Allosteric activation of VCP, an AAA unfoldase, by small molecule mimicry.

The loss of function of AAA (ATPases associated with diverse cellular activities) mechanoenzymes has been linked to diseases, and small molecules that activate these proteins can be powerful tools to probe mechanisms and test therapeutic hypotheses. Unlike chemical inhibitors that can bind a single conformational state to block enzyme function, activator binding must be permissive to different conformational states needed for mechanochemistry. However, we do not know how AAA proteins can be activated by small molecules. Here, we focus on valosin-containing protein (VCP)/p97, an AAA unfoldase whose loss of function has been linked to protein aggregation-based disorders, to identify druggable sites for chemical activators. We identified VCP ATPase Activator 1 (VAA1), a compound that dose-dependently stimulates VCP ATPase activity up to ~threefold. Our cryo-EM studies resulted in structures (ranging from ~2.9 to 3.7 Å-resolution) of VCP in apo and ADP-bound states and revealed that VAA1 binds an allosteric pocket near the C-terminus in both states. Engineered mutations in the VAA1-binding site confer resistance to VAA1, and furthermore, modulate VCP activity. Mutation of a phenylalanine residue in the VCP C-terminal tail that can occupy the VAA1 binding site also stimulates ATPase activity, suggesting that VAA1 acts by mimicking this interaction. Together, our findings uncover a druggable allosteric site and a mechanism of enzyme regulation that can be tuned through small molecule mimicry.

Design of a 1 × 4 micro-magnetic stimulation device and its targeted, coordinated regulation on LTP of Schaffer-CA1 in the hippocampus of rats.

Magnetic technology has been a hotspot of neuromodulation research in recent years. However, magnetic coil is limited by their size, and it is impossible to realize precise targeted magnetic stimulation to the target area at the cellular scale. To this end, this study designs a 1 × 4 array micro-magnetic stimulation (µMS) device with four sub-millimeter-sized elements, enabling precise magnetic stimulation of the CA1-CA3-DG tri-synaptic positions in the rat hippocampal region. First, it is determined that 70 KHz/2 mT/1 min magnetic stimulation parameter has a modulatory effect on the long-term potentiation (LTP) of Schaffer-CA1 in rat hippocampus. Then, a 1 × 4 array µMS device is used to perform magnetic stimulation at 70 KHz/2 mT/1 min, targeting the CA1, CA3, and DG regions individually with single-point magnetic stimulation; and multi-region magnetic stimulation is applied to the double-point targeting regions of CA1-CA3, CA1-DG, and CA3-DG, as well as the triple-point targeting region of CA1-CA3-DG, so as to investigate the regulation of LTP by single-region magnetic stimulation and multi-region magnetic stimulation. The experimental results indicate that, in the case of single-region magnetic stimulation, the magnitude of the increase in LTP in the CA1 region is the greatest, followed by the CA3 region, while the effect of magnetic stimulation on the DG region is less pronounced. In multi-region magnetic stimulation, synergistic magnetic stimulation of the three-point CA1-CA3-DG results in a greater increase in LTP compared to stimulation of two individual areas, and the enhancement of LTP induction with multi-region magnetic stimulation surpasses that of single-region stimulation. This study has implications for the collaborative targeted magnetic stimulation application of arrayed micro-magnetic devices.

SARS-CoV-2 neutralising antibody therapies: Recent advances and future challenges.

The COVID-19 pandemic represents an unparalleled global public health crisis. Despite concerted research endeavours, the repertoire of effective treatment options remains limited. However, neutralising-antibody-based therapies hold promise across an array of practices, encompassing the prophylaxis and management of acute infectious diseases. Presently, numerous investigations into COVID-19-neutralising antibodies are underway around the world, with some studies reaching clinical application stages. The advent of COVID-19-neutralising antibodies signifies the dawn of an innovative and promising strategy for treatment against SARS-CoV-2 variants. Comprehensively, our objective is to amalgamate contemporary understanding concerning antibodies targeting various regions, including receptor-binding domain (RBD), non-RBD, host cell targets, and cross-neutralising antibodies. Furthermore, we critically examine the prevailing scientific literature supporting neutralising antibody-based interventions, and also delve into the functional evaluation of antibodies, with a particular focus on in vitro (vivo) assays. Lastly, we identify and consider several pertinent challenges inherent to the realm of COVID-19-neutralising antibody-based treatments, offering insights into potential future directions for research and development.

