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PurposeNoninvasively assessing the tumor biology and microenvironment before treatment is greatly important, and glypican-3 (GPC-3) is a new-generation immunotherapy target for hepatocellular carcinoma (HCC). This study investigated the application value of a nomogram based on LI-RADS features, quantitative contrast-enhanced MRI parameters and clinical indicators in the noninvasive preoperative prediction of GPC-3 expression in HCC.Methods and materialsWe retrospectively reviewed 127 patients with pathologically confirmed solitary HCC who underwent Gd-EOB-DTPA MRI examinations and related laboratory tests. Quantitative contrast-enhanced MRI parameters and clinical indicators were collected by an abdominal radiologist, and LI-RADS features were independently assessed and recorded by three trained intermediate- and senior-level radiologists. The pathological and immunohistochemical results of HCC were determined by two senior pathologists. All patients were divided into a training cohort (88 cases) and validation cohort (39 cases). Univariate analysis and multivariate logistic regression were performed to identify independent predictors of GPC-3 expression in HCC, and a nomogram model was established in the training cohort. The performance of the nomogram was assessed by the area under the receiver operating characteristic curve (AUC) and the calibration curve in the training cohort and validation cohort, respectively.ResultsBlood products in mass, nodule-in-nodule architecture, mosaic architecture, contrast enhancement ratio (CER), transition phase lesion-liver parenchyma signal ratio (TP-LNR), and serum ferritin (Fer) were independent predictors of GPC-3 expression, with odds ratios (ORs) of 5.437, 10.682, 5.477, 11.788, 0.028, and 1.005, respectively. Nomogram based on LI-RADS features (blood products in mass, nodule-in-nodule architecture and mosaic architecture), quantitative contrast-enhanced MRI parameters (CER and TP-LNR) and clinical indicators (Fer) for predicting GPC-3 expression in HCC was established successfully. The nomogram showed good discrimination (AUC of 0.925 in the training cohort and 0.908 in the validation cohort) and favorable calibration. The diagnostic sensitivity and specificity were 76.9% and 92.3% in the training cohort, 76.8% and 93.8% in the validation cohort respectively.ConclusionThe nomogram constructed from LI-RADS features, quantitative contrast-enhanced MRI parameters and clinical indicators has high application value, can accurately predict GPC-3 expression in HCC and may help noninvasively identify potential patients for GPC-3 immunotherapy.

Abstract Background Traditional CRISPR/Cas9 systems that rely on U6 or U3 snRNA promoters (RNA polymerase III-dependent promoters) can only achieve constitutive gene editing in plants, hampering the functional analysis of specifically expressed genes. Ribozyme-mediated CRISPR/Cas9 systems increase the types of promoters which can be used to transcribe sgRNA. Therefore, such systems allow specific gene editing; for example, transcription of the artificial gene Ribozyme-sgRNA-Ribozyme (RGR) is initiated by an RNA polymerase II-dependent promoter. Genetic transformation is indispensable for editing plant genes. In certain plant species, including pyrethrum, genetic transformation remains challenging to do, limiting the functional verification of novel CRISPR/Cas9 systems. Thus, this study’s aim was to develop a simple Agrobacterium rhizogenes-mediated hairy root transformation system to analyze the function of a ribozyme-mediated CRISPR/Cas9 system in pyrethrum. Results A hairy root transformation system for pyrethrum is described, with a mean transformation frequency of 7%. Transgenic hairy roots transformed with the pBI121 vector exhibited significantly increased beta-glucuronidase staining as a visual marker of transgene expression. Further, a ribozyme-based CRISPR/Cas9 vector was constructed to edit the TcEbFS gene, which catalyzes synthesis of the defense-related compound (E)-β-farnesene in pyrethrum. The vector was transferred into the hairy roots of pyrethrum and two stably transformed hairy root transgenic lines obtained. Editing of the TcEbFS gene in the hairy roots was evaluated by gene sequencing, demonstrating that both hairy root transgenic lines had DNA base loss at the editing target site. Gas chromatography–mass spectrometry showed that the (E)-β-farnesene content was significantly decreased in both hairy root transgenic lines compared with the empty vector control group. Altogether, these results show that RGR can be driven by the CaMV35S promoter to realize TcEbFS gene editing in pyrethrum hairy roots. Conclusion An A. rhizogenes-mediated hairy root transformation and ribozyme-mediated CRISPR/Cas9 gene editing system in pyrethrum was established, thereby facilitating gene editing in specific organs or at a particular developmental stage in future pyrethrum research.

Abstract Background Recent studies show that human gut microbial composition can determine whether a patient is a responder or non-responder to immunotherapy but have not identified a common microbial signal shared by responding patients. The functional relationship between immunity, intestinal microbiota, and NSCLC response to immune checkpoint inhibitor/inhibition (ICI) in an American cohort remains unexplored. Methods RNAlater-preserved fecal samples were collected from 65 pre-treatment (baseline) and post-treatment stage III/IV NSCLC patients undergoing ICI therapy, categorized as responders or non-responders according to RECIST criteria. Pooled and individual responder and non-responder microbiota were transplanted into a gnotobiotic mouse model of lung cancer and treated with ICIs. 16S rDNA and RNA sequencing was performed on patient fecal samples, 16S rDNA sequencing on mouse fecal samples, and flow cytometric analysis on mouse tumor tissue. Results Responder patients have both a different microbial community structure than non-responders (P = 0.004) and a different bacterial transcriptome (PC2 = 0.03) at baseline. Taxa significantly enriched in responders include amplicon sequence variants (ASVs) belonging to the genera Ruminococcus, Akkermansia, and Faecalibacterium. Pooled and individual responder microbiota transplantation into gnotobiotic mice decreased tumor growth compared to non-responder colonized mice following ICI (P = 0.023, P = 0.019, P = 0.008, respectively). Responder tumors showed an increased anti-tumor cellular phenotype following ICI treatment. Responder mice are enriched with ASVs belonging to the genera Bacteroides, Blautia, Akkermansia, and Faecalibacterium. Overlapping taxa mapping between human and mouse cohorts correlated with tumor size and weight revealed a network highlighting responder-associated ASVs belonging to the genera Colidextribacter, Frisingicoccus, Marvinbryantia, and Blautia which have not yet been reported. Conclusions The role of isolate-specific function and bacterial gene expression in gut microbial-driven responsiveness to ICI has been underappreciated. This work supports further investigation using isolate-driven models to characterize the mechanisms underlying this phenomenon.

Non-small cell lung cancer (NSCLC) is one of the principal causes of death worldwide. The disease is often diagnosed late, at the stage of metastasis, which leads to a poor prognosis. With currently available treatment, most patients experience relapse and drug resistance. This study aimed to determine the potential role of insulin growth factor-like family member 1 (IGFL1) in lung adenocarcinoma (LUAD). We analyzed the expression of IGFL1 using TIMER, UALCAN, and GEPIA. The association of IGFL1 expression with symptoms and overall survival (OS) in LUAD patients was evaluated using a tissue microarray (TMA). Moreover, A549 and H1299 cells with selective IGFL1 knockdown were used to observe their proliferation and apoptosis in vitro. From the TIMER, UALCAN and GEPIA databases, we found that IGFL1 was upregulated in LUAD (p < 0.001). The level of promoter methylation in IGFL1 was significantly downregulated in LUAD and patient groups with different gender. Similar results were obtained in UALCAN. The semi-quantitative analysis revealed that IGFL1 expression is correlated with TNM stage (p < 0.001) and tumor size (p < 0.001) in TMA. High levels of IGFL1 expression were associated with poor OS (p < 0.05). Functional tests in A549 and H1299 cells showed that knocking down the expression of IGFL1 inhibited proliferation and enhanced apoptosis. Our study revealed the potential utility of IGFL1 as a predictive biomarker, which may play a biological role by regulating the proliferation and apoptosis of tumor cells.

