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The metalloid arsenic, known for its toxic properties, is widespread presence in the environment. Our previous research has confirmed that prolonged exposure to arsenic can lead to liver fibrosis injury in rats, while the precise pathogenic mechanism still requires further investigation. In the past few years, the Nod-like receptor protein 3 (NLRP3) inflammasome has been found to play a pivotal role in the occurrence and development of liver injury. In this study, we administered varying doses of sodium arsenite (NaAsO 2) and 10 mg/kg.bw MCC950 (a particular tiny molecular inhibitor targeting NLRP3) to Sprague-Dawley (SD) rats for 36 weeks to explore the involvement of NLRP3 inflammasome in NaAsO 2 -induced liver injury. The findings suggested that prolonged exposure to NaAsO 2 resulted in pyroptosis in liver tissue of SD rats, accompanied by the fibrotic injury, extracellular matrix (ECM) deposition and liver dysfunction. Moreover, long-term NaAsO 2 exposure activated NLRP3 inflammasome, leading to the release of pro-inflammatory cytokines in liver tissue. After treatment with MCC950, the induction of NLRP3-mediated pyroptosis and release of pro-inflammatory cytokines were significantly attenuated, leading to a decrease in the severity of liver fibrosis and an improvement in liver function. To summarize, those results clearly indicate that hepatic fibrosis and liver dysfunction induced by NaAsO 2 occur through the activation of NLRP3 inflammasome-mediated pyroptosis, shedding new light on the potential mechanisms underlying arsenic-induced liver damage. [Display omitted] • Prolonged exposure to arsenite triggered pyroptosis in the liver cells of rats. • Prolonged exposure to arsenite caused fibrotic changes and dysfunction in the liver of rats. • The NLRP3 inflammasome in liver tissue of rats was activated upon prolonged exposure to arsenite. • MCC950 alleviated arsenite-induced pyroptosis in liver cells, ameliorated liver fibrosis and dysfunction in rats. [ABSTRACT FROM AUTHOR]

Six new polyoxygenated seco-cyclohexenes, artahongkongenes A–F ( 1–6 ), together with six known analogues ( 7–12 ) were isolated from the stems and leaves of Artabotrys hongkongensis . Their structures were elucidated by extensive spectroscopic methods. All new compounds were evaluated for their cytotoxicities against five human cancer cell lines: HL-60, SMMC-7721, A-549, MCF-7 and SW480 in vitro . New seco-cyclohexenes 1–6 showed significant inhibitory effects against various human cancer cell lines with IC 50 values ranging from 0.26 to 16.58 μM. [ABSTRACT FROM AUTHOR]

Arsenic is a well known environmental hazardous material, chronic arsenic exposure results in different types of liver damage. Among them, liver fibrosis has become a research hotspot because of its reversibility, while the underlying mechanism is still unclear. Previous studies revealed that EGFR/ERK signaling appears to play an important role in fibrosis diseases. In this study, sprague-dawley rats were exposed to different doses of arsenite for 36 weeks to investigate the roles of EGFR/ERK signaling on arsenite-induced liver fibrogenesis. Our results showed that long-term arsenite exposure induced liver fibrosis, accompanied by hepatic stellate cells (HSCs) activation, excessive serum secretion of extracellular matrix (ECM), and hepatocytes epithelial-mesenchymal transformation (EMT). In addition, arsenite exposure caused hyperphosphorylation of EGFR/ERK signaling in liver tissue of rats, indicating that EGFR/ERK signaling may be involved in arsenite-induced liver fibrosis. Indeed, erlotinib (a specific phosphorylation inhibitor of EGFR) intervention significantly decreased arsenite induced hyperphosphorylation of EGFR/ERK signaling, thereby suppressed hepatocytes EMT process and alleviated liver fibrogenesis in arsenite exposed rats. In summary, the present study provides evidences showing that hyperphosphorylation of EGFR/ERK signaling facilitates long-term arsenite-induced hepatocytes EMT and liver fibrosis in rats, which brings new insights into the pathogenesis of arsenic-induced liver injury. [Display omitted] • Long-term arsenite exposure induces liver fibrosis in rats. • Arsenite exposure causes hyperphosphorylation of EGFR/ERK signaling in liver tissue of rats. • Hyperphosphorylation of EGFR/ERK signaling promotes arsenite-induced hepatocytes EMT in liver tissue of rats. • Erlotinib attenuates arsenite-induced hepatocytes EMT and liver fibrosis in rats. [ABSTRACT FROM AUTHOR]

Fish morphological colouration is essential for their survival and reproduction success; however, it is vulnerable to environmental factors, such as pollutants. Triphenyltin (TPT) is widespread in aquatic ecosystems, and its impacts on fish have been problematic. Therefore, the purpose of this study was to investigate the effects of TPT at environment-related concentrations (0, 1, 10 and 100 ng Sn/L) on morphological colouration in male guppies (Poecilia reticulata). The results showed that TPT exposure affected both orange/red and dark morphological colouration in guppies. The faded orange/red colouration might be related to the decrease of coloured pteridine and Pts (6-Pyruvoyltetrahydropterin Synthase) expression. In addition, TPT exposure induced melanogenesis, however, much melanin was distributed diffusely in the skin and did not seem to form a spot pattern, giving the fish a dull appearance. According to the skin transcriptional profiles, the changes of dark morphological colouration might be related to the changes in genes related to the functions of melanosome components (Gpnmb , Slc45a2 and Tyr), construction (Ap3d1 , Fig4 , Hps3 , Hps5 , Lyst , Rabggta , Txndc5 and Vps33a), and transport (Rab27a). Additionally, genes related to the regulation of melanogenesis (Atrn and Pomc) and system effects (Atox1 , Atp6ap2 , Atp6v1f , Atp6v1h , Rpl24 , Rps19 and Rps20) might also be involved in the molecular mechanisms of abnormal morphological colouration induced by TPT. The present study provides crucial data on the molecular basis of abnormal morphological colouration in fish exposed to TPT and underscores the importance of toxicological studies of the effects of pollutants in aquatic environments on fish morphological colouration. • Effects of triphenyltin on morphological colouration in male guppies were investigated. • Skin transcriptional profiles were analyzed to clarify the molecular mechanisms. • Triphenyltin exposure affected both orange/red and dark morphological colouration. • Mechanisms of melanosome, melanogenesis, and pteridine synthesis might be involved. [ABSTRACT FROM AUTHOR]

Spinal cord concussion is characterized by a transient loss of motor and sensory function that generally resolves without permanent deficits. Spinal cord concussions usually occur during vehicular accidents, falls, and sport activity, but unlike brain concussions, have received much less attention despite the potential for repeated injury leading to permanent neurological sequelae. Consequently, there is no consensus regarding decisions related to return to play following an episode of spinal concussion, nor an understanding of the short- and long-term consequences of repeated injury. Importantly, there are no models of spinal concussion to study the anatomical and functional sequelae of single or repeated injury. We have developed a new model of spinal cord concussion focusing on the anatomical and behavioral outcomes of single and repeated injury. Rats received a very mild (50 kdyn, IH impactor) spinal contusion at C5 and were separated into two groups three weeks after the initial injury — C1, which received a second, sham surgery, and C2, which received a second contusion at the same site. To track motor function and recovery, animals received weekly behavioral tests — BBB, CatWalk™, cylinder, and Von Frey. Analysis of locomotor activity by BBB demonstrated that rats rapidly recovered, regaining near-normal function by one week after the first and second injury, which was confirmed using the more detailed CatWalk™ analysis. The cylinder test showed that a single contusion did not induce significant deficits of the affected limb, but that repeated injury resulted in significant alteration in paw preference, with animals favoring the unaffected limb. Intriguingly, Von Frey analysis demonstrated an increased sensitivity in the contralateral hindlimb in the C2 group vs. the C1 group. Anatomical analyses revealed that while the lesion volume of both groups was minimal, the area of spared white matter in the C2 group was significantly reduced 1 and 2 mm rostral to the lesion epicenter. Reactive astrocytes were present in both groups, with the majority found at the lesion epicenter in the C1 group, whereas the C2 group demonstrated increased reactive astrocytes extending 1 mm caudal to the lesion epicenter. Macrophages accumulated within the injured, dorsal and ipsilateral spinal cord, with significant increases at 2 and 3 mm rostral to the epicenter in the C2 group. Our model is designed to represent the clinical presentation of spinal cord concussion, and highlight the susceptibility and functional sequelae of repeated injury. Future experiments will examine the temporal and spatial windows of vulnerability for repeated injuries. [ABSTRACT FROM AUTHOR]

