Subsequent Trigger Research Articles

Matthew effect: General design strategy of ultra‐fluorogenic nanoprobes with amplified dark–bright states in aggregates

AbstractFluorescence imaging, a key technique in biological research, frequently utilizes fluorogenic probes for precise imaging in living systems. Tetrazine is an effective emission quencher in fluorogenic probe designs, which can be selectively damaged upon bioorthogonal click reactions, leading to considerable emission enhancement. Despite significant efforts to increase the emission enhancement ratio (IAC/IBC) of tetrazine‐functionalized fluorogenic probes, the influence of molecular aggregation on the emission properties has been largely overlooked in these probe designs. In this study, we reveal that an ultrahigh IAC/IBC can be realized in the aggregate system when tetrazine is paired with aggregation‐induced emission (AIE) luminogens. Tetrazine amplifies its quenching efficiency upon aggregation and drastically reduce background emissions. Subsequent click reactions damage tetrazine and trigger significant AIE, leading to considerably enhanced IAC/IBC. We further showcase the capability of these ultra‐fluorogenic systems in selective imaging of multiple organelles in living cells. We term this unique fluorogenicity of AIE luminogen‐quencher complexes with amplified dark‐bright states as “Matthew effect” in aggregate emission, potentially providing a universal approach to attain ultrahigh IAC/IBC in diverse fluorogenic systems.

Analysis of a National Database Investigating Development of Trigger Finger after Treatment of Dupuytren Disease.

A commercial database encompassing 53 million patients was utilized from January 1, 2010 to March 31, 2020. The study cohort included patients diagnosed with either Dupuytren disease or trigger finger utilizing International Classification Codes 9 and 10. Terminology codes were used to identify common Dupuytren procedures, as well as trigger finger release. Logistic regression analysis was used to define independent risk factors for developing trigger finger. A total of 593,606 patients were diagnosed with trigger finger. Of these patients, 15,416 (2.6%) were diagnosed with trigger finger after diagnosis of Dupuytren disease, whereas 2603 (0.4%) patients were diagnosed with trigger finger after treatment of Dupuytren contracture. Independent risk factors for trigger finger included age 65 years or older (OR 1.00, P < 0.05), diabetes (OR 1.12, P < 0.05) and obesity (OR 1.20, P < 0.005). Patients who received collagenase clostridium histolyticum treatment (OR 0.34, P < 0.005) for Dupuytren contracture were significantly less likely to develop trigger finger. Dupuytren contracture is associated with inflammation and subsequent trigger finger development at a higher rate than the background population frequency. Collagenase clostridium histolyticum injection may lead to a decreased risk of trigger finger requiring surgical intervention in patients with risk factors.

Comparison of advanced generation cryoballoon ablation and ablation index-guided pulmonary vein isolation with non-pulmonary vein trigger induction test and additional ablation in paroxysmal atrial fibrillation.

An ablation index (AI)-guided pulmonary vein isolation (PVI) or 2nd generation cryoballoon (CB)-PVI has been shown to reduce the atrial fibrillation (AF) burden by 99% despite the absence of ablation of non-pulmonary vein (PV) triggers in patients with paroxysmal AF. The purpose of this study was to investigate the effects of PVI alone strategy using 2nd generation CB compared with AI-guided PVI with an additional induction test and subsequent AF trigger ablation. We investigated 223 patients with symptomatic paroxysmal AF who underwent an initial PVI between August 2018 and August 2020. The study patients were divided into 2 groups: CB-PVI without an induction test (CB-PVI alone group, n = 82) and AI-guided PVI with an induction test and subsequent additional ablation of non-PV triggers (AI-PVI plus group, n = 141). In the AI-PVI plus group, a total of 62 non-PV triggers were induced in 38 patients, and non-PV triggers in 22 patients were completely ablated. The procedure time and left atrium dwell time were significantly shorter in the CB-PVI alone group than AI-PVI plus group. There were no significant differences in the incidence of procedural complications between the 2 groups (P = 0.650). The AF free survival rate in the CB-PVI alone group and AI-PVI plus group was 80% vs. 80% at 24months (P = 0.969). An PVI alone strategy using advanced generation CB did not differ in the clinical outcomes compared with an AI-guided PVI strategy with an induction test and subsequent ablation of non-PV triggers in the patients with paroxysmal AF.

