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Despite many changes in alternative splicing events (ASEs) are frequently involved in various cancers, prognosis-related ASEs and drug treatment targets in glioblastoma multiforme (GBM) have not been well explored. ASEs participate in many biological behaviors in the initiation and progression of tumors, the aberrant ASE has been considered another hallmark of cancer, and the systematic study of alternative splicing may provide potential biomarkers for malignancies. In this study, we carried out a systematic analysis to characterize the ASE signatures in GBM cohort. Through comparing GBM tissues and nontumor tissues, a total of 48,191 differently expressed ASEs from 10,727 genes were obtained, and these aberrant ASEs play an important role in the oncogenic process. Then, we identified 514 ASEs independently associated with patient survival in GBM by univariate and multivariate Cox regression, including exon skip in CD3D, alternate acceptor site in POLD2, and exon skip in DCN. Those prognostic models built on ASEs of each splice type can accurately predict the outcome of GBM patients, and values for the area under curve were 0.97 in the predictive model based on alternate acceptor site. In addition, the splicing-regulatory network revealed an interesting correlation between survival-associated splicing factors and prognostic ASE corresponding genes. Moreover, these three hub splicing factors in splicing regulation network are the potential targets of some drugs. In conclusion, a systematic analysis of ASE signatures in GBM could serve as an indicator for identifying novel prognostic biomarkers and guiding clinical treatment.

To use structural magnetic resonance imaging and graph theory approaches to investigate the topological organization of the brain morphological network based on gray matter in essential tremor, and its potential relation to disease severity. In this prospective study conducted from November 2018 to November 2019, 36 participants with essential tremor and 37 matched healthy controls underwent magnetic resonance imaging. Brain networks based on the morphological similarity of gray matter across regions were analyzed using graph theory. Nonparametric permutation testing was used to assess group differences in topological metrics. Support vector machine was applied to the gray matter morphological matrices to classify participants with essential tremor vs. healthy controls. Compared with healthy controls, participants with essential tremor showed increased global efficiency (p < 0.01) and decreased path length (p < 0.01); abnormal nodal properties in frontal, parietal, and cerebellar lobes; and disconnectivity in cerebello-thalamo-cortical network. The abnormal brain nodal centralities (left superior cerebellum gyrus; right caudate nucleus) correlated with clinical measures, both motor (Fahn–Tolosa–Marin tremor rating, p = 0.017, r = − 0.41) and nonmotor (Hamilton depression scale, p = 0.040, r = − 0.36; Hamilton anxiety scale, p = 0.008, r = − 0.436). Gray matter morphological matrices classified individuals with high accuracy of 80.0%. Participants with essential tremor showed randomization in global properties and dysconnectivity in the cerebello-thalamo-cortical network. Participants with essential tremor could be distinguished from healthy controls by gray matter morphological matrices.

Neuroimaging studies using a variety of techniques have demonstrated abnormal patterns of spontaneous brain activity in patients with essential tremor (ET). However, the findings are variable and inconsistent, hindering understanding of underlying neuropathology. We conducted a meta‐analysis of whole‐brain resting‐state functional neuroimaging studies in ET compared to healthy controls (HC), using anisotropic effect‐size seed‐based d mapping, to identify the most consistent brain activity alterations and their relation to clinical features. After systematic literature search, we included 13 studies reporting 14 comparisons, describing 286 ET patients and 254 HC. Subgroup analyses were conducted considering medication status, head tremor status, and methodological factors. Brain activity in ET is altered not only in the cerebellum and cerebral motor cortex, but also in nonmotor cortical regions including prefrontal cortex and insula. Most of the results remained unchanged in subgroup analyses of patients with head tremor, medication‐naive patients, studies with statistical threshold correction, and the large subgroup of studies using functional magnetic resonance imaging. These findings not only show consistent and robust abnormalities in specific brain regions but also provide new information on the biology of patient heterogeneity, and thus help to elucidate the pathophysiology of ET., Neuroimaging studies using a variety of techniques have demonstrated abnormal patterns of spontaneous brain activity in patients with essential tremor (ET). However, the findings are variable and inconsistent, hindering understanding of underlying neuropathology. We conducted a meta‐analysis of whole‐brain resting‐state functional neuroimaging studies in ET compared to healthy controls, brain activity in ET is altered not only in the cerebellum and cerebral motor cortex, but also in non‐motor cortical regions including prefrontal cortex and insula.

We propose a data and knowledge driven approach for SPECT by combining a classical iterative algorithm of SPECT with a convolutional neural network. The classical iterative algorithm, such as ART and ML-EM, is employed to provide the model knowledge of SPECT. A modified U-net is then connected to exploit further features of reconstructed images and data sinograms of SPECT. We provide mathematical formulations for the architecture of the proposed networks. The networks are trained by supervised learning using the technique of mini-batch optimization. We apply the trained networks to the problems of simulated lung perfusion imaging and simulated myocardial perfusion imaging, and numerical results demonstrate their effectiveness of reconstructing source images from noisy data measurements.

The goals of the current study were to determine whether topological organization of brain structural networks is altered in youth with bipolar disorder, whether such alterations predict treatment outcomes, and whether they are normalized by treatment. Youth with bipolar disorder were randomized to double-blind treatment with quetiapine or lithium and assessed weekly. High-resolution MRI images were collected from children and adolescents with bipolar disorder who were experiencing a mixed or manic episode (n = 100) and healthy youth (n = 63). Brain networks were constructed based on the similarity of morphological features across regions and analyzed using graph theory approaches. We tested for pretreatment anatomical differences between bipolar and healthy youth and for changes in neuroanatomic network metrics following treatment in the youth with bipolar disorder. Youth with bipolar disorder showed significantly increased clustering coefficient (Cp) (p = 0.009) and characteristic path length (Lp) (p = 0.04) at baseline, and altered nodal centralities in insula, inferior frontal gyrus, and supplementary motor area. Cp, Lp, and nodal centrality of the insula exhibited normalization in patients following treatment. Changes in these neuroanatomic parameters were correlated with improvement in manic symptoms but did not differ between the two drug therapies. Baseline structural network matrices significantly differentiated medication responders and non-responders with 80% accuracy. These findings demonstrate that both global and nodal structural network features are altered in early course bipolar disorder, and that pretreatment alterations in neuroanatomic features predicted treatment outcome and were reduced by treatment. Similar connectome normalization with lithium and quetiapine suggests that the connectome changes are a downstream effect of both therapies that is related to their clinical efficacy.

Supplemental Digital Content is available in the text., Background: It is unclear whether confounding accounts for the increased risk of preterm birth and small for gestational age (SGA) birth in opioid analgesic exposed pregnancies. Methods: Using universal coverage health data for Ontario, we assembled a cohort of mother–infant pairs without opioid use disorder (627,172 pregnancies and 509,522 women). We estimated risk ratios (RRs) between opioid analgesics and preterm birth, SGA birth, and stillbirth; neonatal abstinence syndrome was a secondary outcome. We used high-dimensional propensity scores and sensitivity analyses for confounding adjustment. Results: 4% of pairs were exposed, mainly to codeine (2%), morphine (1%), and oxycodone (1%). Compared with unexposed, the adjusted risk of preterm birth was higher with any (1.3, 95% confidence interval [CI] = 1.2, 1.3), first- (RR: 1.2, 95% CI = 1.2, 1.3), and second-trimester (RR: 1.3, 95% CI = 1.2, 1.4) opioid analgesic exposure. Preterm birth risk was higher for first- and second-trimester codeine, morphine, and oxycodone exposure, and for third-trimester morphine. There was a small increase in SGA with first-trimester exposure to any opioid analgesic or to codeine. Exposed pregnancies had an elevated stillbirth risk with any (RR: 1.6, 95% CI = 1.4, 1.8), first- and second-trimester exposure. Few infants had neonatal abstinence syndrome (N = 143); the risk was higher in exposed (RR: 3.6, 95% CI = 2.1, 6.0). In sensitivity analyses of unmeasured confounding, an elevated risk in exposed pregnancies persisted for preterm birth but not SGA. Conclusions: Opioid analgesic-exposed pregnancies had a small increased risk of preterm birth and possibly stillbirth after accounting for confounding by indication and sociodemographic factors.

Ferroptosis is a newly discovered form of programmed cell death, which has unique biological effects on metabolism and redox biology. In this study, the prognostic value of ferroptosis‐related genes was investigated in lower‐grade gliomas (LGG). We downloaded the ferroptosis‐related genes from the FerrDb dataset. Univariate Cox and LASSO regression analyses were applied to identify genes correlated with overall survival (OS). Subsequently, 12 ferroptosis‐related genes were screened to establish the prognostic signature using stepwise multivariate Cox regression. According to the median value of risk scores, patients were divided into low‐ and high‐risk subgroups. The Kaplan‐Meier curves showed the high‐risk group had a lower OS. The predictive power of the risk model was validated using the CGGA. Functional analysis revealed that the terms associated with plasma membrane receptor complex, immune response and glutamate metabolic process were primarily related to the risk model. Moreover, we established a nomogram that had a strong forecasting ability for the 1‐, 3‐ and 5‐year OS. In addition, we compared the risk scores between different clinical features. We also detected infiltration of macrophages and monocytes in different subgroups. Overall, our study identified the prognostic signature of 12 ferroptosis‐related genes, which has the potential to predict the prognosis of LGG.

