Thiopeptide Antibiotics Exhibit a Dual Mode of Action against Intracellular Pathogens by Affecting Both Host and Microbe

SummaryThiostrepton (TSR) is an archetypal thiopeptide antibiotic possessing a quinaldic acid (QA) moiety in the side ring system. According to the mechanism of TSR previously known to target bacterial ribosome, we recently designed and biosynthesized several TSR derivatives that varied in QA substitution. Utilizing these thiopeptide antibiotics to treat the intracellular pathogen Mycobacterium marinum, we herein report a novel mode of action of TSRs, which induce ER stress-mediated autophagy to enhance host cell defense. This intracellular response, which is sensitive to the modification of the QA group, serves as an indirect but unignorable mechanism for eliminating intracellular pathogens. TSRs are thus the only type of antibiotics, to our knowledge, with the dual action on both the parasitic bacteria and the infected host cells. The newly observed mechanism of TSRs may inspire the future change in the treatment of intracellular pathogens, by taking host response into account

Orientin Ameliorates LPS-Induced Inflammatory Responses through the Inhibitory of the NF- κ

Inflammation is a complex response to diverse pathological conditions, resulting in negative rather than protective effects when uncontrolled. Orientin (Ori), a flavonoid component isolated from natural plants, possesses abundant properties. Thus, we aimed to discover the potential therapeutic effects of orientin on lipopolysaccharide- (LPS-) induced inflammation in RAW 264.7 cells and the underlying mechanisms. In our studies, we evaluated the effects of Ori on proinflammatory mediator production stimulated by LPS, including tumor necrosis factor- (TNF-) α, interleukin- (IL-) 6, IL-18, and IL-1β, along with prostaglandin E2 (PGE2) and NO. Our data indicated that orientin dramatically inhibited the levels of these mediators. Consistent with these results, the expression levels of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) were also reduced. Further study demonstrated that such inhibitory effects of Ori were due to suppression of the nuclear factor-kappa B (NF-κB) pathway and nucleotide-binding domain- (NOD-) like receptor protein 3 (NLRP3) inflammasome activation, which may contribute to its anti-inflammatory effects. Together, these findings show that Ori may be an effective candidate for ameliorating LPS-induced inflammatory responses

Dynamic Responses of Continuous Girder Bridges with Uniform Cross-Section under Moving Vehicular Loads

To address the drawback of traditional method of investigating dynamic responses of the continuous girder bridge with uniform cross-section under moving vehicular loads, the orthogonal experimental design method is proposed in this paper. Firstly, some empirical formulas of natural frequencies are obtained by theoretical derivation and numerical simulation. The effects of different parameters on dynamic responses of the vehicle-bridge coupled vibration system are discussed using our own program. Finally, the orthogonal experimental design method is proposed for the dynamic responses analysis. The results show that the effects of factors on dynamic responses are dependent on both the selected position and the type of the responses. In addition, the interaction effects between different factors cannot be ignored. To efficiently reduce experimental runs, the conventional orthogonal design is divided into two phases. It has been proved that the proposed method of the orthogonal experimental design greatly reduces calculation cost, and it is efficient and rational enough to study multifactor problems. Furthermore, it provides a good way to obtain more rational empirical formulas of the DLA and other dynamic responses, which may be adopted in the codes of design and evaluation

Lipid and glucose metabolism in senescence

Senescence is an inevitable biological process. Disturbances in glucose and lipid metabolism are essential features of cellular senescence. Given the important roles of these types of metabolism, we review the evidence for how key metabolic enzymes influence senescence and how senescence-related secretory phenotypes, autophagy, apoptosis, insulin signaling pathways, and environmental factors modulate glucose and lipid homeostasis. We also discuss the metabolic alterations in abnormal senescence diseases and anti-cancer therapies that target senescence through metabolic interventions. Our work offers insights for developing pharmacological strategies to combat senescence and cancer

CNS-Native Myeloid Cells Drive Immune Suppression in the Brain Metastatic Niche through Cxcl10

Brain metastasis (br-met) develops in an immunologically unique br-met niche. Central nervous system-native myeloid cells (CNS-myeloids) and bone-marrow-derived myeloid cells (BMDMs) cooperatively regulate brain immunity. The phenotypic heterogeneity and specific roles of these myeloid subsets in shaping the br-met niche to regulate br-met outgrowth have not been fully revealed. Applying multimodal single-cell analyses, we elucidated a heterogeneous but spatially defined CNS-myeloid response during br-met outgrowth. We found Ccr2+ BMDMs minimally influenced br-met while CNS-myeloid promoted br-met outgrowth. Additionally, br-met-associated CNS-myeloid exhibited downregulation of Cx3cr1. Cx3cr1 knockout in CNS-myeloid increased br-met incidence, leading to an enriched interferon response signature and Cxcl10 upregulation. Significantly, neutralization of Cxcl10 reduced br-met, while rCxcl10 increased br-met and recruited VISTAHi PD-L1+ CNS-myeloid to br-met lesions. Inhibiting VISTA- and PD-L1-signaling relieved immune suppression and reduced br-met burden. Our results demonstrate that loss of Cx3cr1 in CNS-myeloid triggers a Cxcl10-mediated vicious cycle, cultivating a br-met-promoting, immune-suppressive niche