Exploring the Effect of Arsenic-Containing Hydrocarbon on the Bidirectional Synaptic Plasticity of the Dorsal Hippocampus.

Arsenic-containing hydrocarbons (AsHCs) are common in marine organisms. However, there is little research on their effects on the central nervous system's advanced activities, such as cognition. Bidirectional synaptic plasticity dynamically regulates cognition through the balance of long-term potentiation (LTP) and long-term depression (LTD). However, the effects of AsHCs on bidirectional synaptic plasticity and the underlying molecular mechanisms remain unexplored. This study provides the first evidence that 15 µg As L-1 AsHC 360 enhances bidirectional synaptic plasticity, occurring during the maintenance phase rather than the baseline phase. Further calcium gradient experiments hypothesize that AsHC 360 may enhance bidirectional synaptic plasticity by affecting calcium ion levels. The enhancement of bidirectional synaptic plasticity by 15 µg As L-1 AsHC 360 holds significant implications in improving cognitive function, treating neuro-psychiatric disorders, promoting neural recovery, and enhancing brain adaptability.

Epidemiological study of capillary malformation among 7299 infants under 1 year of age in China.

BACKGROUND: Capillary malformation (CM) is the most common vascular malformation. Large scale studies on its incidence and risk factors are limited in China. OBJECTIVE: Our study aimed to investigate the incidence of CM in Chinese infants and to evaluate its potential risk factors. METHODS: A cross-sectional study, including 7299 infants (aged < 1 year) were collected by a self-administered questionnaire. Independent-samples T tests or χ2 tests and multivariable logistic models were used to examine the potential risk factors for CM. RESULTS: The incidences of salmon patches and port-wine stains (PWSs) were 9.10% and 0.80%, respectively. In analyses, male sex (OR: 1.32, 95% CI: 1.12-1.55) and birth hypoxia (OR: 5.61, 95% CI: 4.39-7.16) were risk factors for salmon patches. Birth hypoxia (OR: 12.58, 95% CI: 7.26-21.79) and pregnancy-induced hypertension syndrome (PIH; OR: 3.66, 95% CI: 1.49-8.99) were associated with a higher risk of PWSs. CONCLUSION: This epidemiological study had the largest sample size of infants with CM in the world thus far, which updated its incidence in Chinese infants and found the potential risk factors for CM.

Immunoassay and mass cytometry revealed immunological profiles induced by inactivated BBIBP COVID-19 vaccine.

With the global prevalence of COVID-19 and the constant emergence of viral variants, boosters for COVID-19 vaccines to enhance antibody titers in human bodies will become an inevitable trend. However, there is a lack of data on antibody levels and the protective effects of booster injections. This study monitored and analyzed the antibody potency and the antibody responses induced by the booster injection in the subjects who received three vaccine doses. The study was conducted in a multicenter collaboration and recruited 360 healthy adults aged 20-74. Participants received the first, second, and booster doses of inactivated Sinopharm/BBIBP COVID-19 vaccine at 0, 1, and 7 months. Vaccine-induced virus-specific antibody levels (SARS-COV-2-IgA/IgM/IgG) were monitored at multiple time points, surrogate virus neutralization test (sVNT), and the spatial distribution and proportion of immune cells and markers were analyzed using the CyTOF method before vaccination and a month after the second dose. The titers of SARS-CoV-2-IgA/IgM/IgG and neutralizing antibodies increased to a high level in the first month after receiving the second dose of vaccine and declined slowly after that. The antibody levels of SARS-CoV-2-IgG and sVNT were significantly increased at 0.5 months after the induction of the booster (p < 0.05). Despite a downward trend, the antibody levels were still high in the following 6 months. The B cell concentration (in humoral sample) a month after the second injection was significantly reduced compared to that before the vaccine injection (p < 0.05). The proportion of the C01 cell cluster was significantly decreased compared with that before vaccine injection (p < 0.05). Individual cell surface markers showed distinctions in spatial distribution but were not significantly different. This study has shown that serum antibody titer levels will decrease with time by monitoring and analyzing the antibody efficacy and the antibody reaction caused by the booster injection of healthy people who received the whole vaccination (completed three injections). Still, the significant peak of the antibody titer levels after booster highlights the recall immune response. It can maintain a high concentration of antibody levels for a long time, which signifies that the protection ability has been enhanced following the injection of booster immunization. Additionally, CyTOF data shows the active production of antibodies and the change in the immunity environment.

