Perturbation of the apoptosis and necroptosis pathways critically influences embryogenesis. Receptor-associated protein kinase-1 (RIPK1) interacts with Fas-associated via death domain (FADD)-caspase-8-cellular Flice-like inhibitory protein long (cFLIPL) to regulate both extrinsic apoptosis and necroptosis. Here, we describe Ripk1-mutant animals (Ripk1R588E [RE]) in which the interaction between FADD and RIPK1 is disrupted, leading to embryonic lethality. This lethality is not prevented by further removal of the kinase activity of Ripk1 (Ripk1R588E K45A [REKA]). Both Ripk1RE and Ripk1REKA animals survive to adulthood upon ablation of Ripk3. While embryonic lethality of Ripk1RE mice is prevented by ablation of the necroptosis effector mixed lineage kinase-like (MLKL), animals succumb to inflammation after birth. In contrast, Mlkl ablation does not prevent the death of Ripk1REKA embryos, but animals reach adulthood when both MLKL and caspase-8 are removed. Ablation of the nucleic acid sensor Zbp1 largely prevents lethality in both Ripk1RE and Ripk1REKA embryos. Thus, the RIPK1-FADD interaction prevents Z-DNA binding protein-1 (ZBP1)-induced, RIPK3-caspase-8-mediated embryonic lethality, affected by the kinase activity of RIPK1.

The endoplasmic reticulum is a subcellular organelle key in the control of synthesis, folding, and sorting of proteins. Under endoplasmic reticulum stress, an adaptative unfolded protein response is activated; however, if this activation is prolonged, cells can undergo cell death, in part due to oxidative stress and mitochondrial fragmentation. Here, we report that endoplasmic reticulum stress activates c-Abl tyrosine kinase, inducing its translocation to mitochondria. We found that endoplasmic reticulum stress-activated c-Abl interacts with and phosphorylates the mitochondrial fusion protein MFN2, resulting in mitochondrial fragmentation and apoptosis. Moreover, the pharmacological or genetic inhibition of c-Abl prevents MFN2 phosphorylation, mitochondrial fragmentation, and apoptosis in cells under endoplasmic reticulum stress. Finally, in the amyotrophic lateral sclerosis mouse model, where endoplasmic reticulum and oxidative stress has been linked to neuronal cell death, we demonstrated that the administration of c-Abl inhibitor neurotinib delays the onset of symptoms. Our results uncovered a function of c-Abl in the crosstalk between endoplasmic reticulum stress and mitochondrial dynamics via MFN2 phosphorylation.

The absence of Caspase-8 or its adapter, Fas-associated death domain (FADD), results in activation of receptor interacting protein kinase-3 (RIPK3)- and mixed-lineage kinase-like (MLKL)–dependent necroptosis in vivo. Here, we show that spontaneous activation of RIPK3, phosphorylation of MLKL, and necroptosis in Caspase-8– or FADD-deficient cells was dependent on the nucleic acid sensor, Z-DNA binding protein-1 (ZBP1). We genetically engineered a mouse model by a single insertion of FLAG tag onto the N terminus of endogenous MLKL ( Mlkl FLAG/FLAG ), creating an inactive form of MLKL that permits monitoring of phosphorylated MLKL without activating necroptotic cell death. Casp8 −/− Mlkl FLAG/FLAG mice were viable and displayed phosphorylated MLKL in a variety of tissues, together with dramatically increased expression of ZBP1 compared to Casp8 +/+ mice. Studies in vitro revealed an increased expression of ZBP1 in cells lacking FADD or Caspase-8, which was suppressed by reconstitution of Caspase-8 or FADD. Ablation of ZBP1 in Casp8 −/− Mlkl FLAG/FLAG mice suppressed spontaneous MLKL phosphorylation in vivo. ZBP1 expression and downstream activation of RIPK3 and MLKL in cells lacking Caspase-8 or FADD relied on a positive feedback mechanism requiring the nucleic acid sensors cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING), and TBK1 signaling pathways. Our study identifies a molecular mechanism whereby Caspase-8 and FADD suppress spontaneous necroptotic cell death.

