Search

Abstract Resistance to chemotherapy has been a major hurdle that limits therapeutic benefits for many types of cancer. Here we systematically identify genetic drivers underlying chemoresistance by performing 30 genome-scale CRISPR knockout screens for seven chemotherapeutic agents in multiple cancer cells. Chemoresistance genes vary between conditions primarily due to distinct genetic background and mechanism of action of drugs, manifesting heterogeneous and multiplexed routes towards chemoresistance. By focusing on oxaliplatin and irinotecan resistance in colorectal cancer, we unravel that evolutionarily distinct chemoresistance can share consensus vulnerabilities identified by 26 second-round CRISPR screens with druggable gene library. We further pinpoint PLK4 as a therapeutic target to overcome oxaliplatin resistance in various models via genetic ablation or pharmacological inhibition, highlighting a single-agent strategy to antagonize evolutionarily distinct chemoresistance. Our study not only provides resources and insights into the molecular basis of chemoresistance, but also proposes potential biomarkers and therapeutic strategies against such resistance.

BackgroundIt is challenging to predict the occurrence of non-suicidal self-injury (NSSI) among adolescents over short periods. Moreover, the predictive value of indices for NSSI remains elusive. Thus, this study aimed to identify predictors of NSSI within 6 months among adolescents after psychiatric hospitalization by establishing a risk assessment model.MethodsA total of 632 high-risk participants were included in this study. The distribution characteristics of adolescent NSSI were initially assessed through a cross-sectional survey, following which risk factors were identified using logistic regression analysis. The risk score method was then used to construct a 6-month risk assessment model for NSSI. Lastly, the predictive effect of the model was evaluated by indicators such as the area under the receiver operating characteristic (ROC) curve and the positive predictive value.ResultsAfter 6 months, 412 cases of NSSI were identified. According to the logistic regression model, the frequency of relapses, medication status, and NSSI history were identified as influencing factors. Higher scores on the Impulsive Behavior Scale and Pittsburgh Sleep Quality Index were associated with a higher risk of NSSI. Conversely, higher scores on the Pain and Belief Perception Scale were correlated with a lower risk of NSSI. Moreover, the area under the ROC curve for the predictive model was 0.9989, with a 95% confidence interval of (0.9979, 0.9999), highlighting its high predictive ability and accuracy. The predictive model was validated using 78 patients, yielding an area under the ROC curve of 0.9703 and a 95% confidence interval of (0.9167, 0.9999), demonstrating outstanding predictability.ConclusionThese results collectively showed that the predictive model could accurately predict adolescent NSSI. Thus, the model’s primary variables may be applied to predict the risk of NSSI in the clinical setting.

Williams syndrome (WS) is a relatively rare genetic disorder. It arises from a microdeletion in chromosome 7q11.23, resulting in the loss of one copy of more than 20 genes. Disorders in multiple systems, including cardiovascular and nervous systems, occur in patients with WS. Here, we generated two human induced pluripotent stem cell (iPSC) lines from WS patients. Both lines expressed pluripotency markers at gene and protein levels. They possessed normal karyotypes and the potential to differentiate into three germ layers. They serve as a useful tool to study disease mechanism, test drugs, and identify promising therapeutics for patients with WS.

To study the mechanism of bongkrekic acid production by Pseudomonas cocovenenans subsp. farinofermentans at proteome level, data-dependent acquisition (DDA) unlabeled quantitative proteomics technique was used to analyze the protein changes of P. cocovenenans before and after toxin production. The results showed that 25 proteins were up-regulated and 31 proteins were down-regulated in toxin-producing strains. Among them, ABC transporters, response regulatory receptor protein, methyl-accepting chemotaxis protein II were related to bacterial chemotactic signal transduction. And flagellins such as P-cyclin, M-cyclin and FlgE were all related to chemotaxis. It is supposed that chemotactic movement plays an important role in the production of bongkrekic acid. The study on the production mechanism of bongkrekic acid can provide theoretical evidence to decrease the incidence of foodborne diseases.

Hematopoietic stem cell transplantation (HSCT) is a crucial treatment option for hematological disorders. This study aims to design and develop a blockchain-based system tailored explicitly for HSCT typing and evaluate its performance and capabilities. The system, built on Hyperledger Fabric 2.4.6 and integrated with LevelDB and MySQL databases, implements features such as data on-chaining, access control, information retrieval, and matching through chaincode. It ensures accurate and efficient human leukocyte antigen (HLA) typing while protecting patient and hospital data security. Tests demonstrate the system’s ability to safeguard data security and reliability effectively. Performance metrics, including block size, CPU utilization, network throughput, and response latency, were evaluated on Ubuntu 20.04.2 operating systems using VMware Workstation 16 Pro and Docker containerization. By leveraging blockchain’s traceability and immutability, the system achieves data security, reliability, and verifiability, enabling faster and more accurate typing and improved healthcare efficiency. This innovative approach optimizes user experience, maintains data integrity, and ensures privacy. Future integration with existing databases could enable secure data sharing among healthcare institutions, allowing rapid verification of data ownership and unified authentication. This study contributes a significant advancement in hematologic disease treatment and research, offering practical implications for improving HSCT processes.

