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Metal-organic frameworks (MOFs) have gained tremendous notice for the application in alkaline water/seawater oxidation due to their tunable structures and abundant accessible metal sites. However, exploring cost-effective oxygen evolution reaction (OER) electrocatalysts with high catalytic activity and excellent stability remains a great challenge. In this work, a promising strategy is proposed to regulate the crystalline structures and electronic properties of NiFe-metal-organic frameworks (NiFe-MOFs) by altering the organic ligands. As a representative sample, NiFe-BDC (BDC: C 8 H 6 O 4 ) synthesized on nickel foam (NF) shows extraordinary OER activity in alkaline condition, delivering ultralow overpotentials of 204, 234 and 273 mV at 10, 100, and 300 mA cm -2 , respectively, with a small Tafel slope of 21.6 mV dec -1 . Only a slight decrease is observed when operating in alkaline seawater. The potential attenuation is barely identified at 200 mA cm -2 over 200 h continuous test, indicating the remarkable stability and corrosion resistance. In-situ measurements indicate that initial Ni 2+ /Fe 2+ goes through oxidation process into Ni 3+ /Fe 3+ during OER, and eventually presents in the form of NiFeOOH/NiFe-BDC heterojunction. The unique self-reconstructed surface is responsible for the low reaction barrier and fast reaction kinetics. This work provides an effective strategy to develop efficient MOF-based electrocatalysts and an insightful view on the dynamic structural evolution during OER., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The development of high-activity photocatalysts is crucial for the current large-scale development of photocatalytic hydrogen applications. Herein, we have developed a strategy to significantly enhance the hydrogen photocatalytic activity of Cu/Pr di-atom co-modified TiO 2 architectures by selectively anchoring Cu single atoms on the oxygen vacancies of the TiO 2 surface and replacing a trace of Ti atoms in the bulk with rare earth Pr atoms. Calculation results demonstrated that the synergistic effect between Cu single atoms and Pr atoms regulates the electronic structure of Cu/Pr-TiO 2 , thus promoting the separation of photogenerated carriers and their directional migration to Cu single atoms for the photocatalytic reaction. Furthermore, the d-band center of Cu/Pr-TiO 2 , which is located at -4.70 eV, optimizes the adsorption and desorption behavior of H*. Compared to TiO 2 , Pr-TiO 2 , and Cu/TiO 2 , Cu/Pr-TiO 2 displays the best H* adsorption Gibbs free energy (-0.047 eV). Furthermore, experimental results confirmed that the photogenerated carrier lifetime of Cu/Pr-TiO 2 is not only the longest (2.45 ns), but its hydrogen production rate (34.90 mmol g -1 h -1 ) also significantly surpasses those of Cu/TiO 2 (13.39 mmol g -1 h -1 ) and Pr-TiO 2 (0.89 mmol g -1 h -1 ). These findings open up a novel atomic perspective for the development of optimal hydrogen activity in dual-atom-modified TiO 2 photocatalysts.

Morphological novelties, or key innovations, are instrumental to the diversification of the organisms. In plants, one such innovation is the evolution of zygomorphic flowers, which is thought to promote outcrossing and increase flower morphological diversity. We isolated three allelic mutants from two Mimulus species displaying altered floral symmetry and identified the causal gene as the ortholog of Arabidopsis BLADE-ON-PETIOLE . We found that MlBOP and MlCYC2A physically interact and this BOP-CYC interaction module is highly conserved across the angiosperms. Furthermore, MlBOP self-ubiquitinates and suppresses MlCYC2A self-activation. MlCYC2A, in turn, impedes MlBOP ubiquitination. Thus, this molecular tug-of-war between MlBOP and MlCYC2A fine-tunes the expression of MlCYC2A , contributing to the formation of bilateral symmetry in flowers, a key trait in angiosperm evolution.

Background: Methicillin-resistant Staphylococcus aureus (MRSA) pneumonia is one of the leading causes of death and an immense financial burden on healthcare systems. Rifaximin (RFX) has good antibacterial activity against MRSA, but its clinical application is limited due to its poor oral absorption. Solid lipid nanoparticles have good biocompatibility, high drug loading, sustained release performance, and the inertia of lipids in gastric acid, which facilitates oral drug delivery., Objective: In order to improve the oral bioavailability of rifaximin and expand the clinical application of RFX for MRSA pneumonia, this study developed RFX-loaded myristic acid solid lipid nanoparticles (RFX-SLNs)., Methods: This study first prepared RFX-SLNs through hot melt emulsification and ultrasonic methods and selected the optimal formula of RFX-SLNs through single-factor screening. Afterward, the particle size, zeta potential, and polydispersity index (PDI) of the RFX-SLNs were measured, the morphology of RFX-SLNs was observed by transmission electron microscopy, and the encapsulation efficiency (EE) and drug loading capacity (LC) of RFX-SLNs were detected by high-performance liquid chromatography. Then, the sustained release ability and oral bioavailability of RFX-SLNs were studied through in vitro release and pharmacokinetics. Finally, the therapeutic effect of RFX-SLNs on MRSA pneumonia infection was studied by using a mouse MRSA pneumonia infection model., Results: The optimal formulation of RFX-SLNs was 1% RFX with water (3% PVA) and oil (myristic acid) ratio of 1:19. RFX-SLNs were spherical in shape with a smooth surface and uniform size. The EE and LC of three different batches of RFX-SLNs were 89.35±2.47%, 90.45±3.69%, 88.72±1.18%, and 9.50 ± 0.01%, 10.09±0.01%, and 9.68±0.00%, respectively. In vitro release and pharmacokinetic studies showed that the myristic acid solid lipid nanoparticles showed excellent sustained release as expected and increased the oral bioavailability of RFX by 2.18 times. This indicates that RFX-SLNs can be used for the oral treatment of bacterial infections. Compared to RFX, RFX-SLNs showed good therapeutic effects in a mouse MRSA pneumonia infection model., Conclusion: This study indicates that the myristic acid solid lipid nanoparticles might be an effective way to enhance the oral absorption and therapy effects of RFX and other insoluble drugs. This not only opens up avenues for the clinical application of RFX but also provides a way for the development of new dosage forms of water-soluble drugs and the expansion of their clinical application scope., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The radiation-induced skin injury (RISI) remains a great challenge for clinical wound management and care after radiotherapy, as patients will suffer from the acute radiation injury and long-term chronic inflammatory damage during the treatment. The excessive ROS in the early acute stage and prolonged inflammatory response in the late healing process always hinder therapeutic efficiency. Herein, we developed an extracellular matrix (ECM)-mimetic multifunctional glycopeptide hydrogel (oCP@As) to promote and accelerate RISI repair via a dual-modulation strategy in different healing stages. The oCP@As hydrogel not only can form an ECM-like nanofiber structure through the Schiff base reaction but also exhibits ROS scavenging and DNA double-strand break repair abilities, which can effectively reduce the acute radiation damage. Meanwhile, the introduction of oxidized chondroitin sulfate, which is the ECM polysaccharide-like component, enables regulation of the inflammatory response by adsorption of inflammatory factors, accelerating the repair of chronic inflammatory injury. The animal experiments demonstrated that oCP@As can significantly weaken RISI symptoms, promote epidermal tissue regeneration and angiogenesis, and reduce pro-inflammatory cytokine expression. Therefore, this multifunctional glycopeptide hydrogel dressing can effectively attenuate RISI symptoms and promote RISI healing, showing great potential for clinical applications in radiotherapy protection and repair.

