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Deficiency of adenosine deaminase 2 (DADA2) was first described as a monogenic form of systemic vasculitis that closely resembles polyarteritis nodosa (PAN). The phenotypic spectrum of DADA2 has vastly expanded in recent years and now includes pure red cell aplasia, bone marrow failure syndrome, lymphoproliferative disease, and humoral immunodeficiency. Vasculitis remains the most common presentation of DADA2, and treatment with tumor necrosis factor inhibitors (TNFi) has shown remarkable efficacy in preventing stroke and ameliorating features of systemic inflammation. The precise function of ADA2 has not been elucidated, and how absence of ADA2 ignites inflammation is an active area of research. In this review, we will discuss the current understanding of DADA2 from research and clinical perspectives. We will evaluate several proposed functions of ADA2, including polarization of monocyte phenotype, regulation of neutrophil extracellular trap formation, and modulation of innate immunity. We will also review the role of inflammatory cytokines including TNF and type I interferons. Lastly, we will provide future perspectives on understanding the phenotypic heterogeneity of DADA2 and discuss potential treatment options.

BACKGROUNDPediatric SARS-CoV-2 infection can be complicated by a dangerous hyperinflammatory condition termed multisystem inflammatory syndrome in children (MIS-C). The clinical and immunologic spectrum of MIS-C and its relationship to other inflammatory conditions of childhood have not been studied in detail.METHODSWe retrospectively studied confirmed cases of MIS-C at our institution from March to June 2020. The clinical characteristics, laboratory studies, and treatment response were collected. Data were compared with historic cohorts of Kawasaki disease (KD) and macrophage activation syndrome (MAS).RESULTSTwenty-eight patients fulfilled the case definition of MIS-C. Median age at presentation was 9 years (range: 1 month to 17 years); 50% of patients had preexisting conditions. All patients had laboratory confirmation of SARS-CoV-2 infection. Seventeen patients (61%) required intensive care, including 7 patients (25%) who required inotrope support. Seven patients (25%) met criteria for complete or incomplete KD, and coronary abnormalities were found in 6 cases. Lymphopenia, thrombocytopenia, and elevation in inflammatory markers, D-dimer, B-type natriuretic peptide, IL-6, and IL-10 levels were common but not ubiquitous. Cytopenias distinguished MIS-C from KD and the degree of hyperferritinemia and pattern of cytokine production differed between MIS-C and MAS. Immunomodulatory therapy given to patients with MIS-C included intravenous immune globulin (IVIG) (71%), corticosteroids (61%), and anakinra (18%). Clinical and laboratory improvement were observed in all cases, including 6 cases that did not require immunomodulatory therapy. No mortality was recorded in this cohort.CONCLUSIONMIS-C encompasses a broad phenotypic spectrum with clinical and laboratory features distinct from KD and MAS.FUNDINGThis work was supported by the National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases; the National Institute of Allergy and Infectious Diseases; Rheumatology Research Foundation Investigator Awards and Medical Education Award; Boston Children's Hospital Faculty Career Development Awards; the McCance Family Foundation; and the Samara Jan Turkel Center.

