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The molecular underpinnings of the uncontrolled release of proinflammatory cytokines and chemokines ('cytokine storm'), which can cause organ damage and even mortality, are not completely understood. Furthermore, targeted therapeutic options to dampen such hyperinflammation are scarce. Here, we highlight the ways in which technological advances have set the stage for a new age of synergy between experimental and computational researchers to guide the discovery of novel therapeutic targets for modulating hyperinflammation.

Candida albicans is the most common cause of fungal sepsis. Inhibition of inflammasome activity confers resistance to polymicrobial and LPS-induced sepsis; however, inflammasome signaling appears to protect against C. albicans infection, so inflammasome inhibitors are not clinically useful for candidiasis. Here we show disruption of GSDMD, a known inflammasome target and key pyroptotic cell death mediator, paradoxically alleviates candidiasis, improving outcomes and survival of Candida-infected mice. Mechanistically, C. albicans hijacked the canonical inflammasome-GSDMD axis-mediated pyroptosis to promote their escape from macrophages, deploying hyphae and candidalysin, a pore-forming toxin expressed by hyphae. GSDMD inhibition alleviated candidiasis by preventing C. albicans escape from macrophages while maintaining inflammasome-dependent but GSDMD-independent IL-1β production for anti-fungal host defenses. This study demonstrates key functions for GSDMD in Candida’s escape from host immunity in vitro and in vivo and suggests that GSDMD may be a potential therapeutic target in C. albicans-induced sepsis., Inflammasome signalling has been shown to protect Candida albicans during infection and as such limits inflammasome inhibitors in this context. Here the authors implicate Gasdermin D in C.ablicans immune evasion and suggests its targeting therapeutically.

Inflammasomes are important sentinels of innate immune defence, sensing pathogens and inducing cell death in infected cells1. There are several inflammasome sensors that each detect and respond to a specific pathogen- or damage-associated molecular pattern (PAMP or DAMP, respectively)1. During infection, live pathogens can induce the release of multiple PAMPs and DAMPs, which can simultaneously engage multiple inflammasome sensors2–5. Here we found that AIM2 regulates the innate immune sensors pyrin and ZBP1 to drive inflammatory signalling and a form of inflammatory cell death known as PANoptosis, and provide host protection during infections with herpes simplex virus 1 and Francisella novicida. We also observed that AIM2, pyrin and ZBP1 were members of a large multi-protein complex along with ASC, caspase-1, caspase-8, RIPK3, RIPK1 and FADD, that drove inflammatory cell death (PANoptosis). Collectively, our findings define a previously unknown regulatory and molecular interaction between AIM2, pyrin and ZBP1 that drives assembly of an AIM2-mediated multi-protein complex that we term the AIM2 PANoptosome and comprising multiple inflammasome sensors and cell death regulators. These results advance the understanding of the functions of these molecules in innate immunity and inflammatory cell death, suggesting new therapeutic targets for AIM2-, ZBP1- and pyrin-mediated diseases. AIM2 responds to infection with herpes simplex virus 1 or Francisella novicida by driving assembly of a large multi-protein complex containing multiple inflammasome sensors and cell death regulators.

Transplant center performance and practice variation for pediatric post-liver transplantation (LT) outcomes other than survival are understudied. This was a retrospective cohort study of pediatric LT recipients who received transplants between January 1, 2006, and May 31, 2017, using United Network for Organ Sharing (UNOS) data that were merged with the Pediatric Health Information System database. Center effects for the acute rejection rate at 1 year after LT (AR1) using UNOS coding and the biliary complication rate at 1 year after LT (BC1) using inpatient billing claims data were estimated by center-specific rescaled odds ratios that accounted for potential differences in recipient and donor characteristics. There were 2216 pediatric LT recipients at 24 freestanding children's hospitals in the United States during the study period. The median unadjusted center rate of AR1 was 36.92% (interquartile range [IQR], 22.36%-44.52%), whereas that of BC1 was 32.29% (IQR, 26.14%-40.44%). Accounting for recipient case mix and donor factors, 5/24 centers performed better than expected with regard to AR1, whereas 3/24 centers performed worse than expected. There was less heterogeneity across the center effects for BC1 than for AR1. There was no relationship observed between the center effects for AR1 or BC1 and center volume. Beyond recipient and allograft factors, differences in transplant center management are an important driver of center AR1 performance, and less so of BC1 performance. Further research is needed to identify the sources of variability so as to implement the most effective solutions to broadly enhance outcomes for pediatric LT recipients.

Cytokine storm syndrome (CSS) has generally been described as a collection of clinical manifestations resulting from an overactivated immune system. Cytokine storms (CSs) are associated with various pathologies, as observed in infectious diseases, certain acquired or inherited immunodeficiencies and autoinflammatory diseases, or following therapeutic interventions. Despite the role of CS in tissue damage and multiorgan failure, a systematic understanding of its underlying molecular mechanisms is lacking. Recent studies demonstrate a positive feedback loop between cytokine release and cell death pathways; certain cytokines, pathogen-associated molecular patterns (PAMPs), and damage-associated molecular patterns (DAMPs), can activate inflammatory cell death, leading to further cytokine secretion. Here, we discuss recent progress in innate immunity and inflammatory cell death, providing insights into the cellular and molecular mechanisms of CSs and therapeutics that might quell ensuing life-threatening effects.

