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A two-terminal npn device based on 4H-SiC has been employed as a radiation detector for the first time. This device was designed as a vertical npn structure with a sensitive area of up to 1 cm2, and the thickness of the sensitive layer was about $30~\mu $ m. The detector exhibited a low dark current of $\sim ~0.12$ nA $\cdot $ cm $^{-{2}}$ with a fully depleted sensitive region at 200 V. The sensitivity of unit area of the detector achieved $36.67~\mu $ C $\cdot $ Gy $^{-{1}} \cdot $ cm $^{-{2}}$ ( $28.09~\mu $ A @ 0.766 Gy/s) to X-ray illumination (generated by bremsstrahlung with a tungsten target with tube voltage 30 kV) at 200 V, which was attributed to the amplification mechanism of the npn structure. Compared with the response characteristics of a SiC-PiN detector with the same sensitive volume, the gain of the two-terminal SiC npn detector was estimated to be 11.46 at 200 V. Specifically, the internal gain of the detector increased with the X-ray dose rate, where the X-ray photocurrent worked as the base current in the BJT devices. The internal gain also increased with the bias voltage due to the Early effect. Moreover, the two-terminal SiC npn detectors had a good switching response to X-rays and showed great potential in the applications of radiation detection.

Recently, the retained austenite (RA) with chemically heterogeneous has attracted great attention in medium Mn steel. In this work, we designed a two-step intercritical annealing (TIA) heat treatment process to prepare high-strength medium Mn steel with the chemical composition of Fe–0.20C–8.0Mn–1.6Si–1.3Al (wt.%). Compared with the normal intercritical annealing (IA) heat treatment process, the TIA process can not only increase the volume fraction of RA but also obtain the RA with inhomogeneous Mn distribution. Meanwhile, it was found that the Mn content on the outer side of this structured RA was higher than that on the inner side, forming a nanoscale Mn-enriched layer on the outer side of RA, which played a significant role in improving the stability of RA. Finally, we used the TIA process to obtain medium Mn steel with an ultimate tensile strength (UTS) of 1611.83 MPa, a total elongation (TE) of 45.02%, and a product of strength and elongation (PSE) of 72.56 GPa·%, which achieves a superior combination of high strength and high ductility in medium Mn steel.

Sleep loss is associated with cognitive dysfunction. However, the detailed mechanisms remain unclear. In this study, we established a para-chlorophenylalanine (PCPA)-induced insomniac mouse model with impaired cognitive function. Mass-spectrometry-based proteomics showed that the expression of 164 proteins was significantly altered in the hippocampus of the PCPA mice. To identify critical regulators among the potential markers, a transcriptome-wide association screening was performed in the BXD mice panel. Among the candidates, the expression of pleiotrophin (Ptn) was significantly associated with cognitive functions, indicating that Ptn-mediates sleep-loss-induced cognitive impairment. Gene co-expression analysis further revealed the potential mechanism by which Ptn mediates insomnia-induced cognitive impairment via the MAPK signaling pathway; that is, the decreased secretion of Ptn induced by insomnia leads to reduced binding to Ptprz1 on the postsynaptic membrane with the activation of the MAPK pathway via Fos and Nr4a1, further leading to the apoptosis of neurons. In addition, Ptn is genetically trans-regulated in the mouse hippocampus and implicated in neurodegenerative diseases in human genome-wide association studies. Our study provides a novel biomarker for insomnia-induced cognitive impairment and a new strategy for seeking neurological biomarkers by the integration of proteomics and systems genetics.

In recent years, researchers have developed many deep-learning-based methods to count crowd numbers in static images. However, much fewer works focus on video-based crowd counting, in which the critical challenge of temporal correlation has not been well explored. This paper proposes a Spatial-Temporal Graph Network (STGN) to achieve efficient and accurate crowd counting in videos via learning pixel-wise and patch-wise relations in local spatial-temporal domains. Specifically, we design a pyramid graph module to leverage multi-scale features. In each scale, we sequentially construct three graphs: spatial-temporal pixel graph, temporal patch graph, and spatial pixel graph, in which we apply the self-attention mechanism to capture pixel-wise relation, learn structure-aware relation, and aggregate local features, respectively. Furthermore, we propose spatial-aware channel-wise attention to effectively fuse multi-scale features. To demonstrate the effectiveness of the proposed method, we conduct experiments on five crowd counting datasets, including a large-scale video crowd dataset (FDST). Moreover, the proposed model is also applied in the vehicle counting dataset (TRANCOS). The results show that the proposed model outperforms existing spatial-temporal crowd counting models and achieves state-of-the-art. The code is available at https://github.com/wuzhe71/STGN

