Modified parameterization for near-inertial waves

The near-inertial waves(NIWs)are important for energy cascade in the ocean.They are usually significantly reinforced by strong winds,such as typhoon.Due to relatively coarse resolutions in contemporary climate models,NIWs and associated ocean mixing need to be parameterized.In this study,a parameterization for NIWs proposed by Jochum in 2013(J13 scheme),which has been widely used,is compared with the observations in the South China Sea,and the observations are treated as model outputs.Under normal conditions,the J13 scheme performs well.However,there are noticeable discrepancies between the J13 scheme and observations during typhoon.During Typhoon Kalmaegi in 2014,the inferred value of the boundary layer is deeper in the J13 scheme due to the weak near-inertial velocity shear in the vertical.After typhoon,the spreading of NIWs beneath the upper boundary layer is much faster than the theoretical prediction of inertial gravity waves,and this fast process is not rendered well by the J13 scheme.In addition,below the boundary layer,NIWs and associated diapycnal mixing last longer than the direct impacts of typhoon on the sea surface.Since the energy dissipation and diapycnal mixing below the boundary layer are bounded to the surface winds in the J13 scheme,the prolonged influences of typhoon via NIWs in the ocean interior are missing in this scheme.Based on current examination,modifications to the J13 scheme are proposed,and the modified version can reduce the discrepancies in the temporal and vertical structures of diapycnal mixing.

Colony-stimulating factor-1 receptor inhibition combined with paclitaxel exerts effective antitumor effects in the treatment of ovarian cancer

Ovarian cancer is the tumor with the highest mortality among gynecological malig-nancies.Studies have confirmed that paclitaxel chemoresistance is associated with increased infiltration of tumor-associated macrophages(TAMs)in the microenvironment.Colony-stimu-lating factor 1(CSF-1)receptor(CSF-1R)plays a key role in regulating the number and differ-entiation of macrophages in certain solid tumors.There are few reports on the effects of targeted inhibition of CSF-1R in combination with chemotherapy on ovarian cancer and the tu-mor microenvironment.Here,we explored the antitumor efficacy and possible mechanisms of the CSF-1R inhibitor pexidartinib(PLX3397)when combined with the first-line chemothera-peutic agent paclitaxel in the treatment of ovarian cancer.We found that CSF-1R is highly ex-pressed in ovarian cancer cells and correlates with poor prognosis.Treatment by PLX3397 in combination with paclitaxel significantly inhibited the growth of ovarian cancer both in vitro and in vivo.Blockade of CSF-1R altered the macrophage phenotype and reprogrammed the immunosuppressive cell population in the tumor microenvironment.

Low levels of neutralizing antibodies against XBB Omicron subvariants after BA.5 infection

The COVID-19 response strategies in Chinese mainland were recently adjusted due to the reduced pathogenicity and enhanced infectivity of Omicron subvariants.In Chengdu,China,an infection wave was predominantly induced by the BA.5 subvariant.It is crucial to determine whether the hybrid anti-SARS-CoV-2 immunity following BA.5 infection.

Tripterin liposome relieves severe acute respiratory syndrome as a potent COVID-19 treatment

For coronavirus disease 2019(COVID-19),caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),15–30%of patients are likely to develop COVID-19-related acute respiratory distress syndrome(ARDS).There are still few effective and well-understood therapies available.Novel variants and short-lasting immunity are posing challenges to vaccine efficacy,so finding antiviral and antiinflammatory treatments remains crucial.Here,tripterin(TP),a traditional Chinese medicine,was encapsulated into liposome(TP lipo)to investigate its antiviral and antiinflammatory effects in severe COVID-19.By using two severe COVID-19 models in human ACE2-transgenic(hACE2)mice,an analysis of TP lipo’s effects on pulmonary immune responses was conducted.Pulmonary pathological alterations and viral burden were reduced by TP lipo treatment.TP lipo inhibits SARS-CoV-2 replication and hyperinflammation in infected cells and mice,two crucial events in severe COVID-19 pathophysiology,it is a promising drug candidate to treat SARS-CoV-2-induced ARDS.