SARS-CoV-2 has still been threatening global public health with its emerging variants. Our previous work reported lead compound JZD-07 that displayed good 3CL pro inhibitory activity. Here, an in-depth structural optimization for JZD-07 was launched to obtain more desirable drug candidates for the therapy of SARS-CoV-2 infection, in which 54 novel derivatives were designed and synthesized by a structure-based drug design strategy. Among them, 24 compounds show significantly enhanced 3CL pro inhibitory potencies with IC 50 values less than 100 nM, and 11 compounds dose-dependently inhibit the replication of the SARS-CoV-2 delta variant. In particular, compound 49 has the most desirable antiviral activity with EC 50 of 0.272 ± 0.013 μM against the delta variant, which was more than 20 times stronger than JZD-07 . Oral administration of 49 could significantly reduce the lung viral copies of mice, exhibiting a more favorable therapeutic potential. Overall, this investigation presents a promising drug candidate for further development to treat SARS-CoV-2 infection.

Aims: Pemafibrate substantially lowers serum triglyceride (TG) levels and increases high-density lipoprotein cholesterol (HDL-C) levels primarily in Japan, but it has not been evaluated in China. We aimed to confirm the efficacy and safety of pemafibrate in Chinese patients with hypertriglyceridemia and low HDL-C levels by comparing placebo and fenofibrate., Methods: A multicenter, double-masked trial was conducted in China involving 344 patients with high TG and low HDL-C levels randomly assigned to one of four groups: pemafibrate 0.2 mg/d, pemafibrate 0.4 mg/d, fenofibrate 200 mg/d, or placebo for 12 weeks. The primary endpoint was the percentage change in fasting TG levels., Results: The percentage change in TG levels from baseline was -34.1%, -44.0%, -30.5%, and 6.5% in the pemafibrate 0.2 mg/d, pemafibrate 0.4 mg/d, fenofibrate 200 mg/d, and placebo groups, respectively. Pemafibrate 0.4 mg/d significantly reduced TG levels compared with that in both placebo (p＜0.0001) and fenofibrate groups (p=0.0083). Significant improvements in HDL-C, remnant cholesterol, and apolipoprotein A1 levels were also observed with both doses of pemafibrate than with the placebo. Pemafibrate showed significantly smaller changes in alanine aminotransferase, aspartate aminotransferase, and serum creatinine levels than those with fenofibrate., Conclusions: In Chinese patients, pemafibrate exhibited superior efficacy in improving TG levels and enhanced hepatic and renal safety compared to fenofibrate. Thus, pemafibrate may represent a promising therapeutic option for dyslipidemia in Chinese patients.

Bovine mastitis is a prevalent infectious disease in dairy herds worldwide, resulting in substantial economic losses. Staphylococcus aureus is a major cause of mastitis in animals, and its antibiotic resistance poses challenges for treatment. Recently, renewed interest has focused on the development of alternative methods to antibiotic therapy, including bacteriophages (phages), for controlling bacterial infections. In this study, 2 lytic phages, vB_SauM_JDYN (JDYN) and vB_SauM_JDF86 (JDF86), were isolated from the cattle sewage effluent samples collected from dairy farms in Shanghai. The 2 phages have a broad bactericidal spectrum against Staphylococcus of various origins. Genomic and morphological analyses revealed that the 2 phages belonged to the Myoviridae family. Moreover, JDYN and JDF86 remained stable under a wide temperature and pH range and were almost unaffected in chloroform. In this study, we prepared a phage cocktail (PHC-1) which consisted of a 1:1:1 ratio of JDYN, JDF86, and SLPW (a previously characterized phage). We found that PHC-1 showed the strongest bacteriolytic effect and the lowest frequency of emergence of bacteriophage insensitive mutants compared with monophages. Bovine mammary epithelial cells and lactating mice mastitis models were used to evaluate the effectiveness of PHC-1 in vitro and in vivo, respectively. The results demonstrated that PHC-1 treatment significantly reduced bacterial load, alleviated inflammatory response, and improved mastitis pathology. Altogether, these results suggest that PHC-1 has the potential to treat S. aureus-induced bovine mastitis and that phage cocktails can combat antibiotic-resistant S. aureus infections., (© 2024, The Authors. Published by Elsevier Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

The increasing emergence and re-emergence of RNA virus outbreaks underlines the urgent need to develop effective antivirals. RNA interference (RNAi) is a sequence-specific gene silencing mechanism that is triggered by small interfering RNAs (siRNAs) or short hairpin RNAs (shRNAs), which exhibits significant promise for antiviral therapy. AGO2-dependent shRNA (agshRNA) generates a single-stranded guide RNA and presents significant advantages over traditional siRNA and shRNA. In this study, we applied a logistic regression algorithm to a previously published chemically siRNA efficacy dataset and built a machine learning-based model with high predictive power. Using this model, we designed siRNA sequences targeting diverse RNA viruses, including human enterovirus A71 (EV71), Zika virus (ZIKV), dengue virus 2 (DENV2), mouse hepatitis virus (MHV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and transformed them into agshRNAs. We validated the performance of our agshRNA design by evaluating antiviral efficacies of agshRNAs in cells infected with different viruses. Using the agshRNA targeting EV71 as an example, we showed that the anti-EV71 effect of agshRNA was more potent compared with the corresponding siRNA and shRNA. Moreover, the antiviral effect of agshRNA is dependent on AGO2-processed guide RNA, which can load into the RNA-induced silencing complex (RISC). We also confirmed the antiviral effect of agshRNA in vivo. Together, this work develops a novel antiviral strategy that combines machine learning-based algorithm with agshRNA design to custom design antiviral agshRNAs with high efficiency., Competing Interests: Conflict of interest Professor Xi Zhou is an editorial board member for Virologica Sinica and were not involved in the editorial review or the decision to publish this article. The authors declare that they have no conflict of interest., (Copyright © 2024 The Authors. Publishing services by Elsevier B.V. All rights reserved.)