Synergetic delivery of artesunate and isosorbide 5-mononitrate with reduction-sensitive polymer nanoparticles for ovarian cancer chemotherapy.

Ovarian cancer is a highly fatal gynecologic malignancy worldwide. Chemotherapy remains the primary modality both for primary and maintenance treatments of ovarian cancer. However, the progress in developing chemotherapeutic agents for ovarian cancer has been slow in the past 20 years. Thus, new and effective chemotherapeutic drugs are urgently needed for ovarian cancer treatment. A reduction-responsive synergetic delivery strategy (PSSP@ART-ISMN) with co-delivery of artesunate and isosorbide 5-mononitrate was investigated in this research study. PSSP@ART-ISMN had various effects on tumor cells, such as (i) inducing the production of reactive oxygen species (ROS), which contributes to mitochondrial damage; (ii) providing nitric oxide and ROS for the tumor cells, which further react to generate highly toxic reactive nitrogen species (RNS) and cause DNA damage; and (iii) arresting cell cycle at the G0/G1 phase and inducing apoptosis. PSSP@ART-ISMN also demonstrated excellent antitumor activity with good biocompatibility in vivo. Taken together, the results of this work provide a potential delivery strategy for chemotherapy in ovarian cancer.

Cocrystals of Praziquantel with Phenolic Acids: Discovery, Characterization, and Evaluation.

Solvent-assisted grinding (SAG) and solution slow evaporation (SSE) methods are generally used for the preparation of cocrystals. However, even by using the same solvent, active pharmaceutical ingredient (API), and cocrystal coformer (CCF), the cocrystals prepared using the two methods above are sometimes inconsistent. In the present study, in the cocrystal synthesis of praziquantel (PRA) with polyhydroxy phenolic acid, including protocatechuic acid (PA), gallic acid (GA), and ferulic acid (FA), five different cocrystals were prepared using SAG and SSE. Three of the cocrystals prepared using the SAG method have the structural characteristics of carboxylic acid dimer, and two cocrystals prepared using the SSE method formed cocrystal solvates with the structural characteristics of carboxylic acid monomer. For phenolic acids containing only one phenolic hydroxyl group (ferulic acid), when preparing cocrystals with PRA by using SAG and SSE, the same product was obtained. In addition, the weak molecular interactions that were observed in the cocrystal are explained at the molecular level by using theoretical calculation methods. Finally, the in vitro solubility of cocrystals without crystal solvents and in vivo bioavailability of PRA-FA were evaluated to further understand the influence on the physicochemical properties of API for the introduction of CCF.

Organocatalytic Enantioselective Cross-Vinylogous Rauhut-Currier Reaction of Methyl Coumalate with Enals.

The organocatalytic enantioselective intermolecular cross-vinylogous Rauhut-Currier (RC) reaction of methyl coumalate with α,ß-unsaturated aldehydes is reported, and the enals are activated by iminium catalysis to serve as the Michael acceptors and methyl coumalate is used as an activated diene to generate a latent enolate. The excellent selectivity is driven by the aromaticity of methyl coumalate, and the post transformation of this heterocyclic structure into other electron-deficient arenes and heterocycles have addressed, in part, the challenging selectivity issues of the intermolecular cross-RC reactions and the limited scope of iminium catalysis.

Passive array micro-magnetic stimulation device based on multi-carrier wireless flexible control for magnetic neuromodulation.