Applications of genome editing technology in the targeted therapy of human diseases:mechanisms,advances and prospects

Based on engineered or bacterial nucleases,the development of genome editing technologies has opened up the possibility of directly targeting and modifying genomic sequences in almost all eukaryotic cells.Genome editing has extended our ability to elucidate the contribution of genetics to disease by promoting the creation of more accurate cellular and animal models of pathological processes and has begun to show extraordinary potential in a variety of fields,ranging from basic research to applied biotechnology and biomedical research.Recent progress in developing programmable nucleases,such as zinc-finger nucleases(ZFNs),transcription activator-like effector nucleases(TALENs)and clustered regularly interspaced short palindromic repeat(CRISPR)–Cas-associated nucleases,has greatly expedited the progress of gene editing from concept to clinical practice.Here,we review recent advances of the three major genome editing technologies(ZFNs,TALENs,and CRISPR/Cas9)and discuss the applications of their derivative reagents as gene editing tools in various human diseases and potential future therapies,focusing on eukaryotic cells and animal models.Finally,we provide an overview of the clinical trials applying genome editing platforms for disease treatment and some of the challenges in the implementation of this technology.

Spontaneous apoptosis of cells in therapeutic stem cell preparation exert immunomodulatory effects through release of phosphatidylserine

Mesenchymal stem cell(MSC)-mediated immunomodulation has been harnessed for the treatment of human diseases,but its underlying mechanism has not been fully understood.Dead cells,including apoptotic cells have immunomodulatory properties.It has been repeatedly reported that the proportion of nonviable MSCs in a MSC therapeutic preparation varied from 5-50%in the ongoing clinical trials.It is conceivable that the nonviable cells in a MSC therapeutic preparation may play a role in the therapeutic effects of MSCs.We found that the MSC therapeutic preparation in the present study had about 5%dead MSCs(DMSCs),characterized by apoptotic cells.Namely,1×10^(6) MSCs in the preparation contained about 5×10^(4) DMSCs.We found that the treatment with even 5×10^(4) DMSCs alone had the equal therapeutic effects as with 1×10^(6) MSCs.This protective effect of the dead MSCs alone was confirmed in four mouse models,including concanavalin A(ConA)-and carbon tetrachloride(CCI4)-induced acute liver injury,LPS-induced lung injury and spinal cord injury.We also found that the infused MSCs died by apoptosis in vivo.Furthermore,the therapeutic effect was attributed to the elevated level of phosphatidylserine(PS)upon the injection of MSCs or DMSCs.The direct administration of PS liposomes(PSLs)mimic apoptotic cell fragments also exerted the protective effects as MSCs and DMSCs.The Mer tyrosine kinase(MerTK)deficiency or the knockout of chemokine receptor C-C motif chemokine receptor 2(CCR2)reversed these protective effects of MSCs or DMSCs.These results revealed that DMSCs alone in the therapeutic stem cell preparation or the apoptotic cells induced in vivo may exert the same immunomodulatory property as the'living MSCs preparation"through releasing PS,which was further recognized by MerTK and participated in modulating immune cells.

Recent progress in targeted delivery vectors based on biomimetic nanoparticles

Over the past decades,great interest has been given to biomimetic nanoparticles(BNPs)since the rise of targeted drug delivery systems and biomimetic nanotechnology.Biological vectors including cell membranes,extracellular vesicles(EVs),and viruses are considered promising candidates for targeted delivery owing to their biocompatibility and biodegradability.BNPs,the integration of biological vectors and functional agents,are anticipated to load cargos or camouflage synthetic nanoparticles to achieve targeted delivery.Despite their excellent intrinsic properties,natural vectors are deliberately modified to endow multiple functions such as good permeability,improved loading capability,and high specificity.Through structural modification and transformation of the vectors,they are pervasively utilized as more effective vehicles that can deliver contrast agents,chemotherapy drugs,nucleic acids,and genes to target sites for refractory disease therapy.This review summarizes recent adva门ces in targeted delivery vectors based on cell membranes,EVs,and viruses,highlighting the potential applications of BNPs in the fields of biomedical imaging and therapy industry,as well as discussing the possibility of clinical translation and exploitation trend of these BNPs.

Neurological complications and infection mechanism of SARS-CoV-2

Currently,SARS-CoV-2 has caused a global pandemic and threatened many lives.Although SARS-CoV-2 mainly causes respiratory diseases,growing data indicate that SARS-CoV-2 can also invade the central nervous system(CNS)and peripheral nervous system(PNS)causing multiple neurological diseases,such as encephalitis,encephalopathy,Guillain-Barrésyndrome,meningitis,and skeletal muscular symptoms.Despite the increasing incidences of clinical neurological complications of SARS-CoV-2,the precise neuroinvasion mechanisms of SARS-CoV-2 have not been fully established.In this review,we primarily describe the clinical neurological complications associated with SARS-CoV-2 and discuss the potential mechanisms through which SARS-CoV-2 invades the brain based on the current evidence.Finally,we summarize the experimental models were used to study SARS-CoV-2 neuroinvasion.These data form the basis for studies on the significance of SARS-CoV-2 infection in the brain.