Graphical abstract, Pyroptosis, apoptosis and necroptosis are the most genetically well-defined programmed cell death (PCD) pathways, and they are intricately involved in both homeostasis and disease. Although the identification of key initiators, effectors and executioners in each of these three PCD pathways has historically delineated them as distinct, growing evidence has highlighted extensive crosstalk among them. These observations have led to the establishment of the concept of PANoptosis, defined as an inflammatory PCD pathway regulated by the PANoptosome complex with key features of pyroptosis, apoptosis and/or necroptosis that cannot be accounted for by any of these PCD pathways alone. In this review, we provide a brief overview of the research history of pyroptosis, apoptosis and necroptosis. We then examine the intricate crosstalk among these PCD pathways to discuss the current evidence for PANoptosis. We also detail the molecular evidence for the assembly of the PANoptosome complex, a molecular scaffold for contemporaneous engagement of key molecules from pyroptosis, apoptosis, and/or necroptosis. PANoptosis is now known to be critically involved in many diseases, including infection, sterile inflammation and cancer, and future discovery of novel PANoptotic components will continue to broaden our understanding of the fundamental processes of cell death and inform the development of new therapeutics.

Resistance to cell death is a hallmark of cancer. Immunotherapy, particularly immune checkpoint blockade therapy, drives immune-mediated cell death and has greatly improved treatment outcomes for some patients with cancer, but it often fails clinically. Its success relies on the cytokines and cytotoxic functions of effector immune cells to bypass the resistance to cell death and eliminate cancer cells. However, the specific cytokines capable of inducing cell death in tumors and the mechanisms that connect cytokines to cell death across cancer cell types remain unknown. In this study, we analyzed expression of several cytokines that are modulated in tumors and found correlations between cytokine expression and mortality. Of several cytokines tested for their ability to kill cancer cells, only TNF-α and IFN-γ together were able to induce cell death in 13 distinct human cancer cell lines derived from colon and lung cancer, melanoma, and leukemia. Further evaluation of the specific programmed cell death pathways activated by TNF-α and IFN-γ in these cancer lines identified PANoptosis, a form of inflammatory cell death that was previously shown to be activated by contemporaneous engagement of components from pyroptosis, apoptosis, and/or necroptosis. Specifically, TNF-α and IFN-γ triggered activation of gasdermin D, gasdermin E, caspase-8, caspase-3, caspase-7, and MLKL. Furthermore, the intratumoral administration of TNF-α and IFN-γ suppressed the growth of transplanted xenograft tumors in an NSG mouse model. Overall, this study shows that PANoptosis, induced by synergism of TNF-α and IFN-γ, is an important mechanism to kill cancer cells and suppress tumor growth that could be therapeutically targeted.

Background: Para nasal sinuses are air-filled cavities present in facial bones. Sinusitis is a common medical problem affecting millions of people annually. CT screening of paranasal sinuses has the advantages of showing bony details and good soft tissue outlines. CT is valuable in the identification of variations in pneumatisation of sphenoid sinuses and characterization of sphenoid variations prior to FESS and trans-sphenoidal surgeries. Materials and Methods: This was a cross-sectional study conducted at Dr. PSIMS & RF, Chinnavutapalli. This study was done on SIEMENS SOMATOM EMOTION 16 slice spiral CT machine. We included a total of 100 patients clinically diagnosed with chronic sinusitis, who were referred for CT scan of PNS in our hospital. Results: Out of 100 patients, 52 males and 48 females. Most of the patients were in the 20-30 years age group comprising 55% of the study population. Presellar type of pneumatisation found in (83%), Postsellar type of pneumatisation (11%). Pneumatisation of pterygoid process (42%), anterior clinoid process (28%), greater wing of sphenoid (22%). Bilateral protrusion of internal carotid artery (19 cases), right side (5 cases) and on left side (3 cases). Protrusion of optic nerve noted in 21 cases, among these 14 bilaterally, (4) right N and (3) left side, maxillary nerve protrusion (16 cases), among these 8 (bilaterally), (5) right and (3) left side, Vidian nerve protrusion (20 cases), among these (8) bilaterally, (7) right and (5) left side. Conclusion: Computed Tomography plays an important role in visualization of variation in sphenoid sinus and its pneumatisation patterns and has re-emphasized the concept that variations especially in the sphenoid sinus region is the key factor in the causation of accidental damage to vital structures like ICA, Optic nerve, Maxillary nerve and Vidian nerve.