Abstract: Moderate and severe spinal cord contusion injuries have been extensively studied, yet much less is known about mild injuries. Mild contusions result in transient functional deficits, proceeding to near-complete recovery, but they may render the spinal cord vulnerable to future injuries. However, to date there have been no appropriate models to study the behavioral consequences, anatomical changes, and susceptibility of a mild contusion to repeated injuries, which may occur in children as well as adults during competitive sport activities. We have developed a novel mild spinal cord contusion injury model characterized by a sequence of transient functional deficits after the first injury and restoration to near-complete motor and sensory function, which is then followed up by a second injury. This model can serve not only to study the effects of repeated injuries on behavioral and anatomical changes, but also to examine the relationship between successive tissue damage and recovery of function. In the present study, we confirmed that mild thoracic spinal cord contusion, utilizing the NYU impactor device, resulted in localized tissue damage, characterized by a cystic cavity and peripheral rim of spared white matter at the injury epicenter, and rapid functional recovery to near-normal levels utilizing several behavioral tests. Repeated injury after 3weeks, when functional recovery has been completed, resulted in worsening of both motor and sensory function, which did not recover to prior levels. Anatomical analyses showed no differences in the volumes of spared white matter, lesion, or cyst, but revealed modest extension of lesion area rostral to the injury epicenter as well as an increase in inflammation and apoptosis. These studies demonstrate that a mild injury model can be used to test efficacy of treatments for repeated injuries and may serve to assist in the formulation of policies and clinical practice regarding mild SCI injury and spinal concussion. [Copyright &y& Elsevier]

Abstract: T-cell surface glycoprotein CD8 consists of two distinguished chains, termed α and β chains, and functions as a co-receptor for the T-cell receptor by binding to MHC class I proteins. In this study we report the cloning and identification of both CD8α and CD8β genes from orange-spotted grouper (Epinephelus coioides). The predicted grouper CD8α and CD8β proteins were structurally similar to other fish especially to those of Pleuronectiformes. Real-time RT-PCR revealed that the CD8 mRNA was much higher in the thymus than in other immune organs, and the expression level were very low in stomach, liver, and brain. During embryonic development of the grouper, the highest CD8 transcripts were detected in the multi-cell stage, followed by muscle burl stage, which suggested that the multi-cell stage may be critical in CD8 transcript synthesis. Moreover, CD8 mRNA levels were examined in lymphocytes at different time treated with lipopolysaccharide (LPS), polyriboinosinic polyribocytidylic acid (PolyI:C), phytohemagglutinin (PHA), and concanavalin A (ConA). The result showed that the CD8 mRNA levels were significantly affected in time-dependent manner by PolyI:C, PHA, and ConA, but not by LPS. [Copyright &y& Elsevier]

Abstract: Periodic acceleration (pGz), sinusoidal motion of the whole body in a head–foot direction in the spinal axis, is a novel noninvasive means for cardiopulmonary support and induction of pulsatile shear stress. pGz increases plasma nitrite levels, in vivo and in vitro. Additionally, pGz confers cardioprotection in models of ischemia reperfusion injury. We hypothesize that pGz may also confer a cardiac phenotypic change by upregulation of the expression of the various NO synthase (NOS) isoforms in vivo. pGz was applied for 1h to awake restrained male rats at 2 frequencies (360 and 600cpm) and acceleration (Gz) of ±3.4m/s2. pGz did not affect arterial blood gases or electrolytes. pGz significantly increased total nitrosylated protein levels, indicating increased NO production. pGz also increased mRNA and protein levels of eNOS and nNOS, and phosphorylated eNOS in heart. pGz increased Akt phosphorylation (p-AKT), but not total Akt, or phosphorylated ERK1/2. Inducible (i) NOS levels were undetectable with or without pGz. Immunoblotting revealed the localization of nNOS, exclusively in cardiomyocyte, and pGz increased its expression. We have demonstrated that pGz changes myocardial NOS phenotypes. Such upregulation of eNOS and nNOS was still evident 24h after pGz. Further studies are needed to understand the biochemical and biomechanical signal transduction pathway for the observed NOS phenotype changed induced by pGz. [Copyright &y& Elsevier]

Abstract: Our previous studies showed that axonal outgrowth from dorsal root ganglia (DRG) transplants in the adult rat brain could be directed toward a specific target location using a preformed growth-supportive pathway. This pathway induced axon growth within the corpus callosum across the midline to the opposite hemisphere. In this study, we examined whether such pathways would also support axon growth either through or around a lesion of the corpus callosum. Pathways expressing GFP, NGF, or FGF2/NGF were set up by multiple injections of adenovirus along the corpus callosum. Each pathway included the transplantation site in the left corpus callosum, 2.8 mm away from the midline, and a target site in the right corpus callosum, 2.5 mm from the midline. At the same time, a 1 mm lesion was made through the corpus callosum at the midline in an anteroposterior direction. A group of control animals received lesions and Ad-NGF injections only at the transplant and target sites, without a bridging pathway. DRG cell suspensions from postnatal day 1 or 2 rats were injected at the transplantation site three to four days later. Two weeks after transplantation, brain sections were stained using an anti-CGRP antibody. The CGRP+ axons were counted at 0.5 mm and 1.5 mm from the lesion site in both hemispheres. Few axons grew past the lesion in animals with control pathways, but there was robust axon growth across the lesion site in the FGF2/NGF and NGF-expressing pathways. This study indicated that preformed NGF and combination guidance pathways support more axon growth past a lesion in the adult mammalian brain. [Copyright &y& Elsevier]

Abstract: In plants, ZnF-AN1 genes are part of a multigene family with 13 members in Arabidopsis thaliana, 19 members in Populus trichocarpa, 17 members in Oryza sativa, at least 11 members in Zea mays, and 2 members in Chlamydomonas reinhardtii. All ZnF-AN1 genes contain the ZnF-AN1 domain. According to the phylogenetic analysis of the ZnF-AN1 domain, we divided plant ZnF-AN1 genes into two types. The coding sequences of most type I members do not possess any introns, while most type II members do possess intron(s). Through Northern blot analysis of maize members and digital Northern analysis of Arabidopsis members, we found that most ZnF-AN1 genes are involved in responses to abiotic stresses. The evolutionary analysis indicated that the expansion rate of type I was higher than that of type II. After expansion, some ZnF-AN1 genes may have gained new functions, some may have lost their functions, and some were specialized to perform their functions in stress-specific or tissue-specific modes. In addition, we propose an evolutionary model of type II ZnF-AN1 genes in plants. [Copyright &y& Elsevier]

Abstract: The antioxidant activity and liver protective effect of Morus bombycis Koidzumi were investigated. Aqueous extracts of M. bombycis Koidzumi had higher superoxide radical scavenging activity than other types of extracts. The aqueous extract at a dose of 100mg/kg showed significant hepatoprotective activity when compared with that of a standard agent. The biochemical results were confirmed by histological observations indicating that M. bombycis Koidzumi extract together with CCl4 treatment decreased ballooning degeneration. The water extract recovered the CCl4-induced liver injury and showed antioxidant effects in assays of FeCl2–ascorbic acid-induced lipid peroxidation in rats. Based on these results, we suggest that the hepatoprotective effect of the M. bombycis Koidzumi extract is related to its antioxidative activity. [Copyright &y& Elsevier]

