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Abstract Ketamine has recently become an anesthetic drug used in human and veterinary clinical medicine for illicit abuse worldwide, but the detection of illicit abuse and inference of time intervals following ketamine abuse are challenging issues in forensic toxicological investigations. Here, we developed methods to estimate time intervals since ketamine use is based on significant metabolite changes in rat serum over time after a single intraperitoneal injection of ketamine, and global metabolomics was quantified by ultra-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF–MS). Thirty-five rats were treated with saline (control) or ketamine at 3 doses (30, 60, and 90 mg/kg), and the serum was collected at 21 time points (0 h to 29 d). Time-dependent rather than dose-dependent features were observed. Thirty-nine potential biomarkers were identified, including ketamine and its metabolites, lipids, serotonin and other molecules, which were used for building a random forest model to estimate time intervals up to 29 days after ketamine treatment. The accuracy of the model was 85.37% in the cross-validation set and 58.33% in the validation set. This study provides further understanding of the time-dependent changes in metabolites induced by ketamine abuse.

Summary: Recognizing the indispensability of hard materials in industrial applications, the persistent pursuit of ultra-strong and superhard materials has been a subject of extensive research. Carbon, with its versatile hybridization possibilities, emerges as a promising avenue for the creation of such materials. Herein, based on first-principles calculations, we predict an all-sp3 hybrid orthorhombic carbon allotrope named C10. It exhibits greater incompressibility along the [010] direction than diamond, demonstrating an extreme hardness with Vickers hardness of up to 72.8 GPa. The Young’s modulus of C10 displays anisotropy, closely comparable to diamond along the x axis direction, while maintaining excellent mechanical stability within the range of 100 GPa. Notably, under the influence of shear force, it undergoes transformation into diamond. Functioning as a transparent semiconductor with a wide indirect band gap of 4.55 eV, C10 holds promise as a potential superhard material in the semiconductor industry, especially under extreme conditions.

Silicosis is a systemic disease caused by long-term exposure to high concentrations of free silica dust particles in the workplace. It is characterized by a persistent inflammatory response, fibroblast proliferation, and excessive collagen deposition, leading to pulmonary interstitial fibrosis. Epithelial interstitial transformation (EMT) can cause epithelial cells to lose their tight junctions, cell polarity, and epithelial properties, thereby enhancing the properties of interstitial cells, which can lead to the progression of fibrosis and the formation of scar tissue. Integrin 1 (ITGB1) is considered an important factor for promoting EMT and tumor invasion in a variety of tumors and also plays an important role in the progression of fibrotic diseases. Therefore, ITGB1 can be used as a potential target for the treatment of silicosis. In this study, we found that silica exposure induced epithelial-mesenchymal transformation in rats and that the expression of integrin ITGB1 was elevated along with the EMT. We used CRISPR/Cas9 technology to construct integrin ITGB1 knockdown cell lines for in vitro experiments. We compared the expression of the EMT key proteins E-cadherin and vimentin in the ITGB1 knockdown cells and wild-type cells simultaneously stimulated by silica and detected the aggregation point distribution of E-cadherin and vimentin in the cells using laser confocal microscopy. Our results showed that ITGB1 knockout inhibited the ITGB1/ILK/Snail signaling pathway and attenuated the EMT occurrence compared to control cells. These results suggested that ITGB1 is associated with silica-induced EMT and may be a potential target for the treatment of silicosis.

With the expansion of the “Arctic Amplification” effect, the navigable period of the Arctic Northeast Passage (NEP) has gradually been lengthened, and its regular operation in summer has become a realistic possibility. Starting from the actual voyage data of Chinese merchant ships navigating the NEP, this paper analyzes the number of ships and voyages, ice class and ship type distribution, cargo volume and cargo type, transportation route distribution, navigable period and ice-breaking pilotage, and then calculates the profit of merchant ships. The results show that the voyage number and cargo volume of Chinese merchant ships shipping via the NEP are at a relatively low level, but in terms of the general trend, the number of voyages of Chinese merchant ships shipping via the NEP is increasing year by year, and the cargo volume of Chinese merchant ships is also increasing. With the accelerated melting of the Arctic sea ice, the navigable period for ships to pass has been prolonged, which has greatly increased the possibility of regular commercial operation in the NEP; At present, Chinese merchant ships have a chance to operate in the NEP; With the accelerated melting of sea ice, the period for Chinese merchant ships to pass has been extended, thus making it possible for the NEP to realize regular commercial operation.

Abstract In 2017, a novel influenza A virus (IAV) was isolated from an Egyptian fruit bat. In contrast to other bat influenza viruses, the virus was related to avian A(H9N2) viruses and was probably the result of a bird-to-bat transmission event. To determine the cross-species spill-over potential, we biologically characterize features of A/bat/Egypt/381OP/2017(H9N2). The virus has a pH inactivation profile and neuraminidase activity similar to those of human-adapted IAVs. Despite the virus having an avian virus–like preference for α2,3 sialic acid receptors, it is unable to replicate in male mallard ducks; however, it readily infects ex-vivo human respiratory cell cultures and replicates in the lungs of female mice. A/bat/Egypt/381OP/2017 replicates in the upper respiratory tract of experimentally-infected male ferrets featuring direct-contact and airborne transmission. These data suggest that the bat A(H9N2) virus has features associated with increased risk to humans without a shift to a preference for α2,6 sialic acid receptors.

Epithelial cell adhesion molecule negative circulating tumor cells (EpCAM- CTCs) and EpCAM positive CTCs (EpCAM + CTCs) have different biological characteristics. Therefore, the isolation of EpCAM + CTCs and EpCAM- CTCs is a new strategy to study the heterogeneity of tumor cells. The azobenzene group (Azo) and cyclodextrin (CD) composite system forms a photosensitive molecular switch based on the effect of external light stimulation. We used the technology of specifically capturing CTCs using anti-EpCAM and aptamers functionalized nanochips. Both anti-EpCAM and aptamers can be connected to Azo through the 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide/N-hydroxysuccinimide (EDC/NHS) modification process. Therefore, we assume that a photosensitive intelligent nanoreactor (PSINR) modified with anti-EpCAM can be used to capture EpCAM + CTCs; Utilizing the characteristics of aptamer and ligand binding, a PSINR modified with aptamer is used to capture EpCAM- CTCs; Then, two PSINRs were separated and stimulated with light to release EpCAM + CTCs and EpCAM- CTCs, respectively. Based on the isolation the EpCAM + CTCs and EpCAM- CTCs, we expected to reveal the key biological mechanisms of tumor recurrence, metastasis and drug resistance, and make the individualized treatment of liver cancer more targeted, safe and effective, and provide a new basis for the final realization of accurate and individualized treatment of tumors.