Echinochloa is an important genus in the grass family as many of them are either problematic weeds or domesticated millets. Here, the authors assemble three polyploidy genomes in this genus using the diploid-assisted scaffolding method DipHic and provide genomic insights into the dual roles of some species as weeds and orphan crops.

Cellular senescence is a dynamic process driven by epigenetic and genetic changes. Although some transcriptomic signatures of senescent cells have been discovered, how these senescence-related signals change over time remains largely unclear. Here, we profiled the transcriptome dynamics of human dermal fibroblast (HDF) cells in successive stages of growth from proliferation to senescence. Based on time-series expression profile analysis, we discovered four trajectories (C1, C2, C3, C4) that are dynamically expressed as senescence progresses. While some genes were continuously up-regulated (C4) or down-regulated (C2) with aging, other genes did not change linearly with cell proliferation, but remained stable until entering the senescent state (C1, C3). Further analysis revealed that the four modes were enriched in different biological pathways, including regulation of cellular senescence. These findings provide a new perspective on understanding the dynamic regulatory mechanism of cellular senescence.

For semantic segmentation of remote sensing images (RSI), trade-off between representation power and location accuracy is quite important. How to get the trade-off effectively is an open question, where current approaches of utilizing very deep models result in complex models with large memory consumption. In contrast to previous work that utilizes dilated convolutions or deep models, we propose a novel two-stream deep neural network for semantic segmentation of RSI (RSI-Net) to obtain improved performance through modeling and propagating spatial contextual structure effectively and a decoding scheme with image-level and graph-level combination. The first component explicitly models correlations between adjacent land covers and conduct flexible convolution on arbitrarily irregular image regions by using graph convolutional network, while densely connected atrous convolution network (DenseAtrousCNet) with multi-scale atrous convolution can expand the receptive fields and obtain image global information. Extensive experiments are implemented on the Vaihingen, Potsdam and Gaofen RSI datasets, where the comparison results demonstrate the superior performance of RSI-Net in terms of overall accuracy (91.83%, 93.31% and 93.67% on three datasets, respectively), F1 score (90.3%, 91.49% and 89.35% on three datasets, respectively) and kappa coefficient (89.46%, 90.46% and 90.37% on three datasets, respectively) when compared with six state-of-the-art RSI semantic segmentation methods.

MDA5 is the primary immune sensor for SARS-CoV-2 and many other viruses. Mutations in MDA5 can cause disease. Here the authors employ CryoEM and biochemical methods to show how steric constraints cause MDA5 to misrecognize endogenous RNA as viral RNA.

Nature-inspired gradients can be implemented in metallic materials to achieve a synergy of strength and ductility. However, due to the small (often microscale) size of the gradient structured samples, their fracture properties have remained relatively unexplored. By fabricating centimeter-sized gradient-structured pure nickel samples using direct-current electroplating technique, we demonstrate that a dual-gradient architecture in pure nickel, comprising grain-size transitions from coarse grains to nano grains and then back to coarse grains (CG→NG→CG), achieves an optimized combination of strength-ductility synergy and exceptional fracture resistance – a crack-initiation toughness exceeding 300 MPa m½ – while minimizing the problem of final unstable catastrophic failure. Significantly, this dual-gradient CG→NG→CG structure can effectively arrest any brittle fracture in the nano grains by inducing a stable rising R-curve with an enhanced crack-growth toughness exceeding 350 MPa m½. We believe that this dual-gradient CG→NG→CG structure provides a promising prototype for designing multi-layer graded structures with exceptional combinations of mechanical properties which can be readily tuned to meet the advanced requirements of safety-critical applications.

Abstract Background Pulmonary tuberculosis (PTB) remains the world’s deadliest infectious killer. Serum CA-125 test are useful in the diagnosis of PTB. Although studies on the relation between CA-125 and PTB have been reported, the specificity and sensitivity of serum CA-125 in diagnosing PTB vary widely among different studies. The present study was performed to evaluate the accuracy of CA-125 for the diagnosis of PTB via a meta-analysis of data obtained from previous studies. Methods English and Chinese medical electronic databases were searched for eligible studies published up to February 2020. STATA software was used to obtain a pooled estimation of the diagnostic accuracy of CA-125 and analyze the heterogeneity of the recruited studies. Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) was used to evaluate the quality of the obtained studies. Results A total of 16 articles were included in this study. The pooled sensitivity and specificity of CA-125 were 0.85 [95% confidence interval (CI) 0.75–0.91] and 0.87 (95% CI 0.78–0.93), respectively. Moreover, the pooled positive likelihood ratio (LR+), negative likelihood ratio (LR−), and diagnostic odds ratio (DOR) of CA-125 were 6.65 (95% CI 3.62–12.20), 0.18 (95% CI 0.10–0.31), and 37.82 (95% CI 13.17–108.60), respectively. The area under the summary receiver operating characteristic curve (AUC) was 0.93. Conclusions Taken together, the results indicate that serum CA-125 presents potential practical value for diagnosing PTB, but its clinical applicability must be further examined.

ABSTRACT During eukaryotic evolution, the TOR-AGC kinase signaling module is involved in the coordinated regulation of cell growth and survival. However, the AGC kinases in plant-pathogenic fungi remain poorly understood. In this study, we have identified 20 members of the AGC family of protein kinases. Evolutionary and biological studies have revealed that AGC kinases are highly conserved and involved in the growth (8 genes), conidiation (13 genes), conidial germination (9 genes), appressorium formation (9 genes), and pathogenicity (5 genes) of Magnaporthe oryzae, in which a subfamily protein of the AGC kinases, MoFpk1, the activator of flippase, specifically exhibited diverse roles. Two kinase sites were screened and found to be critical for MoFpk1: 230K and 326D. Moreover, MoFpk1 is involved in cell wall integrity through the negative regulation of MoMps1 phosphorylation. The deletion of MoFpk1 resulted in defective phosphatidylacetamide (PE) and phosphatidylserine (PS) turnover and a series of lipid metabolism disorders. Under hyperosmotic stress, since the ΔMofpk1 mutant is unable to maintain membrane asymmetry, MoYpk1 phosphorylation and MoTor activity were downregulated, thus enhancing autophagy. Our results provide insights into the evolutionary and biological relationships of AGC kinases and new insight into plasma membrane (PM) homeostasis, i.e., responses to membrane stress and autophagy through lipid asymmetry maintenance. IMPORTANCE Our identification and analysis of evolutionary and biological relationships provide us with an unprecedented high-resolution view of the flexible and conserved roles of the AGC family in the topmost fungal pathogens that infect rice, wheat, barley, and millet. Guided by these insights, an AGC member, MoFpk1, was found to be indispensable for M. oryzae development. Our study defined a novel mechanism of plasma membrane homeostasis, i.e., adaptation to stress through the asymmetric distribution of phospholipids. Furthermore, defects in the asymmetric distribution of phospholipids in the membrane enhanced autophagy under hyperosmotic stress. This study provides a new mechanism for the internal linkage between lipid metabolism and autophagy, which may help new fungicide target development for controlling this devastating disease.