Abstract Background Elderly patients with acute myeloid leukemia or myelodysplastic syndromes (AML/MDS) have historically had poor prognoses. However, there has been a recent increase in the use of allogenic hematopoietic stem cell transplantation (allo-HSCT) are in this patient population. Nevertheless, the optimal choice of donor type for the patients remains an unmet need. Limited data exist on the use of allo-HSCT in elderly patients with AML/MDS from China. To better understand and optimize the selection of donor type for the elderly patients, particularly for those with refractory or relapsed disease, in comparison with the previous studies in the US and Europe. Methods Our retrospective study enrolled 259 patients aged over 55 years who underwent their first allo-HSCT between April 2015 and August 2022. These patients were divided into three groups based on donor type: haploidentical related donor group (haploidentical related donor transplantation [HID], n = 184), matched sibling donor group (matched sibling donor transplantation [MSD], n = 39), and matched unrelated donor group (matched unrelated donor transplantation [MUD], n = 36). Statistics were performed with the chi-square test, the log-rank and Fine-Gray tests. Results The median age of the cohort was 57 years (range: 55–75) and 26.25% of patients were over 60 years old. Younger patients had a higher incidence of acute graft-versus-host disease (HR = 1.942, P = 0.035), faster neutrophil recovery (HR = 1.387, P = 0.012), and better overall survival (HR = 0.567, P = 0.043) than patients aged ≥ 60 years across the entire cohort. Patients with refractory or relapsed (R/R) diseases had delayed neutrophil engraftment (P = 0.010, HR = 0.752) and platelet engraftment (P

Abstract Scintillators, which can convert high‐energy particles (X‐rays) into detectable low‐energy ultraviolet–visible–near‐infrared photons, are essential components of X‐ray detectors and show extensive practical applications in nondestructive detection and medical imaging. Traditionally, inorganic scintillators represented by CsI:Tl have achieved definite progress. However, the harsh preparation conditions, high production cost, and poor mechanical properties impede their potential development in the high‐end X‐ray imaging field. Organic–inorganic hybrid metal complexes could be excellent alternatives, by virtue of their structural and spectral tunability, good solution processability, and excellent photophysical properties. This review mainly focuses on eco‐friendly lead‐free metal (Mn2+, Cu+, Sb3+, Sn2+, Ge2+, Ln3+, etc.) complex scintillators. The luminescence mechanisms are introduced and the scintillation performance, such as light yield, limit of detection, imaging resolution, etc., is highlighted. Moreover, the current challenges and perspectives in this emerging field are described. It is hoped to provide some theoretical guidance for the continuous development of the new scintillator systems.

Objective To investigate the correlation between early immune reconstitution and clinical outcomes in patients with acute lymphoblastic leukemia (ALL) underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods The basic information and treatment data of 99 patients with ALL undering allo-HSCT from December 2018 to February 2022 were collected. The proportions of CD3+ T, CD3+CD4+ T, CD3+CD8+ T and CD3-CD16+CD56+ NK cells were detected before and 30, 60 and 90 days after transplantation using flow cytometry. The correlation between early cellular immune reconstitution and neutrophil engraftment, platelet engraftment, infection, and acute and chronic graft-versus-host disease (GVHD) was analyzed. Results Among 99 ALL patients, the median time of neutrophil engraftment was day +11 (range, 8-28), and the median time of platelet engraftment was day +14 (range, 10-120). The cumulative incidence of blood stream infection (BSI) was 11.10% and the cumulative incidence of CMV within 100 days of transplantation was 40.40%. The cumulative incidence of EBV within 100 days was 7.10%. The cumulative incidence of acute graft-versus-host disease (aGVHD) was 22.30%. The cumulative incidence of chronic graft-versus-host disease (cGVHD) within 1 year of transplantation was 16.20%. 1 -year cumulative relapse rate was 13.84%. The 1 -year cumulative disease-free survival (DFS) for all patients was 80.60% and the 1-year overall survival (OS) was 90.30%. The CD4+/CD8+ ratio was positively associated with the development of aGVHD at 30 days post-transplant (OR 1.21, 95CI 1.01-1.45, P

In order to clarify the gas-phase carrying capacity after the atomization of water from the bottom of deep coalbed wells, considering characteristics of atomization-assisted production and the dynamic equilibrium principle of gas–liquid two-phase flow in the wellbore, the gas-phase liquid-carrying drop model was established, and the solution method of the upstream and downstream driving force of liquid drop flow was studied. We also verified the theoretical model through physical simulation. Then, the law for the influence of droplet size, wellbore inclination, wellbore diameter, and wellhead back pressure of the critical liquid-carrying velocity in the gas phase is analyzed using the model. The results show the following: ① the larger the diameter of atomized droplets, the greater the gravity force applied to it, the worse the ability to be carried by the gas phase, a onefold increase in droplet diameter corresponds to the increase in the minimum critical velocity of the gas phase by 1.45 times; ② with the increase in wellbore inclination, the liquid-carrying capacity of the gas phase decreases, and the minimum critical liquid-carrying velocity of equal diameter droplets increases by 0.01438 m/s or 1.27 times for the increase in wellbore inclination by 10°; ③ with the increase in wellbore diameter, both the driving force of a droplet of equal diameter and the flow resistance through the gas phase in the wellbore decrease within the range of a driving pressure difference of 0.2 Mpa; the decrease in liquid-carrying velocity caused by the decrease in received flow resistance can reach the maximum value of 0.0473 m/s; ④ with the increase in wellhead back pressure, the driving force of equal-diameter droplets decreases, the resistance against passing through the high-concentration gas phase increases, and the gas-phase-carrying droplets start the game; ⑤ the atomization-assisted production has the function of drainage gas recovery, and the adoption of atomization-assisted production technology can increase the production time of a coalbed gas flowing well, enabling the wells to have a good transition time interval for the conversion of flowing wells to pumping ones, which provides a precise production dynamic basis for the efficient design and implements the overall strategy of drainage gas recovery by deep-well pumping. In short, this technology has the high-efficiency liquid-carrying function of “water atomization to help liquid-phase flow and increase gas production”, as well as obvious technical advantages, which can provide a new idea for the development of deep coalbed methane wells and other types of gas wells with water.