Gliomas, the most common primary tumors in the central nervous system (CNS), can be categorized into 4 grades according to the World Health Organization. The most malignant glioma type is grade Ⅳ, also named glioblastoma multiforme (GBM). However, the standard treatment of concurrent temozolomide (TMZ) chemotherapy and radiotherapy after maximum resection does not improve overall survival in patients with GBM. Targeting components of the CNS microenvironment represents a new strategy for improving the efficacy of glioma treatment. Most recent studies focused on T cells. However, there is a growing body of evidence that tumor‐associated macrophages (TAMs) play an important role in tumor progression and can be regulated by a wide array of cytokines or chemokines. New TAM‐associated immunotherapies may improve clinical outcomes by blocking tumor progression and prolonging survival. However, understanding the exact roles and possible mechanisms of TAMs in the tumor environment is necessary for developing this promising therapeutic target and identifying potential diagnostic markers for improved prognosis. This review summarizes the possible interactions between TAMs and glioma progression and discusses the potential therapeutic directions for TAM‐associated immunotherapies.

Epidermal growth factor receptor (EGFR) amplification and EGFRvIII mutation drive glioblastoma (GBM) pathogenesis, but their regulation remains elusive. Here we characterized the EGFR/EGFRvIII “interactome” in GBM and identified thyroid receptor-interacting protein 13 (TRIP13), an AAA + ATPase, as an EGFR/EGFRvIII-associated protein independent of its ATPase activity. Functionally, TRIP13 augmented EGFR pathway activation and contributed to EGFR/EGFRvIII-driven GBM growth in GBM spheroids and orthotopic GBM xenograft models. Mechanistically, TRIP13 enhanced EGFR protein abundance in part by preventing Cbl-mediated ubiquitination and proteasomal degradation. Reciprocally, TRIP13 was phosphorylated at tyrosine(Y) 56 by EGFRvIII and EGF-activated EGFR. Abrogating TRIP13 Y56 phosphorylation dramatically attenuated TRIP13 expression-enhanced EGFR signaling and GBM cell growth. Clinically, TRIP13 expression was upregulated in GBM specimens and associated with poor patient outcome. In GBM, TRIP13 localized to cell membrane and cytoplasma and exhibited oncogenic effects in vitro and in vivo, depending on EGFR signaling but not the TRIP13 ATPase activity. Collectively, our findings uncover that TRIP13 and EGFR form a feedforward loop to potentiate EGFR signaling in GBM growth and identify a previously unrecognized ATPase activity-independent mode of action of TRIP13 in GBM biology.

This study explores the topological properties of brain gray matter (GM) networks in patients with paroxysmal kinesigenic dyskinesia (PKD) and asks whether GM network features have potential diagnostic value. We used 3D T1‐weighted magnetic resonance imaging and graph theoretical approaches to investigate the topological organization of GM morphological networks in 87 PKD patients and 115 age‐ and sex‐matched healthy controls. We applied a support vector machine to GM morphological network matrices to classify PKD patients versus healthy controls. Compared with the HC group, the GM morphological networks of PKD patients showed significant abnormalities at the global level, including an increase in characteristic path length (Lp) and decreases in local efficiency (E loc), clustering coefficient (Cp), normalized clustering coefficient (γ), and small‐worldness (σ). The decrease in Cp was significantly correlated with disease duration and age of onset. The GM morphological networks of PKD patients also showed significant changes in nodal topological characteristics, mainly in the basal ganglia‐thalamus circuitry, default‐mode network and central executive network. Finally, we used the GM morphological network matrices to classify individuals as PKD patients versus healthy controls, achieving 87.8% accuracy. Overall, this study demonstrated disruption of GM morphological networks in PKD, which might extend our understanding of the pathophysiology of PKD; further, GM morphological network matrices might have the potential to serve as network neuroimaging biomarkers for the diagnosis of PKD., This study explores the topological properties of brain gray matter (GM) networks in patients with paroxysmal kinesigenic dyskinesia (PKD), providing the first demonstration that PKD features disrupted topological organization in GM morphological networks and the GM morphological network matrices might have potential as neuroimaging biomarkers to assist in clinical PKD diagnosis.

Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has spread around the world. However, approaches to distinguish COVID-19 from pneumonia caused by other pathogens have not yet been reported. We retrospectively analyzed the clinical data of 97 children with probable COVID-19. A total of 13 (13.4%) patients were confirmed positive for SARS-CoV-2 infection by nucleic acid RT-PCR testing, and 41 (42.3%) patients were found to be infected with other pathogens. Notably, no pathogen was detected in 43 (44.3%) patients. Among all patients, 25 (25.8%) had familial cluster exposure history, and 52 (53.6%) had one or more coexisting conditions. Fifteen (15.5%) patients were admitted or transferred to the PICU. In the 11 confirmed COVID-19 cases, 5 (45.5%) and 7 (63.6%) were positive for IgM and IgG against SARS-CoV-2, respectively. In 22 patients with suspected COVID-19, 1 (4.5%) was positive for IgG but negative for IgM. The most frequently detected pathogen was Mycoplasma pneumonia (29, 29.9%). One patient with confirmed COVID-19 died. Our results strongly indicated that the detection of asymptomatic COVID-19 or coexisting conditions must be strengthened in pediatric patients. These cases may be difficult to diagnose as COVID-19 unless etiologic analysis is conducted. A serologic test can be a useful adjunctive diagnostic tool in cases where SARS-CoV-2 infection is highly suspected but the nucleic acid test is negative. Electronic Supplementary Material Supplementary material is available in the online version of this article at 10.1007/s11684-020-0820-7 and is accessible for authorized users.

Gamma‐interferon‐inducible lysosomal thiol reductase, the only known lysosomal thiol reductase, is encoded by gene IFI30 and expressed constitutively in antigen‐presenting cells. Our comprehensive study on IFI30 in gliomas found its expression to be high in glioblastomas and in gliomas with a mesenchymal subtype or wild‐type isocitrate dehydrogenase, all of which indicated the malignancy and poor outcomes of gliomas. Kaplan‐Meier survival analysis ascertained that high IFI30 expression conferred poor outcomes. The IFI30 expression levels also showed high efficiency in predicting 1‐, 3‐ and 5‐year overall survival. Univariable and multivariable Cox regression analyses were performed to define IFI30 as an independent prognostic marker. Biological process analysis suggested that IFI30 was involved in immune responses. ESTIMATE and CIBERSORT were applied to evaluate immune cell infiltration, with results indicating that samples with higher IFI30 expression had higher infiltration of immune cells, including regulatory T cells and M0 macrophages. Correlation analysis showed that IFI30 was significantly positively correlated with immune checkpoints that suppress effective antitumour immune responses. Immunohistochemical staining was also performed to confirm the association between IFI30 expression and the immune phenotype. The suggested correlation between high IFI30 expression and an immunosuppressive phenotype contributes to our knowledge about the glioma microenvironment and might provide clues for the development of novel therapeutic targets.

In recent years, the deoxycytidine analogue gemcitabine (2′,2′,-difluorodeoxycytidine) has become the first-line chemotherapeutic agent for patients with pancreatic cancer. However, due to the intrinsic resistance of pancreatic cancer cells, gemcitabine-based chemotherapy yields limited disease control, with >85% disease progression at 6 months from diagnosis. Therefore, elucidating the mechanisms of chemoresistance is a critical step in improving cancer therapy, especially for the treatment of pancreatic cancer. We show PROM2, a transmembrane glycoprotein, is ubiquitously upregulated in pancreatic cancer cell. We also found higher PROM2 expression is associated with shortened overall and disease-free survival times in patients diagnosed with pancreatic cancer. We provide evidence that PROM2 promotes chemoresistance to gemcitabine both in vivo and in vitro. Mechanistically, we demonstrate that PROM2 could directly interacted with Akt and activates the Akt signaling pathway, which thus inhibiting gemcitabine-induced apoptosis. As further evidence, we show PROM2 expression and Akt phosphorylation both promote gemcitabine chemoresistance, and cause poorer survival in clinical samples with pancreatic cancer. Combining gemcitabine with the Akt inhibitor MK-2206 facilitated significant tumor shrinkage and dramatically elevated the survival status in mice xenografted with pancreatic cancer cells. Our findings not only establish PROM2 as a novel positive regulator of the Akt signaling pathway and a candidate prognostic indicator of gemcitabine response, but also provide a neo-therapeutic approach for patients resistant to gemcitabine treatment., Pancreatic cancer: Exploring a pathway to drug resistance A cell membrane protein called PROM2 promotes the resistance of pancreatic cancer to the anti-cancer drug gemcitabine, suggesting PROM2 and the molecular signaling pathway it stimulates could be targeted by new treatments. Researchers in China led by Jian Sun at Sun Yat-Sen University, Guangzhou, investigated the role of PROM2 in cultured human pancreatic cancer cells and in a mouse model of pancreatic cancer. Production and activity of PROM2 were increased in cancer cells, leading to increased resistance to gemcitabine. The researchers found that PROM2’s promotion of gemcitabine resistance was linked to its ability to bind to another protein called Akt. This interaction stimulates the Akt signaling pathway, sustaining cancer cells. Combining gemcitabine therapy with an Akt pathway inhibitor restored cancer cell sensitivity to gemcitabine, revealing a potential approach to developing drugs to overcome gemcitabine resistance.