Activation of RIPK1 controls TNF-mediated apoptosis, necroptosis and inflammatory pathways 1 . Cleavage of human and mouse RIPK1 after residues D324 and D325, respectively, by caspase-8 separates the RIPK1 kinase domain from the intermediate and death domains. The D325A mutation in mouse RIPK1 leads to embryonic lethality during mouse development 2 , 3 . However, the functional importance of blocking caspase-8-mediated cleavage of RIPK1 on RIPK1 activation in humans is unknown. Here we identify two families with variants in RIPK1 (D324V and D324H) that lead to distinct symptoms of recurrent fevers and lymphadenopathy in an autosomal-dominant manner. Impaired cleavage of RIPK1 D324 variants by caspase-8 sensitized patients’ peripheral blood mononuclear cells to RIPK1 activation, apoptosis and necroptosis induced by TNF. The patients showed strong RIPK1-dependent activation of inflammatory signalling pathways and overproduction of inflammatory cytokines and chemokines compared with unaffected controls. Furthermore, we show that expression of the RIPK1 mutants D325V or D325H in mouse embryonic fibroblasts confers not only increased sensitivity to RIPK1 activation-mediated apoptosis and necroptosis, but also induction of pro-inflammatory cytokines such as IL-6 and TNF. By contrast, patient-derived fibroblasts showed reduced expression of RIPK1 and downregulated production of reactive oxygen species, resulting in resistance to necroptosis and ferroptosis. Together, these data suggest that human non-cleavable RIPK1 variants promote activation of RIPK1, and lead to an autoinflammatory disease characterized by hypersensitivity to apoptosis and necroptosis and increased inflammatory response in peripheral blood mononuclear cells, as well as a compensatory mechanism to protect against several pro-death stimuli in fibroblasts. A dominantly inherited human autoinflammatory disease caused by mutations in RIPK1 is identified, and RIPK1 mutations that prevent caspase-8 cleavage sensitize cells to apoptosis, necroptosis and inflammation.

Anion-intercalation lithium metal batteries (AILMBs) are appealing due to their low cost and fast intercalation/de-intercalation kinetics of graphite cathodes. However, the safety and cycliability of existing AILMBs are constrained by the scarcity of compatible electrolytes. Herein, we showcase that a difluoroester can be applied as electrolyte solvent to realize high-performance AILMBs, which not only endows high oxidation resistance, but also efficiently tunes the solvation shell to enable highly reversible and kinetically fast cathode reaction beyond the trifluoro counterpart. The difluoroester-based electrolyte demonstrates nonflammability, high ionic conductivity, and electrochemical stability, along with excellent electrode compatibility. The Li| |graphite AILMBs reach a high durability of 10000 cycles with only a 0.00128% capacity loss per cycle under fast-cycling of 1 A g −1 , and retain ~63% of room-temperature capacity when discharging at −65 °C, meanwhile supply stable power output under deformation and overcharge conditions. The electrolyte design paves a promising path toward fast-rate, low-temperature, durable, and safe AILMBs. The authors report a difluoroester electrolyte to enhance anion intercalation lithium metal batteries (AILMBs), improving safety and cyclability. This enables cost-effective graphitic carbon cathodes, with high durability, stability, and performance.

The Cloud-Aerosol Lidar and Infrared Pathfinder Satellite Operations (CALIPSO) mission released version 4.1 (V4) of their lidar level 2 cloud and aerosol data products in November 2016. These new products were derived from the CALIPSO V4 lidar level 1 data, in which the calibration of the measured backscatter data at both 532 and 1064 nm was significantly improved. This paper describes updates to the V4 level 2 cloud–aerosol discrimination (CAD) algorithm that more accurately differentiate between clouds and aerosols throughout the Earth's atmosphere. The level 2 data products are improved with new CAD probability density functions (PDFs) that were developed to accommodate extensive calibration changes in the level 1 data. To enable more reliable identification of aerosol layers lofted into the upper troposphere and lower stratosphere, the CAD training dataset used in the earlier data releases was expanded to include stratospheric layers and representative examples of volcanic aerosol layers. The generic “stratospheric layer” classification reported in previous versions has been eliminated in V4, and cloud–aerosol classification is now performed on all layers detected everywhere from the surface to 30 km. Cloud–aerosol classification has been further extended to layers detected at single-shot resolution, which were previously classified by default as clouds. In this paper, we describe the underlying rationale used in constructing the V4 PDFs and assess the performance of the V4 CAD algorithm in the troposphere and stratosphere. Previous misclassifications of lofted dust and smoke in the troposphere have been largely improved, and volcanic aerosol layers and aerosol layers in the stratosphere are now being properly classified. CAD performance for single-shot layer detections is also evaluated. Most of the single-shot layers classified as aerosol occur within the dust belt, as may be expected. Due to changes in the 532 nm calibration coefficients, the V4 feature finder detects ∼9.0 % more features at night and ∼2.5 % more during the day. These features are typically weakly scattering and classified about equally as clouds and aerosols. For those tropospheric layers detected in both V3 and V4, the CAD classifications of more than 95 % of all cloud and daytime aerosol layers remain unchanged, as do the classifications of ∼89 % of nighttime aerosol layers. Overall, the nighttime net cloud and aerosol fractions remain unchanged from V3 to V4, but the daytime net aerosol fraction is increased by about 2 % and the daytime net cloud fraction is decreased by about 2 %.

