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Because of the sequence and number of calls of functions, software network cannot reflect the real execution of software. Thus, to detect crucial functions (DCF) based on software network is controversial. To address this issue, from the viewpoint of software dynamic execution, a novel approach to DCF is proposed in this paper. It firstly models, the dynamic execution process as an execution sequence by taking functions as nodes and tracing the stack changes occurring. Second, an algorithm for deleting repetitive patterns is designed to simplify execution sequence and construct software sequence pattern sets. Third, the crucial function detection algorithm is presented to identify the distribution law of the numbers of patterns at different levels and rank those functions so as to generate a decision-function-ranking-list (DFRL) by occurrence times. Finally, top-k discriminative functions in DFRL are chosen as crucial functions, and similarity the index of decision function sets is set up. Comparing with the results from Degree Centrality Ranking and Betweenness Centrality Ranking approaches, our approach can increase the node coverage to 80%, which is proven to be an effective and accurate one by combining advantages of the two classic algorithms in the experiments of different test cases on four open source software. The monitoring and protection on crucial functions can help increase the efficiency of software testing, strength software reliability and reduce software costs.

Background To combat the COVID-19 pandemic, nonpharmaceutical interventions (NPI) were implemented worldwide, which impacted a broad spectrum of acute respiratory infections (ARI). Methods Etiologically diagnostic data from 142 559 cases with ARIs, who were tested for eight viral pathogens (influenza virus, IFV; respiratory syncytial virus, RSV; human parainfluenza virus, HPIV; human adenovirus; human metapneumovirus; human coronavirus, HCoV; human bocavirus, HBoV, and human rhinovirus, HRV) between 2012 and 2021, were analyzed to assess the changes of respiratory infections in China during the first COVID-19 pandemic year compared to pre-pandemic years. Results Test positive rates of all respiratory viruses decreased during 2020, compared to the average levels during 2012−2019, with changes ranging from -17·2% for RSV to -87·6% for IFV. Sharp decreases mostly occurred between February and August when massive NPIs remained active, although HRV rebounded to the historical level during the summer. While IFV and HMPV were consistently suppressed year round, RSV, HPIV, HCoV, HRV HBov resurged and went beyond historical levels during September, 2020−January, 2021, after NPIs were largely relaxed and schools reopened. Resurgence was more prominent among children younger than 18 years and in Northern China. These observations remain valid after accounting for seasonality and long-term trend of each virus. Conclusions Activities of respiratory viral infections were reduced substantially in the early phases of the COVID-19 pandemic, and massive NPIs were likely the main driver. Lifting of NPIs can lead to resurgence of viral infections, particularly in children.

Alizarin (1,2-dihydroxyanthraquinone) is a natural red dye extracted from the roots of Rubia cordifolia L. (family Rubiaceae). Alizarin has been used as a biological red stain for calcium. The aryl hydrocarbon receptor (AhR) has critical roles in multiple physiological pathways. This study aimed to determine whether alizarin is an unreported ligand of AhR. In the present study, we investigated the effects on cytochrome P450 (CYP) 1A1 mRNA, protein expression, AhR nuclear translocation, aryl hydrocarbon response element (AHRE) reporter activity, and AhR-specific antagonist following alizarin treatment of cells of the human hepatoma cell line, HepG2, and murine hepatoma cell line, Hepa-1c1c7. Alizarin induced CYP1A1 mRNA and protein expression in HepG2 and Hep-1c1c7 cells. Such induction was not present in C4 (B13NBii1) cells, which are AhR signal deficient, C12 (B15ECiii2) cells, which reduce AhR protein levels. The alizarin-induced responses were blocked by CH-223191, which is an AhR antagonist. Alizarin, the same as with the AhR ligand, induced the nuclear localization of AhR, as well as stimulated the transcriptional activity of AHRE. The results of this study suggest that alizarin is an AhR agonist.