Protein content (PC) and oil content (OC) are important breeding traits of soybean [Glycine max(L.) Merr.]. Quantitative trait locus (QTL) mapping for PC and OC is important for molecular breeding in soybean; however, the negative correlation between PC and OC influences the accuracy of QTL mapping. In the current study, a four-way recombinant inbred lines (FW-RILs) population comprising 160 lines derived from the cross (Kenfeng14 × Kenfeng15) × (Heinong48 × Kenfeng19) was planted in eight different environments and PC and OC measured. Conditional and unconditional QTL analyses were carried out by interval mapping (IM) and inclusive complete IM based on linkage maps of 275 simple sequences repeat markers in a FW-RILs population. This analysis revealed 59 unconditional QTLs and 52 conditional QTLs among the FW-RILs. An analysis of additive effects indicated that the effects of 13 protein QTLs were not related to OC, whereas OC affected the expression of 13 and eight QTLs either partially or completely, respectively. Eight QTLs affecting OC were not influenced by PC, whereas six and 26 QTLs were partially and fully affected by PC, respectively. Among the QTLs detected in the current study, two protein QTLs and five oil QTLs had not been previously reported. These findings will facilitate marker-assisted selection and molecular breeding of soybean.

Background As a photoperiod-sensitive and self-pollinated species, the growth periods traits play important roles in the adaptability and yield of soybean. To examine the genetic architecture of soybean growth periods, we performed a genome-wide association study (GWAS) using a panel of 278 soybean accessions and 34,710 single nucleotide polymorphisms (SNPs) with minor allele frequencies (MAF) higher than 0.04 detected by the specific-locus amplified fragment sequencing (SLAF-seq) with a 6.14-fold average sequencing depth. GWAS was conducted by a compressed mixed linear model (CMLM) involving in both relative kinship and population structure. Results GWAS revealed that 37 significant SNP peaks associated with soybean flowering time or other growth periods related traits including full bloom, beginning pod, full pod, beginning seed, and full seed in two or more environments at -log10(P) > 3.75 or -log10(P) > 4.44 were distributed on 14 chromosomes, including chromosome 1, 2, 3, 5, 6, 9, 11, 12, 13, 14, 15, 17, 18, 19. Fourteen SNPs were novel loci and 23 SNPs were located within known QTLs or 75 kb near the known SNPs. Five candidate genes (Glyma.05G101800, Glyma.11G140100, Glyma.11G142900, Glyma.19G099700, Glyma.19G100900) in a 90 kb genomic region of each side of four significant SNPs (Gm5_27111367, Gm11_10629613, Gm11_10950924, Gm19_34768458) based on the average LD decay were homologs of Arabidopsis flowering time genes of AT5G48385.1, AT3G46510.1, AT5G59780.3, AT1G28050.1, and AT3G26790.1. These genes encoding FRI (FRIGIDA), PUB13 (plant U-box 13), MYB59, CONSTANS, and FUS3 proteins respectively might play important roles in controlling soybean growth periods. Conclusions This study identified putative SNP markers associated with soybean growth period traits, which could be used for the marker-assisted selection of soybean growth period traits. Furthermore, the possible candidate genes involved in the control of soybean flowering time were predicted.

Background: Most prior studies have explored surgery for the treatment of failed autologous arteriovenous fistulas (AVFs) with limited follow-up times and a lack of end point mortality. Accordingly, we conducted a retrospective cohort study to evaluate the clinical outcomes of the surgery of new AVF proximal to the failed forearm AVF. Methods: In this study, 538 end-stage renal disease patients (group A, 418 with primary AVF; and group B, 120 with failed AVF) were consecutively enrolled between January 2013 and June 2016, with a median follow-up time of 41 months. Primary and secondary patency, all-cause mortality, and risk factors associated with AVF failure were explored by the Kaplan–Meier method or Cox proportional hazards model. Results: In group A (n = 418), the primary and secondary patencies of AVF were 85.6% vs. 96.8%, 79.7% vs. 95.0%, 75.1% vs.93.9%, 73.2% vs. 93.6% and 73.2% vs. 93.6% at 12, 24, 36, 48 and 60 months, respectively. The primary patencies of AVF in group B were 95.0%, 91.7%, 89.2%, 88.3% and 88.3% at 12, 24, 36, 48 and 60 months, respectively. After adjusting for potential confounders, age, angiotensin-converting inhibitors or angiotensin-receptor blockers (anti-RAAS) drugs and D-dimer were independent predictors of AVF failure. However, there were no differences between functional and failed AVF regarding all-cause mortality. Conclusions: The study revealed that the primary and secondary patiencies of the surgery of new AVF proximal to the failed ones were ideal operations to restore failed forearm AVF.

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. SET and MYND domain-containing protein 3 (SMYD3) has been shown to promote the progression of various types of human cancers, including liver cancer; however, the detailed molecular mechanism is still largely unknown. Here, we report that SMYD3 expression in HCC is an independent prognostic factor for survival and promotes the proliferation and migration of HCC cells. We observed that SMYD3 upregulated sphingosine-1-phosphate receptor 1 (S1PR1) promoter activity by methylating histone 3 (H3K4me3). S1PR1 was expressed at high levels in HCC samples, and high S1PR1 expression was associated with shorter survival. S1PR1 expression was also positively correlated with SMYD3 expression in HCC samples. We confirmed that SMYD3 promotes HCC cell growth and migration in vitro and in vivo by upregulating S1PR1 expression. Further investigations revealed that SMYD3 affects critical signaling pathways associated with the progression of HCC through S1PR1. These findings strongly suggest that SMYD3 has a crucial function in HCC progression that is partially mediated by histone methylation at the downstream gene S1PR1, which affects key signaling pathways associated with carcinogenesis and the progression of HCC.

Photoperiod strictly controls vegetative and reproductive growth stages in soybean (Glycine max). A soybean GmRAV (Related to ABI3/VP1) transcription factor containing both AP2 and B3 domains was shown to be a key component of this process. We identified six polymorphisms in the GmRAV promoter that showed significant association with flowering time and maturity of soybean in one or multiple environments. Soybean varieties with minor polymorphism exhibited a longer growth period contributing to soybean adaptation to lower latitudes. The cis-acting element GT1CONSENSUS motif of the GmRAV promoter controlled the growth period, and the major allele in this motif shortened duration of late reproductive stages by reducing GmRAV expression levels. Three GmRAV-overexpressing (GmRAV-ox) transgenic lines displayed later flowering time and maturity, shorter height and fewer numbers of leaves compared with control plants, whereas transgenic inhibition of GmRAV expression resulted in earlier flowering time and maturity and increased plant height. Combining DNA affinity purification sequencing and RNA sequencing analyses revealed 154 putative target genes directly bound and transcriptionally regulated by GmRAV. Two GmRAV binding motifs [C(A/G)AACAA(G/T)A(C/T)A(G/T)] and [C(T/A)A(C)C(T/G)CTG] were identified, and acting downstream of E3E4, GmRAV repressed GmFT5a transcriptional activity through binding a CAACA motif, thereby delaying soybean growth and extending both vegetative and reproductive phases.

PurposeGlioma is a classical type of primary brain tumors that is most common seen in adults, and its high heterogeneity used to be a reference standard for subgroup classification. Glioma has been diagnosed based on histopathology, grade, and molecular markers including IDH mutation, chromosome 1p/19q loss, and H3K27M mutation. This subgroup classification cannot fully meet the current needs of clinicians and researchers. We, therefore, present a new subgroup classification for glioma based on the expression levels of Gβ and Gγ genes to complement studies on glioma and Gβγ subunits, and to support clinicians to assess a patient’s tumor status.MethodsGlioma samples retrieved from the CGGA database and the TCGA database. We clustered the gliomas into different groups by using expression values of Gβ and Gγ genes extracted from RNA sequencing data. The Kaplan–Meier method with a two-sided log-rank test was adopted to compare the OS of the patients between GNB2 group and non-GNB2 group. Univariate Cox regression analysis was referred to in order to investigate the prognostic role of each Gβ and Gγ genes. KEGG and ssGSEA analysis were applied to identify highly activated pathways. The “estimate” package, “GSVA” package, and the online analytical tools CIBERSORTx were employed to evaluate immune cell infiltration in glioma samples.ResultsThree subgroups were identified. Each subgroup had its own specific pathway activation pattern and other biological characteristics. High M2 cell infiltration was observed in the GNB2 subgroup. Different subgroups displayed different sensitivities to chemotherapeutics. GNB2 subgroup predicted poor survival in patients with gliomas, especially in patients with LGG with mutation IDH and non-codeleted 1p19q.ConclusionThe subgroup classification we proposed has great application value. It can be used to select chemotherapeutic drugs and the prognosis of patients with target gliomas. The unique relationships between subgroups and tumor-related pathways are worthy of further investigation to identify therapeutic Gβγ heterodimer targets.

The flowering time and plant height of soybean are important agronomic characters, which control the adaptability and yield of soybean. R2R3 MYB transcription factor plays an important regulatory role in plant growth and development. In this study, soybean GmGAMYB gene of R2R3-MYB type was induced by long-days (LDs). GmGAMYB showed higher transcriptional levels in the flowers, leaves and pods of soybean. Overexpression of GmGAMYB in transgenic soybean showed earlier flowering time and maturity in LDs and short-days (SDs). GmGAMYB interacted with GmGBP1 and might promote flowering time by up-regulating the expression of GmFULc gene in soybean. Moreover, the expression level of GmGAMYB was also induced by gibberellins (GAs) and the plant height of GmGAMYB-ox plants was significantly increased, which was caused by the enlargement of internode cell in stem. Furthermore, GmGAMYB overexpression led to increased GA sensitivity in the hypocotyl of soybean seedlings compared with WT. GmGAMYB may be a positive regulator of GA response of promoting plant height by up-regulating the expression of GmGA20ox gene in soybean. Together, our studies preliminarily showed that the partial functions of GmGAMYB in regulating flowering time and GA pathway.

