AcMNPV P74 is cleaved at R325 and R334 by proteinases of both OB and BBMV to expose a potential fusion peptide for oral infection.

Baculoviruses enter insect midgut epithelial cells via a set of occlusion-derived virion (ODV) envelope proteins called per os infectivity factors (PIFs). P74 of Autographa californica multicapsid nucleopolyhedrovirus (AcMNPV), which was the first identified PIF, is cleaved by an endogenous proteinase embedded within the occlusion body during per os infection, but the target site(s) and function of the cleavage have not yet been ascertained. Here, based on bioinformatics analyses, we report that cleavage was predicted at an arginine and lysine-rich region in the middle of P74. A series of recombinant viruses with site-directed mutants in this region of P74 were generated. R325 or R334 was identified as primary cleavage site. In addition, we showed that P74 is also cleaved by brush border membrane vesicles (BBMV) of the host insect at R325 or R334, instead of R195, R196, and R199, as previously reported. Simultaneous mutations in R195, R196, and R199 lead to instability of P74 during ODV release. Bioassays showed that mutations at both R325 and R334 significantly affected oral infectivity. Taken together, our data show that both R325 and R334 of AcMNPV P74 are the primary cleavage site for both occlusion body endogenous proteinase and BBMV proteinase during ODV release and are critical for oral infection. IMPORTANCE: Cleavage of viral envelope proteins is usually an important trigger for viral entry into host cells. Baculoviruses are insect-specific viruses that infect host insects via the oral route. P74, a per os infectivity factor of baculoviruses, is cleaved during viral entry. However, the function and precise cleavage sites of P74 remain unknown. In this study, we found that R325 or R334 between the N- and C-conserved domains of P74 was the primary cleavage site by proteinase either from the occlusion body or host midgut. The biological significance of cleavage seems to be the release of the potential fusion peptide at the N-terminus of the cleaved C-terminal P74. Our results shed light on the cleavage model of P74 and imply its role in membrane fusion in baculovirus per os infection.

A Nonbactericidal Anionic Antimicrobial Peptide Provides Prophylactic and Therapeutic Efficacies against Bacterial Infections in Mice by Immunomodulatory-Antithrombotic Duality.

Although bactericidal cationic antimicrobial peptides (AMPs) have been well characterized, less information is available about the antibacterial properties and mechanisms of action of nonbactericidal AMPs, especially nonbactericidal anionic AMPs. Herein, a novel anionic antimicrobial peptide (Gy-CATH) with a net charge of -4 was identified from the skin of the frog Glyphoglossus yunnanensis. Gy-CATH lacks direct antibacterial effects but exhibits significantly preventive and therapeutic capacities in mice that are infected with Staphylococcus aureus, Enterobacteriaceae coli, methicillin-resistant Staphylococcus aureus (MRSA), or carbapenem-resistant E. coli (CREC). In vitro and in vivo investigations proved the regulation of Gy-CATH on neutrophils and macrophages involved in the host immune defense against infection. Moreover, Gy-CATH significantly reduced the extent of pulmonary fibrin deposition and prevented thrombosis in mice, which was attributed to the regulatory role of Gy-CATH in physiological anticoagulants and platelet aggregation. These findings show that Gy-CATH is a potential candidate for the treatment of bacterial infection.

A Gated Recurrent Generative Transfer Learning Network for Fault Diagnostics Considering Imbalanced Data and Variable Working Conditions.

Transfer learning (TL) and generative adversarial networks (GANs) have been widely applied to intelligent fault diagnosis under imbalanced data and different working conditions. However, the existing data synthesis methods focus on the overall distribution alignment between the generated data and real data, and ignore the fault-sensitive features in the time domain, which results in losing convincing temporal information for the generated signal. For this reason, a novel gated recurrent generative TL network (GRGTLN) is proposed. First, a smooth conditional matrix-based gated recurrent generator is proposed to extend the imbalanced dataset. It can adaptively increase the attention of fault-sensitive features in the generated sequence. Wasserstein distance (WD) is introduced to enhance the construction of mapping relationships to promote data generation ability and transfer performance of the fault diagnosis model. Then, an iterative "generation-transfer" co-training strategy is developed for continuous parallel training of the model and the parameter optimization. Finally, comprehensive case studies demonstrate that GRGTLN can generate high-quality data and achieve satisfactory cross-domain diagnosis accuracy.