Drug-tolerant persister cells (persisters) evade apoptosis upon targeted and conventional cancer therapies and represent a major non-genetic barrier to effective cancer treatment. Here, we show that cells that survive treatment with pro-apoptotic BH3 mimetics display a persister phenotype that includes colonization and metastasis in vivo and increased sensitivity toward ferroptosis by GPX4 inhibition. We found that sublethal mitochondrial outer membrane permeabilization (MOMP) and holocytochrome c release are key require-ments for the generation of the persister phenotype. The generation of persisters is independent of apoptosome formation and caspase activation, but instead, cytosolic cytochrome c induces the activation of heme-regulated inhibitor (HRI) kinase and engagement of the integrated stress response (ISR) with the consequent synthesis of ATF4, all of which are required for the persister phenotype. Our results reveal that sublethal cytochrome c release couples sublethal MOMP to caspase-independent initiation of an ATF4-dependent, drug-tolerant persister phenotype.

BACKGROUND:Patients with D-transposition of the great arteries and atrial switch have a high incidence of atrial arrhythmias. We sought to analyze the arrhythmia substrate, ablation strategies, and outcomes for catheter ablation in this population.METHODS:An in-depth analysis of all clinical and procedural data in patients with D-transposition of the great arteries, atrial baffles, and atrial arrhythmia ablation was performed.RESULTS:A cohort of 32 patients (72% male, mean age 38±7 years) underwent ablation for non-AV nodal reentrant tachycardia atrial arrhythmias, and 4 patients underwent AV nodal reentrant tachycardia ablation. Cavotricuspid isthmus flutter (CTI-flutter) was the most common arrhythmia, encountered in 75% of patients, followed by scar-related intraatrial reentrant tachycardia (non-CTI intraatrial reentrant tachycardia, 53%) and focal atrial tachycardia (focal atrial tachycardia, 6%). Among the 32 patients, 26 underwent 31 procedures at our institution. For patients with prior outside intervention, the index ablation at our institution revealed CTI-dependent flutter in 3/5 cases. However, redo ablation after an index ablation with demonstrated bidirectional CTI block revealed different/new arrhythmia substrates (80% non-CTI intraatrial reentrant tachycardia, 40% focal atrial tachycardia). Achieving bidirectional block across the CTI often required ablating on both sides of the baffle (retroaortic access, 81%; using a baffle leak, 11.5%; or transbaffle puncture, 7.7%). Combined approaches were necessary in 19% to reach the critical tissue. Acute procedural success was 81%, and recurrence was documented in 58% of patients. Despite recurrence, clinical arrhythmia burden was significantly reduced post-ablation (P<0.001), with rare episodes, amenable to antiarrhythmic therapy. Redo ablation was required in 5 (19%) patients and uncovered new arrhythmia substrates. AV nodal reentrant tachycardia ablation also required transbaffle approaches in 3/4 patients.CONCLUSIONS:CTI-dependent flutter was the most common arrhythmia in patients with Dextro-Transposition of the Great Arteries and atrial switch. Transbaffle approaches were often necessary, and, provided that bidirectional CTI block was achieved at the index ablation, late recurrence was due to different arrhythmia mechanisms. Despite recurrence, ablation was associated with significant clinical improvement.

Introduction: Atrial arrhythmias are common in patients with D-TGA and atrial switch. We sought to analyze the arrhythmia substrate and catheter ablation approaches and outcomes. Methods: We performed a retrospective review of all clinical and procedural data in patients with D-TGA followed at a large tertiary care center. Results: In a cohort of 152 patients (mean age 30±11 years), atrial tachycardia was present in 69(45%) patients. Ablations were performed in 39(26%) patients: macro-reentrant atrial flutter (N=37), atrial fibrillation (N=4), and focal automatic atrial tachycardia (N=3). Detailed electrophysiology study data was available for 34 patients. At first ablation (N=28), cavo-tricuspid isthmus dependent flutter (CTI, 23(82%)) was most common, followed by right atriotomy-related flutter (IART, 16(57%)) and focal atrial tachycardia (FAT, 1(3.5%)). Bidirectional CTI block often required ablation on both sides of the baffle to complete the isthmus line. Access to the pulmonary venous atrium was obtained in 82% of first-time ablations (via retrograde aortic access, 74%, baffle puncture, 6%, or baffle fenestration, 12%) and in 100% of redo procedures. The first ablation was acutely successful in 25 (89%) patients; the other 3 patients had either partial procedural success (1), failed ablation (1), or underwent an empirical ablation (1). Long-term arrhythmia recurrence occurred in 13(46%) after the first ablation and class III antiarrhythmic medications were utilized in 12 patients. At least one long-term recurrence occurred in 11(44%) patients. Importantly, clinical arrhythmia burden was significantly reduced post-ablation, with rare and short-limited episodes amenable to antiarrhythmic drugs or cardioversion. Repeat ablation was required in 3 cases. Long-term arrhythmia recurrence after a previously completed CTI line involved different arrhythmia mechanisms: scar-related reentry (80%) and automatic atrial tachycardia (40%). Conclusions: Atrial arrhythmia in patients with D-TGA often involves the CTI and atriotomy scars. Ablation of the CTI typically requires access to the pulmonary venous atrium to achieve bidirectional block. Despite late recurrence, the clinical arrhythmic burden is substantially improved.

