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BACKGROUND: Axillary lymph node metastasis (LNM) affects the progression of breast cancer. However, it is difficult to preoperatively diagnose axillary lymph node status with high sensitivity. Therefore, we hypothesized that platelets/lymphocytes ratio (PLR) and lymphocytes/ red blood cells ratio (LRR) might help in the prognosis of lymph node metastasis in T1-T2 breast cancer. METHODS: 166 patients (Chang Ning Maternity & Infant Health Institute) were included in our study, and the associations of PLR and LPR with lymph node metastasis were investigated. Peripheral blood was collected one week before the surgery, and the patients were divided into different categories based on their PLR and LRR. RESULTS: The incidence of LNM was significantly increased in the high PLR group (p = 0.002) compared with the low PLR group; LNM was also significantly increased in the low LRR group (p = 0.036) compared with the high LPR group. Further, our study revealed that high PLR (p < 0.001, OR = 4.397, 95% CI = 2.005–9.645), low LRR (p = 0.017, OR = 0.336, 95%CI = 0.136–0.825) and high clinical T stage (p < 0.001, OR = 3.929, 95%CI = 1.913–8.071) are independent predictors of LNM. CONCLUSIONS: PLR and LRR could be identified as predictors of LNM in patients with T1/T2 breast cancer. [ABSTRACT FROM AUTHOR]

The extremely broad flight envelope brings remarkable uncertainties to hypersonic vehicles. This paper investigates the longitudinal control problem of hypersonic vehicles with synthetical considerations on multiple modelling uncertainties, especially on time-varying aerodynamic coefficients. To overcome the efficiency loss of aerodynamic control surfaces (ACS), the reaction control system (RCS) is employed to assist the attitude control. An adaptive ACS-RCS compound control is proposed, which deals with uncertain RCS parameters, simultaneously. Other factors including scramjet input saturation, variable geometry inlet, external disturbances and structural flexibilities are also taken into account. Analysis and simulation indicate that preset references can be well tracked with prescribed performances. [ABSTRACT FROM AUTHOR]

In ultrahigh dimensional data analysis, to keep computational performance well and good statistical properties still working, nonparametric additive models face increasing challenges. To overcome them, we introduce a methodology of model selection for high dimensional nonparametric additive models. Our approach is to propose a novel group screening procedure via nonparametric smoothing ridge estimation (GRIE) to find the importance of each covariate. It is then combined with the sure screening property of GRIE and the model selection property of extended Bayesian information criteria (EBIC) to select the suitable sub-models in nonparametric additive models. Theoretically, we establish the strong consistency of model selection for the proposed method. Extensive simulations and two real datasets illustrate the outstanding performance of the GRIE-EBIC method. [ABSTRACT FROM AUTHOR]

In order to study the influence of compliance parts on spatial multibody systems, a rigid-flexible coupling dynamic equation of a spatial crank-slider mechanism is established based on the finite element method. Specifically, absolute node coordinate formulation (ANCF) is used to formulate a three-dimensional, two-node flexible cable element. The rigid-flexible coupling dynamic equation of the mechanism is derived by the Lagrange multiplier method and solved by the generalized α method and Newton–Raphson iteration method combined. Comparison of the kinematics and dynamics response between rigid-flexible coupling system and pure rigid system implies that the flexible part causes a certain degree of nonlinearity and reduces the reaction forces of joints. The elastic modulus of the flexible part is also important to the dynamics of the rigid-flexible multibody system. With smaller elastic modulus, the motion accuracy and reaction forces become lower. [ABSTRACT FROM AUTHOR]