Actin depolymerization factors (ADFs), as actin-binding proteins, act a crucial role in plant development and growth, as well as in response to abiotic and biotic stresses. Here, we found that CARK3 plays a role in regulating hypocotyl development and links a cross-talk between actin filament and drought stress through interaction with ADF4. By using bimolecular fluorescence complementation (BiFC) and GST pull-down, we confirmed that CARK3 interacts with ADF4 in vivo and in vitro. Next, we generated and characterized double mutant adf4cark3-4 and OE-ADF4:cark3-4. The hypocotyl elongation assay indicated that the cark3-4 mutant seedlings were slightly longer hypocotyls when compared with the wild type plants (WT), while CARK3 overexpressing seedlings had no difference with WT. In addition, overexpression of ADF4 significantly inhibited long hypocotyls of cark3-4 mutants. Surprisingly, we found that overexpression of ADF4 markedly enhance drought resistance in soil when compared with WT. On the other hand, drought tolerance analysis showed that overexpression of CARK3 could rescue adf4 drought susceptibility. Taken together, our results suggest that CARK3 acts as a regulator in hypocotyl elongation and drought tolerance likely via regulating ADF4 phosphorylation.

Flag leaf size is a crucial trait influencing plant architecture and yield potential in wheat. A recombinant inbred line (RIL) population derived from the cross of W7268 and Chuanyu 12 was employed to identify quantitative trait loci (QTL) controlling flag leaf length (FLL), flag leaf width (FLW), and flag leaf area (FLA) in six environments and the best linear unbiased estimator (BLUE) datasets. Using a 55 K SNP-based genetic map, six major and stable QTL were detected with 6.33–53.12% of explained phenotypic variation. Except for QFlw.cib-4B.3, the other five major QTL were co-located within two intervals on chromosomes 2B and 2D, namely QFll/Fla.cib-2B and QFll/Flw/Fla.cib-2D, respectively. Their interactions and effects on the corresponding traits and yield-related traits were also assessed based on flanking markers. QFll/Fla.cib-2B showed pleiotropic effects on spikelet number per spike (SNS). QFlw.cib-4B.3 and QFll/Flw/Fla.cib-2D had effects on grain number per spike (GNS) and thousand-grain weight (TGW). Comparison analysis suggested that QFll/Fla.cib-2B was likely a new locus. Two candidate genes, TraesCS2B03G0222800 and TraesCS2B03G0230000, associated with leaf development within the interval of QFll/Fla.cib-2B were identified based on expression-pattern analysis, gene annotation, ortholog analysis, and sequence variation. The major QTL and markers reported here provide valuable information for understanding the genetic mechanism underlying flag leaf size as well as breeding utilization in wheat.

Preclinical data demonstrate that the gut microbiota can promote pancreatic ductal adenocarcinoma (PDAC), but mechanisms remain unclear. We hypothesized that intestinal microbiota alters anti-tumor innate immunity response to facilitate PDAC progression. Human PDAC L3.6pl cells were heterotopically implanted into Rag1−/− mice after microbiota depletion with antibiotics, while syngeneic murine PDAC Pan02 cells were implanted intrapancreatic into germ-free (GF) C57BL/6 J mice. Natural killer (NK) cells and their IFNγ expression were quantitated by flow cytometry. NK cells were depleted in vivo using anti-Asialo GM1 antibody to confirm the role of NK cells. Bacteria-free supernatant from SPF and GF mice feces was used to test its effect on NK-92MI cell anti-tumor response in vitro. SPF and ex-GF mice (reconstituted with SPF microbiota) developed larger PDAC tumors with decreased NK cell tumor infiltration and IFNγ expression versus GF-Rag1−/−. Microbiota-induced PDAC tumorigenesis was attenuated by antibiotic exposure, a process reversed following NK cell depletion in both Rag1−/− and C57BL/6 J mice. Compared to GF, SPF-Rag1−/− abiotic stool culture supernatant inhibited NK-92MI cytotoxicity, migration, and anti-cancer related gene expression. Gut microbiota promotes PDAC tumor progression through modulation of the intratumoral infiltration and activity of NK cells.

Abstract It’s a challenge for detecting the therapeutic targets of a polypharmacological drug from variations in the responsed networks in the differentiated populations with complex diseases, as stable coronary heart disease. Here, in an adaptive, 31-center, randomized, double-blind trial involving 920 patients with moderate symptomatic stable angina treated by 14-day Danhong injection(DHI), a kind of polypharmacological drug with high quality control, or placebo (0.9% saline), with 76-day following-up, we firstly confirmed that DHI could increase the proportion of patients with clinically significant changes on angina-frequency assessed by Seattle Angina Questionnaire (ΔSAQ-AF ≥ 20) (12.78% at Day 30, 95% confidence interval [CI] 5.86–19.71%, P = 0.0003, 13.82% at Day 60, 95% CI 6.82–20.82%, P = 0.0001 and 8.95% at Day 90, 95% CI 2.06–15.85%, P = 0.01). We also found that there were no significant differences in new-onset major vascular events (P = 0.8502) and serious adverse events (P = 0.9105) between DHI and placebo. After performing the RNA sequencing in 62 selected patients, we developed a systemic modular approach to identify differentially expressed modules (DEMs) of DHI with the Zsummary value less than 0 compared with the control group, calculated by weighted gene co-expression network analysis (WGCNA), and sketched out the basic framework on a modular map with 25 functional modules targeted by DHI. Furthermore, the effective therapeutic module (ETM), defined as the highest correlation value with the phenotype alteration (ΔSAQ-AF, the change in SAQ-AF at Day 30 from baseline) calculated by WGCNA, was identified in the population with the best effect (ΔSAQ-AF ≥ 40), which is related to anticoagulation and regulation of cholesterol metabolism. We assessed the modular flexibility of this ETM using the global topological D value based on Euclidean distance, which is correlated with phenotype alteration (r 2: 0.8204, P = 0.019) by linear regression. Our study identified the anti-angina therapeutic module in the effective population treated by the multi-target drug. Modular methods facilitate the discovery of network pharmacological mechanisms and the advancement of precision medicine. (ClinicalTrials.gov identifier: NCT01681316).

In order to solve the problem that polyester nonwoven are not antibacterial and hydrophilic as medical and health products. The antibacterial and hydrophilic effects of chitosan/graphene oxide on polyester nonwoven fabrics were investigated. Chitosan and graphene oxide were prepared on polyester nonwoven fabrics by layer by layer self-assembly technology using electrostatic adsorption. The K/S value, antibacterial property, moisture regain and tensile property of the polyester nonwoven fabrics were tested. It is found that the assembly state of chitosan and graphene oxide on the surface of nonwoven fabrics can be qualitatively analyzed by investigating the K/S value; the concentration of chitosan is 3 g/mL for finishing; the finished polyester nonwoven fabrics have good antibacterial and hydrophilic properties, and the breaking strength also slightly increases. Through this study, it can be seen that chitosan / graphene oxide can be used to finish polyester nonwoven fabrics with excellent antibacterial and hydrophilic properties by layer by layer self-assembly technology.

ABCG2 is a transporter contributing to multidrug resistance of cancer cells. Here, structures of human ABCG2 under turnover conditions reveal distinct conformational states, provide insight into the transport cycle and suggest a mechanism of discrimination between substrates and inhibitors.