In this study we show that panaxadiol, a ginseng saponin with a dammarane skeleton, induces apoptotic cell death by depolarization of mitochondrial membrane potential in human hepatoma SK-HEP-1 cells. Sequential activation of caspases-9, -3, and -7, but not of caspase-8, occurs after mitochondrial membrane depolarization and cytochrome c release from the mitochondria of panaxadiol-treated cells. Moreover, Cdk2 kinase activity, but not Cdc2 kinase activity, is markedly upregulated in the early stages of apoptosis. Olomoucine or roscovitine, specific Cdks inhibitors, effectively prevent mitochondrial membrane depolarization as well as apoptotic cell death in panaxadiol-treated cells. Thus, panaxadiol-treatment induces cell death-dependent activation of Cdk2 kinase activity, which is functionally associated with depolarization of mitochondrial membrane potential and subsequent cytochrome c release. [Copyright &y& Elsevier]

Transplants of fibroblasts genetically modified to express BDNF (Fb/BDNF) have been shown to promote regeneration of rubrospinal axons and recovery of forelimb function when placed acutely into the injured cervical spinal cord of adult rats. Here we investigated whether Fb/BDNF cells could stimulate supraspinal axon regeneration and recovery after chronic (4 week) injury. Adult female Sprague-Dawley rats received a complete unilateral hemisection injury at the third cervical spinal cord segment (C3). Four–five weeks later the injury site was exposed and rats received transplants of unmodified fibroblasts (Fb/UM) or Fb/BDNF. Four–five weeks after transplantation, locomotor recovery was examined on a test of forelimb usage and regeneration of supraspinal axons was studied following injection of the anterograde tracer biotin dextran amine (BDA). Rubrospinal tract (RST), reticulospinal tract (ReST), and vestibulospinal tract (VST) axons regenerated into transplants of either Fb/UM or Fb/BDNF but the length of axonal growth was significantly different in the two groups. The absolute distance of ReST growth was 1.8-fold greater in Fb/BDNF than in Fb/UM and the absolute distance of growth of RST and VST axons showed a statistically significant 4-fold increase. All three types of regenerated axons occupied a greater proportional length of Fb/BDNF transplants than of Fb/UM transplants. Only VST axons extended into the host spinal cord caudal to the Fb/BDNF grafts, but these axons were sparse. Rats receiving Fb/BDNF used both forelimbs together to explore walls of a cylinder more often than rats receiving Fb/UM, indicating partial recovery of forelimb usage. These results demonstrate that fibroblasts genetically modified to express BDNF promote axon regeneration from supraspinal neurons in the chronically injured spinal cord with accompanying partial recovery of locomotor performance. [Copyright &y& Elsevier]

Diffuse large B-cell lymphoma (DLBCL) is the most common malignant lymphoma in adults, and the use of rituximab has greatly improved the survival of DLBCL patients. Currently, the first-line treatment regimen for DLBCL is still rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP), which significantly improves outcomes for DLBCL patients. However, a percentage of patients still experience refractory or relapsed disease. Since Dr. Brent R Stockwell proposed ferroptosis in 2012, Roudkenar, M. H. Roushandeh, A. M. Valashedi, M. R. and others proved the importance of ferroptosis in cancer drug resistance. The purpose of this study was to elucidate whether rituximab could exert anticancer effects on DLBCL cells by promoting ferroptosis. Cell viability was assessed using the Cell Counting Kit-8. The results showed that rituximab exposure induced ferroptosis in OCI-LY1 cells. However, combination with ferroptosis inhibitor ferrostatin (Fer-1) rescued ferroptosis-induced injury, indicating that ferroptosis plays a key role in rituximab-induced cell death. Western blotting was performed to detect the levels of specific ferroptosis-associated proteins in DLBCL. Moreover, GSH depletion and MDA upregulation was assessed using GSH assays and MDA assay kits in rituximab-treated OCI-LY1 cells. In addition, rituximab failed to induce ferroptosis in rituximab-resistant cell lines. Treatment with RSL3 enhanced the effects of rituximab on DLBCL cells by inhibiting cell viability. In conclusion, we report for the first time that rituximab induces ferroptosis in lymphoma cells, at least partially through the SLC7A11/GPX4 axis. We also identify targeting ferroptosis as a promising therapeutic option for both sensitive cells and resistant cells in the treatment of DLBCL. [Display omitted] • Rituximab promotes ferroptosis in DLBCL cells. • Enhanced antioxidant defense system SLC7A11/GPX4 axis defends Rituximab resistant DLBCL cells against ferroptosis. • Combination of GPX4 inhibitor RSL3 is an option for DLBCL cells. [ABSTRACT FROM AUTHOR]

Mate choice copying refers to an agent copying the choice for a potential sexual/romantic partner made by a relevant model and has been observed across many species. This study investigated the neural profiles of two copying strategies in humans – acceptance and rejection copying – using functional magnetic resonance imaging (fMRI). Female participants observed female models accepting, rejecting, or being undecided about (control), males as potential romantic partners before and after rating their own willingness to choose the same males. We found that observing acceptance shifted participants' own choices towards acceptance, while observing rejection shifted participants' choices towards rejection. A network of motivation-, conflict- and reinforcement learning related brain regions was activated for observing the models' decisions. The rostral anterior cingulate gyrus (rACCg) and the caudate in particular were activated more strongly when observing acceptance. Activation in the inferior parietal lobe directly scaled with the magnitude of changes in choices after observing acceptance, while activation in the ACCg also scaled with changes after observing rejection. These findings point to partly dissociable neural profiles for copying strategies that might be linked to different contributions of incentive-driven and vicarious motivation, potentially reflecting the presence or absence of internalised reward experiences. [ABSTRACT FROM AUTHOR]

Transcription factors are key determinants of lineage commitment during mammalian development. However, the function and molecular mechanism for the transcription factors in the formation of three primary germ layers during human embryonic development are not fully elucidated. Here, we report that homeobox-containing transcription factor HESX1 plays a critical role in mesendodermal (ME) commitment of human embryonic stem cells (hESCs). Our results show that expression of HESX1 in hESCs is regulated by OCT4 and NANOG, and that its expression level changes with hESC differentiation. We find that knockdown of HESX1 does not disrupt the undifferentiated state of hESCs, in terms of cell morphology and expression levels of pluripotency-associated genes. However, HESX1 deficiency in hESCs impairs their ME commitment, whereas forced expression of HESX1 significantly enhances ME marker expression during ME commitment. Interestingly, HESX1 knockdown in hESCs represses ERK1/2 signaling activated by ME induction, while overexpression of HESX1 markedly enhances ERK1/2 activity during ME commitment of hESCs. Of note, MEK inhibitor PD0325901 weakens or even eliminates HESX1 overexpression-mediated promotive effects on ME induction in a dosage-dependent manner. Together, this study identifies a novel role of HESX1 in hESC commitment to ME cells and establishes the functional link between a transcription factor and lineage-associated signaling. These findings would help to better understand early human development and develop more efficient protocols to induce hESC differentiation to desired lineages. • Expression of HESX1 in hESCs is regulated by OCT4 and NANOG. • HESX1 deficiency impairs induction of mesendodermal (ME) transcription program of hESCs. • HESX1 overexpression (OE) enhances ME commitment of hESCs. • HESX1 modulates ERK1/2 signaling during hESC commitment to ME cells. • ERK1/2 signaling inhibition abrogates the enhancement of HESX1 OE on ME induction. [ABSTRACT FROM AUTHOR]

[Display omitted] A series of heterogeneous catalysts, designated as POP- n -Pd (where n = 1, 2, 3, or 4), were synthesized by polymerizing a six-membered N -heterocyclic compound with an alkyl substituted group monomer (S1), using divinylbenzene (DVB) as crosslinkers. This process was followed by the incorporation of palladium (Pd) nanoparticles. The impact of the substituted group and the S1 :DVB ratio in the catalysts, together with the reaction conditions, was investigated to assess their influence on the catalytic performance in converting propylamine, carbon dioxide (CO 2) and 4-iodoanisole to oxazolidinones. The POP-1-Pd catalyst, featuring a methyl substituted group and a S1 :DVB ratio of 1:4, exhibited remarkable efficiency, resulting in an excellent yield of 96 % under room temperature and ambient pressure conditions. Furthermore, it has demonstrated wide applicability across a variety of substrates and in the treatment of lime kiln exhaust gas. Additionally, POP-1-Pd can be used in a gram-scale reaction and maintains its performance after six recycles, with no significant decline in yield. The possible catalytic mechanism is proposed as follows: the catalyst's pores adsorb both CO 2 and substrates, creating a high concentration reactant enrichment microenvironment. This facilitates the activation of both CO 2 and substrates by the imidazole moiety and Pd nanoparticles in the catalyst, thereby generating oxazolidinones. [ABSTRACT FROM AUTHOR]

