Phagosomal granulocytic ROS in septic patients induce the bacterial SOS response
SummarySeptic patients with worst clinical prognosis have increased circulating immature granulocytes (IG),displaying limited phagocytosis and reactive oxygen species (ROS) production. Here,we developed an ex vivo model of incubation of human granulocytes,from septic patients or healthy donors,with Escherichia coli. We showed that the ROS production in Sepsis-IG is lower due to decreased activation and protein expression of the NADPH oxidase complex. We also demonstrated that the low level of ROS production and lower phagocytosis of IG in sepsis induce the bacterial SOS response,leading to the expression of the SOS-regulated quinolone resistance gene qnrB2. Without antimicrobial pressure,the sepsis immune response alone may promote antibiotic resistance expression. Graphical abstract Highlights•Immature granulocytes in sepsis have decreased phagocytosis and ROS production•SOS response is induced in granulocyte-phagocyted bacteria and is ROS dependent•The level of bacterial SOS induction depends on granulocyte maturation and priming•Phagocyted bacteria induce SOS-dependent quinolone resistance qnrB2 expression Immunology; Microbiology; Bacteriology
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产品号#：
19666
100-0404
产品名：
EasySep™ Direct人中性粒细胞分选试剂盒
RoboSep™ 人中性粒细胞分选试剂盒
(May 2024)
Nature Communications 15
C5aR1 inhibition reprograms tumor associated macrophages and reverses PARP inhibitor resistance in breast cancer
Although Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) have been approved in multiple diseases,including BRCA1/2 mutant breast cancer,responses are usually transient requiring the deployment of combination therapies for optimal efficacy. Here we thus explore mechanisms underlying sensitivity and resistance to PARPi using two intrinsically PARPi sensitive (T22) and resistant (T127) syngeneic murine breast cancer models in female mice. We demonstrate that tumor associated macrophages (TAM) potentially contribute to the differential sensitivity to PARPi. By single-cell RNA-sequencing,we identify a TAM_C3 cluster,expressing genes implicated in anti-inflammatory activity,that is enriched in PARPi resistant T127 tumors and markedly decreased by PARPi in T22 tumors. Rps19/C5aR1 signaling is selectively elevated in TAM_C3. C5aR1 inhibition or transferring C5aR1hi cells increases and decreases PARPi sensitivity,respectively. High C5aR1 levels in human breast cancers are associated with poor responses to immune checkpoint blockade. Thus,targeting C5aR1 may selectively deplete pro-tumoral macrophages and engender sensitivity to PARPi and potentially other therapies. PARP inhibitors (PARPi) have been approved for the treatment of metastatic triple-negative breast cancer (BC),however resistance and recurrence are often observed. Here,in preclinical models of BRCA1/2 wild type and homologous recombination competent BC,the authors show that C5aR1-positive tumor associated macrophages are associated with PARPi-resistance,suggesting targeting C5aR1 as a therapeutic option.
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产品号#：
18970
17899
18945
17683
18970RF
17683RF
18780
18780RF
18781
18781RF
18952
18952RF
18954
18954RF
19855
19855RF
产品名：
EasySep™小鼠CD11b正选试剂盒II
EasySep™ 死细胞去除 (Annexin V) 试剂盒
EasySep™ 小鼠CD45正选试剂盒
EasySep™Biotin正选试剂盒
RoboSep™ 小鼠CD11b正选试剂盒II
RoboSep™ Biotin正选试剂盒
EasySep™小鼠CD11c正选试剂盒II
RoboSep™ 小鼠CD11c正选试剂盒II
EasySep™小鼠CD11c正选试剂盒II及脾脏解离液
RoboSep™ 小鼠CD11c正选试剂盒II及脾脏解离液
EasySep™小鼠CD4正选试剂盒II
RoboSep™ 小鼠CD4正选试剂盒II
EasySep™小鼠CD19正选试剂盒II
RoboSep™ 小鼠CD19正选试剂盒II
EasySep™小鼠NK细胞分选试剂盒
RoboSep™ 小鼠NK细胞分选试剂盒
(May 2024)
Nature Communications 15
Small molecule induced STING degradation facilitated by the HECT ligase HERC4
Stimulator of interferon genes (STING) is a central component of the cytosolic nucleic acids sensing pathway and as such master regulator of the type I interferon response. Due to its critical role in physiology and its’ involvement in a variety of diseases,STING has been a focus for drug discovery. Targeted protein degradation (TPD) has emerged as a promising pharmacology for targeting previously considered undruggable proteins by hijacking the cellular ubiquitin proteasome system (UPS) with small molecules. Here,we identify AK59 as a STING degrader leveraging HERC4,a HECT-domain E3 ligase. Additionally,our data reveals that AK59 is effective on the common pathological STING mutations,suggesting a potential clinical application of this mechanism. Thus,these findings introduce HERC4 to the fields of TPD and of compound-induced degradation of STING,suggesting potential therapeutic applications. In this paper,Mutlu et al. identifies a STING degrader,AK59,which inhibits downstream cGAS/STING activity through STING degradation employing a HECT-domain E3 ligase HERC4 and proteasomal ubiquitination pathway.