Internal combustion engines take up the major position in the power facility market and still encounter some challenges; one key issue is liner cavitation erosion. The impact vibration between piston and cylinder generates pressure fluctuation on the wet liner surface and leads to the occurrence of cavitation in the case that coolant pressure falls below its vapor pressure. Piston slap methodology has been improved by considering the dynamic characteristics of the piston. Water coolant passage acoustic features were investigated and the Helmholtz effect between cylinders was confirmed. In order to address the cavitation erosion potential of the engine cylinder, acoustic pressure in the cooling water passage was investigated by boundary element method analysis with the acceleration of the cylinder liner which was obtained from the piston slap program. This study revealed that a certain acoustic mode of the cooling water passage had a dominant effect on the amplitude of water coolant dynamic pressure induced by liner vibration. Measures of eliminating the acoustic mode are believed to be able to suspend pressure fluctuation and furthermore the potential of cavitation. [ABSTRACT FROM AUTHOR]

Cisplatin (DDP) is used for the clinical management of triple-negative breast cancer (TNBC). However, the development of drug resistance limits its therapeutic efficacy. Circular RNAs (circRNAs) are known to be involved in tumor DDP resistance. In our previous study, we reported that circ_0007823 expression is downregulated and correlated with adverse prognosis in TNBC. However, its association with DDP resistance remains unclear. This study aimed to determine the role of circ_0007823 and miR-182-5p in DDP-resistant TNBC and explore the underlying mechanisms. First, expression profiles circ_0007823, microRNA (miR)-182-5p, and forkhead box O1 (FOXO1) in TNBC cells were determined. Additionally, biological characteristics of cells, including apoptosis, cell cycle, proliferation, and migration, were analyzed using various assays. Luciferase reporter and rescue assays were used to determine the correlations among circ_0007823, miR-182-5p, and FOXO1 expression. MiR-182-5p was overexpressed in DDP-resistant TNBC cells. MiR-182-5p knockdown suppressed the invasiveness and increased the apoptosis of drug-resistant cells, contributing to G1 arrest and S phase reduction. Mechanistically, circ_0007823 targeted miR-182-5p, and its overexpression drastically reduced the promotional effects of the miR-182-5p mimic on the aggression and transfer ability of drug-resistant cells. Furthermore, FOXO1 overexpression increased the sensitivity of cells to DDP and reduced their malignant progression. Therefore, FOXO1 was established as the downstream target of miR-182-5p that may be used to treat DDP-resistant TNBC. In summary, circ_0007823 overexpression attenuated DDP resistance in TNBC via the miR-182-5p–FOXO1 axis, indicating the therapeutic potential of circ_0007823 DDP-resistant TNBC treatment. [ABSTRACT FROM AUTHOR]

Accurately measuring the distribution of vitality in urban public spaces and evaluating the attractiveness index of landscape elements can enhance the precision of public space design and the rational planning of urban microupdate strategies. This study introduces a method based on the SLAM algorithm to create a 3D visual exposure analysis and applied in two squares in Macau to calculate the relationship between pathfinding decisions and visual exposure. The results demonstrate that both the extent of visual exposure (seen from the observer) and the area of isovist field (seen from the object) can statistically indicate the attractiveness index of a space. Consequently, an attractiveness map of the site can be constructed. This study effectively captures walking trajectories and visual data in real-world settings, integrating site-specific and pedestrian information into a digital twin system. This approach not only advances quantitative methodologies but also facilitates postoccupancy evaluations of public space usage and environmental behavior research, thereby expanding the potential for future investigations in this domain. [Display omitted] • We distinguish active attention and passive notice in pedestrians via visual exposure comparison. • We developed the SLAM algorithm to create a 3D visual exposure analysis method. • Our work introduces a visual attraction index scoring system for public spaces. • Landmark buildings often dominate visual attraction, overshadowing nearby structures. • Green landscapes generally score lower than average in visual attraction. [ABSTRACT FROM AUTHOR]

The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), poses an unprecedented global health crisis. It is particularly urgent to develop clinically effective therapies to contain the pandemic. The main protease (Mpro) and the RNA-dependent RNA polymerase (RdRP), which are responsible for the viral polyprotein proteolytic process and viral genome replication and transcription, respectively, are two attractive drug targets for SARS-CoV-2. This review summarizes up-to-date progress in the structural and pharmacological aspects of those two key targets above. Different classes of inhibitors individually targeting Mpro and RdRP are discussed, which could promote drug development to treat SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]