A hierarchical virtual screening was applied to identify natural products as new prototypes of PTP1B inhibitors. Ten compounds exhibited IC 50 values at the micromolar level, and nine of them demonstrated evident selectivity to PTP1B over four other PTPs. • Natural hits were identified as PTP1B inhibitors by virtual screening. • Ten hits demonstrated excellent potency with IC 50 at micromolar level against PTP1B. • Several hits showed evident selectivity to PTP1B over four other PTPs, including TCPTP. • A linear furancoumarin skeleton was recognized as a new prototype for PTP1B inhibitors. Protein tyrosine phosphatase 1B (PTP1B) is emerging as a promising yet challenging target for drug discovery. To identify natural products as new prototypes for PTP1B inhibitors, we employed a hierarchical protocol combining ligand-based and structure-based approaches for virtual screening against natural product libraries. Twenty-six compounds were prioritized for enzymatic evaluation against PTP1B, and ten of them were recognized as potent PTP1B inhibitors with IC 50 values at the micromolar level. Notably, nine compounds demonstrated evident selectivity to PTP1B over four other PTPs, including the most homologous T -cell protein tyrosine phosphatase (TCPTP). The results implicated that the structural uniqueness of the natural products might be a potential solution to the selectivity issue associated with the target PTP1B. [ABSTRACT FROM AUTHOR]

[Display omitted] • Novel eye-sensitive Ba 3 Nb 2 O 2 F 12 (H 2 O) 2 :Tb3+/Mn4+ were synthesized by simple co-precipitation strategy. • Red phosphor presents extremely strong ZPL at ∼ 625 nm and high color purity. • Red and green phosphors exhibit inherently outstanding thermal stability and moisture resistance. • Red and green phosphors coated directly on UV chip can achieve white emission. • The fabricated WLED devices show excellent electroluminescent properties. Novel eye-sensitive Ba 3 Nb 2 O 2 F 12 (H 2 O) 2 :Tb3+ green and Ba 3 Nb 2 O 2 F 12 (H 2 O) 2 :Mn4+ red oxyfluoride phosphors with extremely strong absorption in the UV region were designed and synthesized by simple co-precipitation strategy. Particularly, Tb3+ ions were doped in this matrix for the first time, which greatly improves their absorption efficiency in the near ultraviolet region (367 nm) and emits sharp green light (544 nm). In addition, the Ba 3 Nb 2 O 2 F 12 (H 2 O) 2 :Mn4+ red phosphors have strong zero phonon line (ZPL) emission at 625 nm, which is conducive to improving the sensitivity of human eye and color purity. Meanwhile, the optical properties of the red phosphor are significantly enhanced via doping K+ cations as charge compensators. Crystal field environment and nephelauxetic effect of the as-prepared phosphors before and after K+ cation doping were systematically analyzed. Moreover, these synthesized red/green phosphors have good thermal stability and moisture resistance. Remarkably, the as-prepared Ba 3 Nb 2 O 2 F 12 (H 2 O) 2 :5%Mn4+ or K 0.9 Ba 2.1 Nb 2 O 2 F 12 (H 2 O) 2 :5%Mn4+ red phosphors can be directly mixed with the as-synthesized Ba 3 Nb 2 O 2 F 12 (H 2 O) 2 :13%Tb3+ green phosphor coating on 365 nm near-ultraviolet LED chip to package WLED devices with excellent electroluminescence performance. These findings are conducive to opening an avenue for screening the unique structure of optical materials. [ABSTRACT FROM AUTHOR]

[Display omitted] Fine-tuning the surface structure of transition metal oxides at the atomic level is a promising way to improve the catalytic properties of materials. However, the influence of crystal surface structure on electrode reaction kinetics is still limited. In this study, we propose an in-situ synthesis strategy to obtain two-dimensional carbon/cerium oxide core–shell nanosheets by thermal decomposition of Ce-MOF nanosheets grown on the surface of carbon nanostructures, and fine-tuning the surface structure by introducing oxygen vacancies through defect engineering during the oxide nucleation process is conducted to obtain controllable exposed {1 1 1} and {1 1 0} surface CeO 2 @C composites. Both experiments and theoretical calculations show that the {1 1 0} -dominated nanocomplex (CeO 2 @C-350S) has better kinetic behavior and catalytic activity due to its abundant surface defects, which is manifested in higher active surface area, richer carrier concentration, and better promotion of diffusion and adsorption. In addition, CeO 2 @C-350S electrode has an extremely wide linear range and good stability in the electrochemical detection of nitrite. After 1000 times of the accelerated cycle experiments, CeO 2 @C-350S electrode still maintains 79.3 % of its initial current response, and recovers to 87.3 % after 10 min of stopping the test. The electrode stability is excellent, which is attributed to the clever carbon shell structure of the material. This synthesis strategy can be extended to other carbon-based oxide composite catalysts to improve the electrocatalytic performance and overall stability by adjusting the surface structure. [ABSTRACT FROM AUTHOR]

Human embryonic stem cells (hESCs) have the unique feature of unlimited self-renewal and differentiation into derivatives of all three germ layers in human body, providing a powerful in vitro model for studying cell differentiation. FGF2, BMP4 and TGF-β signaling have been shown to play crucial roles in mesendodermal differentiation of hESCs. However, their underlying molecular mechanisms and other signaling pathways potentially involved in mesendodermal differentiation of hESCs remain to be further investigated. In this study, we uncover that VEGF signaling pathway plays a critical role in the mesendodermal induction of hESCs. Treating hESCs with Lenvatinib, a pan-inhibitor of VEGF receptors (VEGFRs), impedes their mesendodermal induction. Conversely, overexpression of VEGFA165, a major human VEGF isoform, promotes the mesendodermal differentiation. Similar to the VEGFR inhibitor, MEK inhibitor PD0325901 hinders mesendodermal induction of hESCs. In contrast, overexpression of ERK2GOF, an intrinsically active ERK2 mutant, markedly reduces the inhibitory effect of the VEGFR inhibitor. Thus, the MEK-ERK cascade plays an important role for the function of VEGF signaling pathway in the mesendodermal induction of hESCs. All together, this study identifies the critical role of VEGF signaling pathway as well as potential crosstalk of VEGF signaling pathway with other known signaling pathways in mesendodermal differentiation of hESCs. • Inhibition of VEGF receptors suppresses mesendodermal induction of hESCs. • Inhibition of VEGF receptors reduces levels of pERK1/2, pSMAD1/5 and pSMAD2/3. • Forced expression of VEGFA165 promotes mesendodermal induction. • Inhibition of MEK-ERK cascade hinders mesendodermal induction of hESCs. • MEK-ERK cascade is implicated in the role of VEGF pathway in mesendodermal induction. [ABSTRACT FROM AUTHOR]