Recently, targeted therapy and immunotherapy have emerged as effective treatment options for non-small cell lung cancer (NSCLC). This progress has been facilitated by the rapid development of diagnostic and therapeutic technologies and the continuous research and development of new drugs, leading to a new era in precision medicine for NSCLC. This is a breakthrough for patients with common mutations in the human epidermal growth factor receptor (EGFR) gene in NSCLC. Consequently, the use of targeted drugs has significantly improved survival. Nevertheless, certain rare genetic mutations are referred to as EGFR exon 20 insertion (ex20ins) mutations, which differ in structure from conventional EGFR gene mutations, namely, exon 19 deletion mutations (19-Del) and exon 21 point mutations. Owing to their distinct structural characteristics, patients harboring these EGFR ex20ins mutations are unresponsive to traditional tyrosine kinase inhibitor (TKI) therapy. This particular group of patients did not fall within the scope of their applicability. However, the activating A763_Y764insFQEA mutation elicits a more pronounced response than mutations in the near and far regions of the C-helix immediately following it and should, therefore, be treated differently. Currently, there is a lack of effective treatments for EGFR ex20ins mutations NSCLC. The efficacy of chemotherapy has been relatively favorable, whereas the effectiveness of immunotherapy remains ambiguous owing to inadequate clinical data. In addition, the efficacy of the first- and second-generation targeted drugs remains limited. However, third-generation and novel targeted drugs have proven to be effective. Although novel EGFR-TKIs are expected to treat EGFR ex20ins mutations in patients with NSCLC, they face many challenges. The main focus of this review is on emerging therapies that target NSCLC with EGFR ex20ins and highlight major ongoing clinical trials while also providing an overview of the associated challenges and research advancements in this area.

BackgroundOlder patients with cancer experience cognitive impairment and a series of neurocognitive symptoms known as chemobrain due to chemotherapy. Moreover, older populations are disproportionately affected by chemobrain and heightened negative mental health outcomes after cytotoxic chemical drug therapy. Chinese acupuncture is an emerging therapeutic option for chemotherapy-induced cognitive impairment in older patients with cancer, despite limited supporting evidence. ObjectiveOur study aims to directly contribute to the existing knowledge of this novel Chinese medicine mode in older patients with cancer enrolled at the Department of Oncology/Chinese Medicine, Nanjing First Hospital, China, thereby establishing the basis for further research. MethodsThis study involves a 2-arm, prospective, randomized, assessor-blinded clinical trial in older patients with cancer experiencing chemobrain-related stress and treated with Chinese acupuncture from September 30, 2023, to December 31, 2025. We will enroll 168 older patients with cancer with clinically confirmed chemobrain. These participants will be recruited through screening by oncologists for Chinese acupuncture therapy and evaluation. Electroacupuncture will be performed by a registered practitioner of Chinese medicine. The electroacupuncture intervention will take about 30 minutes every session (2 sessions per week over 8 weeks). For the experimental group, the acupuncture points are mainly on the head, limbs, and abdomen, with a total of 6 pairs of electrically charged needles on the head, while for the control group, the acupuncture points are mainly on the head and limbs, with only 1 pair of electrically charged needles on the head. ResultsEligible participants will be randomized to the control group or the experimental group in 1:1 ratio. The primary outcome of this intervention will be the scores of the Montreal Cognitive Assessment. The secondary outcomes, that is, attentional function and working memory will be determined by the Digit Span Test scores. The quality of life of the patients and multiple functional assessments will also be evaluated. These outcomes will be measured at 2, 4, 6, and 8 weeks after the randomization. ConclusionsThis efficacy trial will explore whether Chinese electroacupuncture can prevent chemobrain, alleviate the related symptoms, and improve the quality of life of older patients with cancer who are undergoing or are just going to begin chemotherapy. The safety of this electroacupuncture intervention for such patients will also be evaluated. Data from this study will be used to promote electroacupuncture application in patients undergoing chemotherapy and support the design of further real-world studies. Trial RegistrationClinicalTrials.gov NCT05876988; https://clinicaltrials.gov/ct2/show/NCT05876988 International Registered Report Identifier (IRRID)DERR1-10.2196/53853

Abstract Background Peripheral blood‐derived natural killer (NK) cells spontaneously lyse tumor cells without prior sensitization. However, NK cells in peripheral blood (PBNK cells) are in a resting state and exhibit inhibitory phenotypes and impaired cytotoxicity. Thus, strengthening the cytotoxic effector function of PBNK cells and improving NK cell expansion in vitro for a convenient allogeneic therapy are essential. Materials and Methods Pure cytokine activation and expansion of NK cells (super NK [SNK]) from peripheral blood mononuclear cells were studied. Markers of activated and inhibited NK cells and cytokine secretion by NK cells were examined using flow cytometry. NK cell antitumor activity in vitro was assessed using lactate dehydrogenase (LDH) cytotoxicity assay and an Incucyte real‐time imaging system. Additionally, the function of SNK cells against ascites caused by ovarian cancer in NOD‐Prkdc(em26Cd52)il2rg(em26Cd22)/Nju (NCG) mice was determined. In a further investigation of the differences between PBNK and SNK, the mRNA of both cells was sequenced and analyzed. Results Human peripheral blood mononuclear cells showed selective NK cell expansion upon cytokine activation and culture. Both SNK and PBNK cells expressed activation markers, but at different levels, and SNK cells secreted more cytokines related to cytotoxicity than PBNK cells did. Accordingly, SNK cells exhibited strong antitumor activity ex vivo and improved NCG mice survival after intraperitoneal ovarian cancer transplantation. Mechanistically, SNK cells expressed more genes associated with nucleotide metabolism, fatty acid, and ATP metabolism than PBNK cells. Conclusion SNK cells derived from peripheral blood mononuclear cells have sufficiently activated mature characteristics and high antitumor activity, rendering them a highly promising and essential therapeutic approach for cancer treatment.

There are a large number of microorganisms in the gut of insects, which form a symbiotic relationship with the host during the long-term co-evolution process and have a significant impact on the host's nutrition, physiology, development, immunity, stress tolerance and other aspects. However, the composition of the gut microbes of Hyphantria cunea remains unclear. In order to investigate the difference and diversity of intestinal microbiota of H. cunea larvae feeding on different host plants, we used PacBio sequencing technology for the first time to sequence the 16S rRNA full-length gene of the intestinal microbiota of H. cunea. The species classification, β diversity and function of intestinal microflora of the 5th instar larvae of four species of H. cunea feeding on apricot, plum, redbud and Chinese ash were analysed. The results showed that a total of nine phyla and 65 genera were identified by PacBio sequencing, amongst which Firmicutes was the dominant phylum and Enterococcus was the dominant genus, with an average relative abundance of 59.29% and 52.16%, respectively. PERMANOVA analysis and cluster heat map showed that the intestinal microbiomes of H. cunea larvae, fed on different hosts, were significantly different. LEfSe analysis confirmed the effect of host diet on intestinal community structure and PICRUSt2 analysis showed that most of the predictive functions were closely related to material transport and synthetic, metabolic and cellular processes. The results of this study laid a foundation for revealing the interaction between the intestinal microorganisms of H. cunea and its hosts and provided ideas for exploring new green prevention and control strategies of H. cunea.

