Search

Ti-5321 alloy formed by laser cladding has good mechanical properties. By subsequent heat treatment of the alloy, not only can rich microstructures be obtained, but its strength, toughness, or damage tolerance performance can also be improved. Four typical microstructures, including basket-weave structure, large layer structure, ultrafine needle-like structure, and rod-like structure were constructed through different heat treatments. Basket-weave structure is composed of slender lamellar α, which has the best plasticity and toughness. Due to the large orientation difference between adjacent lamellar α and the susceptibility to multiple slip during crack propagation, this will greatly increase the crack propagation resistance and the curvature of the crack propagation path, which is beneficial for improving the damage tolerance performance of the alloy. Large layer structure is composed of large layer α and ultrafine needle-like α, with the highest strength. The orientation difference between adjacent large layer α is extremely small and prone to {10–11} pyramidal slip. The crack propagation resistance is reduced, which in turn damages the damage tolerance performance of the alloy. Ultrafine needle-like structure is entirely composed of ultrafine needle-like α, with high strength and extremely low plasticity and toughness. The orientation difference between adjacent needle-like α is single, making it prone to pyramidal slip and first-order pyramidal slip. The strength of rod-like structure matches well with its plasticity and toughness. There are multiple slip systems in rod-like structure and there is significant difference in orientation between adjacent α. Large orientation differences will have certain hindering effect on crack deflection.

Abstract Understanding of infection dynamics is important for public health measures against monkeypox virus (MPXV) infection. Herein, samples from multiple body sites and environmental fomites of 77 acute MPXV infections (HIV co-infection: N = 42) were collected every two to three days and used for detection of MPXV DNA, surface protein specific antibodies and neutralizing titers. Skin lesions show 100% positivity rate of MPXV DNA, followed by rectum (88.16%), saliva (83.78%) and oropharynx (78.95%). Positivity rate of oropharynx decreases rapidly after 7 days post symptom onset (d.p.o), while the rectum and saliva maintain a positivity rate similar to skin lesions. Viral dynamics are similar among skin lesions, saliva and oropharynx, with a peak at about 6 d.p.o. In contrast, viral levels in the rectum peak at the beginning of symptom onset and decrease rapidly thereafter. 52.66% of environmental fomite swabs are positive for MPXV DNA, with highest positivity rate (69.89%) from air-conditioning air outlets. High seropositivity against A29L (100%) and H3L (94.74%) are detected, while a correlation between IgG endpoint titers and neutralizing titers is only found for A29L. Most indexes are similar between HIV and Non-HIV participants, while HIV and rectitis are associated with higher viral loads in rectum.

Based on classical nucleation and growth theory, the phase evolution of martensite α′ phase of additively manufactured Ti-6.9Al-6.8Zr-2.3Mo-2.2V-0.7Nb alloy under different annealing temperatures (600–960 °C) was systematically investigated. The results show that: Owing to insufficient diffusion of alloy elements during laser deposition, numerous β-stabilizing elements are retained in α′ phase and the microstructure is made up of 95.4% α′ phase and 4.6% β phase. According to TEM, EBSD, SEM/EDX results, the α′ phase can be divided into α′ phase containing more β-stabilizing elements (α′β), α′ phase containing more Al (α′Al). Under annealing condition, martensite decomposition tends to occur at the α′/α' interfaces and the matrix of α′β phase. In the matrix of α′β phase, fine adjacent α′ phase precipitates at β phase because a lot of β-stabilizing elements are consumed by precipitated β phase, thus improving the precipitation of adjacent α′ phase. The decomposition of α′ phase is controlled by diffusion of alloy elements. As the temperature increases, the diffusion of alloy elements and degree of α′ martensitic decomposition become more sufficient. When the Al content in the α′ phase reaches that in equilibrium α phase, the lattice parameters of α′ phase increase from a = 2.97 Å, c = 4.72 Å to a = 3.04 Å, c = 4.77 Å and meanwhile the α′ martensitic decomposition is finished.

