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BackgroundAlthough peripheral blood lymphocyte subsets, particularly PD-1+ T cells, are promising prognostic indicators for patients with cancer. However, their clinical significance remains unclear.MethodsWe prospectively enrolled 157 patients with hepatocellular carcinoma (HCC) treated with transcatheter arterial chemoembolization combined with or without PD-1 inhibitors. Twenty peripheral lymphocyte subsets and cytokines were analyzed. We analyzed the differences in PD-1+ T cells between patients treated with and without PD-1 inhibitors and their associations with tumor response, survival prognosis, and clinical features.ResultsWe found that the baseline CD8+PD-1+ and CD4+PD-1+ T-cell frequencies in patients who had received PD-1 inhibitors were lower than those in patients who had not received PD-1 inhibitors (p < 0.001). In the former patients, there were no differences in PD-1+ T-cell frequencies between the responder and non-responder subgroups (p > 0.05), whereas in the latter patients, the levels of CD8+PD-1+ T cells, CD4+PD-1+ T cells, and CD8+PD-1+/CD4+PD-1+ ratio did not predict tumor response, progression-free survival (PFS), or overall survival (OS) (p>0.05). Furthermore, in multivariate analysis of patients treated with or without PD-1 inhibitors revealed that the levels of CD8+CD38+ T cells (OR = 2.806, p = 0.006) were associated with tumor response, whereas those of CD8+CD28+ T cells (p = 0.038, p = 0.001) and natural killer (NK) cells (p = 0.001, p = 0.027) were associated with PFS and OS. Although, these independent prognostic factors were associated with progressive tumor characteristics (p 0.05).ConclusionCirculating CD8+CD38+ T cells, CD8+CD28+ T cells, and NK cells were identified as potential prognostic factors for tumor response and survival in patients with HCC. Contrastingly, although PD-1 inhibitors can effectively block the T cell PD-1 receptor, the baseline PD-1+ T-cell frequencies and changes in the frequency of these cells have limited prognostic value.

Reverberation time (RT) is an important indicator of room acoustics, however, most studies focus on the mid-high frequency RT, and less on the low-frequency RT. In this paper, a hybrid approach based on geometric and wave methods was proposed to build a more accurate and wide frequency-band room acoustic impulse response. This hybrid method utilized the finite-difference time-domain (FDTD) method modeling at low frequencies and the Odeon simulation at mid-high frequencies, which was investigated in a university classroom. The influence of the low-frequency RT on speech intelligibility was explored. For the low-frequency part, different impedance boundary conditions were employed and the effectiveness of the hybrid method has also been verified. From the results of objective acoustical parameters and subjective listening experiments, the smaller the low-frequency RT was, the higher the Chinese speech intelligibility score was. The syllables, consonants, vowels, and the syllable order also had significant effects on the intelligibility score.

Snoring is a typical and intuitive symptom of the obstructive sleep apnea hypopnea syndrome (OSAHS), which is a kind of sleep-related respiratory disorder having adverse effects on people’s lives. Detecting snoring sounds from the whole night recorded sounds is the first but the most important step for the snoring analysis of OSAHS. An automatic snoring detection system based on the wavelet packet transform (WPT) with an eXtreme Gradient Boosting (XGBoost) classifier is proposed in the paper, which recognizes snoring sounds from the enhanced episodes by the generalization subspace noise reduction algorithm. The feature selection technology based on correlation analysis is applied to select the most discriminative WPT features. The selected features yield a high sensitivity of 97.27% and a precision of 96.48% on the test set. The recognition performance demonstrates that WPT is effective in the analysis of snoring and non-snoring sounds, and the difference is exhibited much more comprehensively by sub-bands with smaller frequency ranges. The distribution of snoring sound is mainly on the middle and low frequency parts, there is also evident difference between snoring and non-snoring sounds on the high frequency part.

In recent years, there has been a significant increase in braking energy regeneration for hybrid electric vehicles. To improve performance and reduce fuel consumption, a better control strategy composed of braking regeneration and gear shifting is needed. This work presents a braking energy regeneration control strategy for a hybrid electric vehicle (HEV). The mathematical model for the vehicle dynamic system is established, and the objective function of braking energy regeneration is presented based on system analysis. Taking the increased electric energy of a battery as the objective function of the economic downshift law, the multi-island genetic algorithm (MIGA) is used to solve the shifting condition factors corresponding to different deceleration speeds and motor torques and the optimal downshifting speed. The presented control strategy of braking energy regeneration is validated in a typical city cycle form in China, and the results show better energy efficiency.