Background: The incidence of non-suicidal self-injury (NSSI) has been on the rise in recent years. Studies have shown that people with NSSI have difficulties in emotion regulation and cognitive control. In addition, some studies have investigated the cognitive emotion regulation of people with NSSI which found that they have difficulties in cognitive emotion regulation, but there was a lack of research on cognitive emotion regulation strategies and related neural mechanisms., Methods: This study included 117 people with NSSI (age = 19.47 ± 5.13, male = 17) and 84 non-NSSI participants (age = 19.86 ± 4.14, male = 16). People with NSSI met the DSM-5 diagnostic criteria, and non-NSSI participants had no mental or physical disorders. The study collected all participants' data of Cognitive Emotion Regulation Questionnaire (CERQ) and functional magnetic resonance imaging (fMRI) to explore the differences in psychological performance and brain between two groups. Afterwards, Machine learning was used to select the found differential brain regions to obtain the highest correlation regions with NSSI. Then, Allen's Human Brain Atlas database was used to compare with the information on the abnormal brain regions of people with NSSI to find the genetic information related to NSSI. In addition, gene enrichment analysis was carried out to find the related pathways and specific cells that may have differences., Results: The differences between NSSI participants and non-NSSI participants were as follows: positive refocusing (t = -4.74, p < 0.01); refocusing on plans (t = -4.11, p < 0.01); positive reappraisal (t = -9.22, p < 0.01); self-blame (t = 6.30, p < 0.01); rumination (t = 3.64, p < 0.01); catastrophizing (t = 9.10, p < 0.01), and blaming others (t = 2.52, p < 0.01), the precentral gyrus (t = 6.04, p FDR  < 0.05) and the rolandic operculum (t = -4.57, p FDR  < 0.05). Rolandic operculum activity was negatively correlated with blaming others (r = -0.20, p < 0.05). Epigenetic results showed that excitatory neurons (p < 0.01) and inhibitory neurons (p < 0.01) were significant differences in two pathways, "trans-synaptic signaling" (p < -log10 8 ) and "modulation of chemical synaptic transmission" (p < -log10 8 ) in both cells., Conclusions: People with NSSI are more inclined to adopt non-adaptive cognitive emotion regulation strategies. Rolandic operculum is also abnormally active. Abnormal changes in the rolandic operculum of them are associated with non-adaptive cognitive emotion regulation strategies. Changes in the excitatory and inhibitory neurons provide hints to explore the abnormalities of the neurological mechanisms at the cellular level of them. Trial registration number NCT04094623., Competing Interests: Declaration of competing interest All authors declare that No conflict of interest exists., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Posttraumatic headache (PTH) is a common and debilitating symptom following repetitive mild traumatic brain injury (rmTBI), and it mainly resembles a migraine-like phenotype. While modulation of the endocannabinoid system (ECS) is effective in treating TBI and various types of pain including migraine, the role of augmentation of endocannabinoids in treating PTH has not been investigated., Methods: Repetitive mild TBI was induced in male C57BL/6J mice using the non-invasive close-head impact model of engineered rotational acceleration (CHIMERA). Periorbital allodynia was assessed using von Frey filaments and determined by the "Up-Down" method. Immunofluorescence staining was employed to investigate glial cell activation and calcitonin gene-related peptide (CGRP) expression in the trigeminal ganglion (TG) and trigeminal nucleus caudalis (TNC) of the rmTBI mice. Levels of 2-arachidonoyl glycerol (2-AG), anandamide (AEA), and arachidonic acid (AA) in the TG, medulla (including TNC), and periaqueductal gray (PAG) were measured by mass spectrometry. The therapeutic effect of endocannabinoid modulation on PTH was also assessed., Results: The rmTBI mice exhibited significantly increased cephalic pain hypersensitivity compared to the sham controls. MJN110, a potent and selective inhibitor of the 2-AG hydrolytic enzyme monoacylglycerol lipase (MAGL), dose-dependently attenuated periorbital allodynia in the rmTBI animals. Administration of CGRP at 0.01 mg/kg reinstated periorbital allodynia in the rmTBI animals on days 33 and 45 post-injury but had no effect in the sham and MJN110 treatment groups. Activation of glial cells along with increased production of CGRP in the TG and TNC at 7 and 14 days post-rmTBI were attenuated by MJN110 treatment. The anti-inflammatory and anti-nociceptive effects of MJN110 were partially mediated by cannabinoid receptor activation, and the pain-suppressive effect of MJN110 was completely blocked by co-administration of DO34, an inhibitor of 2-AG synthase. The levels of 2-AG in TG, TNC and PAG were decreased in TBI animals, significantly elevated and further reduced by the selective inhibitors of 2-AG hydrolytic and synthetic enzymes, respectively., Conclusion: Enhancing endogenous levels of 2-AG appears to be an effective strategy for the treatment of PTH by attenuating pain initiation and transmission in the trigeminal pathway and facilitating descending pain inhibitory modulation., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Competing Interests: The authors declare no conflict of interest.

Among pyroelectric materials, Bi 0.5 Na 0.5 TiO 3 (BNT)-based relaxors are particularly noteworthy due to their significant polarization fluctuation near the depolarization temperature (T d ), resulting in a large pyroelectric response. What has been overlooked is the dynamic behavior of inherent polar structures, particularly the temperature-dependent evolution of polar nanoregions (PNRs), which significantly impacts the pyroelectric behavior. Herein, based on the large pyroelectric response origination (the ferroelectric-relaxor phase transition), the mixed nonergodic and ergodic relaxor (NR+ER) critical state is constructed, which is believed to trigger the easily fluctuating polarization state with excellent pyroelectric response. Composition engineering (with Li + , Sr 2+ , and Ta 5+ ) strategically controls the relaxor process and modulates the dynamic behavior of inherent polar structures by the random field effect. The pyroelectric coefficient of more than 1441 µCm -2 K -1 at room temperature (RT), more than 9221 µCm -2 K -1 (RT), and ≈107911 µCm -2 K -1 (T d ) are achieved in the Li + -doped sample, the Sr 2+ -doped sample, and the (Li + +Ta 5+ ) co-doped sample, respectively. This work earns the highest RT pyroelectric coefficient in BNT-based relaxors, which is suitable for pyroelectric applications. Furthermore, it provides a strategy for modulating the pyroelectric performance of BNT-based relaxors., (© 2024 Wiley‐VCH GmbH.)

Bovine mastitis (BM) is mainly caused by bacterial infection that has a highly impact on dairy production, affecting both economic viability and animal well-being. A cross-sectional study was conducted in dairy farms to investigate the prevalence and antimicrobial resistance patterns of bacterial pathogens associated with BM. The analysis revealed that Staphylococcus (49%), Escherichia (16%), Pseudomonas (11%), and Klebsiella (6%) were the primary bacterial pathogens associated with mastitis. A significant proportion of Staphylococcus strains displayed multiple drug resistance. The use of disinfectants is an important conventional measure to control the pathogenic bacteria in the environment. Bacteriophages (Phages), possessing antibacterial properties, are natural green and effective disinfectants. Moreover, they mitigate the risk of generating harmful disinfection byproducts, which are commonly associated with traditional disinfection methods. Based on the primary bacterial pathogens associated with mastitis in the investigation area, a phage cocktail, named SPBC-SJ, containing seven phages capable of lysing S. aureus, E. coli, and P. aeruginosa was formulated. SPBC-SJ exhibited superior bactericidal activity and catharsis effect on pollutants (glass surface) compared to chemical disinfectants. Clinical trials confirmed that the SPBC-SJ-based superimposed disinfection group (phage combined with chemical disinfectants) not only cut down the dosage of disinfectants used, but significantly reduced total bacterial counts on the ground and in the feeding trough of dairy farms. Furthermore, SPBC-SJ significantly reduced the abundance of Staphylococcus and Pseudomonas in the environment of the dairy farm. These findings suggest that phage-based superimposed disinfection is a promising alternative method to combat mastitis pathogens in dairy farms due to its highly efficient and environmentally-friendly properties., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Photocatalytic water splitting for clean hydrogen production has been a very attractive research field for decades. However, the insightful understanding of the actual active sites and their impact on catalytic performance is still ambiguous. Herein, a Pr-doped TiO 2 -supported Cu single atom (SA) photocatalyst is successfully synthesized (noted as Cu/Pr-TiO 2 ). It is found that Pr dopants passivate the formation of oxygen vacancies, promoting the density of photogenerated electrons on the CuSAs, and optimizing the electronic structure and H * adsorption behavior on the CuSA active sites. The photocatalytic hydrogen evolution rate of the obtained Cu/Pr-TiO 2 catalyst reaches 32.88 mmol g -1  h -1 , 2.3 times higher than the Cu/TiO 2 . Innovatively, the excellent catalytic activity and performance is attributed to the active sites change from O atoms to CuSAs after Pr doping is found. This work provides new insight for understanding the accurate roles of single atoms in photocatalytic water splitting., (© 2024 Wiley‐VCH GmbH.)

