Guideline for the diagnosis and treatment of rheumatoid arthritis with integrated traditional Chinese medicine and Western medicine to increase efficiency and reduce toxicity

Rheumatoid arthritis imposes a huge disease burden.Existing practice guidelines do not meet the needs of integrated traditional Chinese medicine and Western medicine in the treatment of rheumatoid arthritis.We established a guideline working group consists of a steering committee,a secretary group,an evidence evaluation group,a consensus group and a review group and developed a guideline following the guidance of the World Health Organization Handbook and the Chinese Medical Association.The guideline includes 35 recommendations which reached consensus by the two rounds Delphi surveys.These recommendations were formulated to address the following themes of most concern to clinician:diagnostic imaging,disease staging,traditional Chinese medicine syndromes,effectiveness and toxicity of integrated traditional Chinese medicine and Western medicine.

Immune functions of C-type lectins in medical arthropods

C-type lectins(CTLs)are a family of proteins that contain 1 or more carbohydrate-recognition domains(CRDs)and bind to a broad repertoire of ligands in the presence of calcium ions.CTLs play important roles in innate immune defenses against microorganisms by acting as pattern-recognition receptors(PRRs)for invading pathogens,such as bacteria,viruses,and parasites.After binding to pathogen-associated ligands,CTLs mediate immune responses,such as agglutination,phagocytosis,and the activation of phenol oxidase progenitors,thereby clearing pathogens.CTLs are an evolutionarily conserved family found in almost all vertebrates and invertebrates.Medical arthropods can acquire and transmit a range pathogens through various approaches,such as bloodsucking,lancing,and parasitism,thus infecting humans and animals with related diseases,some of which can be life-threatening.Recent studies have shown that lectins are important components of the arthropod immune system and are essential for the immune responses of arthropods to arthropod-borne pathogens.This article reviews the current understanding of the structure,function,and signaling pathways involved in CTLs derived from important medical arthropods.

The role of TIA1 and TIAL1 in germinal center B cell function and survival

B cells are essential components of the adaptive immune system and undergo differentiation and maturation during infection or immune stimulation to produce antibodies that can specifically recognize and bind to antigens.Germinal centers(GCs)are microanatomical sites for the clonal expansion and antibody affinity maturation of B cells.In the dark zone(DZ)of the germinal center,B cells rapidly proliferate,and somatic hypermutation(SHM)of B cell antigen receptors(BCRs)occurs.B cells then migrate to the light zone(LZ).

Deciphering dynamic changes of the aging transcriptome with COVID-19 progression and convalescence in the human blood

Dear Editor,Overwhelming evidence suggests that age itself is a prominent risk factor for COVID-19 morbidity and mortality.^(1,2)However,the molecular basis of aging’s effect on SARS-CoV-2 susceptibility and COVID-19 severity in adults is still not fully understood.Thus,we hypothesized that aging-related cellular landscape alterations influence clinical manifestations,which is critical for determining likely intervention targets to slow the transmission of COVID-19 and reduce severe symptoms.

Motile cilia and microvillar:accomplices of SARS-CoV-2 in penetratingg mucuss barrier and infecting airway epithelium

Recently in Cell,Chien et al.published their new findings on severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)penetrating through the'mucosal,barrier of,respiratory by hijacking the cilia and microvilli of nasal epithelial cells,and elucidated the specific mechanism in detail using electron microscopy as well as phosphoproteomics.This study fully explained the way of SARS-CoV-2 breaking through the mucus barrier to infect nasal epithelial cells,and provided a novel direction for the blocking treatment of respiratory tract infections.The culprit of coronavirus disease 2019(COviD-19)pandemic,SARS-CoV-2.

SENP6 restricts the IFN-I-induced signaling pathway and antiviral activity by deSUMOylating USP8

Type I interferon(IFN-I)exhibits broad-spectrum antiviral properties and is commonly employed in clinical for the treatment of viral infections.In this study,we unveil SENP6 as a potent regulator of IFN-I antiviral activity.SENP6 does not impact the production of IFN-I induced by viruses but rather modulates IFN-I-activated signaling.Mechanistically,SENP6 constitutively interacts with USP8 and inhibits the SUMOylation of USP8,consequently restricting the interaction between USP8 and IFNAR2.The dissociation of USP8 from IFNAR2 enhances IFNAR2 ubiquitination and degradation,thus attenuating IFN-I antiviral activity.Correspondingly,the downregulation of SENP6 promotes the interaction between USP8 and IFNAR2,leading to a reduction in IFNAR2 ubiquitination and,consequently,an enhancement in IFN-I-induced signaling.This study deciphers a critical deSUMOylation-deubiquitination crosstalk that finely regulates the IFN-I response to viral infection.

