ResearchPad - 12 https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[IL-36 signaling in keratinocytes controls early IL-23 production in psoriasis-like dermatitis]]> https://www.researchpad.co/article/N1b891aae-13f8-4b62-a8c8-0b6c69ae164e IL-36R signaling plays an important role in the pathogenesis of psoriasis. We ought to assess the specific function of IL-36R in keratinocytes for the pathology of Aldara-induced psoriasis-like dermatitis. Il36rΔK mice presenting deletion of IL-36R in keratinocytes were similarly resistant to Aldara-induced ear inflammation as Il36r−/− mice, but acanthosis was only prevented in Il36r−/− mice. FACS analysis revealed that IL-36R signaling in keratinocytes is mandatory for early neutrophil infiltration in Aldara-treated ears. RNASeq and qRT-PCR experiments demonstrated the crucial role of IL-36R signaling in keratinocytes for induction of IL-23, IL-17, and IL-22 at early time points. Taken together, our results demonstrate that IL-36R signaling in keratinocytes plays a major role in the induction of Aldara-induced psoriasis-like dermatitis by triggering early production of IL-23/IL-17/IL-22 cytokines and neutrophil infiltration.

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<![CDATA[Immunoglobulin expression in the endoplasmic reticulum shapes the metabolic fitness of B lymphocytes]]> https://www.researchpad.co/article/N6964f0da-e6b4-4f5b-86a0-5e5ef8e23ad0 The major function of B lymphocytes is to sense antigens and to produce protective antibodies after activation. This function requires the expression of a B-cell antigen receptor (BCR), and evolutionary conserved mechanisms seem to exist that ensure that B cells without a BCR do not develop nor survive in the periphery. Here, we show that the loss of BCR expression on Burkitt lymphoma cells leads to decreased mitochondrial function and impaired metabolic flexibility. Strikingly, this phenotype does not result from the absence of a classical Syk-dependent BCR signal but rather from compromised ER expansion. We show that the reexpression of immunoglobulins (Ig) in the absence of the BCR signaling subunits Igα and Igβ rescues the observed metabolic defects. We demonstrate that immunoglobulin expression is needed to maintain ER homeostasis not only in lymphoma cells but also in resting B cells. Our study provides evidence that the expression of BCR components, which is sensed in the ER and shapes mitochondrial function, represents a novel mechanism of metabolic control in B cells.

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<![CDATA[Paneth cell α-defensin misfolding correlates with dysbiosis and ileitis in Crohn’s disease model mice]]> https://www.researchpad.co/article/N4cdc74ff-002c-45bb-8f1d-ad7f957c837c Crohn’s disease (CD) is an intractable inflammatory bowel disease, and dysbiosis, disruption of the intestinal microbiota, is associated with CD pathophysiology. ER stress, disruption of ER homeostasis in Paneth cells of the small intestine, and α-defensin misfolding have been reported in CD patients. Because α-defensins regulate the composition of the intestinal microbiota, their misfolding may cause dysbiosis. However, whether ER stress, α-defensin misfolding, and dysbiosis contribute to the pathophysiology of CD remains unknown. Here, we show that abnormal Paneth cells with markers of ER stress appear in SAMP1/YitFc, a mouse model of CD, along with disease progression. Those mice secrete reduced-form α-defensins that lack disulfide bonds into the intestinal lumen, a condition not found in normal mice, and reduced-form α-defensins correlate with dysbiosis during disease progression. Moreover, administration of reduced-form α-defensins to wild-type mice induces the dysbiosis. These data provide novel insights into CD pathogenesis induced by dysbiosis resulting from Paneth cell α-defensin misfolding and they suggest further that Paneth cells may be potential therapeutic targets.