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产品号#：
20104
20124
产品名：
RoboSep™ 缓冲液
RoboSep™ 缓冲液 （5X浓缩液）
(May 2024)
Frontiers in Immunology 15
IFNγ at the early stage induced after cryo-thermal therapy maintains CD4
IntroductionRecently,more and more research illustrated the importance of inducing CD4+ T helper type (Th)-1 dominant immunity for the success of tumor immunotherapy. Our prior studies revealed the crucial role of CD4+ Th1 cells in orchestrating systemic and durable antitumor immunity,which contributes to the satisfactory outcomes of the novel cryo-thermal therapy in the B16F10 tumor model. However,the mechanism for maintaining the cryo-thermal therapy-mediated durable CD4+ Th1-dominant response remains uncovered. Additionally,cryo-thermal-induced early-stage CD4+ Th1-dominant T cell response showed a correlation with the favorable prognosis in patients with colorectal cancer liver metastasis (CRCLM). We hypothesized that CD4+ Th1-dominant differentiation induced during the early stage post cryo-thermal therapy would affect the balance of CD4+ subsets at the late phase.MethodsTo understand the role of interferon (IFN)-γ,the major effector of Th1 subsets,in maintaining long-term CD4+ Th1-prone polarization,B16F10 melanoma model was established in this study and a monoclonal antibody was used at the early stage post cryo-thermal therapy for interferon (IFN)-γ signaling blockade,and the influence on the phenotypic and functional change of immune cells was evaluated.ResultsIFNγ at the early stage after cryo-thermal therapy maintained long-lasting CD4+ Th1-prone immunity by directly controlling Th17,Tfh,and Tregs polarization,leading to the hyperactivation of Myeloid-derived suppressor cells (MDSCs) represented by abundant interleukin (IL)-1β generation,and thereby further amplifying Th1 response.DiscussionOur finding emphasized the key role of early-phase IFNγ abundance post cryo-thermal therapy,which could be a biomarker for better prognosis after cryo-thermal therapy.
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产品号#：
18952
17667
18952RF
17667RF
18780
18780RF
18781
18781RF
18970
18970RF
产品名：
EasySep™小鼠CD4正选试剂盒II
EasySep™小鼠APC正选试剂盒II
RoboSep™ 小鼠CD4正选试剂盒II
RoboSep™ 小鼠APC正选试剂盒II
EasySep™小鼠CD11c正选试剂盒II
RoboSep™ 小鼠CD11c正选试剂盒II
EasySep™小鼠CD11c正选试剂盒II及脾脏解离液
RoboSep™ 小鼠CD11c正选试剂盒II及脾脏解离液
EasySep™小鼠CD11b正选试剂盒II
RoboSep™ 小鼠CD11b正选试剂盒II
(May 2024)
Cell Reports Medicine 5 5
Monocyte bioenergetics: An immunometabolic perspective in metabolic dysfunction-associated steatohepatitis
SummaryMonocytes (Mos) are crucial in the evolution of metabolic dysfunction-associated steatotic liver disease (MASLD) to metabolic dysfunction-associated steatohepatitis (MASH),and immunometabolism studies have recently suggested targeting leukocyte bioenergetics in inflammatory diseases. Here,we reveal a peculiar bioenergetic phenotype in circulating Mos of patients with MASH,characterized by high levels of glycolysis and mitochondrial (mt) respiration. The enhancement of mt respiratory chain activity,especially complex II (succinate dehydrogenase [SDH]),is unbalanced toward the production of reactive oxygen species (ROS) and is sustained at the transcriptional level with the involvement of the AMPK-mTOR-PGC-1α axis. The modulation of mt activity with dimethyl malonate (DMM),an SDH inhibitor,restores the metabolic profile and almost abrogates cytokine production. Analysis of a public single-cell RNA sequencing (scRNA-seq) dataset confirms that in murine models of MASH,liver Mo-derived macrophages exhibit an upregulation of mt and glycolytic energy pathways. Accordingly,the DMM injection in MASH mice contrasts Mo infiltration and macrophagic enrichment,suggesting immunometabolism as a potential target in MASH. Graphical abstract Highlights•Circulating monocytes (Mos) in patients with MASH show a bioenergetic reprogramming•SDH inhibition in vitro restores MASH Mo bioenergetics,abolishing cytokine production•In mice,energy pathways are upregulated in liver Mo-derived macrophages during MASH•SDH inhibition in vivo reduces Mo infiltration and differentiation in MASH Sangineto et al. investigate the bioenergetics and mitochondrial activity of circulating monocytes in patients with MASH,revealing a hypermetabolic state also identified in liver monocyte-derived macrophages through transcriptomic analysis. Immunometabolic modulation via SDH inhibition attenuates inflammation both in vitro and in vivo,ameliorating MASH.