There are over 50 SARS‐CoV‐2 candidate vaccines undergoing Phase II and III clinical trials. Several vaccines have been approved by regulatory authorities and rolled out for use in different countries. Due to concerns of potential teratogenicity or adverse effect on maternal physiology, pregnancy has been a specific exclusion criterion for most vaccine trials with only two trials not excluding pregnant women. Thus, other than limited animal studies, gradually emerging development and reproductive toxicity data, and observational data from vaccine registries, there is a paucity of reliable information to guide recommendations for the safe vaccination of pregnant women. Pregnancy is a risk factor for severe COVID‐19, especially in women with comorbidities, resulting in increased rates of preterm birth and maternal morbidity. We discuss the major SARS‐CoV‐2 vaccines, their mechanisms of action, efficacy, safety profile and possible benefits to the maternal‐fetal dyad to create a rational approach towards maternal vaccination while anticipating and mitigating vaccine‐related complications. Pregnant women with high exposure risks or co‐morbidities predisposing to severe COVID‐19 infection should be prioritised for vaccination. Those with risk factors for adverse effects should be counselled accordingly. It is essential to support patient autonomy by shared decision‐making involving a risk‐benefit discussion with the pregnant woman., Key points What is already known about this topic? COVID‐19 infection in pregnancy leads to an increase in adverse maternal outcomes.Owing to paucity of data regarding SARS‐CoV‐2 vaccine use in pregnancy there is uncertainty regarding safety of use and subsequent pregnancy outcomes. What does this study add? Provides an overview of the available SARS‐CoV‐2 vaccines, their mechanisms of action and feasibility of use in pregnancy.Summarises recommendations regarding vaccination of pregnant or lactating women.

Cardiotoxicity is a well-established complication of multiple cancer therapeutics, and the one of the most prominent effects that limits the use of these agents is in the form of left ventricular dysfunction, otherwise known as chemotherapy-induced cardiomyopathy (CIMP). Because CIMP can worsen patient outcomes and interfere with a patient's life-saving cancer treatments, it is important to implement a monitoring strategy for patients undergoing potentially cardiotoxic treatments. Efforts have been made by multiple societies to provide recommendations for screening and monitoring for CIMP in at-risk patients, with slight variations between guideline documents and expert consensuses. Most of the recommendations for monitoring for CIMP are specific to anthracyclines and the human epidermal growth factor receptor 2-antagonist trastuzumab, with very limited guidance for other cardiotoxic agents such as Tyr kinase inhibitors and proteasome inhibitors, which we cover in this article. Echocardiography remains the mainstay for imaging surveillance because of its safety profile and widespread availability, but the accuracy of cardiac magnetic resonance imaging (CMR) makes it an important modality when there are discrepancies in left ventricular ejection fraction assessment. Subclinical cardiotoxicity may be detected using laboratory biomarkers such as cardiac troponin and brain natriuretic peptide as well as myocardial deformation (strain) imaging by echocardiography or CMR. Specific recommendations for timing and frequency of laboratory biomarker assessment remain up for debate, but myocardial deformation imaging should be performed with every echocardiogram or CMR assessment. Future studies are needed to evaluate the efficacy of established surveillance recommendations and to develop specific recommendations for novel cancer therapeutics.

Objectives Poor sleep is a vital symptom observed in many psychiatric conditions and is the most neglected and underdiagnosed. The current study aims at assessment of sleep quality among psychiatric patients using the Pittsburgh Sleep Quality Index (PSQI) scale and to identify the predictors of sleep quality. Methods A hospital-based cross-sectional observational study conducted in the Psychiatry department with a sample size of 256 patients for six months. PSQI scale was used to assess sleep quality and multiple logistic regression was used (to identify) the predictors for poor sleep quality. Results The mean age of the study population was 37.95 ± 14.11 years, with 148 (58%) male study participants. 192 (75%) of the study population had poor sleep quality with respect to PSQI scale with a mean score of 9.05 ± 4.65 that was well above the expected range (0–5) suggestive of compromised quality of sleep (p=0.001). Poor sleep satisfaction, waking up after the sleep onset, anorexia, day time drowsiness and at least one completely sleepless night in the past one week of admission were identified as good predictors for poor sleep quality. Conclusions Our study addresses the importance of assessing sleep quality regardless of the psychiatric conditions. We recommend screening patients if they have Poor sleep satisfaction, waking up after the sleep onset, anorexia, day time drowsiness or at least one completely sleepless night in the past one week of admission predictors for comorbid sleep disorders.

Fibromuscular dysplasia is a nonatherosclerotic, under-recognized disorder primarily seen in middle-aged women. It can lead to several complications, such as hypertension, headaches, dissections, aneurysms, myocardial infarctions, and cerebrovascular accidents, to name a few. This article provides a comprehensive review of current literature on epidemiology, etiology, diagnosis, treatment, and long-term surveillance and fibromuscular dysplasia management. In addition, it renders the role of education and prevention for patients living with this condition and family screening. Lastly, it emphasizes the importance of a comprehensive multidisciplinary care model and patient input, given the complexity of this disease and its systemic presence and protean manifestations.