In 2022, the monkeypox virus (mpox virus, MPXV) exhibited global dissemination across six continents, representing a notable challenge owing to the scarcity of targeted antiviral interventions. Passive immunotherapy, such as the use of monoclonal antibodies (mAbs) and bispecific antibodies (bsAbs), has emerged as a promising option for antiviral regimens. Here, we generated several mAbs against M1R and B6R of MPXV, and subsequently characterized the antiviral activity of these antibodies both in vitro and in vivo. Two neutralizing mAbs, M1H11 and M3B2, targeting M1R, and one B6R-specific mAb, B7C9, were identified. They exhibited varying antiviral efficacy against vaccinia virus (VACV) in vitro and in vivo. A cocktail comprising M1H11 and M3B2 demonstrated a superior protective effect in vivo. A bsAb, Bis-M1M3, was engineered by conjugating the fragment crystallizable (Fc) region of the human-mouse chimeric engineered M1H11 with the single-chain fragment variable (scFv) of M3B2. In mice challenged with MPXV, Bis-M1M3 showed a notable protective effects. Analysis of neutralization mechanism showed that these mAbs and Bis-M1M3 exerted virus-neutralizing effects before the virus infects cells. In vivo pharmacokinetic experiments showed that Bis-M1M3 has a long half-life in rhesus macaques. This study provides crucial insights for further research on broad-spectrum antiviral drugs against MPXV and other orthopoxviruses.

Abstract The ongoing mutations of the SARS‐CoV‐2 pose serious challenges to the efficacy of the available antiviral drugs, and new drugs with fantastic efficacy are always deserved investigation. Here, a nanobody called IBT‐CoV144 is reported, which exhibits broad neutralizing activity against SARS‐CoV‐2 by inducing the conformation of spike trimer dimers. IBT‐CoV144 was isolated from an immunized alpaca using the RBD of wild‐type SARS‐CoV‐2, and it showed strong cross‐reactive binding and neutralizing potency against diverse SARS‐CoV‐2 variants, including Omicron subvariants. Moreover, the prophylactically and therapeutically intranasal administration of IBT‐CoV144 confers fantastic protective efficacy against the challenge of Omicron BA.1 variant in BALB/c mice model. The structure analysis of the complex between spike (S) protein, conducted using Cryo‐EM, revealed a special conformation known as the trimer dimers. This conformation is formed by two trimers, with six RBDs in the “up” state and bound by six VHHs. IBT‐CoV144 binds to the lateral region of the RBD on the S protein, facilitating the aggregation of S proteins. This aggregation results in steric hindrance, which disrupts the recognition of the virus by ACE2 on host cells. The discovery of IBT‐CoV144 will provide valuable insights for the development of advanced therapeutics and the design of next‐generation vaccines.

Abstract Consumption of dietary fiber and anthocyanin has been linked to a lower incidence of colorectal cancer (CRC). This study scrutinizes the potential antitumorigenic attributes of a black rice diet (BRD), abundantly rich in dietary fiber and anthocyanin. Our results demonstrate notable antitumorigenic effects in mice on BRD, indicated by a reduction in both the size and number of intestinal tumors and a consequent extension in life span, compared to control diet‐fed counterparts. Furthermore, fecal transplants from BRD‐fed mice to germ‐free mice led to a decrease in colonic cell proliferation, coupled with maintained integrity of the intestinal barrier. The BRD was associated with significant shifts in gut microbiota composition, specifically an augmentation in probiotic strains Bacteroides uniformis and Lactobacillus. Noteworthy changes in gut metabolites were also documented, including the upregulation of indole‐3‐lactic acid and indole. These metabolites have been identified to stimulate the intestinal aryl hydrocarbon receptor pathway, inhibiting CRC cell proliferation and colorectal tumorigenesis. In summary, these findings propose that a BRD may modulate the progression of intestinal tumors by fostering protective gut microbiota and metabolite profiles. The study accentuates the potential health advantages of whole‐grain foods, emphasizing the potential utility of black rice in promoting health.

We propose a lightweight detection algorithm based on the Single Shot MultiBox Detector (SSD) algorithm in order to facilitate sheep management and to realize sheep facial identification, and we take the self-constructed dataset as the research object. First, the SSD replaces the VGG16 backbone network with MobileNetv3, a lightweight neural network, to create a hybrid model that is much smaller. Second, the ECA attention mechanism is incorporated into the backend of the 72 × 160 bottleneck layer. Finally, the SmoothL1 loss function is substituted with the BalancedL1 loss function. The optimized model’s size decreases significantly from the original SSD’s 132 MB to just 22.4 MB. It achieves a mean average precision of 83.47% and maintains an average frame rate of 68.53 frames per second. Compared to the basic SSD model, the mean average precision has increased by 3.25 percentage points, the model size has decreased by 109.6 MB, and the detection speed has improved by 9.55 frames per second. In comparative experiments using the same dataset with different object detection models, the proposed model outperforms the SSD, Faster R-CNN, Retinanet, and CenterNet in terms of mean average precision, with improvements of 3.25 percentage points, 4.71 percentage points, 2.38 percentage points, and 8.13 percentage points, respectively. The detection speed has shown significant improvements, increasing by 9.55, 58.55, 53.1, and 12.37 frames per second, respectively. The improved model presented in this paper significantly reduces the model’s size and computational requirements while maintaining an excellent performance. This provides a valuable reference for the digitalization of animal husbandry and livestock farming.