Polarization of human iPSC-derived macrophages directs their immunological response to secondary pro-inflammatory stimuli

Macrophages can be found in various tissues and play an important role in organ function by sensing and eradicating pathogens, regulating immune responses and contributing to tissue homeostasis and repair. Nowadays, increasing numbers of macrophage-based cell therapies are entering (pre-) clinical studies e.g. for the treatment of liver cirrhosis. Given limited availability of suitable donors as well as problems with variability in quantities and qualities of human monocytes that can be derived from apheresis, induced pluripotent stem cells (iPSC) offer an attractive source of therapeutic macrophages. However, considering the diverse functions, activation stages and overall plasticity of macrophages, further knowledge about (i) the potential to induce different activation stages in iPSC-derived macrophages (iPSC-Mac) as well as (ii) the stability of these phenotypes upon additional external stimuli is of high relevance. We here demonstrate that iPSC-Mac produced in a scalable differentiation platform can be polarized into defined pro- (M1) and anti-inflammatory (M2) activation stages characterized by specific surface marker expression, cytokine secretion and whole transcriptome analysis, similarly to peripheral blood-derived macrophages. Even more importantly, we show that differentially polarized iPSC-Mac maintained key characteristics of their activation status upon a subsequent inflammatory trigger. Interferon (IFN) γ polarized, M1-iPSC-Mac demonstrated an enhanced inflammatory response after additional lipopolysaccharide (LPS) stimulation, whereas Interleukin (IL)-4 stimulated M2a iPSC-Mac and IL-10/TGFβ primed M2c iPSC-Mac showed a reduced activation upon LPS treatment and maintained expression of anti-inflammatory genes. Together, our data demonstrate that defined polarized iPSC-Mac subsets can be generated. Moreover, these cells maintain key characteristics of their activation profile upon a subsequent inflammatory trigger. Thus, the use of stably polarized iPSC-Mac has the potential to further improve the applicability and efficacy of macrophage-based therapies.

Covid Vaccine as a Trigger for Grave’s Hyperthyroidism: Cases and Literature Review

Objective: Grave’s Disease is a systemic autoimmune disease directly caused by circulating auto-antibodies that bind to the thyrotropin receptor, subsequently inducing the production and release of thyroid hormone, proliferation of thyrocytes, and enlargement of the thyroid gland. Clinical practice has shown possible uncovering of Grave’s Disease following SARS-Cov-2 vaccine. The aim of this report is to shed the light on Grave’s Disease cases post SARS-Cov-2 vaccine, while reviewing the link between the vaccine and subsequent trigger of thyroid autoimmune hyperactivity. Cases: We present the case of a middle-aged woman with Grave’s disease following Hashimoto hypothyroidism manifesting 1 month post vaccine. A 36-year-old man presents with asymptomatic Grave’s disease 1 week following the vaccine. A 33-year-old woman presents with full blown Grave’s disease 9 days following vaccination. A 33-year-old man develops symptomatic Grave’s disease 3 weeks after the vaccine. Review: Cases presented above reflect different presentations of Grave’s disease. Moreso, the literature harbors similar cases of Grave’s disease recurrence, initial manifestation and exacerbation following SARS-Cov-2 vaccine. Grave’s disease etiology is autoimmune but environmental, genetic, and immunological factors contribute to its onset. The vaccine can potentially trigger autoimmune hyper-reactivity through the hyper-inflammatory response to the virus itself but also through the adjuvant found in the vaccine (Shoenfeld’s Syndrome) Conclusion: Cases of Grave’s disease manifestation or exacerbation post SARS-Cov-2 vaccines are reported. Theories are like SARS- Cov-2 -induced Grave’s Disease but also other mechanisms are uniquely mediated by vaccines. That vaccination benefit outweighs the potential risks but one should have a low threshold to test and follow patients at risk for auto-immune thyroid diseases after receiving SARS-CovV-2 vaccine.

