Structures of NPAS4-ARNT and NPAS4-ARNT2 heterodimers reveal new dimerization modalities in the bHLH-PAS transcription factor family.

Neuronal PER-ARNT-SIM (PAS) domain protein 4 (NPAS4) is a protective transcriptional regulator whose dysfunction has been linked to a variety of neuropsychiatric and metabolic diseases. As a member of the basic helix-loop-helix PER-ARNT-SIM (bHLH-PAS) transcription factor family, NPAS4 is distinguished by an ability to form functional heterodimers with aryl hydrocarbon receptor nuclear translocator (ARNT) and ARNT2, both of which are also bHLH-PAS family members. Here, we describe the quaternary architectures of NPAS4-ARNT and NPAS4-ARNT2 heterodimers in complexes involving DNA response elements. Our crystallographic studies reveal a uniquely interconnected domain conformation for the NPAS4 protein itself, as well as its differentially configured heterodimeric arrangements with both ARNT and ARNT2. Notably, the PAS-A domains of ARNT and ARNT2 exhibit variable conformations within these two heterodimers. The ARNT PAS-A domain also forms a set of interfaces with the PAS-A and PAS-B domains of NPAS4, different from those previously noted in ARNT heterodimers formed with other class I bHLH-PAS family proteins. Our structural observations together with biochemical and cell-based interrogations of these NPAS4 heterodimers provide molecular glimpses of the NPAS4 protein architecture and extend the known repertoire of heterodimerization patterns within the bHLH-PAS family. The PAS-B domains of NPAS4, ARNT, and ARNT2 all contain ligand-accessible pockets with appropriate volumes required for small-molecule binding. Given NPAS4's linkage to human diseases, the direct visualization of these PAS domains and the further understanding of their relative positioning and interconnections within the NPAS4-ARNT and NPAS4-ARNT2 heterodimers may provide a road map for therapeutic discovery targeting these complexes.

YBX1 promotes stemness and cisplatin insensitivity in intrahepatic cholangiocarcinoma via the AKT/ß-catenin axis.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive malignancy characterized by a poor prognosis and closely linked to tumor stemness. However, the key molecules that regulate ICC stemness remain elusive. Although Y-box binding protein 1 (YBX1) negatively affects prognosis in various cancers by enhancing stemness and chemoresistance, its effect on stemness and cisplatin sensitivity in ICC remains unclear. METHODS: Three bulk and single-cell RNA-seq datasets were analyzed to investigate YBX1 expression in ICC and its association with stemness. Clinical samples and colony/sphere formation assays validated the role of YBX1 in stemness and sensitivity to cisplatin. AZD5363 and KYA1979K explored the interaction of YBX1 with the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/AKT) and WNT/ß-catenin pathways. RESULTS: YBX1 was significantly upregulated in ICC, correlated with worse overall survival and shorter postoperative recurrence time, and was higher in chemotherapy-non-responsive ICC tissues. The YBX1-high group exhibited significantly elevated stemness scores, and genes linked to YBX1 upregulation were enriched in multiple stemness-related pathways. Moreover, YBX1 expression is significantly correlated with several stemness-related genes (SOX9, OCT4, CD133, CD44 and EPCAM). Additionally, YBX1 overexpression significantly enhanced the colony- and spheroid-forming abilities of ICC cells, accelerated tumor growth in vivo and reduced their sensitivity to cisplatin. Conversely, the downregulation of YBX1 exerted the opposite effect. The transcriptomic analysis highlighted the link between YBX1 and the PI3K/AKT and WNT/ß-catenin pathways. Further, AZD5363 and KYA1979K were used to clarify that YBX1 promoted ICC stemness through the regulation of the AKT/ß-catenin axis. CONCLUSIONS: YBX1 is upregulated in ICC and promotes stemness and cisplatin insensitivity via the AKT/ß-catenin axis. Our study describes a novel potential therapeutic target for improving ICC prognosis.

Defect-guided self-tearing in graphene.

The two-dimensional to three-dimensional configuration transition through self-tearing promises the engineering and promising applications of graphene. However, it is challenging to control the tearing path on demand through common thermal and interfacial treatments. In this manuscript, a defect-guided self-tearing technique is proposed to generate wider, longer, and even curved and serrated configurations, which is impossible for defect-free graphene. The underlying tearing mechanisms regarding the advancing displacement are disclosed through molecular dynamics simulations and theoretical model. This study provides a useful guidance to the implementation of complex and functional three-dimensional graphene structures.