Increasing evidence has demonstrated that excessive fructose intake induces liver fibrosis. Epithelial-mesenchymal transition (EMT) driven by transforming growth factor-β1 (TGF-β1)/mothers against decapentaplegic homolog (Smad) signaling activation promotes the occurrence and development of liver fibrosis. Magnesium isoglycyrrhizinate is clinically used as a hepatoprotective agent to treat liver fibrosis, but its underlying molecular mechanism has not been identified. Using a rat model, we found that high fructose intake reduced microRNA (miR)-375-3p expression and activated the janus-activating kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) cascade and TGF-β1/Smad signaling, which is consistent with the EMT and liver fibrosis. To further verify these observations, BRL-3A cells and/or primary rat hepatocytes were exposed to high fructose and/or transfected with a miR-375-3p mimic or inhibitor or treated with a JAK2 inhibitor, and we found that the low expression of miR-375-3p could induce the JAK2/STAT3 pathway to activate TGF-β1/Smad signaling and promote the EMT. Magnesium isoglycyrrhizinate was found to ameliorate high fructose-induced EMT and liver fibrosis in rats. More importantly, magnesium isoglycyrrhizinate increased miR-375-3p expression to suppress the JAK2/STAT3 pathway and TGF-β1/Smad signaling in these animal and cell models. This study provides evidence showing that magnesium isoglycyrrhizinate attenuates liver fibrosis associated with a high fructose diet.

In a software network system, it is of great significance to identify key functions for software fault detection and maintenance. In order to better understand the characteristics and internal structure of software, a key Node Discovery algorithm based on Evidence Theory called NDET is proposed in this paper. First, the software complex network model is constructed according to the execution process of the software. Based on the Dempster-Shafer evidence theory (D-S evidence theory), the discernment frame is formed, the maximum and minimum values of the network degree and strength are determined. Second, the Basic Probability Assignment (BPA) of each node degree is calculated by considering the node degree distribution ratio value. Third, based on Dempster’s rule of combination, the evidential centrality of the node itself and the fluctuation value of the node influenced by neighbor nodes are considered for the key measurement. Finally, by using the Susceptible–Infected–Recovered (SIR) model to simulate the spreading process on real software networks, the performance of NDET is evaluated. Experiment results verify the validity and accuracy of NDET for identifying key function nodes in software.

During the last few decades, the study of microbial ecology has been enabled by molecular and genomic data. DNA sequencing has revealed the surprising extent of microbial diversity and how microbial processes run global ecosystems. However, significant gaps in our understanding of the microbial world remain, and one example is that microbial eukaryotes, or protists, are still largely neglected. To address this gap, we used gene expression data from 17 protist species to create protist.guru: an online database equipped with tools for identifying co-expressed genes, gene families, and co-expression clusters enriched for specific biological functions. Here, we show how our database can be used to reveal genes involved in essential pathways, such as the synthesis of secondary carotenoids in Haematococcus lacustris. We expect protist.guru to serve as a valuable resource for protistologists, as well as a catalyst for discoveries and new insights into the biological processes of microbial eukaryotes. AVAILABILITY: The database and co-expression networks are freely available from http://protist.guru/. The expression matrices and sample annotations are found in the supplementary data. Submitted/Accepted version

Increasing evidence has demonstrated that excessive fructose intake induces liver fibrosis. Epithelial–mesenchymal transition (EMT) driven by transforming growth factor-β1 (TGF-β1)/mothers against decapentaplegic homolog (Smad) signaling activation promotes the occurrence and development of liver fibrosis. Magnesium isoglycyrrhizinate is clinically used as a hepatoprotective agent to treat liver fibrosis, but its underlying molecular mechanism has not been identified. Using a rat model, we found that high fructose intake reduced microRNA (miR)-375-3p expression and activated the janus-activating kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) cascade and TGF-β1/Smad signaling, which is consistent with the EMT and liver fibrosis. To further verify these observations, BRL-3A cells and/or primary rat hepatocytes were exposed to high fructose and/or transfected with a miR-375-3p mimic or inhibitor or treated with a JAK2 inhibitor, and we found that the low expression of miR-375-3p could induce the JAK2/STAT3 pathway to activate TGF-β1/Smad signaling and promote the EMT. Magnesium isoglycyrrhizinate was found to ameliorate high fructose-induced EMT and liver fibrosis in rats. More importantly, magnesium isoglycyrrhizinate increased miR-375-3p expression to suppress the JAK2/STAT3 pathway and TGF-β1/Smad signaling in these animal and cell models. This study provides evidence showing that magnesium isoglycyrrhizinate attenuates liver fibrosis associated with a high fructose diet.