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产品号#：
20144
18000
17858
17858RF
100-0694
07811
07861
100-0780
18060
18061
18651
18651RF
73122
73124
产品名：
EasySep™缓冲液
EasySep™磁极
EasySep™人CD14正选试剂盒II
RoboSep™ 人CD14正选试剂盒II
EasySep™人CD14正选试剂盒II
Lymphoprep™
Lymphoprep™
Lymphoprep™
Lymphoprep™
EasySep™人CD15正选试剂盒
RoboSep™ 人CD15正选试剂盒
依维莫司
依维莫司
(May 2024)
Cell Reports Medicine 5 5
Therapeutic avenues in bone repair: Harnessing an anabolic osteopeptide, PEPITEM, to boost bone growth and prevent bone loss
SummaryThe existing suite of therapies for bone diseases largely act to prevent further bone loss but fail to stimulate healthy bone formation and repair. We describe an endogenous osteopeptide (PEPITEM) with anabolic osteogenic activity,regulating bone remodeling in health and disease. PEPITEM acts directly on osteoblasts through NCAM-1 signaling to promote their maturation and formation of new bone,leading to enhanced trabecular bone growth and strength. Simultaneously,PEPITEM stimulates an inhibitory paracrine loop: promoting osteoblast release of the decoy receptor osteoprotegerin,which sequesters RANKL,thereby limiting osteoclast activity and bone resorption. In disease models,PEPITEM therapy halts osteoporosis-induced bone loss and arthritis-induced bone damage in mice and stimulates new bone formation in osteoblasts derived from patient samples. Thus,PEPITEM offers an alternative therapeutic option in the management of diseases with excessive bone loss,promoting an endogenous anabolic pathway to induce bone remodeling and redress the imbalance in bone turnover. Graphical abstract Highlights•PEPITEM exerts anabolic osteogenic activity to regulate osteoblast-osteoclast coupling•PEPITEM acts directly on osteoblasts to promote formation of new and stronger bone•PEPITEM stimulates an inhibitory paracrine loop via OPG to limit bone resorption•PEPITEM therapy halts disease-induced bone loss in vivo Lewis and Frost et al. identify the anabolic activity of an endogenous osteopeptide (PEPITEM),revealing the cellular and molecular mechanisms by which PEPITEM regulates bone remodeling in vitro and in preclinical disease models,to promote new bone formation. They suggest that PEPITEM offers an alternative therapeutic option for bone loss diseases.
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产品号#：
19359
100-0697
19359RF
产品名：
EasySep™人单核细胞分选试剂盒
EasySep™人单核细胞分选试剂盒
RoboSep™ 人单核细胞分选试剂盒
(May 2024)
Nature Microbiology 9 6
Peptostreptococcus anaerobius mediates anti-PD1 therapy resistance and exacerbates colorectal cancer via myeloid-derived suppressor cells in mice
Bacteria such as the oral microbiome member Peptostreptococcus anaerobius can exacerbate colorectal cancer (CRC) development. Little is known regarding whether these immunomodulatory bacteria also affect antitumour immune checkpoint blockade therapy. Here we show that administration of P. anaerobius abolished the efficacy of anti-PD1 therapy in mouse models of CRC. P. anaerobius both induced intratumoral myeloid-derived suppressor cells (MDSCs) and stimulated their immunosuppressive activities to impair effective T cell responses. Mechanistically,P. anaerobius administration activated integrin α2β1–NF-κB signalling in CRC cells to induce secretion of CXCL1 and recruit CXCR2+ MDSCs into tumours. The bacterium also directly activated immunosuppressive activity of intratumoral MDSCs by secreting lytC_22,a protein that bound to the Slamf4 receptor on MDSCs and promoted ARG1 and iNOS expression. Finally,therapeutic targeting of either integrin α2β1 or the Slamf4 receptor were revealed as promising strategies to overcome P. anaerobius-mediated resistance to anti-PD1 therapy in CRC. Interactions between Peptostreptococcus anaerobius and host cells promote recruitment and activation of myeloid-derived suppressor cells,leading to anti-PD1 immune checkpoint inhibitor resistance and exacerbated colorectal cancer in mice.