Background: Prelabor rupture of membranes (PROM) is associated with maternal and neonatal infections. Although guidelines suggest prophylactic antibiotics for pregnant women with PROM, the optimal antibiotic regimen remains controversial. Synthesizing the data from different studies is challenging due to variations in reported outcomes.Objective: This study aimed to form the initial list of outcomes for the core outcome set (COS) that evaluates antibiotic use in PROM by identifying all existing outcomes and patients’ views.Methods: Relevant studies were identified by searching PubMed, EMBASE, Cochrane Library, Chinese National Knowledge Infrastructure, Wanfang, and VIP databases. We also screened the references of the included studies as a supplementary search. We extracted basic information from the articles and the outcomes. Two reviewers independently selected the studies, extracted the data, extracted the outcomes, and grouped them into domains. Then, semi-structured interviews based on the potential factors collected by the systematic review were conducted at West China Second Hospital of Sichuan University. Pregnant women who met the diagnostic criteria for PROM were enrolled. Participants reported their concerns about the outcomes. Two researchers identified the pregnant women’s concerns.Results: A total of 90 studies were enrolled in this systematic review. The median outcomes in the included studies was 7 (1–31), and 109 different unique outcomes were identified. Pre-term PROM (PPROM) had 97 outcomes, and term PROM (TPROM) had 70 outcomes. The classification and order of the core outcome domains of PPROM and TPROM were consistent. The physiological domain was the most common for PPROM and TPROM outcomes. Furthermore, 35.1 and 57.1% outcomes were only reported once in PPROM and TPROM studies, respectively. Thirty pregnant women participated in the semi-structured interviews; 10 outcomes were extracted after normalized, and the outcomes were reported in the systematic review. However, studies rarely reported pregnant women’s concerns.Conclusion: There was considerable inconsistency in outcomes selection and reporting in studies about antibiotics in PROM. An initial core outcomes set for antibiotics in PROM was formed.

BackgroundThe competing endogenous RNA (ceRNA) network-mediated regulatory mechanisms in small cell lung cancer (SCLC) remain largely unknown. This study aimed to integrate multi-omics profiles, including the transcriptome, regulome, genome and pharmacogenome profiles, to elucidate prioritised ceRNA characteristics, pathways and drug candidates in SCLC.MethodWe determined the plasma messenger RNA (mRNA), microRNA (miRNA), long noncoding RNA (lncRNA) and circular RNA (circRNA) expression levels using whole-transcriptome sequencing technology in our SCLC plasma cohort. Significantly expressed plasma mRNAs were then overlapped with the Gene Expression Omnibus (GEO) tissue mRNA data (GSE 40275, SCLC tissue cohort). Next, we applied a multistep multi-omics (transcriptome, regulome, genome and pharmacogenome) integration analysis to first construct the network and then to identify the lncRNA/circRNA-miRNA-mRNA ceRNA characteristics, genomic alterations, pathways and drug candidates in SCLC.ResultsThe multi-omics integration-based prioritisation of SCLC ceRNA regulatory networks consisted of downregulated mRNAs (CSF3R/GAA), lncRNAs (AC005005.4-201/DLX6-AS1-201/NEAT1-203) and circRNAs (hsa_HLA-B_1/hsa_VEGFC_8) as well as upregulated miRNAs (hsa-miR-4525/hsa-miR-6747-3p). lncRNAs (lncRNA-AC005005.4-201 and NEAT1-203) and circRNAs (circRNA-hsa_HLA-B_1 and hsa_VEGFC_8) may regulate the inhibited effects of hsa-miR-6747-3p for CSF3R expression in SCLC, while lncRNA-DLX6-AS1-201 or circRNA-hsa_HLA-B_1 may neutralise the negative regulation of hsa-miR-4525 for GAA in SCLC. CSF3R and GAA were present in the genomic alteration, and further identified as targets of FavId and Trastuzumab deruxtecan, respectively. In the SCLC-associated pathway analysis, CSF3R was involved in the autophagy pathways, while GAA was involved in the glucose metabolism pathways.ConclusionsWe identified potential lncRNA/cirRNA-miRNA-mRNA ceRNA regulatory mechanisms, pathways and promising drug candidates in SCLC, providing novel potential diagnostics and therapeutic targets in SCLC.

This investigation probed endometriosis treatment using targeted nanoparticles (NPs) to modulate autophagic activity. To that end, a novel form of polymer-based NP gene delivery platform consisting of polyethyleneimine (PEI) conjugated to stearic acid (SA) and nucleotides (DNA/siRNAs) and enclosed by hyaluronic acid (HA) was prepared. CD44 is highly upregulated in cystic lesions, and HA–CD44 binding in this specific nanoplatform was used to achieve targeted drug delivery to CD44-expression endometriotic tissues. The expression of autophagy-related genes was modulated to explore the importance of this process in the development of endometriosis. By inducing autophagic activity, we were able to reduce the size of endometriotic cysts and suppress the development of ectopic endometrium. To further confirm the relationship between autophagic activity and this disease in humans and animals, numbers of autophagic vesicles and autophagic protein expression were assessed in lesion tissue samples from patients, revealing there may be consistency between animal and human data. Overall, these data revealed the ability of this (PEI–SA/DNA) HA gene delivery system to regulate autophagic activity and, thereby, aid in the treatment of endometriosis.

Photocatalytic CO2 reduction to valuable hydrocarbon solar fuel is of great significance but still challenging. Strong CO2 enrichment ability and easily adjustable structures make metal-organic frameworks (MOFs) potential photocatalysts for CO2 conversion. Even though pure MOFs have the potential for photoreduction of CO2, the efficiency is still quite low due to rapid photogenerated electron–hole recombination and other drawbacks. In this work, graphene quantum dots (GQDs) were in situ encapsulated into highly stable MOFs via a solvothermal method for this challenging task. The GQDs@PCN-222 with encapsulated GQDs showed similar Powder X-ray Diffraction (PXRD) patterns to PCN-222, indicating the retained structure. The porous structure was also retained with a Brunauer–Emmett–Teller (BET) surface area of 2066 m2/g. After incorporation of GQDs, the shape of GQDs@PCN-222 particles remained, as revealed by the scanning electron microscope (SEM). As most of the GQDs were covered by thick PCN-222, it was hard to observe those GQDs using a transmission electron microscope (TEM) and a high-resolution transmission electron microscope (HRTEM) directly, the treatment of digested GQDs@PCN-222 particles by immersion in a 1 mM aqueous KOH solution can make the incorporated GQDs visible in TEM and HRTEM. The linker, deep purple porphyrins, make MOFs a highly visible light harvester up to 800 nm. The introduction of GQDs inside PCN-222 can effectively promote the spatial separation of the photogenerated electron–hole pairs during the photocatalytic process, which was proved by the transient photocurrent plot and photoluminescence emission spectra. Compared with pure PCN-222, the obtained GQDs@PCN-222 displayed dramatically enhanced CO production derived from CO2 photoreduction with 147.8 μmol/g/h in a 10 h period under visible light irradiation with triethanolamine (TEOA) as a sacrificial agent. This study demonstrated that the combination of GQDs and high light absorption MOFs provides a new platform for photocatalytic CO2 reduction.

Cr(VI) is one of the most toxic heavy metals, posing multiple threats to humans and ecosystems. Photoreduction of toxic Cr(VI) to para-toxic Cr(III) is one of the most effective ways to remove heavy metal chromium but is still challenging. Herein, Ti3C2/UiO-66-NH2 composites with different ratio of Ti3C2 were synthesized via an in situ solvothermal process and used for the enhanced photocatalytic removal of Cr(VI) for the first time. The UiO-66-NH2 nanoparticles were dispersed on the surface and slits of accordion-like Ti3C2 homogeneously. A strong interfacial interaction between Ti3C2 and UiO-66-NH2 was formed, which was indicated by the XPS. The Fermi level of the MXene cocatalyst is lower than UiO-66-NH2; thus, Ti3C2 can serve as the electron sink and accumulate photogenerated electrons from UiO-66-NH2 on its surface. A depletion layer was also formed due to the different Fermi levels of UiO-66-NH2 and Ti3C2, which prevents electrons from flowing back to UiO-66-NH. The strong interfacial interaction and formed depletion layer are beneficial for the following charge transfer from UiO-66-NH2 to Ti3C2 after light irradiation and for suppressing the photogenerated charge recombination. With suitable band positions and enhanced charge separation ability, Ti3C2/UiO-66-NH2 composites exhibited better photoreduction efficiency of Cr2O72− than pure Ti3C2 and UiO-66-NH2, with optimized samples reaching 100% in 40 min. The photoreduction kinetics of Cr2O72− by 2-T/U was also studied, with a photoreduction rate of 0.0871 min−1, which is about 2.6 times higher than that of the pure UiO-66-NH. This research provides a new type of efficient and environmentally friendly photocatalysts for the photoreduction of Cr2O72−.