To improve the quality and enrich the flavour of fermented sardine, Tetragenococcus halophilus, Staphylococcus xylosus, and Staphylococcus saprophyticus were used as a mixed starter for sardine fermentation. And their proportions were optimised using response surface methodology (RSM). The highest sensory score was obtained when the proportions of T. halophilus, S. xylosus, and S. saprophyticus were 1 : 1 : 1. The optimised fermented sardine had the lowest levels of histamine content (0.0190 μg.g-1), total volatile basic nitrogen (TVBN, 208 μg.g-1), and was richer in volatile compounds (308). The results may provide important evidence that T. halophilus, S. xylosus, and S. saprophyticus may be satisfactorily used as a mixed starter to improve the quality and flavour of fermented sardines.

Abstract Aim The aim of the study was to investigate the incidence of sleep disturbance and its relationship with anxiety and depression symptoms, social support and hope in breast cancer patients in China during chemotherapy. Design A single‐centre cross‐sectional study. Methods A total of 329 breast cancer patients were selected via convenience sampling method before they began chemotherapy (n = 115), before the 5th week of chemotherapy (n = 117) or 1 month after chemotherapy ended (n = 97) and administered paper‐and‐pencil questionnaires to evaluate sleep quality, depression and anxiety symptoms, social support and hope. Risk factors significantly associated with sleep disturbance during bivariate were incorporated in the multivariate analysis. Bivariate analyses showed that age, menopausal status, depression and anxiety symptoms, emotional/informational support, tangible support, affectionate support, positive social interaction and total support were predictors of sleep disturbance. Results Sleep disturbance was prevalent in breast cancer patients before (27.0%), during (32.5%) and after (39.2%) chemotherapy, with 37.4%, 41.9% and 52.6% of participants, respectively, reporting sleeping below the recommended 7 h. Only 8.6%–15.5% of patients reported taking sedative‐hypnotic drugs during the chemotherapy. Multivariate analyses found that participants reporting clinically significant anxiety (HADS > 8) were 3.5 times more likely to report sleep disturbance (PSQI > 8) than participants without clinically significant anxiety, and each increment in emotional/informational support was associated with a 9.04% reduced risk of sleep disturbance. Moreover, age was an independent predictor of sleep disturbance during multivariate modelling.

IntroductionMangroves are the main carbon sinks in tropical regions and have high capabilities for carbon sequestration. Protection and restoration of mangroves are necessary to reduce carbon emissions and fight climate change. While the Qinzhou Bay as the main area of national mangrove restoration plan in the future, studies on its carbon pools, especially assessment of the carbon sink enhancement effect of restored mangroves along forest chronosequence, are lacking.MethodsThis study aimed to quantify the changes in restored mangrove soil carbon stock, vegetation and root carbon stocks along the forest age sequence in Qinzhou Bay through field survey.ResultsThe results revealed that the carbon stocks of vegetation and roots significantly increased with the developing forest age. Only in the soil layer above 30 cm, the soil carbon storage apparently increased with the developing forest age in non-cofferdam area, and then decreased slowly after reaching the peak (at 6 ~ 8 years). Moreover, the soil carbon storage of mangroves was greater in the cofferdam area than in the non-cofferdam area.DiscussionThis implied that the cofferdam restoration efforts may be more effective in enhancing blue carbon storage, during the initial stages of the restoration process. The results of this study suggested that mangrove restoration has substantial potential capacity in carbon storage and nutrient cycling, providing a reference for the protection and restoration efforts concerning mangroves.

Pickled cabbage, a traditional fermented food rich in functional microorganisms, can effectively control hyperuricemia and gout. In this study, a Priestia megaterium ASC-1 strain with strong uric acid (UA) degradation ability was isolated from pickled cabbage. After oral administration for 15 days, ASC-1 was stably colonized in the rats in this study. ASC-1 significantly reduced UA levels (67.24%) in hyperuricemic rats. Additionally, ASC-1 alleviated hyperuricemia-related inflammatory response, oxidative stress, and blood urea nitrogen. Intestinal microbial diversity results showed that ASC-1 restored intestinal injury and gut flora dysbiosis caused by hyperuricemia. These findings suggest that P. megaterium ASC-1 may be used as a therapeutic adjuvant for the treatment of hyperuricemia.

Down syndrome (DS) is caused by trisomy of Homo sapiens chromosome 21 (HSA21) and is by far the most common chromosomal disorder accompanied by neurodevelopmental disorders and congenital heart disease. Here, we generated two induced pluripotent stem cell (iPSC) lines from two patients with DS. These two lines exhibited normal morphology, trisomy 21 karyotype, pluripotency and differentiation capability into derivatives of three germ layers. The patient-specific iPSC lines are an invaluable resource in research to model DS-related cellular and molecular pathologies and test possible therapeutic strategies for DS.

The high dark current of perovskite photodetectors hinders the full potential of perovskites as active material for X-ray detectors. Here, Jin et al. provide a strategy to reduce the dark current to zero and massively enhance the signal-to-noise ratio of perovskite X-ray detectors and photodetectors.

