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Significance To adapt to arboreal lifestyles, treefrogs have evolved a suite of complex traits that support vertical movement and gliding, thus presenting a unique case for studying the genetic basis for traits causally linked to vertical niche expansion. Here, based on two de novo-assembled Asian treefrog genomes, we determined that genes involved in limb development and keratin cytoskeleton likely played a role in the evolution of their climbing systems. Behavioral and morphological evaluation and time-ordered gene coexpression network analysis revealed the developmental patterns and regulatory pathways of the webbed feet used for gliding in Rhacophorus kio .

Considering that photodynamic therapy (PDT)-induced oxygen consumption and microvascular damage could exacerbate hypoxia to drive more glycolysis and angiogenesis, a novel approach to potentiate PDT and overcome the resistances of hypoxia is avidly needed. Herein, morpholine-modified PEGylated bilirubin was proposed to co-deliver chlorin e6, a photosensitizer, and diclofenac (Dc). In acidic milieu, the presence of morpholine could enable the nanocarriers to selectively accumulate in tumor cells, while PDT-generated reactive oxidative species (ROS) resulted in the collapse of bilirubin nanoparticles and rapid release of Dc. Combining with Dc showed a higher rate of apoptosis over PDT alone and simultaneously triggered a domino effect, including blocking the activity and expression of lactate dehydrogenase A (LDHA), interfering with lactate secretion, suppressing the activation of various angiogenic factors and thus obviating hypoxia-induced resistance-glycolysis and angiogenesis. In addition, inhibition of hypoxia-inducible factor-1

Hepatocellular carcinoma (HCC) is one of the most lethal and malignant types of cancer that affects global human health. The present study aimed to investigate the effect of pyruvate kinase muscle isozyme M2 (PKM2) expression on the clinical features and prognosis of HCC. The present study employed univariate logistic regression to investigate the correlation between PKM2 expression and clinical features. Univariate and multivariate Cox regression analyses were performed to estimate the independent effect of PKM2 expression on survival status. The results revealed that patients in the high PKM2 group (≥11.25) exhibited significantly lower creatinine levels (P=0.043), higher fetoprotein levels (P

Several previous genomic studies have focused on adaptation to high elevations, but these investigations have been largely limited to endotherms. Snakes of the genus Thermophis are endemic to the Tibetan plateau and therefore present an opportunity to study high-elevation adaptations in ectotherms. Here, we report the de novo assembly of the genome of a Tibetan hot-spring snake (Thermophis baileyi) and then compare its genome to the genomes of the other two species of Thermophis, as well as to the genomes of two related species of snakes that occur at lower elevations. We identify 308 putative genes that appear to be under positive selection in Thermophis. We also identified genes with shared amino acid replacements in the high-elevation hot-spring snakes compared with snakes and lizards that live at low elevations, including the genes for proteins involved in DNA damage repair (FEN1) and response to hypoxia (EPAS1). Functional assays of the FEN1 alleles reveal that the Thermophis allele is more stable under UV radiation than is the ancestral allele found in low-elevation lizards and snakes. Functional assays of EPAS1 alleles suggest that the Thermophis protein has lower transactivation activity than the low-elevation forms. Our analysis identifies some convergent genetic mechanisms in high-elevation adaptation between endotherms (based on studies of mammals) and ectotherms (based on our studies of Thermophis).

Human immunodeficiency virus (HIV) relies heavily on the host proteins to facilitate its entry and replication. Currently, more than 4000 human proteins are recorded to be involved in the HIV-1 life cycle. Identifying appropriate anti-HIV targets from so many host proteins is crucial to anti-HIV drug development, but a challenging work. Here we combined anti-HIV activity prediction and enrichment analysis to identify novel human targets for anti-HIV therapy. We firstly developed an accurate prediction tool named Anti-HIV-Predictor (AUC>0.96) to predict the anti-HIV activity of given compounds. Using this tool, we predicted 10488 anti-HIV compounds from ChEMBLdb. Then, based on this result and relationships of targets and compounds, we inferred 73 anti-HIV targets that enriched with anti-HIV compounds. The functional annotation and network analysis revealed that they directly or indirectly interact with 20 HIV proteins through neuropeptide signaling, GPCR signaling, cell surface signaling pathway, and so on. Nearly half of these targets overlap with the NCBI HIV dataset. However, the percentage of known therapeutic targets in these targets is significantly higher than that in the NCBI HIV dataset. After a series of feature analysis, we identified 13 novel human targets with high potential as anti-HIV targets, the inhibitors of which have experimentally confirmed anti-HIV activity. It is noteworthy that the inhibitors of REN and CALCA have better anti-HIV activity than CCR5 inhibitors. Taken together, our findings provide novel human targets for the host-oriented anti-HIV drug development and should significantly advance current anti-HIV research.