Nanocrystals (NCs) have the potential to enhance the oral bioavailability of Class IV drugs in the Biopharmaceutical Classification System (BCS) due to the absorption of the intact crystals. The performance is compromised by the dissolution of NCs. Drug NCs have recently been adopted as solid emulsifiers to prepare nanocrystal self-stabilized Pickering emulsions (NCSSPEs). They are advantageous in high drug loading and low side effects due to the specific drug loading mode and the absence of chemical surfactants. More importantly, NCSSPEs may further enhance the oral bioavailability of drug NCs by impeding their dissolution. This is especially true for BCS IV drugs. In this study, curcumin (CUR), a typical BCS IV drug, was adopted to prepare CUR-NCs stabilized Pickering emulsions using either indigestible (isopropyl palmitate, IPP) or digestible (soybean oil, SO) oils, i.e., IPP-PEs and SO-PEs. The optimized formulations were spheric with CUR-NCs adsorbed on the water/oil interface. The CUR concentration in the formulation reached 20 mg/mL, which was far beyond the solubility of CUR in IPP (158.06 ± 3.44 μg/g) or SO (124.19 ± 2.40 μg/g). Moreover, the Pickering emulsions enhanced the oral bioavailability of CUR-NCs, being 172.85% for IPP-PEs and 152.07% for SO-PEs. The digestibility of the oil phase affected the amounts of CUR-NCs that remained intact in lipolysis and, thus, the oral bioavailability. In conclusion, converting NCs into Pickering emulsions provides a novel strategy to enhance the oral bioavailability of CUR and BCS IV drugs.

Natural pyrethrins have high application value, and are widely used as a green pesticide in crop pest prevention and control. Pyrethrins are mainly extracted from the flower heads of Tanacetum cinerariifolium; however, the natural content is low. Therefore, it is essential to understand the regulatory mechanisms underlying the synthesis of pyrethrins through identification of key transcription factors. We identified a gene encoding a MYC2-like transcription factor named TcbHLH14 from T. cinerariifolium transcriptome, which is induced by methyl jasmonate. In the present study, we evaluated the regulatory effects and mechanisms of TcbHLH14 using expression analysis, a yeast one-hybrid assay, electrophoretic mobility shift assay, and overexpression/virus-induced gene silencing experiments. We found that TcbHLH14 can directly bind to the cis-elements of the pyrethrins synthesis genes TcAOC and TcGLIP to activate their expression. The transient overexpression of TcbHLH14 enhanced expression of the TcAOC and TcGLIP genes. Conversely, transient silencing of TcbHLH14 downregulated the expression of TcAOC and TcGLIP and reduced the content of pyrethrins. In summary, these results indicate that the potential application of TcbHLH14 in improving the germplasm resources and provide a new insight into the regulatory network of pyrethrins biosynthesis of T. cinerariifolium to further inform the development of engineering strategies for increasing pyrethrins contents.

Abstract Concurrent natural evolution of glyphosate resistance single‐ and double‐point EPSPS mutations in weed species provides an opportunity for the estimation of resistance fitness benefits and prediction of equilibrium resistance frequencies in environments under glyphosate selection. Assessment of glyphosate resistance benefit was conducted for the most commonly identified single Pro‐106‐Ser and less‐frequent double TIPS mutations in the EPSPS gene evolved in the global damaging weed Eleusine indica. Under glyphosate selection at the field dose, plants with the single Pro‐106‐Ser mutation at homozygous state (P106S‐rr) showed reduced survival and compromised vegetative growth and fecundity compared with TIPS plants. Whereas both homozygous (TIPS‐RR) and compound heterozygous (TIPS‐Rr) plants with the double TIPS resistance mutation displayed similar survival rates when exposed to glyphosate, a significantly higher fecundity in the currency of seed number was observed in TIPS‐Rr than TIPS‐RR plants. The highest plant fitness benefit was associated with the heterozygous TIPS‐Rr mutation, whereas plants with the homozygous Pro‐106‐Ser and TIPS mutations exhibited, respectively, 31% and 39% of the fitness benefit revealed by the TIPS‐Rr plants. Populations are predicted to reach stable allelic and genotypic frequencies after 20 years of glyphosate selection at which the WT allele is lost and the stable genotypic polymorphism is comprised by 2% of heterozygous TIPS‐Rr, 52% of homozygous TIPS‐RR and 46% of homozygous P106S‐rr. The high inbreeding nature of E. indica is responsible for the expected frequency decrease in the fittest TIPS‐Rr in favour of the homozygous TIPS‐RR and P106S‐rr. Mutated alleles associated with the glyphosate resistance EPSPS single EPSPS Pro‐106‐Ser and double TIPS mutations confer contrasting fitness benefits to E. indica under glyphosate treatment and therefore are expected to exhibit contrasting evolution rates in cropping systems under recurrent glyphosate selection.

Abstract Background Decades of efforts have attempted to differentiate the pluripotent stem cells (PSCs) into truly functional hematopoietic stem cells (HSCs), yet the problems of low differentiation efficiency in vitro and poor hematopoiesis reconstitution in vivo still exist, mainly attributing to the lack of solid, reproduced, or pursued differentiation system. Methods In this study, we established an in vitro differentiation system yielding in vivo hematopoietic reconstitution hematopoietic cells from mouse PSCs through a 3D induction system followed by coculture with OP9 stromal cells. The in vivo hematopoietic reconstitution potential of c-kit+ cells derived from the mouse PSCs was evaluated via m-NSG transplantation assay. Flow cytometry analysis, RNA-seq, and cell cycle analysis were used to detect the in vitro hematopoietic ability of endothelial protein C receptor (EPCR, CD201) cells generated in our induction system. Results The c-kit+ cells from 3D self-assembling peptide induction system followed by the OP9 coculture system possessed apparently superiority in terms of in vivo repopulating activity than that of 3D induction system followed by the 0.1% gelatin culture. We interestingly found that our 3D+OP9 system enriched a higher percentage of CD201+c-kit+cells that showed more similar HSC-like features such as transcriptome level and CFU formation ability than CD201-c-kit+cells, which have not been reported in the field of mouse PSCs hematopoietic differentiation. Moreover, CD201+ hematopoietic cells remained in a relatively slow cycling state, consistent with high expression levels of P57 and Ccng2. Further, we innovatively demonstrated that notch signaling pathway is responsible for in vitro CD201+ hematopoietic cell induction from mouse PSCs. Conclusions Altogether, our findings lay a foundation for improving the efficiency of hematopoietic differentiation and generating in vivo functional HSC-like cells from mouse PSCs for clinical application.