Number of pods per plant and number of seeds per pod are quantitative, multigenic traits and important components of yield in soybean [Glycine max (L.) Merr.]. Pods are distributed unevenly in the upper, middle, and lower segments of the plant and this distribution is affected by sowing date (SD). A population of four-way recombinant inbred lines (FW-RIL), containing 160 F2:8 individuals, was generated from the cross (Kenfeng 14 × Kenfeng 15) × (Heinong 48 × Kenfeng 19). A linkage map consisting of 275 simple sequence repeat (SSR) markers was used to map quantitative trait loci (QTL) associated with the production of one, two, three, and four seeds per pod in the upper, middle, and lower segments of plants at two SDs, totaling 12 measurements per SD. A wide range of variation in the twelve characteristics was observed among the four parental lines and the FW-RIL population at the two SDs. The effect of SD2 (May 17, 2016) on pod number was stronger than that of SD1 (May 7, 2016) because the heritability of each trait in the SD1 experiment was generally greater than that of SD2. The study identified 76 QTL controlling pod number, with the phenotypic variation explained by each QTL ranging from 1.86% to 13.71%. The numbers of QTL controlling one, two, three, and four seeds per pod were 28, 23, 23, and 23, respectively. There were 30, 28, and 28 QTL controlling the pod number in the upper, middle, and lower segments of the plant, respectively. Forty-five QTL were identified at SD1 and 38 QTL were identified at SD2. Seventeen QTL were associated with pod-number traits. The QTL qPN-A1–3 was associated with the number of pods containing one seed in the middle segment of the plant at both SDs. Sixty-three QTL were published QTL (common areas existed when integrating on a map GmComposite2003 of Wm82 based on left and right markers). and 13 QTL related to pod number were newly discovered. These results provide a reference for breeders to improve soybean yield by combining advantageous alleles for these QTL. Future studies may reveal candidate genes for these QTL and identify causal alleles for marker-assisted selection. Keywords: Soybean, Pod number, QTL, Sowing date, Vertical distribution

The blood-brain barrier (BBB) is a barrier of the central nervous system (CNS), which can restrict the free exchange of substances, such as toxins and drugs, between cerebral interstitial fluid and blood, keeping the relative physiological stabilization. The brain capillary endothelial cells, one of the structures of the BBB, have a variety of ATP-binding cassette transporters (ABC transporters), among which the most widely investigated is Pglycoprotein (P-gp) that can efflux numerous substances out of the brain. The expression and activity of P-gp are regulated by various signal pathways, including tumor necrosis factor-α (TNF-α)/protein kinase C-β (PKC- β)/sphingosine-1-phosphate receptor 1 (S1P), vascular endothelial growth factor (VEGF)/Src kinase, etc. However, it remains unclear how hypoxic signaling pathways regulate the expression and activity of P-gp in brain microvascular endothelial cells. According to previous research, hypoxia affects the expression and activity of the transporter. If the transporter is up-regulated, some drugs enter the brain's endothelial cells and are pumped back into the blood by transporters such as P-gp before they enter the brain tissue, consequently influencing the drug delivery in CNS; if the transporter is down-regulated, the centrally toxic drug would enter the brain tissue and cause serious adverse reactions. Therefore, studying the mechanism of hypoxia-regulating P-gp can provide an important reference for the treatment of CNS diseases with a hypoxia/reoxygenation (H/R) component. This article summarized the mechanism of regulation of P-gp in BBB in normoxia and explored that of hypoxia.

Background Glioma‐related epilepsy (GRE) is defined as symptomatic epileptic seizures secondary to gliomas, it brings both heavy financial and psychosocial burdens to patients with diffuse glioma and significantly decreases their quality of life. To date, there have been no clinical guidelines that provide recommendations for the optimal diagnostic and therapeutic procedures for GRE patients. Methods In March 2017, the Joint Task Force for GRE of China Association Against Epilepsy and Society for Neuro‐Oncology of China launched the guideline committee for the diagnosis and treatment of GRE. The guideline committee conducted a comprehensive review of relevant domestic and international literatures that were evaluated and graded based on the Oxford Centre for Evidence‐Based Medicine Levels of Evidence, and then held three consensus meetings to discuss relevant recommendations. The recommendations were eventually given according to those relevant literatures, together with the experiences in the diagnosis and treatment of over 3000 GRE cases from 24 tertiary level hospitals that specialize in clinical research of epilepsy, glioma, and GRE in China. Results The manuscript presented the current standard recommendations for the diagnostic and therapeutic procedures of GRE. Conclusions The current work will provide a framework and assurance for the diagnosis and treatment strategy of GRE to reduce complications and costs caused by unnecessary treatment. Additionally, it can serve as a reference for all professionals involved in the management of patients with GRE.

Recently, graph theoretical approaches applied to neuroimaging data have advanced understanding of the human brain connectome and its abnormalities in psychiatric disorders. However, little is known about the topological organization of brain white matter networks in posttraumatic stress disorder (PTSD). Seventy‐six patients with PTSD and 76 age, gender, and years of education‐matched trauma‐exposed controls were studied after the 2008 Sichuan earthquake using diffusion tensor imaging and graph theoretical approaches. Topological properties of brain networks including global and nodal measurements and modularity were analyzed. At the global level, patients showed lower clustering coefficient (p = .016) and normalized characteristic path length (p = .035) compared with controls. At the nodal level, increased nodal centralities in left middle frontal gyrus, superior and inferior temporal gyrus and right inferior occipital gyrus were observed (p

This study aimed to identify the optimal radiomic machine-learning classifier for differentiating glioblastoma (GBM) from solitary brain metastases (MET) preoperatively. Four hundred and twelve patients with solitary brain tumors (242 GBM and 170 solitary brain MET) were divided into training (n = 227) and test (n = 185) cohorts. Radiomic features extraction was performed with PyRadiomics software. In the training cohort, twelve feature selection methods and seven classification methods were evaluated to construct favorable radiomic machine-learning classifiers. The performance of the classifiers was evaluated using the mean area under the curve (AUC) and relative standard deviation in percentile (RSD). In the training cohort, thirteen classifiers had favorable predictive performances (AUC≥0.95 and RSD ≤6). In the test cohort, receiver operating characteristic (ROC) curve analysis revealed that support vector machines (SVM) + least absolute shrinkage and selection operator (LASSO) (AUC, 0.90) classifiers had the highest prediction efficacy. Furthermore, the clinical performance of the best classifier was superior to neuroradiologists in accuracy, sensitivity, and specificity. In conclusion, employing radiomic machine-learning technology could help neuroradiologist in differentiating GBM from solitary brain MET preoperatively.

The effect of chemotherapy on programmed cell death-ligand 1 (PD-L1) expression has been previously studied in lung cancer, while the results remain controversial. The aim of this study was to investigate the variation of PD-L1 expression after neoadjuvant chemotherapy and explore the association between chemotherapy response, prognosis and the variation of PD-L1 expression in lung cancer patients. A total of 63 lung cancer patients who received platinum-based neoadjuvant chemotherapy and subsequently underwent surgical resection were selected. PD-L1 expression on tumor cells (TC) and tumor-infiltrating immune cells (IC) was assessed by immunohistochemistry using 22C3 monoclonal antibody in these 63 matched lung cancer specimens before and after neoadjuvant chemotherapy. The positivity of PD-L1 on TC changed from 17.5% to 39.7% after neoadjuvant chemotherapy and the positivity of PD-L1 on IC changed from 19.0% to 71.4% after neoadjuvant chemotherapy. The elevation of PD-L1 expression on TC after neoadjuvant chemotherapy was more frequently observed in patients achieving stable disease or progressive disease than in patients achieving partial response (P=0.026). Patients with elevated PD-L1 expression on TC after neoadjuvant chemotherapy showed a trend to have a shorter progression-free survival than patients without elevated PD-L1 expression on TC, although the difference was not statistically significant in multivariate analysis (hazard ratio=2.38, 95% confidence interval=0.99-5.73, P=0.053). PD-L1 expression can be elevated by chemotherapy in lung cancer. Furthermore, elevation of PD-L1 expression on TC after neoadjuvant chemotherapy was associated with reduced chemotherapy response and inferior progression-free survival in patients with lung cancer.