Treatment of AIDS still faces multiple challenges such as drug resistance and HIV eradication. Development of new, effective and affordable drugs against HIV is urgently needed. In this study, we developed a world's first web server called Anti-HIV-Predictor (http://bsb.kiz.ac.cn:70/hivpre) for predicting anti-HIV activity of given compounds. This machine learning based web server is rapid and accurate (accuracy >93% and AUC > 0.958), which enables us to screen tens of millions of compounds and discover new anti-HIV agents. We firstly applied the server to screen 1835 approved drugs for anti-HIV therapy. Then the predicted new anti-HIV compounds were experimentally evaluated. Finally, we repurposed 7 approved drugs (cetrorelix, dalbavancin, daunorubicin, doxorubicin, epirubicin, idarubicin and valrubicin) as new anti-HIV agents. The original indication of these drugs is involved in a variety of diseases such as female infertility, acute bacterial infections, leukemia and other cancers. Anti-HIV-Predictor and the 7 repurposed anti-HIV agents provided here demonstrate the efficacy of this strategy for discovery of new anti-HIV agents. This strategy and the server should significantly advance current anti-HIV research.

Interferons (IFNs) represent proteins with antiviral activities that are secreted from cells in response to a variety of stimuli. In addition to antiviral, antibacterial and anti-parasitic host-defense functions they are now also recognized as crucial regulators of cell proliferation, differentiation, survival and death as well as activators of specialized cell functions particularly in the immune system and play important roles in infectious and inflammatory diseases, autoimmunity and cancer. Tree shrews ( Tupaia belangeri ) were found to be susceptible to several human viruses and therefore are widely regarded as good models for analyzing mechanism of human diseases. In this report, we have forecasted the interferon family members of tree shrew from its genome mainly using the methods like Blast (whole genome shotgun sequence) and gene prediction. Our data show that tree shrew interferon system includes: type I IFN: α (five subtypes), β, ω, κ, e, δ; type II IFN: γ; type III IFN: λ1, λ2/3. Furthermore, the predicted structures of α and λ have similar character with those of other mammals. However, there are some differences in cysteine position and N-glycosylation numbers between human and Tree shrew IFNs. These results provide fundamental basis for further molecular cloning and function analysis of tree shrew IFNs in future.

There is a constant demand to develop new, effective, and affordable anti-cancer drugs. The traditional Chinese medicine (TCM) is a valuable and alternative resource for identifying novel anti-cancer agents. In this study, we aim to identify the anti-cancer compounds and plants from the TCM database by using cheminformatics. We first predicted 5278 anti-cancer compounds from TCM database. The top 346 compounds were highly potent active in the 60 cell lines test. Similarity analysis revealed that 75% of the 5278 compounds are highly similar to the approved anti-cancer drugs. Based on the predicted anti-cancer compounds, we identified 57 anti-cancer plants by activity enrichment. The identified plants are widely distributed in 46 genera and 28 families, which broadens the scope of the anti-cancer drug screening. Finally, we constructed a network of predicted anti-cancer plants and approved drugs based on the above results. The network highlighted the supportive role of the predicted plant in the development of anti-cancer drug and suggested different molecular anti-cancer mechanisms of the plants. Our study suggests that the predicted compounds and plants from TCM database offer an attractive starting point and a broader scope to mine for potential anti-cancer agents.

The recent high-throughput sequencing has enabled the composition ofEscherichia colistrains in the human microbial community to be profiled en masse. However, there are two challenges to address: (1) exploring the genetic differences betweenE. colistrains in human gut and (2) dynamic responses ofE. colito diverse stress conditions. As a result, we investigated theE. colistrains in human gut microbiome using deep sequencing data and reconstructed genome-wide metabolic networks for the three most commonE. colistrains, includingE. coliHS, UTI89, and CFT073. The metabolic models show obvious strain-specific characteristics, both in network contents and in behaviors. We predicted optimal biomass production for three models on four different carbon sources (acetate, ethanol, glucose, and succinate) and found that these stress-associated genes were involved in host-microbial interactions and increased in human obesity. Besides, it shows that the growth rates are similar among the models, but the flux distributions are different, even inE. colicore reactions. The correlations between human diabetes-associated metabolic reactions in theE. colimodels were also predicted. The study provides a systems perspective onE. colistrains in human gut microbiome and will be helpful in integrating diverse data sources in the following study.