Abstract Background Prolyl endopeptidase from Aspergillus niger (AN-PEP) is a prominent serine proteinase with various potential applications in the food and pharmaceutical industries. However, the availability of efficient and low-cost AN-PEP remains a challenge owing to its low yield and high fermentation cost. Results Here, AN-PEP was recombinantly expressed in Trichoderma reesei (rAN-PEP) under the control of the cbh1 promoter and its secretion signal. After 4 days of shaking flask cultivation with the model cellulose Avicel PH101 as the sole carbon source, the extracellular prolyl endopeptidase activity reached up to 16.148 U/mL, which is the highest titer reported to date and the secretion of the enzyme is faster in T. reesei than in other eukaryotic expression systems including A. niger and Komagataella phaffii. Most importantly, when cultivated on the low-cost agricultural residue corn cob, the recombinant strain was found to secret a remarkable amount of rAN-PEP (37.125 U/mL) that is twice the activity under the pure cellulose condition. Furthermore, treatment with rAN-PEP during beer brewing lowered the content of gluten below the ELISA kit detection limit (

BackgroundFlail chest is a common and serious traumatic condition in thoracic surgery. The treatment of flail chest often includes open reduction and internal fixation, which is relatively traumatic, complicated, and expensive. As three-dimensional (3D) printing technology is widely used in the clinical field, the application of 3D-printed products to chest trauma will become a new treatment option. To date, the use of 3D-printed external fixation guides for flail chests has not been reported. Thus, we aimed to assess the short-term efficacy of a new technology that treated flail chests with an individualized 3D-printed external fixation guide combined with video-assisted thoracoscopic surgery (VATS).Patients and methodsA retrospective analysis was performed on patients with flail chest treated with this new technique at our center from January 2020 to December 2022. The following parameters were included: operative time, thoracic tube extraction time, intensive care unit time, thoracic volume recovery rate, visual analog scale score 1 month postoperatively, and postoperative complication rate. All patients were followed up for at least 3 months.ResultsFive patients (mean age: 45.7 years) were enrolled; they successfully underwent surgery without chest wall deformity and quickly returned to daily life. The average number of rib fractures was 8.4; all patients had lung contusion, hemopneumothorax, and anomalous respiration. The abnormal breathing of all patients was completely corrected on postoperative day 1, and the chest wall was stable. One case experienced mild loosening of the 3D-printed guide postoperatively; however, the overall stability was not affected. The other four cases did not experience such loosening because we replaced the ordinary silk wire with a steel wire. All cases were discharged from the hospital 2 weeks postoperatively and returned to normal life 1 month after the removal of the 3D-printed guide on average. Only one case developed a superficial wound infection postoperatively, and no perioperative death occurred.ConclusionsThe 3D-printed external fixation guide combined with video-assisted thoracoscopic surgery is a novel technique in the treatment of flail chest and is safe, effective, feasible, and minimally invasive, with satisfactory clinical efficacy.

Microglial surveillance plays an essential role in clearing misfolded proteins such as amyloid-beta, tau, and α-synuclein aggregates in neurodegenerative diseases. However, due to the complex structure and ambiguous pathogenic species of the misfolded proteins, a universal approach to remove the misfolded proteins remains unavailable. Here, we found that a polyphenol, α-mangostin, reprogrammed metabolism in the disease-associated microglia through shifting glycolysis to oxidative phosphorylation, which holistically rejuvenated microglial surveillance capacity to enhance microglial phagocytosis and autophagy-mediated degradation of multiple misfolded proteins. Nanoformulation of α-mangostin efficiently delivered α-mangostin to microglia, relieved the reactive status and rejuvenated the misfolded-proteins clearance capacity of microglia, which thus impressively relieved the neuropathological changes in both Alzheimer's disease and Parkinson's disease model mice. These findings provide direct evidences for the concept of rejuvenating microglial surveillance of multiple misfolded proteins through metabolic reprogramming, and demonstrate nanoformulated α-mangostin as a potential and universal therapy against neurodegenerative diseases.

In this paper, we consider a Thermoelastic system with boundary time-varying delay. Under some appropriate assumptions, the global well-posedness and exponential stability are obtained by using the variable norm technique of Kato and the energy method respectively.

Abstract Objective Uncertainties remain regarding the relationship between sarcopenic obesity and frailty. This study aimed to explore the association of these two common geriatric syndromes among community-dwelling older adults. Methods Baseline data from the West China Health and Aging Trend (WCHAT) study was used. Sarcopenia was assessed based on the criteria established by the Asian working group for sarcopenia. Body fat percentages above the 60th percentile specified by sex were classified as obesity. Sarcopenic obesity was defined as the concurrence of obesity and sarcopenia. Frailty was assessed by Fried criteria. Multinomial logistic regression was adopted to explore associations of sarcopenic obesity with frailty. Results Overall, 2372 older adults (mean age 67.6 ± 5.9) were involved in this study. The prevalence of frailty and sarcopenic obesity was 6.2 and 6.28%, respectively. After adjusting for covariates, sarcopenic obesity was significantly associated with prefrailty (OR = 1.74, 95% CI = 1.15–2.64, P = 0.009) and frailty (OR = 4.42, 95% CI = 2.19–8.93, P

For wind turbine applications, there is a cyclic load-varying process between rolling elements and raceways in pitch bearings. This kind of motion can also lead to radial fretting. However, this is seldom addressed under grease-lubricated conditions in the literature. In this study, grease-lubricated point contact problems have been investigated experimentally under cyclic load-varying conditions. The findings revealed that as the load-varying range diminishes, the variation in grease film distribution becomes more subtle and the rate of discharge of thickener fiber clusters in the stick zone decelerates. This is due to the fact that the rate of change in the Hertz contact radius is reduced and the migration of grease is weakened during the unloading process. Due to the large apparent viscosity of grease with a high soap content, entrapped grease is not easily discharged during loading, and the thickness of the film in the stick zone progressively increases as the soap content of the grease is augmented. This also causes the variable load zone to wear out more easily. As the grease is subjected to repeated loading and unloading, there is a gradual reduction in film thickness, and larger thickener fiber clusters tear, resulting in a flattened form and shear thinning. Grease containing sulphur–phosphorus additives demonstrates a superior effect on reducing fretting wear within the large variable load range but generally proves effective for smaller load-varying ranges. This study may offer insights into the degradation of grease under variable load motion and methods to prevent radial fretting wear.

When dealing with heterogeneous systems, interpreting the mean-square displacement (MSD) data appropriately is crucial. This is due to the limitation that the various interpretations of stochastic differential equations with state-dependent diffusivity may yield the same MSD data, leading to erroneous conclusions. Aided by analytical MSD solutions supported by Langevin simulations, we explore this limitation in diffusion processes exhibiting power-law state-dependent diffusivity, $D_0|x/L|^{-2\mu}$ , with diffusion constant D _0 and scaling index µ . We find that distinct interpretations leading to same MSD data possess different D _0 values. A method is introduced to discern these D _0 -dependent interpretations. When applying the method to subdiffusion MSD data, we observe interpretation transitions depending on the value of the anomalous diffusion coefficient. Furthermore, we demonstrate that these D _0 -dependent interpretations respond diversely to memory effects, which may also be used to decide on the interpretation of MSD data. We believe that these findings offer insights for interpreting MSD data in heterogeneous systems.

Abstract The determination of length of time from the last drinking is critical for cases like drunk driving, sexual assault victims, and also postmortem suspected poisoning cases. The study was aimed to established a method of estimating the time of last drinking through the pharmacokinetic study of conjugation metabolites of alcohol in blood after a single oral dose. Twenty-six volunteers (14 males) consumed alcohol with food at a fixed dose of 0.72 g/kg after fasting for 12 h. Five milliliters of blood were collected 120 h after the start of drinking, and all samples were analyzed with headspace-gas chromatography and high-performance liquid chromatography–tandem mass spectrometry. The time point of last drinking was estimated through the relationship between the concentration ratio of ethyl glucuronide to ethyl sulphate and the length of time after drinking. Pharmacokinetic parameters were analyzed by a pharmacokinetic software DAS according to the non-compartment model. A good correlation model was obtained from the relationship between concentration ratio of ethyl glucuronide to ethyl sulphate in blood and the time of alcohol use, and the margin of error was mostly lower than 10%. The time of maximum concentration, maximum concentration, and elimination half-life of ethyl glucuronide in blood were 4.12 ± 1.07 h, 0.31 ± 0.11 mg/L and 2.56 ± 0.89 h; the time of maximum concentration, maximum concentration, and elimination half-life of ethyl sulphate in blood were 3.02 ± 0.70 h, 0.17 ± 0.04 mg/L, and 2.04 ± 0.76 h. The study established a potential method to estimate the length of time after a moderate oral dose, and provided pharmacokinetic parameters of ethyl glucuronide and ethyl sulphate in Chinese population.