Establishment and validation of lncRNA-related prognostic signatures in cholangiocarcinoma.

BACKGROUND: The prognosis of CCA is extremely poor, making it one of the most lethal cancers. Therefore, there is a need to elucidate the pathogenic mechanisms of CCA. In this study, we aimed at identifying lncRNA-related prognostic signatures for CCA through bioinformatics analysis and further validated their functions in CCA tumorigenesis and progression. METHODS: The RNA-seq data of CCA were downloaded from public databases. Differentially expressed lncRNAs (DElncRNAs) were screened. Then, candidate OS- and DFS-related DElncRNAs were selected through Kaplan-Meier survival analysis. Furthermore, LASSO regression was performed to establish the OS and DFS signatures, respectively. Multivariate COX models and nomograms for overall survival (OS) and disease-free survival (DFS) were established based on OS/DFS signature and clinical data. Hub lncRNAs were identified and enrichment analyses were performed to explore their potential functions. Finally, in vitro and in vivo models were used to validate the effects of the hub lncRNAs in CCA tumorigenesis and progression. RESULTS: A total of 925 DElncRNAs were selected, of which six candidate OS-related lncRNAs and 15 candidate DFS-related lncRNAs were identified. The OS and DFS signatures were then established using four lncRNAs, respectively. We found that the OS signature and vascular invasion were independent risk factors for the OS of CCA, while the DFS signature, vascular invasion, and CA19-9 were independent risk factors for the DFS of CCA. Then, nomograms were established to achieve personalized CCA recurrence and death prediction. Furthermore, our study uncovered that MIR4435-2HG and GAPLINC might play crucial roles in CCA progression and be selected as hub lncRNAs. GO and KEGG enrichment analyses revealed that the two hub lncRNAs were closely related to CCA tumorigenesis. Finally, we demonstrated that MIR4435-2HG and GAPLINC can stimulate CCA proliferation and migration in vitro and in vivo. CONCLUSIONS: The established OS and DFS signatures are independent risk factors for OS and DFS of CCA patients, respectively. MIR4435-2HG and GAPLINC were identified as hub lncRNAs. In vitro and in vivo models revealed that MIR4435-2HG and GAPLINC can prompt CCA progression, which might be novel prognostic biomarkers and therapeutic targets for CCA.

Unraveling the functional characterization of a jasmonate-induced flavonoid biosynthetic CYP45082G24 gene in Carthamus tinctorius.

The cytochrome P450 superfamily of monooxygenases plays a major role in the evolution and diversification of plant natural products. The function of cytochrome P450s in physiological adaptability, secondary metabolism, and xenobiotic detoxification has been studied extensively in numerous plant species. However, their underlying regulatory mechanism in safflower still remained unclear. In this study, we aimed to elucidate the functional role of a putative CtCYP82G24-encoding gene in safflower, which suggests crucial insights into the regulation of methyl jasmonate-induced flavonoid accumulation in transgenic plants. The results showed that methyl jasmonate (MeJA) was associated with a progressive upregulation of CtCYP82G24 expression in safflower among other treatment conditions including light, dark, and polyethylene glycol (PEG). In addition, transgenic plants overexpressing CtCYP82G24 demonstrated increased expression level of other key flavonoid biosynthetic genes, such as AtDFR, AtANS, and AtFLS, and higher content of flavonoid and anthocyanin accumulation when compared with wild-type and mutant plants. Under exogenous MeJA treatment, the CtCYP82G24 transgenic overexpressed lines showed a significant spike in flavonoid and anthocyanin content compared with wild-type and mutant plants. Moreover, the virus-induced gene silencing (VIGS) assay of CtCYP82G24 in safflower leaves exhibited decreased flavonoid and anthocyanin accumulation and reduced expression of key flavonoid biosynthetic genes, suggesting a possible coordination between transcriptional regulation of CtCYP82G24 and flavonoid accumulation. Together, our findings confirmed the likely role of CtCYP82G24 during MeJA-induced flavonoid accumulation in safflower.

The Comparison of Surgical Margins and Type of Hepatic Resection for Hepatocellular Carcinoma With Microvascular Invasion.