Behavior recognition is a vital task in computer vision. While, semantic information extraction is still insufficient in behavior recognition models. In this paper, we propose an improved behavior recognition model, which is called Cnnformer, to alleviate the problem of inadequate semantic information extraction. Cnnformer is transformer-based semantic information enhancement model for behavior recognition. In Cnnformer, a new attention mechanism is designed and introduced into the encoder module. This attention mechanism uses dilated convolution to capture static context information, trigger mining dynamic context information, and obtain the final fused dynamic and static context information. In addition, four layers of convolution are added in front of the encoder module, which has a strong induction bias to extract the superficial feature representation (such as color, geometry, texture, etc.). Finally, Cnnformer combines the convolution module and the attention module into the encoder module to simultaneously learn both local and global features, so as to enhance visual representation. Experimental results show that Cnnformer has higher performance in behavior recognition, and the accuracy of Top-1 is 3.4% higher than that of the basic model in the Kinetics-400 dataset.

High temperature operation of enhancement-mode (E-mode) and depletion-mode (D-mode) AlGaN/GaN metal-insulator-semiconductor high-electron-mobility transistors (MIS-HEMTs) was demonstrated. By using the circular device structure, off-state current was effectively suppressed, and record high Ion/Ioff ratio around 108 was obtained at 400 °C. Atomic layer etching was used for formation of the gate recess structure in the E-mode device, and good interface was made which enabled stable normally-off operation up to 400 °C. D-mode device experienced positive threshold voltage shift during the high temperature operation and after cooling down to room temperature, due to strain relaxation. On the other hand, due to the very thin AlGaN layer retained under the gate of the E-mode device, the threshold voltage of the E-mode device is nearly unchanged when the sample is heated up and cooled down. A direct coupled field-effect transistor logic (DCFL) inverter was fabricated based on the E-mode and D-mode devices and showed stable operation up to 400 °C.

Abstract Single gene disorders are individually rare but collectively common leading causes of neonatal and pediatric morbidity and mortality. Both parents or the mothers of affected individuals with autosomal recessive or X-linked recessive diseases, respectively, are carrier(s). Carrier frequencies of recessive diseases can vary drastically among different ethnicities. This study established a robust pipeline for estimating and ranking carrier frequencies of all known 2699 recessive genes based on genome-wide sequencing data in healthy individuals. The discovery gnomAD cohort contained sequencing data on 76,156 genomes and 125,748 exomes from individuals with seven ethnicity backgrounds. The three validation cohorts composed of the SG10K Project with 4810 genomes on East Asian and South Asian, the ChinaMAP project with 10,588 Chinese genomes, and the WBBC pilot project with 4480 Chinese genomes. Within each cohort, comprehensive selection criteria for various kinds of deleterious variants were instituted, including known pathogenic variants (Type 1), presumably loss-of-function changes (Type 2), predicted deleterious missense variants (Type 3), and potentially harmful in-frame INDELs (Type 4). Subsequently, carrier frequencies of the 2699 genes were calculated and ranked based on ethnicity-specific carrier rates of Type 1 to Type 4 variants. Comparison of results from different cohorts with similar ethnicity background exhibited high degree of correlation, particularly between the ChinaMAP and the WBBC cohorts (Pearson correlation coefficient R = 0.92), confirming the validity of our variant selection criteria and the overall analysis pipeline.

In the original publication [...]

To examine the production time, type, and MFI of post-transplantation de novo HLA antibodies, and their effects on haplo-HSCT outcomes, we retrospectively included 116 patients who were negative for pre-existing HLA antibodies. In total, 322 serum samples from pre-transplantation to post-transplantation were dynamically tested by Luminex and single-antigen bead reagents. Patients were divided into: HLA antibody persistently negative group (group 1), the de novo HLA antibody transiently positive group (group 2), the de novo HLA antibody non-persistently positive group (group 3), and the de novo HLA antibody persistently positive group (group 4). Group 4 included DSA+non-DSA (NDSA) (group 4a) and NDSA (group 4b) groups. The detection rate of de novo HLA antibodies was 75.9% (88/116). The median MFI for de novo HLA antibodies was 2439 (1033-20162). The incidence of II–IV aGvHD was higher in group 2 than in group 1 (52.6% vs 17.9%, P < 0.01); in group 4a than in group 1 (87.5% vs 17.9%, P < 0.001); and in group 4a than in group 4b (87.5% vs 40.0%, P = 0.001). The DFS (37.5% vs 85.7%, P < 0.01) and OS (37.5% vs 85.7%, P < 0.01) of group 4a were lower than those of group 1. The DFS (48.0% vs 85.7%, P < 0.01) and OS (56.0% vs 85.7%, P = 0.03) of group 4b were lower than those of group 1. Multivariate analysis showed that de novo HLA antibody being transiently positive (HR: 5.30; 95% CI: 1.71–16.42, P = 0.01) and persistently positive (HR: 5.67; 95% CI: 2.00–16.08, P < 0.01) were both associated with a higher incidence of II–IV aGvHD. Persistently positive de novo HLA antibodies were a risk factor for reduced DFS (HR: 6.57; 95% CI: 2.08–20.70, P < 0.01) and OS (HR: 5.51; 95% CI: 1.73–17.53, P < 0.01). DSA and NDSA can be detected since 15 days after haplo-HSCT in patients without pre-existing HLA antibodies, and affect aGvHD, DFS, and OS. Haplo-HSCT patients must be monitored for HLA antibodies changes for appropriate preventive clinical management, and we recommend that 1-month post-transplantation is the best test time point.