Targeting Haemaphysalis longicornis serpin to prevent tick feeding and pathogen transmission

Serine proteinase inhibitors(serpins),identified from the hard tick Haemaphysalis longicornis of China,play significant roles in various animal physiological processes.In this study,we showed that H.longicornis serpins(Hlserpin-a and Hlserpin-b)were induced during blood-feeding in nymph ticks and exhibited anticoagulation activity in vitro.Silencing Hlserpins through RNA interference(RNAi)significantly impaired tick feeding.Immunization of mice with recombinant Hlserpins or passive transfer of Hlserpin antiserum significantly curtails the efficacy of tick feeding.Concurrently,the transmission of the Langat virus(LGTV)from ticks to mice witnessed a substantial decrease when Hlserpins were silenced.Our findings suggest that inhibiting Hlserpins can hamper tick engorgement and pathogen transmission,indicating the potential of Hlserpins as a vaccine to countertick-borne diseases.

PARP1-DNA co-condensation:the driver of broken DNA repair

A recent study published by Simon Alberti1 in Cell has revealed that DNA double-strand break(DSB)sites that prevent the disjunction of broken DNA ends are formed through poly(ADPribose)(PAR)polymerase 1(PARP1)-DNA co-condensation.1(Fig.1).Here,a comprehensive and novel model was provided for the ordered assembly of PARP1-DNA condensates,which can rationally make clear broken DNA end synapses and how repair effectors are recruited to repair DSB.

Role of pyroptosis in inflammation and cancer

Pyroptosis is a form of programmed cell death mediated by gasdermin and is a product of continuous cell expansion until the cytomembrane ruptures,resulting in the release of cellular contents that can activate strong inflammatory and immune responses.Pyroptosis,an innate immune response,can be triggered by the activation of inflammasomes by various influencing factors.Activation of these inflammasomes can induce the maturation of caspase-1 or caspase-4/5/11,both of which cleave gasdermin D to release its N-terminal domain,which can bind membrane lipids and perforate the cell membrane.Here,we review the latest advancements in research on the mechanisms of pyroptosis,newly discovered influencing factors,antitumoral properties,and applications in various diseases.Moreover,this review also provides updates on potential targeted therapies for inflammation and cancers,methods for clinical prevention,and finally challenges and future directions in the field.

The function and clinical application of extracellular vesicles in innate immune regulation

The innate immune system plays a crucial role in the host defense against viral and microbial infection.Exosomes constitute a subset of extracellular vesicles(EVs)that can be released by almost all cell types.Owing to their capacity to shield the payload from degradation and to evade recognition and subsequent removal by the immune system,exosomes efficiently transport functional components to recipient cells.Accumulating evidence has recently shown that exosomes derived from tumor cells,host cells and even bacteria and parasites mediate the communication between the invader and innate immune cells and thus play an irreplaceable function in the dissemination of pathogens and donor cell-derived molecules,modulating the innate immune responses of the host.In this review,we describe the current understanding of EVs(mainly focusing on exosomes)and summarize and discuss their crucial roles in determining innate immune responses.Additionally,we discuss the potential of using exosomes as biomarkers and cancer vaccines in diagnostic and therapeutic applications.

A systematic review of SARS-CoV-2 vaccine candidates

Advanced natural killer/T cell lymphoma(NKTL)has demonstrated poor prognosis with currently available therapies.Here,we report the efficacy of anti-programmed death 1(PD-1)antibody with the P-GEMOX(pegaspargase,gemcitabine,and oxaliplatin)regimen in advanced NKTL.Nine patients underwent six 21-day cycles of anti-PD-1 antibody(day 1),pegaspargase 2000 U/m2(day 1),gemcitabine 1 g/m2(days 1 and 8)and oxaliplatin 130 mg/m2(day 1),followed by anti-PD-1 antibody maintenance every 3 weeks.Programmed death-ligand 1(PD-L1)expression and genetic alterations were determined in paraffin-embedded pretreatment tissue samples using immunohistochemistry and next-generation sequencing(NGS)analysis.Responses were assessed using 18F-fluorodeoxyglucose positron emission tomography(18FDG-PET)and computed tomography or magnetic resonance imaging.Eight patients exhibited significant responses,comprising of seven complete remissions and one partial remission(overall response rate:88.9%).After a median follow-up of 10.6 months,6/9 patients(66.7%)remained in complete remission.The most common grade 3/4 adverse events were anemia(33.3%),neutropenia(33.3%),and thrombocytopenia(33.3%);all of which were manageable and resolved.Immunochemotherapy produced a high response rate in patients with positive PD-L1 expression(5/6,83.3%).NGS analysis suggested that STAT3/JAK3/PD-L1 alterations and ARID1A mutation were associated with immunochemotherapy efficacy.Mutation in DDX3X and alteration in epigenetic modifiers of KMT2D,TET2,and BCORL1 might indicate a poor response to immunochemotherapy.In conclusion,the anti-PD-1 antibody plus P-GEMOX regimen demonstrated promising efficacy in advanced NKTL.PD-L1 expression combined with specific genetic alterations could be used as potential biomarkers to predict therapeutic responses to immunochemotherapy.