Objective.The passive micro-magnetic stimulation (µMS) devices typically consist of an external transmitting coil and a single internal micro-coil, which enables a point-to-point energy supply from the external coil to the internal coil and the realization of magnetic neuromodulation via wireless energy transmission. The internal array of micro coils can achieve multi-target stimulation without movement, which improves the focus and effectiveness of magnetic stimulations. However, achieving a free selection of an appropriate external coil to deliver energy to a particular internal array of micro-coils for multiple stimulation targets has been challenging. To address this challenge, this study uses a multi-carrier modulation technique to transmit the energy of the external coil.Approach.In this study, a theoretical model of a multi-carrier resonant compensation network for the arrayµMS is established based on the principle of magnetically coupled resonance. The resonant frequency coupling parameter corresponding to each micro-coil of the arrayµMS is determined, and the magnetic field interference between the external coil and its non-resonant micro-coils is eliminated. Therefore, an effective magnetic stimulation threshold for a micro-coil corresponding to the target is determined, and wireless free control of the internal micro-coil array is achieved by using an external transmitting coil.Main results.The passiveµMS array model is designed using a multi-carrier wireless modulation method, and its synergistic modulation of the magnetic stimulation of synaptic plasticity long-term potentiation in multiple hippocampal regions is investigated using hippocampal isolated brain slices.Significance.The results presented in this study could provide theoretical and experimental bases for implantable micro-magnetic device-targeted therapy, introducing an efficient method for diagnosis and treatment of neurological diseases and providing innovative ideas for in-depth application of micro-magnetic stimulation in the neuroscience field.

Plants of the Genus Mahonia as a Potential Traditional Chinese Medicine for the Prevention and Treatment of Alzheimer's Disease.

Alzheimer's disease (AD), a prevalent multiple neurodegenerative disease, has gained attention, particularly in the aging population. However, presently available therapies merely focus on alleviating the symptoms of AD and fail to slow disease progression significantly. Traditional Chinese medicine (TCM) has been used to ameliorate symptoms or interfere with the pathogenesis of aging-associated diseases for many years based on disease-modifying in multiple pathological roles with multi-targets, multi-systems and multi-aspects. Mahonia species as a TCM present potential for anti-inflammatory activity, antioxidant activity, anti-acetylcholinesterase activity, and antiamyloid- beta activity that was briefly discussed in this review. They are regarded as promising drug candidates for AD therapy. The findings in this review support the use of Mahonia species as an alternative therapy source for treating AD.

Review of therapeutic mechanisms and applications based on SARS-CoV-2 neutralizing antibodies.

COVID-19 pandemic is a global public health emergency. Despite extensive research, there are still few effective treatment options available today. Neutralizing-antibody-based treatments offer a broad range of applications, including the prevention and treatment of acute infectious diseases. Hundreds of SARS-CoV-2 neutralizing antibody studies are currently underway around the world, with some already in clinical applications. The development of SARS-CoV-2 neutralizing antibody opens up a new therapeutic option for COVID-19. We intend to review our current knowledge about antibodies targeting various regions (i.e., RBD regions, non-RBD regions, host cell targets, and cross-neutralizing antibodies), as well as the current scientific evidence for neutralizing-antibody-based treatments based on convalescent plasma therapy, intravenous immunoglobulin, monoclonal antibodies, and recombinant drugs. The functional evaluation of antibodies (i.e., in vitro or in vivo assays) is also discussed. Finally, some current issues in the field of neutralizing-antibody-based therapies are highlighted.

Analytical Solution of Thermo-Mechanical Properties of Functionally Graded Materials by Asymptotic Homogenization Method.

In this work, a general mathematical model for functionally graded heterogeneous equilibrium boundary value problems is considered. A methodology to find the local problems and the effective properties of functionally graded materials (FGMs) with generalized periodicity is presented, using the asymptotic homogenization method (AHM). The present models consist of the matrix metal Mo and the reinforced phase ceramic ZrC, the constituent ratios and the property gradation profiles of which can be described by the designed volume fraction. Firstly, a new threshold segmentation method is proposed to construct the gradient structure of the FGMs, which lays the groundwork for the subsequent research on the properties of materials. Further, a study of FGMs varied along a certain direction and the influence of the varied constituents and graded structures in the behavior of heterogeneous structures are investigated by the AHM. Consequently, the closed-form formulas for the effective thermo-mechanical coupling tensors are obtained, based on the solutions of local problems of FGMs with the periodic boundary conditions. These formulas provide information for the understanding of the traditional homogenized structure, and the results also be verified the correctness by the Mori-Tanaka method and AHM numerical solution. The results show that the designed structure profiles have great influence on the effective properties of the present inhomogeneous heterogeneous models. This research will be of great reference significance for the future material optimization design.