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产品号#：
19867
73722
73724
产品名：
EasySep™小鼠MDSC（CD11b+Gr1+）分选试剂盒
离子霉素（Ionomycin）
离子霉素（Ionomycin）
(Jun 2024)
Nature Communications 15
Cis-regulatory evolution of the recently expanded Ly49 gene family
Comparative genomics has revealed the rapid expansion of multiple gene families involved in immunity. Members within each gene family often evolved distinct roles in immunity. However,less is known about the evolution of their epigenome and cis-regulation. Here we systematically profile the epigenome of the recently expanded murine Ly49 gene family that mainly encode either inhibitory or activating surface receptors on natural killer cells. We identify a set of cis-regulatory elements (CREs) for activating Ly49 genes. In addition,we show that in mice,inhibitory and activating Ly49 genes are regulated by two separate sets of proximal CREs,likely resulting from lineage-specific losses of CRE activity. Furthermore,we find that some Ly49 genes are cross-regulated by the CREs of other Ly49 genes,suggesting that the Ly49 family has begun to evolve a concerted cis-regulatory mechanism. Collectively,we demonstrate the different modes of cis-regulatory evolution for a rapidly expanding gene family. The Ly49 gene family mainly encodes inhibitory or activating surface receptors on natural killer cells. Here the authors show that in mice,inhibitory and activating Ly49 genes are regulated by two distinct sets of cis-regulatory elements,and that different Ly49 genes can be cross-regulated.
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产品号#：
19855
19855RF
产品名：
EasySep™小鼠NK细胞分选试剂盒
RoboSep™ 小鼠NK细胞分选试剂盒
(Jun 2024)
Communications Biology 7
Super-resolution imaging of T lymphocyte activation reveals chromatin decondensation and disrupted nuclear envelope
T lymphocyte activation plays a pivotal role in adaptive immune response and alters the spatial organization of nuclear architecture that subsequently impacts transcription activities. Here,using stochastic optical reconstruction microscopy (STORM),we observe dramatic de-condensation of chromatin and the disruption of nuclear envelope at a nanoscale resolution upon T lymphocyte activation. Super-resolution imaging reveals that such alterations in nuclear architecture are accompanied by the release of nuclear DNA into the cytoplasm,correlating with the degree of chromatin decompaction within the nucleus. The authors show that under the influence of metabolism,T lymphocyte activation de-condenses chromatin,disrupts the nuclear envelope,and releases DNA into the cytoplasm. Taken together,this result provides a direct,molecular-scale insight into the alteration in nuclear architecture. It suggests the release of nuclear DNA into the cytoplasm as a general consequence of chromatin decompaction after lymphocyte activation. The authors show that under the influence of metabolism,T lymphocyte activation de-condenses chromatin,disrupts the nuclear envelope,and releases DNA into the cytoplasm.
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产品号#：
19854
19851
19851RF
19854RF
19855
19855RF
产品名：
EasySep™小鼠B细胞分选试剂盒
EasySep™小鼠T细胞分选试剂盒
RoboSep™ 小鼠T细胞分选试剂盒
RoboSep™ 小鼠B细胞分选试剂盒
EasySep™小鼠NK细胞分选试剂盒
RoboSep™ 小鼠NK细胞分选试剂盒
(May 2024)
Nature 630 8017
Selective haematological cancer eradication with preserved haematopoiesis
Haematopoietic stem cell (HSC) transplantation (HSCT) is the only curative treatment for a broad range of haematological malignancies,but the standard of care relies on untargeted chemotherapies and limited possibilities to treat malignant cells after HSCT without affecting the transplanted healthy cells1. Antigen-specific cell-depleting therapies hold the promise of much more targeted elimination of diseased cells,as witnessed in the past decade by the revolution of clinical practice for B cell malignancies2. However,target selection is complex and limited to antigens expressed on subsets of haematopoietic cells,resulting in a fragmented therapy landscape with high development costs2–5. Here we demonstrate that an antibody–drug conjugate (ADC) targeting the pan-haematopoietic marker CD45 enables the antigen-specific depletion of the entire haematopoietic system,including HSCs. Pairing this ADC with the transplantation of human HSCs engineered to be shielded from the CD45-targeting ADC enables the selective eradication of leukaemic cells with preserved haematopoiesis. The combination of CD45-targeting ADCs and engineered HSCs creates an almost universal strategy to replace a diseased haematopoietic system,irrespective of disease aetiology or originating cell type. We propose that this approach could have broad implications beyond haematological malignancies. An antibody–drug conjugate that targets the pan-haematopoietic marker CD45 combined with transplanted stem cells engineered to be shielded from it can eradicate leukaemic cells while preserving haematopoiesis.