OBJECTIVE: The objective of this study was to investigate the impact of surgical margin and hepatic resection on prognosis and compare their importance on prognosis in patients with hepatocellular carcinoma (HCC). METHODS: The clinical data of 906 patients with HCC who underwent hepatic resection in our hospital from January 2013 to January 2015 were collected retrospectively. All patients were divided into anatomical resection (AR) (n = 234) and nonanatomical resection (NAR) group (n = 672) according to type of hepatic resection. The effects of AR and NAR and wide and narrow margins on overall survival (OS) and time to recurrence (TTR) were analyzed. RESULTS: In all patients, narrow margin (1.560, 1.278-1.904; 1.387, 1.174-1.639) is an independent risk factor for OS and TTR, and NAR is not. Subgroup analysis showed that narrow margins (2.307, 1.699-3.132; 1.884, 1.439-2.468), and NAR (1.481, 1.047-2.095; 1.372, 1.012-1.860) are independent risk factors for OS and TTR in patients with microvascular invasion (MVI)-positive. Further analysis showed that for patients with MVI-positive HCC, NAR with wide margins was a protective factor for OS and TTR compared to AR with narrow margins (0.618, 0.396-0.965; 0.662, 0.448-0.978). The 1, 3, and 5 years OS and TTR rate of the two group were 81%, 49%, 29% versus 89%, 64%, 49% (P = .008) and 42%, 79%, 89% versus 32%, 58%, 74% (P = .024), respectively. CONCLUSIONS: For patients with MVI-positive HCC, AR and wide margins were protective factors for prognosis. However, wide margins are more important than AR on prognosis. In the clinical setting, if the wide margins and AR cannot be ensured at the same time, the wide margins should be ensured first.

Fabrication of an alginate-based ZhiNengCong gel showed an enhanced antiviral and plant growth promoting functions.

Tobacco mosaic disease is a worldwide viral disease that can cause huge economic losses. Plant immune inducers have become the main force in the prevention and treatment of viral disease own to their high efficiency and rapid effect. However, since tobacco mosaic disease can occur at any point in the plant growth cycle, a single application period cannot guarantee the completely management. In this study, an extract from Paecilomyces variotii named ZhiNengCong (ZNC), which can fight against tobacco mosaic disease with 65% control effect, and improve the promotion of tobacco stem girth, was selected from five commercial antiviral medicines, and a sustained release sodium alginate (Alg)-based ZNC (ZNC@Alg) was prepared by physical absorption. ZNC@Alg, who contains only 5 mg/mL ZNC, can release ZNC for 7 consecutive days, and displayed an enhanced effect in inducing the PAL-mediated salicylic acid signaling pathway activation to participate in the inhibition of green fluorescent protein (GFP)-tagged tobacco mosaic virus (TMV-GFP) infection, even after 7 days of the application. Notably, field experiments showed that the control effect of ZNC@Alg was up to 88%, which was significantly better than that of ZNC with the same concentration (10 µg per plant). In addition, ZNC@Alg exhibited a stronger growth-promoting effect than ZNC, which significantly increased the wet weight of tobacco. Taken together, we screened out a plant immune inducer ZNC that can effectively inhibit tobacco virus disease, and created ZNC@Alg with higher control effect and growth promotion effect, laying a foundation for effective field management of tobacco mosaic disease.

Circular RNA ACTN4 promotes intrahepatic cholangiocarcinoma progression by recruiting YBX1 to initiate FZD7 transcription.