Helicoverpa armigera is a polyphagous destructive lepidopteran pest with strong Bacillus thuringiensis (Bt) resistance. Cholesterol, a vital component for insect growth, can only be obtained from food, and its transfer and metabolism are regulated by sterol carrier protein-2 (SCP-2). This study examined whether H. armigera SCP-2 (HaSCP-2) gene expression, involved in cholesterol absorption, can be silenced by nanocarrier fluorescent nanoparticle-RNA interference (FNP-RNAi) by larval feeding and whether the silencing affected H. armigera development. Fluorescence microscopy showed that nanoparticle-siRNA was distributed in Ha cells and the larval midgut. FNP-HaSCP-2 siRNA suppressed HaSCP-2 expression by 52.5% in H.armigera Ha cells. FNP can effectively help deliver siRNA into cells, protect siRNA, and is not affected by serum. FNP-siRNA in vivo biological assays showed that HaSCP-2 transcript levels were inhibited by 70.19%, 68.16%, and 67.66% in 3rd, 4th, and 5th instar larvae, leading to a decrease in the cholesterol level in the larval and prepupal fatbodies. The pupation rate and adult emergence were reduced to 26.0% and 56.52%, respectively. This study demonstrated that FNP could deliver siRNA to cells and improve siRNA knockdown efficiency. HaSCP-2 knockdown by FNP-siRNA in vivo hindered H. armigera growth and development. FNP could enhance RNAi efficiency to achieve pest control by SCP-2-targeted FNP-RNAi.

Based on the structural analysis of the existing Lepelletizer planetary gear mechanism (PGM), an optimal method for searching the feasible shifting sequence by establishing the velocity diagram based on the lever analogy is proposed. In this method, the basic links of PGM and all possible shifting elements are converted into points on the equivalent lever coordinate system, the velocity vector diagram of all possible speed ratios is drawn, and the shifts are classified. The shifting sequence is determined according to the shifting logic of transmission and the number of shifting elements as constraints, the transmission ratio of each shifting is deduced. The ratios of the each line segment in the velocity vector diagram and the characteristic parameters of the ordered lever diagram of PGM are calculated, so as to determine the attributes of all links of the transmission. The transmission which arranged with shifting elements is checked by the planar-graph. This method is used to optimize the 6~10 speed Lepelletier PGM. The results show that the two structures of 6-speed and one structure of 8-speed are the same as those of the patented ones, which proves that the method is correct and feasible.

This paper proposes 3D nonlinear finite element (FE) models to predict the response of corroded reinforced concrete (RC) beam strengthened using a steel plate. Five FE models are developed based on the tests carried out by the authors in a previous investigation, in which three models are used to simulate the corroded RC beams with different schemes. The FE models use the coupled damaged-plasticity constitutive law for concrete in tension and compression and consider the bond-slip between the corroded tensile steel bar and concrete. The cohesive element is also used to model the cohesive bond between the steel plate and concrete. The FE results of load-deflection and the crack distribution are compared with the test data. The FE results are consistent with the test results. The influence of the thickness of the steel plate, the thickness, and location of the U-shaped steel strip on the bearing capacity of the strengthened corroded beam is analyzed through FE models. The results show that the thickness of the steel plate on the bottom surface should not exceed 4 mm for the flexure-strengthened and combined strengthened beams with a 10% corrosion rate. It is most reasonable to improve the bearing capacity using the 3 mm and 2 mm of thick U-shaped steel strips for the shear-strengthened and combined strengthened beams, respectively. The most reasonable location of the U-shaped steel plate is at the end of the steel plate for beams with a 10% corrosion rate.