Emotional Intelligence Contributes to the Feeling of Self-Realization: A Case of Russian Young Adults

Introduction. Young adults compose one of the most dynamic social groups, sensitive to changes. Dependent on various personal characteristics and life circumstances, this sensitivity could lead either to successful social adaptation and subsequent life satisfaction or trigger dysfunctional behaviours and psychological maladaptation. Young adults often face the contradiction between profound need for self-realization and limited capacity for achieving it and need psychological resources to overcome this challenge. This study takes to the next new level empirical exploration of the role emotional intelligence plays in shaping self-realization in young adults. Methods. The sample of study participants included full- (N = 52) and part-time (N = 60) university students. They completed demographic forms, Multidimensional Questionnaire on Personality Self-Realization – personal, professional, and social, and the Emotional Intelligence Questionnaire. Correlational and regression analyses were employed for data processing. Results. Participants’ age, especially in conjunction with the part-time working status was negatively correlated with all three types of self-realization, Hierarchical multiple regression analysis revealed that the general factor of emotional intelligence significantly contributed to self-realization (p &lt; 0.01). Furthermore, its interpersonal component was the strongest predictor, uniquely contributing from 7 % to 16% of explained variability in the criterion variables. Discussion. The findings indicate that emotional intelligence is a strong adaptive factor capable of compensating for the negative influence of challenging changes in life circumstances. Implications for further research and applied practice of psychological aid for young adults in their transition from educational to working environments are considered and discussed.

HUMAN T-CELL LYMPHOTROPIC VIRUS TYPE 1-ASSOCIATED ADULT T-CELL LEUKEMIA/LYMPHOMA AND PROGRESSION TO HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS: A CASE REPORT

TOPIC: Critical Care TYPE: Medical Student/Resident Case Reports INTRODUCTION: Human T-cell lymphotropic virus type 1 (HTLV-1) was the first human retrovirus to be discovered [1]. Its infection can lead to adult T-cell leukemia/lymphoma (ATLL). Hemophagocytic lymphohistiocytosis (HLH) is a syndrome with a mortality of 95% caused by overstimulation of the immune system [2,3,4]. This case report presents a male with HTLV-1—associated ATLL who developed HLH. CASE PRESENTATION: A 75 year-old Haitian male with a 22 pack-year smoking history presented to our hospital after a pre-syncopal episode with a 10 day history of pleuritic chest pain. Labs were significant for leukocytosis of 26.2 *10^9/L with lymphocyte predominance. Chest x-ray showed bilateral pleural effusions. Cytometry of the pleural fluid showed an aberrant population of CD4(+) T lymphocytes consistent with post-thymic T-cell lymphoma and atypical T lymphocytes, positive for CD45RO, CD25, and TCRab and negative for CD26 and CD56, consistent with ATLL. Bronchoscopy with endobronchial ultrasound-guided fine needle aspiration of lymph node stations 4R, 7, and 11L revealed aberrant T-cells. TCR gene rearrangement and HTLV-1 western blot confirmed ATLL due to HTLV-1. He was started on CHOP and brentuximab, but was readmitted weeks later with encephalopathy and acute hypoxic respiratory failure. CMV viremia was confirmed via serum PCR and ganciclovir was initiated. Labs were significant for elevated ferritin 9,464 ng/mL, triglycerides 162 mg/dL, D-dimer 549 ng/mL, low fibrinogen 150 mg/dL, and worsening cytopenia with hematocrit 27.1% and platelets 58*10^9/L. Bone marrow biopsy demonstrated histiocytes with engulfed erythroid cells, confirming HLH. The patient was treated with dexamethasone, but was too unstable for etoposide and died 12 days after readmission. DISCUSSION: Lymphoma is the third most common cause of malignant pleural effusion (MPE) and patients have an overall survival of 3-12 months after diagnosis [5]. Diagnostic tests for ATLL are usually done with serum and rarely from MPE, as was done in this case [6]. Signs of HTLV-1—associated ATLL include marked leukocytosis with atypical lymphocytes, rash, and lymphadenopathy [1]. Our patient did not have a rash, but had other signs and symptoms consistent with the presentation of HTLV-1—associated ATLL. HLH likely occurred from progression of HTLV-1—associated ATLL, but CMV viremia or chemotherapy could have contributed. The diagnosis of HLH is difficult because symptoms are nonspecific, requiring a high index of suspicion [7]. The optimal treatment for HLH is still unknown and a multidisciplinary approach is essential. CONCLUSIONS: This case demonstrates HLTV-1—associated ATLL that initially presented as MPE, and was a subsequent trigger for HLH. REFERENCE #1: Rodriguez-Zuniga MJM, Corte-Franco F, Qujiano-Gomero E. Adult T-Cell Leukemia/Lymphoma. Review of the Literature. Actas Dermosifiliogr. 2018;109(5):399-407 REFERENCE #2: Atteritano M, David A, Bagnato G, et al. Haemophagocytic syndrome in rheumatic patients. A systematic review. Eur Rev Med Pharmacol Sci. 2012;16(10):1414-1424 REFERENCE #3: Bindra BS, Garcia de de Jesus K, Cisneros O, Jorge VM, Kaur H. Hemophagocytic Lymphohistiocytosis: Management and Special Consideration in Human Immunodeficiency Virus Positive Patients with Immune Reconstitution Syndrome. Cureus. 2019;11(8):e5402 DISCLOSURES: No relevant relationships by Michael Bender, source=Web Response No relevant relationships by Liane Emerson, source=Web Response No relevant relationships by Chaim Rube, source=Web Response