Small molecule kinase inhibitors (SMKIs) are being approved at a fast pace under expedited programs for anticancer treatment. Here, the authors employ a machine-learning model to examine the relationships between kinase targets and adverse events in the trials of 16 FDA-approved SMKIs.

In order to further explore the influence of evaluation units and non-landslide sample selection methods on landslide susceptibility prediction, a landslide susceptibility evaluation model is established based on self-organizing feature map network and random forest model in this paper. According to the relationship between grid units and slope units, an optimized calculation method of landslide susceptibility index is proposed. Aiming at the deficiencies of grid units and slope units in the evaluation of landslide susceptibility, this model proposes an optimized calculation method for landslide susceptibility index based on the relationship between grid cells and slope cells. On this basis, a landslide susceptibility evaluation model was established based on the random forest Tree Bagger classifier. By comparing and analyzing the influence of self-organizing feature map network and random non-landslide sample selection methods on the evaluation results, the effectiveness of the three evaluation models of self-organizing feature map network, random forest and self-organizing feature map network -random forest were discussed. The evaluation model has been applied to the landslide susceptibility evaluation in Dayu County. The results show that the prediction accuracy of random forest and self-organizing feature map network-random forest is higher, reaching 91.19% and 94.94% respectively, and the AUC of success rate curve was 0.822 and 0.849 respectively. It shows that self-organizing feature map network-random forest has higher prediction rate and success rate，although the prediction accuracy of self-organizing feature map network clustering is limited, it can effectively improve the evaluation accuracy of random forest model as the basis for selecting non landslide samples.

Summary: Carbon is one of the most versatile atoms and fosters a wealth of carbon allotropes with superior mechanical and electronic properties. A three-dimensional covalent carbon nanotube, named CCN, with a hexagonal honeycomb-like crystalline structure is proposed theoretically. CCN consists of sp3 bonded coaxially teamed (6,0) carbon nanotubes, and the tube walls possess intrinsic wrinkles, which trigger miraculous physical properties. The mechanical and thermal dynamic stabilities are confirmed, and molecular dynamics simulations indicate high temperature thermal stability up to 1500 K. CCN has an unusual cork-like zero Poisson’s ratio along the axial direction of the nanotubes, and the axial/radial stretching or compression rarely effects the radial/axial dimensions of the nanotubes. CCN is superhard with Vickers hardness of 82.8 GPa, matching that of cubic boron nitride. Substitution B and N atoms for C atoms result in superhard CCN-B12N8 and CCN-C8N12 with quasi-zero Poisson’s radio along both axial and radial directions.

Abstract Heterogeneous treatment effect (HTE) analysis focuses on examining varying treatment effects for individuals or subgroups in a population. For example, an HTE‐informed understanding can critically guide physicians to individualize the medical treatment for a certain disease. However, HTE analysis has not been widely recognized and used, even given the explosive increase of data availability attributed to the arrival of the Big Data era. Part of the reason behind its underuse is that data are often of high dimension and high complexity, which pose significant challenges for applying conventional HTE analysis methods. To meet these challenges, a newly developed causal forest HTE method has been derived from the random forest machine‐learning algorithm. We conducted a systematic performance evaluation for the causal forest method against the conventional two‐step method by simulating scenarios with different levels of complexity for the analysis. Our results show that causal forest outperforms the conventional HTE method in assessing treatment effect, especially when data are complex (e.g., nonlinear) and high dimensional, suggesting that causal forest is a promising tool for real‐world applications of HTE analysis.

ABSTRACT Solid‐state nuclear magnetic resonance (SSNMR), a technique capable of studying solid or semisolid biological samples, was first applied to study the cell differentiation and mineralization using the whole‐cell sample. Mesenchymal stromal cells (MSCs) with multipotent differentiation capacity were induced to differentiate into osteoblasts. The whole differentiation process, osteoblast mineralization and the mineral maturation, was investigated using SSNMR, providing intact, atomic level information on the cellular mineral structural transformation. Our research indicated the extent of osteoblast mineralization could vary significantly for different cell populations whereas the difference was not easily shown by other means of characterization. The SSNMR spectra revealed hydroxylapatite (or hydroxyapatite [HAP]) formation around 2 to 4 weeks after osteogenic induction for MSCs with a high differentiation potency. The early mineral phase deposit before HAP formation contained a high amount of HPO42−. The structures of minerals in the extracellular matrix (ECM) of osteoblasts could evolve for a period of time, even after the incubation of cells has been stopped. This observation was only possible by studying the sample in an intact state, where ECM was not disturbed. These findings improved our understanding of MSCs, which had wide applications in bone regeneration and tissue engineering. Meanwhile, this work demonstrated the advantage of studying these cellular systems as a whole without any mineral extraction, which had been largely overlooked. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Intrahepatic cholangiocarcinoma (ICC) is a malignant tumor that originates from bile duct’s epithelial cells and is usually characterized by insidious symptoms and poor prognosis. Cinobufotalin (CB), an active ingredient obtained from the Traditional Chinese Medicine ChanSu, is purported to exhibit a wide range of antitumorigenic activities. However, the mechanism by which it achieves such pharmacological effects remains elusive. Here, we disclosed the mechanism of action by which CB inhibits ICC cells. Initial experiments revealed that the proliferation of RBE and HCCC-9810 cells was significantly inhibited by CB with IC50 values of 0.342 μM and 0.421 μM respectively. CB induced the expression of caspase-3 subsequently leading to the apoptosis of ICC cells. Phosphoproteomics revealed that the phosphorylation of many proteins associated with DNA damage response increased. Kinase-substrate enrichment analysis revealed that ATM was activated after CB treatment, while CDK1 was inactivated. Activated ATM increased p-CHK2-T68 and p-p53-S15, which promoted the expression of FAS, DR4 and DR5 and triggered cell apoptosis. In summary, this work reveals the role of CB in inducing DNA damage and cell apoptosis involved in the activation of the ATM/CHK2/p53 signaling pathway, and indicates that CB may serve as a chemotherapeutic drug candidate for ICC treatment.

Primary liver cancer (PLC) is one of the most common malignant tumors, which clinically characterized by occult onset, rapid development, easy recurrence and poor prognosis. With the rapid development of tumor immunotherapy research, tumor immunotherapy has also achieved remarkable clinical efficacy, and jointly promoted the overall improvement of tumor immunology from mechanism research to clinical transformation, from single discipline to multi-disciplinary integration. Immunotherapy has obvious advantages in treatment-related toxicity and efficacy compared with traditional therapy. In hepatocellular carcinoma (HCC), immunotherapy alone or in combination with other therapies may help to control tumor progression, and there are many immune checkpoint inhibitors (ICIs) widely used in clinical or ongoing clinical trials. However, tumor immunology research is still facing many challenges. How to effectively evaluate the efficacy, whether there are related biomarkers, the generation of immune tolerance and the lack of clinical trials to objectively evaluate the efficacy are still urgent problems to be solved, but it also brings new research opportunities for basic and clinical immunology researchers. The study of treatment of ICIs of PLC has become a hot spot in clinical research field. This paper summarizes and prospects the research progress and challenges of ICIs for PLC.