Apoptotic protease activating factor-1 (Apaf-1) is an adaptor molecule, essential for activating initiator caspase and downstream effector caspases, which directly cause apoptosis. In fruit flies, nematodes, and mammals, Apaf-1 has been extensively studied. However, the structure and function of Apaf-1 in Lepidoptera remain unclear. This study identified a novel Apaf-1 from Spodoptera litura, named Sl-Apaf-1. Sl-Apaf-1 contains three domains: a CARD domain, as well as NOD and WD motifs, and is very similar to mammalian Apaf-1. Interference of Sl-apaf-1 expression in SL-1 cells blocked apoptosis induced by actinomycin D. Overexpression of Sl-apaf-1 significantly enhances apoptosis induced by actinomycin D in Sf9/SL-1/U2OS cells, suggesting that the function of Sl-Apaf-1 is evolutionarily conserved. Furthermore, Sl-Apaf-1 could interact with Sl-caspase-5 (a homologue of mammalian caspase-9) and yielded a binding affinity of 1.37 × 106 M–1 according isothermal titration calorimetry assay. Initiator caspase (procaspase-5) of S. litura could be activated by Sl-Apaf-1 (without WD motif) in vitro, and the activated Sl-caspase-5 could cleave Sl-procaspase-1 (a homologue of caspase-3 in mammals), which directly caused apoptosis. This study demonstrates the key role of Sl-Apaf-1 in the apoptosis pathway, suggesting that the apoptosis pathway in Lepidopteran insects and mammals is conserved.

In order to further understand the carbonation process of concrete structures, the time- and temperature-dependent diffusion process of CO2 in concrete is simulated based on the law of the CO2 mass conservation, and a two-dimensional mass transfer equation is established for the CO2 diffusion in concrete. The concrete block is discretized into triangular elements, and the CO2 concentrations at different positions are calculated based on finite element method. A computational algorithm is programed through the Matlab platform. The time- and temperature-dependent property and difference of the CO2 concentration at different positions of the structure are considered in the proposed model. Then, an accelerated carbonation experiment is carried out using concrete blocks with different mix proportions to investigate the influence of the water-cement ratio and temperature on the concrete carbonation. The experimental results effectively verify the correctness of the finite element model, and the proposed finite element method reasonably simulates the concrete carbonation through calculating the carbonation in practical engineering compared with other methods in references. An experimental-numerical correlation has been performed. The ratio of carbonation depth at the corner of the concrete members to the other positions is about 1.35. The carbonation depth is increased about 1.9 times when the temperature changes from 20°C to 40°C.

Human parvovirus B19 (B19V) infection of primary human erythroid progenitor cells (EPCs) arrests infected cells at both late S-phase and G2-phase, which contain 4N DNA. B19V infection induces a DNA damage response (DDR) that facilitates viral DNA replication but is dispensable for cell cycle arrest at G2-phase; however, a putative C-terminal transactivation domain (TAD2) within NS1 is responsible for G2-phase arrest. To fully understand the mechanism underlying B19V NS1-induced G2-phase arrest, we established two doxycycline-inducible B19V-permissive UT7/Epo-S1 cell lines that express NS1 or NS1mTAD2, and examined the function of the TAD2 domain during G2-phase arrest. The results confirm that the NS1 TAD2 domain plays a pivotal role in NS1-induced G2-phase arrest. Mechanistically, NS1 transactivated cellular gene expression through the TAD2 domain, which was itself responsible for ATR (ataxia-telangiectasia mutated and Rad3-related) activation. Activated ATR phosphorylated CDC25C at serine 216, which in turn inactivated the cyclin B/CDK1 complex without affecting nuclear import of the complex. Importantly, we found that the ATR-CHK1-CDC25C-CDK1 pathway was activated during B19V infection of EPCs, and that ATR activation played an important role in B19V infection-induced G2-phase arrest.

NAD(P)H: quinone oxidoreductase 1 (NQO1) C609T gene polymorphisms have been reported to influence the risk for esophageal cancer (EC) in many studies. However, the results remain controversial and ambiguous. We performed a meta-analysis, which included 13 independent studies with a total of 2357 subjects, to examine the association between NQO1 C609T polymorphism and EC. The association was assessed by five different gene models. The overall analysis suggested that the variant allele and genotypes were significantly related to increased risk of EC (odds ratio [OR] T versus C = 1.15, 95% confidence interval [CI] 0.95–1.40, probability of rejection [POR] = 0.014; OR TT versus CC = 1.32, 95% CI 1.01–1.73, POR = 0.045; OR TC versus CC = 1.32, 95% CI 0.98–1.21, POR = 0.128; OR TT + TC versus CC = 1.10, 95% CI 1.00–1.20, POR = 0.05; OR TT versus CC + TC = 1.26, 95% CI 0.95–1.57, POR = 0.103). Sensitivity analysis confirmed the reliability of these findings. Our study shows that individuals carrying the NQO1 C609T variant allele and genotypes are more susceptible to EC.