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<![CDATA[Caspase-1 cleaves Bid to release mitochondrial SMAC and drive secondary necrosis in the absence of GSDMD]]> https://www.researchpad.co/article/N99bb8269-ea3c-4297-95c3-ad00b279d27a Caspase-1 drives a lytic inflammatory cell death named pyroptosis by cleaving the pore-forming cell death executor gasdermin-D (GSDMD). Gsdmd deficiency, however, only delays cell lysis, indicating that caspase-1 controls alternative cell death pathways. Here, we show that in the absence of GSDMD, caspase-1 activates apoptotic initiator and executioner caspases and triggers a rapid progression into secondary necrosis. GSDMD-independent cell death required direct caspase-1–driven truncation of Bid and generation of caspase-3 p19/p12 by either caspase-8 or caspase-9. tBid-induced mitochondrial outer membrane permeabilization was also required to drive SMAC release and relieve inhibitor of apoptosis protein inhibition of caspase-3, thereby allowing caspase-3 auto-processing to the fully active p17/p12 form. Our data reveal that cell lysis in inflammasome-activated Gsdmd-deficient cells is caused by a synergistic effect of rapid caspase-1–driven activation of initiator caspases-8/-9 and Bid cleavage, resulting in an unusually fast activation of caspase-3 and immediate transition into secondary necrosis. This pathway might be advantageous for the host in counteracting pathogen-induced inhibition of GSDMD but also has implications for the use of GSDMD inhibitors in immune therapies for caspase-1–dependent inflammatory disease.

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<![CDATA[ERS International Congress, Madrid, 2019: highlights from the Basic and Translational Science Assembly]]> https://www.researchpad.co/article/Nf2211aea-35d3-4e6f-892a-97256fe90cde

In this review, the Basic and Translational Sciences Assembly of the European Respiratory Society (ERS) provides an overview of the 2019 ERS International Congress highlights. In particular, we discuss how the novel and very promising technology of single cell sequencing has led to the development of a comprehensive map of the human lung, the lung cell atlas, including the discovery of novel cell types and new insights into cellular trajectories in lung health and disease. Further, we summarise recent insights in the field of respiratory infections, which can aid in a better understanding of the molecular mechanisms underlying these infections in order to develop novel vaccines and improved treatment options. Novel concepts delineating the early origins of lung disease are focused on the effects of pre- and post-natal exposures on neonatal lung development and long-term lung health. Moreover, we discuss how these early life exposures can affect the lung microbiome and respiratory infections. In addition, the importance of metabolomics and mitochondrial function analysis to subphenotype chronic lung disease patients according to their metabolic program is described. Finally, basic and translational respiratory science is rapidly moving forward and this will be beneficial for an advanced molecular understanding of the mechanisms underlying a variety of lung diseases. In the long-term this will aid in the development of novel therapeutic targeting strategies in the field of respiratory medicine.

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<![CDATA[Oxidised metabolites of the omega-6 fatty acid linoleic acid activate dFOXO]]> https://www.researchpad.co/article/N91118500-8b11-473c-aef7-328f25615f52

Oxidised omega-6 fatty acids activate the FOXO transducers of the Insulin signaling pathway potentially linking changes in dietary fatty acid balance and proinflammatory states with insulin resistance.

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<![CDATA[Constitutive CD8 expression drives innate CD8+ T-cell differentiation via induction of iNKT2 cells]]> https://www.researchpad.co/article/Na8bd6ed8-51bb-4857-a48d-fd087d426ae0

Constitutive CD8 expression induces differentiation of innate memory-like CD8+ thymocytes in both cell-intrinsic and cell-extrinsic manner, the latter being accomplished by an increase in the iNKT2 subset.

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<![CDATA[Why does radial head arthroplasty fail today? A systematic review of recent literature]]> https://www.researchpad.co/article/Ne0babf35-a698-4b18-9457-7a400e814025

  • Since the introduction of the radial head prosthesis (RHP) in 1941, many designs have been introduced. It is not clear whether prosthesis design parameters are related to early failure. The aim of this systematic review is to report on failure modes and to explore the association between implant design and early failure.

  • A search was conducted to identify studies reporting on failed primary RHP. The results are clustered per type of RHP based on: material, fixation technique, modularity, and polarity. Chi-square tests are used to compare reasons for failure between the groups.

  • Thirty-four articles are included involving 152 failed radial head arthroplasties (RHAs) in 152 patients. Eighteen different types of RHPs have been used.

  • The most frequent reasons for revision surgery after RHA are (aseptic) loosening (30%), elbow stiffness (20%) and/or persisting pain (17%). Failure occurs after an average of 34 months (range, 0–348 months; median, 14 months).

  • Press-fit prostheses fail at a higher ratio because of symptomatic loosening than intentionally loose-fit prostheses and prostheses that are fixed with an expandable stem (p < 0.01).

  • Because of the many different types of RHP used to date and the limited numbers and evidence on early failure of RHA, the current data provide no evidence for a specific RHP design.