Since its outbreak in late 2019, the COVID-19 pandemic has drawn enormous attention worldwide as a consequence of being the most disastrous infectious disease in the past century. As one of the most immediately druggable targets of SARS-CoV-2, the main protease (Mpro) has been studied thoroughly. In this review, we provide a comprehensive summary of recent advances in structural studies of Mpro, which provide new knowledge about Mpro in terms of its biological function, structural characteristics, substrate specificity, and autocleavage process. We examine the remarkable strides made in targeting Mpro for drug discovery during the pandemic. We summarize insights into the current understanding of the structural features of Mpro and the discovery of existing Mpro-targeting drugs, illuminating pathways for the future development of anti-SARS-CoV-2 therapeutics. • The accurate structures of SARS-CoV-2 Mpro for drug design. • The mechanism of Mpro cleaving replicase polyprotein. • A summary of current drug discovery against SARS-CoV-2 Mpro. [ABSTRACT FROM AUTHOR]

The rigid-flexible coupling cable system under large deformation is studied, and the beam element from absolute node coordinate formulation is used to establish flexible cable body of the system. Different numerical integral algorithms are discussed for solving the rigid-flexible cable system and an integration strategy which combines Implicit Euler with Minimum Residual Method (MINRES) is proposed. The influence of the position and number of rigid components and different the lengths of the flexible elements on the system dynamics are analyzed. With constant total mass of the system, higher number of rigid components and their uniform distribution contribute to stabilization of the swing of the flexible cable body. When the total length of the cable is constant, increasing the number of beam elements enhances the nonlinear characteristics of the swing motion and damages the stability. The influence of different factors on the movement of large deformation flexible cable body is obtained through modeling and simulation of the rigid-flexible coupling cable system. [ABSTRACT FROM AUTHOR]

The instantaneous wind field and air data, including true airspeed, angle of attack, angle of sideslip, cannot be measured and recorded accurately in wind disturbance. A new air data and wind field estimation method is proposed based on flight data in this study. Since the wind field is the horizontal prevailing wind added by turbulence, the slowly time-varying prevailing wind and small-scale turbulence are described by the exponentially correlated stochastic wind model and von Karman turbulence model, respectively. The system update equation of air data is built based on inertial measurements instead of the complex aerodynamic and aero-engine model of aircraft. Benefitted by the post-analysis characteristics of flight data, a forward–backward filtering algorithm was designed to improve the estimation accuracy. Simulation results indicate that the forward–backward filter integrated with the von Karman turbulence model can reduce the estimation error and ensure filtering stability. A further test with actual flight data shows that the forward–backward filter is not only able to track the wide-range change in prevailing wind but also reduce the adverse effects of uncertain disturbance on estimation accuracy. [ABSTRACT FROM AUTHOR]

Inducing civil aviation aircraft to bumpiness, atmospheric turbulence is a typical risk that seriously threatens flight safety. The Eddy Dissipation Rate (EDR) value, as an aircraft-independent turbulence severity indicator, is estimated by a vertical wind-based or aircraft vertical acceleration-based algorithm. Based on the flight data of civil aviation aircraft, the vertical turbulence component is obtained as the input of both algorithms. A new method of computing vertical acceleration response in turbulence is put forward through the Unsteady Vortex Lattice Method (UVLM). The lifting surface of the target aircraft is assumed to be a combination of wing and horizontal tail in a turbulent flight scenario. Vortex rings are assigned on the mean camber surface, forming a non-planar UVLM, to further improve the accuracy. Moreover, the neighboring vortex lattices are placed as close as possible to the structural edge of control surfaces. Thereby, a complete algorithm for estimating vertical acceleration and in situ EDR value from Quick Access Recorder (QAR) flight data is proposed. Experiments show that the aerodynamic performance is computed accurately by non-planar UVLM. The acceleration response by non-planar UVLM is able to track the recorded acceleration data with higher accuracy than that of the linear model. Different acceleration responses at different locations are also obtained. Furthermore, because the adverse effects of aircraft maneuvers are separated from turbulence-induced aircraft bumpiness, the new acceleration-based EDR algorithm shows better accuracy and stability. [ABSTRACT FROM AUTHOR]