Abstract Men demonstrate higher incidence and mortality rates of colorectal cancer (CRC) than women. This study aims to explain the potential causes of such sexual dimorphism in CRC from the perspective of sex‐biased gut microbiota and metabolites. The results show that sexual dimorphism in colorectal tumorigenesis is observed in both ApcMin/+ mice and azoxymethane (AOM)/dextran sulfate sodium (DSS)‐treated mice with male mice have significantly larger and more tumors, accompanied by more impaired gut barrier function. Moreover, pseudo‐germ mice receiving fecal samples from male mice or patients show more severe intestinal barrier damage and higher level of inflammation. A significant change in gut microbiota composition is found with increased pathogenic bacteria Akkermansia muciniphila and deplets probiotic Parabacteroides goldsteinii in both male mice and pseudo‐germ mice receiving fecal sample from male mice. Sex‐biased gut metabolites in pseudo‐germ mice receiving fecal sample from CRC patients or CRC mice contribute to sex dimorphism in CRC tumorigenesis through glycerophospholipids metabolism pathway. Sexual dimorphism in tumorigenesis of CRC mouse models. In conclusion, the sex‐biased gut microbiome and metabolites contribute to sexual dimorphism in CRC. Modulating sex‐biased gut microbiota and metabolites could be a potential sex‐targeting therapeutic strategy of CRC.

In order to improve the light extraction efficiency (LEE) of a plane AlGaAs-based LED (Device A), three different surface periodic micron-scale arrays, micron pillar (Device B), micron truncated cone (Device C) and micron cone (Device D), are prepared by the conventional ultra-violet (UV) lithography. The morphology of the three devices B–D is characterized by a scanning electron microscopy (SEM). The periodic array structures improve the photon escape probabilities. In comparison to the Device A, the light output powers (LOPs) of the Devices B–D increase 54.0%, 145.5% and 157.2% at an injection current of 500 mA, respectively. Moreover, we use the Monte Carlo ray-tracing method to simulate the LEE of the four devices. The energy distribution of the Devices B-D is more concentrated in the middle region in contrast with the Device A.

Azahetereocycles represent promising scaffolds in drug discovery. Here, the authors report a Pd-catalyzed migratory cycloannulation strategy for efficient construction of a wide range of azahetereocycles from unactivated aliphatic alkenes.

Summary: This study aims to characterize the impaired immune regulatory function of Mφ obtained from UC patient colon lavage fluid (CLF). Mφs were the largest proportion (21.3 4.0%) of the CLF-derived cellular components. Less abundant and weaker immune suppressive function were observed in M2 Mφs (M2 cells) of the ulcerative colitis (UC) group. High levels of endoplasmic reticulum (ER) stress associated molecules were detected in UC M2 cells. The spliced X box binding protein-1 (XBP1) gene was negatively correlated with programmed death ligand-1 (PD-L1) in UC M2 cells. XBP1 promoted the expression of ring-finger protein 20 (Rnf20) in M2 cells. Rnf20 reduced PD-L1 abundance in UC M2 cells and impaired the immune suppressive ability. Inhibition of Rnf20 restored the immune regulating capacity of M2 cells and suppressed experimental colitis.

Abstract The SARS-CoV-2 nucleocapsid protein (NP) is an important indicator for the virus infection, highlighting the crucial role of NP-specific monoclonal antibodies (mAbs) used in multiple biochemical assays and clinical diagnosis for detecting the NP antigen. Here, we reported a pair of noncompeting human NP-specific mAbs, named P301-F7 and P301-H5, targeting two distinct linear epitopes on SARS-CoV-2 or SARS-CoV. We evaluated the application of P301-F7 in the analysis of enzyme linked immunosorbent assay, western blot, flow cytometry, immunofluorescence, and focus reduction neutralization test. We for the first time report a broad mAb effectively recognizing various live viruses of SARS-CoV-2 variants including Alpha, Beta, Delta, and Omicron, indicating a wide range of application prospects.