BACKGROUND & AIMS: Intrahepatic cholangiocarcinoma (ICC) is a primary liver cancer with high aggressiveness and extremely poor prognosis. The role of circular RNAs (circRNAs) in ICC carcinogenesis and progression remains to be determined. METHODS: CircRNA microarray was performed to screen significantly upregulated circRNAs in paired ICC and non-tumor tissues. Colony formation, transwell, and xenograft models were used to examine the role of circRNAs in ICC proliferation and metastasis. RNA pulldown, mass spectrometry, chromatin immunoprecipitation, RNA-binding protein immunoprecipitation, chromatin isolation by RNA purification, electrophoretic mobility shift assay, and luciferase reporter assays were used to explore the molecular sponge role of the circRNA (via miRNA binding), and the interaction between circRNA and RNA-binding proteins. RESULTS: Hsa_circ_0050898, which originated from exon 1 to exon 20 of the ACTN4 gene (named circACTN4), was significantly upregulated in ICC. High circACTN4 expression was associated with enhanced tumor proliferation and metastasis in vitro and in vivo, as well as a worse prognosis following ICC resection. In addition, circACTN4 upregulated Yes-associated protein 1 (YAP1) expression by sponging miR-424-5p. More importantly, circACTN4 also recruited Y-box binding protein 1 (YBX1) to stimulate Frizzled-7 (FZD7) transcription. Furthermore, circACTN4 overexpression in ICC cells enhanced the interaction between YAP1 and ß-catenin, which are the core components of the Hippo and Wnt signaling pathways, respectively. CONCLUSIONS: CircACTN4 was upregulated in ICC and promoted ICC proliferation and metastasis by acting as a molecular sponge of miR-424-5p, as well as by interacting with YBX1 to transcriptionally activate FZD7. These results suggest that circACTN4 is a potential prognostic marker and therapeutic target for ICC. LAY SUMMARY: Intrahepatic cholangiocarcinoma is a primary liver cancer associated with aggressiveness and extremely poor prognosis. It is essential for therapeutic development that we uncover relevant pathogenic pathways. Herein, we showed that a circular RNA (circACTN4) was highly expressed in intrahepatic cholangiocarcinoma and was positively associated with tumor growth and metastasis through key developmental signaling pathways. Thus, circACTN4 could be a prognostic biomarker and therapeutic target for intrahepatic cholangiocarcinoma.

Diversification of phenolic glucosides by two UDP-glucosyltransferases featuring complementary regioselectivity.

BACKGROUND: Glucoside natural products have been showing great medicinal values and potentials. However, the production of glucosides by plant extraction, chemical synthesis, and traditional biotransformation is insufficient to meet the fast-growing pharmaceutical demands. Microbial synthetic biology offers promising strategies for synthesis and diversification of plant glycosides. RESULTS: In this study, the two efficient UDP-glucosyltransferases (UGTs) (UGT85A1 and RrUGT3) of plant origin, that are capable of recognizing phenolic aglycons, are characterized in vitro. The two UGTs show complementary regioselectivity towards the alcoholic and phenolic hydroxyl groups on phenolic substrates. By combining a developed alkylphenol bio-oxidation system and these UGTs, twenty-four phenolic glucosides are enzymatically synthesized from readily accessible alkylphenol substrates. Based on the bio-oxidation and glycosylation systems, a number of microbial cell factories are constructed and applied to biotransformation, giving rise to a variety of plant and plant-like O-glucosides. Remarkably, several unnatural O-glucosides prepared by the two UGTs demonstrate better prolyl endopeptidase inhibitory and/or anti-inflammatory activities than those of the clinically used glucosidic drugs including gastrodin, salidroside and helicid. Furthermore, the two UGTs are also able to catalyze the formation of N- and S-glucosidic bonds to produce N- and S-glucosides. CONCLUSIONS: Two highly efficient UGTs, UGT85A1 and RrUGT3, with distinct regioselectivity were characterized in this study. A group of plant and plant-like glucosides were efficiently synthesized by cell-based biotransformation using a developed alkylphenol bio-oxidation system and these two UGTs. Many of the O-glucosides exhibited better PEP inhibitory or anti-inflammatory activities than plant-origin glucoside drugs, showing significant potentials for new glucosidic drug development.

Structural overview and perspectives of the nuclear receptors, a major family as the direct targets for small-molecule drugs.

The nuclear receptors (NRs) are an evolutionarily related family of transcription factors, which share certain common structural characteristics and regulate the expressions of various genes by recognizing different response elements. NRs play important roles in cell differentiation, proliferation, survival and apoptosis, rendering them indispensable in many physiological activities including growth and metabolism. As a result, dysfunctions of NRs are closely related to a variety of diseases, such as diabetes, obesity, infertility, inflammation, the Alzheimer's disease, cardiovascular diseases, prostate and breast cancers. Meanwhile, small-molecule drugs directly targeting NRs have been widely used in the treatment of above diseases. Here we summarize recent progress in the structural biology studies of NR family proteins. Compared with the dozens of structures of isolated DNA-binding domains (DBDs) and the striking more than a thousand of structures of isolated ligand-binding domains (LBDs) accumulated in the Protein Data Bank (PDB) over thirty years, by now there are only a small number of multi-domain NR complex structures, which reveal the integration of different NR domains capable of the allosteric signal transduction, or the detailed interactions between NR and various coregulator proteins. On the other hand, the structural information about several orphan NRs is still totally unavailable, hindering the further understanding of their functions. The fast development of new technologies in structural biology will certainly help us gain more comprehensive information of NR structures, inspiring the discovery of novel NR-targeting drugs with a new binding site beyond the classic LBD pockets and/or a new mechanism of action.