Dockless e-scooter sharing, as a new shared micromobility service, has quickly gained popularity in recent years. In this paper, we present a practical approach to estimating e-scooter flow patterns without knowing the actual routes taken by the e-scooter riders. Our method takes advantage of a huge open dataset that contains the origins and destinations of millions of trips. We show that our models can help cities better support the emerging shared micromobility service. The additional information generated in the modeling process can also be useful for a more refined analysis of e-scooter trips. [ABSTRACT FROM AUTHOR]

• A fast hybrid dimensionality reduction method for classification is proposed. • Multi-strategy based feature selection is used to filter out irrelevant features. • Grouped feature extraction is used to remove redundancy among features. • The proposed method shows excellent efficiency and competitive classification performance. Dimensionality reduction is one basic and critical technology for data mining, especially in current "big data" era. As two different types of methods, feature selection and feature extraction each have their pros and cons. In this paper, we combine multi-strategy feature selection and grouped feature extraction and propose a novel fast hybrid dimension reduction method, incorporating their advantages of removing irrelevant and redundant information. Firstly, the intrinsic dimensionality of the data set is estimated by the maximum likelihood estimation method. Fisher Score and Information Gain based feature selection are used as multi-strategy methods to remove irrelevant features. With the redundancy among the selected features as clustering criterion, they are grouped into a certain amount of clusters. In every cluster, Principal Component Analysis (PCA) based feature extraction is carried out to remove redundant information. Four classical classifiers and representation entropy are used to evaluate the classification performance and information loss of the reduced set. The runtime results of different methods show that the proposed hybrid method is consistently much faster than the other three in almost all of the sets used. Meanwhile, the proposed method shows competitive classification performance, which has no significant difference basically compared with the other methods. The proposed method reduces the dimensionality of the raw data fast and it has excellent efficiency and competitive classification performance compared with the contrastive methods. [ABSTRACT FROM AUTHOR]

The main challenge for future sustainable societies is dealing with the high portion of released CO2 throughout smart power transmission systems; consequently, a comprehensive carbon-based framework is required that directly calculates stakeholders' contribution to the network's CO2 emissions. In this case, this paper proposes a mechanism driven by the carbon-tracing (CTR) process to tackle carbon emissions in smart transmission networks. Using the CTR mechanism enables the digitalized independent system operator (ISO) to allocate the total emissions among participants using the real-time data received from smart grid infrastructures. Furthermore, a carbon-based nodal pricing mechanism for gas and power systems is proposed, which reflects the received data from CTR analysis. To reduce carbon emissions in the smart power transmission network, a carbon-based demand response (DR) procedure is suggested, under which consumers will receive higher incentives for reducing their consumption, especially in high-carbon-intensity buses. In addition, in this paper, for effective management of carbon pollution, the uncertainties of wind and loads and leading risks to carbon and operation costs have been modeled. Hence, the conditional value-at-risk (CVaR) method is utilized for modeling the risks related to uncertainties. It can be seen that applying the proposed CVaR-based risk assessment framework and carbon-incentive-based DR programs led to a decrease in daily total carbon and operation costs by 0.66% and 1.02%, respectively. • Distribution of carbon in power systems, aiding stockholders in carbon management. • Introducing environmental impacts to pricing promoting eco-conscious consumption. • Utilizing CVaR to manage risk, leading to significant carbon and cost variation. • Managing client consumption based on distributed carbon flow intensity in network. [ABSTRACT FROM AUTHOR]