Objective: To explore the effect of dynamic changes in free triiodothyronine (FT3) level for predicting the 90 day prognosis of patients with hepatitis B virus–related acute-on-chronic liver failure (HBV-ACLF). Methods: The clinical data of 122 hospitalised patients with HBV-ACLF between September 2018 and January 2020 were collected and divided into a survival group (77 cases) and a death group (45 cases) according to the 90 day prognosis. We statistically analysed the characteristics of FT3 changes in the two groups of patients. Binary logistic regression one-way analysis was used to assess the degree of influence of each factor. The Kaplan–Meier survival curve and receiver operating characteristic curve were used to evaluate the effect of a single change in FT3 level difference (single △FT3) and the FT3 level change range (△FT3 range) in predicting the 90-day prognosis of patients. Results: There were only three types of changes in FT3 levels, which included 19 (15.6%) cases of continuous normal type, 35 (28.7%) cases of continuous decrease type and 68 (55.7%) cases of U-shaped change type. The difference in survival curves between the three types of patients was statistically significant (P< 0.001). Conclusion: The dynamic change type of FT3 is related to the disease severity and 90-day prognosis of patients with HBV-ACLF. The single FT3 value and FT3 range could be used as a predictive factor for the 90-day prognosis of patients with HBV-ACLF. These results have a degree of research value and are worth further exploration in the future.

Background: Elabela, a recently discovered hormonal peptide containing 32 amino acids, is a ligand for the apelin receptor. It can lower blood pressure and attenuate renal fibrosis. However, the clinicopathological relationship between Elabela level and renal damage caused by benign hypertension (BHT) and malignant hypertension (MHT) has not been elucidated. Therefore, we investigated the clinicopathological correlation between serum Elabela level and renal damage caused by BHT and MHT. Methods: The participants comprised 50 patients and 25 age-matched healthy adults. The 50 patients were separated into two groups: MHT (n= 25) and BHT groups (n= 25). We analyzed their medical histories, demographics, and clinical examinations, including physical and laboratory tests. Results: The results showed that serum Elabela level decreased gradually with a continuous increase in blood pressure from the healthy control group, BHT, to MHT. Moreover, Elabela levels negatively correlated with BMI (R=  − 0.27, P= 0.02), SBP (r=  − 0.64, P< 0.01), DBP (r=  − 0.58, P< 0.01), uric acid (r=  − 0.39, P< 0.01), bun (r=  − 0.53, P< 0.01), and Scr (r=  − 0.53 P< 0.01) but positively correlated with eGFR (r= 0.54, P< 0.01). Stepwise multivariate linear regression analysis showed that SBP was the variable most related to Elabela (t=  − 5.592, P< 0.01). Conclusions: Serum Elabela levels decreased in patients with hypertension, especially malignant hypertension, and has the potential to be a marker of hypertension-related kidney damage.

AbstractDiamond is an ultrawide bandgap semiconductor with excellent electronic and photonic properties, which has great potential applications in microelectronic and optoelectronic devices. As an allotrope of diamond, graphene also has many fantastic properties like diamond, which caught much attention in combing them together. In this work, a direct sp3-to-sp2conversion method was proposed to fabricate graphene layers on single crystal diamond by thermal treatment with Ni film catalyst. By optimizing the conversing conditions, a thin graphene layer with low sheet resistance was obtained on diamond. Based on this, an all-carbon sandwich structural graphene-diamond-graphene (GDG) detector was fabricated, which shows low dark current of 0.45 nA at 0.5 V μm−1applied electric field. The maximum sensitivity of this detector is obtained when the incident X-ray is 12 keV, with the value of 2.88 × 10−8C Gy−1. Moreover, the rise time and delay time of the GDG detector is about 1.2 and 22.8 ns, respectively, which are very close to that of diamond detector with Ti/Au electrode. The realization of the direct in-situsp3-to-sp2conversion on diamond shows a promising approach for fabricating diamond-based all-carbon electronic devices.

Aldo-keto reductase family 1 member C3 (AKR1C3) serves as a contributor to numerous kinds of tumors, and its expression is elevated in patients with hepatocellular carcinoma (HCC). However, the biological function of AKR1C3 in HCC remains unclear. Here we investigated the role of AKR1C3 in liver carcinogenesis using in vitro and in vivo models. We determined that AKR1C3 is frequently increased in HCC tissues with poor prognosis. Genetically manipulated cells with AKR1C3 construction were examined to highlight the pro-tumoral growth of both wild-type AKR1C3 and mutant in vitro and in vivo. We observed promising treatment effects of AKR1C3 shRNA by intratumoral injection in mice. Mechanically, we demonstrated that the transcription factor heterodimer NRF2/MAFG was able to bind directly to AKR1C3 promoter to activate its transcription. Further, AKR1C3 stabilized PARP1 by decreasing its ubiquitination, which resulted in HCC cell proliferation and low sensitivity of Cisplatin. Moreover, we discovered that the tumorigenic role of AKR1C3 was non-catalytic dependent and the NRF2/MAFG-AKR1C3-PARP1 axis might be one of the important proliferation pathways in HCC. In conclusion, blockage of AKR1C3 expression provides potential therapeutic benefits against HCC.