Compartmentalized biosynthesis of mycophenolic acid.

Mycophenolic acid (MPA) from filamentous fungi is the first natural product antibiotic to be isolated and crystallized, and a first-line immunosuppressive drug for organ transplantations and autoimmune diseases. However, some key biosynthetic mechanisms of such an old and important molecule have remained unclear. Here, we elucidate the MPA biosynthetic pathway that features both compartmentalized enzymatic steps and unique cooperation between biosynthetic and ß-oxidation catabolism machineries based on targeted gene inactivation, feeding experiments in heterologous expression hosts, enzyme functional characterization and kinetic analysis, and microscopic observation of protein subcellular localization. Besides identification of the oxygenase MpaB' as the long-sought key enzyme responsible for the oxidative cleavage of the farnesyl side chain, we reveal the intriguing pattern of compartmentalization for the MPA biosynthetic enzymes, including the cytosolic polyketide synthase MpaC' and O-methyltransferase MpaG', the Golgi apparatus-associated prenyltransferase MpaA', the endoplasmic reticulum-bound oxygenase MpaB' and P450-hydrolase fusion enzyme MpaDE', and the peroxisomal acyl-coenzyme A (CoA) hydrolase MpaH'. The whole pathway is elegantly comediated by these compartmentalized enzymes, together with the peroxisomal ß-oxidation machinery. Beyond characterizing the remaining outstanding steps of the MPA biosynthetic steps, our study highlights the importance of considering subcellular contexts and the broader cellular metabolism in natural product biosynthesis.

ESR1 as a recurrence-related gene in intrahepatic cholangiocarcinoma: a weighted gene coexpression network analysis.

BACKGROUND: Intrahepatic cholangiocarcinoma (iCCA) is the second most common malignant hepatic tumor and has a high postoperative recurrence rate and a poor prognosis. The key roles of most tumor recurrence-associated molecules in iCCA remain unclear. This study aimed to explore hub genes related to the postsurgical recurrence of iCCA. METHOD: Differentially expressed genes (DEGs) between iCCA samples and normal liver samples were screened from The Cancer Genome Atlas (TCGA) database and used to construct a weighted gene coexpression network. Module-trait correlations were calculated to identify the key module related to recurrence in iCCA patients. Genes in the key module were subjected to functional enrichment analysis, and candidate hub genes were filtered through coexpression and protein-protein interaction (PPI) network analysis. Validation studies were conducted to detect the "real" hub gene. Furthermore, the biological functions and the underlying mechanism of the real hub gene in iCCA tumorigenesis and progression were determined via in vitro experiments. RESULTS: A total of 1019 DEGs were filtered and used to construct four coexpression modules. The red module, which showed the highest correlations with the recurrence status, family history, and day to death of patients, was identified as the key module. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses demonstrated that genes in the red module were enriched in genes and pathways related to tumorigenesis and tumor progression. We performed validation studies and identified estrogen receptor 1 (ESR1), which significantly impacted the prognosis of iCCA patients, as the real hub gene related to the recurrence of iCCA. The in vitro experiments demonstrated that ESR1 overexpression significantly suppressed cell proliferation, migration, and invasion, whereas ESR1 knockdown elicited opposite effects. Further investigation into the mechanism demonstrated that ESR1 acts as a tumor suppressor by inhibiting the JAK/STAT3 signaling pathway. CONCLUSIONS: ESR1 was identified as the real hub gene related to the recurrence of iCCA that plays a critical tumor suppressor role in iCCA progression. ESR1 significantly impacts the prognosis of iCCA patients and markedly suppresses cholangiocarcinoma cell proliferation, migration and invasion by inhibiting JAK/STAT3 signaling pathway.

Bacterial Biosynthetic P450 Enzyme PikCD50N: A Potential Biocatalyst for the Preparation of Human Drug Metabolites.