The arginine deiminase system (ADS) has been identified in various bacteria and functions to supplement energy production and enhance biological adaptability. The current understanding of the regulatory mechanism of ADS and its effect on bacterial pathogenesis is still limited. Here, we found that the XRE family transcriptional regulator XtrSs negatively affected Streptococcus suis virulence and significantly repressed ADS transcription when the bacteria were incubated in blood. Electrophoretic mobility shift (EMSA) and lacZ fusion assays further showed that XtrSs directly bind to the promoter of ArgR, an acknowledged positive regulator of bacterial ADS, to repress ArgR transcription. Moreover, we provided compelling evidence that S. suis could utilize arginine via ADS to adapt to acid stress, while Δ xtrSs enhanced this acid resistance by upregulating the ADS operon. Moreover, whole ADS-knockout S. suis increased arginine and antimicrobial NO in the infected macrophage cells, decreased intracellular survival, and even caused significant attenuation of bacterial virulence in a mouse infection model, while Δ xtrSs consistently presented the opposite results. Our experiments identified a novel ADS regulatory mechanism in S. suis , whereby XtrSs regulated ADS to modulate NO content in macrophages, promoting S. suis intracellular survival. Meanwhile, our findings provide a new perspective on how Streptococci evade the host's innate immune system.

Raffinose mitigates plant heat-, drought- and cold- stresses; however, whether raffinose contributes to plant waterlogging tolerance is unknown. The maize zmrafs-1 mutant seedlings lacking raffinose, generate fewer and shorter adventitious root (AR) and are more sensitive to waterlogging stress, while overexpression of ZmRAFS increases raffinose content, stimulates AR formation, and enhances the waterlogging tolerance of maize seedlings. Transcriptome analysis of NS (Null segregant) seedlings compared with that of zmrafs-1, particularly when waterlogged, revealed that the expression of genes related to galactose metabolism and the auxin biosynthetic pathway were upregulated by raffinose. Additionally, Indole-3-acetic acid (IAA) amounts significantly decreased or increased in zmrafs-1 or ZmRAFS-overexpressing seedlings, respectively. Inhibition of the hydrolysis of raffinose by DGJ (1-deoxygalactonojirimycin) decreased the waterlogging tolerance of maize seedlings, decreased the expression of genes encoding proteins related to auxin transport-related genes as well as the IAA level in the seedlings, suggesting that the hydrolysis of raffinose is necessary for maize waterlogging tolerance. These data demonstrate that raffinose catabolism stimulates adventitious root formation via auxin signaling pathway to enhance maize waterlogging tolerance., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Electromigration, as a common reason for interconnect failure, is becoming increasingly important in the ongoing decrease in the integrated circuit manufacturing process. A study is being carried out utilizing the ab initio calculational method to gain a deeper understanding of electromigration, with a focus on the atom diffusion process in the Ag-Pd alloy system, a commonly used interconnect material. We begin by establishing that the primary mechanism of diffusion is step-edge diffusion on the (111) surface. Following this, we examine the current-induced force exerted on the migrating Ag atom. The Pd substitutional defect reveals an effect that increases the energy barrier of diffusion and decreases the current-induced force that powers the directional migration., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Pyroelectric effect which refers to electrical responses induced by time temperature-dependent fluctuations has received extensive attention, showing promising application prospects for infrared (IR) technology. Although enhanced pyroelectric performances are obtained in potassium sodium niobate-based ceramics at room temperature via multi-symmetries coexistence design, the poor pyroelectric temperature stability is still an urging desire that needs to be resolved. Herin, by constructing multilayer composite ceramics and adjusting the proportion of stacked layers, improved pyroelectric coefficient, and figures of merit (FOMs), as well as enhanced temperature stabilities can be achieved. With a remained high pyroelectric coefficient of 5.45 × 10 -4  C m -2 °C -1 at room temperature, the pyroelectric parameters almost keep unchanged in the temperature range of 30-100 °C, showing great properties advantages compared with previous reports. The excellent properties can be attributed to the graded polarization rotation states among each lamination induced by successive phase transitions. The novel strategy for achieving stable pyroelectric sensing can further promote the application in the IR sensors field., (© 2024 Wiley‐VCH GmbH.)

Few-shot medical image segmentation has achieved great progress in improving accuracy and efficiency of medical analysis in the biomedical imaging field. However, most existing methods cannot explore inter-class relations among base and novel medical classes to reason unseen novel classes. Moreover, the same kind of medical class has large intra-class variations brought by diverse appearances, shapes and scales, thus causing ambiguous visual characterization to degrade generalization performance of these existing methods on unseen novel classes. To address the above challenges, in this paper, we propose a Prototype correlation Matching and Class-relation Reasoning (i.e., PMCR) model. The proposed model can effectively mitigate false pixel correlation matches caused by large intra-class variations while reasoning inter-class relations among different medical classes. Specifically, in order to address false pixel correlation match brought by large intra-class variations, we propose a prototype correlation matching module to mine representative prototypes that can characterize diverse visual information of different appearances well. We aim to explore prototypelevel rather than pixel-level correlation matching between support and query features via optimal transport algorithm to tackle false matches caused by intra-class variations. Meanwhile, in order to explore inter-class relations, we design a class-relation reasoning module to segment unseen novel medical objects via reasoning inter-class relations between base and novel classes. Such inter-class relations can be well propagated to semantic encoding of local query features to improve few-shot segmentation performance. Quantitative comparisons illustrates the large performance improvement of our model over other baseline methods.

Microglia are the residential immune cells in the central nervous system. Their roles as innate immune cells and regulators of synaptic remodeling are critical to the development and the maintenance of the brain. Numerous studies have depleted microglia to elucidate their involvement in healthy and pathological conditions. PLX3397, a blocker of colony stimulating factor 1 receptor (CSF1R), is widely used to deplete mouse microglia due to its non-invasiveness and convenience. Recently, other small rodents, including Syrian hamsters (Mesocricetus auratus) and Mongolian gerbils (Meriones unguiculatus), have been recognized as valuable animal models for studying brain functions and diseases. However, whether microglia depletion via PLX3397 is feasible in these species remains unclear. Here, we administered PLX3397 orally via food pellets to hamsters and gerbils. PLX3397 successfully depleted gerbil microglia but had no effect on microglial density in hamsters. Comparative analysis of the CSF1R amino acid sequence in different species hints that amino acid substitutions in the juxtamembrane domain may potentially contribute to the inefficacy of PLX3397 in hamsters., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest associated with this manuscript., (Copyright © 2024 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Introduction: Ephedra sinica polysaccharide (ESP) exerts substantial therapeutic effects on rheumatoid arthritis (RA). However, the mechanism through which ESP intervenes in RA remains unclear. A close correlation has been observed between enzymes and derivatives in the gut microbiota and the inflammatory immune response in RA., Methods: A type II collagen-induced arthritis (CIA) mice model was treated with Ephedra sinica polysaccharide. The therapeutic effect of ESP on collagen-induced arthritis mice was evaluated. The anti-inflammatory and cartilage-protective effects of ESP were also evaluated. Additionally, metagenomic sequencing was performed to identify changes in carbohydrate-active enzymes and resistance genes in the gut microbiota of the ESP-treated CIA mice. Liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry were performed to observe the levels of serum metabolites and short-chain fatty acids in the gut. Spearman's correlational analysis revealed a correlation among the gut microbiota, antibiotic-resistance genes, and microbiota-derived metabolites., Results: ESP treatment significantly reduced inflammation levels and cartilage damage in the CIA mice. It also decreased the levels of pro-inflammatory cytokines interleukin (IL)-6, and IL-1-β and protected the intestinal mucosal epithelial barrier, inhibiting inflammatory cell infiltration and mucosal damage. Here, ESP reduced the TLR4, MyD88, and TRAF6 levels in the synovium, inhibited the p65 expression and pp65 phosphorylation in the NF-κB signaling pathway, and blocked histone deacetylase (HDAC1 and HDAC2) signals. ESP influenced the gut microbiota structure, microbial carbohydrate-active enzymes, and microbial resistance related to resistance genes. ESP increased the serum levels of L-tyrosine, sn-glycero-3-phosphocholine, octadecanoic acid, N-oleoyl taurine, and decreased N-palmitoyl taurine in the CIA mice., Conclusion: ESP exhibited an inhibitory effect on RA. Its action mechanism may be related to the ability of ESP to effectively reduce pro-inflammatory cytokines levels, protect the intestinal barrier, and regulate the interaction between mucosal immune systems and abnormal local microbiota. Accordingly, immune homeostasis was maintained and the inhibition of fibroblast-like synoviocyte (FLS) proliferation through the HDAC/TLR4/NF-κB pathway was mediated, thereby contributing to its anti-inflammatory and immune-modulating effects., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer J-ST declared a shared affiliation with the author(s) to the handling editor at the time of review., (Copyright © 2024 Ma, Wei, Peng, Wei, Wen, Liu, Song, Wang, Zhang and Peng.)