We explored the catalytic activity and magnetic resonance imaging (MRI) capacity of Cu-doped ultrasmall iron oxides with different doping ratios. Then, we screened a highly efficient ultrasmall active catalyst (UAC). Subsequently, a biodegradable magnetic nanoliposome was developed for multimodal cancer theranostics through pH-sensitive liposome coating of these UACs. Upon entering the body, the magnetic nanoliposomes significantly prolonged the metabolic time of UACs and promoted their accumulation in tumors. Then, the strong photothermal (PT) effect of the magnetic nanoliposome quickly ablated the tumor, showing promising PT therapy. Upon entering tumor cells, the magnetic nanoliposome rapidly degraded into many UACs and released chemotherapeutic drugs, contributing to chemotherapy. In addition, UACs not only catalyzed Fenton-type reaction to produce excessive reactive oxygen species (ROS) but also inhibited the synthesis of endogenous GSH by inactivating glutamyl cysteine ligase, contributing to cancer ferroptosis. Furthermore, the assembly-dissociation process of UACs showed the function of magnetic relaxation switches, significantly enhancing tumor MRI signal change, achieving a more accurate diagnosis of the tumor. Therefore, this magnetic nanoliposome splits into many UACs upon drug release and regulates the tumor microenvironment to overproduce ROS for enhanced synergistic tumor theranostics, which provides a strategy for developing next-generation magnetic catalysts with biodegradability and multimodal antitumor theranostics.

Background: There are arguments for individualized treatments and the necessity of non-invasive biomarkers for patients with IgA nephropathy (IgAN) according to gender, but the rationale remains unclear. We aimed to investigate the relationship between urine exosomal circular RNA (circRNA) levels, related genes, clinical features, and renal pathological features in IgA nephropathy patients of different genders. Methods: Clinicopathological data from patients of different genders from a multicenter cohort were retrospectively analyzed. We used the Oxford classification to examine the severity of pathological damage in these patients. We compared clinical features and renal pathologies between IgAN patients of different genders. Using findings of urine exosomal circRNAs from male IgAN patients, we analyzed the relationship between this factor, the regulated genes located on the sex chromosomes, and renal pathologies. Results: A total of 502 IgAN patients were included. The proportion of male patients with crescent formation was higher than that of females (p= 0.019). Multivariate logistic regression analysis showed that proteinuria was an independent marker for crescent formation in male and female patients with IgAN, while smoking and higher low-density lipoprotein cholesterol (LDL-C) levels were independent risk factors for crescent formation in males alone. Urine exosomal circRNA chrY:15478147-15481229- located on the Y chromosome in male patients was negatively correlated with the expressions of UTY in specific regions of the Y chromosome. Conclusion: Compared with female patients, males with IgAN had more severe renal dysfunction and a higher probability of glomerular crescent formation. Urine exosomal circRNA chrY:15478147-15481229- might participate in the pathogenesis of IgAN in male patients by altering UTY expressions. Graphic abstract:

Background: Evaluating the risk of metastasis and recurrence of a cervical cancer patient iscritical for appropriate adjuvant therapy. However, current risk assessment models usually involve thetesting of tens to thousands of genes from patients tissue samples, which is expensive and timeconsuming.Therefore, computer-aided diagnosis and prognosis prediction based on Hematoxylin and Eosin(H&E) pathological images have received much attention recently. Objective: The prognosis of whether patients will have metastasis and recurrence can support accuratetreatment for patients in advance and help reduce patient loss. It is also important for guiding treatmentafter surgery to be able to quickly and accurately predict the risk of metastasis and recurrence of a cervicalcancer patient. Methods: To address this problem, we propose a hybrid method. Transfer learning is used to extract features,and it is combined with traditional machine learning in order to analyze and determine whetherpatients have the risks of metastasis and recurrence. First, the proposed model retrieved relevant patchesusing a color-based method from H&E pathological images, which were then subjected to image preprocessingsteps such as image normalization and color homogenization. Based on the labeled patchedimages, the Xception model with good classification performance was selected, and deep features ofpatched pathological images were automatically extracted with transfer learning. After that, the extractedfeatures were combined to train a random forest model to predict the label of a new patched image.Finally, a majority voting method was developed to predict the metastasis and recurrence risk of a patientbased on the predictions of patched images from the whole-slide H&E image. Results: In our experiment, the proposed model yielded an area under the receiver operating characteristiccurve of 0.82 for the whole-slide image. The experimental results showed that the high-level featuresextracted by the deep convolutional neural network from the whole-slide image can be used to predictthe risk of recurrence and metastasis after surgical resection and help identify patients who might receiveadditional benefit from adjuvant therapy. Conclusion: This paper explored the feasibility of predicting the risk of metastasis and recurrence fromcervical cancer whole slide H&E images through deep learning and random forest methods.