Prevalence of social anxiety disorder and symptoms among Chinese children, adolescents and young adults: A systematic review and meta-analysis.

The objective of the study is to provide a reliable estimate of the pooled prevalence of social anxiety disorder (SAD) and social anxiety symptoms (SAS) among children, adolescents, and young adults (CAYA) in China. Meta-analysis is used to provide pooled-prevalence rate of SAD and SAS. Literature searches were conducted in both English and Chinese databases from the database's inception to April 2019. Eleven studies were identified for SAD, and 17 were included for SAS. The results revealed a pooled prevalence of SAD of 2.1% (95% CI: 1.2-3.8%) with high between-studies heterogeneity (Q = 1,055.2, I 2 = 99.1%, p < 0.001). The pooled prevalence estimate of SAS was 23.5% (95% CI: 18.6-29.3%), also with significant heterogeneity (Q = 1,019.3, I 2 = 98.4%, p < 0.001). Different diagnostic tools or self-report scales reported significant different prevalence of SAD or SAS. Further analysis stratified by gender, age, sampling methods, economic status, and risk of bias were performed. Limitations include the high level of heterogeneity between studies, inadequate number of the studies, and significant differences in prevalence caused by measurements. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020149591, identifier: PROSPERO CRD42020149591.

Functionalized 12 µm Polyethylene Separator to Realize Dendrite-Free Lithium Deposition toward Highly Stable Lithium-Metal Batteries.

Direct application of metallic lithium (Li) as the anode in rechargeable lithium metal batteries (LMBs) is still hindered by some annoying issues such as lithium dendrites formation, low Coulombic efficiency, and safety concerns arising therefrom. Herein, an advanced composite separator is prepared by facilely blade coating lightweight and thin functional layers on commercial 12 µm polyethylene separator to stabilize the Li anode. The composite separator simultaneously improves the Li ion transport and lithium deposition behaviors with uniform lithium ion distribution properties, enabling the dendrite-free Li deposition. As a result, the lithium anode can stably cycle up to 3000 cycles with the high capacity of 3.5 mAh cm-2 . Moreover, the composite separator exhibits wide compatibility in LMBs (Li-S and Li-ion battery) and delivers stable cycling performance and high Coulombic efficiency both in coin and lab-level soft-pack cells. Thus, this cost-effective modification strategy exhibits great application potential in high-energy LMBs.

Optimizing low loss negative index metamaterial for visible spectrum using differential evolution.

A novel negative index metamaterial design methodology for the visible spectrum with low losses was presented in this paper. A robust differential evolution (DE) was employed to optimize the metamaterial design to achieve a desired set of values for the index of refraction. By using numerical simulation of a wedge-shaped model and S-parameter retrieval method, we found that the DE-designed optimal solution can exhibit a low loss LH frequency band with simultaneously negative values of effective permittivity and permeability at the violet-light wavelength of 408 nm, and the figure of merit is 15.2, that means it may have practical applications because of its low loss and high transmission. Therefore, the design methodology presented in this paper is a very convenient and efficient way to pursue a novel metamaterial with desired electromagnetic characteristics in the visible spectrum.

Crack Growth Simulation of Functionally Graded Materials Based on Improved Bond-Based Peridynamic Model.

Functionally graded materials (FGMs) are widely used in the aerospace industry, especially for the thermal protection shields of aerospace vehicles. Studies show that the initiation and expansion of micro-cracks are important factors that adversely affect the service life of these shields. Based on the peridynamic theory of bonds, an improved peridynamic model is proposed in the present study for FGMs. In the proposed model, integral equivalence is applied to calculate the required material parameters. Obtained results reveal that this method can better reflect the gradient change of material properties.