The Peculiar Trialogue between Pediatric Obesity, Systemic Inflammatory Status, and Immunity.

Simple SummaryThe dogma that adipose tissue is a simple energy storage tissue is no longer accepted since it has been proved that it also has an incontestable multifunctional role acting like a true standalone organ resembling to endocrine or immune organs. Nevertheless, the scarcity of longitudinal studies involving pediatric subjects hinder disclosure regarding the long-term effect of this inflammation into adulthood and the outcome of interventional strategies on reducing the complications associated with this low-grade systemic inflammation.Pediatric obesity is not only an energetic imbalance, but also a chronic complex multisystem disorder that might impair both the life length and quality. Its pandemic status should increase worldwide awareness regarding the long-term life-threatening associated complications. Obesity related complications, such as cardiovascular, metabolic, or hepatic ones, affect both short and long-term wellbeing, and they do not spare pediatric subjects, defined as life-threatening consequences of the systemic inflammatory status triggered by the adipose tissue. The energetic imbalance of obesity clearly results in adipocytes hypertrophy and hyperplasia expressing different degrees of chronic inflammation. Adipose tissue might be considered an immune organ due to its rich content in a complex array of immune cells, among which the formerly mentioned macrophages, neutrophils, mast cells, but also eosinophils along with T and B cells, acting together to maintain the tissue homeostasis in normal weight individuals. Adipokines belong to the class of innate immunity humoral effectors, and they play a crucial role in amplifying the immune responses with a subsequent trigger effect on leukocyte activation. The usefulness of complete cellular blood count parameters, such as leukocytes, lymphocytes, neutrophils, erythrocytes, and platelets as predictors of obesity-triggered inflammation, was also proved in pediatric patients with overweight or obesity. The dogma that adipose tissue is a simple energy storage tissue is no longer accepted since it has been proved that it also has an incontestable multifunctional role acting like a true standalone organ resembling to endocrine or immune organs.