Long noncoding RNAs are a group of more than 200 nt, nonprotein coding RNAs, some of which are dysregulated in many pathophysiological processes including endometriosis. This study aims to clarify the roles of dysregulated growth arrest‐specific 5 (GAS5) in patients with endometriosis, and unveil the underlying mechanisms. We obtained endometrium samples from 37 patients with endometriosis and 23 controls without endometriosis. Primary endometrial stromal cells (ESCs) and endothelial cells were separated from the endometrium. Levels of GAS5 were quantified using quantitative real‐time polymerase chain reaction, and levels of p27, cleaved caspase‐3, cleaved poly (ADP‐Ribose) polymerase 1, vascular endothelial growth factor A, tissue inhibitor of metalloproteinases 3 (TIMP3), and trypsin‐modified soy protein 10 were assessed by immunoblotting. Cell viability was examined using MTT assays, and the cell cycle and apoptosis were analyzed by flow cytometry. Endothelial cell tube formation capacity was assayed in vitro. GAS5 and p27 levels were found lower in the endometrium samples from patients with endometriosis. Primary ESCs from patients with endometriosis had increased viability, reduced apoptosis, and a relatively uncontrolled cell cycle. Gain‐ and loss‐of‐function studies confirmed that GAS5 regulated p27 expression in ESCs. Furthermore, GAS5 level was relatively low in primary endothelial cells from patients with endometriosis and GAS5 acted as an angiogenesis inhibitor by regulating the miR‐181c‐TIMP3 axis. Thus, lower GAS5 level in endometrium might be related to endometriosis by regulating cell proliferation, apoptosis, cell cycle, and angiogenesis.

Controlled release of pesticides by light regulation is one of the most viable strategies recently developed for the highly efficient utilization of agrochemicals. Herein, we report an infrared-light-responsive pesticide delivery system for the controlled release of imidacloprid (IMI) by preparation of functional hollow carbon microspheres (HCMs). After IMI loading and surface functionalization with polyethylene glycol (PEG) and α-cyclodextrin (α-CD), IMI was sequestered in the pesticide system (denoted as HCMs/IMI/PEG/α-CD) as a result of the formation of a PEG/α-CD gel network. Upon the irradiation of infrared light, HCMs with high photothermal conversion efficiency (42.8%) raised the local temperature effectively, leading to the collapse of the gel network and the release of IMI. In comparison to the amount of pesticide release (29%) under sunlight, it could reach 77% driven by infrared light, which was an intriguing improvement. Consequently, HCMs/IMI/PEG/α-CD under infrared light showed significantly higher pest control efficacy on corn borers by 125% than itself alone. This work provides a promising method to intentionally regulate pesticide release and enhance utilization efficiency.

Background: Microsatellite instability (MSI) is a prognostic biomarker used to guide medication selection in multiple cancers, such as colorectal cancer. Traditional PCR with capillary electrophoresis and next-generation sequencing using paired tumor tissue and leukocyte samples are the main approaches for MSI detection due to their high sensitivity and specificity. Currently, patient tissue samples are obtained through puncture or surgery, which causes injury and risk of concurrent disease, further illustrating the need for MSI detection by liquid biopsy. Methods: We propose an analytic method using paired plasma/leukocyte samples and MSI detection using next-generation sequencing technology. Based on the theoretical progress of oncogenesis, we hypothesized that the microsatellite site length in plasma equals the combination of the distribution of tumor tissue and leukocytes. Thus, we defined a window-judgement method to identify whether biomarkers were stable. Results: Compared to traditional PCR as the standard, we evaluated three methods in 20 samples (MSI-H:3/MSS:17): peak shifting method using tissue vs. leukocytes, peak shifting method using plasma vs. leukocytes, and our method using plasma vs. leukocytes. Compared to traditional PCR, we observed a sensitivity of 100%, 0%, and 100%, and a specificity of 100.00%, 94.12%, and 88.24%, respectively. Conclusion: Our method has the advantage of possibly detecting MSI in a liquid biopsy and provides a novel direction for future studies to increase the specificity of the method.

Theoretically, the Fenton catalytic efficiency of the Cu-based nanoplatform is approximately 160 times that of traditional Fe-based agents. However, the coordination interaction between Cu(ii) and intracellular GSH significantly inhibits the high catalytic activity of Cu(i) generation, dramatically decreasing the Fenton-like catalytic efficiency. Herein, we designed a completely new and highly efficient hierarchical structural nanoplatform to enhance the mimic-peroxidase activity through utilizing comproportionation between CuO and elemental Cu core to self-supply Cu(i). The catalytic rate of this nanoplatform was approximately 55-fold that of traditional Fe-based agents. In a cell assay, this nanoplatform could function as an antagonist of GPX4 and agonist of SOD-1, resulting in intracellular ROS and H2O2accumulation. Next, the accumulated H2O2could be quickly catalyzed to highly toxic OH by self-supplying Cu(i), causing strong oxidative stress damage to mitochondria and cell membranes. Under 808 nm laser irradiation, this nanoplatform exhibited a stronger inhibition of tumor growth, and effectively overcame the tumor resistance and recurrence. In addition, this hierarchical structure significantly promoted the interaction between water molecules and gadolinium centers, making TRF-mCuGd possess an ultrahigh T1MRI contrast performance, and hence, more pathological information of the tumor could be achieved. Overall, this work provides a promising pattern for the design and development of cancer theranostics.