Air-data, recorded in the flight data of civil aviation aircraft, can be disturbed by wind disturbance, thus leading to measurement error. A two-stage air-data estimation in wind disturbance was studied to obtain accurate true airspeed, angle of attack, and sideslip angle based on flight data. To separate the prevailing wind from the wind disturbance, the first stage involved the preliminary air-data optimization by the immune clone algorithm (ICA) and prevailing wind optimization by the Gauss-Newton algorithm. In the second stage, a new filtering system combining air-data and the von Kármán turbulence model was built with the initial value provided by the first stage. A weighted adaptive extended Kalman filtering (WAEKF) algorithm was proposed, in which an exponential weighting in the innovation covariance matrix was used to reduce the estimation error further. Simulation results indicate that the optimized initial value provided by the first stage is fundamental to ensuring the convergence rate and stability. The WAEKF algorithm with initial value (WAEKF-INIT) can improve the estimation accuracy and alleviate the effects of uncertain measuring noise. A further test with flight data shows that weighted adaptive filtering is capable of reducing the estimation error further in uncertain disturbance. [ABSTRACT FROM AUTHOR]

There is a significant impact of the radon diffusion coefficient and the free radon production rate on the exhalation of radon from porous materials that can be regarded as spheres, hexahedrons, or cylinders. To understand this effect, the radon exhalation rules of spherical porous media with different radii were studied according to the radon diffusion migration theory. A specialized method for simultaneous determination of the radon diffusion coefficient and the free radon production rate of the spherical porous media was proposed, and applied to determine the above two parameters for two hemispherical test blocks with different radii. The results show that:(1) For spherical porous media with a certain radon diffusion length (L d), as the radius (r 0) of the sphere increases, the radon exhalation rate first increases, and tends to stabilize at r 0 ≥ 6 L d ; The free radon release share gradually decreases from approximately 1, and drops to a steady state at r 0 ≥ 18 L d. (2) Compared with conventional methods, the relative error of the free radon production rate determined by the proposed method is within 3.9%, which verifies the reliability of the new method. • The 222Rn exhalation rules of spherical porous emanation media are studied. • A method for simultaneously measuring the 222Rn migration parameters is proposed. • Experiments are designed to verify the feasibility of the proposed method.\. [ABSTRACT FROM AUTHOR]

Abstract: A category of gas sensing hollow core waveguide that was operated in near infrared was designed to solve their major obstacles in application including high scattering and high losses. An attenuated total reflection structure was developed by using MS theory and dynamic liquid phase processing. An explanation on how the loss was reduced by total reflectance was provided and a suitable thickness of Ag film by controlling the deposition time was achieved. The guide we designed had a simple structure, low loss and hence increased the sensitivity. [Copyright &y& Elsevier]

• Acoustic cavitation and impact effects generated by the ultrasonic field promote the detachment of hydrogen bubbles from the surface of the catalytic layer. • The evolutionary stages of hydrogen bubbles include nucleation, adherent growth, detachment and even polymerization. • Energy and mechanical analyses were used to reveal the mechanism and evolution of hydrogen bubbles. • The influence of working temperature on hydrogen bubble parameters (nucleation frequency, bubble radius, growth rate, etc) was studied. To improve the hydrogen precipitation performance on the surface of the catalytic layer of the proton exchange membrane (PEM) hydrogen cathode, ultrasonic vibration was employed to accelerate the detachment of hydrogen bubbles on the surface of the catalytic layer. Based on the energy and mechanical analyses of nano and microbubbles, the hydrogen bubble generation mechanism and the effect of temperature on bubble parameters during the evolution process when the ultrasonic field is coupled with the electric field are investigated. The nucleation frequency of the hydrogen bubbles, the relationship between the pressure and temperature and the operating temperature during the generation and detachment of bubbles as well as the detachment radius of bubbles under the action of the ultrasonic field are obtained. The effects of ultrasound and temperature on hydrogen production were verified by visual experiments. The results show that the operating temperature affects the nucleation, growth, and detachment processes of hydrogen bubbles. The effect of temperature on the nucleation frequency of bubbles mainly comes from the Gibbs free energy required for the electrolysis reaction. The bubble radius and growth rate are both related to the temperature to the power of one-third. Ultrasonic waves enhance the separation of hydrogen bubbles from the catalyst surface by acoustic cavitation and impact effects. An increase in the working temperature reduces the activation energy barriers to be overcome for the electrolysis reaction of water, which together with a decrease in the Gibbs free energy and the surface tension coefficient, leads to an increase in the nucleation frequency of the catalytic layer and a decrease in the radius of bubble detachment, and thus improves the hydrogen precipitation performance. Visualization experiments show that in actual PEM hydrogen production, ultrasonic intensification can promote the formation of nucleation sites. The ultrasonic induced fine bubble flow not only has a drag effect on the bubble, but also intensifies the polymerization growth of the bubble due to the impact of the fine bubble flow, thus speeding up the detachment of the bubble, shortening the covering time of the hydrogen bubble on the surface of the catalytic electrode, reducing the activation voltage loss and improve the hydrogen production efficiency of PEM. The experimental results show that when the electrolyte is 60°C, the maximum hydrogen production efficiency of ultrasound is increased by 7.34%, and the average hydrogen production efficiency is increased by 5.83%. [ABSTRACT FROM AUTHOR]