A new and promising application of gene editing: CRISPR-controlled smart materials for tissue engineering,bioelectronics, and diagnostics

A recent study published in the journal Science by Collins et al.proposed a programmable clustered regularly interspaced short palindromic repeats(CRISPR)-responsive smart material containing the CRISPR-associated nuclease,Casl2a,and hydrogels containing DNA to deliver biological information via changes in material properties(English et al.,2019).

Histones released by NETosis enhance the infectivity of SARS-CoV-2 by bridging the spike protein subunit 2 and sialic acid on host cells

Neutrophil extracellular traps(NETs)can capture and kill viruses,such as influenza viruses,human immunodeficiency virus(HIV),and respiratory syncytial virus(RSV),thus contributing to host defense.Contrary to our expectation,we show here that the histones released by NETosis enhance the infectivity of SARS-CoV-2,as found by using live SARS-CoV-2 and two pseudovirus systems as well as a mouse model.The histone H3 or H4 selectively binds to subunit 2 of the spike(S)protein,as shown by a biochemical binding assay,surface plasmon resonance and binding energy calculation as well as the construction of a mutant S protein by replacing four acidic amino acids.Sialic acid on the host cell surface is the key molecule to which histones bridge subunit 2 of the S protein.Moreover,histones enhance cell-cell fusion.Finally,treatment with an inhibitor of NETosis,histone H3 or H4,or sialic acid notably affected the levels of sgRNA copies and the number of apoptotic cells in a mouse model.These findings suggest that SARS-CoV-2 could hijack histones from neutrophil NETosis to promote its host cell attachment and entry process and may be important in exploring pathogenesis and possible strategies to develop new effective therapies for COVID-19.

Reduction of BCL11A in hematopoietic stem cells through gene editing:new strategy to ameliorate the severe b-globin disorders sickle cell disease

Site-specific gene editing is of great importance in precise medicine. Two conventional genome editing methods, Zine finger nucleases (ZFNs) and transcription activator-like effector nucleases(TALENs), are based on protein-DNA recognition, with tedious work in constructing target protein [1,2]. Developed from immune response of bacteria, CRISPR/Cas9 has been widely investigated as a promising tool for therapeutic genome editing in clinical settings nowadays[3,4].

Correction: Spontaneous apoptosis of cells in therapeutic stemcell preparation exert immunomodulatory effects throughrelease of phosphatidylserine

After online publication of the article1,the authors noticed one inadvertent mistake in Fig.5a that needs to be corrected.In detail,the pathological picture of PBS group in Fig.5a is inadvertently duplicated as the image of PBS group in Fig.7b in the main text.This duplication is a result of errors in figure assembly,and the correct Fig.5 is provided as follows.The key findings of the article are not affected by these corrections.

Spike protein of SARS‐CoV‐2 Omicron(B.1.1.529)variant has a reduced ability to induce the immune response

Dear Editor,The severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)variant Omicron(B.1.1.529)has attracted great concerns since its identification in South Africa.Omicron is the fifth variant of concern(VOC)after Alpha(B.1.1.7),Beta(B.1.351),Gamma(P.1)and Delta(B.1.617.2),and set a record with the shortest duration from variants of interest(VOI)to VOC so far.Within 2 months after its first report,over 80%of global sequenced samples are verified as Omicron according to GISAID(https://cov-spectrum.org/explore/World/AllSamples/from=2021-12-15&to=2022-01-15/variants?pangoLineage=B.1.1.529*).

Inactivated SARS-CoV-2 induces acute respiratory distress syndrome in human A CE2-transgenic mice

The development of animal models for COVID-19 is essential for basic research and drug/vaccine screening.Previously reported COVID-19 animal models need to be established under a high biosafety level condition for the utilization of live SARS-CoV-2,which greatly limits its application in routine research.Here,we gen erate a mouse model of COVID-19 un der a gen eral laboratory condition that captures multiple characteristics of SARS-CoV-2-induced acute respiratory distress syndrome(ARDS)observed in huma ns.Briefly,human ACE2-tra nsge nic(MCE2)mice were in tratracheally in stilled with the formaldehyde-inactivated SARS-CoV-2,resulting in a rapid weight loss and detrimental changes in lung structure and function.The pulmonary pathologic changes were characterized by diffuse alveolar damage with pulmonary consolidation,hemorrhage,necrotic debris,and hyaline membrane formation.The production of fatal cytokines(IL-β,TNF-α,and IL-6)and the infiltration of activated neutrophils,inflammatory monocyte-macrophages,and T cells in the lung were also determined,suggesting the activation of an adaptive immune response.Therapeutic strategies,such as dexamethasone or passive antibody therapy,could effectively ameliorate the disease progression in this model.Therefore,the established mouse model for SARS-CoV-2-induced ARDS in the current study may provide a robust tool for researchers in the standard open laboratory to investigate the pathological mechanisms or develop new therapeutic strategies for COVID-19 and ARDS.