The proteasome mediates most selective protein degradation. Proteolysis occurs within the 20S core particle (CP), a barrel-shaped chamber with an α7β7β7α7configuration. CP biogenesis proceeds through an ordered multistep pathway requiring five chaperones, Pba1–4 and Ump1. Using Saccharomycescerevisiae, we report high-resolution structures of CP assembly intermediates by cryogenic-electron microscopy. The first structure corresponds to the 13S particle, which consists of a complete α-ring, partial β-ring (β2–4), Ump1 and Pba1/2. The second structure contains two additional subunits (β5–6) and represents a later pre-15S intermediate. These structures reveal the architecture and positions of Ump1 and β2/β5 propeptides, with important implications for their functions. Unexpectedly, Pba1’s N terminus extends through an open CP pore, accessing the CP interior to contact Ump1 and the β5 propeptide. These results reveal how the coordinated activity of Ump1, Pba1 and the active site propeptides orchestrate key aspects of CP assembly.

Background: Thymidylate Synthase (TS) is an important target for folic acid inhibitors such as pemetrexed, which has considerable effects on the first-line treatment, second-line treatment and maintenance therapy for patients with late-stage Non-Small Cell Lung Cancer (NSCLC). Therefore, detecting mutations in the TYMS gene encoding TS is critical in clinical applications. With the development of Next-Generation Sequencing (NGS) technology, the accuracy of TYMS mutation detection is getting higher and higher. However, traditional methods suffer from false positives and false-negatives caused by factors like limited sequencing read length and sequencing errors. Objective: A method was needed to overcome the short sequencing read length and sequencing errors of NGS to make the detection of TYMS more accurate. Methods: In this study, we developed a novel method based on "Paired Seed Sequence Distance” (PSSD) to detect the Variable Number of Tandem Repeat (VNTR) mutation for TYMS. Results: With the 121 samples validated by sanger, the consistency rate of PSSD method was 85.95% (104/121), higher than the strict matching method (78.51% (95/121)). The consistency rate of the two methods was 89.26% (108/121). We also found that the PSSD method was significantly better than the strict matching method, especially in the 4R typing. Conclusion: Our method not only improves the detection rate and accuracy of TYMS VNTR mutations but also avoids problems caused by sequencing errors and limited sequencing length. This method provides a new solution for similar polymorphism analyses and other sequencing analyses.

Background: Identification of genomic markers using NGS (next-generation sequencing) technology would be valuable for guiding precision medicine treatments for pancreatic cancers. Traditional somatic mutation methods require both tumor and matched non-tumor samples. However, only tumor samples are available mostly, especially in retrospective studies. In this study, we tried to analyze the associations between clinical features and oncogenic somatic mutations in genome-wide tumor-only samples. Methods: Fifty-four tumor-only samples derived from pancreatic cancer patients were used for whole-exome sequencing. An approach involving SNP filtering of variants included in the Catalogue of Somatic Mutations in Cancer (COSMIC) database was used to identify oncogenic somatic mutations. The relationships between oncogenic mutations and clinical features were analyzed and simultaneously compared with those from the TCGA database. Results: By analyzing the mutations from tumor only samples, divergent mutation profiles were observed in different locations (head vs. body/tail) of pancreatic tumors. The divergences between pancreatic head and body/tail cancers were also confirmed by the TCGA data. Furthermore, mutations of several genes were found to be significantly associated with clinical features, such as pathological stage and the degree of tumor differentiation. Conclusion: The results confirmed the efficiency of our approach in identifying oncogenic somatic mutations from tumor only samples and revealed the associations between somatic mutations and clinical features in pancreatic cancer.

Situated in China’s Great Leap Forward (GLF) campaign in 1958, this study examines the spatial diffusion of “launching high-yield satellites”—exaggerating grain yields, which contributed to the 1959–61 GLF famine that claimed millions of human lives. The authors conceptualize exaggerating grain yields as a political innovation adopted by local cadres to endorse the GLF and signal political loyalty to their superiors. Using geocoded county-level event history data from historical newspaper archives, the authors found that the diffusion of exaggerating grain yields across the country was primarily driven by the interaction between geographic proximity and political proximity.

Background: Breast cancer is a complex disease with high prevalence in women, the molecular mechanisms of which are still unclear at present. Most transcriptomic studies on breast cancer focus on differential expression of each gene between tumor and the adjacent normal tissues, while the other perturbations induced by breast cancer including the gene regulation variations, the changes of gene modules and the pathways, which might be critical to the diagnosis, treatment and prognosis of breast cancer are more or less ignored. Objective: We presented a complete process to study breast cancer from multiple perspectives, including differential expression analysis, constructing gene co-expression networks, modular differential connectivity analysis, differential gene connectivity analysis, gene function enrichment analysis key driver analysis. In addition, we prioritized the related anti-cancer drugs based on enrichment analysis between differential expression genes and drug perturbation signatures. Methods: The RNA expression profiles of 1109 breast cancer tissue and 113 non-tumor tissues were downloaded from The Cancer Genome Atlas (TCGA) database. Differential expression of RNAs was identified using the “DESeq2” bioconductor package in R, and gene co-expression networks were constructed using the weighted gene co-expression network analysis (WGCNA). To compare the module changes and gene co-expression variations between tumor and the adjacent normal tissues, modular differential connectivity (MDC) analysis and differential gene connectivity analysis (DGCA) were performed. Results: Top differential genes like MMP11 and COL10A1 were known to be associated with breast cancer. And we found 23 modules in the tumor network had significantly different co-expression patterns. The top differential modules were enriched in Goterms related to breast cancer like MHC protein complex, leukocyte activation, regulation of defense response and so on. In addition, key genes like UBE2T driving the top differential modules were significantly correlated with the patients’ survival. Finally, we predicted some potential breast cancer drugs, such as Eribulin, Taxane, Cisplatin and Oxaliplatin. Conclusion: As an indication, this framework might be useful in understanding the molecular pathogenesis of diseases like breast cancer and inferring useful drugs for personalized medication.