[Display omitted] • 27 PAB derivatives were designed and synthesized for evaluation against four cancer cell lines. • Compound D3 had a superior safety profile with a selectivity index (SI) of 20.38 compared to PAB's SI of 0.95. • Compound D3 suppressed cell proliferation, reduced colony formation, induced apoptosis, and arrested HCT-116 cells in specific phases. • In vivo experiments demonstrated low toxicity of compound D3 and its ability to suppress tumor growth in mice. Pseudolaric Acid B (PAB), a natural product with remarkable anti-tumor activity, is a starting point for new anticancer therapeutics. We designed and synthesized 27 PAB derivatives and evaluated their anti-proliferative activities against four cancer cell lines: MCF-7, HCT-116, HepG2, and A549. Compared with unmodified PAB, the PAB derivatives showed stronger anti-proliferative activity. The ability of compound D3 (IC 50 = 0.21 μM) to inhibit HCT-116 cells was approximately 5.3 times that of PAB (IC 50 = 1.11 μM) and the antiproliferative action was unrelated to cytotoxicity (SI=20.38), indicating its superior safety profile (PAB; SI=0.95). Compound D3 effectively suppressed the EdU-positive rate and reduced colony formation, arrested HCT-116 cells in the S and G2/M phases and induced apoptosis. In vivo experiments further demonstrated low toxicity of compound D3 while suppressing tumor growth in mice. In summary, given its strong anti-proliferative effect and relative safety, further development of compound D3 is warranted. [ABSTRACT FROM AUTHOR]

Human embryonic stem cells (hESCs) can self-renew infinitely and differentiate into the cell types of all lineages of our body, holding great promise for investigating early human embryo development and providing functional cells for disease treatment. For the full application of hESCs, it is necessary to elucidate how hESCs maintain their identity. Recent studies have shown that glycolysis and mitochondrial respiration are linked to pluripotency states. However, the function of mitochondrial respiration in hESCs has not been fully understood. Herein, we report that the adenosine triphosphate (ATP) production rate is comparable between mitochondrial respiration and glycolysis, suggesting an important contribution of mitochondrial respiration to ATP production in conventionally cultured hESCs. To investigate the function of mitochondrial respiration, we silence OGDH expression in hESCs by the inducible CRISPRi method, and find that OGDH knockdown (KD) results in disrupted TCA (tricarboxylic acid) cycle, and diminished mitochondrial respiration activity and total ATP level. Moreover, OGDH KD leads to hESC death and aberrant transcriptional program. Interestingly, blockage of the electron transport chain (ETC) by small molecule inhibitors gives rise to the phenotype similar to that observed in OGDH deficient hESCs. Therefore, genetic and pharmacological perturbations of the mitochondrial respiration impair identity of hESCs. Collectively, our study highlights the pivotal role of the mitochondrial respiration activity for the stemness maintenance of primed hESCs, and unveils OGDH as a key regulator for the proper production of ATP and TCA cycle metabolites in primed hESCs. • Mitochondrial respiration contributes to ATP production in primed hESCs. • Inducible knockdown of OGDH provides a useful model to study TCA cycle. • OGDH deficiency reduces maximal mitochondrial respiration and ATP levels. • OGDH deficiency leads to hESC death and an aberrant transcriptomic profile. • Electron transport chain inhibition causes hESC death and aberrant gene expression. [ABSTRACT FROM AUTHOR]

[Display omitted] • Hollow sphere structure of poly(ionic liquid)s (HPILs) was fabricated as nanoreactor. • HPILs nanoreactor efficiently enhanced the activity of metal catalysts and showed high selectivity of AA. • HPILs could storage and stabilize catalysts during reaction with high activity for 7 times. • HPILs could promote the generation of free radicals to enhance the reaction. • The reaction process of HPILs was theoretically calculated to verify high activity and selectivity. Hollow structure nanoreactors take advantage of catalyst loading and enhanced activity by shell construction. In this work, functionalized poly(ionic liquid)s (PILs) with hollow spherical structures were synthesized by polymerization- and quaternization-based approaches. These hollow structure PILs (HPILs) could be controllable designed from IL monomer easily, giving HPILs various properties. In the subsequent selective oxidation of cyclohexane, the HPILs acting as nanoreactors could efficiently improve the activity of metal salt catalysts (CoCl 2) and displayed adjustable selectivity for cyclohexanone, cyclohexanol (KA) or adipic acid (AA) by different types of HPILs. In kinetic study, it follows first-order reaction kinetics which CoCl 2 /HPIL-C12 had a lower the activation energy of 29.1 kJ/mol. Importantly, these nanoreactors storing the catalysts could be recovered and reused more than 7 times without significant loss of activity. A theoretical model for the hollow spherical reactor was further established to support the advance of the HPILs reactor, which could also help to predict reaction process in other core-shell catalytic system. Due to controlled substrate transfer and enhanced radical generation in HPILs, the reaction process could be adjusted to enhance the conversion of cyclohexane and selective oxidation to AA. [ABSTRACT FROM AUTHOR]

Acute lung injury (ALI) is a severe disease for which effective drugs are still lacking at present. Forsythia suspensa is a traditional Chinese medicine commonly used to relieve respiratory symptoms in China, but its functional mechanisms remain unclear. Therefore, forsythoside A (FA), the active constituent of F. suspensa , was studied in the present study. Inflammation models of type II alveolar epithelial MLE-12 cells and BALB/c mice stimulated by lipopolysaccharide (LPS) were established to explore the effects of FA on ALI and the underlying mechanisms. We found that FA inhibited the production of monocyte chemoattractant protein-1 (MCP-1/CCL2) in LPS-stimulated MLE-12 cells in a dose-dependent manner. Moreover, FA decreased the adhesion and migration of monocytes to MLE-12 cells. Furthermore, miR-124 expression was upregulated after FA treatment. The luciferase report assay showed that miR-124 mimic reduced the activity of CCL2 in MLE-12 cells. However, the inhibitory effects of FA on CCL2 expression and monocyte adhesion and migration to MLE-12 cells were counteracted by treatment with a miR-124 inhibitor. Critically, FA ameliorated LPS-induced pathological damage, decreased the serum levels of tumor necrosis factor-α and interleukin-6, and inhibited CCL2 secretion and macrophage infiltration in lungs in ALI mice. Meanwhile, administration of miR-124 inhibitor attenuated the protective effects of FA. The present study suggests that FA attenuates LPS-induced adhesion and migration of monocytes to type II alveolar epithelial cells though upregulating miR-124, thereby inhibiting the expression of CCL2. These findings indicate that the potential application of FA is promising and that miR-124 mimics could also be used in the treatment of ALI. • Acute lung injury is a life-threatening disease without effective treatments now. • Forsythia suspense is used to treat pneumonia with its anti-inflammatory activity. • Forsythoside A is a natural product from Forsythia suspense. • Forsythoside A protects mice from lipopolysaccharide-induced acute lung injury. [ABSTRACT FROM AUTHOR]

• Component screening by intelligent MS data analysis and network pharmacology. • BE-DDA for non-targeted acquiring HRMS2 Data of TCM' s metabolites in vivo. • First report on comprehensive study on in vivo exposure of Xiaokewan in rats. Xiaokewan is a typical Traditional Chinese medicine (TCM) for diabetes and contains various natural chemicals, such as lignans, flavonoids, saponins, polysaccharides, and western medicine glibenclamide. In the current study, a highly efficient system for screening hypoglycemic efficacy constituents of Xiaokewan has been developed with the integration of intelligent data acquisition, data mining, network pharmacology, and computer assisted target fishing. With the combination of background exclusion data dependent acquisition (BE-DDA) and non-targeted precise-and-thorough background-subtraction (PATBS) techniques, a novel workflow has been established for the non-targeted recognition and identification of TCM constituents in vivo, and has been applied to the exposure study of Xiaokewan in rat. In this case, an interesting correlation among drug, target, and disease can be established, by combining the screening or characterization results with the strategy of network pharmacology and multiple computer assisted techniques. Consequently, five main constituents (puerarin, daidzein, formononetin, deoxyschizandrin and glibenclamide) exposed in vivo have been selected as effective hypoglycemic components. Meanwhile, the network pharmacology experimental results showed that these five constituents could act on various drug targets, such as PI3K, PTP1B, MAPK, AKT, TNF, and NF-κB. These five constituents might be involved in the regulation of β-cell function or exhibit inflammation inhibition ability to relieve the pathophysiological process of disease from multiple links. Furthermore, the pharmacological effects of these five constituents have been verified by diabetic zebrafish model. The zebrafish model results showed that the TCM monomer mixture without glibenclamide exhibited similar hypoglycemic activity with Xiaokewan. Although the monomer mixture with glibenclamide showed better activity than Xiaokewan only, the deoxyschizandrin (TCM constituent of Xiaokewan) exhibited best hypoglycemic performance. In summary, the above results indicated that the application of both intelligent recognition technology in mass spectrometry dataset and computerized network pharmacology might provide a pioneering approach for investigating the substance basis of TCM and searching lead compounds from natural sources. [ABSTRACT FROM AUTHOR]