Phalaenopsis-type Dendrobium is a popular orchid with good ornamental and market value. Despite their popularity, molecular regulation of anthocyanin biosynthesis during flower development remains poorly understood. In this study, we systematically investigated the regulatory roles of the transcription factors DhMYB2 and DhbHLH1 in anthocyanins biosynthesis. Gene expression analyses indicated that both DhMYB2 and DhbHLH1 are specifically expressed in flowers and have similar expression patterns, showing high expression in purple floral tissues with anthocyanin accumulation. Transcriptomic analyses showed 29 differentially expressed genes corresponding to eight enzymes in anthocyanin biosynthesis pathway have similar expression patterns to DhMYB2 and DhbHLH1, with higher expression in the purple lips than the yellow petals and sepals of Dendrobium ‘Suriya Gold’. Further gene expression analyses and Pearson correlation matrix analyses of Dendrobium hybrid progenies revealed expression profiles of DhMYB2 and DhbHLH1 were positively correlated with the structural genes DhF3’H1, DhF3’5’H2, DhDFR, DhANS, and DhGT4. Yeast one-hybrid and dual‐luciferase reporter assays revealed DhMYB2 and DhbHLH1 can bind to promoter regions of DhF3’H1, DhF3’5’H2, DhDFR, DhANS and DhGT4, suggesting a role as transcriptional activators. These results provide new evidence of the molecular mechanisms of DhMYB2 and DhbHLH1 in anthocyanin biosynthesis in Phalaenopsis-type Dendrobium.

The impact of short-term nitrogen fertilizer input on the structure and diversity of peanut rhizosphere microbiota (RM) at different growth stages (GSs) was explored in the southern paddy soil planting environment. Three levels of nitrogen were applied in the field: control (LN, 0 kg/hm2), medium nitrogen (MN, 55.68 kg/hm2), and high nitrogen (HN, 111.36 kg/hm2). The rhizosphere soil was collected during four GSs for high-throughput sequencing and chemical properties analysis. The effect of nitrogen fertilizer application on peanut RM was minimal and was obvious only at the seedling stage. In the four peanut GSs, a significant increase in relative abundance was observed for only one operational taxonomic unit (OTU) of Nitrospira under HN conditions at the seedling stage and mature stage, while there was no consistent change in other OTUs. The difference in RM among different peanut GSs was greater than that caused by the amount of nitrogen fertilizer. This may be due to the substantial differences in soil chemical properties (especially alkali-hydrolyzable nitrogen, pH, and available potassium or total potassium) among peanut GSs, as these significantly affected the RM structure. These results are of great value to facilitate deeper understanding of the effect of nitrogen fertilizer on peanut RM structure.

Hepatocellular carcinoma (HCC) remains one of the most lethal cancers around the world. Precision oncology will be crucial for further improving the prognosis of HCC patients. Compared with traditional bulk RNA-seq, single-cell RNA sequencing (scRNA-seq) enables the transcriptomes of a great deal of individual cells assayed in an unbiased manner, showing the potential to deeply reveal tumor heterogeneity. In this study, based on the scRNA-seq results of primary neoplastic cells and paired normal liver cells from eight HCC patients, a new strategy of machine learning algorithms was applied to screen core biomarkers that distinguished HCC tumor tissues from the adjacent normal liver. Expression profiles of HCC cells and normal liver cells were first analyzed by maximum relevance minimum redundancy (mRMR) to get a top 50 signature gene feature. For further analysis, the incremental feature selection (IFS) method and leave-one-out cross validation (LOOCV) were conducted to build an optimal classification model and to extract 21 potentially essential biomarkers for HCC cells. Our results provided new insights into HCC pathogenesis that might be valuable for HCC diagnosis and therapy.

A simple and efficient sample pretreatment technology is very important for the accurate determination of trace drug residues in foods to ensure food safety. Herein, we report a new carboxyl group-functionalized ionic liquid hybrid solid- phase adsorbent (PS-IL-COOH) for the highly efficient extraction and quantitative determination of diclofenac sodium (DS) residue in milk samples. It was found that the adsorption efficiency of PS-IL-COOH for the ppb level of DS was greater than 93.0%, the adsorption capacity was 934.1 mg/g, and the enrichment factor was 620.0, which surpass most of the previously reported values for DS adsorbents. The high concentration of salts did not interfere with the adsorption of DS. Importantly, the recovery of DS was above 90% after 16 adsorption–-regeneration cycles. The synergistic effect of the multiple interactions was found to be the main factor for the high efficiency of DS adsorption. The proposed method was applied to the extraction and detection of DS in milk samples, with the relative recovery ranging from 88.2 to 103.0%.

Abstract All‐inorganic perovskite quantum dots (QDs) CsPbX3 (X = Cl, Br, and I) have recently emerged as a new promising class of X‐ray scintillators. However, the instability of perovskite QDs and the strong optical scattering of the thick opaque QD scintillator film imped it to realize high‐quality and robust X‐ray image. Herein, the europium (Eu) doped CsPbBr3 QDs are in situ grown inside transparent amorphous matrix to form glass‐ceramic (GC) scintillator with glass phase serving as both matrix and encapsulation for the perovskite QD scintillators. The small amount of Eu dopant optimizes the crystallization of CsPbBr3 QDs and makes their distribution more uniform in the glass matrix, which can significantly reduce the light scattering and also enhance the photoluminescence emission of CsPbBr3 QDs. As a result, a remarkably high spatial resolution of 15.0 lp mm−1 is realized thanks to the reduced light scattering, which is so far a record resolution for perovskite scintillator based X‐ray imaging, and the scintillation stability is also significantly improved compared to the bare perovskite QD scintillators. Those results provide an effective platform particularly for the emerging perovskite nanocrystal scintillators to reduce light scattering and improve radiation hardness.