Although the roles of the Hippo pathway in organogenesis and tumorigenesis have been well studied in multiple organs, its role in sperm maturation and male fertility has not been investigated. The initial segment (IS) of the epididymis plays a critical role in sperm maturation. IS differentiation is governed by ERK1/2, but the mechanisms of ERK1/2 activation in IS are not fully understood. Here we show that double knockout (dKO) of mammalian sterile 20-like kinases 1 and 2 (Mst1 and Mst2), homologs of Hippo in Drosophila, in the epididymal epithelium led to male infertility in mice. Sperm in the cauda epididymides of mutant mice were immotile with flagellar angulation and severely disorganized structures. Loss of Mst1/2 activated YAP and increased proliferation and cell death in all the segments of epididymis. The mutant mice showed substantially suppressed MEK/ERK signaling in the IS and failed IS differentiation. Deletion of Yap restored the reduced MEK/ERK signaling, and partially rescued the defective IS differentiation and fertility in Mst1/2 dKO mice. Our results demonstrate that YAP inhibits the MEK/ERK pathway in IS epithelial cells, and MST1/2 control IS differentiation and fertility at least partially by repressing YAP. Taken together, the Hippo pathway is essential for sperm maturation and male fertility.

This work finds that Fe3O4nanoclusters can rearrange by Gd doping and then self-assemble to a hollow magnetic nanocluster (HMNC), providing larger magnetic moments to obtain an excellent MRI capability and increasing the number of oxygen vacancies in HMNC. The hollow structure makes platinum(IV) prodrugs effectively load into HMNC. Second, plenty of oxygen vacancy defects can capture oxygen molecules, enhance the catalytic activity of HMNC, and then promote intracellular ROS generation. On the basis of this, a targeting iRGD-labeled HMNC nanosystem (iHMNCPt-O2) is developed through loading oxygen molecules and platinum(IV) prodrugs for chemo- and chemodynamic therapy of cancer. This nanosystem shows an excellent response ability to weak acid and GSH, which can cause a series of cascade reactions in a cell. These cascade reactions are dramatically enhanced at the intracellular ROS level, cause mitochondria and DNA damage, and then induce cancer cell death. Besides, systemic delivery of iHMNCPt-O2significantly enhanced the MRI contrast signal of tumors and improved the quality of MR images, accurately diagnosing tumors. Therefore, this work provides a novel method for accelerating the Fenton-like reaction and enhancing the MRI capability and fabricates a promising “all-in-one” system to overwhelm the problems of cancer theranostic.

ABSTRACTSingle-cell RNA sequencing (scRNA-seq) technologies allow numerous opportunities for revealing novel and potentially unexpected biological discoveries. scRNA-seq clustering helps elucidate cell-to-cell heterogeneity and uncover cell subgroups and cell dynamics at the group level. Two important aspects of scRNA-seq data analysis were introduced and discussed in the present review: relevant datasets and analytical tools. In particular, we reviewed popular scRNA-seq datasets and discussed scRNA-seq clustering models including K-means clustering, hierarchical clustering, consensus clustering, and so on. Seven state-of-the-art scRNA clustering methods were compared on five public available datasets. Two primary evaluation metrics, the Adjusted Rand Index (ARI) and the Normalized Mutual Information (NMI), were used to evaluate these methods. Although unsupervised models can effectively cluster scRNA-seq data, these methods also have challenges. Some suggestions were provided for future research directions.