There is strong evidence that nicotine can enhance cognitive functions and growing evidence that this effect may be larger in young healthy APOE e4 carriers. However, the moderating effects of the APOE e4 allele on cognitive impairments caused by nicotine deprivation in chronic smokers have not yet been studied with brain indices. We sought to determine whether young female carriers of the APOE e4 allele, relative to noncarriers, would exhibit larger abstinence-induced decreases in P3b amplitude during a two-stimulus auditory oddball task. We compared parietal P3bs in female chronic smokers with either APOE e3/e3 (n = 54) or e3/e4 (n = 20) genotype under nicotine-sated conditions and after 12–17-h nicotine deprivation. Nicotine deprivation significantly reduced P3b amplitudes in APOE e4 carriers, but not in APOE-e3/e3 individuals, such that the difference seen prior to nicotine deprivation was eliminated. The results suggest that subjects with the APOE e4 allele are more sensitive to nicotine, which could influence smoking patterns, the risk for nicotine dependence, and the cognitive effects of nicotine use in these individuals.

The innate immune system, the first line of defense against pathogens and host tissue damage, initiates pro-inflammatory responses which, when dysregulated, promote inflammation to drive a broad range of autoimmune diseases. Immunomodulatory therapies have been developed to successfully treat several autoimmune diseases, but still many others lack effective treatments. Here, we explore recent advances in how the innate immune system contributes to autoinflammation, from the innate immune sensors that initiate immune responses to how this system regulates the activation of programmed cell death pathways including pyroptosis, apoptosis, necroptosis, and PANoptosis, which involves machinery from the pyroptotic, apoptotic, and necroptotic pathways. Recent advances in our understanding of innate immunity raise important considerations for developing new inflammatory disease treatments that target innate immune signaling and programmed cell death pathways.

Introduction: Pregnant women are reported to be at increased risk of severe coronavirus disease 2019 (COVID-19) due to underlying immunosuppression during pregnancy. However, the clinical course of COVID-19 in pregnancy and risk of vertical and horizontal transmission remain relatively unknown. We aim to describe and evaluate outcomes in pregnant women with COVID-19 in Singapore. Methods: Prospective observational study of 16 pregnant patients admitted for COVID-19 to 4 tertiary hospitals in Singapore. Outcomes included severe disease, pregnancy loss, and vertical and horizontal transmission. Results: Of the 16 patients, 37.5%, 43.8% and 18.7% were infected in the first, second and third trimesters, respectively. Two gravidas aged ≥35 years (12.5%) developed severe pneumonia; one patient (body mass index 32.9kg/m2) required transfer to intensive care. The median duration of acute infection was 19 days; one patient remained reverse transcription polymerase chain reaction (RT-PCR) positive >11 weeks from diagnosis. There were no maternal mortalities. Five pregnancies produced term live-births while 2 spontaneous miscarriages occurred at 11 and 23 weeks. RT-PCR of breast milk and maternal and neonatal samples taken at birth were negative; placenta and cord histology showed non-specific inflammation; and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific immunoglobulins were elevated in paired maternal and umbilical cord blood (n=5). Conclusion: The majority of COVID-19 infected pregnant women had mild disease and only 2 women with risk factors (obesity, older age) had severe infection; this represents a slightly higher incidence than observed in age-matched non-pregnant women. Among the women who delivered, there was no definitive evidence of mother-to-child transmission via breast milk or placenta. Keywords: Pregnancy outcomes, maternal morbidity, mother-child transmission, SARS-CoV-2, transferred immunity

Hospital labour room policies restrict oral intake of women in labour to clear liquids, due to fears of pulmonary aspiration in cases of emergency C-sections under general anesthesia. Professional organizations have provided varying recommendations for oral intake in labour with some advocating clear fluids alone, which are unlikely to meet the 50-100 kcal/hour energy requirements of labour; and others recommending ad-lib intake. The objective was to explore intra partum food choices and compare the effect of ad-lib oral calorific clear fluid intake vs solids and calorific clear liquids on obstetric and neonatal outcomes. A prospective observational study was conducted in low-risk pregnant women >18 years of age with 36+ gestational age in the labour wards of urban maternity tertiary centres in Hyderabad (N=211). Women were given the option of eating and drinking from a standardised low residue menu. 72.2, 22.4 and 5.38 % of the women consumed liquids, a combination of liquids and solids, and fasted respectively. Women consuming solids and fluids consumed 350.5 ± 171.9 kcal whereas those consuming only calorific clear liquids consumed 168.35 ± 106.2 kcal during the intra partum period (p