Evaporation Dynamics of Macro- and Nanodroplets on Heated Hydrophilic Rough Substrates: The Effect of Roughness and Scale.

Droplet evaporation on rough substrates plays an essential role in cooling and micro/nanoparticle assembly. Currently, there are numerous macroscopic experiments and theoretical models to investigate the droplet evaporation behavior on rough substrates. However, due to the complexity of this phenomenon, understanding its mechanisms solely through macroscale studies is difficult. To this end, molecular dynamics simulations of the models with distinct roughness factors are performed, and the obtained results are compared with those of relevant experiments of droplet evaporation on three hydrophilic substrates with different roughness average of 0.1, 0.15, and 0.2 µm, respectively. In this way, we assess the evaporation on these rough systems and the effect of scale on macro- and nanodroplets, which allows us to explore deeper the mechanism of droplet evaporation on rough hydrophilic substrates. In particular, we find that in the case of macroscale droplets, the evaporation mode remains the same with increasing roughness, pointing to a combined mixed and constant-contact-radius (CCR) mode. In the case of nanoscale droplets, the evaporation model is the constant-contact-angle mode when the roughness factor r = 1, while the mixed and CCR modes are found for r = 1.5 and 2, respectively. The scale effect has significant influence on the evaporation pattern of droplets on rough hydrophilic substrates. Moreover, it is also found that increasing the roughness of substrates expands the substrate-droplet contact area on both the macro- and nanoscale, which in turn enhances the heat transfer from the substrate toward the droplet. We anticipate that this first systematic analysis of scale effects provides further insights into the evaporation dynamics of droplets on rough hydrophilic substrates and has significant implications for the advancement of nanotechnology.

Heritable changes in chromatin contacts linked to transgenerational obesity.

Burgeoning evidence demonstrates that effects of environmental exposures can be transmitted to subsequent generations through the germline without DNA mutations1,2. This phenomenon remains controversial because underlying mechanisms have not been identified. Therefore, understanding how effects of environmental exposures are transmitted to unexposed generations without DNA mutations is a fundamental unanswered question in biology. Here, we used an established murine model of male-specific transgenerational obesity to show that exposure to the obesogen tributyltin (TBT) elicited heritable changes in chromatin interactions (CIs) in primordial germ cells (PGCs). New CIs were formed within the Ide gene encoding Insulin Degrading Enzyme in the directly exposed PGCs, then stably maintained in PGCs of the subsequent (unexposed) two generations. Concomitantly, Ide mRNA expression was decreased in livers of male descendants from the exposed dams. These males were hyperinsulinemic and hyperglycemic, phenocopying Ide-deficient mice that are predisposed to adult-onset, diet-induced obesity. Creation of new CIs in PGCs, suppression of hepatic Ide mRNA, increased fat mass, hyperinsulinemia and hyperglycemia were male-specific. Our results provide a plausible molecular mechanism underlying transmission of the transgenerational predisposition to obesity caused by gestational exposure to an environmental obesogen. They also provide an entry point for future studies aimed at understanding how environmental exposures alter chromatin structure to influence physiology across multiple generations in mammals.

miR-223 Plays a Key Role in Obesogen-Enhanced Adipogenesis in Mesenchymal Stem Cells and in Transgenerational Obesity.

Exposure of pregnant F0 mouse dams to the obesogen tributyltin (TBT) predisposes unexposed male descendants to obesity and diverts mesenchymal stem cells (MSCs) toward the adipocytic lineage. TBT promotes adipogenic commitment and differentiation of MSCs in vitro. To identify TBT-induced factors predisposing MSCs toward the adipocytic fate, we exposed mouse MSCs to TBT, the peroxisome proliferator activated receptor gamma (PPARγ)-selective agonist rosiglitazone, or the retinoid X receptor (RXR)-selective agonist LG-100268. Then we determined their transcriptomal profiles to determine candidate microRNAs (miR) regulating adipogenic commitment and differentiation. Of the top 10 candidate microRNAs predicted by Ingenuity Pathway Analysis, miR-21, miR-33, and miR-223 were expressed consistent with an ability to differentially regulate target genes during adipogenesis. We found that 24-hour exposure to 50nM TBT caused miR-223 levels in MSCs to increase; expression of its target genes ZEB1, NFIB, and FOXP1 was decreased. Rosiglitazone and TBT increased miR-223 levels. This induction was inhibited by the PPARγ antagonist T0070907 but not by the RXR antagonists HX531 or UVI3003, placing miR-223 downstream of PPARγ. Chromatin immunoprecipitation confirmed TBT-induced binding of PPARγ to regulatory elements in the miR-223 promoter. miR-223 levels were elevated in white adipose tissue of F2 and F3 male descendants of pregnant F0 mouse dams exposed to 50nM TBT throughout gestation. miR-223 levels were potentiated in males fed an increased fat diet. We infer that TBT induced miR-223 expression and increased adipogenesis in MSCs through the PPARγ pathway and that transgenerationally increased expression of miR-223 plays an important role in the development of obesity caused by TBT exposure.

