest regression model, and the KNN (k-Nearest Neighbor) regression model. Using R-squared and MSE (Mean Squared Error) as measurements, we perform an extensive experimental evaluation. The results demonstrate that CPRQ achieves high accuracy and the random forest regression model obtains the best predictive performance (R-squared is 0.9695 and MSE is 0.154).