Mutations in MEFV, the gene encoding pyrin in humans, are associated with the autoinflammatory disorder familial Mediterranean fever. Pyrin is an innate sensor that assembles into an inflammasome complex in response to Rho-modifying toxins, including Clostridium difficile toxins A and B. Cell death pathways have been shown to intersect with and modulate inflammasome activation, thereby affecting host defense. Using bone marrow–derived macrophages and a murine model of peritonitis, we show in this study that receptor-interacting protein kinase (RIPK) 3 impacts pyrin inflammasome activation independent of its role in necroptosis. RIPK3 was instead required for transcriptional upregulation of Mefv through negative control of the mechanistic target of rapamycin (mTOR) pathway and independent of alterations in MAPK and NF-κB signaling. RIPK3 did not affect pyrin dephosphorylation associated with inflammasome activation. We further demonstrate that inhibition of mTOR was sufficient to promote Mefv expression and pyrin inflammasome activation, highlighting the cross-talk between the mTOR pathway and regulation of the pyrin inflammasome. Our study reveals a novel interaction between molecules involved in cell death and the mTOR pathway to regulate the pyrin inflammasome, which can be harnessed for therapeutic interventions.

Objective To evaluate the results of microsurgical clipping for single intracranial aneurysm (SIA) and multiple intracranial aneurysms (MIA) and compare the outcomes. Methods All patients who underwent surgery for intracranial aneurysm (IA) at our institution over a 3-year period (June 2013 to May 2016) were included in this study. Results A total of 157 patients with 225 IAs were included. Forty-one of these patients had MIA (109 IAs, mean, 2.7 ± 1.2; range, 2–7), and remaining 116 had SIA. In the patients with MIA, all aneurysms were secured during the same admission whenever possible. Depending on the locations of the IAs and condition of brain during surgery (tense/lax), all aneurysms were secured on same day (in a single session, single or multiple craniotomy in 28 patients) or on different days (multiple sessions in 13 patients). Postoperative control angiography (DSA) before discharge could be done for 216 aneurysms (MIA, n = 105; SIA, n = 111). Successful occlusion of the aneurysm from circulation was noted in 96.2% (101/105) of MIA and 93.7% (104/111) of SIA. Follow-up of 6 months or longer was available for 146 patients. A modified Rankin Scale score ≤2 was considered a good outcome. Univariate analysis of the entire group revealed no significant difference in clinical outcomes between patients with SIA and MIA both at discharge (good outcome: MIA, 82.9%; SIA, 93.1%; P = 0.068) and at a final follow-up of ≥6 months (good outcome: MIA, 87.2%; SIA, 94.4%; P = 0.164). Clipping for MIA was not associated with poor outcome in multivariate analysis. Conclusions Comparable clinical outcomes and high rates of complete aneurysm occlusion following microsurgical clipping can be expected in patients with SIA and patients with MIA.

Coronaviruses have caused several zoonotic infections in the past two decades, leading to significant morbidity and mortality globally. Balanced regulation of cell death and inflammatory immune responses is essential to promote protection against coronavirus infection; however, the underlying mechanisms that control these processes remain to be resolved. Here we demonstrate that infection with the murine coronavirus mouse hepatitis virus (MHV) activated the NLRP3 inflammasome and inflammatory cell death in the form of PANoptosis. Deleting NLRP3 inflammasome components or the downstream cell death executioner gasdermin D (GSDMD) led to an initial reduction in cell death followed by a robust increase in the incidence of caspase-8- and receptor-interacting serine/threonine-protein kinase 3 (RIPK3)-mediated inflammatory cell deathafter coronavirus infection. Additionally, loss of GSDMD promoted robust NLRP3 inflammasome activation. Moreover, the amounts of some cytokines released during coronavirus infection were significantly altered in the absence of GSDMD. Altogether, our findings show that inflammatory cell death, PANoptosis, is induced by coronavirus infection and that impaired NLRP3 inflammasome function or pyroptosis can lead to negative consequences for the host. These findings may have important implications for studies of coronavirus-induced disease.

Inflammasomes are multimeric heterogeneous mega-Dalton protein complexes that play key roles in the host innate immune response to infection and sterile insults. Assembly of the inflammasome complex following infection or injury begins with the oligomerization of the upstream inflammasome-forming sensor and proceeds through a multistep process of well-coordinated events and downstream effector functions. Together, these steps enable elegant experimental readouts with which to reliably assess the successful activation of the inflammasome complex and cell death. Here, we describe a comprehensive protocol that details several in vitro (in bone marrow–derived macrophages) and in vivo (in mice) strategies for activating the inflammasome and explain how to subsequently assess multiple downstream effects in parallel to unequivocally establish the activation status of the inflammasome and cell death pathways. Our workflow assesses inflammasome activation via the formation of the apoptosis-associated speck-like protein containing a CARD (ASC) speck; cleavage of caspase-1 and gasdermin D; release of IL-1β, IL-18, caspase-1, and lactate dehydrogenase from the cell; and real-time analysis of cell death by imaging. Analyses take up to ~24 h to complete. Overall, our multifaceted approach provides a comprehensive and consistent protocol for assessing inflammasome activation and cell death. This protocol describes a toolbox for comprehensive characterization of inflammasome activation and cell death in response to both in vivo (in mice) and in vitro (using bone marrow–derived macrophages) models of infection, sterile insults, and cancer.