HomeCirculation: Arrhythmia and ElectrophysiologyVol. 14, No. 5Impact of ECG Characteristics on the Performance of an Artificial Intelligence Enabled ECG for Predicting Left Ventricular Dysfunction Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessLetterPDF/EPUBImpact of ECG Characteristics on the Performance of an Artificial Intelligence Enabled ECG for Predicting Left Ventricular Dysfunction Julio Perez-Downes, DO Patrick Fitzgerald, MD Demilade Adedinsewo, MD, MPH Rickey E. Carter, PhD Peter A. Noseworthy, MD Fred KusumotoMD Julio Perez-DownesJulio Perez-Downes Correspondence to: Julio Perez-Downes, DO, Department of Cardiovascular Disease, Mayo Clinic Florida, 4500 San Pablo Rd. S, Jacksonville, FL 32204. Email E-mail Address: [email protected] https://orcid.org/0000-0001-9675-2896 Department of Cardiovascular Diseases (J.P.-D., D.A., F.K.), Mayo Clinic, Jacksonville, FL. , Patrick FitzgeraldPatrick Fitzgerald https://orcid.org/0000-0003-3191-7308 Internal Medicine (P.F.), Mayo Clinic, Jacksonville, FL. , Demilade AdedinsewoDemilade Adedinsewo https://orcid.org/0000-0002-8629-2029 Department of Cardiovascular Diseases (J.P.-D., D.A., F.K.), Mayo Clinic, Jacksonville, FL. , Rickey E. CarterRickey E. Carter https://orcid.org/0000-0002-0818-273X Department of Health Sciences Research (R.E.C.), Mayo Clinic, Rochester, MN. , Peter A. NoseworthyPeter A. Noseworthy https://orcid.org/0000-0002-4308-0456 Department of Cardiovascular Diseases (P.A.N.), Mayo Clinic, Rochester, MN. , Fred KusumotoFred Kusumoto https://orcid.org/0000-0002-8300-6277 Department of Cardiovascular Diseases (J.P.-D., D.A., F.K.), Mayo Clinic, Jacksonville, FL. Originally published17 May 2021https://doi.org/10.1161/CIRCEP.121.009871Circulation: Arrhythmia and Electrophysiology. 2021;14:e009871The use of artificial intelligence (AI) is rapidly expanding in clinical care,1 including the use of neural networks for mortality predictions and identification of cardiac pathologies based on an ECG.2 The ubiquity of the ECG holds much promise as a screening tool with the goal of enhancing patient care. An ideal setting for utilization of this technology is the emergency department (ED), specifically among patients with dyspnea. In light of this, the AI-enabled ECG algorithm has received emergency use authorization by the Food and Drug Administration to screen patients with confirmed or suspected coronavirus disease 2019 (COVID-19) disease for left ventricular dysfunction (LVD).3,4 Our objective was to evaluate the effect of ECG characteristics on AI-ECG performance among ED patients.A retrospective review of patients who presented to the ED at Mayo Clinic, Florida, who had an ECG and transthoracic echocardiogram within 48 hours of one another between May 1, 2020 and December 31, 2020, was performed and 1300 unique patients were selected for study inclusion. Demographics, left ventricular ejection fraction (EF), and ECG parameters (PR interval, QT duration, corrected QT duration, presence of right bundle branch block, left bundle branch block, and ventricular pacing) were obtained. Details of the AI-ECG algorithm have been previously published.2 The diagnostic performance of the AI-ECG in predicting LVD (based on left ventricular EF assessment by echocardiography) was evaluated using area under the receiver operating characteristic curve (AUROC), sensitivity, specificity, negative, and positive predictive values. A numeric predicted probability between 0 and 1 is generated by the AI model for each ECG analyzed and the threshold value used to indicate a positive screen was ≥0.256 as determined from the initial study.Consistent with the STARD criteria (Standards for Reporting of Diagnostic Accuracy Studies),5 estimates of diagnostic accuracy are provided with 95% confidence intervals. Statistical analysis was performed with R Statistical Software (version 3.6.2; R Foundation for Statistical Computing, Vienna, Austria). The data that support the findings of this study are available from the corresponding author upon reasonable request. The study was approved by the Mayo Clinic Florida Institutional Review Board.Median age of patients was 69 years (Q1: 58 years Q3: 78 years), and 43.3% were female. Overall, for detection of LVD at EF threshold ≤35%, the AI-ECG had an AUROC of 0.893, accuracy of 82.7%, a sensitivity of 78.6%, a specificity of 83.1%, a positive predictive value of 30.4%, and a negative predictive value of 97.6%. Within a prespecified subset of patients, the AI-ECG performance remained stable with an AUROC of 0.822 among those with ventricular pacing, 0.857 for right bundle branch block, 0.784 for left bundle branch block, and 0.859 for wide QRS (Figure).Download figureDownload PowerPointFigure. Forrest plot depicting the performance of the artificial intelligence–ECG algorithm for detection of left ventricular dysfunction (defined as ejection fraction ≤35%). Percentage values in parenthesis represent 95% exact CIs while the fraction shows the number of subjects in each group. For sensitivity: true positive (TP)/(TP +false negative); for specificity true negative (TN)/(TN+false positive). AUROC indicates area under the receiver operator characteristic curve; LBBB, left bundle branch block; and RBBB, right bundle branch block.To detect LVD at EF threshold <50%, the AI-ECG had an AUROC of 0.841, accuracy of 81.8%, sensitivity of 59.9%, specificity of 87.3%, positive predictive value of 54.3%, and negative predictive value of 89.6%. The AI-ECG algorithm had an AUROC of 0.752 among those with ventricular pacing, 0.825 for right bundle branch block, 0.834 for left bundle branch block, and 0.832 for wide QRS.The effectiveness of the AI-ECG tool is further highlighted in our study, specifically among patients with conduction abnormalities on a resting ECG. The AI-ECG performs well independent of ventricular pacing, wide QRS, or right bundle branch block at baseline. However, a modestly reduced performance is observed among patients with left bundle branch block (at an EF threshold of ≤35%) or ventricular pacing (at an EF threshold of < 50%). Although the AUROC values in our patient population appear slightly lower than in the original study, the performance of the AI-ECG remained strong and similar to subsequent validation studies of this AI model among ED patients (AUROC, 0.89).1 Changes in the AUROC value are likely due to expected statistical variation in patient data and a small sample size. Our findings suggest that the presence of a specific wide QRS pattern, pacer spikes, or QRS shape might be important variables in the AI-ECG's determination of an individual's probability of LVD.Our findings identify an important caveat for clinicians to be aware of when utilizing this tool in daily practice. Reporting AI model results without a measure of the certainty of the model may make it hard for clinicians to incorporate the results into their decision-making. Our study suggests that models should be reported not only as a standalone value but also in the context of other features that can be discerned from the model. We note that, in developing and training these models, we generally wish to include as broad a sample as possible (so that the model can be more broadly applied in practice), but it is important to be aware of the caveats that may inform model implementation. Our study was retrospective in nature with a relatively small sample size derived from ED where echocardiography was deemed to be clinically indicated. Efforts are currently underway to validate the AI-ECG tool in larger patient populations.Nonstandard Abbreviations and AcronymsAIartificial intelligenceEDemergency departmentLVDleft ventricular dysfunctionSources of FundingNone.Disclosures None.FootnotesFor Sources of Funding and Disclosures, see page 534.Correspondence to: Julio Perez-Downes, DO, Department of Cardiovascular Disease, Mayo Clinic Florida, 4500 San Pablo Rd. S, Jacksonville, FL 32204. Email perez-downes.[email protected]eduReferences1. Adedinsewo D, Carter RE, Attia Z, Johnson P, Kashou AH, Dugan JL, Albus M, Sheele JM, Bellolio F, Friedman PA, et al.. Artificial intelligence-enabled ECG algorithm to identify patients with left ventricular systolic dysfunction presenting to the emergency department with dyspnea.Circ Arrhythm Electrophysiol. 2020; 13:e008437. doi: 10.1161/CIRCEP.120.008437LinkGoogle Scholar2. Attia ZI, Kapa S, Lopez-Jimenez F, McKie PM, Ladewig DJ, Satam G, Pellikka PA, Enriquez-Sarano M, Noseworthy PA, Munger TM, et al.. Screening for cardiac contractile dysfunction using an artificial intelligence-enabled electrocardiogram.Nat Med. 2019; 25:70–74. doi: 10.1038/s41591-018-0240-2CrossrefMedlineGoogle Scholar3. Ladejobi AO, Cruz J, Attia ZI, van Zyl M, Tri J, Lopez-Jimenez F, Noseworthy PA, Friedman PA, Kapa S, Asirvatham SJ. Digital health innovation in cardiology.Cardiovasc Digit Health J. 2020; 1:6–8. doi: 10.1016/j.cvdhj.2020.07.003CrossrefMedlineGoogle Scholar4. US FDA. Emergent use of the Eko electrocardiogram Low Ejection Fraction Tool (ELEFT) during the COVID-19 pandemic.May 11, 2020.Google Scholar5. Bossuyt PM, Reitsma JB, Bruns DE, Gatsonis CA, Glasziou PP, Irwig L, Lijmer JG, Moher D, Rennie D, de Vet HC, et al.; STARD Group. STARD 2015: an updated list of essential items for reporting diagnostic accuracy studies.BMJ. 2015; 351:h5527. doi: 10.1136/bmj.h5527CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails May 2021Vol 14, Issue 5Article InformationMetrics Download: 162 © 2021 American Heart Association, Inc.https://doi.org/10.1161/CIRCEP.121.009871PMID: 33993719 Originally publishedMay 17, 2021 Keywordsechocardiographyartificial intelligencedyspneaCOVID-19patientsPDF download SubjectsArrhythmiasMachine Learning and Artificial IntelligenceElectrophysiologyHeart Failure