gem -Difluoroalkene is a bioisostere of carbonyl group for improving bioavailability of drug candidates. Herein we develop structurally diverse 2,2-difluorovinyl benzoates (BzO-DFs) as versatile building blocks for modular synthesis of gem- difluoroenol ethers (44 examples) and gem- difluoroalkenes (2 examples) by Ni-catalyzed cross coupling reactions. Diverse BzO-DFs derivatives bearing sensitive functional groups (e.g., C = C, TMS, strained carbocycles) are readily prepared from their bromodifluoroacetates and bromodifluoroketones precursors using metallic zinc as reductant. With Ni(COD) 2 and dppf [1,1’-bis(diphenylphosphino)ferrocene] as catalyst, reactions of BzO-DFs with arylboronic acids and arylmagnesium/alkylzinc reagents afforded the desired gem- difluoroenol ethers and gem- difluoroalkenes in good yields. The Ni-catalyzed coupling reactions features highly regioselective C(vinyl)–O(benzoate) bond activation of the BzO-DFs. Results from control experiments and DFT calculations are consistent with a mechanism involving initial oxidative addition of the BzO-DFs by the Ni(0) complex. By virtue of diversity of the BzO-DFs and excellent functional group tolerance, this method is amenable to late-stage functionalization of multifunctionalized bioactive molecules. The gem -difluoroalkene functionality is relevant to drug design as it is a bioisostere of a carbonyl group. Here, the authors report the synthesis of 2,2-difluorovinyl benzoates as versatile building blocks for modular synthesis of gem -difluoroenol ethers and gem -difluoroalkenes by nickel-catalyzed cross coupling.

Neutrophils are cells at the frontline of innate immunity that can quickly activate effector functions to eliminate pathogens upon stimulation. However, little is known about the metabolic adaptations that power these functions. Here we show rapid metabolic alterations in neutrophils upon activation, particularly drastic reconfiguration around the pentose phosphate pathway, which is specifically and quantitatively coupled to an oxidative burst. During this oxidative burst, neutrophils switch from glycolysis-dominant metabolism to a unique metabolic mode termed ‘pentose cycle’, where all glucose-6-phosphate is diverted into oxidative pentose phosphate pathway and net flux through upper glycolysis is reversed to allow substantial recycling of pentose phosphates. This reconfiguration maximizes NADPH yield to fuel superoxide production via NADPH oxidase. Disruptions of pentose cycle greatly suppress oxidative burst, the release of neutrophil extracellular traps and pathogen killing by neutrophils. Together, these results demonstrate the remarkable metabolic flexibility of neutrophils, which is essential for their functions as the first responders in innate immunity. Upon activation, neutrophils undergo rapid metabolic reconfigurations towards pentose cycling, which powers their effector functions.