Calcium mediated functional interplay between myocardial cells upon laser-induced single-cell injury: an in vitro study of cardiac cell death signaling mechanisms

BackgroundThe electromechanical function of myocardial tissue depends on the intercellular communication between cardiomyocytes (CMs) as well as their crosstalk with other cell types. Cell injury, and subsequent death trigger inflammation as in myocardial infarction (MI) resulting in myocardial remodeling. Although mechanisms underlying myocardial cell death have been studied so far, the signaling events following single cell death and spontaneous response of connected cells in the myocardial tissue is still barely understood.MethodsHere, we investigated the effect of laser-induced single cell death on Calcium (Ca2+) concentrations and transport in myocardial cell clusters in vitro. Spatial and temporal changes in intracellular Ca2+ concentrations [Ca2+]i were studied using a fluorescent calcium indicator, Fluo-4AM. Spontaneous signaling events following cell death were studied in rat embryonic cardiomyocytes and non-myocytes using separate cell culture systems.ResultsCell death triggered spontaneous increase in intracellular Ca2+ levels ([Ca2+]i) of surrounding cells. The spread of the observed propagating Ca2+ signal was slow and sustained in myocytes while it was rapid and transient in fibroblasts (Fbs). Further, sustained high Ca2+ levels temporarily impaired the contractility in CMs. The cell-type specific effect of ablation was confirmed using separate cultures of CMs and Fbs. Comparing Ca2+ propagation speed in myocytes and fibroblasts, we argue for a diffusion-driven Ca2+ propagation in myocytes, but not in fibroblasts. Radial and sequential Ca2+ diffusion across the CMs through cell–cell contacts and presence of Cx43-based intercellular junctions indicated a gap junction flow of Ca2+.ConclusionsThese findings illustrate the spontaneous Ca2+-mediated functional interplay in myocardial cell clusters upon mechanical injury and, further, the difference in Ca2+ signaling in cardiomyocytes and fibroblasts.4bat72YCtX52-s34xWN96rVideo

The determinants of consumer engagement in restaurant food waste mitigation in Poland: An exploratory study

Abstract The growing magnitude of restaurant food waste undermines the environmental sustainability of the global sector of food service provision. The challenge of restaurant food waste is of particular concern for transitional and developing economies where food consumption out of home is becoming increasingly popular. In these markets, a large share of restaurant food waste comes from customer plates, which highlights changes to consumer behaviour as an important mitigation opportunity. Little is however known about how these behavioural changes can be activated and subsequently reinforced. This study explores the prerequisites of consumer involvement in mitigating restaurant food waste in Poland, a transitional economy in East-Central Europe. It tests the role of such prerequisites of pro-environmental consumer behaviour as public environmental knowledge, environmental concern, anticipated regret and pro-environmental behaviour at home in shaping positive customer attitudes towards the need to mitigate restaurant food waste with a subsequent trigger of behavioural intentions to engage in mitigation. The study offers policy and management recommendations on how these behavioural intentions can be reinforced.

New test helps track lurking HIV

A team of HIV researchers has created a test that could allow clinicians and scientists to better track efforts to cure the disease. Most HIV drugs attack the active virus but, after infection, HIV can also make a DNA copy of its RNA genome and insert that DNA into its host’s genome, lurking as something called a provirus. A subsequent immunological trigger can prompt these proviruses to become active and attack immune cells. These lurking proviruses are a key barrier to curing the disease. But current tests that measure the number of proviruses in someone who is HIV positive can’t distinguish between highly mutated proviruses that would be harmless and ones that are more pristine and therefore potentially more harmful should they be woken up, says Robert Siliciano of the Johns Hopkins University School of Medicine. He and his team now report a test that can make this important distinction