Human drug metabolites (HDMs) are important chemicals widely used in drug-related studies. However, acquiring these enzyme-derived and regio-/stereo-selectively modified compounds through chemical approaches is complicated. PikC is a biosynthetic P450 enzyme involved in pikromycin biosynthesis from the bacterium Streptomyces venezuelae. Here, we identify the mutant PikCD50N as a potential biocatalyst, with a broad substrate scope, diversified product profile, and high catalytic efficiency, for preparation of HDMs. Remarkably, PikCD50N can mediate the drug-metabolizing reactions using the low-cost H2O2 as a direct electron and oxygen donor.

Association between air pollutants and atrial fibrillation in general population: A systematic review and meta-analysis.

BACKGROUND: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia with several risk factors. Recent studies have suggested that the exposure to air pollutants may increase the prevalence of AF, we evaluated those studies systematically to better elucidate the correlation between exposure to air pollution and AF. METHOD: We conducted a systematic review of publications using PubMed, Embase, the Cochrane library and Web of Science to explore the association between air pollutants and AF within the general population. The chosen studies were published until 7 July 2020. According to different study designs, we divided the outcomes into "short-term-exposure group" and "long-term-exposure group" for each pollutant. We used I2 statistics and Q-test to examine statistical heterogeneity, and sensitivity analysis to exclude the heterogeneous study. Fixed or random-effect model was used to combine the effects. Final result was presented as the OR and 95% CI of AF prevalence for every 10 µg/m3 increase in the concentration of PM2.5 and PM10;10 ppb increase in the concentration of SO2 ,NO2 ,O3; and 1 ppm increase in the CO concentration. RESULTS: Our analysis contain 18 studies. Underlying short-term exposure effect, for each increment of 10 µg/m3 in the PM2.5 concentration, the combined OR of AF prevalence was 1.01(1.00-1.02), for PM10 was 1.03(1.01-1.05). For a 10 ppb increment in the concentration of SO2, NO2, and O3 was 1.05(1.01-1.09), 1.03(1.01-1.04), and 1.01(0.97-1.06), respectively, for a 1 ppm increase of CO concentration was 1.02(0.99-1.06). Underlying long-term-exposure effect for each increment of 10 µg/m3 in the PM2.5 concentration; the combined OR of AF prevalence was 1.07(1.04-1.10) and that for PM10 was 1.03(1.03-1.04) For a 10 ppb increment in the NO2 concentration was 1.02(1.00-1.04). CONCLUSION: Our meta-analysis indicated that all air pollutants exposure had an adverse effect on AF prevalence in general population.

Compression-driven collapse of nanotubes.

Nanotubes are prone to collapsing under compression due to the competition between the bending stiffness of the walls and the van der Waals interactions. The different radial morphologies during collapse may affect the electrical properties of nanotube, which may find promising potential applications in strain engineering. In this paper, the finite-deformation model is introduced to determine the radial morphologies, energy barrier and radial deformability of a nanotube under compression, in which the adhesion interactions are analytically obtained. The analytical solutions of the radial morphologies during compression are consistent with the molecular dynamics simulations results, indicating the effectiveness of the finite-deformation model. The analytical results reveal that both the energy barrier and the radial deformability show a decreasing tendency with the increase of the nanotube diameter.

Mechanics of the folding of a nanotube.

Nanotubes fold due to the competition between their mechanical stability and van der Waals interactions. The caused dramatic morphology change promises exciting applications of nanotubes in responsive and reconfigurable nanodevices. To investigate the folding mechanism, a curvature-based finite-deformation theoretical model simultaneously considering both the folding of a nanotube and the possible collapsing of the cross-section is developed. The predicted critical condition and the profiles in both axial and transverse directions agree well with molecular dynamics (MD) solutions, demonstrating that the cross-sectional deformation should be taken into account when investigating the folding of a nanotube with a large diameter. Moreover, simple scaling laws of the critical conditions are proposed through a small-deformation theoretical model. With these scaling laws, one can easily and quickly determine both the collapsing state of the cross-section and the folding state of the nanotube with only geometrical parameters [Formula: see text] rather than the difficult-to-determine material properties [Formula: see text].

Impeding the interaction between Nur77 and p38 reduces LPS-induced inflammation.