Descriptions are provided of the aerosol classification algorithms and the extinction-to-backscatter ratio (lidar ratio) selection schemes for the Cloud-Aerosol Lidar and Infrared Pathfinder Satellite Observations (CALIPSO) aerosol products. One year of CALIPSO level 2 version 2 data are analyzed to assess the veracity of the CALIPSO aerosol-type identification algorithm and generate vertically resolved distributions of aerosol types and their respective optical characteristics. To assess the robustness of the algorithm, the interannual variability is analyzed by using a fixed season (June–August) and aerosol type (polluted dust) over two consecutive years (2006 and 2007). The CALIPSO models define six aerosol types: clean continental, clean marine, dust, polluted continental, polluted dust, and smoke, with 532-nm (1064 nm) extinction-to-backscatter ratios Sa of 35 (30), 20 (45), 40 (55), 70 (30), 65 (30), and 70 (40) sr, respectively. This paper presents the global distributions of the CALIPSO aerosol types, the complementary distributions of integrated attenuated backscatter, and the volume depolarization ratio for each type. The aerosol-type distributions are further partitioned according to surface type (land/ocean) and detection resolution (5, 20, and 80 km) for optical and spatial context, because the optically thick layers are found most often at the smallest spatial resolution. Except for clean marine and polluted continental, all the aerosol types are found preferentially at the 80-km resolution. Nearly 80% of the smoke cases and 60% of the polluted dust cases are found over water, whereas dust and polluted continental cases are found over both land and water at comparable frequencies. Because the CALIPSO observables do not sufficiently constrain the determination of the aerosol, the surface type is used to augment the selection criteria. Distributions of the total attenuated color ratios show that the use of surface type in the typing algorithm does not result in abrupt and artificial changes in aerosol type or extinction.

PurposeGold porphyrin (AuP) is a complex that has been shown to be potent against various tumors. A biocompatible interpenetrating network (IPN) system comprised of polyethyleneglycol diacrylate (PEGdA) and chemically-modified gelatin has been shown to be an effective implantable drug depot to deliver AuP locally. Here we designed IPN microparticles complexed with AuP to facilitate intravenous administration and to diminish systemic toxicity.MethodsWe have synthesized and optimized an IPN microparticle formulation complexed with AuP. Tumor cell cytotoxicity, antitumor activity, and survival rate in lung cancer bearing nude mice were analyzed.ResultsIPN microparticles maintained AuP bioactivity against lung cancer cells (NCI-H460). In vivo study showed no observable systemic toxicity in nude mice bearing NCI-H460 xenografts after intravenous injection of 6 mg/kg AuP formulated with IPN microparticles. An anti-tumor activity level comparable to free AuP was maintained. Mice treated with 6 mg/kg AuP in IPN microparticles showed 100% survival rate while the survival rate of mice treated with free AuP was much less. Furthermore, microparticle-formulated AuP significantly reduced the intratumoral microvasculature when compared with the control.ConclusionAuP in IPN microparticles can reduce the systemic toxicity of AuP without compromising its antitumor activity. This work highlighted the potential application of AuP in IPN microparticles for anticancer chemotherapy.

ObjectivesWe aim to investigate the genetic basis of a case of late-onset autoinflammatory disease characterised by arthritis, recurrent fever and skin rashes.MethodsWe performed whole-exome/genome sequencing and digital droplet PCR (ddPCR) to identify the pathogenic somatic mutation. We used single-cell RNA sequencing (scRNA-seq), intracellular cytokine staining, quantitative PCR, immunohistochemistry and western blotting to define inflammatory signatures and to explore the pathogenic mechanism.ResultsWe identified a somatic mutation in NLRC4 (p.His443Gln) with the highest mosaicism ratio in the patient’s monocytes (5.69%). The somatic mutation resulted in constitutive NLRC4 activation, spontaneous apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) aggregation, caspase-1 hyperactivation and increased production of interleukin (IL)-1β and IL-18. Moreover, we demonstrated effective suppression of inflammatory cytokine production by targeting gasdermin D, an approach that could be considered as a novel treatment strategy for patients with NLRC4-associated autoinflammatory syndrome.ConclusionsWe reported a case of a late-onset autoinflammatory disease caused by a somatic NLRC4 mutation in a small subset of leucocytes. We systemically analysed this condition at a single-cell transcriptomic level and revealed specific enhancement of inflammatory response in myeloid cells.