Acute Eosinophilic Pneumonia Following Marijuana Inhalation

SESSION TITLE: Diffuse Lung Disease SESSION TYPE: Affiliate Case Report Poster PRESENTED ON: Tuesday, October 31, 2017 at 01:30 PM - 02:30 PM INTRODUCTION: Acute eosinophilic pneumonia (AEP), first described in 1989, is a rare disorder of accumulated eosinophils within lung interstitium and alveoli. The pathogenesis of this disease is not fully known and continued reporting of clinical cases is beneficial, including AEP in association with the mold, Phoma betae. CASE PRESENTATION: A 20 year old male smoker was admitted for community acquired pneumonia. He reported inhaled marijuana use, acquired from a stranger, the day before admission. Initial chest radiograph showed bilateral consolidations and he was noted to require 2 lpm supplemental oxygen. Broad spectrum antibiotics were initiated. Over the next 24 hours he developed rapidly progressive hypoxic respiratory failure and was transferred to the ICU for high flow oxygen. Physical examination revealed a febrile and tachycardic thin man with bilateral diffuse crackles and expiratory wheezing on lung auscultation. Initial laboratory data showed a leukocytosis with 3% eosinophils. A CT thorax revealed diffuse ground glass and tree-in-bud opacities with bilateral pleural effusions. A thoracentesis revealed a transudative fluid with 30% eosinophils. Serum IgE was 333 and a hypersensitivity pneumonitis panel was positive for Phoma betae. HIV, ANCA, galactomannan and fungitel were negative. Bronchoscopy showed 67% eosinophils with an otherwise negative infectious work up. Antibiotics were discontinued and he received pulse-dose steroids with rapid improvement of his hypoxia and symptoms. He was discharged on an extended prednisone taper over the following 2 months. He was seen at an outpatient follow up visit and was notably asymptomatic with repeat CT thorax demonstrating complete resolution of prior infiltrates. DISCUSSION: Acute eosinophilic pneumonia (AEP) causes diffuse alveolar damage with accumulation of eosinophils within interstitial and alveolar spaces typically leading to rapid hypoxic respiratory failure. It is hypothesized that AEP is an immune mediated reaction to antigens, leading to eosinophilic infiltration. There is a strong association with cigarette smoking and the development of AEP. Case reports following smoke inhalation from camp fires, burning buildings, and exposure to cigarette smoke after cessation have been described. There is a paucity of cases with regard to AEP and marijuana inhalation. P. betae is a mold which naturally grows on plants, including sugar beet leaves. It has also been shown to stimulate an IgE mediated reaction in susceptible individuals. Our patient tested positive for P. betae and had smoked marijuana from a new dealer prior to developing respiratory failure. CONCLUSIONS: It is probable the marijuana was grown or transported in an area with Phoma betae exposure with subsequent trigger of AEP. Reference #1: Allen JN, Pacht ER, Gadek JE, Davis WB. Acute Eosinophilic Pneumonia as a Reversible Cause of Noninfectious Respiratory Failure. New England Journal of Medicine. 1989;321(9):569-574. doi:10.1056/nejm198908313210903. DISCLOSURE: The following authors have nothing to disclose: Maureen McElligott, Joseph Carrington, Candace Huebert No Product/Research Disclosure Information

Ammonia exposure and subsequent recovery trigger oxidative stress responses in juveniles of Brazilian flounder Paralichthys orbignyanus.

The effects of ammonia exposure and recovery on oxidative stress parameters and histology of juvenile Brazilian flounder Paralichthys orbignyanus were evaluated. The fish were exposed to 0.12, 0.28 and 0.57mgNH3-NL-1, plus a control, for 10days followed by the same recovery time in ammonia-free water. Gill, liver and muscle samples (n=9) were collected after 1, 5 and 10days of exposure and after recovery for oxidative stress analysis (antioxidant capacity against peroxyl radicals (ACAP); glutathione S-transferase (GST) activity; lipoperoxidation levels measured through thiobarbituric acid reactive substances (TBARS) content). For histological assessment, gill, liver and brain samples were collected. Exposure to all NH3-N concentrations induced different time- and dose-dependent changes in oxidative stress parameters. Reduced antioxidant capacity of the liver and muscle and enhanced TBARS levels in the gills and liver were demonstrated. Differently, a high ammonia concentration elicited lower hepatic TBARS levels. Enhanced GST activity in all organs and increased antioxidant capacity of the gills were also observed. No ammonia-induced histopathological effects were demonstrated. After recovery, most parameters (liver ACAP, GST activity in the muscle and liver and TBARS in the gills) returned to baseline levels. However, liver TBARS and gill GST activity remained altered 0.57mgNH3-NL-1 treatment. The recovery period also led to a decrease in gill antioxidant capacity and an increase in muscle antioxidant capacity. In conclusion, a concentration of 0.12mgNH3-NL-1 induces oxidative stress and antioxidant responses in juvenile Brazilian flounder. Moreover, a 10-day recovery period is not sufficient to restore fish homeostasis.