• Three pigeons performed social cooperation tasks by using neural feedback training. • They can achieve cross-brain neural synchronization after training. • The intra- and inter-brain functional connectivity enhance with the training time. • This phenomenon is related to the promotion of social cooperation among pigeons. Multi-brain network, also known as social cooperative network, is formed by multiple animal or human brains, whose changes of functional connectivity in the intra- and inter-brain during construction are unclear at present. To investigate the intra- and inter-brain functional connectivity of pigeons while performing a social cooperation task, we designed an inter-brain synchronization task to train three pigeons to synchronize their neural activities using cross-brain neurofeedback. Then the neural signals of three pigeons were simultaneously recorded by using a hyperscanning approach, and inter-brain synchronization was calculated using the phase-locked value (PLV) online. Finally, the intra- and inter-brain functional connectivity of three pigeons were analyzed. We found that during long-term neurofeedback training, with the increase of the inter-brain synchronization of three pigeons, the intra- and inter-brain functional connectivity also enhance significantly. Moreover, we also found that the above phenomenon relies on the external visual cue. These results suggest that the promotion of social cooperation is the result of the modulation between the intra- and inter-brain, which may be an underlying neural mechanism of the communication and cooperation among individuals in social networks. [ABSTRACT FROM AUTHOR]

Nucleotide analog inhibitors, including broad-spectrum remdesivir and favipiravir, have shown promise in in vitro assays and some clinical studies for COVID-19 treatment, this despite an incomplete mechanistic understanding of the viral RNA-dependent RNA polymerase nsp12 drug interactions. Here, we examine the molecular basis of SARS-CoV-2 RNA replication by determining the cryo-EM structures of the stalled pre- and post- translocated polymerase complexes. Compared with the apo complex, the structures show notable structural rearrangements happening to nsp12 and its co-factors nsp7 and nsp8 to accommodate the nucleic acid, whereas there are highly conserved residues in nsp12, positioning the template and primer for an in-line attack on the incoming nucleotide. Furthermore, we investigate the inhibition mechanism of the triphosphate metabolite of remdesivir through structural and kinetic analyses. A transition model from the nsp7-nsp8 hexadecameric primase complex to the nsp12-nsp7-nsp8 polymerase complex is also proposed to provide clues for the understanding of the coronavirus transcription and replication machinery. • Structures of SARS-CoV-2 RNA polymerase in complexes with RNA revealed • Conformational changes in nsp8 and its interaction with the exiting RNA are observed • Incorporation and delayed-chain-termination mechanism of remdesivir is elucidated • Transition model from primase complex to polymerase complex is proposed Cryo-EM structures of the SARS-CoV-2 RNA polymerase in complexes with RNA, before and after RNA translocation, reveals structural rearrangements that the RNA-dependent RNA polymerase (RdRp) nsp12 and its co-factors (nsp7 and nsp8) undergo to accommodate nucleic acid binding. Further insights into how the complex is inhibited by remdesivir, and into the primase to polymerase transition, are also presented. [ABSTRACT FROM AUTHOR]