Background TP53 mutations are the most prevalent mutations detected in non‐small‐cell lung cancer (NSCLC) and have been revealed as a negative prognostic biomarker of outcome. The impact of concomitant TP53 mutations in ALK‐rearranged NSCLC remains uncertain. Methods Tumor samples from 64 ALK‐rearranged NSCLC patients receiving crizotinib treatment were subjected to next‐generation sequencing (NGS) to identify TP53 mutational status. The clinicopathologic features of the TP53 mutations and its impact on the effect of crizotinib treatment were analyzed. Results Among the 64 ALK‐rearranged patients, 15 (23.4%) patients showed a TP53 mutation. Of these, six cases had disruptive mutations and nine with nondisruptive mutations. The objective response rate (ORR) and disease control rate (DCR) for TP53 mutated patients were both significantly lower compared with those for TP53 wild‐type patients (p = 0.003 and 0.023, respectively). A significantly shorter progression‐free survival (PFS) was found in TP53 mutated patients compared with TP53 wild‐type patients (p = 0.045). Nondisruptive TP53 mutations were associated with a shorter PFS in comparison with disruptive TP53 mutations in ALK‐rearranged patients (p = 0.069). When nondisruptive TP53 mutated patients were in comparison with TP53 wild‐type patients, nondisruptive TP53 mutations were associated with a significant reduced PFS (p = 0.003). Conclusions TP53 mutations, especially nondisruptive mutations, negatively affected the response to crizotinib and correlated with shorter PFS in ALK‐rearranged NSCLC patients.

Potential effects of initiating acute antipsychotic treatment on white matter (WM) microstructure in schizophrenia patients remain poorly characterized. Thirty-five drug-naïve first-episode schizophrenia patients were scanned before and after six weeks of treatment with second-generation antipsychotic medications. Nineteen demographically matched healthy subjects were scanned twice over the same time interval. Tract-based spatial statistics was used to test for changes in WM microstructural integrity after treatment. Widespread fractional anisotropy (FA) decrease was found in patients after antipsychotic treatment in bilateral posterior corona radiata, anterior corona radiata, superior corona radiata and posterior thalamic radiation, left posterior limb of the internal capsule, and mid-body of the corpus callosum. These effects appeared to result primarily from decreased axial diffusivity. These findings suggest an effect on brain white matter from acute antipsychotic therapy in schizophrenia.

Automatic diagnosis and classification of schizophrenia based on functional magnetic resonance imaging (fMRI) data have attracted increasing attention in recent years. Most previous studies abstracted highly compressed functional features from the view of brain science and fed them into shallow classifiers for this purpose. However, their classification performance in practical applications is unstable and unsatisfactory. As an acute psychotic disorder, schizophrenia shows functional complexity in fMRI data. Therefore, additional features and deep classification methods are needed to improve classification performance. In this study, we propose a multiple feature image capsule network ensemble approach for schizophrenia classification. The proposed approach proceeds in three steps: 1) extracting multiple image features from the perspective of linear sparse representation, nonlinear multiple kernel representation, and function connection of brain areas respectively; 2) feeding these image features into three specially designed independent capsule networks for classification; 3) obtaining the final results by fusing the outputs of these three deep capsule network using a ensemble approach. To further improve the classification performance, we design a optimization model of maximizing the square of correlation coefficients and propose a weighted ensemble technology based on this model, which is mathematically proved to be solved as a eigenvalue decomposition problem in certain case. Finally, the proposed approach is implemented and evaluated on the schizophrenia fMRI dataset from COBRE, UCLA and WUSTL. From the experimental results, we conclude that the proposed method outperforms some current methods and further improves the accuracy of schizophrenia classification.

Soybean is valued in foods, animal feed and some industrial applications, and agronomic traits are important targets for soybean breeding. In this study, two sets of recombinant inbred line (RIL) populations were used to map yield and quality trait quantitative trait loci (QTLs) across three environments. In total, we detected 37 QTLs in two RIL populations grown in three locations. In the 3613 RIL population, three QTLs related to quality traits and 13 related to yield traits were identified among the 16 QTLs. In the 6013 population, we identified six QTLs related to quality traits and 15 related to yield traits. Among these QTLs, some genomic regions showed pleiotropic effects on yield and quality traits. We further identified candidate genes from these regions. Our results lay the foundation for producing high-yielding soybean with excellent quality traits via molecular breeding.

Soybean is globally cultivated primarily for its protein and oil. The protein and oil contents of the seeds are quantitatively inherited traits determined by the interaction of numerous genes. In order to gain a better understanding of the molecular foundation of soybean protein and oil content for the marker-assisted selection (MAS) of high quality traits, a population of 185 soybean germplasms was evaluated to identify the quantitative trait loci (QTLs) associated with the seed protein and oil contents. Using specific length amplified fragment sequencing (SLAF-seq) technology, a total of 12,072 single nucleotide polymorphisms (SNPs) with a minor allele frequency (MAF) ≥ 0.05 were detected across the 20 chromosomes (Chr), with a marker density of 78.7 kbp. A total of 31 SNPs located on 12 of the 20 soybean chromosomes were correlated with seed protein and oil content. Of the 31 SNPs that were associated with the two target traits, 31 beneficial alleles were identified. Two SNP markers, namely rs15774585 and rs15783346 on Chr 07, were determined to be related to seed oil content both in 2015 and 2016. Three SNP markers, rs53140888 on Chr 01, rs19485676 on Chr 13, and rs24787338 on Chr 20 were correlated with seed protein content both in 2015 and 2016. These beneficial alleles may potentially contribute towards the MAS of favorable soybean protein and oil characteristics.

Background The nutritional value of soybean oil is largely influenced by the proportions of unsaturated fatty acids (FAs), including oleic acid (OA, 18:1), linoleic acid (LLA, 18:2), and linolenic acid (LNA, 18:3). Genome-wide association (GWAS) studies along with gene expression studies in soybean [Glycine max (L.) Merr.] were leveraged to dissect the genetics of unsaturated FAs. Results A association panel of 194 diverse soybean accessions were phenotyped in 2013, 2014 and 2015 to identify Single Nucleotide Polymorphisms (SNPs) associated with OA, LLA, and LNA content, and determine putative candidate genes responsible for regulating unsaturated FAs composition. 149 SNPs that represented 73 genomic regions were found to be associated with the unsaturated FA contents in soybean seeds according to the results of GWAS. Twelve novel genes were predicted to be involved in unsaturated FA synthesis in soybean. The relationship between expression pattern of the candidate genes and the accumulation of unsaturated FAs revealed that multiple genes might be involved in unsaturated FAs regulation simultaneously but work in very different ways: Glyma.07G046200 and Glyma.20G245500 promote the OA accumulation in soybean seed in all the tested accessions; Glyma.13G68600 and Glyma.16G200200 promote the OA accumulation only in high OA germplasms; Glyma.07G151300 promotes OA accumulation in higher OA germplasms and suppresses that in lower OA germplasms; Glyma.16G003500 has the effect of increasing LLA accumulation in higher LA germplasms; Glyma.07G254500 suppresses the accumulation of LNA in lower OA germplasms; Glyma.14G194300 might be involved in the accumulation of LNA content in lower LNA germplasms. Conclusions The beneficial alleles and candidate genes identified might be valuable for improving marker-assisted breeding efficiency and exploring the molecular mechanisms underlying unsaturated fatty acid of soybean. Electronic supplementary material The online version of this article (10.1186/s12864-019-5449-z) contains supplementary material, which is available to authorized users.

BACKGROUND PD-L1 expression in tumor cells has been associated with the efficacy of immune checkpoint inhibitors in non-small cell lung cancer (NSCLC). The aim of this study was to explore correlations between smoking, genetic profiles, patient outcomes, and PD-L1 expression in NSCLC. METHODS PD-L1 expression was evaluated in 241 surgically resected specimens by immunostaining and 50% was set as the cutoff value. RESULTS Of the 241 tumors analyzed, a PD-L1 tumor proportion score (TPS) of ≥ 50% was detected in 35 cases (14.5%) and a TPS of < 50% in 206 cases (85.5%). A PD-L1 TPS ≥ 50% was significantly associated with smoking and EGFR wild-type status (P < 0.001 and P = 0.039, respectively). Detailed assessment of smoking variables showed that total smoking duration was a predictor of a PD-L1 TPS ≥ 50% (P = 0.001). Univariate and multivariate survival analyses revealed that patients with a PD-L1 TPS ≥ 50% had poorer disease-free and overall survival than those with a PD-L1 TPS < 50% (P = 0.001 and P < 0.001, respectively). CONCLUSION The incidence of a PD-L1 TPS ≥ 50% was significantly higher in smoking and EGFR wild-type NSCLC patients, particularly in long-term smokers. A PD-L1 TPS of ≥ 50% was an independent adverse prognostic factor for survival in patients with NSCLC.

To prepare a tissue-engineered pulmonary valved conduit (PVC) with good tensile strength and biocompatibility. Sixty adult porcine PVCs were used to determine the optimal decellularization time. Five juvenile porcine decellularized PVCs and five juvenile porcine crosslinked PVCs were subsequently prepared according to the optimized decellularization and crosslinking methods. All PVCs were implanted into juvenile sheep for 8 months and then were harvested for staining. With a low concentration of detergent (0.25% Triton X-100+0.25% sodium deoxycholate), the decellularization effect on porcine PVCs was complete by 24 hours, and there was minimal damage to the matrix. Gelatin embedding and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) crosslinking improved the biomechanical properties of decellularized PVCs and reduced their immunogenicity. After implantation, the diameter and thickness of the PVCs in the decellularized and crosslinked groups increased significantly. In both groups, the conduits were unobstructed, with soft and smooth inner walls and without thrombosis, ulceration or neoplasia. The valves slightly degenerated with mild to moderate regurgitation. CD31-positive endothelial cells were visible on the inner surface of the conduits and valves. Scattered smooth muscle actin-positive cells were found in the middle layer of the conduit. The percentage of CD4- and CD68-positive cells and the calcium content were highest in decellularized porcine PVCs and lowest in ovine PVCs. The percentage of the matrix that was laminin-positive in decellularized and crosslinked porcine PVCs was lower than it was in ovine PVCs. Gelatin-embedded and EDC-crosslinked porcine PVCs can be "hosted" in sheep, with good biocompatibility, growth potential, and reduced calcification.