In this study, experimental research, a numerical simulation, and a theoretical analysis were performed on the bearing capacity of an aluminum alloy circular tube filled with a lightweight filler (ATLF). Bearing capacity tests were conducted for six ATLF columns and two aluminum alloy hollow tubes (AAHTs), and their local buckling failure modes and mechanical properties were obtained. A finite element model was developed using ABAQUS software (ABAQUS 2016, ABAQUS Inc., Palo Alto, CA, USA) for numerical calculations. Furthermore, a large-scale numerical analysis was performed to investigate the effect of structural parameters, such as the tube thickness, diameter, column length, and initial geometric imperfections, as well as the aluminum alloy’s properties and the lightweight filler’s properties, on the bearing capacity of the ATLF columns and AAHTs under axial compression. Based on the test and numerical analysis results, a formula for calculating the local buckling stress of AAHTs under axial compression is proposed. An improved coefficient of bearing capacity for the ATLF columns caused by the internal lightweight filler was obtained by fitting, and based on the results, a formula for computing the bearing capacity of ATLF columns under axial compression is proposed in this study.

Abstract The outbreak of the novel coronavirus severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2), the causative agent of coronavirus disease 2019 (COVID‐19) respiratory disease, led to a global pandemic with high morbidity and mortality. Despite frenzied efforts in therapeutic development, there are currently no effective drugs for treatment, nor are there vaccines for its prevention. Drug repurposing, representing as an effective drug discovery strategy from existing drugs, is one of the most practical treatment options against the outbreak. In this study, we present a novel strategy for in silico molecular modeling screening for potential drugs that may interact with multiple main proteins of SARS‐CoV‐2. Targeting multiple viral proteins is a novel drug discovery concept in that it enables the potential drugs to act on different stages of the virus’ life cycle, thereby potentially maximizing the drug potency. We screened 2631 US Food and Drug Administration (FDA)‐approved small molecules against 4 key proteins of SARS‐CoV‐2 that are known as attractive targets for antiviral drug development. In total, we identified 29 drugs that could actively interact with 2 or more target proteins, with 5 drugs (avapritinib, bictegravir, ziprasidone, capmatinib, and pexidartinib) being common candidates for all 4 key host proteins and 3 of them possessing the desirable molecular properties. By overlaying docked positions of drug candidates onto individual host proteins, it has been further confirmed that the binding site conformations are conserved. The drugs identified in our screening provide potential guidance for experimental confirmation, such as in vitro molecular assays and in vivo animal testing, as well as incorporation into ongoing clinical studies.

Background: Hypertensive nephropathy is one of the major causes of ESRD. Exercise has been considered a nonpathological therapy for hypertension and its complications, yet mechanisms remain unclear. We sought to investigate whether periodic swimming could ameliorate hypertension-induced kidney dysfunction and its underlying mechanisms. Methods: Four-week male spontaneously hypertensive rats (SHRs) were randomly divided into the hypertension group (SHR, n = 8) and exercise group (SE, n = 8, 60 min swimming/day, 6 days per week, for 8 weeks). Wistar-Kyoto rats (WKY, n = 8) were served as a sedentary normotensive group. Bodyweight and blood pressure (BP) were recorded weekly. After 8-week sedentary or swimming exercise, lipids profile, BUN, and Cr were measured. The renal interstitial fibrosis was examined by the histopathological analysis using Masson’s trichrome staining and hematoxylin and eosin staining. The kidney cell apoptosis was tested by TUNEL staining. The expressions of critical proteins responsible for the TGF-β1/Smad signaling of fibrosis, that is, TGF-β1, Smad2/3, and Smad7, as well as apoptosis related proteins, Bax and Bcl-2 in kidney cortex tissues were measured. Results: The 8-week swimming exercise reduced BP and bodyweight, lowered concentrations of BUN, and serum Cr, compared with SHR. Exercise remarkably inhibited hypertension-induced tubular degeneration, cellular cluster, and tubular cell swelling as well as glomerular degeneration in the kidney cortical tissues, attenuated renal interstitial fibrosis, and renal cell apoptosis. Moreover, expressions of TGF-β1, Smad2/3, and Bax were higher in the SHR than the WKY, which were significantly suppressed by the exercise. In contrast, hypertension-reduced expressions of Smad7 and Bcl-2 were enhanced by the swimming exercise. Strong correlations were found between kidney function indices, blood lipids, and key protein expressions. Conclusion: Our results demonstrate beneficial effects of the periodic swimming on ameliorating hypertension-induced kidney dysfunction highlighting the potential of swimming exercise as a nonpathological therapy for early prevention of hypertension-caused kidney diseases.

In forest ecosystems, elevation gradient is one of the most influential factors on soil characteristics, vegetation types, and soil microorganisms. However, it remains unclear how the elevation gradient and the soil environment under its influence affect soil microbial communities under two distinct vegetation types. In this study, high-throughput sequencing technology from Illumina was utilized to examine the response of soil microbial communities to elevation and their driving factors in forests of Pinus taiwanensis and Pinus massoniana in various Jiangxi Province locales. The results demonstrated that the elevation gradients of the two pines had significant effects on soil organic carbon (SOC) and total nitrogen (TN), both in unimodal mode as well as on the alpha diversity of soil microbes. The community structure of soil bacteria is more sensitive to elevation than that of soil fungus. At different elevations in the two pine forests, Acidobacteria, Proteobacteria, Chloroflexi, Verrucomicrobia, Bacteroidetes, Patescibacteria, and Thaumarchaeota are the dominant bacterial phyla, and Ascomycota, Basidiomycota, and Mucoromycota are the dominant fungal phyla. This investigation revealed that SOC and TN were the two most influential factors on the alteration of the soil microbial community in two pine forests. In summary, there were substantial changes in soil microbial diversity and community composition across the two different pine forests, with elevation and soil characteristics (SOC and TN) serving as the primary drivers.

Glassy carbon (GC) is a type of non-graphitizing disordered carbon material at ambient pressure and high temperatures, which has been widely used due to its excellent mechanical properties. Here we report the changes in the microstructure and mechanical properties of GC treated at high pressures (up to 5 GPa) and high temperatures. The formation of intermediate sp2–sp3 phases is identified at moderate treatment temperatures before the complete graphitization of GC, by analyzing synchrotron X-ray diffraction, Raman spectra, and transmission electron microscopy images. The intermediate metastable carbon materials exhibit superior mechanical properties with hardness reaching up to 10 GPa and compressive strength reaching as high as 2.5 GPa, nearly doubling those of raw GC, and improving elasticity and thermal stability. The synthesis pressure used in this study can be achieved in the industry on a commercial scale, enabling the scalable synthesis of this type of strong, hard, and elastic carbon materials.