Antisense oligonucleotide (ASO) is a novel therapeutic platform for targeted cancer therapy. Previously, we have demonstrated that miR-146b-5p plays an important role in colorectal cancer progression. However, a safe and effective strategy for delivery of an ASO to its targeted RNA remains as a major hurdle in translational advances. Human umbilical cord mesenchymal cell (hUC-MSC)-derived exosomes were used as vehicles to deliver an anti-miR-146b-5p ASO (PMO-146b). PMO-146b was assembled onto the surface of exosomes (e) through covalent conjugation to an anchor peptide CP05 (P) that recognized an exosomal surface marker, CD63, forming a complex named ePPMO-146b. After ePPMO-146b treatment, cell proliferation, uptake ability, and migration assays were performed, and epithelial-mesenchymal transition progression was evaluated in vitro. A mouse xenograft model was used to determine the antitumor effect and distribution of ePPMO-146b in vivo. ePPMO-146b was taken up by SW620 cells and effectively inhibited cell proliferation and migration. The conjugate also exerted antitumor efficacy in a xenograft mouse model of colon cancer by systematic administration, where PPMO-146b was enriched in tumor tissue. Our study highlights the potential of hUC-MSC-derived exosomes anchored with PPMO-146b as a novel safe and effective approach for PMO backboned ASO delivery., (© 2023. The Author(s).)

The extensive spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) throughout China in late 2022 has underscored the correlation between this virus and severe psychiatric disorders. Nevertheless, there remains a dearth of reported corresponding clinical and pathological features. Accordingly, we retrospectively reviewed the electronic medical records of psychiatric inpatients for seven days from early January 2023. Twenty-one inpatients who developed first-episode psychiatric disorders within two weeks after SARS-CoV-2 infection were recruited, while 24 uninfected the first-episode psychiatric inpatients were selected as controls. Comparative analyses of clinical manifestations, routine laboratory, and imaging examinations were performed. Our investigation revealed a 330% increase in first-episode psychiatric inpatients incidence after SARS-CoV-2 infection in 2023 compared to the preceding year without infections. Most cases exhibited psychiatric symptoms within a week of infection, resolving about two weeks with no residual symptoms after a three month. One-way ANOVA analysis between inpatients characterized by psychotic symptoms and hyperthermia was significant. Infected inpatients displayed elevated cytokine levels of interleukin-4, interleukin-8, and interferon-α, and decreased levels of eosinophils and basophils. These finding suggested that SARS-CoV-2 may contribute to the development of psychiatric disorders, likely mediated by the virus-induced inflammatory response and neuronal dysfunction in the context of psychological distress.

An efficient and green method for synthesizing 3-methyl-4-(hetero) arylmethylene isoxazole-5(4H)-ones was developed using a recyclable and environmental-friendly catalyst, Na 2 S 2 O 3 , and 16 target compounds were successfully synthesized under the obtained optimal reaction condition. Using rifampicin as a positive control, the antibacterial activity of all synthesized compounds was tested by micro dilution method, among them, 3-methyl-4-[(2,4-dimethoxyphenyl) methylene]-isoxazole-5-one (4 m) presented wonderful antimicrobial activity, which may contribute to the development of anti-tuberculosis drugs., (© 2024 Wiley‐VHCA AG, Zurich, Switzerland.)

Dispersion plays a great role in ultrafast laser oscillators, ultrashort pulse amplifiers, and many other nonlinear optical dynamics. Therefore, dispersion measurement is crucial for device characterization, system design and nonlinear dynamics investigation therein. In this work, we demonstrate a versatile approach, i.e., Kalman filtering-aided white-light interferometry, for group delay dispersion (GDD) characterization. Extended Kalman filter is adopted to track the cosine-like interferogram, and to eliminate the unintended bias and the envelope, providing a nearly ideal phase retrieval and GDD estimation. The measurement range could span from tens of fs 2 to tens of ps 2 , with an uncertainty of about 0.1%, enabling precise GDD measurement for diverse optical components, ranging from a millimeter-thick glass slide to highly dispersive chirped fiber Bragg gratings. Benefited by the simplicity, convenient setup, and easy operation as well as relatively low cost, this approach would help photonic device characterization, dispersion management and nonlinear dynamics investigation in the laboratory and work plant.

CuI films present promising optoelectronic properties for transparent conductors. However, the high hole concentration in CuI films hinders the controllable modulation of hole mobility, limiting their application in low-dimensional thin-film transistors. In this study, CuI films were prepared through a Cu film iodination method at room temperature, and a systematic investigation was conducted on the modulation of hole concentration and mobility with varying film thickness. The films exhibited a zinc blende structure (γ-phase) with increasing grain size as the thickness increased. The transmittance and optical bandgap of the films decreased with increasing thickness. The correlation of vacancy concentration with changing film thickness was analyzed through photoluminescence spectroscopy, revealing the influence of grain boundary migration on vacancy formation. The reduction in film thickness diminishes the migration of CuI grain boundaries, consequently reducing the probability of Cu vacancy and I vacancy formation, resulting in diminished hole concentration and enhanced hole mobility and film conductivity. The film with a thickness of 20 nm demonstrated optimal performance, with a transmittance of 90%, hole concentration of 4.09 × 10 17 cm -3 , hole mobility of 506.50 cm 2 V -1 s -1 , and conductivity of 33.19 S cm -1 . This work deepens the understanding of hole transport such as hole concentration and mobility modulation in CuI films, highlighting the importance of controlling grain boundary migration during the film growth process., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