This study aimed to define the most consistent white matter microarchitecture pattern in Parkinson's disease (PD) reflected by fractional anisotropy (FA), addressing clinical profiles and methodology-related heterogeneity. Web-based publication databases were searched to conduct a meta-analysis of whole-brain diffusion tensor imaging studies comparing PD with healthy controls (HC) using the anisotropic effect size-signed differential mapping. A total of 808 patients with PD and 760 HC coming from 27 databases were finally included. Subgroup analyses were conducted considering heterogeneity with respect to medication status, disease stage, analysis methods, and the number of diffusion directions in acquisition. Compared with HC, patients with PD had decreased FA in the left middle cerebellar peduncle, corpus callosum (CC), left inferior fronto-occipital fasciculus, and right inferior longitudinal fasciculus. Most of the main results remained unchanged in subgroup meta-analyses of medicated patients, early stage patients, voxel-based analysis, and acquisition with 30 diffusion directions. The subgroup meta-analysis of medication-free patients showed FA decrease in the right olfactory cortex. The cerebellum and CC, associated with typical motor impairment, showed the most consistent FA decreases in PD. Medication status, analysis approaches, and the number of diffusion directions have an important impact on the findings, needing careful evaluation in future meta-analyses.

Objectives Previous studies and meta-analyses suggested that N-acetylcysteine (NAC) was superior to placebo in improving depression in bipolar disorder. However, more recent data, including two larger trials, found that NAC was no more effective than placebo. We conducted a meta-analysis to appraise the possible efficacy of NAC in treating bipolar depression. Methods A systematic review and meta-analysis of double-blind, placebo-controlled trials of NAC as a treatment augmentation strategy for bipolar depression was carried out in PubMed (1966-2020). We utilized random-effect analysis to evaluate improvement in depressive symptoms from baseline to endpoint as the primary efficacy measure. Results Six trials including 248 patients were included. Treatment augmentation with NAC showed a moderate effect size favoring NAC over placebo (d = 0.45, 95% C.I.: 0.06-0.84). There was substantial heterogeneity (I2 = 49%). Meta-regression analyses did not identify any moderator that might explain variation in heterogeneity, including baseline depressive symptom scores, mean NAC dose, or duration of study. Conclusions Results from six clinical trials suggest that treatment augmentation with NAC for bipolar depression appears to be superior to placebo, with a moderate effect size, but a large confidence interval. Larger clinical trials, investigating possible moderating factors, such as NAC dose, treatment duration, baseline depression severity, or chronicity of illness, are warranted.

Since the outbreak of COVID-19 in China at the end of 2019, the world has experienced a large-scale epidemic caused by the SARS-CoV-2. Epidemiological and clinical course of COVID-19 patients have been reported, but there have been few analyses about the characteristics, predictive risk factors and outcomes of critical patients. In this single-center retrospective case-control study, 90 adult inpatients hospitalized at Tongji Hospital (Wuhan, China) were included. Demographic, clinical, laboratory test and treatment data were obtained and compared between critical and non-critical patients. We found that compared with non-critical patients, the critical patients had higher SOFA score and qSOFA scores. Critical patients had lower lymphocyte and platelet count, elevated D-dimer, decreased fibrinogen, and elevated high-sensitivity C-reactive protein (hsCRP) and interleukin-6(IL-6). More critical patients received treatment including antibiotics, anticoagulation, corticosteroid and oxygen therapy than non-critical ones. Multivariable regression showed higher qSOFA score and elevation of IL-6 were related to critical patients. Antibiotic usage and anticoagulation were associated with decreased in-hospital mortality. And critical grouping contributed greatly to in-hospital death. Critical COVID-19 patients have a more severe clinical cours. qSOFA score and elevation of IL-6 are risk factors for critical condition. Non-critical grouping, positive antibiotic application and anticoagulation may be beneficial for patient survival.

As the second most destructive disease in soybean (Glycine max (L.) Merr), Phytophthora root or stem-rot (PRR) of soybean, which was caused by Phytophthora sojae (P. sojae), could lead to a 10–40% or complete yield loss annually. Researches were needed to perform to identify the P. sojae-resistant germplasm and to better understand the genetic basis of P. sojae resistance in soybean. A total of 225 diverse soybean cultivars and 109 recombinant inbred lines (RILs) derived from crossing ‘DongnongL-28’ (resistant to P. sojae race 1) and ‘Hefeng 25’ (susceptible to P. sojae race 1) were used to evaluate P. sojae race 1 resistance. These 225 soybean cultivars were sequenced using the Specific Locus Amplified Fragment Sequencing (SLAF-seq) approach, and 28,722 single-nucleotide polymorphisms (SNPs) were obtained from the mapping of resistant loci through genome-wide association. Eight quantitative trait nucleotides (QTNs) were associated with resistance to P. sojae race 1. The QTN on Chr.03 was colocalised according to linkage mapping of the RILs. A total of 18 candidate genes were predicted in the flanking region of the colocalised locus on Chr.03. There were stress response-related motifs, such as cis-acting regulatory elements involved in salicylic acid or MeJA responsiveness, in the 1-kb upstream region of sixteen genes. Quantitative RT-PCR showed that the Glyma.03G033700 was induced by P. sojae race 1. Association analysis for Rps loci showed that Glyma.03G033700 and Glyma.03G033800 were the candidates near peak SNP. The identified loci along with the candidate genes could be valuable for studying the molecular mechanisms underlying soybean resistance to P. sojae race 1 and breeding resistant varieties.

Tocopherol (Toc) occurs in soybean seeds and is extracted together with the soybean oil. Toc is utilized as an antioxidant in food and an additive in animal feed. A total of 180 representative accessions and 144 recombinant inbred lines (RILs) from the cross of ‘Hefeng 25’ and ‘OAC Bayfield’ were selected to evaluate individuals and total Toc concentrations in soybean seeds. The 180 soybean samples were sequenced by the approach of Specific Locus Amplified Fragment Sequencing (SLAF-seq). A total of 22,611 single nucleotide polymorphisms (SNPs) were developed. Nineteen quantitative trait nucleotides (QTNs) were identified associated with individual or total-Toc based on genome-wide association analysis (GWAS). Among them, three QTNs located near known QTLs, and 16 were novel. Eighteen QTLs and nine eQTLs were also detected by linkage mapping. The QTN rs9337368 on Chr.02 was colocalized according to the linkage mapping of the RILs and genome-wide association analysis and regarded as a stable locus for mining the candidate genes in association with Toc. A total of 42 candidate genes near the 200 kbp flanking region of this identified locus were found. Upon a gene-based association, 11 SNPs from five genes out of the 42 candidates were detected. Expression level analysis of five candidate genes revealed that two genes were significantly related to Toc content. The identified loci, along with the candidate genes, might be valuable for increasing the Toc concentration in soybean seeds and improving the nutritional value of soybean oil.

Sclerotinia stem rot (SSR) is a disease of soybean [Glycine max (L.) Merr] that causes severe yield losses. We studied 185 representative soybean accessions to evaluate partial SSR resistance and sequenced these by the specific-locus amplified fragment sequencing method. In total, 22,048 single-nucleotide polymorphisms (SNPs), with minor allele frequencies (MAF) ≥5% and missing data

Introduction: To explore association of excision repair cross-complementing 5 ( ERCC5) genetic polymorphisms with cirrhosis and liver cancer. Methods: A total of 365 patients were enrolled, including control group (n = 133), cirrhosis group (n = 122), and liver cancer group (n = 110). The genotyping of ERCC5 rs2016073, rs751402, rs2094258, rs2296147, and rs2296148 was measured by using MassARRAY iPLEX technology. Results: There were no significant differences in gender and drinking among the 3 groups ( P > .05). There were significant differences among the 3 groups in both age-group ≤60 and >60 subgroup patients. Locus rs2016073 was significantly different among 3 groups, and genotype GG (n = 0) was not observed in liver cancer group. As for locus rs751402, there were significant differences among 3 groups, and genotype AA (n = 0) was not observed in liver cancer group. As for locus rs2094258, there were no significant differences among 3 groups. Locus rs2296147 showed no significant differences among 3 groups ( P > .05), but genotype CC was not observed in liver cancer group (n = 0). As for locus rs2296148, there were significant differences among 3 groups, and genotype TC (n = 0) was not observed in cirrhosis group. Regression analysis found locus rs751402 had significant difference between control group and cirrhosis group, patients with genotype AA and genotype GG were more likely to have cirrhosis than those with genotype GA. Conclusion: Our study suggested that genotype AA, genotype GG of ERCC5 locus rs751402, and genotype TC of locus rs2296148 may be important targets for cirrhosis, while ERCC5 polymorphisms (rs2016073 and ERCC5 polymorphisms, rs2016073 with genotype GG, and rs751402 with genotype AA) may be potential markers for liver cancer.