Keratinocyte hyperproliferation is an essential link in skin cancer pathogenesis. Peroxiredoxin I (Prx I) is known to regulate cancer cell proliferation, differentiation, and apoptosis, but its role in skin cancer remains unclear. This study aimed to elucidate the role and mechanism of Prx I in skin cancer pathogenesis. Dimethylbenz[a]anthracene (DMBA) and 12-O-tetradecanoyl-phorbol-13-acetate (TPA) were used to create a skin tumor model of the initiation/promotion stage of cancer. The role of Prx I in H 2 O 2 -induced keratinocyte apoptosis was also investigated. After DMBA/TPA treatment, Prx I deficiency was significantly associated with less skin tumors, lower Bcl-2 expression, and higher p-p38 and cleaved caspase-3 expressions in Prx I knockout tumors than in wild-type controls. H 2 O 2 stimulation caused more cellular apoptosis in Prx I knockdown HaCaT cells than in normal HaCaT cells. The signaling study revealed that Bcl-2, p-p38, and cleaved caspase-3 expressions were consistent with the results in the tumors. In conclusion, the deletion of Prx I triggered the DMBA/TPA-induced skin tumor formation in vivo and in vitro by regulating the reactive oxygen species (ROS)-p38 mitogen-activated protein kinase (MAPK) pathway. These findings provide a theoretical basis for treating skin cancer. • Peroxiredoxin I deficiency was associated with a smaller number of skin tumors. • Peroxiredoxin I deficiency was related to lower Bcl-2 and higher p-p38 and c-C3. • Peroxiredoxin I had no significant effect on the later stage of tumor development. • H 2 O 2 stimulation caused more cellular apoptosis in peroxiredoxin I-deficient mice. [ABSTRACT FROM AUTHOR]

A wealth of studies illustrate the powerful antioxidant activities and health-promoting functions of dietary phenolic compounds, e.g., anthocyanins, flavonoids, and phenolic compounds. Ferulate is methylated from caffeoyl CoA using S-adenosyl-L-methionine (SAM) as methyl donor catalyzed by caffeoyl CoA methyltransferase (CCoAOMT). Here we show that Arabidopsis CCoAOMT7 contributes to ferulate content in the stem cell wall. CCoAOMT7 was further shown to bind S-adenosyl-L-homocysteine hydrolase (SAHH), a critical step in SAM synthesis to release feedback suppression on CCoAOMT. CCoAOMT7 also bound S-adenosyl-L-methionine synthases (SAMSs) in vivo , which were mediated by SAHH1. Interruptions of endogenous SAHH1 by artificial miRNA or SAMSs by T-DNA insertion significantly reduced ferulate contents in the stem cell wall. This data reveals a novel protein complex of SAM synthesis cycle associated with O-methyltransferase and provides new insights into cellular methylation processes. Image 1 • CCoAOMT7 contributes to ferulate accumulation in cell wall. • SAHH1 and SAHH2 protein directly interact with CCoAOMT7. • SAMSs associate with CCoAOMT7-SAHH complex mediated by SAHH1. [ABSTRACT FROM AUTHOR]

Abstract Alpinetin, a type of novel plant flavonoid derived from Alpinia katsumadai Hayata, has been reported to have anti-inflammatory effects. The aim of this investigation was designed to reveal the protective effects of alpinetin on Lipopolysaccharide (LPS)/ d -galactosamine (D-Gal)-induced liver injury in mice. Alpinetin (12.5, 25, 50 mg/kg) were given 1 h before LPS and D-Gal treatment. 12 h after LPS and D-Gal treatment, the liver tissues and serum were collected. Our results showed that alpinetin treatment improved liver histology, indicating a marked decrease of inflammatory cell infiltration and restore hepatic lobular architecture. Alpinetin also inhibited liver myeloperoxidase (MPO) activity and malondialdehyde (MDA) level. Furthermore, LPS/D-Gal-induced tumor necrosis factor-α (TNF-α) and Interleukin-1β (IL-1β) production were dose-dependently inhibited by alpinetin. Alpinetin also attenuated LPS/D-Gal-induced expression of phospho-NF-κB p65 and phospho-IκBα. In addition, alpinetin was found to increase the expression of nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). In conclusion, these findings suggested that alpinetin inhibited liver injury through inhibiting NF-κB and activating the Nrf2 signaling pathway. Highlights • Alpinetin inhibited liver MPO activity and MDA level. • LPS/D-Gal-induced TNF-α and IL-1β production were dose-dependently inhibited by alpinetin. • Alpinetin also attenuated LPS/D-Gal-induced expression of phospho-NF-κB p65 and phospho-IκBα. • In addition, alpinetin was found to increase the expression of Nrf2 and HO-1. [ABSTRACT FROM AUTHOR]

Two novel γ -lactone derivatives, trigoheterophines A ( 1 ) and B ( 2 ), together with four known furan derivatives ( 3 – 6 ), were isolated from the stems and leaves of Trigonostemon heterophyllus . The structures of 1 and 2 were elucidated by extensive spectroscopic methods and the known compounds were identified by comparing with the data reported in literature. Among them, trigoheterophines A ( 1 ) and B ( 2 ) represent an unusual type of γ -lactone derivatives, possessing 21 carbon atoms on the carbon skeleton, and known compouds ( 3 – 6 ) are rare furan derivatives in the plant kingdom with diverse long-chain hydrocarbyl groups as substituents at C-4. All isolated compounds were evaluated for their antiproliferative activities against five human cancer cell lines: HL-60, SMMC-7721, A-549, MCF-7 and SW480 in vitro . Compounds 1 – 6 showed significant antiproliferative effects against various human cancer cell lines with IC 50 values ranging from 0.28 to 12.06 μM. These findings suggest that the discoveries of these novel γ -lactone derivatives and furan derivatives with significant antiproliferative activities isolated from T. heterophyllus could be of great importance to the development of new anticancer agents. [ABSTRACT FROM AUTHOR]

N 6 -Methyladenosine (m 6 A) represents the most prevalent internal modification in mammalian mRNAs. Emerging evidences suggest that m 6 A modification is profoundly implicated in many biological processes, including cancer development. However, limited knowledge is available about the functional importance of m 6 A in lung cancer. In this study, by data mining The Cancer Genome Atlas (TCGA) database, we first identified fat mass- and obesity-associated protein (FTO) as a prognostic factor for lung squamous cell carcinoma (LUSC). Then we showed that FTO, but not other m 6 A modification genes including METTL3, METTL14 and ALKBH5, was the major dysregulated factor responsible for aberrant m 6 A modification in LUSC. Loss-of-function studies suggested that FTO knockdown effectively inhibited cell proliferation and invasion, while promoted cell apoptosis of L78 and NCI-H520 cells. Furthermore, overexpression of FTO, but not its mutant form, facilitated the malignant phenotypes of CHLH-1 cells. Mechanistically, FTO enhanced MZF1 expression by reducing m 6 A levels and mRNA stability in MZF1 mRNA transcript, leading to oncogenic functions. Taken together, our study demonstrates the functional importance of FTO in the tumor progression of LUSC and provides a potential therapeutic target for LUSC treatment. [ABSTRACT FROM AUTHOR]

[Display omitted] PTP1B plays an important role as a key negative regulator of tyrosine phosphorylation associated with insulin receptor signaling in the therapy for diabetes and obesity. In this study, the anti-diabetic activity of dianthrone derivatives from Polygonum multiflorum Thunb., as well as the structure–activity relationships, mechanism, and molecular docking were explored. Among these analogs, trans -emodin dianthrone (compound 1) enhances insulin sensitivity by upregulating the insulin signaling pathway in HepG2 cells and displays considerable anti-diabetic activity in db/db mice. By using photoaffinity labeling and mass spectrometry-based proteomics, we discovered that trans -emodin dianthrone (compound 1) may bind to PTP1B allosteric pocket at helix α6/α7, which provides fresh insight into the identification of novel anti-diabetic agents. [ABSTRACT FROM AUTHOR]