Leishmania spp. infection is a global health problem affecting more than 2 million people every year with 300 million at risk worldwide. It is well established that a dominant Th1 response (IFN-γ, a hallmark Th1 cytokine) provides resistance, whereas a dominant Th2 response (IL-4, a hallmark Th2 cytokine) confers susceptibility during infection. Given the important role of IL-4 during L. major infection, we used IL-4–neutralizing Abs to investigate the cellular and molecular events regulated by IL-4 signaling. As previously published, neutralization of IL-4 in L. major–infected BALB/c mice (a Leishmania susceptible strain) provided protection when compared with control L. major–infected BALB/c mice. Despite this protection, IFN-γ production by T cells was dramatically reduced. Temporal neutralization of IL-4 revealed that acute IL-4 produced within the first days of infection is critical for not only programming IL-4–producing Th2 CD4+ T cells, but for promoting IFN-γ produced by CD8+ T cells. Mechanistically, IL-4 signaling enhances anti-CD3–induced Tbet and IFN-γ expression in both CD4+ and CD8+ T cells. Given the pathogenic role of IFN-γ–producing CD8+ T cells, our data suggest that IL-4 promotes cutaneous leishmaniasis pathology by not only promoting Th2 immune responses but also pathogenic CD8+ T cell responses. Our studies open new research grounds to investigate the unsuspected role of IL-4 in regulating both Th1 and Th2 responses.

Background and Aim The purpose of this study was to review and analyze the nature of industry payments to gastroenterology and hepatology (GI) physicians. Methods We conducted a retrospective study of open payments (OP) data for the year 2017. Payments to individual physicians were aggregated using a unique physician profile identification number. General payments to Centers for Medicare and Medicaid Services regions were also analyzed. The nature of financial transactions in general payments was reported overall and per physician payment. Research, ownership, and general payments were aggregated and analyzed by drug/device companies. Results During the study period, more GI physicians received contributions in the form of general payments compared to ownership or research payments. A small percentage of physicians received contributions greater than $100 000. The most frequent contributions were for food and beverages. Only 10 manufacturers made about 71% ($43 271 938) of general payments. Conclusions We found that only a small number of GI physicians received a significant portion of industry payments. A large portion of those payments came from drug or device companies. The impact of these payments on gastroenterologists needs to be examined further., We found that only a small number of GI physicians received a significant portion of industry payments. A large portion of those payments came from drug or device companies. The impact of these payments on gastroenterologists needs to be examined further.

ZBP1 has been characterized as a critical innate immune sensor of not only viral RNA products but also endogenous nucleic acid ligands. ZBP1 sensing of the Z-RNA produced during influenza virus infection induces cell death in the form of pyroptosis, apoptosis, and necroptosis (PANoptosis). PANoptosis is a coordinated cell death pathway that is driven through a multiprotein complex called the PANoptosome and enables crosstalk and co-regulation among these processes. During influenza virus infection, a key step in PANoptosis and PANoptosome assembly is the formation of the ZBP1-NLRP3 inflammasome. When Z-RNA is sensed, ZBP1 recruits RIPK3 and caspase-8 to activate the ZBP1-NLRP3 inflammasome. Several other host factors have been found to be important for ZBP1-NLRP3 inflammasome assembly, including molecules involved in the type I interferon signaling pathway and caspase-6. Additionally, influenza viral proteins, such as M2, NS1, and PB1-F2, have also been shown to regulate the ZBP1-NLRP3 inflammasome. This review explains the functions of ZBP1 and the mechanistic details underlying the activation of the ZBP1-NLRP3 inflammasome and the formation of the PANoptosome. Improved understanding of the ZBP1-NLRP3 inflammasome will direct the development of therapeutic strategies to target infectious and inflammatory diseases.

The crosstalk between cellular stress responses and innate immune signaling pathways remains poorly understood. Cells can respond to stressors by assembling stress granules that store 40S ribosomes, translation initiation factors, and mRNAs, and allow the cell to survive. Some stressors can activate the NLRP3 inflammasome, which leads to pyroptotic cell death. Stress granules and the NLRP3 inflammasome provide distinct cell fate choices to the cell. These complexes also involve distinct types of phase transitions-liquid-liquid phase separation for stress granules and prionoid phase transition for the NLRP3 inflammasome. We recently reported that DDX3X modulates this crosstalk by acting as a common essential factor for NLRP3 inflammasome activation and stress granule assembly. Here, we discuss the role of DDX3X in modulating the liquid-liquid phase separation and prionoid phase transition required for making cell fate decisions under stress conditions.

Caspases are a family of conserved cysteine proteases that play key roles in programmed cell death and inflammation. In multicellular organisms, caspases are activated via macromolecular signaling complexes that bring inactive procaspases together and promote their proximity-induced autoactivation and proteolytic processing. Activation of caspases ultimately results in programmed execution of cell death, and the nature of this cell death is determined by the specific caspases involved. Pioneering new research has unraveled distinct roles and cross talk of caspases in the regulation of programmed cell death, inflammation, and innate immune responses. In-depth understanding of these mechanisms is essential to foster the development of precise therapeutic targets to treat autoinflammatory disorders, infectious diseases, and cancer. This review focuses on mechanisms governing caspase activation and programmed cell death with special emphasis on the recent progress in caspase cross talk and caspase-driven gasdermin D–induced pyroptosis.