Summary: Bicuspid aortic valve (BAV) with ∼1%–2% prevalence is the most common congenital heart defect (CHD). It frequently results in valve disease and aorta dilation and is a major cause of adult cardiac surgery. BAV is genetically linked to rare left-heart obstructions (left ventricular outflow tract obstructions [LVOTOs]), including hypoplastic left heart syndrome (HLHS) and coarctation of the aorta (CoA). Mouse and human studies indicate LVOTO is genetically heterogeneous with a complex genetic etiology. Homozygous mutation in the Pcdha protocadherin gene cluster in mice can cause BAV, and also HLHS and other LVOTO phenotypes when accompanied by a second mutation. Here we show two common deletion copy number variants (delCNVs) within the PCDHA gene cluster are associated with LVOTO. Analysis of 1,218 white individuals with LVOTO versus 463 disease-free local control individuals yielded odds ratios (ORs) at 1.47 (95% confidence interval [CI], 1.13–1.92; p = 4.2 × 10−3) for LVOTO, 1.47 (95% CI, 1.10–1.97; p = 0.01) for BAV, 6.13 (95% CI, 2.75–13.7; p = 9.7 × 10−6) for CoA, and 1.49 (95% CI, 1.07–2.08; p = 0.019) for HLHS. Increased OR was observed for all LVOTO phenotypes in homozygous or compound heterozygous PCDHA delCNV genotype comparison versus wild type. Analysis of an independent white cohort (381 affected individuals, 1,352 control individuals) replicated the PCDHA delCNV association with LVOTO. Generalizability of these findings is suggested by similar observations in Black and Chinese individuals with LVOTO. Analysis of Pcdha mutant mice showed reduced PCDHA expression at regions of cell-cell contact in aortic smooth muscle and cushion mesenchyme, suggesting potential mechanisms for BAV pathogenesis and aortopathy. Together, these findings indicate common variants causing PCDHA deficiency play a significant role in the genetic etiology of common and rare LVOTO-CHD.

Anti-inflammatory therapies have the potential to become an effective treatment for obesity-related diseases. However, the huge gap of immune system between human and rodent leads to limitations of drug discovery. This work aims at constructing a transgenic pig model with higher risk of metabolic diseases and outlining the immune responses at the early stage of metaflammation by transcriptomic strategy. We used CRISPR/Cas9 techniques to targeted knock-in three humanized disease risk genes, GIPRdn, hIAPP and PNPLA3I148M. Transgenic effect increased the risk of metabolic disorders. Triple-transgenic pigs with short-term diet intervention showed early symptoms of type 2 diabetes, including glucose intolerance, pancreatic lipid infiltration, islet hypertrophy, hepatic lobular inflammation and adipose tissue inflammation. Molecular pathways related to CD8+ T cell function were significantly activated in the liver and visceral adipose samples from triple-transgenic pigs, including antigen processing and presentation, T-cell receptor signaling, co-stimulation, cytotoxicity, and cytokine and chemokine secretion. The similar pro-inflammatory signaling in liver and visceral adipose tissue indicated that there might be a potential immune crosstalk between the two tissues. Moreover, genes that functionally related to liver antioxidant activity, mitochondrial function and extracellular matrix showed distinct expression between the two groups, indicating metabolic stress in transgenic pigs’ liver samples. We confirmed that triple-transgenic pigs had high coincidence with human metabolic diseases, especially in the scope of inflammatory signaling at early stage metaflammation. Taken together, this study provides a valuable large animal model for the clinical study of metaflammation and metabolic diseases.

BackgroundColorectal carcinoma (CRC) often arises from benign adenoma after a stepwise accumulation of genetic alterations. Here, we profiled the dynamic landscapes of transcription factors (TFs) in the mucosa-adenoma-carcinoma progression sequence.MethodsThe transcriptome data of co-occurrent adenoma, carcinoma, and normal mucosa samples were obtained from GSE117606. Identification of differentially expressed TFs (DE-TFs) and subsequent function annotation were conducted in R software. Expression patterns of DE-TFs were clustered by Short Time-series Expression Miner software. Thereafter, modular co-expression analysis, Kaplan-Meier survival analysis, mutation profiling, and gene set enrichment analysis were conducted to investigate TF dynamics in colorectal tumorigenesis. Finally, tissue microarrays, including 51 tumors, 32 adenomas, and 53 normal tissues, were employed to examine the expression of significant candidates by immunohistochemistry staining.ResultsCompared to normal tissues, 20 (in adenoma samples) and 29 (in tumor samples) DE-TFs were identified. During the disease course, 28 expression patterns for DE-TFs and four co-expression modules were clustered. Notably, six DE-TFs, DACH1, GTF2IRD1, MEIS2, NR3C2, SOX9, and SPIB, were identified as having a dynamic signature along the colorectal adenoma-carcinoma sequence. The dynamic signature was of significance in GO enrichment, prognosis, and co-expression analysis. Among the 6-TF signature, the roles of GTF2IRD1, SPIB and NR3C2 in CRC progression are unclear. Immunohistochemistry validation showed that GTF2IRD1 enhanced significantly throughout the mucosa-adenoma-carcinoma sequence, while SPIB and NR3C2 kept decreasing in stroma during the disease course.ConclusionsOur study provided a dynamic 6-TF signature throughout the course of colorectal mucosa-adenoma-carcinoma. These findings deepened the understanding of colorectal cancer pathogenesis.