Sepsis, a hyperinflammatory response that can result in multiple organ dysfunctions, is a leading cause of mortality from infection. Here, we show that orphan nuclear receptor Nur77 (also known as TR3) can enhance resistance to lipopolysaccharide (LPS)-induced sepsis in mice by inhibiting NF-κB activity and suppressing aberrant cytokine production. Nur77 directly associates with p65 to block its binding to the κB element. However, this function of Nur77 is countered by the LPS-activated p38α phosphorylation of Nur77. Dampening the interaction between Nur77 and p38α would favor Nur77 suppression of the hyperinflammatory response. A compound, n-pentyl 2-[3,5-dihydroxy-2-(1-nonanoyl) phenyl]acetate, screened from a Nur77-biased library, blocked the Nur77-p38α interaction by targeting the ligand-binding domain of Nur77 and restored the suppression of the hyperinflammatory response through Nur77 inhibition of NF-κB. This study associates the nuclear receptor with immune homeostasis and implicates a new therapeutic strategy to treat hyperinflammatory responses by targeting a p38α substrate to modulate p38α-regulated functions.

GC-MS, FTIR and Raman Analysis of Antioxidant Components of Red Pigments from Stemphylium lycopersici.

Many microorganisms can generate pigments with different colours and structures during the growth process. In this study, an endophytic fungus producing red pigments was isolated from Cynanchum auriculatum Royle ex Wight tissue. PCR amplification sequencing was conducted, and phylogenetic analysis was performed on the ITS region sequences. Combined with morphological observation, the fungus was identified as Stemphylium lycopersici. The antioxidant activities of the pigments were evaluated in vitro and showed good antioxidant properties. Ultraviolet (UV), Raman, and Fourier transform infrared (FTIR) spectroscopy and gas chromatography-mass spectroscopy (GC-MS) were used to analyse the pigments' components, which were shown to contain phenolics and anthraquinones. Most of these components have not been previously reported in Stemphylium lycopersici, especially physcione. This study is the first report of Stemphylium lycopersici secondary metabolites and their potential use as red pigments and antioxidants. Further optimisation of the culture conditions of this fungal strain might permit its application for pigment production.

Orphan nuclear receptor TR3 acts in autophagic cell death via mitochondrial signaling pathway.

Autophagy is linked to cell death, yet the associated mechanisms are largely undercharacterized. We discovered that melanoma, which is generally resistant to drug-induced apoptosis, can undergo autophagic cell death with the participation of orphan nuclear receptor TR3. A sequence of molecular events leading to cellular demise is launched by a specific chemical compound, 1-(3,4,5-trihydroxyphenyl)nonan-1-one, newly acquired from screening a library of TR3-targeting compounds. The autophagic cascade comprises TR3 translocation to mitochondria through interaction with the mitochondrial outer membrane protein Nix, crossing into the mitochondrial inner membrane through Tom40 and Tom70 channel proteins, dissipation of mitochondrial membrane potential by the permeability transition pore complex ANT1-VDAC1 and induction of autophagy. This process leads to excessive mitochondria clearance and irreversible cell death. It implicates a new approach to melanoma therapy through activation of a mitochondrial signaling pathway that integrates a nuclear receptor with autophagy for cell death.

Extraction Optimization, Purification and Physicochemical Properties of Polysaccharides from Gynura medica.

Extraction of polysaccharides from Gynura medica (GMPs) was optimized by response surface methodology (RSM). A central composition design including three parameters, namely extraction temperature (X1), ratio of water to raw material (X2) and extraction time (X3), was used. The best conditions were extraction temperature of 91.7 °C, extraction time of 4.06 h and ratio of water to raw material of 29.1 mL/g. Under the optimized conditions, the yield of GMPs was 5.56%, which was similar to the predicted polysaccharides yield of 5.66%. A fraction named GMP-1 was obtained after isolation and purification by DEAE-52 and Sephadex G-100 gel chromatography, respectively. GMP-1, with a molecular weight of 401 kDa, mainly consisted of galacturonic acid (GalA), xylose (Xyl), glucose (Glu). Infrared spectroscopy was used to characterize the major functional groups of GMP-1 and the results indicated that it was an acidic polysaccharide. The antioxidant and α-glucosidase inhibitory activities of GMPs and GMP-1 were determined in vitro. The results indicated that GMPs and GMP-1 show potential for use in functional foods or medicines.