Atg8 proteins fused with tags are commonly used to detect autophagy. The expression patterns of Lepidopteran insect Atg8 are relatively well documented. However, the influence of protein tags on characterization of Atg8 is still not very clear. Our results showed that endogenous Spodoptera litura Atg8 and HA tagged Atg8 driven by the baculovirus ie2 promoter were enriched in cytoplasm. The recombinant plasmid pEGFP-Atg8(EGFP) in which Atg8 contained a stop codon was constructed and expressed. Green fluorescence was accumulated in cytoplasm. However, red fluorescence was located in both cytoplasm and nucleoplasm in most cells transfected with the recombinant plasmid pmCherry-Atg8(EGFP). In contrast to pEGFP-Atg8(EGFP), green fluorescence was also located in both cytoplasm and nucleoplasm in most cells transfected with the recombinant plasmid pie2/EGFP-Atg8 driven by the baculovirus ie2 promoter in which the CMV promoter and EGFP nucleotide sequences were removed, and the high level of the EGFP-Atg8 expression significantly increased its abundance in nucleoplasm. HA-Atg8 expressed at high level through baculovirus under the control of polyherin promoter was also localized in cytoplasm and nucleoplasm. The cleavage of mCherry-Atg8 was different from that of EGFP-Atg8. Both the mutant mCherry-Atg8F77/79A resulting in non-cleavage of the Atg8 and the mutant mCherry-Atg8G exposing its glycine residue at the end of C-terminus were also localized in cytoplasm and nucleoplasm. The increase of autophagosomes decreased the abundance of mCherry-Atg8 in nucleoplasm. In addition, the ratio of HA-Atg8-PE/HA-Atg8 was less than that of endogenous Atg8-PE/Atg8. These results demonstrated that the Atg8 is located in both nucleus and cytoplasm when expressed at high level and exported to the cytoplasm when autophagy is activated, and the fusion tags of Atg8 might have influence on the processing of Atg8 fusion proteins.

There are conflicting reports on the role of cytochrome c during insect apoptosis. Our previous studies have showed that cytochrome c released from the mitochondria was an early event by western blot analysis and caspase-3 activation was closely related to cytochrome c release during apoptosis induced by baculovirus in Spodoptera litura cells (Sl-1 cell line). In the present study, alteration in mitochondrial morphology was observed by transmission electron microscopy, and cytochrome c release from mitochondria in apoptotic Sl-1 cells induced with Anagrapha falcifera multiple nuclear polyhedrosis virus (AfMNPV) has further been confirmed by immunofluoresence staining protocol, suggesting that structural disruption of mitochondria and the release of cytochrome c are important events during Lepidoptera insect cell apoptosis. We also used Sl-1 cell-free extract system and the technique of RNA interference to further investigate the role of cytochrome c in apoptotic Sl-1 cells induced by AfMNPV. Caspase-3 activity in cell-free extracts supplemented with exogenous cytochrome c was determined and showed an increase with the extension of incubation time. DsRNA-mediated silencing of cytochrome c resulted in the inhibition of apoptosis and protected the cells from AfMNPV-induced cell death. Silencing of expression of cytochrome c had a remarkable effect on pro-caspase-3 and pro-caspase-9 activation and resulted in the reduction of caspase-3 and caspase-9 activity in Sl-1 cells undergoing apoptosis. Caspase-9 inhibitor could inhibit activation of pro-caspase-3, and the inhibition of the function of Apaf-1 with FSBA blocked apoptosis, hinting that Apaf-1 could be involved in Sl-1 cell apoptosis induced by AfMNPV. Taken together, these results strongly demonstrate that cytochrome c plays an important role in apoptotic signaling pathways in Lepidopteran insect cells.