To better understand the effects of heavy metal stress on inducible defenses of woody plants, contents of nutritional substances and secondary metabolites, plus the activities of defense enzymes and protease inhibitors in the leaves of Populus alba berolinensis seedlings that were planted in either non-contaminated soil (control) or Pb-contaminated soil (at 300, 500 and 700 mg/kg) were studied. Our results showed that protein and soluble sugar contents in leaves 30–50 days after the Pb stress were significantly lower than those in the control group in a dose-dependent manner, whereas the lignin and flavonoid contents were significantly higher. Polyphenol oxidase (PPO) and phenylalnine ammonialyase (PAL) activities in leaves were significantly enhanced by the low Pb concentration stress (300 mg/kg) for all three sampling dates (30, 40 and 50 days after the Pb treatments), while at the two higher Pb concentrations (500 and 700 mg/kg), PPO activities were always inhibited and PAL activities presented a tendency of “promoting first and then restraining” with the increase of exposure duration. The response patterns of trypsin inhibitor (TI) and chymotrypsin inhibitor (CI) activities to Pb stress were similar to that of PPO, and presented a “low-promotion, high-inhibition” effect of Pb concentrations in leaves. These results suggest that the inducible defense responses in P. alba berolinensis leaves to Pb stress depend on both the Pb concentrations and the exposure duration, and the low Pb concentration at 300 mg/kg seemed to induce the strongest defense responses in the poplar seedlings, much stronger than those at the higher Pb concentrations.

Prunus mumequot;Langmeiquot; is a relict tree species, which fruit has good medicinal value. To understand the biosynthesis pathway of citric acid, the Illumina HiSeq XTen high-throughput sequencing technology was used to get the transcriptome fromquot;Langmeiquot;. A total of 38 936 unigenes were obtained by assembling the fruit transcripts, of which 28 311 unigenes were successfully annotated in public databases, 15 193 unigenes were mapped to 265 KEGG metabolic pathways, and 18 908 unigenes were classified into 59 GO functional subclasses, 103 unigenes encoding 15 key enzymes involved in citric acid synthesis pathway were identified and analyzed. The structural model of citrate synthetase inquot;Langmeiquot; showed that it was a homodimer and the secondary structure of each monomer was mainly composed of alpha helixes. Moreover, the residues in the active site of the citrate synthetase were highly conserved. This study provides a valuable resource for identifying candidate genes involved in the citric acid biosynthesis pathway, and will promote the development and sustainable utilization of genetic resources ofquot;Langmeiquot;.

Graphical abstract, The fungi kingdom is composed of eukaryotic heterotrophs, which are responsible for balancing the ecosystem and play a major role as decomposers. They also produce a vast diversity of secondary metabolites, which have antibiotic or pharmacological properties. However, our lack of knowledge of gene function in fungi precludes us from tailoring them to our needs and tapping into their metabolic diversity. To help remedy this, we gathered genomic and gene expression data of 19 most widely-researched fungi to build an online tool, fungi.guru, which contains tools for cross-species identification of conserved pathways, functional gene modules, and gene families. We exemplify how our tool can elucidate the molecular function, biological process and cellular component of genes involved in various biological processes, by identifying a secondary metabolite pathway producing gliotoxin in Aspergillus fumigatus, the catabolic pathway of cellulose in Coprinopsis cinerea and the conserved DNA replication pathway in Fusarium graminearum and Pyricularia oryzae. The tool is available at www.fungi.guru.

Sorafenib is an orally administered inhibitor of several tyrosine protein kinases. Treatment with sorafenib induces autophagy, which may suppress the growth of hepatocellular carcinoma (HCC) and other cancers. Aryl hydrocarbon receptor (AhR) is activated by xenbiotics and is involved in detoxification, but also plays other physiological roles. The following results were obtained. ITE and β-NF are endogenous and synthetic AhR ligands, respectively. One μM sorafenib can strongly suppress baseline as well as 0.5 μM ITE- and 1 μM β-NF-induced transcriptional activity of the aryl hydrocarbon response element (AHRE) in both human and mouse cells. Cytochrome p450 (CYP) 1A1 is mainly transcribed by activated AhR. Sorafenib (2-15 μM) strongly and dose-dependently suppressed baseline as well as 2 μM ITE- and 10 μM β-NF-induced CYP1A1 mRNA and protein expression. Ligand-activated AhR translocates from the cytoplasm to the nucleus. While sorafenib was found to suppress AhR activity, the drug alone was able to induce AhR translocation into the nucleus. Sorafenib's antagonistic action on AhR was comparable to that of the known AhR antagonist CH-223191 in human liver and ovarian cell lines. In summary, we demonstrate that sorafenib is a potent AhR antagonist and likely endocrine disruptor of the AhR. Moreover, sorafenib offers potential benefit for diseases treatable through AhR suppression strategies. Further investigation is warranted into sorafenib's AhR antagonistic behavior.