Enhancing m^(6)A modification in the motor cortex facilitates corticospinal tract remodeling after spinal cord injury

Spinal cord injury typically causes corticospinal tract disruption. Although the disrupted corticospinal tract can self-regenerate to a certain degree, the underlying mechanism of this process is still unclear. N6-methyladenosine(m^(6)A) modifications are the most common form of epigenetic regulation at the RNA level and play an essential role in biological processes. However, whether m^(6)A modifications participate in corticospinal tract regeneration after spinal cord injury remains unknown. We found that expression of methyltransferase 14 protein(METTL14) in the locomotor cortex was high after spinal cord injury and accompanied by elevated m^(6)A levels. Knockdown of Mettl14 in the locomotor cortex was not favorable for corticospinal tract regeneration and neurological recovery after spinal cord injury. Through bioinformatics analysis and methylated RNA immunoprecipitation-quantitative polymerase chain reaction, we found that METTL14 regulated Trib2 expression in an m^(6)A-regulated manner, thereby activating the mitogen-activated protein kinase pathway and promoting corticospinal tract regeneration. Finally, we administered syringin, a stabilizer of METTL14, using molecular docking. Results confirmed that syringin can promote corticospinal tract regeneration and facilitate neurological recovery by stabilizing METTL14. Findings from this study reveal that m^(6)A modification is involved in the regulation of corticospinal tract regeneration after spinal cord injury.

Kdm6a-CNN1 axis orchestrates epigenetic control of traumainduced spinal cord microvascular endothelial cell senescence to balance neuroinflammation for improved neurological repair

Cellular senescence assumes pivotal roles in various diseases through the secretion of proinflammatory factors.Despite extensive investigations into vascular senescence associated with aging and degenerative diseases,the molecular mechanisms governing microvascular endothelial cell senescence induced by traumatic stress,particularly its involvement in senescence-induced inflammation,remain insufficiently elucidated.In this study,we present a comprehensive demonstration and characterization of microvascular endothelial cell senescence induced by spinal cord injury(SCI).Lysine demethylase 6A(Kdm6a),commonly known as UTX,emerges as a crucial regulator of cell senescence in injured spinal cord microvascular endothelial cells(SCMECs).Upregulation of UTX induces senescence in SCMECs,leading to an amplified release of proinflammatory factors,specifically the senescenceassociated secretory phenotype(SASP)components,thereby modulating the inflammatory microenvironment.Conversely,the deletion of UTX in endothelial cells shields SCMECs against senescence,mitigates the release of proinflammatory SASP factors,and promotes neurological functional recovery after SCI.UTX forms an epigenetic regulatory axis by binding to calponin 1(CNN1),orchestrating trauma-induced SCMECs senescence and SASP secretion,thereby influencing neuroinflammation and neurological functional repair.Furthermore,local delivery of a senolytic drug reduces senescent SCMECs and suppresses proinflammatory SASP secretion,reinstating a local regenerative microenvironment and enhancing functional repair after SCI.In conclusion,targeting the UTX-CNN1 epigenetic axis to prevent trauma-induced SCMECs senescence holds the potential to inhibit SASP secretion,alleviate neuroinflammation,and provide a novel treatment strategy for SCI repair.

Local delivery of EGFR+NSCs-derived exosomes promotes neural regeneration post spinal cord injury via miR-34a-5p/HDAC6 pathway

Spinal cord injury(SCI)causes severe axon damage,usually leading to permanent paraparesis,which still lacks effective regenerative therapy.Recent studies have suggested that exosomes derived from neural stem cells(NSCs)may hold promise as attractive candidates for SCI treatment.Epidermal Growth Factor Receptor positive NSC(EGFR+NSC)is a subpopulation of endogenous NSCs,showing strong regenerative capability in central nervous system disease.In the current study,we isolated exosomes from the EGFR+NSCs(EGFR+NSCs-Exos)and discovered that local delivery of EGFR+NSCs-Exos can effectively promote neurite regrowth in the injury site of spinal cord-injured mice and improve their neurological function recovery.Using the miRNA-seq,we firstly characterized the microRNAs(miRNAs)cargo of EGFR+NSCs-Exos and identified miR-34a-5p which was highly enriched in EGFR+NSCs derived exosomes.We further interpreted that exosomal miR-34a-5p could be transferred to neurons and inhibit the HDAC6 expression by directly binding to its mRNA,contributing to microtubule stabilization and autophagy induction for aiding SCI repair.Overall,our research demonstrated a novel therapeutic approach to improving neurological functional recovery by using exosomes secreted from a subpopulation of endogenous NSCs and providing a precise cell-free treatment strategy for SCI repair.