Noncanonical functions of autophagy proteins have been implicated in neurodegenerative conditions, including Alzheimer's disease (AD). The WD domain of the autophagy protein Atg16L is dispensable for canonical autophagy but required for its noncanonical functions. Two-year-old mice lacking this domain presented with robust β-amyloid (Aβ) pathology, tau hyperphosphorylation, reactive microgliosis, pervasive neurodegeneration, and severe behavioral and memory deficiencies, consistent with human disease. Mechanistically, we found this WD domain was required for the recycling of Aβ receptors in primary microglia. Pharmacologic suppression of neuroinflammation reversed established memory impairment and markers of disease pathology in this novel AD model. Therefore, loss of the Atg16L WD domain drives spontaneous AD in mice, and inhibition of neuroinflammation is a potential therapeutic approach for treating neurodegeneration and memory loss. A decline in expression of ATG16L in the brains of human patients with AD suggests the possibility that a similar mechanism may contribute in human disease.

Introduction: Patients with D-TGA palliated with atrial switch operations have the morphologic right ventricle in the systemic position. There is increased risk of atrial arrhythmias and systemic right ventricle (SRV) failure. We sought to analyze the long term outcomes of these patients. Methods: All patients with D-TGA and SRV followed in the Adult Congenital Heart Disease Clinic of a large tertiary care institution were reviewed. A comprehensive retrospective analysis of the medical record was performed, including consult notes, ECGs, echocardiograms and electrophysiology reports. Results: A total of 154 patients (63% male) aged 29±11 years were followed for a mean of 10±9 years (range 0-51). During follow-up, 3 patients underwent cardiac transplantation and 15 died; 5 had sudden death, 2 had cardiogenic shock, 5 had non-cardiac death (i.e., infective endocarditis, sepsis) and 3 had unknown causes of death. Heart failure symptoms were present in 53(34%) patients. Severe SRV systolic dysfunction occurred in 37(24%) patients, with a mean EF of 23±5.5%; moderate SRV dysfunction occurred in 67(44%) patients, mean EF 35±4%. Sinus node dysfunction was present in 75(49%) patients, complete AV block in 9(5%) patients, and a pacemaker placed in 60(39%) patients, with cardiac resynchronization therapy in 5. Atrial arrhythmias occurred in 94(61%) patients and ablations were performed in 47(31%) patients. An ICD was implanted in 37 patients; 5 patients had appropriate shocks, but 7 had inappropriate shocks due to atrial arrhythmias. Age (HR 1.07, p=001), heart failure symptoms (HR 4.9, p= 0.007), severe SRV enlargement (HR 3.7, p=0.03), severe systolic dysfunction (HR 5.4, p=0.003), severe systemic AV valve regurgitation (HR 5.2, p=0.002) and a QRS duration> 122ms (HR 3.7, p=0.02) were significant predictors of mortality. The 15 year probability of sudden death was 3.2%(95% CI 0-6.9%). Conclusions: Atrial arrhythmias are common after atrial switch operations secondary to atriotomy scars. Further studies will need to determine whether restoration of sinus rhythm or cardiac synchrony may prevent further deterioration of the systemic right ventricle. Severe SRV dysfunction and prolonged QRS duration >122ms were significantly correlated with mortality.