Abstract Background Endometriosis is a refractory and recurrent disease and it affects nearly 10% of reproductive-aged women and 40% of infertile patients. The commonly accepted theory for endometriosis is retrograde menstruation where endometrial tissues invade into peritoneal cavity and fail to be cleared due to immune dysfunction. Therefore, the comprehensive understanding of immunologic microenvironment of peritoneal cavity deserves further investigation for the previous studies mainly focus on one or several immune cells. Results High-quality transcriptomes were from peritoneal fluid samples of patients with endometriosis and control, and firstly subjected to 10 × genomics single-cell RNA-sequencing. We acquired the single-cell transcriptomes of 10,280 cells from endometriosis sample and 7250 cells from control sample with an average of approximately 63,000 reads per cell. A comprehensive map of overall cells in peritoneal fluid was first exhibited. We unveiled the heterogeneity of immune cells and discovered new cell subtypes including T cell receptor positive (TCR+) macrophages, proliferating macrophages and natural killer dendritic cells in peritoneal fluid, which was further verified by double immunofluorescence staining and flow cytometry. Pseudo-time analysis showed that the response of macrophages to the menstrual debris might follow the certain differentiation trajectory after endometrial tissues invaded into the peritoneal cavity, that is, from antigen presentation to pro-inflammation, then to chemotaxis and phagocytosis. Our analyses also mirrored the dysfunctions of immune cells including decreased phagocytosis and cytotoxic activity and elevated pro-inflammatory and chemotactic effects in endometriosis. Conclusion TCR+ macrophages, proliferating macrophages and natural killer dendritic cells are firstly reported in human peritoneal fluid. Our results also revealed that immune dysfunction happens in peritoneal fluid of endometriosis, which may be responsible for the residues of invaded menstrual debris. It provided a large-scale and high-dimensional characterization of peritoneal microenvironment and offered a useful resource for future development of immunotherapy.

Abstract Background Multiple myeloma (MM) is a major health concern. Understanding the different burden and tendency of MM in different regions is crucial for formulating specific local strategies. Therefore, we evaluated the epidemiologic patterns and explored the risk factors for MM death. Methods Data on MM were collected from the 2019 Global Burden of Disease study. We used incidence, mortality, and disability adjusted life-years to estimate the global, regional, and national burden of MM. Results In 2019, there were 155,688 (95% UI, 136,585 – 172,577) MM cases worldwide, of which 84,516 (54.3%, 70,924 – 94,910) were of men. The age-standardized incidence rate (ASIR) was 1.72/100,000 persons (95% UI, 1.59–1.93) in 1990 and 1.92/100,000 persons (95% UI, 1.68–2.12) in 2019. The number of MM deaths increased 1.19-fold from 51,862 (95% UI, 47,710–58,979) in 1990 to 113,474 (95% UI, 99,527 – 121,735) in 2019; the age-standardized death rate (ASDR) was 1.42/100,000 persons (95% UI, 1.24–1.52) in 2019. In recent 15 years, ASDR showed a steady tendency for men, and a downward tendency for women. Countries with high social-demographic indexes exhibited a higher ASIR and ASDR. Australasia, North America, and Western Europe had the highest ASIR and ASDR, with 46.3% incident cases and 41.8% death cases. Monaco had the highest ASIR and ASDR, which was almost half as high as the second highest country Barbados. In addition, United Arab Emirates and Qatar had the largest growth multiple in ASIR and ASDR, which was twice the third country Djibouti. Conclusions Globally, incident and death MM cases have more than doubled over the past 30 years. The increasing global burden may continue with population aging, whereas mortality may continue to decrease with the progression of medical technology. The global burden pattern of MM was diverse, therefore specific local strategies based on different burden patterns for MM are necessary.

Abstract The coronary slow flow phenomenon (CSFP) is common in coronary angiography, however its impact on left atrial (LA) function is still controversial. This study aims to evaluate the LA structure and function of patients with CSFP using two-dimensional speckle tracking echocardiography (2D-STE). Consecutive patients scheduled for coronary angiography from January 2016 to September 2017 were enrolled in this study. Patients’ demographic data, clinical histories, laboratory and angiographic findings were collected and recorded. Diagnostic criteria for CSFP is based on Beltrame et al. proposed in 2012. Meanwhile 139 patients who have no significant stenosis (≤ 40%) and normal blood flow were selected as control. All patients received an echocardiographic examination 24 h before coronary angiography. LA structure and function were measured with echocardiography and 2D-STE. Our results showed that among the 1,954 patients who had received coronary angiography, 512 patients were included in the analysis after the exclusion criteria was implemented. Of those, 101 patients met the CSFP criteria (5.5%). CSFP is mainly seen in LAD (~ 70%). There was no statistical difference in baseline characteristics between the CSFP group and control group, except for a higher proportion of smokers in the CSFP group (P = 0.001). The percentage of monocytes is an independent risk factor for the occurrence of CSFP (P = 0.036) after binary logistic regression analysis. The LA global longitudinal strain (LA-GLS, represents reservoir functions) decreased and LA strain rate at late diastole (LA-SRa, represents booster function) increased in patients with CSFP compared to the control group (P

Abstract The genetically engineered chimeric antigen receptor T cell (CAR‐T) therapy has shown remarkable clinical efficacy in the treatment of hematological malignancies. Nonetheless, it is difficult to harvest adequate autologous T cells to manufacture potent CAR‐T cell products in patients with high tumor burden and prior tumor‐reductive treatment. Here we reported a relapsed/refractory acute lymphoblastic leukemia patient with high leukemia burden and central nervous system (CNS) involvement. The patient responded to donor‐derived HLA‐matched allogeneic CAR‐T treatment, with the achievement of quick complete remission. And for the first time, we revealed the development of a cerebral CRS in situ after allogeneic CAR‐T therapy.

Background: Drug use safety in children is a global public health problem. The potentially inappropriate prescription screening tools are expected to reduce adverse drug reactions and promote rational drug use.Objectives: To systematically evaluate children’s potentially inappropriate prescription screening tools and validation studies on these tools.Methods: We systematically searched six databases PubMed, Embase, Cochrane Library, CNKI, VIP and Wanfang Data. Two reviewers independently selected articles by the eligible criteria and extracted data. Then we evaluated the coverage of diseases or drugs in these tools and the consistency of items between tools.Results: Five children’s potentially inappropriate prescription screening tools were identified, most tools were formed by Delphi expert consensus and focused on respiratory system drugs, anti-infective drugs, and gastrointestinal drugs. The coincidence rates of items between the POPI and the POPI Int, the POPI and the POPI United Kingdom, the POPI United Kingdom and the POPI int, and the POPI United Kingdom and the PIPc were 82.0, 55.1, 51.0 and 2.2% respectively, and the KIDs List did not overlap other four tools. Only the POPI tool developed by French experts was comprehensively validated by studies and most tools have not been validated.Conclusion: The development of screening tools for potentially inappropriate prescribing in children is a neglected field and most tools lack studies to validate clinical applicability. More researchers need to form their national potentially inappropriate prescription screening tools for children based on the best available clinical evidence and the actual clinical situation in their countries.