A New Covalent Organic Framework of Dicyandiamide-Benzaldehyde Nanocatalytic Amplification SERS/RRS Aptamer Assay for Ultratrace Oxytetracycline with the Nanogold Indicator Reaction of Polyethylene Glycol 600.

In this paper, dicyandiamide (Dd) and p-benzaldehyde (Bd) were heated at 180 °C for 3 h to prepare a new type of stable covalent organic framework (COF) DdBd nanosol with high catalysis. It was characterized by molecular spectroscopy and electron microscopy. The study found that DdBd had a strong catalytic effect on the new indicator reaction of polyethylene glycol 600 (PEG600)-chloroauric acid to form gold nanoparticles (AuNPs). AuNPs have strong resonance Rayleigh scattering (RRS) activity, and in the presence of Victoria Blue B (VBB) molecular probes, they also have a strong surface-enhanced Raman scattering (SERS) effect. Combined with a highly selective oxytetracycline (OTC) aptamer (Apt) reaction, new dual-mode scattering SERS/RRS methods were developed to quantitatively analyze ultratrace OTC. The linear range of RRS is 3.00 × 10-3 -6.00 × 10-2 nmol/L, the detection limit is 1.1 × 10-3 nmol/L, the linear range of SERS is 3.00 × 10-3-7.00 × 10-2 nmol/L, and the detection limit is 9.0 × 10-4 nmol/L. Using the SERS method to analyze OTC in soil samples, the relative standard deviation is 1.35-4.78%, and the recovery rate is 94.3-104.9%.

A Review on Mechanical Models for Cellular Media: Investigation on Material Characterization and Numerical Simulation.

Cellular media materials are used for automobiles, aircrafts, energy-efficient buildings, transportation, and other fields due to their light weight, designability, and good impact resistance. To devise a buffer structure reasonably and avoid resource and economic loss, it is necessary to completely comprehend the constitutive relationship of the buffer structure. This paper introduces the progress on research of the mechanical properties characterization, constitutive equations, and numerical simulation of porous structures. Currently, various methods can be used to construct cellular media mechanical models including simplified phenomenological constitutive models, homogenization algorithm models, single cell models, and multi-cell models. This paper reviews current key mechanical models for cellular media, attempting to track their evolution from their inception to their latest development. These models are categorized in terms of their mechanical modeling methods. This paper focuses on the importance of constitutive relationships and microstructure models in studying mechanical properties and optimizing structural design. The key issues concerning this topic and future directions for research are also discussed.

Universal lithiophilic interfacial layers towards dendrite-free lithium anodes for solid-state lithium-metal batteries.

Solid-state lithium-metal batteries (SSLMBs) using garnet Li6.4La3Zr1.4Ta0.6O12 (LLZTO) as the solid electrolyte are expected to conquer the safety concerns of high energy Li batteries with organic liquid electrolytes owing to its nonflammable nature and good mechanical strength. However, the poor interfacial contact between the Li anode and LLZTO greatly restrains the practical applications of the electrolyte, because large polarization, dendritic Li formation and penetration can occur at the interfaces. Here, an effective method is proposed to improve the wettability of the LLZTO toward lithium and reduce the interfacial resistance by engineering universal lithiophilic interfacial layers. Thanks to the in-situ formed lithiophilic and ionic conductive Co/Li2O interlayers, the symmetric Li/CoO-LLZTO/Li batteries present much smaller overpotential, ultra-low areal specific resistance (ASR, 12.3 Ω cm2), high critical current density (CCD, 1.1 mA cm-2), and outstanding cycling performance (1696 h at a current density of 0.3 mA cm-2) at 25 °C. Besides, the solid-state Li/CoO-LLZTO/LFP cells deliver an excellent electrochemical performance with a high coulombic efficiency of ~100% and a long cycling time over 185 times. Surprisingly, the high-voltage (4.6 V) solid state Li/CoO-LLZTO/Li1.4Mn0.6Ni0.2Co0.2O2.4 (LMNC622) batteries can also realize an ultra-high specific capacity (232.5 mAh g-1) under 0.1 C at 25 °C. This work paves an effective way for practical applications of the dendrite-free SSLMBs.