Deep eutectic solvents are a new generation of green solvents composed of hydrogen bond acceptors and donors. However, when used as extractants in liquid–liquid separation, they are difficult to recycle and easy to lose. In order to solve these problems, herein, immobilized hydrogen bond acceptor adsorbent material was prepared for the separation and enrichment of antiviral drug arbidol from seven kinds of environmental water samples by in situ formation of hydrophobic deep eutectic solvents. The structure, morphology and thermal stability of the adsorbents were characterized, the separation and enrichment conditions for the targeted analyte were optimized, and the adsorption thermodynamics and kinetics were investigated. It was found that the adsorbent material could effectively enrich trace arbidol with the recovery more than 95% at the concentration above 7.5 ng/mL, and the enrichment factor was as high as 634.7. Coexisting substances, such as NaCl, KCl, CaCl2 and MgCl2, did not interfere with the adsorption of arbidol, even if their concentration was high, up to 1.0 mol/L, and the relative recovery for real samples was in the range from 92.5% to 100.3%. Furthermore, the immobilized hydrogen bond acceptor could be recycled and reused, and the recovery of arbidol was still above 95% after 12 adsorption–desorption cycles. The mechanism study demonstrates that the synergistic effect of hydrogen bonding and π-π stacking is the primary factor for the high adsorption efficiency.

Graphene consists of two-dimensional sp2-bonded carbon sheets, a single or a few layers thick, which has attracted considerable interest in recent years due to its good conductivity and biocompatibility. Three-dimensional graphene foam (3DG) has been demonstrated to be a robust scaffold for culturing neural stem cells (NSCs) in vitro that not only supports NSCs growth, but also maintains cells in a more active proliferative state than 2D graphene films and ordinary glass. In addition, 3DG can enhance NSCs differentiation into astrocytes and especially neurons. However, the underlying mechanisms behind 3DG's effects are still poorly understood. Metabolism is the fundamental characteristic of life and provides substances for building and powering the cell. Metabolic activity is tightly tied with the proliferation, differentiation, and self-renewal of stem cells. This study focused on the metabolic reconfiguration of stem cells induced by culturing on 3DG. This study established the correlation between metabolic reconfiguration metabolomics with NSCs cell proliferation rate on different scaffold. Several metabolic processes have been uncovered in association with the proliferation change of NSCs. Especially, culturing on 3DG triggered pathways that increased amino acid incorporation and enhanced glucose metabolism. These data suggested a potential association between graphene and pathways involved in Parkinson's disease. Our work provides a very useful starting point for further studies of NSC fate determination on 3DG.

Fermented soybean meal (FSM) is an important feed material that can replace fish meal to solve the shortage of animal protein. To improve the utilization of FSM, we optimized the co-fermentation conditions of soybean meal using Bacillus subtilis and Enterococcus faecium and studied the effects of replacing fish meal with different proportions of FSM on serum antioxidant indices and gut microbiota (GM) composition of crucian carp (Carassius auratus). Our results showed that the co-fermentation of soybean meal was the most effective when the ratio of B. subtilis X-2 and E. faecium X-4 was 2:3, glucose addition was 4.5%, KH2PO4 addition was 0.15%, MgSO4·7H2O addition was 0.1%, anhydrous sodium acetate addition was 0.4%, fermentation time was 120 h, and the solid–water ratio was 1:1. Replacing 40% fish meal with FSM in the feed significantly improved the serum T-AOC, POD, and IgM levels in C. auratus. Although there were significant differences in the midgut and hindgut microbiota structures of C. auratus, the addition of FSM to the feed did not cause significant differences in the GM structure, whether in the midgut or hindgut. Therefore, 40% FSM is the most suitable substitute for fish meal in the feed of C. auratus.

The poly(acrylic acid-acrylamide/starch) composite was synthesized by solution polymerization, aiming to adsorb mercury (II) in water. The resulted copolymer was characterized by particle size exclusion chromatography (SEC), Fourier transform infrared spectroscopy (FTIR), thermogravimetry (TG), scanning electron microscopy (SEM) and dynamic light scattering particle size analyzer (DLS). It turned out that starch was successfully incorporated with the macromolecular polymer matrix and played a key role for improving the performance of the composites. These characterization results showed that the graft copolymer exhibited narrow molecular weight distribution, rough but uniform morphology, good thermal stability and narrow particle size distribution. The graft copolymer was used to remove Hg(II) ions from aqueous solution. The effects of contact time, pH value, initial mercury (II) concentration and temperature on the adsorption capacity of Hg(II) ions were researched. It was found that after 120 min of interaction, poly(acrylic acid-acrylamide/starch) composite achieved the maximum adsorption capacity of 19.23 mg·g−1 to Hg(II) ions with initial concentration of 15 mg·L−1, pH of 5.5 at 45 °C. Compared with other studies with the same purpose, the composites synthesized in this study present high adsorption properties for Hg(II) ion in dilute solution. The adsorption kinetics of Hg(II) on the poly(acrylic acid-acrylamide/starch) composite fits well with the pseudo second order model.

Human CD133 + stem cells were injected into the bone marrow cavity of NOG (NOD Shi-SCID IL2Rγc null ) mice with or without preconditioning of busulfan in order to assess the efficiency of human CD133 + cells engraftment. Peripheral blood from CD133 + -engrafted NOG mice was analyzed by flow cytometry. The results showed that human CD19 + B lymphocytes could be detected at 4 weeks post-transplantation, and human CD4 + , CD8 + subsets of T lymphocytes, CD19 – CD14 – HLA-DR + DCs and CD19 – CD14 + monocytes could be detected at 16 weeks post-transplantation. The survival rate of mice in busulfan-untreated group (100%) was slightly higher than that in the busulfan-pretreated group (83%) ( P > 0.05). However, the differentiation efficiency of CD133 + stem cells in busulfan-pretreated group was significantly higher than that in the untreated group ( P < 0.05). This data imply that CD133 + cells could be a good resource for a humanized mouse model, and the preconditioning of busulfan could be more conducive to accelerating the differentiation of human CD133 + cells in NOG mice by intra-bone marrow injection.