Spike compactness (SC) and length (SL) are the components of spike morphology and are strongly related to grain yield in wheat (Triticum aestivum L.). To investigate quantitative trait loci (QTL) associated with SC and SL, a recombinant inbred lines (RIL) population derived from the cross of Bailangmai (BLM, a Tibet landrace) and Chuanyu 20 (CY20, an improved variety) was employed in six environments. Three genomic regions responsible for SC and SL traits were identified on chromosomes 2A and 2D using bulked segregant exome sequencing (BSE-Seq). By constructing genetic maps, six major QTL were repeatedly detected in more than four environments and the best linear unbiased estimation (BLUE) datasets, explaining 7.00–28.56% of the phenotypic variation and the logarithm of the odd (LOD) score varying from 2.50 to 13.22. They were co-located on three loci, designed as QSc/Sl.cib-2AS, QSc/Sl.cib-2AL, and QSc/Sl.cib-2D, respectively. Based on the flanking markers, their interactions and effects on the corresponding trait and other agronomic traits were also analyzed. Comparison analysis showed that QSc/Sl.cib-2AS and QSc/Sl.cib-2AL were possibly two novel loci for SC and SL. QSc/Sl.cib-2AS and QSc/Sl.cib-2D showed pleiotropic effects on plant height and grain morphology, while QSc/Sl.cib-2AL showed effects on spikelet number per spike (SNS) and grain width (GW). Based on the gene annotation, orthologous search, and spatiotemporal expression patterns of genes, TraesCS2A03G0410600 and TraesCS2A03G0422300 for QSc/Sl.cib-2AS, and TraesCS2D03G1129300 and TraesCS2D03G1131500 for QSc/Sl.cib-2D were considered as potential candidate genes, respectively. These results will be useful for fine mapping and developing new varieties with high yield in the future.

As the first-line clinical drugs for tuberculosis (TB), isoniazid (INH), pyrazinamide (PZA), and rifampicin (RMP) are playing important roles for preventing the rapid spread of TB. Precise quantification of these drugs in biological samples is crucial to evaluate or improve the efficacy of advanced TB drug delivery systems, which are designed for reducing drug resistance, minimizing side effects, etc. Herein, a simple and sensitive method based on UPLC–UV was established and investigated for simultaneous quantification of PZA, INH, and RMP in human plasma and was applied to anti-TB drug therapeutic drug monitoring. The analytes were implemented on an HSS T3 C18 column at 40°C. The separation was performed with a gradient elution with methanol–acetonitrile–water (3:3:94) at 0.1 ml/min. The analysis only involved plasma with a small volume of 100 µL and a rapid one-step protein precipitation with methanol–acetonitrile (1:1). The results showed that the calibration curves for INH, PZA, and RMP were linear in a range of 0.5–20 μg/ml, 5–60 μg/ml, and 5–60 μg/ml, respectively. The intra- and inter-day precisions were both smaller than 15%, and the lower limit of quantitation (LLOQ) was identifiable and reproducible at 0.5 μg/ml for INH and 5 μg/ml for both PZA and RMP, respectively. The target drugs in plasma were stable after 21 days of storage at −80°C. The results indicated that our developed method is suitable for the simultaneous monitoring of INH, PZA, and RMP in human plasma.

BackgroundA study of the current situation and characteristics of hepatitis B virus (HBV) infection among Chinese pregnant women is meaningful to provide baseline information for future research and policy making, with an aim to eliminate HBV in China.ObjectivesTo provide the epidemiological status of HBV infection among pregnant women in China.MethodsPubMed, EMbase, The Cochrane Library, and three Chinese databases were searched. Cohort studies and cross-sectional studies on HBV prevalence in Chinese pregnant women, published after 2016, were retrieved. In addition, combined HBV prevalence and 95% confidence interval (CI) were calculated. This research was registered in PROSPERO (CRD42021289123).Main ResultsA total of 42 studies were included in the study, with a sample size of 4,007,518 cases, and 20 provinces in China. The prevalence of HBV in Chinese pregnant women was 6.64% (95% CI: 5.72–7.57%) during the period between 2016 and 2021. Among HBsAg positive pregnant women, the HBeAg positive rate was 25.80% (95% CI: 22.26–29.69%). Moreover, geographic regions with HBV prevalence ranking from high to low were in western China, eastern China, and central China, successively.ConclusionThe prevalence of HBV in Chinese pregnant women is intermediate endemic, although disparities exist between different regions. Among pregnant women with HBV infection, a high proportion of the patients have strong infectivity. Factors affecting HBV prevalence remain controversial, which demands further studies.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier: CRD42021289123.

Objective: To explore the correlation between characteristics of myocardial energy expenditure (MEE) and the degree of diastolic dysfunction in patients of heart failure with preserved ejection fraction (HFpEF) and its clinical significance.Methods: 125 consecutive patients diagnosed with HFpEF in the Department of Cardiology, Affiliated Zhongshan Hospital of Dalian University from January 2018 to October 2018 were enrolled. According to the degree of diastolic dysfunction, patients were divided into group A (8 ≤ E/e' ≤15) and group B (E/e'> 15), and MEE was calculated, patients finished 1-year clinical follow-up.Results: The level of MEE in group A was significantly lower than that in group B (p < 0.05). During 1-year follow up, MEE over 3145.69 kcal/systole was associated with increased risk of death as compared to patients with MEE less 3145.69 kcal/systole, and in patients with MEE over 101.68 kcal/min than in patients with MEE less than 101.68 kcal/min.Conclusion: There is a significant correlation between MEE and diastolic dysfunction and MEE over 3145.69 kcal/systole as well as MEE over 101.68 kcal/min are linked with increased risk of 1-year mortality in HFpEF.

Pancreatic ductal adenocarcinoma is the third leading cause of cancer-related death in the United States. As one of the most lethal cancer types, the prognosis for patients diagnosed with pancreatic cancer remains dismal and novel investigations are urgently needed. Evidence for an association of microbes with pancreatic cancer risk, development, treatment response, and post-treatment survivorship is rapidly developing. Herein, we provide an overview on the role of the microbiome as it relates to the natural history of pancreatic cancer, including host immune interactions, alterations in metabolism, direct carcinogenic effect, and its role in treatment response.

Abstract Most speech separation studies in monaural channel use only a single type of network, and the separation effect is typically not satisfactory, posing difficulties for high quality speech separation. In this study, we propose a convolutional recurrent neural network with an attention (CRNN-A) framework for speech separation, fusing advantages of two networks together. The proposed separation framework uses a convolutional neural network (CNN) as the front-end of a recurrent neural network (RNN), alleviating the problem that a sole RNN cannot effectively learn the necessary features. This framework makes use of the translation invariance provided by CNN to extract information without modifying the original signals. Within the supplemented CNN, two different convolution kernels are designed to capture information in both the time and frequency domains of the input spectrogram. After concatenating the time-domain and the frequency-domain feature maps, the feature information of speech is exploited through consecutive convolutional layers. Finally, the feature map learned from the front-end CNN is combined with the original spectrogram and is sent to the back-end RNN. Further, the attention mechanism is further incorporated, focusing on the relationship among different feature maps. The effectiveness of the proposed method is evaluated on the standard dataset MIR-1K and the results prove that the proposed method outperforms the baseline RNN and other popular speech separation methods, in terms of GNSDR (gloabl normalised source-to-distortion ratio), GSIR (global source-to-interferences ratio), and GSAR (gloabl source-to-artifacts ratio). In summary, the proposed CRNN-A framework can effectively combine the advantages of CNN and RNN, and further optimise the separation performance via the attention mechanism. The proposed framework can shed a new light on speech separation, speech enhancement, and other related fields.