In this study, catalytic ozonation by Fe-Al 2 O 3 was used to investigate the defluorination of PFOA and PFOS, assessing the effects of different experimental conditions on the defluorination efficiency of the system. The oxidation mechanism of the Fe-Al 2 O 3 /O 3 system and the specific degradation and defluorination mechanisms for PFOA and PFOS were determined. Results showed that compared to the single O 3 system, the defluorination rates of PFOA and PFOS increased by 2.32- and 5.92-fold using the Fe-Al 2 O 3 /O 3 system under optimal experimental conditions. Mechanistic analysis indicated that in Fe-Al 2 O 3 , the variable valence iron (Fe) and functional groups containing C and O served as important reaction sites during the catalytic process. The co-existence of 1 O 2 , OH, O 2 - and high-valence Fe(IV) constituted a synergistic oxidation system consisting of free radicals and non-radicals, promoting the degradation and defluorination of PFOA and PFOS. DFT theoretical calculations and the analysis of intermediate degradation products suggested that the degradation pathways of PFOA and PFOS involved Kolbe decarboxylation, desulfonation, alcoholization and intramolecular cyclization reactions. The degradation and defluorination pathways of PFOA and PFOS consisted of the stepwise removal of -CF 2 -, with PFOS exhibiting a higher defluorination rate than PFOA due to its susceptibility to electrophilic attack. This study provides a theoretical basis for the development of heterogeneous catalytic ozonation systems for PFOA and PFOS treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Respiratory disease caused by coronavirus infection remains a global health crisis. Although several SARS-CoV-2-specific vaccines and direct-acting antivirals are available, their efficacy on emerging coronaviruses in the future, including SARS-CoV-2 variants, might be compromised. Host-targeting antivirals provide preventive and therapeutic strategies to overcome resistance and manage future outbreak of emerging coronaviruses. Cathepsin L (CTSL) and calpain-1 (CAPN1) are host cysteine proteases which play crucial roles in coronaviral entrance into cells and infection-related immune response. Here, two peptidomimetic α-ketoamide compounds, 14a and 14b, were identified as potent dual target inhibitors against CTSL and CAPN1. The X-ray crystal structures of human CTSL and CAPN1 in complex with 14a and 14b revealed the covalent binding of α-ketoamide groups of 14a and 14b to C25 of CTSL and C115 of CAPN1. Both showed potent and broad-spectrum anticoronaviral activities in vitro, and it is worth noting that they exhibited low nanomolar potency against SARS-CoV-2 and its variants of concern (VOCs) with EC 50 values ranging from 0.80 to 161.7 nM in various cells. Preliminary mechanistic exploration indicated that they exhibited anticoronaviral activity through blocking viral entrance. Moreover, 14a and 14b exhibited good oral pharmacokinetic properties in mice, rats and dogs, and favorable safety in mice. In addition, both 14a and 14b treatments demonstrated potent antiviral potency against SARS-CoV-2 XBB 1.16 variant infection in a K18-hACE2 transgenic mouse model. And 14b also showed effective antiviral activity against HCoV-OC43 infection in a mouse model with a final survival rate of 60%. Further evaluation showed that 14a and 14b exhibited excellent anti-inflammatory effects in Raw 264.7 mouse macrophages and in mice with acute pneumonia. Taken together, these results suggested that 14a and 14b are promising drug candidates, providing novel insight into developing pan-coronavirus inhibitors with antiviral and anti-inflammatory properties., (© 2024. The Author(s).)

Streptococcus suis ( S. suis ) is a zoonotic pathogen with multiple serotypes, and thus, multivalent vaccines generating cross-protection against S. suis infections are urgently needed to improve animal welfare and reduce antibiotic abuse. In this study, we established a systematic and comprehensive epitope prediction pipeline based on immunoinformatics. Ten candidate epitopes were ultimately selected for building the multi-epitope vaccine (MVSS) against S. suis infections. The ten epitopes of MVSS were all derived from highly conserved, immunogenic, and virulence-associated surface proteins in S. suis . In silico analyses revealed that MVSS was structurally stable and affixed with immune receptors, indicating that it would likely trigger strong immunological reactions in the host. Furthermore, mice models demonstrated that MVSS elicited high titer antibodies and diminished damages in S. suis serotype 2 and Chz infection, significantly reduced sequelae, induced cytokine transcription, and decreased organ bacterial burdens after triple vaccination. Meanwhile, anti-rMVSS serum inhibited five important S. suis serotypes in vitro, exerted beneficial protective effects against S. suis infections and significantly reduced histopathological damage in mice. Given the above, it is possible to develop MVSS as a universal subunit vaccine against multiple serotypes of S. suis infections.

Recasting is the adult rephrasing of a child's immediately preceding utterance. It has been shown to have outstanding effects on promoting language development in autistic children. This study used lag sequential analysis to explore the impact of mothers' conversational styles on the communicative behavior of autistic children when using recasting. This study recruited 30 Chinese autistic children (aged 3-6 years) and their mothers. The utterances of the children and their mothers during 30-min interactions were transcribed, coded, and analyzed. The mothers' conversational styles were determined by the percentages of child-dominant, mother-dominant, and equality styles. The results indicated that mothers' conversational styles were predominantly child-dominant, differing from the expected mother-dominant style that is typical in Eastern cultures and traditions. However, some mothers still demonstrated a significant proportion of mother-dominant style in their conversation, while some exhibited a considerable amount of equality style. Moreover, mothers with a mainly child-dominant style and minimal use of mother-dominant and equality styles used recasting after the child's response, triggering the child to initiate new topics. Mothers with a child-dominant style combined with prominent mother-dominant features implemented untargeted self-recasting, the children did not respond significantly. Mothers with a child-dominant style combined with prominent equality features used recasting after the children responded, initiated, or expanded the conversation, which often facilitated the child's expansion of the conversation. These findings provide suggestions for designing parent-mediated early language interventions for autistic children., (© 2023 International Society for Autism Research and Wiley Periodicals LLC.)

Rationale: 17α-Hydroxylase/17, 20-lyase deficiency (17OHD) is a recessively inherited autosomal disease caused by CYP17A1 gene mutations. It is characterized by failure to synthesize cortisol, adrenal androgens and gonadal steroids. However, it is rare in clinic combining with type 2 diabetes mellitus (T2DM)., Patient Concerns: A 21-year-old woman was transferred to an endocrinology clinic because of paroxysmal paralysis. In addition, she presented with hypertension, primary amenorrhea and lack of pubertal development. Blood evaluation revealed hypokalemia, and a low cortisol level with an increased adrenocorticotropic hormone concentration. The renin activity and testosterone and estrogen levels were suppressed, and the gonadotropin levels were high. CT scan showed bilateral adrenal hyperplasia. Besides, this patient had hyperglycemia, hyperinsulinism and negative diabetes type 1 related antibodies. A homozygous mutation c. 985 to 987delinsAA in exon 6 was found in the patient which caused the missense mutation (p.Y329fs)., Diagnoses: 17α-hydroxylase/17, 20-lyase deficiency combined with T2DM was considered., Interventions: The patient received dexamethasone, estradiol valerate, metformin, amlodipine besylate and D3 calcium carbonate tablets. The doses of dexamethasone was changed according to her blood potassium levels., Outcomes: After treatment, the blood pressure, blood potassium and blood glucose returned to normal range. Besides, she had restored her menstrual cycle., Lessons: For patients with hypertension, hypokalemia and lack of pubertal development, the possibility of 17OHD should be considered. The subsequent treatment would be challenging in patients with combined 17OHD and T2DM, considering the potential contribution of glucocorticoids to diabetic balance and osteoporosis., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Oxygen vacancies play an essential role in gas-sensitive materials, but the intrinsic oxides are poorly controlled and contain low oxygen vacancy concentrations. In this work, we prepared La 0.9 Fe 1- x Sn x O 3 microspheres with high sensitivity and controllability by a simple hydrothermal method, and then, we demonstrated that it has many oxygen ion defects by X-ray photoelectron spectroscopy and electron paramagnetic resonance characterization. The gas sensor exhibited ultrahigh response, specific recognition of formaldehyde gas, and excellent moisture resistance. By comparing the composites with different doping ratios, it was found that the highest catalytic activity was reached when x = 0.75, and the response value of La 0.9 Fe 0.75 Sn 0.25 O 3 hollow microspheres at 200 °C reached 73-10 ppm of formaldehyde, which is 188% higher than that of intrinsic LaFeO 3 hollow microspheres. On the one hand, due to the absence of A-site La 3+ and the replacement of B-site Fe 3+ by Sn 4+ , a large number of oxygen vacancies are induced on the surface and in the interior of the materials; on the other hand, it is also related to the large specific surface area and gas channels caused by the particular structure.