A novel coronavirus [severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2)] outbreak has caused a global coronavirus disease 2019 (COVID-19) pandemic, resulting in tens of thousands of infections and thousands of deaths worldwide. The RNA-dependent RNA polymerase [(RdRp), also named nsp12] is the central component of coronaviral replication and transcription machinery, and it appears to be a primary target for the antiviral drug remdesivir. We report the cryo–electron microscopy structure of COVID-19 virus full-length nsp12 in complex with cofactors nsp7 and nsp8 at 2.9-angstrom resolution. In addition to the conserved architecture of the polymerase core of the viral polymerase family, nsp12 possesses a newly identified b-hairpin domain at its N terminus. A comparative analysis model shows how remdesivir binds to this polymerase. The structure provides a basis for the design of new antiviral therapeutics that target viral RdRp. [ABSTRACT FROM AUTHOR]

Age-related cognitive decline is one of the major aspects that impede successful aging in humans. Repeated abortion in adulthood can accelerate or aggravate cognitive deficiency during aging. Here we used repeated abortion in female mice adulthood and investigated the consequences of this treatment on cognitive performance during aging. We observed a substantial impairment of learning memory in 15 months old. This cognitive dysfunction was supported by Aβ elevation in CA region. Repeated abortion mice have uniform estrous cycles and decreased ERα expression in hypothalamus and hippocampus. Furthermore, repeated abortion not only significantly increased the HMGB1 expression in hippocampus but also increased the plasma and hippocampal protein levels of IL-1β, IL-6, and TNF-α. Finally, we identified that MPP-induced cell apoptosis and increased HMGB1 expression as well as IL-1β, IL-6, and TNF-α expression as following Aβ elevation. Taken together, our results identify possible molecular mechanisms underlying cognitive impairment during aging, and demonstrated the repeated abortion in adulthood on cognitive function in aged mice. [ABSTRACT FROM AUTHOR]

Social connections are the consequences and causes of rural settlement distribution. Although numerous studies have examined rural restructuring, the relationship between social connections and rural restructuring has been neglected. This study proposed a novel restructuring method of rural settlement based on an analysis of inter-village social connections that include both spatial and non-spatial connections. A questionnaire survey was conducted from a sample comprising 925 people from Chengui Township in Hubei Province, Central China. The characteristics of the social networks of the residents were analyzed using a node degree and node symmetry index ( NSI ), and the causes of network formations were analyzed according to the connection types of the rural residents. Both consolidated settlements and relocation areas were identified using a measurement of ideal radius based on social connection analysis. Spatial connection orientation, non-spatial orientation and ideal radius orientation were proposed to guide rural settlement restructuring. The results indicated that the hierarchy of village-town systems can be effectively identified by the features of social connection networks. Social connection strength is an important guiding factor for rural reconstruction. This study puts forward a new view of rural settlement reconstruction and aids in our understanding of both the changing mechanism of rural settlement and the relationship between social connections and rural settlement reconstruction. [ABSTRACT FROM AUTHOR]

New anti-tubercular agents are urgently needed to address the emerging threat of drug resistance to human tuberculosis. Here, we have used structure-assisted methods to develop compounds that target mycobacterial membrane protein large 3 (MmpL3). MmpL3 is essential for the transport of mycolic acids, an important cell-wall component of mycobacteria. We prepared compounds that potently inhibit the growth of Mycobacterium tuberculosis (Mtb) and other mycobacteria in cell culture. The cryoelectron microscopy (cryo-EM) structure of mycobacterial MmpL3 in complex with one of these compounds (ST004) was determined using lipid nanodiscs at an overall resolution of 3.36 Å. The structure reveals the binding mode of ST004 to MmpL3, with the S4 and S5 subsites of the inhibitor-binding pocket in the proton translocation channel playing vital roles. These data are a promising starting point for the development of anti-tuberculosis drugs that target MmpL3. [Display omitted] • Compounds with antibacterial activity that target MmpL3 are reported • Compound ST004 potently inhibits the growth of Mtb as well as other mycobacteria • Cryo-EM structure of MmpL3 in complex with ST004 is determined in lipid nanodiscs • The scaffolds at the S4 and S5 subsites are important for the efficacy of the compounds MmpL3 is an important target for TB drug discovery. Hu et al. report the structure-based development of potent compounds that target MmpL3. These data are a promising starting point for the development of anti-mycobacterial drugs targeting MmpL3. [ABSTRACT FROM AUTHOR]