A critical ideology of the existing Material Genome Project refers to the application of data and artificial intelligence to facilitate material innovation. The lack of data hinders the development of novel materials. The figures and captions in the material literature cover essential information regarding the entire document and have sufficient image sample data for research. Accordingly, how to extract figures and captions from the literature is critical to solve the lack of data. Though some PDF parsing tools are capable of extracting information from documents, they generally identify a document's figures by parsing the document into a concrete structure. As impacted by the inconsistency of the form of different journals, they commonly achieve wrong recognition results. Thus, an efficient figure and caption extraction network FCENet is proposed in the present study. Inconsistent with other extraction tools, this study first attempts to adopt instance segmentation models to detect figures and their captions, and then extract them. FCENet developed in this study builds upon BlendMask and introduces a horizontal and vertical attention module. This study splits the BlendMask detection head into two branches, i.e., figure detection and caption detection, which increases final detection accuracy and speed. This study collects nearly 3000 material documents for model training and testing. As revealed from the last experiments and results, the performance of FCENet is significantly compared with that of other existing instance segmentation models. Its box and mask mAP (mean Average Precision) are 8.51% and 12.59% higher than those of BlendMask, respectively. This study hopes that considerable material image data can be acquired via FCENet and sufficiently support image data for machine learning and data mining in the material area.

Voting is one of the most prominent components of democracy. The one-vote veto, which requires the voting result to be only “yes” or “no”, is a particularly noteworthy type of voting with widespread application. When obtaining a “no” result, no useful information about the number of “no” votes and who votes “no” is disclosed. In this paper, we introduce a protocol for anonymous one-vote veto utilizing qubits and local Pauli operations $\mathbb {Z}$ and $\mathbb {X}$ , building simple processes for easy implementation under the current technology. For better elaboration, we give two examples: all voters cast “yes” votes and only one voter casts a “no.” Then, the corresponding experiment tests are conducted on the simulated IBM quantum computer to verify their feasibility. We also show that the proposed protocol has the desirable properties of privacy, fairness, verifiability and robustness. Furthermore, we analyze the proposed protocol’s security against cheating from eavesdroppers, a semi-honest server and malicious voters. This work is the first attempt to illustrate how qubits can be useful for building a secure anonymous one-vote veto strategy.

Head and neck squamous cell carcinoma (HNSCC) constitute approximately 4% of all cancers worldwide. In this study, we analyzed the expression profile of the long noncoding RNA (lncRNA) of 502 HNSCC patients from The Cancer Genome Atlas database. Among the differentially expressed lncRNAs between HNSCC and normal samples, LNCAROD is overexpressed in HNSCC and associated with advanced T stage and shortened overall survival. The N6‐methyladenosine (m6A) modification mediated by METTL3 and METTL14 enhanced the stability of LNCAROD in HNSCC cells. Depletion of LNCAROD attenuated cell proliferation, mobility in vitro, and tumorigenicity in vivo, whereas overexpression of LNCAROD exerted opposite effects. LNCAROD is mainly distributed in nucleus and binds with YBX1 and HSPA1A proteins. Silencing either YBX1 or HSPA1A did not affect the level of LNCAROD. However, loss of LNCAROD led to shortened half‐life of YBX1 protein. Mechanistically, LNCAROD protected YBX1 from proteasomal degradation by facilitating YBX1‐HSPA1A protein–protein interaction. Depletion of HSPA1A in LNCAROD‐overexpressing cells resulted in accelerated proteasomal degradation of YBX1 protein. Moreover, re‐expression of Flag‐YBX1 in LNCAROD‐silenced cells rescued malignant behavior of HNSCC cells. Our study indicates that LNCAROD is an oncogenic lncRNA and dysregulation of m6A modification might account for aberrant expression of LNCAROD in HNSCC. LNCAROD acts as a scaffold for the interaction between YBX1 and HSPA1A, preventing proteasomal degradation of YBX1 in HNSCC cells.

Distributed energy trading has become an essential part of the energy trading market and provides a useful supplement to traditional centralized energy trading, but there are still problems such as opaque trading information and asymmetric user data. The blockchain technology has the advantages of traceability, trade openness, and data transparency, which is naturally suitable for distributed energy transactions. The electricity information data transmission represented by distributed energy transaction has the characteristics of real-time, which has a high-efficiency requirement on the selected blockchain technology. The consensus algorithm is the core of blockchain technology and affects the efficiency of the blockchain system. The efficiency of the existing consensus algorithms for energy transaction-oriented blockchain still needs to be improved. In this paper, a consensus resource slicing model(CRSM) is designed to meet the requirements of consensus efficiency in energy trading scenarios. Specifically, CRSM divides consensus nodes into different consensus domains for concurrent consensus, and the storage domain only stores block information without consensus. By building an experimental platform, the efficiency of CRSM was verified, the communication pressure of the blockchain system was reduced, and the consensus speed was effectively improved.

The vapor-liquid equilibrium (VLE) of CO2 in a reactive solvent is essential for the proper simulation and design of CO2 absorption processes. This work presents a systematic investigation on CO2 absorption in various aqueous monoethanolamine (MEA) solutions. CO2 solubility in MEA was measured at 298, 313, 333, and 353 K with CO2 partial pressure ranging from 34.5 to 78.0 kPa. A modified Kent-Eisenberg model was developed based on the measured solubility data, showing good predictions over the liquid phase speciation for the CO2-H2O-MEA system. We presented a new analysis based on the first-order difference curve of distribution profiles of the species. Based on the main reactions that occurred, the CO2 absorption process was demonstrated to be divided into four regions with increasing CO2 loading from 0 to 1. Accordingly, kinetic study was proposed to be conducted in the first region, whereas measuring of mass transfer in the first three regions. The findings in this work extend the existing knowledge of CO2 absorption process in terms of speciation and can provide important guidance for further study of the process characteristics using aqueous amine absorbents.

Calcium and magnesium are major nutrient elements of plants, and both play an important role in plant growth and development. Pinus massoniana and P. hwangshanensis are important afforestation tree species in barren mountains in China. However, observation and research on calcium and magnesium nutrition of dominant forest species in China are still limited. This study determined the concentration of calcium and magnesium in needles for two species from five sites in East China by inductively coupled plasma optical emission spectrometry (ICP-OES). We then explored the inter- and intra-population variation pattern of calcium and magnesium and their relationship with environmental factors. There were significant differences in traits among populations. The strongest factors, which impacted the variation of calcium and magnesium concentration, were elevation and individual differences, respectively. Element concentration was correlated to environmental factors such as longitude, latitude, elevation, and mean annual temperature. The results of this study can be helpful for a better understanding of tree growth, population survival, and forest succession.

The degree of coupling and coordination between the pharmaceutical manufacturing industry and the medical service industry crucially requires improvement by promoting the development of the pharmaceutical manufacturing industry through industrial structure upgrading to narrow the gap between them. First, this article uses the coupling coordination degree model to measure the coupling coordination degree of the Chinese pharmaceutical manufacturing industry and medical service industry; then, it theoretically analyzes the mechanism through which upgrading the pharmaceutical manufacturing industry's industrial structure can improve the coupling coordination degree. Finally, we empirically test the impact of upgrading the pharmaceutical manufacturing industry's industrial structure on the coupling and coordination degree between it and the medical service industry. The main conclusions are as follows: (1). The quantile regression model shows that having an advanced pharmaceutical manufacturing industry positively affects its coupling and coordination with the medical service industry; (2). A threshold regression model is tested, and it is found that only when the pharmaceutical manufacturing industry reaches an advanced level can it significantly promote joint and coordinated development with the medical service industry; (3). Rationalizing the pharmaceutical manufacturing industry structure will inhibit a high level of coordination between it and the medical service industry and their coordinated development.