Since 2019, SARS-CoV-2 has evolved rapidly and gained resistance to multiple therapeutics targeting the virus. Development of host-directed antivirals offers broad-spectrum intervention against different variants of concern. Host proteases, TMPRSS2 and CTSL/CTSB cleave the SARS-CoV-2 spike to play a crucial role in the two alternative pathways of viral entry and are characterized as promising pharmacological targets. Here, we identify compounds that show potent inhibition of these proteases and determine their complex structures with their respective targets. Furthermore, we show that applying inhibitors simultaneously that block both entry pathways has a synergistic antiviral effect. Notably, we devise a bispecific compound, 212-148, exhibiting the dual-inhibition ability of both TMPRSS2 and CTSL/CTSB, and demonstrate antiviral activity against various SARS-CoV-2 variants with different viral entry profiles. Our findings offer an alternative approach for the discovery of SARS-CoV-2 antivirals, as well as application for broad-spectrum treatment of viral pathogenic infections with similar entry pathways., (© 2023. The Author(s).)

To address the growing health threat posed by drug-resistant pathogenic microorganisms, the development of novel antimicrobial medications with multiple mechanisms of action is in urgent demand. With traditional antibacterial drug resources challenging to push forward, developing new antibacterial drugs has become a hot spot in biomedical research. In this study, we tested the antibacterial activity of 119 phenanthridine derivatives via the antibacterial assay and obtained 5 candidates. The cytotoxicity assay showed one phenanthridine derivative, HCK20, was safe for mammalian cells below 125 µM. HCK20 was verified to possess significant antibacterial activity to Streptococcus spp., such as Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus suis, Streptococcus dysgalactiae, and Streptococcus equi with MICs ranging from 15 to 60 µM. Furthermore, we found that HCK20 probably achieved its bacterial inhibition by influencing the permeability of bacterial cell walls via interacting with Streptococcal penicillin-binding proteins (PBPs). Our results suggest that this phenanthridine derivative, HCK20, has great potential to become a novel antibacterial agent that can be a potent treatment for streptococcal infections., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Peripheral nerve injuries are common and can cause catastrophic consequences. Although peripheral nerves have notable regenerative capacity, full functional recovery is often challenging due to a number of factors, including age, the type of injury, and delayed healing, resulting in chronic disorders that cause lifelong miseries and significant financial burdens. Fluorescence imaging, among the various techniques, may be the key to overcome these restrictions and improve the prognosis because of its feasibility and dynamic real-time imaging. Intraoperative dynamic fluorescence imaging allows the visualization of the morphological structure of the nerve so that surgeons can reduce the incidence of medically induced injury. Axoplasmic transport-based neuroimaging allows the visualization of the internal transport function of the nerve, facilitating early, objective, and accurate assessment of the degree of regenerative repair, allowing early intervention in patients with poor recovery, thereby improving prognosis. This review briefly discusses peripheral nerve fluorescent dyes that have been reported or could potentially be employed, with a focus on their role in visualizing the nerve's function and anatomy.

The design of chimeric antigen receptors (CAR) significantly enhances the antitumor efficacy of T cells. Although some CAR-T products have been approved by FDA in treating hematological tumors, adoptive immune therapy still faces many difficulties and challenges in the treatment of solid tumors. In this study, we reported a new strategy to treat solid tumors using a natural killer-like T (NKT) cell line which showed strong cytotoxicity to lyse 15 cancer cell lines, safe to normal cells and had low or no Graft-versus-host activity. We thus named it as universal NKT (UNKT). In both direct and indirect 3D tumor-like organ model, UNKT showed efficient tumor-killing properties, indicating that it could penetrate the microenvironment of solid tumors. In mesothelin (MSLN)-positive tumor cells (SKOV-3 and MCF-7), MSLN targeting CAR modified-UNKT cells had enhanced killing potential against MSLN positive ovarian cancer compared with the wild type UNKT, as well as MSLN-CAR-T cells. Compared with CAR-T, Single-cell microarray 32-plex proteomics revealed CAR-UNKT cells express more effector cytokines, such as perforin and granzyme B, and less interleukin-6 after activation. Moreover, our CAR-UNKT cells featured in more multifunctionality than CAR-T cells. CAR-UNKT cells also demonstrated strong antitumor activity in mouse models of ovarian cancer, with the ability to migrate and infiltrate the tumor without inducing immune memory. The fast-in and -out, enhanced and prolonged tumor killing properties of CAR-UNKT suggested a novel cure option of cellular immunotherapy in the treatment of MSLN-positive solid tumors., Competing Interests: Declaration of Competing Interest UNKT and CAR-UNKT have been submitted for patent protection by Abelow Pharmaceuticals Inc., Excepted for GG, HJ, FJ and WX from Abelow Pharmaceuticals Inc., other authors declare no potential conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Locating distinct objects within a thick scattering medium remains a long-standing challenge in the fields of materials science, health, and engineering. Transmission Raman spectroscopy (TRS) with the use of surface-enhanced Raman scattering (SERS) nanoparticles has proven to be an effective approach to detect deep-seated lesions inside thick biological tissues. However, it has not yet been proven to spatially locate deep lesions in three dimensions using optical modalities. Herein, we present the concept of tomographic TRS and report its successful use for accurately locating SERS nanoparticles in elongated rod-like thick tissues. Our work starts with theoretical simulations of Raman photon propagation in tissues. We discovered a linear relationship between the Raman spectral peak ratio and propagation distance of Raman photons in tissues, allowing us to predict the location of lesions tagged by SERS NPs. Based on this, we propose a two-step tomographic TRS strategy, which includes axial scanning and ring scanning. We demonstrate the robustness of our approach using ex vivo thick tissue (4.5 cm in thickness) and locate an embedded SERS phantom lesion, with a ring scanning step of 10-30°. We successfully locate multiple SERS phantom lesions in the ex vivo porcine muscle stack with high accuracy (absolute error of <2 mm). Our method is rapid, efficient, and of low cost compared to current tomographic medical imaging techniques. This work advances Raman techniques for three-dimensional positioning and offers new insights toward practical diagnosis applications.