Autophagy plays a central role in regulating important cellular functions such as cell survival during starvation and control of infectious pathogens. On the other hand, many pathogens have evolved mechanisms of inhibition of autophagy such as blockage of the formation of autophagosomes or the fusion of autophagosomes with lysosomes. Baculoviruses are important insect pathogens for pest control, and autophagy activity increases significantly during insect metamorphosis. However, it is not clear whether baculovirus infection has effects on the increased autophagy. In the present study, we investigated the effects of the Autographa californica nucleopolyhedrovirus (AcMNPV) infection on autophagy in SL-HP cell line from Spodoptera litura induced under amino acid deprivation. The results revealed that AcMNPV infection did not inhibit autophagy but triggered apoptosis under starvation pressure. In the early stage of infection under starvation, mitochondrial dysfunction was detected, suggesting the organelles might be involved in cell apoptosis. The semi-quantitative PCR assay revealed that the expression of both p35 and ie-1 genes of AcMNPV had no significant difference between the starved and unstarved SL-HP cells. The western blot analysis showed that no cleavage of endogenous Atg6 occurred during the process of apoptosis in SL-HP cells. These data demonstrated that some permissive insect cells may defend baculovirus infection via apoptosis under starvation and apoptosis is independent of the cleavage of Atg6 in SL-HP cells.

Despite antibiotics and sterile technique, postoperative infections remain a real and present danger to patients. Recent estimates suggest that 50% of the pathogens associated with postoperative infections have become resistant to the standard antibiotics used for prophylaxis. Risk factors identified in such cases include obesity and antibiotic exposure. To study the combined effect of obesity and antibiotic exposure on postoperative infection, mice were allowed to gain weight on an obesogenic Western-type diet (WD), administered antibiotics and then subjected to an otherwise recoverable sterile surgical injury (30% hepatectomy). The feeding of a WD alone resulted in a major imbalance of the cecal microbiota characterized by a decrease in diversity, loss of Bacteroidetes, a bloom in Proteobacteria, and the emergence of antibiotic-resistant organisms among the cecal microbiota. When WD-fed mice were administered antibiotics and subjected to 30% liver resection, lethal sepsis, characterized by multiple-organ damage, developed. Notable was the emergence and systemic dissemination of multidrug-resistant (MDR) pathobionts, including carbapenem-resistant, extended-spectrum β-lactamase-producing Serratia marcescens, which expressed a virulent and immunosuppressive phenotype. Analysis of the distribution of exact sequence variants belonging to the genus Serratia suggested that these strains originated from the cecal mucosa. No mortality or MDR pathogens were observed in identically treated mice fed a standard chow diet. Taken together, these results suggest that consumption of a Western diet and exposure to certain antibiotics may predispose to life-threating postoperative infection associated with MDR organisms present among the gut microbiota.IMPORTANCE Obesity remains a prevalent and independent risk factor for life-threatening infection following major surgery. Here, we demonstrate that when mice are fed an obesogenic Western diet (WD), they become susceptible to lethal sepsis with multiple organ damage after exposure to antibiotics and an otherwise-recoverable surgical injury. Analysis of the gut microbiota in this model demonstrates that WD alone leads to loss of Bacteroidetes, a bloom of Proteobacteria, and evidence of antibiotic resistance development even before antibiotics are administered. After antibiotics and surgery, lethal sepsis with organ damage developed in in mice fed a WD with the appearance of multidrug-resistant pathogens in the liver, spleen, and blood. The importance of these findings lies in exposing how the selective pressures of diet, antibiotic exposure, and surgical injury can converge on the microbiome, resulting in lethal sepsis and organ damage without the introduction of an exogenous pathogen.

Obstructive sleep apnea-hypopnea syndrome (OSAHS) is a common and high-risk sleep-related breathing disorder. Snoring detection is a simple and non-invasive method. In many studies, the feature maps are obtained by applying a short-time Fourier transform (STFT) and feeding the model with single-channel input tensors. However, this approach may limit the potential of convolutional networks to learn diverse representations of snore signals. This paper proposes a snoring sound detection algorithm using a multi-channel spectrogram and convolutional neural network (CNN). The sleep recordings from 30 subjects at the hospital were collected, and four different feature maps were extracted from them as model input, including spectrogram, Mel-spectrogram, continuous wavelet transform (CWT), and multi-channel spectrogram composed of the three single-channel maps. Three methods of data set partitioning are used to evaluate the performance of feature maps. The proposed feature maps were compared through the training set and test set of independent subjects by using a CNN model. The results show that the accuracy of the multi-channel spectrogram reaches 94.18%, surpassing that of the Mel-spectrogram that exhibits the best performance among the single-channel spectrograms. This study optimizes the system in the feature extraction stage to adapt to the superior feature learning capability of the deep learning model, providing a more effective feature map for snoring detection. [ABSTRACT FROM AUTHOR]