Individual persistence under changing climate conditions can be aided by phenotypic plasticity. Needle morphology reflects pine species’ adaptation to their habitats, and adaptive plasticity is beneficial to pine survival. As two closely related pines, Pinusmassoniana Lamb. and Pinus hwangshanensis W. Y. Hsia sympatrically occur in the subtropical region of China, forming hilly forests (i.e., subtropical evergreen needleleaf forests) at lower elevations and montane forests (i.e., temperate evergreen needleleaf forests) at medium and high elevations. However, little is known about the intraspecific phenotypic variation patterns of the two pine species and their relationship with environmental factors. Here, we investigated the interspecific and intraspecific variation patterns of needle traits in the two sympatric pine species, focusing on six traits—i.e., leaf length, leaf thickness, leaf width, leaf area, specific leaf area, and leaf dry matter content—as well as the relationship between needle traits and environmental factors. We found significant phenotypic trait differences among populations of each species. Except for leaf length and leaf width, variation within species was greater than variation between species in the needle traits measured. Even more intriguingly, the leaf size traits (i.e., length, width, thickness) were more conservative than the leaf economic traits (i.e., specific leaf area and leaf dry matter content). In other words, the intraspecific variability of the former was weaker than that of the latter. The nature of P. massoniana needle traits was mainly shaped by latitude, while the needle traits of P. hwangshanensis were significantly affected by annual precipitation. Therefore, phenotypic plasticity may be an essential mechanism for the two pine species to better cope with changing external conditions. The intraspecific variation patterns found in the two pine species and the relationships between traits and environmental factors can provide substantial scientific data for large-scale exploration of intraspecific phenotypic variation in pine species and their breeding practice.

The genetic and metabolic diversity of deep-sea microorganisms play important roles in phosphorus and sulfur cycles in the ocean, distinguishing them from terrestrial counterparts. Malathion is a representative organophosphorus component in herbicides, pesticides, and insecticides and is analogues of neurotoxic agent. Malathion has been one of the best-selling generic organophosphate insecticides from 1980 to 2012. Most of the sprayed malathion has migrated by surface runoff to ocean sinks, and it is highly toxic to aquatic organisms. Hitherto, there is no report on bacterial cultures capable of degrading malathion isolated from deep-sea sediment. In this study, eight bacterial strains, isolated from sediments from deep-sea hydrothermal regions, were identified as malathion degradators. Two of the tested strains, Pseudidiomarina homiensis strain FG2 and Pseudidiomarina sp. strain CB1, can completely degrade an initial concentration of 500 mg/L malathion within 36 h. Since the two strains have abundant carboxylesterases (CEs) genes, malathion monocarboxylic acid (MMC α and MMC β) and dibasic carboxylic acid were detected as key intermediate metabolites of malathion degradation, and the pathway of malathion degradation between the two strains was identified as a passage from malathion monocarboxylic acid to malathion dicarboxylic acid.

Towards the objectives of the UnitedStates Food and Drug Administration (FDA) generic drug science and research program, it is of vital importance in developing product-specific guidances (PSGs) with recommendations that can facilitate and guide generic product development. To generate a PSG, the assessor needs to retrieve supportive information about the drug product of interest, including from the drug labeling, which contain comprehensive information about drug products and instructions to physicians on how to use the products for treatment. Currently, although there are many drug labeling data resources, none of them including those developed by the FDA (e.g., Drugs@FDA) can cover all the FDA-approved drug products. Furthermore, these resources, housed in various locations, are often in forms that are not compatible or interoperable with each other. Therefore, there is a great demand for retrieving useful information from a large number of textual documents from different data resources to support an effective PSG development. To meet the needs, we developed a Natural Language Processing (NLP) pipeline by integrating multiple disparate publicly available data resources to extract drug product information with minimal human intervention. We provided a case study for identifying food effect information to illustrate how a machine learning model is employed to achieve accurate paragraph labeling. We showed that the pre-trained Bidirectional Encoder Representations from Transformers (BERT) model is able to outperform the traditional machine learning techniques, setting a new state-of-the-art for labelling food effect paragraphs from drug labeling and approved drug products datasets.

Objective To investigate the clinical significance of cyclin-dependent kinase (CDK) 15 in breast cancer. Methods This prospective observational study enrolled 154 patients with breast cancer. Tumor tissues and paired paracancerous normal tissues were collected. Additionally, 85 samples of benign breast lesions were obtained from patients with mammary gland hyperplasia. Patient characteristics were recorded, and CDK15, human epidermal growth factor receptor (HER)2, estrogen receptor, progesterone receptor, and Ki67 immunohistochemical expression were determined. Results The rate of strong CDK15 expression was 63.6% (98/154) in breast cancer tissues, which was remarkably higher than that in benign breast lesions (34.1%, 29/85). Similarly, the ratio of strong CDK15 expression was markedly higher in tumor tissues (63.6%, 98/15) than in paracancerous normal tissues (27.3%, 42/154). Pearson’s analysis showed that the CDK15 expression score was positively correlated with HER2 and Ki67. Patients with high CDK15 expression showed markedly higher ratios of TNM stage III to IV, lymph node metastasis, and increased tumor diameters but a significantly lower rate of ductal carcinoma in situ. The median survival time of these patients was significantly shorter. Kaplan–Meier curve analysis showed that low CDK15 expression predicted longer survival times. Conclusion Upregulated CDK15 predicted poor clinical outcomes in breast cancer.

Abstract Background T-cell acute lymphoblastic leukemia (T-ALL) is a lymphoid malignancy caused by the oncogenic transformation of immature T-cell progenitors with poor outcomes. WP1130 has shown potent activity against a variety of cancer but whether WP1130 has anti-T-ALL activity is not clear. USP24, one target of WP1130, is one of the largest deubiquitinases and its detailed mechanism is poorly understood. The aim of this study was to explore whether WP1130 could suppress T-ALL and the role of USP24 in T-ALL. Methods Molecular docking and cellular thermal shift assay were performed to determine whether and how WP1130 directly interact with USP24. Mitochondrial transmembrane potential assay was measured via Rhodamine 123 staining. USP24 was reactivated using the deactivated CRISPR-associated protein 9 (dCas9)-synergistic activation mediator (SAM) system. The in vivo results were examined by tumor xenografts in NOD-SCID mice. All statistical analyses were performed with the SPSS software package. Results WP1130 treatment decreased the viability and induces apoptosis of T-ALL cells both in vitro and in vivo. Furthermore, we demonstrated that knockdown of USP24 but not USP9X could significantly induce growth inhibition and apoptosis of T-ALL cells. Oncomine database showed that USP24 expression was upregulated in T-ALL samples and Kaplan–Meier results indicated that the USP24 was negatively but USP9X was positively associated with survival in T-ALL patients. Additionally, we proposed that WP1130 directly interacts with the activity site pocket of USP24 in T-ALL cells, which leads to the decrease of its substrates Mcl-1. Mechanistically, WP1130 induces apoptosis by accelerating the collapse of mitochondrial transmembrane potential via USP24-Mcl-1 axis. Conclusions Altogether, using WP1130 as a chemical probe, we demonstrate that USP24 but not USP9X is a novel target in T-ALL cells. Moreover, we uncovered that WP1130 induces apoptosis by accelerating the collapse of mitochondrial transmembrane potential via USP24-Mcl-1 axis. These results provide that USP24-Mcl-1 axis may represent a novel strategy in the treatment of T-ALL and WP1130 is a promising lead compound for developing anti-T-ALL drugs.