A Kalman Filter-Based Method for Diagnosing the Structural Condition of Medium- and Small-Span Beam Bridges during Brief Traffic Interruptions

Load tests are a popular way to diagnose the structural condition of bridges, however, such tests usually interrupt traffic for many hours. To address this issue, a Kalman filter-based method is proposed to diagnose the structural condition of medium- and small-span beam bridges by using the acceleration responses obtained from the bridge during a brief traffic interruption. First, a condition diagnosis feature based on the Kalman filter innovation (i.e., the optimal difference between the filter predictions and measured responses) is presented. Second, a condition diagnosis index, which is the energy ratio between the innovation and the measured acceleration, is generated by calculating the null space of the Hankel matrix consisting of condition diagnosis features. Then, on the basis of the novel detection, a method is used to diagnose the structural condition of a bridge during a brief traffic interruption. Finally, the validity and dependability of the proposed method is demonstrated through experimental tests with a model bridge and field tests on an actual bridge. Using the proposed method, the long-time interruption of traffic flow and the reliance on finite element model are effective avoided during the process of condition diagnosis of bridges

Dynamic Responses of Simply Supported Girder Bridges to Moving Vehicular Loads Based on Mathematical Methods

For dynamic responses of highway bridges to moving vehicles, most of studies focused on single-factor analysis or multifactor analysis based on full factorial design. The defect of the former one is that it has no consideration of interaction effects, while that of the latter one is that it has large calculation. To avoid these defects, simplified theoretical derivations are presented at first; then some numerical simulations based on the proposed method of the orthogonal experimental design in batches have been done by our own program VBCVA. According to simplified theoretical derivations, three factors (κ, γ, and α) are proved as the most important factors to determine dynamic responses. Based on the modal synthesis method, the program VBCVA has been introduced in detail. Then on the basis of the orthogonal experimental design, both main effects and interaction effects are studied. The results show that, for different indices of dynamic responses, the influences of each factor are not the same. Additionally, the interaction effects have proved to be so small that they can be neglected. In the end, this method provides a good way to obtain more rational empirical formulas of the DLA and other dynamic responses, which may be adopted in the revision of codes for design and evaluation

Investigating the Hysteretic Behavior of Concrete-Filled Steel Tube Arch by Using a Fiber Beam Element

A fiber beam finite element that could account for the nonlinear constitutive relationship between steel and concrete was applied to investigate the hysteretic behavior of concrete filled steel tube (CFT) arch ribs of bridges. At first, the effectiveness of this fiber beam element using for nonlinear analysis was verified by comparing the analytical results with the experimental data, and then this composite element was applied to analyze the hysteretic performance of CFT arch ribs. The following hysteretic behavior of CFT arch ribs of bridges was investigated such as the hysteretic behaviors of moment-curvature of arch ribs in vertical direction of bridge and the hysteretic relationship between load and displacement of arch ribs in longitudinal and transverse direction of bridge. Finally, some parameters affecting the hysteretic behaviors of CFT arch ribs were presented by evaluating the capacity of ductility of CFT arch ribs

Numerical Investigation of the Dynamic Performance and Riding Comfort of a Straddle-Type Monorail Subjected to Moving Trains

The driving comfort of a straddle-type monorail, while considering the influence of the bridge structure, was studied on the basis of multibody dynamics and the finite element method. In this study, the coupled vehicle-bridge model was established through SIMPACK and ANSYS; the 3D model of the bridge was established in ANSYS, and the vehicle model with 35 degrees of freedom (DOFs) was established in SIMPACK. The influence of the vehicle speed, pier height, track irregularity, and vehicle load on riding comfort was studied. Overall, straddle-type monorails had a good running stability, and the lateral comfort of the vehicle was better than the vertical comfort, due to symmetrical horizontal wheels. As the vehicle speed increased, the acceleration of the bridge and vehicle increased accordingly. Track irregularity had a substantial influence on riding comfort. Three types of track irregularity were simulated, and this factor should be strictly controlled to be smoother than the Chinese national A-level road roughness. The bridge pier height had a notable influence on the lateral riding comfort. In addition, this study attempted to improve riding comfort from the perspective of increasing the bridge stiffness, which could be achieved by increasing the cross-beam thickness or the track beam height

Formulation of Ice Resistance in Level Ice Using Double-Plates Superposition

The estimation of ship resistance in ice is a fundamental area of research and poses a substantial challenge for the design and safe use of ships in ice-covered waters. In order to estimate the ice resistance with greater reliability, we develop in this paper an improved Lindqvist formulation for the estimation of bending resistance in level ice based on the superposition of double-plates. In the developed method, an approximate model of an ice sheet is firstly presented by idealizing ice sheeta as the combination of a semi-infinite elastic plate and an infinite one resting on an elastic foundation. The Mohr–Coulomb criterion is then introduced to determine the ice sheet’s failure. Finally, an improved Lindqvist formulation for estimation of ice resistance is proposed. The accuracy of the developed formulation is validated using full-scale test data of the ship KV Svalbard in Norway, testing the model as well as the numerical method. The effect of ice thickness, stem angle and breadth of bow on ship resistance is further investigated by means of the developed formulation