Abstract Ovarian cancer is the most fatal gynecological cancer worldwide, yet the fundamental mechanism of malignancy acquisition in ovarian cancer remains unknown. miRNA has been implicated to a variety of diseases, including cancer initiation and progression. Cyclin-D2 (CCND2) is ubiquitously implicated in cancer uncontrol cell proliferation. Bioinformatic research revealed that CCND2 is a candidate gene for miR-93-5p with a binding site in its 3′UTR region in the current study. Using our ovarian cancer sample, we verified that miR-93-5p is negatively correlated with CCND2 mRNA and protein levels. Luciferase report assay revealed miR-93-5p inhibits CCND2 production through binding to the 3′UTR region. The expression of miR-93-5p in ovarian cancer patient samples was then determined, and a survival analysis was performed. Our findings showed that miR-93-5p is downregulated in ovarian cancer and is a favorable predictive factor in ovarian cancer patient. CCK8 assay, wound healing assay and flow cytometry-based cell cycle and apoptotic cell analyses were employed here. We found that miR-93-5p suppresses ovarian cancer cell proliferation and migration while enhances cell death. Our research certified that miR-93-5p reduces ovarian cancer malignancy by targeting CCND2.

Due to the early formation of rolling bearing fault characteristics in an environment with strong background noise, the single use of the time-varying filtering empirical mode decomposition (TVFEMD) method is not effective for the extraction of fault characteristics. To solve this problem, a new method for early fault detection of rolling bearings is proposed, which combines multipoint optimal minimum entropy deconvolution adjusted (MOMEDA) with parameter optimization and TVFEMD. Firstly, a new weighted envelope spectrum kurtosis index is constructed using the correlation coefficient and envelope spectrum kurtosis, which is used to identify the effective component and noise component of the bearing fault signal decomposed by TVFEMD, and the intrinsic mode function (IMF) containing rich fault information is selected for reconstruction. Then, a new synthetic impact index (SII) is constructed by combining the maximum value of the autocorrelation function and the kurtosis of the envelope spectrum. The SII index is used as the fitness function of the gray wolf optimization algorithm to optimize the fault period, T, and the filter length, L, of MOMDEA. The signal reconstructed by TVF-EMD undergoes adaptive filtering using the MOMEDA method after parameter optimization. Finally, an envelope spectrum analysis is performed on the signal filtered by the adaptive MOMEDA method to extract fault feature information. The experimental results of the simulated and measured signals indicate that this method can effectively extract early fault features of rolling bearings and has good reliability. Compared to the classical FSK, MCKD, and TVFEMD-MOMEDA methods, the first-order correlated kurtosis (FCK) and fault feature coefficient (FFC) of the filtered signal obtained using the proposed method are the largest, while the sample entropy (SE) and envelope spectrum entropy (ESE) are the smallest.

Abstract The current COVID-19 pandemic caused by constantly emerging SARS-CoV-2 variants still poses a threat to public health worldwide. Effective next-generation vaccines and optimized booster vaccination strategies are urgently needed. Here, we sequentially immunized mice with a SARS-CoV-2 wild-type inactivated vaccine and a heterologous mutant RBD vaccine, and then evaluated their neutralizing antibody responses against variants including Beta, Delta, Alpha, Iota, Kappa, and A.23.1. These data showed that a third booster dose of heterologous RBD vaccine especially after two doses of inactivated vaccines significantly enhanced the GMTs of nAbs against all SARS-CoV-2 variants we tested. In addition, the WT and variants all displayed good cross-immunogenicity and might be applied in the design of booster vaccines to induce broadly neutralizing antibodies.

Time-restricted feeding (TRF) is an emerging dietary intervention that improves metabolic disorders such as obesity, insulin resistance and dyslipidemia. Inflammatory bowel disease (IBD) is a chronic inflammatory disorder affecting the gastrointestinal tract, where nutrition plays an important role in its pathogenesis. Although numerous strategies of nutritional intervention have been reported, whether TRF can improve IBD has been elusive. In this study, we investigated the effect of two cycles of 7-day TRF intervention in a dextran sulfate sodium-induced IBD mouse model. We found that TRF was able to reduce the disease activity index and ameliorate the IBD-associated symptoms, as well as increase the number of colonic crypts and decrease the histological score in the colon. Furthermore, TRF lowered the percentage of CD4+ T cells in the peripheral blood and mesenteric lymph node, and increased the number of CD4+CD25+ T cells in the mesenteric lymph nodes. Additionally, TRF reduced the infiltration of leukocytes and macrophages around the crypt base in the colon. However, unlike the intermittent caloric restriction with fasting-mimicking diet, TRF was not able to increase the markers of progenitor and cell proliferation in the colon. Collectively, these results demonstrated that TRF is able to improve IBD in mice via reduction in intestinal inflammation.

Antibodies (Abs) targeting highly conserved epitopes are important tools against emerging virus variants. Here, the authors characterize Abs that recognize a cryptic epitope in the receptor-binding domain of SARS-CoV-2 spike that is well conserved and show that these Abs can neutralize several variants of concerns.