Although long non coding RNAs (lncRNAs) and circular RNAs (circRNAs) play important roles in the pathogenesis of diseases, endometriosis related lncRNAs and circRNAs are still rarely reported. This study focused on the potential molecular mechanism of endometriosis related competitive endogenous RNA (ceRNA) composed of lncRNAs and circRNAs. We performed high-throughout sequencing of six normal endometria, six eutopic endometria and six ectopic endometria for the first time to describe and analyze the expression profile of lncRNA, circRNA and mRNA. Our results showed that 140 lncRNAs, 107 circRNAs and 1,206 mRNAs were differentially expressed in the ectopic group, compared with the normal and eutopic groups. We established an lncRNA/circRNA-mRNA co-expression network using pearson correlation test. Meanwhile, the results of Gene set enrichment analysis analysis showed that the 569 up-regulated differentially expressed mRNA (DEmRNA) were mainly related to the epithelial-mesenchymal transition, regulation of immune system process and immune effector process. Subsequently, we established a DElncRNA-miRNA and DEcircRNA-miRNA network using the starbase database, identified the common miRNAs and constructed DElncRNA/DEcircRNA-miRNA pairs. miRDB, Targetscan, miRwalk and circRNA/lncRNA-mRNA pairs jointly determined the miRNA-mRNA portion of the circRNA/lncRNA-miRNA-mRNA co-expression network. RT-qPCR results of 15 control samples and 25 ectopic samples confirmed that circGLIS2, circFN1, LINC02381, IGFL2-AS1, CD84, LYPD1 and FAM163A were significantly overexpressed in ectopic tissues. In conclusion, this is the first study to illustrate ceRNA composed of differentially expressed circRNA, lncRNA and mRNA in endometriosis. We also found that lncRNA and circRNA exerted a pivotal function on the pathogenesis of endometriosis, which can provide new insights for further exploring the pathogenesis of endometriosis and identifying new targets.

Background: Essential medicines for children are those medicines that satisfy the priority health care needs of children. Access to essential medicines for children is a big challenge, particularly in low- and middle-income countries. Our study aimed to assess the accessibility of essential medicines for children in public sector in Sichuan Province of China, based on availability, affordability, and price.Methods: We adopted the modified World Health Organization/Health Action International (WHO/HAI) standardization methodology to measure the availability, affordability, and prices of 30 essential medicines for children in 20 public hospitals in nine regions of the Sichuan Province, China. Availability was expressed as the percentage of public medicine outlets that stocked surveyed medicines on the day of data collection, and prices were expressed as median price ratio (MPR). Affordability was assessed as the number of Sichuan Province’s daily wages required for the lowest-paid government unskilled worker (11.03 USD per day) to purchase one standard treatment of an acute disease or treatment for chronic disease for a month.Results: The mean availability of originator brands (OBs) and lowest priced generics (LPGs) were 9.7 and 46.5% in public sector. MPRs of only 3 OBs could be calculated, ranging from 0.55 to 13.37. MPRs of 18 LPGs ranged from 0.07 to 25.05. Among them, 2 OBs and 11 LPGs were priced at more than 1.5 times their international reference prices (IRPs) in public sector, most of which were injections. Except for cefazolin injection and ceftriaxone injection, most LPGs were affordable for the treatment of childhood diseases in public sector, as they each cost one or less than the daily wage for the lowest-paid unskilled government worker.Conclusions: Although the availability of LPGs for children was higher than OBs in public sector, the availability of children’s essential medicines was low in surveyed public sector in Sichuan Province, which was similar to previous studies in other provinces of China. The price of most medicines surveyed was higher than their IRPs in surveyed public sector, especially for some injections. The affordability of most surveyed LPGs was reasonable in surveyed public sector, except for ceftriaxone injection and cefazolin injection.

The Lateral Organ Boundaries Domain (LBD) genes encode highly conserved plant-specific LOB domain proteins which regulate growth and development in various species. However, members of the LBD gene family have yet to be identified in Brassica rapa var. rapa. In the present study, fifty-nine LBD genes were identified and distributed on 10 chromosomes. The BrrLBD proteins are predicted to encode hydrophobic polypeptides between 118 and 394 amino acids in length and with molecular weights ranging from 13.31 to 44.24 kDa; the theoretical pI for these proteins varies from 4.83 to 9.68. There were 17 paralogous gene pairs in the BrrLBD family, suggesting that the amplification of the BrrLBD gene family involved large-scale gene duplication events. Members of the BrrLBD family were divided into 7 subclades (class I a to e, class II a and b). Analysis of gene structure and conserved domains revealed that most BrrLBD genes of the same subclade had similar gene structures and protein motifs. The expression profiles of 59 BrrLBD genes were determined through Quantitative Real-time fluorescent PCR (qRT-PCR). Most BrrLBD genes in the same subclade had similar gene expression profiles. However, the expression patterns of 7 genes differed from their duplicates, indicating that although the gene function of most BrrLBD genes has been conserved, some BrrLBD genes may have undergone evolutionary change. Keywords: LBD, Transcription factors, LBD gene sequence analysis, Expression profiles, Brassica rapa var. rapa

BackgroundMyometrial invasion has been demonstrated to correlate to clinicopathological characteristics and prognosis in endometrial cancer. However, not all the studies have the consistent results and no meta-analysis has investigated the association of myometrial invasion with lymphovascular space invasion (LVSI), lymph node metastasis (LNM), recurrence, and overall survival (OS). Therefore, a meta-analysis was performed to evaluate the relationship between myometrial invasion and clinicopathological characteristics or overall survival in endometrial cancer.Materials and MethodsA search of Pubmed, Embase, and Web of Science was carried out to collect relevant studies from their inception until June 30, 2021. The quality of each included study was evaluated using Newcastle–Ottawa scale (NOS) scale. Review Manager version 5.4 was employed to conduct the meta-analysis.ResultsA total of 79 articles with 68,870 endometrial cancer patients were eligible including 9 articles for LVSI, 29 articles for LNM, 8 for recurrence, and 37 for OS in this meta-analysis. Myometrial invasion was associated with LVSI (RR 3.07; 95% CI 2.17–4.35; p < 0.00001), lymph node metastasis (LNM) (RR 4.45; 95% CI 3.29–6.01; p < 0.00001), and recurrence (RR 2.06; 95% CI 1.58–2.69; p < 0.00001). Deep myometrial invasion was also significantly related with poor OS via meta-synthesis of HRs in both univariate survival (HR 3.36, 95% CI 2.35–4.79, p < 0.00001) and multivariate survival (HR 2.00, 95% CI 1.59–2.53, p < 0.00001). Funnel plot suggested that there was no significant publication bias in this study.ConclusionDeep myometrial invasion correlated to positive LVSI, positive LNM, cancer recurrence, and poor OS for endometrial cancer patients, indicating that myometrial invasion was a useful evaluation criterion to associate with clinical outcomes and prognosis of endometrial cancer since depth of myometrial invasion can be assessed before surgery. The large scale and comprehensive meta-analysis suggested that we should pay more attention to myometrial invasion in clinical practice, and its underlying mechanism also deserves further investigation.

Many studies reported that spontaneous fluctuation of the blood oxygen level-dependent signal exists in multiple frequency components and changes over time. By assuming a reliable energy contrast between low- and high-frequency bands for each voxel, we developed a novel spectrum contrast mapping (SCM) method to decode brain activity at the voxel-wise level and further validated it in designed experiments. SCM consists of the following steps: first, the time course of each given voxel is subjected to fast Fourier transformation; the corresponding spectrum is divided into low- and high-frequency bands by given reference frequency points; then, the spectral energy ratio of the low- to high-frequency bands is calculated for each given voxel. Finally, the activity decoding map is formed by the aforementioned energy contrast values of each voxel. Our experimental results demonstrate that the SCM (1) was able to characterize the energy contrast of task-related brain regions; (2) could decode brain activity at rest, as validated by the eyes-closed and eyes-open resting-state experiments; (3) was verified with test-retest validation, indicating excellent reliability with most coefficients > 0.9 across the test sessions; and (4) could locate the aberrant energy contrast regions which might reveal the brain pathology of brain diseases, such as Parkinson’s disease. In summary, we demonstrated that the reliable energy contrast feature was a useful biomarker in characterizing brain states, and the corresponding SCM showed excellent brain activity-decoding performance at the individual and group levels, implying its potentially broad application in neuroscience, neuroimaging, and brain diseases.