As a key part of the method of improving traffic capacity, traffic flow prediction is becoming a research hot-spot of traffic science and intelligent technology, in which the accuracy of traffic flow prediction is particularly concerned. In this paper, a novel fuzzy-based convolutional neural network (F-CNN) method is proposed to predict the traffic flow more accurately, in which a fuzzy approach has been applied to represent the traffic accident features when introducing uncertain traffic accidents information into the CNN at the first time. First, for the sake of extracting the spatial-temporal characteristics of the traffic flow data, this paper divides the whole area into small blocks of 32 × 32 and constructs three trend sequences with inflow and outflow types. Second, uncertain traffic accident information is generated from the real traffic flow data by utilizing a fuzzy inference mechanism. Finally, the F-CNN model is realized to train the internal information of the trend sequence, the uncertain traffic accident information, and the external information. Moreover, pre-training and fine-tuning strategies are efficiently developed to learn the parameters of the F-CNN. At last, the real Beijing taxicab trajectory and the meteorology datasets are employed to show that the proposed method has superior performance compared with the state-of-the-art approaches.

Fusing conflict evidences is one of the fundamental needs to data fusion, but this task is challenging in the decision-making domain because of the fusion of ever-increasing uncertain data. In this paper, a novel fuzzy-based multi-sensor data fusion method is proposed for fusing high-conflict uncertain data and avoiding the counter-intuition problem. Our key idea is to introduce the fuzzy inference mechanism into the similarity measurement model to measure conflict degree between the evidences. On this basis, belief entropy is used to calculate the uncertainty of evidences, so as to express the relative importance of the evidences. The reliability of evidences can be obtained by the credibility which is gained through the above method, and the quantitative information volume is used to revise each credibility degree to get the final weight according to the evidence. The numerical experimental results demonstrate that the presented method is feasible and effective in dealing with conflicting evidences. In addition, the application of fault diagnosis is given to show that the proposed approach is effective and advantageous compared with state-of-the-art approaches.

In this paper, the signal-to-noise ratios (SNR) of two image channels were enhanced with the fast digital lock-in algorithm. In order to simultaneously improve the quality of white and fluorescence images obtained by fluorescence endoscope, and improve the SNR to achieve a better image processing effect, two sources of white light and near-infrared light of a fluorescence endoscope were modulated, then the acquired images were demodulated into white and fluorescence images. A fluorescent endoscope experimental platform was setup to acquire endoscopic images of a target dyed by indocyanine green. The experimental results showed that the SNR of white and fluorescent images without the lock-in algorithm were 36.56 dB and 33.47 dB, respectively. However, with the lock-in algorithm, the SNR of white and fluorescent images were 39.54 dB and 35.70 dB, respectively. The SNR of white and fluorescent images was increased by 8.2% and 6.7%, respectively, by appling the digital lock-in algorithm. Therefore, this novel fluorescence endoscope based on the fast digital lock-in algorithm can rapidly and simultaneously obtain two-channel images of white light and fluorescence, effectively enhance the SNR of white and fluorescent images, and improve the imaging quality.

Pandemic influenza A viruses can emerge from swine, an intermediate host that supports adaptation of human-preferred receptor-binding specificity by the hemagglutinin (HA) surface antigen. Other HA traits necessary for pandemic potential are poorly understood. For swine influenza viruses isolated in 2009–2016, gamma-clade viruses had less stable HA proteins (activation pH 5.5–5.9) than pandemic clade (pH 5.0–5.5). Gamma-clade viruses replicated to higher levels in mammalian cells than pandemic clade. In ferrets, a model for human adaptation, a relatively stable HA protein (pH 5.5–5.6) was necessary for efficient replication and airborne transmission. The overall airborne transmission frequency in ferrets for four isolates tested was 42%, and isolate G15 airborne transmitted 100% after selection of a variant with a stabilized HA. The results suggest swine influenza viruses containing both a stabilized HA and alpha-2,6 receptor binding in tandem pose greater pandemic risk. Increasing evidence supports adding HA stability to pre-pandemic risk assessment algorithms.

The current study investigated the effect of dietary l-histidine and beta-alanine supplementation on growth performance, meat quality, carnosine content, and gene expression of carnosine-related enzymes in broilers. A two-factor design was adopted in this study. A total of 640 1-day-old male broilers were assigned to eight treatments with factorial arrangement containing four levels of l-histidine (0, 650, 1300, or 1950 mg/kg) and two levels of beta-alanine (0 or 1200 mg/kg) supplementation; 0 mg/kg histidine and/or 0 mg/kg were treated as control groups. Each treatment including eight replicates with 10 birds each and the feeding trial lasted for 42 days. Dietary supplementation with l-histidine and beta-alanine did not affect average daily gain (ADG), average daily feed intake (ADFI), and feed conversion ratio (FCR) of broilers during the grower (22–42 days) and the entire phase (1–42 days), compared with the control group (p > 0.05). The only exception was a significantly reduced ADG in the 1950 mg/kg l-histidine group in the starter period (1–21 days, p < 0.05). l-Histidine at 1950 mg/kg significantly decreased redness (a*) and yellowness (b*) values of the meat at 45 min postmortem (p < 0.05), whereas it increased b* value and pH in breast muscle at 24 h postmortem. Moreover, dietary supplementation with beta-alanine alone or combination with l-histidine significantly increased ΔpH in breast muscle (p < 0.01). Dietary l-histidine markedly increased total superoxide dismutase activity and total antioxidant capacity (T-AOC) both in breast muscle (p < 0.01) and in plasma (p < 0.01), and it decreased malondialdehyde (MDA) concentration in breast muscle (p < 0.01). Dietary addition of beta-alanine, alone or combination, significantly increased T-AOC in breast muscle (p < 0.01) and markedly decreased MDA content both in breast muscle and in plasma (p < 0.01). Addition of l-histidine and beta-alanine significantly increased muscle peptide (carnosine and anserine) content (p < 0.05) and upregulated the expression of carnosine synthase, transporter of carnosine/ l-histidine, and l-histidine decarboxylase genes (p < 0.05), with greater change occurring in the combination group of 1300 mg/kg l-histidine and 1200 mg/kg beta-alanine. Overall, dietary l-histidine and beta-alanine could improve meat quality and antioxidant capacity, enhance the carnosine and anserine content, and upregulate the gene expression of carnosine synthesis-related enzymes in broilers.

Abstract Understanding the underlying molecular mechanisms of liver fibrosis is important to develop effective therapy. Herein, we show that focal-adhesion-kinse (FAK) plays a key role in promoting hepatic stellate cells (HSCs) activation in vitro and liver fibrosis progression in vivo. FAK activation is associated with increased expression of α-smooth muscle actin (α-SMA) and collagen in fibrotic live tissues. Transforming growth factor beta-1 (TGF-β1) induces FAK activation in a time and dose dependent manner. FAK activation precedes the α-SMA expression in HSCs. Inhibition of FAK activation blocks the α-SMA and collagen expression, and inhibits the formation of stress fibers in TGF-β1 treated HSCs. Furthermore, inhibition of FAK activation significantly reduces HSC migration and small GTPase activation, and induces apoptotic signaling in TGF-β1 treated HSCs. Importantly, FAK inhibitor attenuates liver fibrosis in vivo and significantly reduces collagen and α-SMA expression in an animal model of liver fibrosis. These data demonstrate that FAK plays an essential role in HSC activation and liver fibrosis progression, and FAK signaling pathway could be a potential target for liver fibrosis.