Here, the authors combine structural, binding, mutational in vitro and in vivo assays to characterize neutralizing antibodies derived from IGHV3-53/3-66 against SARS-CoV-2, finding one antibody, named P5A-3C8, to exhibit protective efficacy in a golden Syrian hamster model of infection while showing the emergence of mutations at position 417 of the Spike protein that confer resistance.

Homogeneous earth-abundant metal catalysis based on well-defined metal complexes is of interest for organic synthesis, but typically employs expensive catalysts, air sensitive or synthetically challenging chemicals. Here, the authors report an efficient and regio-selective catalytic system for hydroboration of vinylarenes and organic nitriles with HBPin, using commercially available CoI2 and KO t Bu under ligand-free conditions.

BackgroundDietary restriction has a profound effect in altering immune system and promoting metabolic health and aging. However, how dietary restriction impacts erythroid system is largely unknown. We found that a short-term caloric restriction (CR) stimulates expression of KLF1, a master regulator of erythroid development, in the spleen of mouse, and thus explored the potential effect of CR on erythropoiesis.MethodsWe analyzed the effects of intermittent CR and continuous CR for different lengths of time on parameters of peripheral blood and erythroid profiles in the spleen and bone marrow in C57BL/6 mice. We next assessed how different types of CR affect phenylhydrazine-induced anemia in the mice. Colony formation assay was also used to analyze LK + progenitors and BFU-E in the bone marrow.ResultsIntermittent CR for 2 weeks raised the number of reticulocytes in the blood, while continuous CR for 2 weeks elevated red blood cells and hemoglobin level. Intermittent CR for 2 weeks promoted extramedullary hematopoiesis in the spleen, while continuous CR mainly promoted erythropoiesis in the bone marrow. Interestingly, a short-term intermittent CR but not continuous CR was able to ameliorate phenylhydrazine-induced anemia. Intermittent CR reduced early-stage erythroblasts and increased late-stage erythroblasts/mature RBCs in the spleen, indicating an accelerated transition from early-stage to late-stage erythroblasts/mature red blood cells. Furthermore, a short-term intermittent CR elevated LK + progenitors and the committed erythroid progenitor cells BFU-E in the bone marrow.ConclusionOur study demonstrated that a short-term intermittent CR, but not continuous CR, has a significant effect to promote hematopoiesis and such activity can ameliorate phenylhydrazine-induced acute anemia in the mouse.

Summary: The different variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have attracted most public concern because they caused “wave and wave” COVID-19 pandemic. The initial step of viral infection is mediated by the SARS-CoV-2 Spike (S) protein, which mediates the receptor recognition and membrane fusion between virus and host cells. Neutralizing antibodies (nAbs) targeting the S protein of SARS-CoV-2 have become promising candidates for clinical intervention strategy, while multiple studies have shown that different variants have enhanced infectivity and antibody resistance. Here, we explore the structure and function of STS165, a broadly inter-Spike bivalent nAb against SARS-CoV-2 variants and even SARS-CoV, contributing to further understanding of the working mechanism of nAbs.

Abstract The emergence and rapid spread of the B.1.1.7 lineage (VOC-202012/01) SARS-CoV-2 variant has aroused global concern. The N501Y substitution is the only mutation in the interface between the RBD of B.1.1.7 and ACE2, raising concerns that its recognition by neutralizing antibodies may be affected. Here, we assessed the neutralizing activity and binding affinity of a panel of 12 monoclonal antibodies against the wild type and N501Y mutant SARS-CoV-2 pseudovirus and RBD protein, respectively. We found that the neutralization activity and binding affinity of most detected antibodies (10 out of 12) were unaffected, although the N501Y substitution decreased the neutralizing and binding activities of CB6 and increased that of BD-23. These findings could be of value in the development of therapeutic antibodies.

In this study, we investigated the sliding mode control (SMC) for the spacecraft rendezvous maneuver under unknown system parameters and input saturations. On the basis of the attitude and position tracking subsystem, two anti-saturation sliding mode surfaces (SMSs) are constructed to guarantee the exponential convergence of tracking errors between the target spacecraft and the pursuer spacecraft. In connection with hyperbolic tangent, a modified auxiliary system is established to compensate the nonlinear constraint caused by the actuator saturation. Meanwhile, in order to enhance the practicability and reliability of the controller, unknown inertial information is taken into consideration. The resulting system uncertainties are estimated accurately via adaptive laws. Additionally, it is concluded that the designed controller is capable of ensuring the boundedness of the closed-loop signals with reasonable selection of control parameters. Finally, the effectiveness and advantages of the proposed methods are verified through numerical simulations.