Type III IFNs (IFN-λs) constitute a new subfamily with antiviral activities by signaling through a unique receptor complex composed of IFN-λs receptor 1 (IFNλR1) and interleukin-10 receptor 2 (IL10R2). As tree shrews (Tupaia belangeri) have shown susceptiblility to several human viruses, they are a potentially important model for analyzing viral infection. However, little is known about their IFN-λs system. We used the tree shrew genome to retrieve IFN-λs and their receptor contig sequences by BLASTN and BLASTZ algorithms, and GenScan was used to scan transcripts from the putative contig sequences. RT-PCR and bioinformatic methods were then used to clone and characterize the IFN-λs system. Due to its highest identity with human IFN-λ3, we opted to define one intact IFN-λ gene, tsIFN-λ3, as well as its two receptor subunits, tsIFNλR1 and tsIL10R2. Additionally, our results showed that tsIFN-λ3 contained many features conserved in IFN-λ3 genes from other mammals, including conserved signal peptide cleavage and glycosylation sites, and several residues responsible for binding to the type III IFNR. We also found six transcript variants in the receptors: three in tsIFNλR1, wherein different extracellular regions exist in three transmembrane proteins, resulting in different affinities with IFN-λs; and three more variants in tsIL10R2, encoding one transmembrane and two soluble proteins. Based on tissue distribution in the liver, heart, brain, lung, intestine, kidney, spleen, and stomach, we found that IFN-λs receptor complex was expressed in a variety of organs although the expression level differed markedly between them. As the first study to find transcript variants in IL-10R2, our study offers novel insights that may have important implications for the role of IFN-λs in tree shrews’ susceptibility with a variety of human viruses, bolstering the arguments for using tree shrews as an animal model in the study of human viral infections.

The anti-HIV-1 activity of mangiferin was evaluated. Mangiferin can inhibit HIV-1(Ⅲ)(B) induced syncytium formation at non-cytotoxic concentrations, with a 50% effective concentration (EC₅₀) at 16.90 μM and a therapeutic index (TI) above 140. Mangiferin also showed good activities in other laboratory-derived strains, clinically isolated strains and resistant HIV-1 strains. Mechanism studies revealed that mangiferin might inhibit the HIV-1 protease, but is still effective against HIV peptidic protease inhibitor resistant strains. A combination of docking and pharmacophore methods clarified possible binding modes of mangiferin in the HIV-1 protease. The pharmacophore model of mangiferin consists of two hydrogen bond donors and two hydrogen bond acceptors. Compared to pharmacophore features found in commercially available drugs, three pharmacophoric elements matched well and one novel pharmacophore element was observed. Moreover, molecular docking analysis demonstrated that the pharmacophoric elements play important roles in binding HIV-1 protease. Mangiferin is a novel nonpeptidic protease inhibitor with an original structure that represents an effective drug development strategy for combating drug resistance.

HIV type 1 (HIV-1) is characterized by its rapid genetic evolution, leading to challenges in anti-HIV therapy. However, the sequence variations in HIV-1 proteins are not randomly distributed due to a combination of functional constraints and genetic drift. In this study, we examined patterns of sequence variability for evidence of linked sequence changes (termed as coevolution or covariation) in 15 HIV-1 proteins. It shows that the percentage of charged residues in the coevolving residues is significantly higher than that in all the HIV-1 proteins. Most of the coevolving residues are spatially proximal in the protein structures and tend to form relatively compact and independent units in the tertiary structures, termed as "protein sectors". These protein sectors are closely associated with anti-HIV drug resistance, T cell epitopes, and antibody binding sites. Finally, we explored candidate peptide inhibitors based on the protein sectors. Our results can establish an association between the coevolving residues and molecular functions of HIV-1 proteins, and then provide us with valuable knowledge of pathology of HIV-1 and therapeutics development.