[Display omitted] • Six new oligostilbenes obtained from the stems of Caragana sinica. • Natural tetrastilbenes were determined as absolute configuration for the first time. • Obvious inhibition of α -glucosidase in vitro with IC 50 values of 0.1 ∼ 0.4 μ M. • Leachianol (7) showed significant inhibition (88.8%, 10 μ M) of protein tyrosine phosphatase (PTP1B) with IC 50 value of 1.1 μ M in vitro. Six new oligostilbenes, carastilphenols A-E (1 – 5) and (–)-hopeachinol B (6), with three reported oligostilbenes were obtained from the stems of Caragana sinica. The structures of compounds 1 – 6 were determined by comprehensive spectroscopy analysis, and their absolute configurations were determined by electronic circular dichroism calculations. Thus, natural tetrastilbenes were determined as absolute configuration for the first time. Also, we did several pharmacological essays. In the antiviral tests, compounds 2 , 4 and 6 showed moderate anti-coxsackie virus B3 type (CVB3) effect on Vero cells activities in vitro with IC 50 values of 19.2 ∼ 69.3 μ M; and compounds 3 and 4 showed different levels of anti-respiratory syncytial virus (RSV) effect on Hep2 cells activities in vitro with IC 50 values of 23.1 and 33.3 μ M, respectively. As for hypoglycemic activity, compounds 6 – 9 (10 μ M) showed the inhibition of α -glucosidase in vitro with IC 50 values of 0.1 ∼ 0.4 μ M; and compound 7 showed significant inhibition (88.8%, 10 μ M) of protein tyrosine phosphatase 1B (PTP1B) with IC 50 value of 1.1 μ M in vitro. [ABSTRACT FROM AUTHOR]

Highlights: [•] Wwp2 and SRG3 form protein complexes in the nucleus in mammalian cells. [•] Wwp2 promotes ubiquitination of SRG3 both in vivo and in vitro. [•] Wwp2 promotes degradation of SRG3 through the ubiquitin-proteasome system. [ABSTRACT FROM AUTHOR]

Abstract: Tau aggregation and amyloidogenesis are common hallmarks for neurodegenerative disorders called tauopathies. The molecular chaperone network constitutes the cellular defense against insults such as tau aggregation. However, chaperone effects on tau are dichotomous. Loss of tau''s microtubule-binding activity facilitates an inappropriate chaperone interaction that promotes an amyloidogenic tau conformation. Conversely, other chaperones are capable of promoting tau clearance. Here, we demonstrate that a critical contributor to tau triage is the DnaJ-binding domain of Hsp70 proteins. In particular, over-expression of the constitutive DnaJ, DnaJA1, mediated tau clearance, while knockdown facilitated tau accumulation. This clearance was not specific to distinct pathogenic tau species. The activity of DnaJA1 was attenuated by concomitant increases in Hsp70. Tau reductions facilitated by DnaJA1 were dependent on the integrity of lysines known to be poly-ubiquitinated in human Alzheimer''s brain. In vivo, DnaJA1 and tau levels were inversely correlated. The effects of DnaJA1 were partially specific: DnaJA1 reduced the levels of a polyQ protein but had no significant effect on α-synuclein levels. These data suggest that DnaJA1 triages all tau species for ubiquitin-dependent clearance mechanisms. Moreover, the levels of DnaJA1 and Hsp70 seem to play against each other with regard to tau: as DnaJA1 levels increase, tau levels are reduced, but this can be prevented if Hsp70 levels are simultaneously induced. Thus, the DnaJ repertoire possibly represents a powerful set of genetic modifiers for tau pathogenesis. Further investigations could provide new insights about triage decisions that facilitate or prevent amyloidogenesis of tau and other proteins associated with neurodegenerative disease. [Copyright &y& Elsevier]

Abstract: Objectives: Infection with high-risk human papillomavirus (hr-HPV) is an important factor associated with cervical cancer. The genetic mutation of HPV16 E6 and integration of HPV16 DNA in the cervical carcinoma tissues are considered important genetic changes in cervical lesion progression. But the studies of hr-HPV epidemiology are relatively less in the area of Sichuan, China. Therefore, we investigated the prevalence of 9 high-risk subtypes and analyzed the genetic mutation characteristic of HPV16 E6 and physical state of HPV16 DNA. Methods: The fragments of L1 and E6 genes were amplified by PCR or nested PCR and then directly sequenced. Further, the multiplex PCR for HPV16 E2 and E6 genes was performed for detection of integration. Results: HPV16, 58 and 18 were prominent, accounting for 78.6%, 20.0% and 9.7%, respectively in 145 isolates. E6 variants revealed that the European (EP) prototype and East Asia (EA) strain were 26 (23.0%) and 34 (30.1%), respectively. Furthermore, there were 14 base substitutions in E6 regions of the study group, of which 12 resulted in amino acid changes and the rest was silent mutation. Significantly, the 240G substitution exactly located the P53 degradation site. Overall, 8 of 114 (7.0%) isolates only contained integrated HPV16 DNA, 43 (37.7%) only contained episomal DNA and 63 (55.3%) contained both integrated and episomal DNA. The proportion of disruption of an intact E2 gene in the patients with cervical cancer is much lower than that in the previous studies. Conclusions: HPV16, 58 and 18 were mainly prevailing subtypes in patients with cervical cancer from Sichuan areas, China and EP/EA strains were predominant in these areas. Some mutations of E6 gene, which lead to the amino acid changes, may be more potentially carcinogenic and the proportion of disruption of an intact E2 gene is much lower. [Copyright &y& Elsevier]

Abstract: The tetracycline (Tc)-inducible small interference RNA (siRNA) is a powerful tool for studying gene function in mammalian cells. However, the system is infrequently utilized in embryonic stem (ES) cells. Here, we present the first application of the Tc-inducible, stably integrated plasmid-based siRNA system in mouse ES cells to down-regulate expression of Npm1, an essential gene for embryonic development. The physiological role of Npm1 in ES cells has not been defined. Our data show that the knock-down of Npm1 expression by this siRNA system was not only highly efficient, but also Tc- dose- and induction time-dependent. Particularly, the down-regulation of Npm1 expression was reversible. Importantly, suppression of Npm1 expression in ES cells resulted in reduced cell proliferation. Taken together, this system allows for studying gene function in a highly controlled manner, otherwise difficult to achieve in ES cells. Moreover, our results demonstrate that Npm1 is essential for ES cell proliferation. [Copyright &y& Elsevier]

Previous studies show that isogenic mutants deficient in streptococcal pyrogenic exotoxin B (SPE B) cause less mortality and skin tissue damage than wild-type strains of Streptococcus pyogenes when inoculated into mice via an air pouch. In this study, the growth and dissemination of bacteria, pathologic changes in various organs, and their correlation with SPE B production were examined. Bacterial numbers in the air pouch from wild-type strain NZ131-infected mice increased at 48 h, while those from speB mutant SW510-infected mice continuously reduced. Mice infected with NZ131 developed bacteremia and greater dissemination in the kidney, liver, and spleen; those infected with SW510 showed either no or slight bacteremia and dissemination. Co-inoculation of SW510 with recombinant SPE B showed a higher bacterial count in the air pouch, bacteremia, and organ dissemination compared to co-inoculation with a C192S mutant lacking protease activity. The histopathologic changes examined showed lesions in kidney and liver in the NZ131-infected but not in SW510-infected mice. The elevation in sera of BUN, AST, and ALT correlated positively with renal and liver impairment. Taken together, SPE B produced during S. pyogenes infection plays a pathogenic role. A direct effect of SPE B on vessel permeability change was also demonstrated. [Copyright &y& Elsevier]