Background: Ultrasound test is one of the routine tests for the diagnosis of thyroid cancer. The diagnosis accuracy depends largely on the correct interpretation of ultrasound images of thyroid nodules. However, human eye-based image recognition is usually subjective and sometimes error-prone especially for less experienced doctors, which presents a need for computeraided diagnostic systems. Objective: To our best knowledge, there is no well-maintained ultrasound image database for the Chinese population. In addition, though there are several computational methods for image-based thyroid cancer detection, a comparison among them is missing. Finally, the effects of features like the choice of distance measures have not been assessed. The study aims to give the improvement of these limitations and proposes a highly accurate image-based thyroid cancer diagnosis system, which can better assist doctors in the diagnosis of thyroid cancer. Methods: We first establish a novel thyroid nodule ultrasound image database consisting of 508 images collected from the Third Hospital of Hebei Medical University in China. The clinical information for the patients is also collected from the hospital, where 415 patients are diagnosed to be benign and 93 are malignant by doctors following a standard diagnosis procedure. We develop and apply five machine learning methods to the dataset including deep neural network, support vector machine, the center clustering method, k-nearest neighbor, and logistic regression. Results: Experimental results show that deep neural network outperforms other diagnosis methods with an average cross-validation accuracy of 0.87 in 10 runs. Meanwhile, we also explore the performance of four image distance measures including the Euclidean distance, the Manhattan distance, the Chebyshev distance, and the Minkowski distance, among which the Chebyshev distance is the best. The resource can be directly used to aid doctors in thyroid cancer diagnosis and treatment. Conclusions: The paper establishes a novel thyroid nodule ultrasound image database and develops a high accurate image-based thyroid cancer diagnosis system which can better assist doctors in the diagnosis of thyroid cancer.

To develop a quality consistency evaluation strategy for traditional Chinese medicine (TCM) granules using sugar free Yangwei Granules as a model drug, and demonstrate the effectiveness of the developed method.

In order to solve the solidification microstructure of Zn-1.7Al-1.1Mg alloy on the surface of steel plate during hot dip plating, the solidification path and microstructure of Zn-1.7Al-1.1Mg alloy were studied by Thermo-Calc thermodynamic software, differential thermal analysis (DSC) and scanning electron microscopy (SEM). The results show that during cooling from melting to room temperature, Zn-1.7Al-1.1Mg alloy begins to precipitate Zn-rich η phase at 386.5 °C, binary eutectic structure consisting of η phase and Mg2Zn11at 350.0 °C, and ternary eutectic structure consisting of η phase, Al-rich metastable β phase and Mg2Zn11at 343.4 °C,at 276.7 °C, β phase transforms into stable aluminum-rich α and η phases.

Deposition of dopamine and tannic acid has received great attention in the fields of surface and interface science and technology. The deposition behaviors of various metal–phenolic systems have been investigated, and it is generally accepted that at least one catechol group is essential to the formation of the coatings. Herein, we report a novel and effective surface-coating system based on the coordination complexes of FeIIIions with a natural product juglone that contains only one phenolic hydroxyl. We investigated the deposition behaviors of this novel system on various substrates. Microporous polypropylene membrane modified with juglone/FeIIIcoatings is superhydrophilic and underwater superoleophobic, showing high separation efficiency and good reusability for various oil/water emulsions. In addition, the modified membrane can adsorb anionic dyes and selectively remove them from dye mixtures with high efficiency. We further demonstrated that the coating is a result of the synergetic effect of juglone/FeIIIcoordination and FeIIIhydrolysis. This work not only provides new insights into surface deposition systems but also expands the polyphenol family for surface coatings of multifunctional materials.

BackgroundEarly detection of lung cancer to allow curative treatment remains challenging. Cell-free circulating tumour (ct) DNA (ctDNA) analysis may aid in malignancy assessment and early cancer diagnosis of lung nodules found in screening imagery.MethodsThe multicentre clinical study enrolled 192 patients with operable occupying lung diseases. Plasma ctDNA, white cell count genomic DNA (gDNA) and tumour tissue gDNA of each patient were analysed by ultra-deep sequencing to an average of 35 000× of the coding regions of 65 lung cancer-related genes.ResultsThe cohort consists of a quarter of benign lung diseases and three quarters of cancer patients with all histopathology subtypes. 64% of the cancer patients are at stage I. Gene mutations detection in tissue gDNA and plasma ctDNA results in a sensitivity of 91% and specificity of 88%. When ctDNA assay was used as the test, the sensitivity was 69% and specificity 96%. As for the lung cancer patients, the assay detected 63%, 83%, 94% and 100%, for stages I, II, III and IV, respectively. In a linear discriminant analysis, combination of ctDNA, patient age and a panel of serum biomarkers boosted the overall sensitivity to 80% at a specificity of 99%. 29 out of the 65 genes harboured mutations in the patients with lung cancer with the largest number found in TP53(30% plasma and 62% tumour tissue samples) and EGFR(20% and 40%, respectively).ConclusionPlasma ctDNA was analysed in lung nodule assessment and early cancer detection, while an algorithm combining clinical information enhanced the test performance.Trial registration numberNCT03081741.

Objective:The aim of this research was to probe the effect of isobavachalcone inhibiting the high-fat diet (HFD) and streptozotocin (STZ) induced hyperglycemia and hyperlipemia in mice and its underlying mechanisms. Methods:A mouse model with type 2 diabetes mellitus (T2DM) was established by the HFD and low-dose streptozotocin. T2DM mice were treated with 10 mg/kg of isobavachalcone for 4 weeks. The levels of fasting blood glucose (FBG), blood lipids, and relative proteins in the PI3K/AKT signaling pathway as well as the histological structural changes in the liver were determined. Results:The results showed that the expression levels of FBG (42%, P< .001), triglyceride (70%, P< .001), and glucose transporter 2 were significantly reduced by isobavachalcone. The proteinic and mRNA expressions of IRS1, PI3K, and AKT genes of T2DM mice were dramatically increased with the isobavachalcone treatment. Furthermore, isobavachalcone ameliorated the morphology of the liver in T2DM model mice. Conclusion:The results suggested that isobavachalcone controls the development of T2DM as well as the regulatory mechanism involved in glucose and lipid metabolism through the PI3K/AKT signal pathway in the liver.