Chronic recurrent multifocal osteomyelitis (CRMO) in humans can be modeled in Pstpip2cmo mice, which carry a missense mutation in the proline–serine–threonine phosphatase–interacting protein 2 (Pstpip2) gene. As cmo disease in mice, the experimental model analogous to human CRMO, is mediated specifically by IL-1β and not by IL-1α, delineating the molecular pathways contributing to pathogenic IL-1β production is crucial to developing targeted therapies. In particular, our earlier findings support redundant roles of NLR family pyrin domain-containing 3 (NLRP3) and caspase-1 with caspase-8 in instigating cmo. However, the signaling components upstream of caspase-8 and pro-IL-1β cleavage in Pstpip2cmo mice are not well-understood. Therefore, here we investigated the signaling pathways in these mice and discovered a central role of a nonreceptor tyrosine kinase, spleen tyrosine kinase (SYK), in mediating osteomyelitis. Using several mutant mouse strains, immunoblotting, and microcomputed tomography, we demonstrate that absent in melanoma 2 (AIM2), receptor-interacting serine/ threonine protein kinase 3 (RIPK3), and caspase recruitment domain–containing protein 9 (CARD9) are each dispensable for osteomyelitis induction in Pstpip2cmo mice, whereas genetic deletion of Syk completely abrogates the disease phenotype. We further show that SYK centrally mediates signaling upstream of caspase-1 and caspase-8 activation and principally up-regulates NF-κB and IL-1β signaling in Pstpip2cmo mice, thereby inducing cmo. These results provide a rationale for directly targeting SYK and its downstream signaling components in CRMO.

Recognition of invading pathogens and execution of defensive responses are crucial steps in successfully combating infectious diseases. Inflammasomes are a group of diverse, signal-transducing complexes with key roles in both processes. While the responses mediated by inflammasomes are vital to host defense, aberrations in inflammasome regulation or activity can lead to the development of autoimmune and sterile inflammatory diseases, including cancer. The field of inflammasome research has rapidly expanded to identify novel regulatory pathways, new inflammasome components, and the mechanistic details of the activation of these complexes. In this review, we discuss recent insights into the regulation of inflammasomes by interferon regulatory factor proteins, newly discovered mechanisms of activation for the NLRP1b and NLRP6 inflammasomes, and recent studies exploring the viability of inflammasome-modulating immunotherapies.

Background: C-type lectin receptors, including Dectin-2, are pattern recognition receptors on monocytes and macrophages that mainly recognize sugars and sugar-like structures present on fungi. Activation of C-type lectin receptors induces downstream CARD9 signalling, leading to the production of cytokines. We hypothesized that under hyperglycaemic conditions, as is the case in diabetes mellitus, glycosylated protein (sugar-like) structures activate C-type lectin receptors, leading to immune cell activation and increased atherosclerosis development. Methods: Low-density lipoprotein receptor-deficient mice were lethally irradiated and transplanted with bone marrow from control wild-type, Dectin-2−/− or Card9−/− mice. After 6 weeks of recovery, mice received streptozotocin injections (50 mg/g BW; 5 days) to induce hyperglycaemia. After an additional 2 weeks, mice were fed a Western-type diet (0.1% cholesterol) for 10 weeks. Results and Conclusion: Deletion of haematopoietic Dectin-2 reduced the number of circulating Ly6Chi monocytes, increased pro-inflammatory cytokine production, but did not affect atherosclerosis development. Deletion of haematopoietic CARD9 tended to reduce macrophage and collagen content in atherosclerotic lesions, again without influencing the lesion size. Deletion of haematopoietic Dectin-2 did not influence atherosclerosis development under hyperglycaemic conditions, despite some minor effects on inflammation. Deletion of haematopoietic CARD9 induced minor alterations in plaque composition under hyperglycaemic conditions, without affecting lesion size.

BACKGROUND In the United States, nearly 30% of liver transplants (LT) are performed for hepatocellular carcinoma (HCC). Although overall long-term survival is highest with LT, there are limited data on the incremental survival benefit of LT versus other curative options (resection or ablation) due to shunting of patients towards LT. METHODS We performed a retrospective cohort study of patients aged 50-69 with cirrhosis and HCC in the Veterans Health Administration (population enriched with 3 curative treatments) from 2008 to 2016. The cohort was restricted to patients who received LT, resection, or ablation and a calculated model for end-stage liver disease score