M6PR interacts with the HA2 subunit of influenza A virus to facilitate the fusion of viral and endosomal membranes

Influenza A virus(IAV) commandeers numerous host cellular factors for successful replication. However, very few host factors have been revealed to be involved in the fusion of viral envelope and late endosomal membranes. In this study, we identified cation-dependent mannose-6-phosphate receptor(M6PR) as a crucial host factor for the replication of IAV. We found that siRNA knockdown of M6PR expression significantly reduced the growth titers of different subtypes of IAV, and that the inhibitory effect of M6PR siRNA treatment on IAV growth was overcome by the complement of exogenously expressed M6PR. When A549 cells were treated with siRNA targeting M6PR,the nuclear accumulation of viral nucleoprotein(NP) was dramatically inhibited at early timepoints post-infection, indicating that M6PR engages in the early stage of the IAV replication cycle. By investigating the role of M6PR in the individual entry and post-entry steps of IAV replication, we found that the downregulation of M6PR expression had no effect on attachment, internalization, early endosome trafficking,or late endosome acidification. However, we found that M6PR expression was critical for the fusion of viral envelope and late endosomal membranes. Of note, M6PR interacted with the hemagglutinin(HA) protein of IAV, and further studies showed that the lumenal domain of M6PR and the ectodomain of HA2 mediated the interaction and directly promoted the fusion of the viral and late endosomal membranes,thereby facilitating IAV replication. Together, our findings highlight the importance of the M6PR–HA interaction in the fusion of viral and late endosomal membranes during IAV replication.

Discussion on the Misunderstandings of Mental Health Education in Colleges and Universities and the Improvement

Colleges and universities are the educational institutions of training young students. The reform of the modem higher education system requires the personnel training in colleges and universities to lay a stress on the diversified development, so that the traditional single professional course education can be changed. Mental health has a close tie with the personal development trend of each student in colleges and universities, and also developing mental health education is one of the most important parts in higher education. For a long time, colleges and universities always adhere to the personnel-based educational idea and attach high importance to the work of professional course education, but fail to provide enough importance for guiding the detailed mental health of students. Thus, the mental health education in colleges and universities is misunderstood in many aspects, and this is studied in this paper.

The on-chip thermoelectric cooler:advances,applications and challenges

With the development of 5G technology and increasing chip integration,traditional active cooling methods struggle to meet the growing thermal demands of chips.Thermoelectric coolers(TECs)have garnered great attention due to their rapid response,significant cooling differentials,strong compatibility,high stability and controllable device dimensions.In this review,starting from the fundamental principles of thermoelectric cooling and device design,high-performance thermoelectric cooling materials are summarized,and the progress of advanced on-chip TECs is comprehensively reviewed.Finally,the paper outlines the challenges and opportunities in TEC design,performance and applications,laying great emphasis on the critical role of thermoelectric cooling in addressing the evolving thermal management requirements in the era of emerging chip technologies.

Leveraging the One Health concept for arsenic sustainability

Arsenic(As)is a naturally occurring chemical element widely distributed in the Earth's crust.Human activities have significantly altered As presence in the environment,posing significant threats to the biota as well as human health.The environmental fates and adverse outcomes of As of various species have been extensively studied in the past few decades.It is imperative to summarize these advances as a whole to provide more profound insights into the As cycle for sustainable development.Embracing the One Health concept,we systematically reviewed previous studies in this work and explored the following three fundamental questions,i.e.,what the trends and associated changes are in As contamination,how living organisms interact and cope with As contamination,and most importantly what to do to achieve a sustainable future with As.By focusing on one critical question in each section,this review aims to provide a full picture of the complexity of environmental As.To tackle the significant research challenges and gaps in As pollution and mitigation,we further proposed a One Health framework with potential coping strategies,guiding a coordinated agenda on dealing with legacy As in the environment and ensuring a sustainable As future.