Quercetin alleviates intestinal inflammation and improves intestinal functions via modulating gut microbiota composition in LPS-challenged laying hens.

Quercetin, a well-known flavonoid, has been demonstrated to exert beneficial effects on intestinal functions and gut microbiota in birds. In this study, we investigated the effects of quercetin supplementation on inflammatory responses, intestinal barrier functions and gut microbial community in LPS-challenged laying hens. A total of two hundred eighty-eight 32-wk-old Jingfen No.6 laying hens were randomly assigned to 3 groups, the CON group, the LC group and the LQ group. LQ group was fed with 0.4 mg/kg quercetin and at the end of 12 wk, LC and LQ groups were challenged intraperitoneally with lipopolysaccharide (LPS). After LPS challenge, 8 birds of each group were randomly selected and sampled. LPS challenge induced an obvious intestinal mucosal injury, necrosis and shedding, while quercetin intervention maintained its structure. Quercetin significantly decreased the elevated malondialdehyde contents (P < 0.05), and increased the activity of total antioxidant capacity and glutathione peroxidase (P < 0.05) in intestinal mucosa of LPS-challenged laying hens. Quercetin rescued the LPS-induced decreases in goblet cell density and mucin2 expression levels (P < 0.05). There was a significant decline (P < 0.05) in the mRNA expression of Claudin1 and Occludin in intestinal mucosa of LPS-challenged layers, which could be alleviated (P < 0.05) by dietary quercetin. LPS challenge induced the increased expression levels (P < 0.05) of IL-1ß and TLR-4 in intestinal mucosa, while these rises could be reversed (P < 0.05) following dietary quercetin supplementation. LPS challenge induced a shift in gut microenvironment, and quercetin addition could elevate the relative abundance of some short chain fatty acids (SCFA)-producing or health-promoting bacteria such as Phascolarctobacterium, Negativicutes, Selenomonadales, Megamonas, Prevotellaceae, and Bacteroides_salanitronis. In conclusion, dietary quercetin addition ameliorated the LPS challenge-induced intestinal inflammation and improved intestinal functions, possibly associated with its modulation on gut microbiota, particularly the increased population of SCFA-producing bacteria.

Structural Characterization of Per Os Infectivity Factor 5 (PIF5) Reveals the Essential Role of Intramolecular Interactions in Baculoviral Oral Infectivity.

Baculoviruses initiate oral infection in the highly alkaline midgut of insects via a group of envelope proteins called per os infectivity factors (PIFs). To date, no high-resolution structural information has been reported for any PIF. Here, we present the crystal structure of the PIF5 ectodomain (PIF5e) from Autographa californica multiple nucleopolyhedrovirus (AcMNPV) at a 2.2-Å resolution. It revealed an open cavity between the N-terminal E1 domain and the C-terminal E2 domain and a cysteine-rich region with three pairs of disulfide bonds in the E2 domain. Multiple conserved intramolecular interactions within PIF5 are essential for maintaining its tertiary structure. Two conserved arginines (Arg8 and Arg74) play critical roles in E1-E2 interactions, and mutagenesis analysis supported their crucial role in oral infection. Importantly, the reduction in the oral infectivity of the Arg8, Arg74, or cysteine mutant viruses was related to the proteolytic cleavage of PIF5 by the endogenous protease embedded in occlusion bodies during alkaline treatment. This suggested that the structural stability of PIF5 under physiological conditions in the insect midgut is critical for baculoviral oral infectivity. IMPORTANCEPer os infection mediated by PIFs is the highly complex mechanism by which baculoviruses initiate infection in insects. Previous studies revealed that multiple PIF proteins form a large PIF complex on the envelope of virions, while PIF5 functions independently of the PIF complex. Here, we report the crystal structure of AcMNPV PIF5e, which, to our knowledge, is the first atomic structure reported for a PIF protein. The structure revealed the precise locations of three previously proposed disulfide bonds and other conserved intramolecular interactions, which are important for the structural stability of PIF5 and are also essential for oral infectivity. These findings advance our understanding of the molecular mechanism of baculovirus oral infection under alkaline conditions.