The possibility of using the supplementary cementitious materials (SCM’s) in order to suppress the impact of CO2 emissions and preserve the natural resources from manufacturing of cement is being explored for further refinement in the field of construction. In this paper, GGBS and Fly Ash have been utilized as a replacement for cement in 3 different grades, apart from studying the mechanical properties of the blended concrete we are learning durability characteristics for sulphuric acid, sulphate and chloride attacks through experimental research. The replacements of SCM’s are from 40% to 60% relative in percentage with cement weight (Cement: SCM’s) with 3 proposed mixes (PM) established under the name PM1 (60:40), PM2 (50:50) and PM3 (40:60) for 3 different grades namely ordinary (M20), standard (M40) and high strength concrete (M60). The best proposed mix is selected among the three mixes of each grade depending upon the withstanding capacity of loss in mass and compressive strength when subjected to chemical exposure. The chloride ingress percentage is also calculated from the cubes subjected to chloride attack. The 50% replacement to cement is expected to satisfy the required durability criteria of all the three grades.

International audience; Invasive fungal infections remain highly problematic for human health. Collectively, they account for more than 1 million deaths a year in addition to more than 100 million mucosal infections and 1 billion skin infections. To be able to make progress it is important to understand the pathobiology of fungal interactions with the immune system. Here, we highlight new advancements pointing out the pivotal role of fungal cell wall components (β-glucan, mannan, galactosaminogalactan and melanin) in modulating host immunity and discuss how these open new opportunities for the development of immunomodulatory strategies to combat deadly fungal infectious diseases.

Summary Sepsis remains a deadly disease with limited treatment options. In this issue of Immunity, Tang et al. propose that heparin provides protection during gram-negative sepsis by dampening harmful CASP11-dependent signaling through inhibition of HMGB1- and heparanase-mediated cytosolic delivery of LPS.

International audience; Galactosaminogalactan of Aspergillus fumigatus acts as a pathogen-associated molecular pattern that activates the NLRP3 inflammasome, which is crucial for anti-fungal host defence.Inflammasomes are important sentinels of innate immune defence that are activated in response to diverse stimuli, including pathogen-associated molecular patterns (PAMPs)(1). Activation of the inflammasome provides host defence against aspergillosis(2,3), which is a major health concern for patients who are immunocompromised. However, the Aspergillus fumigatus PAMPs that are responsible for inflammasome activation are not known. Here we show that the polysaccharide galactosaminogalactan (GAG) of A. fumigatus is a PAMP that activates the NLRP3 inflammasome. The binding of GAG to ribosomal proteins inhibited cellular translation machinery, and thus activated the NLRP3 inflammasome. The galactosamine moiety bound to ribosomal proteins and blocked cellular translation, which triggered activation of the NLRP3 inflammasome. In mice, a GAG-deficient Aspergillus mutant (Delta gt4c) did not elicit protective activation of the inflammasome, and this strain exhibited enhanced virulence. Moreover, administration of GAG protected mice from colitis induced by dextran sulfate sodium in an inflammasome-dependent manner. Thus, ribosomes connect the sensing of this fungal PAMP to the activation of an innate immune response.

NOD-like receptor (NLR), family pyrin domain containing 3 (NLRP3) assembles an intracellular protein complex known as the NLRP3 inflammasome upon sensing certain pathogen products or sterile danger signals. Gain-of-function mutations such as the D301N substitution in NLRP3, which cause its constitutive activation (NLRP3(CA)) also results in inflammasome assembly. This inflammasome processes pro-interleukin-1 β (pro-IL-1β) and pro-IL-18 into bioactive IL-1β and IL-18, respectively, and cleaves gasdermin D (GSDMD). GSDMD N-terminal fragments form plasma membrane pores that facilitate the secretion of IL-1β and IL-18 and lead to the inflammatory cell death pyroptosis. Accordingly, GSDMD inactivation results in negligible spontaneous inflammation in various experimental models such as in Nlrp3(CA/+) mice lacking GSDMD (Nlrp3(CA/+);Gsdmd(−/−) mice). Here, we found that Nlrp3(CA/+);Gsdmd(−/−) mice, when challenged with LPS or TNF-α, still secreted IL-1β and IL-18, indicating inflammasome activation independent of GSDMD. Accordingly, Gsdmd(−/−) macrophages failed to secrete IL-1β and undergo pyroptosis when briefly exposed to NLRP3 inflammasome activators (LPS and nigericin), but released these cytokines when persistently activated. Sustained NLRP3 inflammasome induced caspase-8/−3 and GSDME cleavage, and IL-1β maturation in vitro in Gsdmd(−/−) macrophages. Thus, a salvage inflammatory pathway involving caspase-8/−3-GSDME was activated following NLRP3 activation when the canonical NLRP3-GSDMD signaling was blocked. Consistent with genetic data, the active metabolite of FDA-approved disulfiram CuET, which inhibited GSDMD and GSDME cleavage in macrophages, reduced the severe inflammation and tissue damage that occurred in the Nlrp3(CA) mice. Thus, NLRP3 inflammasome activation overwhelms the protection afforded by GSDMD deficiency, rewiring signaling cascades through mechanisms that include GSDME to propagate inflammation.