Vaccination of poultry successfully eliminated human infection with H7N9 virus in China

The H7 N9 viruses that emerged in China in 2013 were nonpathogenic in chickens but mutated to a highly pathogenic form in early 2017 and caused severe disease outbreaks in chickens. The H7 N9 influenza viruses have caused five waves of human infection, with almost half of the total number of human cases(766 of 1,567) being reported in the fifth wave, raising concerns that even more human infections could occur in the sixth wave. In September 2017, an H5/H7 bivalent inactivated vaccine for chickens was introduced, and the H7 N9 virus isolation rate in poultry dropped by 93.3% after vaccination. More importantly,only three H7 N9 human cases were reported between October 1, 2017 and September 30, 2018, indicating that vaccination of poultry successfully eliminated human infection with H7 N9 virus. These facts emphasize that active control of animal disease is extremely important for zoonosis control and human health protection.

Influenza A virus use of BinCARD1 to facilitate the binding of viral NP to importinα7 is counteracted by TBK1-p62 axis-mediated autophagy

As a major component of the viral ribonucleoprotein(vRNP)complex in influenza A virus(IAV),nucleoprotein(NP)interacts with isoforms of importinαfamily members,leading to the import of itself and vRNP complex into the nucleus,a process pivotal in the replication cycle of IAV.In this study,we found that BinCARD1,an isoform of Bcl10-interacting protein with CARD(BinCARD),was leveraged by IAV for efficient viral replication.BinCARD1 promoted the nuclear import of the vRNP complex and newly synthesized NP and thus enhanced vRNP complex activity.Moreover,we found that BinCARD1 interacted with NP to promote NP binding to importinα7,an adaptor in the host nuclear import pathway.However,we also found that BinCARD1 promoted RIG-I-mediated innate immune signaling by mediating Lys63-linked polyubiquitination of TRAF3,and that TBK1 appeared to degrade BinCARD1.We showed that BinCARD1 was polyubiquitinated at residue K103 through a Lys63 linkage,which was recognized by the TBK1-p62 axis for autophagic degradation.Overall,our data demonstrate that IAV leverages BinCARD1 as an important host factor that promotes viral replication,and two mechanisms in the host defense system are triggered—innate immune signaling and autophagic degradation—to mitigate the promoting effect of BinCARD1 on the life cycle of IAV.

Continued evolution of the Eurasian avian-like H1N1 swine influenza viruses in China

Animal influenza viruses continue to pose a threat to human public health. The Eurasian avian-like H1N1(EA H1N1) viruses are widespread in pigs throughout Europe and China and have caused human infections in several countries, indicating their pandemic potential. To carefully monitor the evolution of the EA H1N1 viruses in nature, we collected nasal swabs from 103,110pigs in 22 provinces in China between October 2013 and December 2019, and isolated 855 EA H1N1 viruses. Genomic analysis of 319 representative viruses revealed that these EA H1N1 viruses formed eight different genotypes through reassortment with viruses of other lineages circulating in humans and pigs, and two of these genotypes(G4 and G5) were widely distributed in pigs.Animal studies indicated that some strains have become highly pathogenic in mice and highly transmissible in ferrets via respiratory droplets. Moreover, two-thirds of the EA H1N1 viruses reacted poorly with ferret serum antibodies induced by the currently used H1N1 human influenza vaccine, suggesting that existing immunity may not prevent the transmission of the EA H1N1 viruses in humans. Our study reveals the evolution and pandemic potential of EA H1N1 viruses and provides important insights for future pandemic preparedness.

Simultaneous 3D Visualization of the Microvascular and Neural Network in Mouse Spinal Cord Using Synchrotron Radiation Micro-Computed Tomography

Effective methods for visualizing neurovascular morphology are essential for understanding the normal spinal cord and the morphological alterations associated with diseases.However,ideal techniques for simultaneously imaging neurovascular structure in a broad region of a specimen are still lacking.In this study,we combined Golgi staining with angiography and synchrotron radiation micro-computed tomography(SRμCT)to visualize the 3D neurovascular network in the mouse spinal cord.Using our method,the 3D neurons,nerve fibers,and vasculature in a broad region could be visualized in the same image at cellular resolution without destructive sectioning.Besides,we found that the 3D morphology of neurons,nerve fiber tracts,and vasculature visualized by SRjiCT were highly consistent with that visualized using the histological method.Moreover,the 3D neurovascular structure could be quantitatively evaluated by the combined methodology.The method shown here will be useful in fundamental neuroscience studies.