[Display omitted] • Nine undescribed monoterpene phenol dimers bisbakuchiols D-L (1 – 9) were isolated from the fruits of Psoralea corylifolia L. • A single crystal of compound 1 was obtained, and the absolute configurations of 1 was established by X-ray diffraction. • Compounds 5 and 9 exhibited significant PTP1B inhibitory activities with IC 50 values of 0.69 and 0.73 μ M. • A Molecular docking simulation of PTP1B and compounds 5 and 9 exhibited that these active compounds possess low binding affinities ranging from −6.9 to −7.1 kcal/mol. Nine undescribed monoterpene phenol dimers, bisbakuchiols D-L (1 – 9), were isolated from the fruits of Psoralea corylifolia L. Their structures were elucidated based on extensive spectral analysis. The absolute configurations of 1 – 9 were specified by experimental and quantum chemical calculations of ECD spectra, and that of 1 was further established by X-ray diffraction analysis using Cu Kα radiation. Bisbakuchiols (1 – 4) were composed of two bakuchiols, one of which was cyclized via a C-7′/ C-12′ single bond to form a six-member ring, and connect to each other by C–4–O–C–13 ' bonds. Bisbakuchiols (7 – 9) had a pyran ring by linkage of C–8–O–C–12. In the enzyme assay, compounds 5 and 9 exhibited significant PTP1B inhibitory activities with IC 50 values of 0.69 and 0.73 μ M, and compounds 1 and 3 showed moderate PTP1B inhibitory activities. Furthermore, a molecular docking simulation of PTP1B and active compounds 5 and 9 showed that these active compounds possess low binding affinities ranging from −6.9 to −7.1 kcal/mol. [ABSTRACT FROM AUTHOR]

The use of β-blockers for acute coronary syndrome (ACS) patients without heart failure (HF) is controversial, and lacks of evidence in the era of reperfusion and intensive secondary preventions. This study aimed to investigate the prognostic impacts of β-blockers on patients with ACS but no HF treated by percutaneous coronary intervention (PCI). A total of 2397 consecutive patients with ACS but no HF treated by PCI were retrospectively recruited from January 2010 to June 2017. Univariable Cox regression was used to assess the prognostic impacts of β-blockers, followed by adjusted analysis, one-to-one propensity score matching (PSM), and inverse probability treatment weighting (IPTW) analysis, in order to control for systemic between-group differences. The primary outcome was all-cause death. Among the included patients, 2060 (85.9%) were prescribed with β-blockers at discharge. The median follow-up time was 727 (433–2016) days, with 55 (2.3%) cases of all-cause death. Unadjusted analysis showed that the use of β-blockers was associated with lower risk of death (hazard ratio [HR]: 0.42, 95% confidence interval [CI]: 0.23–0.76, P = 0.004), which was sustained in adjusted analysis (HR: 0.53, 95% CI: 0.29–0.98, P = 0.044), PSM analysis (HR: 0.44, 95% CI: 0.20–0.96, P = 0.039) and IPTW analysis (HR: 0.49. 95% CI: 0.35–0.70, P < 0.001). Risk reduction was also seen in β-blocker users for cardiac death, but not for major adverse cardiovascular events. The use of β-blockers was associated with reduced long-term mortality for ACS-PCI patients without HF. [Display omitted] [ABSTRACT FROM AUTHOR]

Forest ecosystem conservation practice frequently sacrifices human livelihood, since there exists a structural conflict between both aspects in the degraded forest ecosystem. To reconcile the conflict has been widely viewed as a core issue, in which the payment of ecosystem service (PES) may play a critical role in solving this issue. In order to better understand the practical effectiveness of PES and explore the solution to reconcile the contradiction between conservation and livelihood, we investigated the decadal changes in the Sloping Land Conversion Program as a PES strategy in the Qilian Mountains, a degraded forest ecosystem of northwest China, and its effects on natural and social systems across the 10-year implementation period (2001–2011). The regional NDVI of study site was promoted from 46.24% to 61.28%, showing that vegetation cover had a massive increase during the whole implementation period. Also, the PES strategy had impelled more labor forces as migrant workers into the non-agricultural industries or urban areas. The migration dynamics in three industries demonstrated that the population of primary industry followed a gradually declining trend, and its percentage in total population was lowered from 33.44% to 19.82%. According to our household survey, local farmers reduced the economic investment in agriculture, and this enabled more labor forces to be released from agricultural industry. Interestingly, the attitudes towards the PES program for local inhabitants were gradually shifted from negative at initial stage to acceptable at middle stage, and finally to positive at late stage, as a consequence of PES application. In such case, the PES-led vegetation restoration strategy has been effectively implemented, which can reconcile the contradiction between conservation and livelihood, and ultimately achieve a win-win consequence. Our study provided a successful practical paradigm of coupled human and natural system (CHANS) in forest ecosystem restoration. • We analyzed the dilemma between forest conservation and human livelihood in China. • Sloping Land Conversion Program acted as the Payment for Ecosystem Service (PES). • The PES strategy accelerated the transfer of labors into non-agricultural industries. • Livelihood improvements promoted a fine shift of farmers' attitudes towards PES. • We established a CHANS model to highlight the role of PES in forest conservation. [ABSTRACT FROM AUTHOR]

This paper investigates a new finite-time fault-tolerant control (FTC) using a fractional-order backstepping iterative design strategy for a fixed-wing unmanned aerial vehicle (UAV) in the presence of actuator faults and input saturation. To compensate for the lumped disturbance induced by the actuator faults, a neural network disturbance observer (NNDO) with finite-time observation capability is first developed as the fault diagnostic unit. Then, based on the diagnosed fault information, fractional-order (FO) calculus is artfully utilized to enhance the FTC performance within the backstepping design architecture. The salient feature of the developed control scheme is that the finite-time NNDO and FO calculus are simultaneously used to significantly increase the FTC performance against unexpected actuator faults. Moreover, to address the input saturation problem, the faulty UAV dynamics is augmented by a new auxiliary system. Furthermore, a Nussbaum function is incorporated into the FTC scheme to further avoid the calculation of the inverse gain matrix involved within the auxiliary system. It is shown by Lyapunov analysis that the tracking errors are convergent in finite time. Finally, comparative simulations are conducted to show the effectiveness of the developed FTC scheme. Some hardware-in-the-loop (HIL) experimental results are illustrated to further demonstrate the feasibility of the proposed finite-time fractional-order fault-tolerant control (FTFOFTC) method. [ABSTRACT FROM AUTHOR]

[Display omitted] High heterogeneity has been reported among epidemiological studies exploring the relationship between metformin and the risk of gastric cancer. Immortal time bias might be one of the vital factors causing heterogeneity because of its widespread existence in pharmacological observational studies and it could severely exaggerate the drug's effectiveness. Immortal time bias could occur in an observational study if exposure status is determined based on a measurement or event that occurs after baseline. In this study, we aimed to assess whether immortal time bias is responsible for the false assumption that metformin reduces the risk of gastric cancer. We searched PubMed, Embase, Web of Science and Cochrane Library databases for relevant studies from the inception to August 9, 2020. The strength of the relationship was assessed using pooled relative risks (RRs) with corresponding 95% confidence intervals (95% CIs). Statistical analyses were carried out using a random-effects model. Pooled RR from 6 cohort studies with immortal time bias found a clear 33% reduced risk associated with metformin use (RR = 0.67, 95% CI = 0.59, 0.77; P < 0.001; I2 = 48.5%). However, pooled RR from 8 cohort studies without immortal time bias indicated no association between the use of metformin and gastric cancer risk (RR = 0.95, 95% CI = 0.85, 1.05; P = 0.317; I2 = 64.5%). From a univariate meta-regression model, the presence of immortal time bias was associated with a significant reduction of 29% in the effect estimate of metformin on gastric cancer risk (ratio of RR = 0.71, 95% CI = 0.58, 0.86; P = 0.002). This meta-analysis indicates that metformin use has no protective effect on gastric cancer risk. The relationship between metformin use and gastric cancer risk has been exaggerated as a result of the presence of immortal time bias. Further studies are required to confirm the results by controlling for immortal time bias based on appropriate study designs and statistical methods. [ABSTRACT FROM AUTHOR]