Na/K-ATPases are membrane-associated enzymes responsible for the active transport of Na and K ions across cell membranes, generating chemical and electrical gradients. These enzymes' α-subunit provides catalytic function, binding and hydrolyzing ATP, and itself becoming phosphorylated during the transport cycle. In this study, Na/K-ATPase α-subunit cDNA was cloned from gill tissue of the swimming crab Portunus trituberculatus by reverse-transcription polymerase chain reaction (RT-PCR) and rapid amplification of cDNA end methods. Analysis of the nucleotide sequence revealed that the cDNA had a full-length of 3 833 base pairs (bp), with an open reading frame of 3 120 bp, 5′ untranslated region (UTR) of 317 bp, and 3′ UTR of 396 bp. The sequence encoded a 1 039 amino acid protein with a predicted molecular weight of 115.57 kDa and with estimated pI of 5.21. It was predicted here to possess all expected features of Na/K-ATPase members, including eight transmembrane domains, putative ATP-binding site, and phosphorylation site. Comparison of amino acid sequences showed that the P. trituberculatus α-subunit possessed an overall identity of 75%-99% to that of other organisms. Phylogenetic analysis revealed that this α-subunit was in the same category as those of crustaceans. Quantitative real-time RT-PCR analysis indicated that this α-subunit's transcript were most highly expressed in gill and lowest in muscle. RT-PCR analysis also revealed that α-subunit expression in crab gill decreased after 2 and 6 h, but increased after 12, 24, 48, and 72 h. In addition, α-subunit expression in hepatopancreas of crab decreased after 2-72 h. These facts indicated that the crab's Na/K-ATPase α-subunit was potentially involved in the observed acute response to low salinity stress. [ABSTRACT FROM AUTHOR]

Transcription of SARS-CoV-2 mRNA requires sequential reactions facilitated by the replication and transcription complex (RTC). Here, we present a structural snapshot of SARS-CoV-2 RTC as it transitions toward cap structure synthesis. We determine the atomic cryo-EM structure of an extended RTC assembled by nsp7-nsp8 2 -nsp12-nsp13 2 -RNA and a single RNA-binding protein, nsp9. Nsp9 binds tightly to nsp12 (RdRp) NiRAN, allowing nsp9 N terminus inserting into the catalytic center of nsp12 NiRAN, which then inhibits activity. We also show that nsp12 NiRAN possesses guanylyltransferase activity, catalyzing the formation of cap core structure (GpppA). The orientation of nsp13 that anchors the 5′ extension of template RNA shows a remarkable conformational shift, resulting in zinc finger 3 of its ZBD inserting into a minor groove of paired template-primer RNA. These results reason an intermediate state of RTC toward mRNA synthesis, pave a way to understand the RTC architecture, and provide a target for antiviral development. • Structure of SARS-CoV-2 elongation complex with nsp9 has been determined • Nsp9 binds to the catalytic center of the nsp12 (RdRp) NiRAN domain • The nsp12 NiRAN domain catalyzes the formation of the cap core structure (GpppA) • The structure reveals an intermediate state for RTC in cap synthesis Yan et al. present a cryo-EM structure of the SARS-CoV-2 replication and transcription complex that includes the single RNA-binding protein nsp9. The structural snapshot provides insight into how the viral machinery catalyzes a crucial step in viral mRNA cap synthesis, which is important for virus survival. [ABSTRACT FROM AUTHOR]