Generation and application of replication-competent Venus-expressing H5N1,H7N9,and H9N2 influenza A viruses

The generation and application of replication-competent influenza A virus （IAV） expressing a reporter gene represent a valuable tool to elucidate the mechanism of viral pathogenesis and establish new coun- termeasures to combat the threat of influenza. Here, replication-competent 1AVs with a neuraminidase （NA） segment harboring a fluorescent reporter protein, Venus, were generated in the background of H5N1, H7N9, and H9N2 influenza viruses, the three subtypes of viruses with imminent pandemic poten- tial. All three reporter viruses maintained virion morphology, replicated with similar or slightly reduced titers relative to their parental viruses, and stably expressed the fluorescent signal for at least two pas- sages in embryonated chicken eggs. As a proof of concept, we demonstrated that these reporter viruses, used in combination with a high-content imaging system, can serve as a convenient and rapid tool for the screening of antivirals and host factors involved in the virus life cycle. Moreover. the reporter viruses demonstrated similar growth properties and tissue tropism as their parental viruses in mice, among which the HTN9 NA-Venus virus could potentially be used in ex vivo studies to better understand H7N9 pathogenesis or to develop novel therapeutics.

Functional analysis of zona pellucida domain protein Dusky in Tribolium castaneum

The zona pellucida domain protein Dusky(Dy)plays a vital role in wing morphogenesis in insects,but little information on its function has been reported.In this study,we found that dy regulated wing cell size,larval and pupal duration,and the metabolism of amino acid and 20-hydroxyecdysone in Tribolium castaneum.Using RNA-seq,413 differentially expressed genes were identified between physiological buffer-injected and dy-double-stranded RNA-treated larvae,including 88 downregulated genes and 325 upregulated genes.Among these genes,dy knockdown increased CYP18A1 expression to elevate the 26-hydroxylation of 20-hydroxyecdysone,which ultimately led to growth defects in wing cells.Silencing of dy upregulated the transcription of genes encoding tyrosine aminotransferase,4-hydroxyphenylpyruvate dioxygenase,homogentisate 1,2-dioxygenase,and Pale to promote the catabolism of tyrosine and phenylalanine,which eventually reduced amino acid content.Furthermore,dy knockdown upregulated 4E-BP expression,and 4E-BP silencing partially phenocopied dy RNA interference-mediated wing morphogenesis.These results suggest that Dy controls 20-hydroxyecdysone and amino acid metabolism to regulate wing morphogenesis in the insect.

Stimuli-responsive combination therapy of cisplatin and Nrf2 siRNA for improving antitumor treatment of osteosarcoma

Cisplatin is a widely applied therapeutics for the treatment of osteosarcoma.However,its clinical applications have been hindered due to low efficacy and bioavailability,and particularly frequent emergence of reactive oxygen species(ROS)-decrease induced drug resistance.The transcription factor NF-E2-related factor 2(Nrf2)is increased in cancer patients and induces poor outcome in osteosarcoma treatment,making it a novel target to improve the efficacy of chemotherapy.Herein,a hyaluronidase-responsive multi-layer liposome(HLCN)for co-delivery of cisplatin and Nrf2 siRNA(siNrf2)is developed.It is composed of Vpr52-96 modified liposome covered with hyaluronic acid(HA).HLCN selectively accumulates in osteosarcoma by targeting tumor-specific CD44,and can be degraded by endosomal hyaluronidase to generate cationic liposome,which promotes the endosomal escape of Vpr52-96,cisplatin and siNrf2.HLCN can effectively decrease Nrf2 level,promote ROS generation,activate itochondrial apoptotic pathway,and consequently enhance anticancer efficacy of cisplatin.Particularly,HLCN shows high cytotoxicity to osteosarcoma cells with an IC50 value of about 1µM,which is four-fold lower than liposomal cisplatin(IC504µM),indicating that Nrf2 silence can significantly improve cisplatin sensitivity in cancer cells.Importantly,HLCN can remarkably inhibit tumor growth in the xenograft osteosarcoma mice with minimal systemic adverse effects.Therefore,this novel stimuli-responsive combination therapy of cisplatin and siNrf2 provides a promising strategy for the treatment of osteosarcoma.

Application of 5G telesurgery in urology

The fifth generation of mobile communication technology(5G technology)features large system capacity,fast data transmission rate,support for large-scale device connection,low latency,and high reliability.With the development and popularization of 5G technology,it is also widely used in medicine.In recent years,5G telesurgery has been paid attention to and made continuous progress,and the research related to its combination with urology has also made significant achievements.We collect the combination of 5G technology and urology improves the uneven distribution of medical resources,provides timely,highquality remote surgical interventions for urology patients,reduces the financial burden on patients,surgical complications,and the difficulty of accessing medical care from a distance,and brings new opportunities for medical development.