Quantitative assessment of ventilation-perfusion relationships with gallium-68 positron emission tomography/computed tomography imaging in lung cancer patients.

Pulmonary functional imaging has demonstrated potential to improve thoracic radiotherapy. The purpose of this study was twofold: 1) to quantify ventilation/perfusion relationships in lung cancer patients using a new functional imaging approach, gallium-68 (68Ga)-positron emission tomography/computed tomography (PET/CT); and 2) to compare ventilation/perfusion matching with diffusing capacity of the lung for carbon monoxide (DLCO). Voxel-wise correlations between ventilation and perfusion varied widely among 19 patients (range: 0.26-0.88). 68Ga-PET/CT-measured percent gas exchanging lung volume was moderately correlated with DLCO (≤0.59). Our findings suggested that 68Ga-PET/CT ventilation/perfusion imaging provided complementary information and a reasonable surrogate for gas exchange in lung cancer patients.

Obesity II: Establishing causal links between chemical exposures and obesity.

Obesity is a multifactorial disease with both genetic and environmental components. The prevailing view is that obesity results from an imbalance between energy intake and expenditure caused by overeating and insufficient exercise. We describe another environmental element that can alter the balance between energy intake and energy expenditure: obesogens. Obesogens are a subset of environmental chemicals that act as endocrine disruptors affecting metabolic endpoints. The obesogen hypothesis posits that exposure to endocrine disruptors and other chemicals can alter the development and function of the adipose tissue, liver, pancreas, gastrointestinal tract, and brain, thus changing the set point for control of metabolism. Obesogens can determine how much food is needed to maintain homeostasis and thereby increase the susceptibility to obesity. The most sensitive time for obesogen action is in utero and early childhood, in part via epigenetic programming that can be transmitted to future generations. This review explores the evidence supporting the obesogen hypothesis and highlights knowledge gaps that have prevented widespread acceptance as a contributor to the obesity pandemic. Critically, the obesogen hypothesis changes the narrative from curing obesity to preventing obesity.

Urchin-like hollow SiO2@γ-MnO2 microparticles for the rapid degradation of organic dyes.

In this paper, using hollow silica microspheres as carriers, we developed a facile one-pot method for the preparation of hollow SiO2@MnO2 composite microparticles. Under a certain proportion of hollow silica microspheres and manganese salt, a novel kind of hollow urchin-like SiO2@γ-MnO2 microparticles was obtained. The structure and morphology of the composite microparticles were characterized by XRD, SEM and TEM. On this basis, using rhodamine B and methyl orange as model molecules, the oxidative degradation ability of the hollow SiO2@γ-MnO2 microparticles for organic dyes in water was investigated through UV-vis analysis technology. The urchin-like SiO2@γ-MnO2 microparticles showed excellent performance for the rapid oxidative degradation of organic dyes under acidic conditions. This study indicated that γ-MnO2 loaded on hollow materials can be used as an efficient tool for treating organic dye wastewater, and shows broad application prospects for solving environmental problems in the related industry.

Cannabidiol promotes adipogenesis of human and mouse mesenchymal stem cells via PPARγ by inducing lipogenesis but not lipolysis.