The anti-sigma factor RsrA responds to oxidative stress by reburying its hydrophobic core.

Redox-regulated effector systems that counteract oxidative stress are essential for all forms of life. Here we uncover a new paradigm for sensing oxidative stress centred on the hydrophobic core of a sensor protein. RsrA is an archetypal zinc-binding anti-sigma factor that responds to disulfide stress in the cytoplasm of Actinobacteria. We show that RsrA utilizes its hydrophobic core to bind the sigma factor σR preventing its association with RNA polymerase, and that zinc plays a central role in maintaining this high-affinity complex. Oxidation of RsrA is limited by the rate of zinc release, which weakens the RsrA–σR complex by accelerating its dissociation. The subsequent trigger disulfide, formed between specific combinations of RsrA's three zinc-binding cysteines, precipitates structural collapse to a compact state where all σR-binding residues are sequestered back into its hydrophobic core, releasing σR to activate transcription of anti-oxidant genes.

The ATLAS Trigger Core Configuration and Execution System in Light of the ATLAS Upgrade for LHC Run 2

During the 2013/14 shutdown of the Large Hadron Collider (LHC) the ATLAS first level trigger (L1) and the data acquisition system (DAQ) were substantially upgraded to cope with the increase in luminosity and collision multiplicity, expected to be delivered by the LHC in 2015. Upgrades were performed at both the L1 stage and the single combined subsequent high level trigger (HLT) stage that has been introduced to replace the two-tiered HLT stage used from 2009 to 2012 (Run 1). Because of these changes, the HLT execution framework and the trigger configuration system had to be upgraded. Also, tools and data content were adapted to the new ATLAS analysis model.

Microglia activation and interaction with neuronal cells in a biochemical model of mevalonate kinase deficiency.

Mevalonate kinase deficiency is a rare disease whose worst manifestation, characterised by severe neurologic impairment, is called mevalonic aciduria. The progressive neuronal loss associated to cell death can be studied in vitro with a simplified model based on a biochemical block of the mevalonate pathway and a subsequent inflammatory trigger. The aim of this study was to evaluate the effect of the mevalonate blocking on glial cells (BV-2) and the following effects on neuronal cells (SH-SY5Y) when the two populations were cultured together. To better understand the cross-talk between glial and neuronal cells, as it happens in vivo, BV-2 and SH-SY5Y were co-cultured in different experimental settings (alone, transwell, direct contact); the effect of mevalonate pathway biochemical block by Lovastatin, followed by LPS inflammatory trigger, were evaluated by analysing programmed cell death and mitochondrial membrane potential, cytokines' release and cells' morphology modifications. In this experimental condition, glial cells underwent an evident activation, confirmed by elevated pro-inflammatory cytokines release, typical of these disorders, and a modification in morphology. Moreover, the activation induced an increase in apoptosis. When glial cells were co-cultured with neurons, their activation caused an increase of programmed cell death also in neuronal cells, but only if the two populations were cultured in direct contact. Our findings, being aware of the limitations related to the cell models used, represent a preliminary step towards understanding the pathological and neuroinflammatory mechanisms occurring in mevalonate kinase diseases. Contact co-culture between neuronal and microglial cells seems to be a good model to study mevalonic aciduria in vitro, and to contribute to the identification of potential drugs able to block microglial activation for this orphan disease. In fact, in such a pathological condition, we demonstrated that microglial cells are activated and contribute to neuronal cell death. We can thus hypothesise that the use of microglial activation blockers could prevent this additional neuronal death.