A mouse model for SARS-CoV-2-induced acute respiratory distress syndrome

Dear Editor,The COVID-19 pandemic has covered more than 200 countries and regions around the world since its outbreak in January 2020.To date,the SARS-CoV-2 virus has caused>1.2 million deaths.The mortality rate of COVID-19 is closely concerned with the clinical symptoms of the patients from mild-to-severe disease.Notably,in its most severe form,COVID-19 leads to life-threatening pneumonia and acute respiratory distress syndrome(ARDS),which is mostly accom-panied by a hyperactive immune response called"cytokine storm"and has high death rates from 40 to 50%.

Cationic nanocarriers as potent adjuvants for recombinant S-RBD vaccine of SARS-CoV-2

Dear Editor,The worldwide outbreak of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection has urged the investigation of preventive vaccines.Recently,our team has developed a recombinant protein vaccine,targeting receptor binding domain(RBD)of the spike protein(S-RBD)of SARS-CoV-2,which could induce a potent antibody response and protect non-human primates from SARS-CoV-2 challenge.1 The recombinant RBD protein is proved as a potent antigen and a novel adjuvant is in demand for the effective stimulation of adaptive immunity.

Cationic nanocarriers as potent adjuvants for recombinant S-RBD vaccine of SARS-CoV-2

Dear Editor,The worldwide outbreak of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection has urged the investigation of preventive vaccines.Recently,our team has developed a recombinant protein vaccine,targeting receptor binding domain(RBD)of the spike protein(S-RBD)of SARS-CoV-2,which could induce a potent antibody response and protect non-human primates from SARS-CoV-2 challenge.1 The recombinant RBD protein is proved as a potent antigen and a novel adjuvant is in demand for the effective stimulation of adaptive immunity.Therefore,to improve the efficacy of the vaccine and seek a novel adjuvant that can stimulate both humoral and cellular immunity,we investigated the potential of series of cationic nanocarriers as adjuvants of the recombinant S-RBD vaccine for SARS-CoV-2.As the surface charge of a nanocarrier might dramatically affect the immunogenicity of a vaccine and enhance and/or shape antigen-specific immune responses,we also used anionic nanocarriers and neutral nanocarriers as controls(Supplementary Table S1).S-RBD vaccines with adjuvant candidates were administered intranasally or intramuscularly in the present study.

Intranasal boosting with RBD-HR protein vaccine elicits robust mucosal and systemic immune responses

The emergence of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)variants has decreased the efficacy of SARs-CoV-2 vaccines in containing coronavirus disease 2019(CoVID-19)over time,and booster vaccination strategies are urgently necessitated to achieve sufficient protection.Intranasal immunization can improvemucosal immunity,offer-ing protection against the infection and sustaining the spread of SARS-CoV-2.In this study,an intranasal booster of the RBD-HR vaccine after two doses of the mRNA vaccine significantly increased the levels of specific binding antibodies in serum,nasal lavage fluid,and bronchoal-veolar lavage fluid compared with only two doses of mRNA vaccine.After intranasal boosting with the RBD-HR vaccine,the levels of serum neutralizing antibodies against prototype and variant strains of SARS-Cov-2 pseudoviruses weremarkedly higher than those in mice receiving mRNA vaccine alone,and intranasal boosting with the RBD-HR vaccine also inhibited the bind-ing of RBD to hACE2 receptors.Furthermore,the heterologous intranasal immunization regimen promoted extensive memory T cell responses and activated CD103+dendritic cells in the respiratory mucosa,and potently enhanced the formation of T follicular helper cells and germinal center B cells in vital immune organs,including mediastinal lymph nodes,inguinal lymph nodes,and spleen.Collectively,these data infer that heterologous intranasal boosting with the RBD-HR vaccine elicited broad protective immunity against SARS-CoV-2 both locallyandsystemically.