Cannabidiol (CBD) is a non-psychoactive phytocannabinoid found in the Cannabis sativa plant. Human exposure to CBD can be through recreational marijuana use, commercially available CBD-containing products, and medical treatments. Previous studies found that cannabidiol may activate the master regulator of adipogenesis, peroxisome proliferator activated receptor gamma (PPARγ). Here we investigated the effects of CBD on adipogenesis in human and mouse multipotent mesenchymal stromal stem cells (MSCs). We tested the effects of CBD on nuclear receptor activation and adipogenic potential to demonstrate the mechanism of CBD effects and employed the in vitro MSC differentiation models to assess adipogenic effects of CBD.Using transient transfection assays, we demonstrated that CBD activated mouse and human PPARγ, but not its heterodimeric partner, the retinoid 'X' receptor, RXR. Our results showed that CBD increased lipid accumulation and the expression of adipogenic genes in mouse and human MSCs in vitro. Adipogenic differentiation induced by CBD was significantly decreased by the PPARγ antagonist T0070907, supporting the hypothesis that CBD promoted differentiation via PPARγ. Taken together, our results indicate that in humans and in mice, CBD induced adipogenic differentiation in MSCs through a PPARγ-dependent mechanism.

A novel based-performance degradation indicator RUL prediction model and its application in rolling bearing.

Aiming at the problem of poor prediction performance of rolling bearing remaining useful life (RUL) with single performance degradation indicator, a novel based-performance degradation indicator RUL prediction model is established. Firstly, the vibration signal of rolling bearing is decomposed into some intrinsic scale components (ISCs) by piecewise cubic Hermite interpolating polynomial-local characteristic-scale decomposition (PCHIP-LCD), and the effective ISCs are selected to reconstruct signals based on kurtosis-correlation coefficient (K-C) criteria. Secondly, the multi-dimensional degradation feature set of reconstructed signals is extracted, and then the sensitive degradation indicator IICAMD is calculated by fusing the improved independent component analysis (IICA) and Mahalanobis Distance (MD). Thirdly, the false fluctuation of the IICAMD is repaired by using the gray regression model (GM) to obtain the health indicator (HI) of the rolling bearing, and the start prediction time (SPT) of the rolling bearing is determined according to the time mutation point of HI. Finally, generalized regression neural network (GRNN) model based on HI is constructed to predict the RUL of rolling bearing. The experimental results of two groups of different rolling bearing data-sets show that the proposed method achieves better performance in prediction accuracy and reliability.

Enhanced Catalytic Activity of Magnetic Bimetallic Ag-Au Nanoparticles Mediated by Surface Plasmon Resonance.

We firstly discover the enhanced catalytic activity of magnetic noble metal nanoparticles mediated by surface plasmon resonance. Under light irradiation with certain wavelength, the catalytic performance of magnetic noble metal nanoparticles shows changes with different degrees and directions that are associated with the surface plasmon resonance (SPR) of the noble metal. Moreover, the coupling of silver and gold allows the catalytic performance of magnetic bimetallic Ag-Au nanoparticles to show more positive response to surface plasmon resonance. The magnetic bimetallic Ag-Au nanoparticles show excellent catalytic performance toward the reduction reaction of aromatic nitro group, and corresponding rate constant of the catalytic reduction reaction increases about three times with light irradiation.

An Optimal Parameter Selection Method for MOMEDA Based on EHNR and Its Spectral Entropy.

As a vital component widely used in the industrial production field, rolling bearings work under complicated working conditions and are prone to failure, which will affect the normal operation of the whole mechanical system. Therefore, it is essential to conduct a health assessment of the rolling bearing. In recent years, Multipoint Optimal Minimum Entropy Deconvolution Adjusted (MOMEDA) is applied to the fault feature extraction for rolling bearings. However, the algorithm still has the following problems: (1) The selection of fault period T depends on prior knowledge. (2) The accuracy of signal denoising is affected by filter length L. To solve the limitations, an improved MOMEDA (IMOMEDA) method is proposed in this paper. Firstly, the envelope harmonic-to-noise ratio (EHNR) spectrum is adopted to estimate the fault period of MOMEDA. Then, the improved grid search method with EHNR spectral entropy as the objective function is constructed to calculate the optimal filter length used in the MOMEDA. Finally, a feature extraction method based on the improved MOMEDA (IMOMEDA) and Teager-Kaiser energy operator (TKEO) is applied in the field of rolling bearing fault diagnosis. The effectiveness and generalization performance of the proposed method is verified through comparison experiment with three data sets.

Murine interfollicular epidermal differentiation is gradualistic with GRHL3 controlling progression from stem to transition cell states.