Licochalcone A as a potent antitumor agent suppresses growth of human oral cancer SCC-25 cells in vitro via caspase-3 dependent pathways

The majority of anticancer drugs are of natural origin. However, it is unknown whether licochalcone A is cytotoxic towards oral squamous cell carcinoma (OSCC) cells. The goal of this study was to investigate the cytotoxic effects of licochalcone A on the human OSCC SCC-25 cells and to identify the underlying molecular mechanism. Exposure of SCC-25 cells to licochalcone A dose- and time-dependently decreased cell viability by arresting cell cycle at the S and G2/M phase as well as inducing apoptosis. Furthermore, the proapoptotic activity of licochalcone A was revealed by DNA fragmentation. Concomitantly, we observed activation of the effector caspases-3, induced by activation of the initiator caspases -8 and -9, which subsequent trigger both death receptor pathway and the mitochondrial apoptotic pathway in licochalcone A-mediated SCC-25 cell apoptosis. Besides, treatment with 50 μg/mL of licochalcone A for 36 h led to the cleavage of PARP, an indicator of apoptosis induction. Therefore licochalcone A may be a good candidate for development as a possible chemopreventive agent against OSCC.

Thinking outside the Box: Rotor Modulation in the Treatment of Atrial Fibrillation.

Ablation for atrial fibrillation (AF) is an important and exciting therapy whose results remain suboptimal. Although most clinical trials show that ablation eliminates AF more effectively than medications, it is disappointing that the continued single procedural success remains ≈50% despite the substantial advances that have taken place in imaging, catheter positioning and energy delivery. Focal impulse and rotor modulation (FIRM), on the other hand, offers the opportunity to precisely define and then ablate patient-specific sustaining mechanisms for AF, rather than trying to eliminate all possible AF triggers. For over a decade, electrophysiologists have described cases in which AF terminates after only limited ablation - usually that cannot be explained by 'random' meandering wavelets. Indeed, recent studies from several laboratories show that all forms of clinical AF are typically 'driven' by stable electrical rotors and focal sources, not by multiple meandering waves. FIRM mapping enables an operator to place a catheter at typically 1-3 predicted sites in the atria, and with <5-10 minutes of RF ablation, terminate AF and potentially render it non-inducible. Several independent laboratories have now shown that such FIRM ablation alone can terminate or substantially slow AF in >80% of patients with persistent and paroxysmal AF and increase the single procedure rate of AF elimination from 50% with PV isolation alone to >80%. Ongoing studies hint that FIRM only ablation, enabling ablation times in the range observed for typical atrial flutter, may also achieve these high success rates without subsequent trigger ablation. This review summarizes the current state-of-the-art on FIRM mapping and ablation.

Modeling Traumatic-Hemorrhagic Shock—Nothing Is Simple and Easy

Modeling Traumatic-Hemorrhagic Shock—Nothing Is Simple and Easy

Lashing Out after Stewing over Public Insults: The Effects of Public Provocation, Provocation Intensity, and Rumination on Triggered Displaced Aggression

Four studies present the first evidence showing that public (vs. private) provocation augments triggered displaced aggression by increasing the perceived intensity of the provocation. This effect is shown to be independent of face-saving motivation. Following a public or private provocation, Study 1 participants were induced to ruminate or were distracted for 20 min. They then had an opportunity to aggress against another person who either acted in a neutral or mildly annoying fashion (viz. triggering event). As expected, the magnitude of the greater displaced aggression of those who ruminated before the triggering event compared with those distracted was greater under public than private provocation. Study 2 replicated the findings of Study 1 and confirmed that public provocations are experienced as more intense. Studies 3 and 4 both manipulated provocation intensity directly to show that it mediated the moderating effect of public/private provocation found in Study 1. The greater intensity of a public provocation increases reactivity to a subsequent trigger, which in turn, augments triggered displaced aggression.