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产品号#：
09600
09605
09650
09655
22001
22005
22006
22007
22008
22009
22011
22012
17951
100-0695
17951RF
07930
07931
07940
07952
07955
07959
100-1061
85450
85460
产品名：
StemSpan™ SFEM
StemSpan™ SFEM II
StemSpan™ SFEM
StemSpan™ SFEM II
STEMvision™ 人脐带血7-天CFU分析包
STEMvision™人脐带血14天CFU分析套装
STEMvision™人骨髓14天CFU分析套装
STEMvision™人动员外周血14天CFU分析套装
STEMvision™ 小鼠总CFU分析包
STEMvision™ 小鼠髓系CFU分析包
STEMvision™ 小鼠红系CFU分析包
STEMvision™小鼠CFU分析套装组合
EasySep™人T细胞分选试剂盒
EasySep™人T细胞分选试剂盒
RoboSep™ 人T细胞分选试剂盒
CryoStor® CS10
CryoStor® CS10
CryoStor® CS10
CryoStor® CS10
CryoStor® CS10
CryoStor® CS10
CryoStor® CS10
SepMate™-50 (IVD)
SepMate™-50 (IVD)
(May 2024)
Nature Medicine 30 6
Multiomic analyses uncover immunological signatures in acute and chronic coronary syndromes
Acute and chronic coronary syndromes (ACS and CCS) are leading causes of mortality. Inflammation is considered a key pathogenic driver of these diseases,but the underlying immune states and their clinical implications remain poorly understood. Multiomic factor analysis (MOFA) allows unsupervised data exploration across multiple data types,identifying major axes of variation and associating these with underlying molecular processes. We hypothesized that applying MOFA to multiomic data obtained from blood might uncover hidden sources of variance and provide pathophysiological insights linked to clinical needs. Here we compile a longitudinal multiomic dataset of the systemic immune landscape in both ACS and CCS (n = 62 patients in total,n = 15 women and n = 47 men) and validate this in an external cohort (n = 55 patients in total,n = 11 women and n = 44 men). MOFA reveals multicellular immune signatures characterized by distinct monocyte,natural killer and T cell substates and immune-communication pathways that explain a large proportion of inter-patient variance. We also identify specific factors that reflect disease state or associate with treatment outcome in ACS as measured using left ventricular ejection fraction. Hence,this study provides proof-of-concept evidence for the ability of MOFA to uncover multicellular immune programs in cardiovascular disease,opening new directions for mechanistic,biomarker and therapeutic studies. Multiomic factor analysis of blood multiomic data,including single-cell transcriptomics,for individuals with either acute or chronic coronary syndrome identifies immune cell signatures that correlate with treatment outcomes.
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Integrated Single-cell Multiomic Analysis of HIV Latency Reversal Reveals Novel Regulators of Viral Reactivation
AbstractDespite the success of antiretroviral therapy,human immunodeficiency virus (HIV) cannot be cured because of a reservoir of latently infected cells that evades therapy. To understand the mechanisms of HIV latency,we employed an integrated single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin with sequencing (scATAC-seq) approach to simultaneously profile the transcriptomic and epigenomic characteristics of ∼ 125,000 latently infected primary CD4+ T cells after reactivation using three different latency reversing agents. Differentially expressed genes and differentially accessible motifs were used to examine transcriptional pathways and transcription factor (TF) activities across the cell population. We identified cellular transcripts and TFs whose expression/activity was correlated with viral reactivation and demonstrated that a machine learning model trained on these data was 75%–79% accurate at predicting viral reactivation. Finally,we validated the role of two candidate HIV-regulating factors,FOXP1 and GATA3,in viral transcription. These data demonstrate the power of integrated multimodal single-cell analysis to uncover novel relationships between host cell factors and HIV latency.
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EasySep™小鼠TIL（CD45）正选试剂盒
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