The interfollicular epidermis (IFE) forms a water-tight barrier that is often disrupted in inflammatory skin diseases. During homeostasis, the IFE is replenished by stem cells in the basal layer that differentiate as they migrate toward the skin surface. Conventionally, IFE differentiation is thought to be stepwise as reflected in sharp boundaries between its basal, spinous, granular and cornified layers. The transcription factor GRHL3 regulates IFE differentiation by transcriptionally activating terminal differentiation genes. Here we use single cell RNA-seq to show that murine IFE differentiation is best described as a single step gradualistic process with a large number of transition cells between the basal and spinous layer. RNA-velocity analysis identifies a commitment point that separates the plastic basal and transition cell state from unidirectionally differentiating cells. We also show that in addition to promoting IFE terminal differentiation, GRHL3 is essential for suppressing epidermal stem cell expansion and the emergence of an abnormal stem cell state by suppressing Wnt signaling in stem cells.

An improved local mean decomposition method based on improved composite interpolation envelope and its application in bearing fault feature extraction.

In order to overcome the influence of non-adaptive selection of non-stationary coefficient threshold of compound interpolation envelope (CIE) method on decomposition performance of local mean decomposition (LMD), a LMD method based on improved compound interpolation envelope (ICIE) is proposed in this paper. Firstly, combining the CIE with fractal box dimension, an improved envelope processing method, named ICIE, is proposed. Secondly, an improved LMD-based ICIE is presented and abbreviated as ICIELMD. Finally, three different data-sets, including simulation signal, rolling bearing data-sets from Case Western Reserve University (CWRU) and National Aeronautics and Space Administration (NASA), are used to complete the comparative experiments between the proposed ICIELMD and state-of-the-art methods (CIELMD) and demonstrate the effectiveness of the ICIELMD method. The experimental results show that the proposed method achieves comparable or slightly better than the other methods, and provides a new solution for complex signal analysis of rolling bearing faults.

MVMD-MOMEDA-TEO Model and Its Application in Feature Extraction for Rolling Bearings.

In order to extract fault features of rolling bearings to characterize their operation state effectively, an improved method, based on modified variational mode decomposition (MVMD) and multipoint optimal minimum entropy deconvolution adjusted (MOMEDA), is proposed. Firstly, the MVMD method is introduced to decompose the vibration signal into intrinsic mode functions (IMFs), and then calculate the energy ratio of each IMF component. The IMF component is selected as the effective component from high energy ratio to low in turn until the total energy proportion Esum(t) ≥ 90%. The IMF effective components are reconstructed to obtain the subsequent analysis signal x_new(t). Secondly, the MOMEDA method is introduced to analyze x_new(t), extract the fault period impulse component x_cov(t), which is submerged by noise, and demodulate the signal x_cov(t) by Teager energy operator demodulation (TEO) to calculate Teager energy spectrum. Thirdly, matching the dominant frequency in the spectrum with the fault characteristic frequency of rolling bearings, the fault feature extraction of rolling bearings are completed. Finally, the experiments have compared MVMD-MOEDA-TEO with MVMD-TEO and MOMEDA-TEO based on two different data sets to verify the superiority of the proposed method. The experimental results show that MVMD-MOMEDA-TEO method has better performance than the other two methods, and provides a new solution for condition monitoring and fault diagnosis of rolling bearings.

[Expression of receptor activator of NF-κB ligand and osteoprotegerin in peri-implant tissues during unloading period].

OBJECTIVE: To observe the expression of receptor activator of NF-κB ligand (RANKL) and its decoy receptor osteoprotegerin (OPG) during unloading period of dental implants. METHODS: An animal model of dental implants was established in Beagle dogs. Bone remodeling was tested at 3, 7, 15, 30, 60 and 90 days after the placement of implants. RANKL and OPG mRNA expression were quantified by real-time PCR. Then mandibular bones were resected and some sections were observed. RESULTS: The most prominent period of bone remodeling occurred at 7 day after the placement of implants (OPG/RANKL mRNA, 2.15 ± 0.1). The expression of RANKL and OPG increased in a time-dependent manner in both soft and hard tissue. After 7 days they gradually decreased. CONCLUSIONS: Both OPG and RANKL were expressed in peri-implant tissues, and the changing tendency of RANKL and OPGmRNA was consistent with the change of bone remodeling. The active stage for bone remodelling in peri-implant tissues during unloading period is about 7 days after implantation.