Here, the authors compare the crystal structures and investigate the neutralization mechanisms of three neutralizing antibodies against SARS-CoV-2 and find that one antibody, P2C-1F11, closely mimics binding of receptor ACE2 and displays the most potent neutralizing activity in vitro, as well as conferring protection against SARS-CoV-2 infection in Ad5-hACE2-sensitized mice.

Recent studies adopted models of user acceptance of information technology to predict and explain drivers’ acceptance of traffic information. Among these frameworks, the most commonly used is the Technology Acceptance Model (TAM). However, TAM is too general and does not consider drivers’ response in specific traffic conditions or choice scenarios. This study combines an extended TAM with different choice scenarios displayed by Variable Message Signs (VMS) into a Hybrid Choice Model (HCM). Two models are proposed. The first model takes into account the causal relationships among latent variables based on the following hypotheses: Information Quality (IQ) has a positive effect on Perceived Usefulness (PU) and Perceived Ease of Use (PEOU) which, in turn, have a positive effect on the Behavioural Intention (BI) to use traffic information. In the second model, the four latent variables PU, PEOU, IQ, and BI are directly added to the utility function without any causal relationships. 339 drivers with valid licence were interviewed via Stated Preference (SP) survey and the results show that TAM can explain travellers’ response to VMS if the causal relationships among latent variables are taken into account. In addition, all hypothesized relationships are strongly supported. Practical and academic implications are also discussed. First published online 27 April 2020

An effective vaccine for human papillomavirus (HPV) needs to protect from several genotypes. Here, Wang et al. provide a strategy to produce single capsomere-hybrid virus-like particle (chVLP) composed of capsomers of different genotypes and show that a nona-type chVLP induces similar levels of neutralizing antibodies as an approved HPV vaccine.

The CO2 emissions from the cement industry and the production of waste wood chips are increasing with the rapid growth of the construction industry. In order to develop a green environmental protection building material with low thermal conductivity and up to standard mechanical properties, in this study, pine waste wood chips were mixed into cement-based materials as fine aggregate, and three different kinds of cementitious binders were used, including sulfur aluminate cement (SAC), ordinary Portland cement (OPC), and granulated blast furnace slag (GBFS), to prepare a recycled light cementitious composite material. The mechanical, thermal conductivity, shrinkage, water absorption, and pore structure of a wood chip light cementitious composite material were studied by changing the Ch/B (the mass ratio of wood chip to binder). The results showed that the strength, dry density, and thermal conductivity of the specimens decreased significantly with the increase in the Ch/B, while the shrinkage, water absorption, and pore size increased with the increase in the Ch/B. By comparing three different kinds of cementitious binders, the dry density of the material prepared with OPC was 942 kg/m3, the compressive strength of the material prepared with SAC was 13.5 MPa, and the thermal conductivity of the material prepared with slag was the lowest at 0.15 W/m/K. From the perspective of low-cost and low-carbon emissions, it was determined that the best way to prepare a light cementitious composite with waste wood chips is to use granulated blast furnace slag (GBFS) as the cementitious binder.

The intestinal pathogen Clostridioides (C.) difficile is a major cause of diarrhea both in hospitals and outpatient in industrialized countries. This bacterium produces two large exotoxins, toxin A (TcdA) and toxin B (TcdB), which are directly responsible for the onset of clinical symptoms of C. difficile-associated diseases (CDADs), such as antibiotics-associated diarrhea and the severe, life-threatening pseudomembranous colitis. Both toxins are multidomain proteins and taken up into host eukaryotic cells via receptor-mediated endocytosis. Within the cell, TcdA and TcdB inactivate Rho and/or Ras protein family members by glucosylation, which eventually results in cell death. The cytotoxic mode of action of the toxins is the main reason for the disease. Thus, compounds capable of inhibiting the cellular uptake and/or mode-of-action of both toxins are of high therapeutic interest. Recently, we found that the sterol regulatory element-binding protein 2 (SREBP-2) pathway, which regulates cholesterol content in membranes, is crucial for the intoxication of cells by TcdA and TcdB. Furthermore, it has been shown that membrane cholesterol is required for TcdA- as well as TcdB-mediated pore formation in endosomal membranes, which is a key step during the translocation of the glucosyltransferase domain of both toxins from endocytic vesicles into the cytosol of host cells. In the current study, we demonstrate that intoxication by TcdA and TcdB is diminished in cultured cells preincubated with the compound U18666A, an established inhibitor of cholesterol biosynthesis and/or intracellular transport. U18666A-pretreated cells were also less sensitive against TcdA and TcdB variants from the epidemic NAP1/027 C. difficile strain. Our study corroborates the crucial role of membrane cholesterol for cell entry of TcdA and TcdB, thus providing a valuable basis for the development of novel antitoxin strategies in the context of CDADs.