The transplantation of neural stem cells (NSCs) has become an emerging treatment for neural degeneration. A key factor in such treatments is to manipulate NSC behaviors such as proliferation and differentiation, resulting in the eventual regulation of NSC fate. Novel bionanomaterials have shown usefulness in guiding the proliferation and differentiation of NSCs due to the materials’ unique morphological and topological properties. Among the nanomaterials, graphene has drawn increasing attention for neural regeneration applications based on the material’s excellent physicochemical properties, surface modifications, and biocompatibility. In this review, we summarize recent works on the use of graphene-based biomaterials for regulating NSC behaviors and the potential use of these materials in clinical treatment. We also discuss the limitations of graphene-based nanomaterials for use in clinical practice. Finally, we provide some future prospects for graphene-based biomaterial applications in neural regeneration.

Salmonella is a globally distributed zoonotic pathogen. Among them, S. pullorum is a host-specific pathogen that seriously affects the development of the poultry breeding industry in China. It mainly infects chickens and can cause white scabs, and the mortality rate after infection is almost 100%. As antibiotics are widely used in animal feed and other production processes, Salmonella resistance has gradually increased. Therefore, there is an increasing need to develop new technologies to control multi-drug resistant (MDR) pathogens and confirm their actual effectiveness in the target food matrix. Bacteriophage can efficiently and specifically lyse bacteria, and will be a potential bactericide to replace antibiotics. In this study, 34 strains of Salmonella bacteriophages were isolated from environmental resources. Therein, phage Pu20 with the widest host spectrum had the strongest ability to lyse tested Salmonella strains. Further studies showed that Pu20 had high pH tolerance and heat resistance, short incubation period. Pu20 can effectively inhibit the growth of two strains of MDR Salmonella in liquid egg white and yolk at 4 °C and 25 °C, respectively. According to morphological and phylogenetic analysis, Pu20 belongs to the Podoviridae family. Genomic analysis of Pu20 indicates a linear 59435 bp dsDNA sequence with no homology to virulence or antibiotic resistance-related genes. Together, these results sheds light on the potential biocontrol application value of Pu20 in food products.

Solution polymerization synthesized alt-resistant superabsorbent poly (acrylic acid-acrylamide/fly ash) composites. The mass ratio of acrylic acid (AA) to acrylamide (AM), the concentration of crosslinker, the neutralization degree (ND) of AA, and the polymerization temperature were investigated by single-factor method. Optimized conditions for the synthesis of poly (acrylic acid-acrylamide/fly ash) (PAA-AM/FA) are, as following: m (AA)/m (AM) is 1.5, the content of crosslinker N, N-methylenebisacrylamide. (MBA) is 0.7%, neutralization degree of AA is 70%, polymerization temperature is 70 °C, and fly ash (FA) content is 50%. The prepared PAA-AM/FA demonstrated superior water absorption performance. The absorption capacities of PAA-AM/FA for pure water and 0.9% NaCl solution were found to be 976 g·g−1 and 81 g·g−1, respectively. Furthermore, PAA-AM/FA was found to have excellent adsorption capacity (148 mg·g−1) for Rhodamine B in water. Fourier Transform-Infrared Spectroscopy (FT-IR), Thermogravimetric Analysis (TGA), and Scanning Electron Microscopy (SEM) characterized the prepared materials. Results showed that fly ash was incorporated into the macromolecular polymer matrix and played a key role in improving the performance of the polymer composites.

In this paper, Tin (Ⅳ) oxide nanoparticles/graphene (SnO2/GR) nanocomposites were prepared via vacuum thermo treatment of Tin (0) and graphene oxide (GO). A redox reaction would occur readily in this process, in which the novel oxygen donor: GO could act as the oxidizing agent to oxidize Tin (0) to Tin (Ⅳ), meanwhile, the graphene precursor: GO would be simultaneously reduced to graphene by Tin (0) readily. The resulted composites were characterized by Fourier transform infrared spectrometry, scanning electron microscopy, and X-ray diffraction spectroscopy ect.. The novel SnO2/GR nanocomposites could combine both advantages of inorganic metal nanoparticles and graphene for near infrared spectroscopy (NIR) light absorption to generate heat, which fosters SnO2/GR a special candidate for photothermal ablation therapy (PTA) with NIR. Further investigations show that the SnO2/GR nanocomposites with NIR features could provide viable option for enhancing the thermal deposition and specificity of hyperthermia treatments for elimination of human prostate cancer (PC3).

To tackle the exponentially increasing throughput of Next-Generation Sequencing (NGS), most of the existing short-read aligners can be configured to favor speed in trade of accuracy and sensitivity. SOAP3-dp, through leveraging the computational power of both CPU and GPU with optimized algorithms, delivers high speed and sensitivity simultaneously. Compared with widely adopted aligners including BWA, Bowtie2, SeqAlto, CUSHAW2, GEM and GPU-based aligners BarraCUDA and CUSHAW, SOAP3-dp was found to be two to tens of times faster, while maintaining the highest sensitivity and lowest false discovery rate (FDR) on Illumina reads with different lengths. Transcending its predecessor SOAP3, which does not allow gapped alignment, SOAP3-dp by default tolerates alignment similarity as low as 60%. Real data evaluation using human genome demonstrates SOAP3-dp's power to enable more authentic variants and longer Indels to be discovered. Fosmid sequencing shows a 9.1% FDR on newly discovered deletions. SOAP3-dp natively supports BAM file format and provides the same scoring scheme as BWA, which enables it to be integrated into existing analysis pipelines. SOAP3-dp has been deployed on Amazon-EC2, NIH-Biowulf and Tianhe-1A.