In this work, a near-infrared probe-based confocal microendoscope (pCM) with a 785 nm laser source, a long working distance, and a probe with diameter of 2.6 mm that can be compatible with a conventional endoscope is demonstrated to produce deep-tissue images at cellular resolutions with enhanced contrast and signal-to-noise ratio. Theoretical simulations and experiments confirm that near-infrared light can optimize the image quality. Abundant details of mouse esophagus obtained at different depths demonstrate the system’s ability to image deep tissues at cellular resolutions, which makes it possible to diagnose diseases in the digestive tract in real time, laying a solid foundation for clinical applications.

Transgenic adenocarcinoma of the mouse prostate (TRAMP) mice is a widely used transgenic animal model of prostate cancer (PCa). We performed a label-free quantitative proteomics analysis combined with a bioinformatics analysis on the entire prostate protein extraction from TRAMP mice and compared it with WT littermates. From 2379 total identified proteins, we presented a modest mice prostate reference proteome containing 919 proteins. 61 proteins presented a significant expression difference between two groups. The integrative bioinformatics analysis predicted the overexpression of platelet-derived growth factor B (PDGF-B) in tumor tissues and supports the hypothesis of the PDGF-B signaling network as a key upstream regulator in PCa progression. Furthermore, we demonstrated that Crenolanib, a novel PDGF receptor inhibitor, inhibited PCa cell proliferation in a dose-dependent manner. Finally, we revealed the importance of PDGF-B regulatory network in PCa progression, which will assist us in understanding the role and mechanisms of PDGF-B in promoting cancer growth and provide valuable knowledge for future research on anti-PDGF therapy.

In this study, a novel phoswich detector for beta–gamma coincidence detection is designed. Unlike the triple crystal phoswich detector designed by researchers at the University of Missouri, Columbia, this phoswich detector is of the semi-well type, so it has a higher detection efficiency. The detector consists of BC-400 and NaI:Tl with decay time constants of 2.4 and 230 ns, respectively. The BC-400 scintillator detects beta particles, and the NaI:Tl cell is used for gamma detection. Geant4 simulations of this phoswich detector find that a 2-mm-thick BC-400 scintillator can absorb nearly all of the beta particles whose energies are below 700 keV. Further, for a 2.00-cm-thick NaI:Tl crystal, the gamma source peak efficiency for photons ranges from a maximum of nearly 90% at 30 keV to 10% at 1 MeV. The self-absorption effect is also discussed in this paper in order to determine the carrier gas’s influence.

The first domestic inorganic scintillator, Cs2LiYCl6:Ce3+(CLYC), was grown at Beijing Glass Research Institute using the vertical Bridgman method. In this work, we evaluated the performance of this new CLYC crystal in terms of its gamma-ray energy resolution and pulse shape discrimination (PSD) capability between neutrons and gamma rays. The decay times associated with different scintillation mechanisms were obtained by fitting decay functions to the neutron and gamma-ray waveform structures. We found an energy resolution of ~ 4.5% for 662-keV gamma rays and efficient neutron/gamma PSD with a figure of merit of ~ 2.6. Under gamma-ray excitation, there is an ultrafast scintillation mechanism in CLYC with a decay time of approximately 2 ns, whereas there is no evidence of ultrafast decay under thermal neutron excitation. This work contributes to the promotion of domestic development of CLYC.

N6-methyladenosine (m6A) modification controls cell fate determination. Here, we show that liquid-liquid phase separation (LLPS) of YTH N6-methyladenosine RNA binding protein 1 (YTHDF1), a pivotal m6A “reader” protein, promotes the transdifferentiation of spermatogonial stem cells (SSCs) into neural stem cell-like cells by activating the IκB-nuclear factor κB (NF-κB)-CCND1 axis. The inhibition of IκBα/βmRNA translation mediated by YTHDF1 LLPS is the key to the activation of the IκB-NF-κB-CCND1 axis. Disrupting either YTHDF1 LLPS or NF-κB activation inhibits transdifferentiation efficiency. Moreover, overexpression of the YTH domain of YTHDF1 inhibits the activation of the IκB-NF-κB-CCND1 axis by promoting IκBα/βmRNA translation. Overexpression of the tau-YTH fusion protein reactivates IκB-NF-κB-CCND1 axis by inhibiting the translation of IκBα/βmRNAs, and tau LLPS is observed, which can restore transdifferentiation efficiency. Our findings demonstrate that the protein-RNA LLPS plays essential roles in cell fate transition and provide insights into translational medicine and the therapy of neurological diseases.