A dual-wavelength continuous-wave (CW) and passively Q-switched alexandrite laser based on a MoS2 saturable absorber (SA) operating at 736.7 nm and 752.8 nm with a simple and compact 18 mm plano–plano resonator is reported. In the CW mode, the output power is 1014 mW at the linear-polarized pump power of 5.44 W, with a slope efficiency of 28.7%. In the pulsed operation, the narrowest pulse width and the maximal peak power are 154 ns and 10.6 W, respectively. This laser can be used to generate 8.71 THz-wave light based on a suitable nonlinear optical crystal.

ABSTRACTHuman papillomavirus type 6 (HPV6) is the major etiologic agent of genital warts and recurrent respiratory papillomatosis. Although the commercial HPV vaccines cover HPV6, the neutralization sites and mode for HPV6 are poorly understood. Here, we identify the HPV6 neutralization sites and discriminate the inhibition of virus attachment and entry by three potent neutralizing antibodies (nAbs), 5D3, 17D5, and 15F7. Mutagenesis assays showed that these nAbs predominantly target surface loops BC, DE, and FG of HPV6 L1. Cryo-EM structures of the HPV6 pseudovirus (PsV) and its immune complexes revealed three distinct binding modalities – full-occupation-bound to capsid, top-center-bound-, and top-rim-bound to pentamers – and illustrated a structural atlas for three classes of antibody-bound footprints that are located at center-distal ring, center, and center-proximal ring of pentamer surface for 5D3, 17D5, and 15F7, respectively. Two modes of neutralization were identified: mAb 5D3 and 17D5 block HPV PsV from attaching to the extracellular matrix (ECM) and the cell surface, whereas 15F7 allows PsV attachment but prohibits PsV from entering the cell. These findings highlight three neutralization sites of HPV6 L1 and outline two antibody-mediated neutralization mechanisms against HPV6, which will be relevant for HPV virology and antiviral inhibitor design. HighlightsMajor neutralization sites of HPV6 were mapped on the pseudovirus cryo-EM structuremAb 15F7 binds HPV6 capsid with a novel top-rim binding modality and confers a post-attachment neutralizationmAb 17D5 binds capsid in top-centre manner but unexpectedly prevents virus from attachment to cell surface

More than 18 human papillomaviruses (HPV) are associated with cervical cancer, and ideally vaccines should protect from all of them. Here, the authors engineer a triple-type, chimeric HPV vaccine, using loop swapping, that elicits robust neutralizing antibody titers in mice and non-human primates.

This paper provides a solution for the trajectory tracking control of a hypersonic flight vehicle (HFV), which is encountered performance constraints, actuator faults, external disturbances, and system uncertainties. For the altitude and velocity control subsystems, the backstepping-based dynamic surface control (DSC) strategy is constructed to guarantee the predefined constraint of tracking errors. The introduction of first-order low-pass filters effectively remedies the problem of “complexity explosion” existing in high-order backstepping design. Simultaneously, radial basis function neural networks (RBFNNs) are adopted for approximating the unavailable dynamics, in which the minimum learning parameter (MLP) algorithm brilliantly alleviates the excessive occupation of the computational resource. Specially, in consideration of the unknown actuator failures, the adaptive signals are designed to enhance the reliability of the closed-loop system. Finally, according to rigorous theoretical analysis and simulation experiment, the stability of the proposed controller is verified, and its superiority is exhibited intuitively.

This paper concentrates on the problem of finite-time altitude and velocity tracking control for hypersonic flight vehicles that encounter unmodeled dynamics and input saturations. An adaptive neural finite-time backstepping control strategy is constructed by designing modified virtual commands and compensation signals. The minimum learning parameter algorithm based on a radial basis function is employed to approximate the unknown dynamics with low computational burden. Furthermore, an auxiliary system is established to cope with the nonlinearity caused by actuator saturation. It is concluded by a Lyapunov-based analysis that the finite-time stability is guaranteed under the developed architecture. Finally, numeral simulation is provided to demonstrate the effectiveness of the proposed controller.