Alterations in microbiota of patients with COVID-19:potential mechanisms and therapeutic interventions

The global coronavirus disease 2019(COVID-19)pandemic is currently ongoing.It is caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).A high proportion of COVID-19 patients exhibit gastrointestinal manifestations such as diarrhea,nausea,or vomiting.Moreover,the respiratory and gastrointestinal tracts are the primary habitats of human microbiota and targets for SARS-CoV-2 infection as they express angiotensin-converting enzyme-2(ACE2)and transmembrane protease serine 2(TMPRSS2)at high levels.There is accumulating evidence that the microbiota are significantly altered in patients with COVID-19 and post-acute COVID-19 syndrome(PACS).

Protein N-myristoylation:functions and mechanisms in control of innate immunity

Protein N-myristoylation is an important fatty acylation catalyzed by N-myristoyltransferases(NMTs),which are ubiquitous enzymes in eukaryotes.Specifically,attachment of a myristoyl group is vital for proteins participating in various biological functions,including signal transduction,cellular localization,and oncogenesis.Recent studies have revealed unexpected mechanisms indicating that protein N-myristoylation is involved in host defense against microbial and viral infections.In this review,we describe the current understanding of protein N-myristoylation(mainly focusing on myristoyl switches)and summarize its crucial roles in regulating innate immune responses,including TLR4-dependent inflammatory responses and demyristoylation-induced innate immunosuppression during Shigella flexneri infection.Furthermore,we examine the role of myristoylation in viral assembly,intracellular host interactions,and viral spread during human immunodeficiency virus-1(HIV-1)infection.Deeper insight into the relationship between protein N-myristoylation and innate immunity might enable us to clarify the pathogenesis of certain infectious diseases and better harness protein N-myristoylation for new therapeutics.

The way of SARS-CoV-2 vaccine development:success and challenges

Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is the causative agent of coronavirus disease 2019(COVID-19).To halt the pandemic,multiple SARS-CoV-2 vaccines have been developed and several have been allowed for emergency use and rollout worldwide.With novel SARS-CoV-2 variants emerging and circulating widely,whether the original vaccines that were designed based on the wild-type SARS-CoV-2 were effective against these variants has been a contentious discussion.Moreover,some studies revealed the long-term changes of immune responses post SARS-CoV-2 infection or vaccination and the factors that might impact the vaccine-induced immunity.Thus,in this review,we have summarized the influence of mutational hotspots on the vaccine efficacy and characteristics of variants of interest and concern.We have also discussed the reasons that might result in discrepancies in the efficacy of different vaccines estimated in different trials.Furthermore,we provided an overview of the duration of immune responses after natural infection or vaccination and shed light on the factors that may affect the immunity induced by the vaccines,such as special disease conditions,sex,and pre-existing immunity,with the aim of aiding in combating COVID-19 and distributing SARS-CoV-2 vaccines under the prevalence of diverse SARS-CoV-2 variants.

NSC-640358 acts as RXRa ligand to promote TNFa-mediated apoptosis of cancer cell

Retinoid X receptor a （RXRα） and its N-terminally trun- cated version tRXRα play important roles in tumorige. nesis, while some RXRg ligands possess potent anti- cancer activities by targeting and modulating the tumorigenic effects of RXRo and tRXRa. Here we describe NSC-640358 （N-6）, a thiazolyl-pyrazole derived compound, acts as a selective RXRα ligand to promote TNFα-mediated apoptosis of cancer cell. N-6 binds to RXRa and inhibits the transactivation of RXRα homod- imer and RXRa/TR3 heterodimer. Using mutational analysis and computational study, we determine that Arg316 in RXRa, essential for 9-cis-retinoic acid binding and activating RXRg transactivation, is not required for antagonist effects of N-6, whereas Trp305 and Phe313 are crucial for N-6 binding to RXRα by forming extra w-w stacking interactions with N-6, indicating a distinct RXRα binding mode of N-6. N-6 inhibits TR3-stimulated transactivation of Gal4-DBD-RXRα-LBD by binding to the ligand binding pocket of RXRa-LBD, suggesting a strategy to regulate TR3 activity indirectly by using small molecules to target its interacting partner RXRα. For its physiological activities, we show that N-6 strongly inhibits tumor necrosis factor a （TNFα）-induced AKT activation and stimulates TNFa-mediated apoptosis in cancer cells in an RXRa/tRXRo dependent manner.The inhibition of TNFα-induced tRXRα/p85α complex formation by N-6 implies that N-6 targets tRXRa to inhibit TNFα-induced AKT activation and to induce cancer cell apoptosis. Together, our data illustrate a new RXRa ligand with a unique RXRα binding mode and the abilities to regulate TR3 activity indirectly and to induce TNFa-mediated cancer cell apoptosis by targeting RXRα/tRXRα.