Background: The role of cytarabine on newly diagnosed primary central nervous system lymphoma (PCNSL) remains controversial. The present study mainly aimed to assess the efficacy and safety of cytarabine in the induction treatment of PCNSL.Methods: We systematically searched PubMed, Embase, and the Cochrane library for randomized controlled trials comparing treatment of PCNSL patients with or without cytarabine. A meta-analysis was conducted to compare the odds ratios (ORs) with corresponding 95% confidence intervals (95% CI) for complete remission (CR) rate, overall response rate (ORR), grade 3–4 toxic effects, hazard ratios (HRs) with 95% CIs for progression-free survival (PFS), and overall survival (OS) using Stata 12.0.Results: In total, three randomized clinical trials were analyzed in this study. The result of our statistical analysis demonstrated that the application of cytarabine was closely correlated with a higher CR (OR: 2.27, 95% CI: 1.29–3.99, P < 0.01) and ORR (OR: 2.11, 95% CI: 1.14–3.93, P = 0.02). No significant difference was found in OS (HR: 0.75, 95% CI: 0.50–1.13, P = 0.17), but PFS had been improved (HR: 0.66, 95% CI: 0.45–0.97, P = 0.04) when cytarabine was added to the treatment regimen. The grade 3–4 side effect rate of the cytarabine group was higher (overall OR: 2.95, 95% CI: 1.37–6.34, P < 0.01) than that of the cytarabine-free group.Conclusions: This meta-analysis verifies that adding cytarabine to the therapeutic regimen is helpful for newly diagnosed PCNSL patients in terms of CR, ORR, and PFS. Moreover, it should be noted that the grade 3–4 toxic effects, especially hematological toxicity, are higher in the cytarabine group than in the cytarabine-free group. The results indicate that cytarabine plays an important role in the induction therapy of PCNSL. Large-sample and high-quality RCTs should be conducted to verify our results and confirm the effects of cytarabine on newly diagnosed PCNSL.

Nuclear Factor Y (NF-Y) gene family regulates numbers of flowering processes. Two independent transgenic Arabidopsis lines overexpressing (OX) GmNFY-B1 and GmNFYB1-GR (GmNFYB1 fused with the glucocorticoid receptor) were used to investigate the function of NFY-B1 in flowering. Furthermore, GmNFYB1-GR lines were chemically treated with dexamethasone (Dex, synthetic steroid hormone), cycloheximide (Cyc, an inhibitor of protein biosynthesis), and ethanol to examine their effects on different flowering related marker genes. Our results indicated that the transgenic lines produced longer hypocotyl lengths and had fewer numbers of rosette leaves compared to the wild-type and nf-yb1 mutant plants under both long and short-day (LD and SD) conditions. The qRT-PCR assays revealed that transcript levels of all flowering time regulating genes, i.e. SOC, FLC, FT, TSF, LFY, GI2, AGL, and FCA showed higher transcript abundance in lines OX GmNFYB1-GR. However, FT and GI genes showed higher transcript levels under Dex and Dex/Cyc treatments compared to Cyc and ethanol. Additionally, 24 differentially expressed genes were identified and verified through RNA-seq and RT-qPCR in GmNF-YB1-GR lines under Cyc and Dex/Cyc treatments from which 14 genes were up-regulated and 10 were down-regulated. These genes are involved in regulatory functions of circadian rhythm, regulation of flower development in photoperiodic, and GA pathways. The overexpression of GmNF-YB1 and GmNF-YB1-GR promote flowering through the higher expression of flowering-related genes. Further GmNF-YB1 and its attachment with the GR receptor can regulate its target genes under Dex/Cyc treatment and might act as flowering inducer under LD and SD conditions.

Background Glioma is the most common primary brain tumor, occurring due to the carcinogenesis of glial cells in the brain and spinal cord. Many aspects of the mechanism of its tumorigenesis remain unknown. The relationship between viral infection and glioma is one of the most important research aspects in this field. Currently, there is a lack of systematic reviews and meta-analyses to evaluate the effect of viral infection on the prognosis of glioma patients. The purpose of this study was to evaluate the relationship between viral infection and the prognosis of glioma patients, aimed at evaluating the prognostic value of the detection of viral infection. Methods Through careful and comprehensive retrieval of results from the PubMed, Embase, and Cochrane databases, eligible articles were selected strictly according to the inclusion and exclusion criteria. The regional sources, detection methods, detection indicators, patient survival, and other data from the samples in the papers were extracted, and the integrated analysis was conducted using Stata 15.1. We conducted a subgroup analysis of the relationship between the degree of infection and prognosis in cytomegalovirus (CMV) patients. Results A total of 11 studies were included in the analysis. Among them, 7 studies involved the relationship between CMV infection and the prognosis of patients with glioma, 2 studies involved human papillomavirus (HPV), 2 studies involved human herpesvirus-6 (HHV-6), and one study involved simian virus 40 (SV40), woolly monkey sarcoma virus (WMSV) and human endogenous retrovirus K113 (HERV-K113). In the CMV study, the pooled Hazard ratio (HR) of Overall survival (OS) was 1.024 (CI: 0.698–1.501), with a P value of 0.905. The pooled HR of Progression free survival (PFS) was 1.067 (CI: 0.770–1.478), with a P value of 0.697. The pooled HR value of low-degree infection versus high-degree infection was 1.476 (CI: 0.799–2.727), with a P value of 0.213. In the HPV study, the pooled HR of OS was 1.467 (CI: 0.552–3.901), with a P value of 0.443. Conclusion CMV infection has no significant effect on the prognosis of glioma patients. Using the IEA as the detection index, the degree of CMV infection was found to have a significant impact on the prognosis of glioma patients; it was not found to possess a significant prognostic value after the integration of different indicators. Neither HPV nor HHV-6 infection has a significant effect on the prognosis of glioma patients. SV40 and WMSV infection are associated with poor prognosis in patients with low-grade glioma. Trial Registration This meta-analysis registered in https://www.crd.york.ac.uk/PROSPERO/, PROSPERO ID: CRD42019127648.

Weighted correlation network analysis (WGCNA) is a statistical method that has been widely used in recent years to explore gene co-expression modules. Competing endogenous RNA (ceRNA) is commonly involved in the cancer gene expression regulation mechanism. Some ceRNA networks are recognized in gastric cancer; however, the prognosis-associated ceRNA network has not been fully identified using WGCNA. We performed WGCNA using datasets from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) to identify cancer-associated modules. The criteria of differentially expressed RNAs between normal stomach samples and gastric cancer samples were set at the false discovery rate (FDR) < 0.01 and |fold change (FC)| > 1.3. The ceRNA relationships obtained from the RNAinter database were examined by both the Pearson correlation test and hypergeometric test to confirm the mRNA–lncRNA regulation. Overlapped genes were recognized at the intersections of genes predicted by ceRNA relationships, differentially expressed genes, and genes in cancer-specific modules. These were then used for univariate and multivariate Cox analyses to construct a risk score model. The ceRNA network was constructed based on the genes in this model. WGCNA-uncovered genes in the green and turquoise modules are those most associated with gastric cancer. Eighty differentially expressed genes were observed to have potential prognostic value, which led to the identification of 12 prognosis-related mRNAs (KIF15, FEN1, ZFP69B, SP6, SPARC, TTF2, MSI2, KYNU, ACLY, KIF21B, SLC12A7, and ZNF823) to construct a risk score model. The risk genes were validated using the GSE62254 and GSE84433 datasets, with 0.82 as the universal cutoff value. 12 genes, 12 lncRNAs, and 35 miRNAs were used to build a ceRNA network with 86 dysregulated lncRNA–mRNA ceRNA pairs. Finally, we developed a 12-gene signature from both prognosis-related and tumor-specific genes, and then constructed a ceRNA network in gastric cancer. Our findings may provide novel insights into the treatment of gastric cancer.

Background: The clinical and prognostic value of programmed death-ligand 1, PD-L1, in glioblastoma (GBM) remains controversial. The present study aimed to identify the expression of PD-L1 for its prognostic value in glioblastoma.\ud Methods: A comprehensive literature search was performed using the PubMed and CNKI databases. The overall survival (OS) and disease-free survival (DFS) of GBM was analyzed based on Hazard ratios (HRs) and 95% confidence intervals (CIs). Furthermore, Odds ratios (ORs) and 95% CIs were summarized for clinicopathological parameters. The statistical analysis was using RevMan 5.3 software.\ud Results: The meta-analysis was performed by using total nine studies including 806 patients who had glioblastoma. The pooled results indicated that PD-L1 expression in tumour tissues was significantly related to a poor OS (HR=1.63, 95%CI: 1.19-2.24, P=0.003, random effects model) with heterogeneity (I2=51%). In subgroup analyses, PD-L1 positivity was significantly associated with a worse OS for patients of American and Asian regions, but not for those of European regions. Moreover, PD-L1 expression implied a trend toward the mutation status of the IDH1 gene (coding the Isocitrate Dehydrogenase (NADP(+))-1 protein) (HR=9.92, 95%CI: 1.85-53.08, P=0.007, fixed effects model). However, the prediction overall survival (OS) of the patients showed that PD-L1 expression was independent from other clinicopathological features, such as gender, age and tumour progression/recurrence.\ud Conclusions: Our analyses indicated that high expression of PD-L1 in glioblastoma tumour tissues is associated with poor survival of patients, and PD-L1 may act as a prognostic predictor and an effective therapeutic target for glioblastoma.