Highlights • N-terminal truncations promote the soluble expression of HPV L1 proteins in E. coli and their self-assembly of T = 7 icosahedral particle in vitro • An HPV 9-valent vaccine candidate was formulated with E. coli-derived HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58 VLPs, and conferred comparable immunogenicity with Gardasil 9

Epstein–Barr virus (EBV) was the first human virus proved to be closely associated with tumor development, such as lymphoma, nasopharyngeal carcinoma, and EBV-associated gastric carcinoma. Despite many efforts to develop prophylactic vaccines against EBV infection and diseases, no candidates have succeeded in effectively blocking EBV infection in clinical trials. Previous investigations showed that EBV gp350 plays a pivotal role in the infection of B-lymphocytes. Nevertheless, using monomeric gp350 proteins as antigens has not been effective in preventing infection. Multimeric forms of the antigen are more potently immunogenic than monomers; however, the multimerization elements used in previous constructs are not approved for human clinical trials. To prepare a much-needed EBV prophylactic vaccine that is potent, safe, and applicable, we constructed an Fc-based form of gp350 to serve as a dimeric antigen. Here, we show that the Fc-based gp350 antigen exhibits dramatically enhanced immunogenicity compared with wild-type gp350 protein. The complete or partial gp350 ectodomain was fused with the mouse IgG2a Fc domain. Fusion with the Fc domain did not impair gp350 folding, binding to a conformation-dependent neutralizing antibody (nAb) and binding to its receptor by enzyme-linked immunosorbent assay and surface plasmon resonance. Specific antibody titers against gp350 were notably enhanced by immunization with gp350-Fc dimers compared with gp350 monomers. Furthermore, immunization with gp350-Fc fusion proteins elicited potent nAbs against EBV. Our data strongly suggest that an EBV gp350 vaccine based on Fc fusion proteins may be an efficient candidate to prevent EBV infection in clinical applications.

ABSTRACT Persistent, high-risk human papillomavirus (HPV) infection is the primary cause of cervical cancer. Neutralizing antibodies elicited by L1-only virus-like particles (VLPs) can block HPV infection; however, the lack of high-resolution structures has limited our understanding of the mode of virus infection and the requirement for type specificity at the molecular level. Here, we describe two antibodies, A12A3 and 28F10, that specifically bind to and neutralize HPV58 and HPV59, respectively, through two distinct binding stoichiometries. We show that the epitopes of A12A3 are clustered in the DE loops of two adjacent HPV58 L1 monomers, whereas 28F10 recognizes the HPV59 FG loop of a single monomer. Via structure-based mutagenesis and analysis of antibody binding, we further identified the residues HPV58 D154, S168, and N170 and HPV59 M267, Q270, E273, Y276, K278, and R283, which play critical roles in virus infection. By substituting these strategic epitope residues into other HPV genotypes, we could then redirect the type-specific binding of the antibodies to these genotypes, thus highlighting the importance of these specific residues, HPV58 R161, S168, and N308 and HPV59 Q270, E273, and D281. Overall, our findings provide molecular insights into potential structural determinants of HPV required for infectivity and type specificity. IMPORTANCE High-risk human papillomaviruses (HPVs) are considered the major causative pathogens of cancers that affect epithelial mucosa, such as cervical cancer. However, because of the lack of high-resolution structural information on the sites of neutralization, we have yet to determine the precise mode of HPV infection and how different types of HPV cause infection. Our crystal structures in this study have uncovered discrete binding stoichiometries for two different antibodies. We show that one A12A3 Fab binds to the center of one HPV58 pentamer, whereas five 28F10 Fabs bind along the top fringe of one HPV59 pentamer. Furthermore, through targeted epitope analysis, we show that 6 to 7 discontinuous residues of the L1 major capsid protein of HPV are determinants, at least in part, for virus infection and type specificity. This knowledge will help us to unravel the process of HPV infection and can potentially be used to drive the development of therapeutics that target neutralization-sensitive sites.

The main technological difficulties of developing an intracellular (transmembrane) transport system for protein drugs lie in two points: i) overcoming the barriers in the cellular membrane, and ii) loading enough protein drugs, and particularly high-dose proteins, into particles. To address these two technological problems, we recently developed a novel cholesterol tag (C-Tag)-based transmembrane transport system. This pilot study found that the C-Tag dramatically improved the cellular uptake of Fab (902-fold, vs. Fab alone) into living cells, indicating that it successfully achieved transmembrane transport. Moreover, C-Tag-mediated membrane transport was verified using micron-scale large unilamellar vesicles (LUVs, approximately 1.5 μm)-based particles. The C-Tagged Fab was able to permeate the liposomal bilayer and it greatly enhanced (a 10.1-fold increase vs. Fab alone) internalization of proteins into the LUV-based particles, indicating that the C-Tag loaded enough proteins into particles for use of high-dose proteins. Accordingly, we established a novel C-Tag-based transport system that has overcome the known technological difficulties of protein transmembrane delivery, and this might be a useful technology for drug development in the future. [ABSTRACT FROM AUTHOR]