Fabrication of multifunctional polydopamine-coated gold nanobones for PA/CT imaging and enhanced synergistic chemo-photothermal therapy

Multimodal imaging-guided chemo-photothermal therapy is an excellent cancer treatment,which can not only efficiently against tumor,but also can offer precise treatment window and real-time monitoring of the treatment efficiency.In our work,polydopamine(PDA)-coated gold nanobones(AuNBs@PDA nanocomplexes)were designed for this approach.The AuNBs@PDA nanocomplexes have strong absorbance in the near infrared(NIR)region and higher photothermal conversion efficiency(75.48%)than gold nanobones alone,which was facilitated for photoacoustic imaging and photothermal therapy.Besides,the loading efficiency of doxorubicin(DOX)by AuNBs@PDA nanocomplexes could be up to about 70%and DOX release from AuNBs@PDA/DOX nanocomplexes sensitively response to the lower pH environment and NIR laser irradiation,which makes them become the excellent nano-carrier for the delivery of chemotherapy drug.In vitro and in vivo studies showed significant cytotoxicity and antitumor efficacy by the AuNBs@PDA/DOX nanoplatform with negligible side effects.Meanwhile,the nanoplatform was also successfully employed for computed tomography(CT)imaging,attributing to the high atomic number and high X-ray attenuation coefficient of gold.Therefore,we believed that the proposed PDA-coated gold nanobones would be a novel multifunctional theranostic nanoagent to realize the PA/CT imaging-guided chemo-photothermal therapy of cancer.

Ubiquitin-specific protease 24 promotes EV71 infection by restricting K63-linked polyubiquitination of TBK1

TANK-binding kinase 1(TBK1)is an essential protein kinase for activation of interferon regulatory factor 3(IRF3)and induction of the type I interferons(IFN-I).Although the biochemical regulation of TBK1 activation has been studied,little is known about how enterovirus 71(EV71)employs the deubiquitinases(DUBs)to regulate TBK1 activation for viral immune evasion.Here,we found that EV71 infection upregulated the expression of ubiquitinspecific protease 24(USP24).Further studies revealed that USP24 physically interacted with TBK1,and can reduce K63-linked polyubiquitination of TBK1.Knockdown of USP24 upregulated TBK1 K63-linked polyubiquitination,promoted the phosphorylation and nuclear translocation of IRF3,and in turn improved IFN-I production during EV71 infection.As a consequence,USP24 knockdown dramatically inhibited EV71 infection.This study revealed USP24 as a novel regulator of TBK1 activation,which promotes the understanding of immune evasion mechanisms of EV71 and could provide a potential strategy for treatment of EV71 infection.

The role of O-GlcNAcylation in innate immunity and inflammation

O-linkedβ-N-acetylglucosaminylation(O-GlcNAcylation)is a highly dynamic and widespread post-translational modification(PTM)that regulates the activity,subcellular localization,and stability of target proteins.O-GlcNAcylation is a reversible PTM controlled by two cycling enzymes:O-linked N-acetylglucosamine transferase and O-GlcNAcase.Emerging evidence indicates that O-GlcNAcylation plays critical roles in innate immunity,inflammatory signaling,and cancer development.O-GlcNAcylation usually occurs on serine/threonine residues,where it interacts with other PTMs,such as phosphorylation.Thus,it likely has a broad regulatory scope.This review discusses the recent research advances regarding the regulatory roles of O-GlcNAcylation in innate immunity and inflammation.A more comprehensive understanding ofO-GlcNAcylation could help to optimize therapeutic strategies regarding inflammatory diseases and cancer.

The loss of epigenetic information:not only consequences but a cause of mammalian aging

In a recent study published in Cell,Yang et al.revealed that changes in epigenetic landscapes caused by faithful DNA repair are key drivers accelerating aging of mammalian organs or tissues.1 Impressively,changes in H3K27ac landscape during aging process influence cell identity maintenance,and this aging process can be reversed by the inducible expression of pioneer transcription factors,Oct4,Sox2,and Klf4(OSK)in the living mammals.In mammals,global and local changes of DNA methylation occur in the genome during aging.Additionally,general loss of histones and global chromatin remodeling have been observed in all aging models,while in reverse reprograming of cell fate can lead to global changes in the epigenetic and rejuvenated epigenome,suggesting the potential of reprogramming for the reversal of aging.2 However,as no systematic studies revealed the characteristics of epigenomic changes during aging,it remains unclear whether the changes in epigenetic landscape are the consequences(marks)or direct cause of aging.