Embracing digital mindsets to ensure a sustainable future

The 19th Asian Games astounded global audiences with an opening spectacle that showcased stunning digital fireworks(International Olympic Committee,2021;Zhe,2023).The groundbreaking display was brought to life through virtual reality(VR)and augmented reality(AR)technologies.It sets a pioneering example to replace conventional fireworks in major international events as well as in other large-scale entertainment activities,marking a historic milestone in the pursuit of a sustainable and healthy future.

Protect the oceans from Japan's radioisotope dumping

In August 2023,Japan started to dump its 1.3 million tons of radioactive wastewater into the oceans[1,2].Most radioisotopes are claimed to be removed from the wastewater except tritium,which needs further dilution before discharge.However,this dilution does not effectively remove any tritium from the wastewater but serves as a measure to bring its abnormally high concentration down to meet emission standards.The most worrisome situation is that many more bioaccumulative long-lived radioisotopes(BLLRs),such as carbon-14 and cobalt-60,slip through the treatment process.There are attempts to reduce the concentrations of BLLRs via repurification to meet the regulatory standards[3];however,even low levels of these BLLRs can undergo biomagnification of up to 50,000 folds in marine fish species[4].

Genetic and biological characteristics of the globally circulating H5N8 avian influenza viruses and the protective efficacy offered by the poultry vaccine currently used in China

The H5N8 avian influenza viruses have been widely circulating in wild birds and are responsible for the loss of over 33 million domestic poultry in Europe, Russia, Middle East, and Asia since January 2020. To monitor the invasion and spread of the H5N8 virus in China, we performed active surveillance by analyzing 317 wild bird samples and swab samples collected from 41,172 poultry all over the country. We isolated 22 H5N8 viruses from wild birds and 14 H5N8 viruses from waterfowls. Genetic analysis indicated that the 36 viruses formed two different genotypes: one genotype viruses were widely detected from different wild birds and domestic waterfowls;the other genotype was isolated from a whopper swan. We further revealed the origin and spatiotemporal spread of these two distinct H5N8 virus genotypes in 2020 and 2021. Animal studies indicated that the H5N8 isolates are highly pathogenic to chickens, mildly pathogenic in ducks, but have distinct pathotypes in mice. Moreover, we found that vaccinated poultry in China could be completely protected against H5N8 virus challenge. Given that the H5N8 viruses are likely to continue to spread in wild birds, vaccination of poultry is highly recommended in high-risk countries to prevent H5N8 avian influenza.

TRIM35 mediates protection against influenza infection by activating TRAF3 and degrading viral PB2

Tripartite motif(TRIM)family proteins are important effectors of innate immunity against viral infections.Here we identified TRIM35 as a regulator of TRAF3 activation.Deficiency in or inhibition of TRIM35 suppressed the production of type I interferon(IFN)in response to viral infection.777m35-deficient mice were more susceptible to influenza A virus(IAV)infection than were wild-type mice.TRIM35 promoted the RIG-Imediated signaling by catalyzing Lys63-linked polyubiquitination of TRAF3 and the subsequent formation of a signaling complex with VISA and TBK1.IAV PB2 polymerase countered the innate antiviral immune response by impeding the Lys63-linked polyubiquitination and activation of TRAF3.TRIM35 mediated Lys48-linked polyubiquitination and proteasomal degradation of IAV PB2,thereby antagonizing its suppression of TRAF3 activation.Our in vitro and in vivo findings thus reveal novel roles of TRIM35,through catalyzing Lys63-or Lys48-linked polyubiquitination,in RIG-I antiviral immunity and mechanism of defense against IAV infection.

Vinyl chloride accident unleashes a toxic legacy

A railroad accident on February 3,2023,led to the release and combustion of 115,580 gallons,equivalent to over 437,000 L,of vinyl chloride monomer(VCM)in East Palestine,Ohio[1].This monomer is used in polyvinyl chloride(PVC)production,and its burning produces additional toxins such as hydrochloric acid and lethal phosgene,known as a notorious chemical weapon during World War I[2].Acute exposure to these chemicals causes immediate adverse effects on local ecosystems,including the deaths of wild and farmed animals and pets.