During the ongoing pandemic, providing treatment consisting of effective, low-cost oral antiviral drugs at an early stage of SARS-CoV-2 infection has been a priority for controlling COVID-19. Although Paxlovid and molnupiravir have received emergency approval from the FDA, some side effect concerns have emerged, and the possible oral agents are still limited, resulting in optimized drug development becoming an urgent requirement. An oral remdesivir derivative, VV116, has been reported to have promising antiviral effects against SARS-CoV-2 and positive therapeutic outcomes in clinical trials. However, whether VV116 has broad-spectrum anti-coronavirus activity and potential synergy with other drugs is not clear. Here, we uncovered the broad-spectrum antiviral potency of VV116 against SARS-CoV-2 variants of concern (VOCs), HCoV-OC43, and HCoV-229E in various cell lines. In vitro drug combination screening targeted RdRp and proteinase, highlighting the synergistic effect of VV116 and nirmatrelvir on HCoV-OC43 and SARS-CoV-2. When co-administrated with ritonavir, the combination of VV116 and nirmatrelvir showed significantly enhanced antiviral potency with noninteracting pharmacokinetic properties in mice. Our findings will facilitate clinical treatment with VV116 or VV116+nirmatrelvir combination to fight coronavirus infection., (© 2023. West China Hospital, Sichuan University.)

Uric acid, the end product of purine degradation, causes hyperuricemia and gout, afflicting hundreds of millions of people. The debilitating effects of gout are exacerbated by dietary purine intake, and thus a potential therapeutic strategy is to enhance purine degradation in the gut microbiome. Aerobic purine degradation involves oxidative dearomatization of uric acid catalyzed by the O 2 -dependent uricase. The enzymes involved in purine degradation in strictly anaerobic bacteria remain unknown. Here we report the identification and characterization of these enzymes, which include four hydrolases belonging to different enzyme families, and a prenyl-flavin mononucleotide-dependent decarboxylase. Introduction of the first two hydrolases to Escherichia coli Nissle 1917 enabled its anaerobic growth on xanthine as the sole nitrogen source. Oral supplementation of these engineered probiotics ameliorated hyperuricemia in a Drosophila melanogaster model, including the formation of renal uric acid stones and a shortened lifespan, providing a route toward the development of purinolytic probiotics., Competing Interests: Declaration of interests Two patent applications related to this work have been filed: WO2021/143725, xanthine amide hydrolase and use thereof (Y. Zhang, P.L., Y.T., Y.H., and D.L.); WO2021/143724, 4-ureido-5-carboxyl-imidazole-amide hydrolase and use thereof (Y. Zhang, P.L., Y.T., Y.H., and D.L.)., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Patients with ALI (acute lung injury)/ARDS (acute respiratory distress syndrome) are often septic and with poor prognosis, which leads to a high mortality rate of 25-40%. Despite the advances in medicine, there are no effective pharmacological therapies for ALI/ARDS due to the short systemic circulation and poor specificity in the lungs. To address this problem, we prepared TP-loaded nanoparticles (TP-NPs) through the emulsification-and-evaporation method, and then the platelet membrane vesicles were extracted and coated onto the surface of the NPs to constitute the biomimetic PM@TP-NPs. In a LPS-induced ALI mouse model, PM@TP-NPs showed good biocompatibility and biosafety, which was evidenced by no significant toxic effect on cell viability and no hemolysis of red blood cells. In ALI mice, the PM@TP-NPs showed favorable anti-inflammation and enhanced therapeutic activity of TPs compared to the free drug. Administration of PM@TP-NPs effectively inhibited lung vascular injury, evidenced by the decreased lung vascular permeability, reduced pro-inflammatory cytokine burden, evidenced by decreased inflammatory cell (macrophages, neutrophils, etc .) infiltration in the bronchoalveolar lavage fluid (BALF) and lung tissues, and inhibited the secretion of pro-inflammatory cytokines and NLRP3 inflammasome activation. ALI/ARDS is defined by damage to the alveolar epithelium and endothelium; thus, effective intervention targeting pulmonary vascular endothelial cells (VECs) is crucial for the treatment of respiratory diseases. For further determination of the targeting of PM cloaked NPs, healthy mice were also administered with the same NPs. Interestingly, the PM cloaked NPs only showed highly efficient targeting to the inflamed lungs and VECs, but no accumulation in healthy lungs and VECs. The data demonstrated that this biomimetic nanoplatform could be used as a potential strategy for personalized therapies in the treatment of inflammatory diseases, such as ALI/ARDS, and even COVID-19-associated pneumonia.

A series of peptidomimetic compounds containing benzothiazolyl ketone and [2.2.1] azabicyclic ring was designed, synthesized and evaluated in the hope of obtaining potent oral 3CL pro inhibitors with improved pharmacokinetic properties. Among the target compounds, 11b had the best enzymatic potency (IC 50  = 0.110 μM) and 11e had the best microsomal stability (t 1/2  > 120 min) and good enzyme activity (IC 50  = 0.868 μM). Therefore, compounds 11b and 11e were chosen for further evaluation of pharmacokinetics in ICR mice. The results exhibited that the AUC (0-t) of 11e was 5143 h*ng/mL following single-dose oral administration of 20 mg/kg, and the F was 67.98%. Further structural modification was made to obtain compounds 11g-11j based on 11e. Among them, 11j exhibited the best enzyme inhibition activity against SARS-CoV-2 3CL pro (IC 50  = 1.646 μM), the AUC (0-t) was 32473 h*ng/mL (20 mg/kg, po), and the F was 48.1%. In addition, 11j displayed significant anti-SARS-CoV-2 activity (EC 50  = 0.18 μM) and low cytotoxicity (CC 50  > 50 μM) in Vero E6 cells. All of the above results suggested that compound 11j was a promising lead compound in the development of oral 3CL pro inhibitors and deserved further research., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Low back pain (LBP) is a leading cause of labour loss and disability worldwide, and it also imposes a severe economic burden on patients and society. Among symptomatic LBP, approximately 40% is caused by intervertebral disc degeneration (IDD). IDD is the pathological basis of many spinal degenerative diseases such as disc herniation and spinal stenosis. Currently, the therapeutic approaches for IDD mainly include conservative treatment and surgical treatment, neither of which can solve the problem from the root by terminating the degenerative process of the intervertebral disc (IVD). Therefore, further exploring the pathogenic mechanisms of IDD and adopting targeted therapeutic strategies is one of the current research hotspots. Among the complex pathophysiological processes and pathogenic mechanisms of IDD, oxidative stress is considered as the main pathogenic factor. The delicate balance between reactive oxygen species (ROS) and antioxidants is essential for maintaining the normal function and survival of IVD cells. Excessive ROS levels can cause damage to macromolecules such as nucleic acids, lipids, and proteins of cells, affect normal cellular activities and functions, and ultimately lead to cell senescence or death. This review discusses the potential role of oxidative stress in IDD to further understand the pathophysiological processes and pathogenic mechanisms of IDD and provides potential therapeutic strategies for the treatment of IDD., (© 2023 The Authors. Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.)

Memory is a fundamental brain function that can be affected by a variety of external factors including environmental pollutants. One of these pollutants is methyl vinyl ketone (MVK), a hazardous substance found in cigarettes, industrial wastes, and car exhaust. Humans can be exposed to MVK under many circumstances; however, it is unclear whether MVK affects higher-order brain functions such as memory. Here, we examined the memory performances of mice receiving systemic MVK administration. We found that 1 mg/kg of MVK impaired spatial memory. We also showed that 1 mg/kg MVK activated glial cells and altered glial functions in several subregions of the hippocampus, a brain region involved in learning and memory. These results suggest that MVK induces memory deficits and activates glial cells in hippocampal subregions., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Sato et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)