Cite this article: EFORT Open Rev 2019;4:659-667. DOI: 10.1302/2058-5241.4.180099

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<![CDATA[Virus-induced transposable element expression up-regulation in human and mouse host cells]]> https://www.researchpad.co/article/Ndbdd434c-7f8d-4bb3-8cc0-b6af110392c2

Genome-wide transposon expression up-regulation in host cells regardless of virus, species, and host cell tissue types occurs early during viral infection and likely contributes to promoting the host innate immune response.

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<![CDATA[Attenuation of capsaicin-induced ongoing pain and secondary hyperalgesia during exposure to an immersive virtual reality environment]]> https://www.researchpad.co/article/Naa481e53-8c34-473d-856c-1a7b8b6e4b75

Abstract

Introduction:

There is growing evidence that virtual reality (VR) can be used in the treatment of chronic pain conditions. However, further research is required to better understand the analgesic mechanisms during sensitised pain states.

Objectives:

We examined the effects of an immersive polar VR environment on capsaicin-induced ongoing pain and secondary hyperalgesia. We also investigated whether the degree of analgesia was related to baseline conditioned pain modulation (CPM) responses.

Methods:

Nineteen subjects had baseline CPM and electrical pain perception (EPP) thresholds measured before the topical application of capsaicin cream. Visual analogue scale ratings were measured to track the development of an ongoing pain state, and EPP thresholds were used to measure secondary hyperalgesia. The effects of a passive polar VR environment on ongoing pain and secondary hyperalgesia were compared with sham VR (ie, 2D monitor screen) in responders to capsaicin (n = 15).

Results:

Virtual reality was associated with a transient reduction in ongoing pain and an increase in EPP thresholds in an area of secondary hyperalgesia. Baseline CPM measurements showed a significant correlation with VR-induced changes in secondary hyperalgesia, but not with VR-induced changes in ongoing pain perception. There was no correlation between VR-induced changes in pain perception and VR-induced changes in secondary hyperalgesia.

Conclusion:

Virtual reality can reduce the perception of capsaicin-induced ongoing pain and secondary hyperalgesia. We also show that CPM may provide a means by which to identify individuals likely to respond to VR therapy.

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<![CDATA[Interactions between analgesic drug therapy and mindfulness-based interventions for chronic pain in adults: protocol for a systematic scoping review]]> https://www.researchpad.co/article/N3394ffea-4258-4698-960b-c9dda2bff59a

Abstract

Introduction:

Most current chronic pain treatment strategies have limitations in effectiveness and tolerability, and accumulating evidence points to the added benefits of rational combinations of different therapies. However, most published clinical trials of treatment combinations have involved combinations of 2 drugs, whereas very little research has been performed to characterize interactions between drug and nondrug interventions. Mindfulness-based interventions (MBIs) have been emerging as a safe and potentially effective treatment option in the management of chronic pain, but it is unclear how MBIs can and should be integrated with various other pain treatment interventions. Thus, we seek to review available clinical trials of MBIs for chronic pain to evaluate available evidence on the interactions between MBIs and various pharmacological treatments.

Methods:

A detailed search of trials of MBIs for the treatment of chronic pain in adults will be conducted on the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and PsycINFO from their inception until the date the searches are run to identify relevant randomized controlled trials. Primary outcomes will include the following: (1) what concomitant analgesic drug therapies (CADTs) were allowed; (2) if and how trials controlled for CADTs and analyzed their interaction; and (3) results of available analyses of interactions between the MBI and CADT.

Perspective:

This review is expected to synthesize available evidence describing the interactions between MBIs and various studied drug therapies for chronic pain. Available evidence may help inform the rational integration of MBIs with drug therapy for chronic pain.

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<![CDATA[Expression of AXL receptor tyrosine kinase relates to monocyte dysfunction and severity of cirrhosis]]> https://www.researchpad.co/article/N0e6a9dad-9dbe-457a-a350-1071f1e934c0

Immune dysfunction determines morbidity and mortality in liver cirrhosis. Distinct AXL-expressing circulating monocytes, which regulate antimicrobial responses, expand with progression of the disease.