The processes of embryonic development that rely on epithelial-mesenchymal transition (EMT) for the implantation of trophoblast cells are co-opted by tumors, reflecting their inherent uncontrolled characteristics, leading to invasion and metastasis. Although tumorigenesis and embryogenesis have similar EMT characteristics, trophoblasts have been shown to exhibit "physiological metastasis" or be "pseudo-malignant", resulting in different outcomes. The gene co-expression network is the basis of embryonic development and tumorigenesis. We hypothesize that if the gene co-expression network in tumors is "off-track" from that in villi, it is more likely to develop into malignant tumors and have a worse prognosis, and we propose the "off-track theory" for the first time. In this study, we examined gene co-expression networks in villi and multiple solid tumors, and through network functional enrichment analyses, we found that most tumors and villi exhibited an significantly enriched EMT, but the genes that performed this function were not identical. Then, we identified the "off-track genes" in the EMT-related gene interaction network using the "off-track theory", and through survival analysis, we discovered that the risk score of "off-track genes" was associated with poor survival of cancer patients. Our study indicated that villi development is a reliable and strictly regulated model that can illuminate the trajectory of human cancer development and that the gene co-expression networks in tumor development are "off-track" from those in villi. These "off-track genes" may have a substantial impact on tumor development and could reveal novel prognostic biomarkers. Funding: This work was supported by the CAMS Innovation Fund for Medical Sciences (CIFMS2016-I2M-3-005). Declaration of Interest: The authors declare that they have no competing interests. Ethical Approval: This study was reviewed and approved by the Ethics Committee of the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College.

Background Previous studies have reported that 30% to 40% of patients with squamous cell carcinoma of the anus will require salvage abdominoperineal resection after chemoradiotherapy. Objective The purpose of this study was to identify the use, risk factors, and impact on survival of salvage abdominal perineal resection for squamous cell carcinoma of the anus. Design This was a retrospective, population-based cohort study. Settings Patients treated in Ontario, Canada through a single-payer universal healthcare system, were included. Patients Patients included all incident cases of squamous cell anal cancer who underwent curative intent radiotherapy from 2007 to 2015. Main outcome measures Risk of salvage abdominoperineal resection, factors associated with salvage abdominoperineal resection, and survival were measured. Results A total of 1125 patients were treated with curative intent radiotherapy for squamous cell cancer of the anus. Within this cohort, salvage surgery was performed in 8% (93/1125), whereas 14% (156/1125) required a permanent colostomy. In log-binomial regression, younger age was associated with salvage surgery, whereas sex, cancer stage, socioeconomic status, and HIV were not. There was a suggested lower risk of salvage surgery in those who completed chemoradiation (relative risk = 0.67 (95% CI, 0.43-1.03)). Crude 5-year overall survival rate was 73% (95% CI, 70%-76%) in those not requiring salvage surgery and 48% (95% CI, 37%-58%) in those who did. In Cox models, mortality was higher in patients requiring salvage surgery compared with those who did not (adjusted HR = 2.20 (95% CI, 1.65-2.94), whereas improved survival was seen in those who completed chemoradiation (HR = 0.65 (95% CI, 0.42-0.82)) LIMITATIONS:: The study was limited by its potential residual confounding by indication for salvage surgery. Conclusions In this large, contemporary cohort of patients with squamous cell carcinoma of the anus, the proportion of patients undergoing salvage surgery was considerably lower than previous reports. Younger age was associated with salvage surgery, and there was a suggestion of lower risk of salvage surgery with completion of chemoradiation. Patients requiring salvage surgery had poor 5-year overall survival. See Video Abstract at http://links.lww.com/DCR/B205. RAP DE RESCATE PARA EL CARCINOMA ANAL DE CeLULAS ESCAMOSAS: USO, FACTORES DE RIESGO Y RESULTADOS EN UNA POBLACIoN CANADIENSE: Estudios anteriores han reportado que 30-40% de los pacientes con carcinoma de celulas escamosas del ano requeriran una reseccion abdominoperineal de rescate despues de la quimiorradioterapia.Identificar la utilizacion, los factores de riesgo y el impacto en la supervivencia de la reseccion abdominoperineal de rescate para el carcinoma de celulas escamosas del ano.Estudio de cohorte retrospectivo, basado en la poblacion.Todos los casos incidentes de cancer anal de celulas escamosas que se sometieron a radioterapia con fines curativos de 2007 a 2015.Pacientes tratados en Ontario, Canada, un sistema de salud universal de un solo pagador.Riesgo de reseccion abdominoperineal de rescate, factores asociados con la reseccion abdominoperineal de rescate y la supervivencia.1125 pacientes fueron tratados con radioterapia de intencion curativa para el cancer de celulas escamosas del ano. Dentro de esta cohorte, la cirugia de rescate se realizo en el 8% (93/1125), mientras que el 14% (156/1125) requirio una colostomia permanente. En la regresion log-binomial, la edad mas joven se asocio con la cirugia de rescate, mientras que el sexo, la etapa del cancer, el estado socioeconomico y el VIH no. Se sugirio un menor riesgo de cirugia de rescate en aquellos que completaron la quimiorradiacion (RR 0,67; IC del 95%: 0,43 a 1,03). La tasa de supervivencia global bruta a 5 anos fue del 73% (IC del 95%: 70-76%) en aquellos que no requirieron cirugia de rescate y del 48% (IC del 95%: 37-58%) en los que si lo requirieron. En los modelos de Cox, la mortalidad fue mayor en los pacientes que requirieron cirugia de rescate en comparacion con aquellos que no lo requirieron (HR ajustado 2.20, IC 95%: 1.65 - 2.94), mientras que se observo una mejor supervivencia en aquellos que completaron la quimiorradiacion (HR 0.65, IC 95% 0.42 - 0,82).Posible confusion residual por indicacion de cirugia de rescate.En esta gran cohorte contemporanea de pacientes con carcinoma de celulas escamosas del ano, la proporcion de pacientes sometidos a cirugia de rescate fue considerablemente menor que los informes anteriores. La edad mas temprana se asocio con la cirugia de rescate, y se sugirio un menor riesgo de cirugia de rescate con la finalizacion de la quimiorradiacion. Los pacientes que requirieron cirugia de rescate tuvieron una deficiente supervivencia general de 5 anos. Consulte Video Resumen en http://links.lww.com/DCR/B205. (Traduccion-Dr Gonzalo Hagerman).

The downregulation of farnesoid X receptor (FXR; gene name, nuclear receptor subfamily 1 group h member 4), an enteric nuclear bile acid receptor, has been reported in colorectal carcinoma (CRC), and FXR expression has been inversely correlated with CRC stage and clinical outcome. FXR knockdown in chronic colitis mouse models of intestinal tumorigenesis results in early mortality and increased tumor progression via promoting Wnt signaling. The aim of the present study was to explore the effects and mechanism of FXR on the Wnt/β-catenin signal pathway in CRC. FXR and β-catenin protein expression levels were detected in an ulcerative colitis mouse model and human colon cancer cell lines (HT-29, Caco-2 and HCT-116). Gain- and loss-of-function studies were conducted by transfecting colon cancer cells with FXR siRNA and treating them with the FXR agonist GW4064. Subsequently, β-catenin transcriptional activity was measured using the dual-luciferase assay, and β-catenin/TCF4 complex levels and β-catenin protein and mRNA expression levels were determined. FXR and β-catenin expression levels were inversely associated in both the animal model and colon cancer cells. The Wnt signaling pathway was activated by increased β-catenin/TCF4 complex levels upon FXR silencing; however, mRNA and protein levels of β-catenin were not significantly affected. The FXR agonist GW4064 significantly inhibited the proliferation of cells but promoted the transcriptional activity of β-catenin. Thus, the present study demonstrated that FXR influences the Wnt/β-catenin signaling pathway. Furthermore, loss of FXR expression promotes the transcriptional activity of β-catenin, whereas FXR activation results in the opposite effect.

Cold stress is a major abiotic factor that inhibits soybean (Glycine max (Linn.) Merr.) yield. MicroRNAs (miRNAs) are prevalent endogenous gene regulators in eukaryotes that can cleave target messenger RNAs and play essential roles in soybean cold response. In this study, 105 genes, including 22 pentatricopeptide repeat (PPR) genes and 4 growth-related genes, were predicted to be the target genes of soybean miRNA miR1508a (gma-miR1508a). The expression of gma-miR1508a was induced by cold treatment but inhibited by drought stress. Compared to the wild type (WT), the overexpression of gma-miR1508a in soybean plants resulted in dwarfing and thick cell walls. Gma-miR1508a transgenic plants exhibited cold tolerance at the germination and young seedling stages, and soluble sugar content was 58.7% higher than that of WT plants under cold stress. The gma-miR1508a transgenic lines showed lower survival rates and greater leaf water loss compared to the WT under drought treatment, which indicated that gma-miR1508a reduced drought resistance in soybean. Transcript abundances of 2 PPR and 4 growth-related predicted target genes decreased in gma-miR1508a transgenic plants. In the above six genes, the expression patterns of Glyma.16G162100 (PPR) and Glyma.17G065400 (xyloglucan endo-trans-glucosylase/hydrolase, XTH) showed opposite trends with gma-miR1508a under cold conditions. 5′-Rapid amplification of complementary DNA ends (5′-RACE) assays of Glyma.16G162100 revealed that the cleavage sites of gma-miR1508a are located at the 15th and 21st nucleotides of the complementary region. This study demonstrated that gma-miR1508a confers dwarfing, cold tolerance, and drought sensitivity in soybean.