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<![CDATA[Essential functions of Runx/Cbfβ in gut conventional dendritic cells for priming Rorγt+ T cells]]> https://www.researchpad.co/article/N18812e98-912d-4ae6-9963-b77d81878a55

Loss of Runx/Cbfβ complexes during DC development leads to a loss of gut CD103+CD11b+ cDC2s, which was accompanied with impaired differentiation of both Rorγt+ Th17 cells and type 3 Rorγt+ Treg cells.

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<![CDATA[Cx3cr1-deficient microglia exhibit a premature aging transcriptome]]> https://www.researchpad.co/article/N638d702c-9e49-4479-a1d0-6b9ec6f25536

Gyoneva et al use RNA-seq to show that Cx3cr1-deficient microglia in young mice display a gene expression profile similar to microglia in aged mice, suggesting premature microglial aging.

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<![CDATA[The AKT isoforms 1 and 2 drive B cell fate decisions during the germinal center response]]> https://www.researchpad.co/article/N4c52b72e-a23c-473e-8d30-a2250d2a366c

B cell–intrinsic AKT1/2 are essential for germinal center formation, antibody production and affinity maturation, and plasma cell differentiation.

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<![CDATA[Worldwide genetic variation of the IGHV and TRBV immune receptor gene families in humans]]> https://www.researchpad.co/article/5c8bfe29d5eed0c484b28512

This article presents a comprehensive study of the IGHV and TRBV gene families in a globally diverse sample of humans and shows that the two gene families exhibit starkly different patterns of variation.

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<![CDATA[Assessing the scales in numerical weather and climate predictions: will exascale be the rescue?]]> https://www.researchpad.co/article/5c8bfbd9d5eed0c484b24aa5

We discuss scientific features and computational performance of kilometre-scale global weather and climate simulations, considering the Icosahedral Non-hydrostatic (ICON) model and the Integrated Forecast System (IFS). Scalability measurements and a performance modelling approach are used to derive performance estimates for these models on upcoming exascale supercomputers. This is complemented by preliminary analyses of the model data that illustrate the importance of high-resolution models to gain improvements in the accuracy of convective processes, a better understanding of physics dynamics interactions and poorly resolved or parametrized processes, such as gravity waves, convection and boundary layer.

This article is part of the theme issue ‘Multiscale modelling, simulation and computing: from the desktop to the exascale’.

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<![CDATA[Association among cytotoxic T-lymphocyte antigen 4 gene, rs231775 polymorphism, and recurrent pregnancy loss risk]]> https://www.researchpad.co/article/5c6863e7d5eed0c484023c41

Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is expressed constitutively on regulatory T cells. So far, several studies have focused on association between CTLA-4 gene polymorphisms and recurrent pregnancy loss (RPL). However, above association between the CTLA-4 gene polymorphism and RPL susceptibility is uncertain. Therefore, we performed a timely meta-analysis of all current publications to clarify this relationship. We located articles from the PubMed and Chinese language (WanFang) databases that were published up until July 25, 2018. Finally, we obtained six case–control studies, containing 2405 total cases and 2607 total controls, based on search criteria for abortion susceptibility related to the CTLA-4 +49 G/A polymorphism. The odds ratios (OR) and 95% confidence intervals (CIs) revealed association strengths. There was significantly decreased association between this polymorphism and whole population risk (e.g. AA vs. GG: OR = 0.56, 95% CI = 0.38–0.81, P=0.002). Additionally, in ethnicity subgroups, similar association was found both in China (e.g. AA vs. GG: OR = 0.49, 95% CI = 0.39–0.63, P=0.002) and non-China (e.g. AG vs. GG: OR = 0.46, 95% CI = 0.34–0.63, P<0.001). Current analysis suggested CTLA-4 +49 G/A polymorphism may weakly decrease RPL risk for women of childbearing age.

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<![CDATA[No evidence of widespread mechanical pressure hyperalgesia after experimentally induced central sensitization through skin nociceptors]]> https://www.researchpad.co/article/5c61b866d5eed0c4849394c7

High-frequency stimulation of the skin induces secondary pinprick hyperalgesia but does not affect pressure pain thresholds either locally or at more distant body sites.

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<![CDATA[Viperin controls chikungunya virus–specific pathogenic T cell IFNγ Th1 stimulation in mice]]> https://www.researchpad.co/article/5c5afb62d5eed0c48425feed

This study shows that Viperin controls the microenvironment pro-inflammatory response and CD4 T cell–mediated pathogenesis during anti-chikungunya virus immune response in mice.

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