Cell death pathways regulate various homeostatic processes. Autoimmune lymphoproliferative syndrome (ALPS) in humans and lymphoproliferative (LPR) disease in mice result from abrogated CD95-induced apoptosis. Because caspase-8 mediates CD95 signaling, we applied genetic approaches to dissect the roles of caspase-8 in cell death and inflammation. Here, we describe oligomerization-deficient Caspase-8(F122GL123G/F122GL123G) and non-cleavable CaSPaSe-8(D387A)(/D3)(87A) mutant mice with defective caspase-8-mediated apoptosis. Although neither mouse developed LPR disease, removal of the necroptosis effector MIkl from CaSPaSe-8(D387A/D387A) mice revealed an inflammatory role of caspase-8. Ablation of one allele of Fasl, Fadd, or Ripk1 prevented the pathology of Casp8(D387A/D387A )Mlkl(-/-) animals. Removing both Fadd alleles from these mice resulted in early lethality prior to post-natal day 15 (P15), which was prevented by co-ablation of either Ripk1 or Caspase-1. Our results suggest an in vivo role of the inflammatory RIPK1-caspase-8-FADD (FADDosome) complex and reveal a FADD-independent inflammatory role of caspase-8 that involves activation of an inflammasome.

Despite improvements in post-operative outcomes, patients with cirrhotic liver disease undergoing orthotopic liver transplantation (OLT) continue to experience major adverse cardiac events (MACE). Use of routine stress testing and coronary angiography is common prior to OLT, however, the utility of

AV conduction abnormalities are observed in 15–30% of patients with hypertrophic cardiomyopathy but are usually not severe enough to require permanent pacemaker implant. Both septal myectomy and alcohol septal ablation are effective options to relieve symptoms due to left ventricular outflow tract gradient in patients with hypertrophic cardiomyopathy but have procedure-specific effects on AV conduction and the His Purkinje system. Septal myectomy is associated with the development of LBBB in 50–100% of patients, while alcohol septal ablation is associated with RBBB in 37–70% of patients. Baseline abnormalities in the contralateral bundles and the presence of conduction disease have an important impact on the likelihood of the development of AV block for both of these therapies. AV block requiring permanent pacing occurs in approximately 2–3% of patients after septal myectomy and 10–15% of patients after alcohol septal ablation. Permanent pacemaker implant after alcohol septal ablation is more common in older patients (> 55 years old 13 vs. < 55 years old 5%; p = 0.06). Improved outcomes for septal myectomy and alcohol septal ablation are observed in experienced centers. Septal reduction therapies should be performed at medical centers with a dedicated hypertrophic cardiomyopathy program using a multidisciplinary approach.

Previous studies have noted the dominance of official sources within the news process and their unique ability to shape media narratives. This research addresses the role and implications of news sources in contributing to the overwhelmingly positive portrayal of the anti-Mubarak opposition protesters within British and American newspaper coverage of the 2011 Egyptian Revolution. Furthermore, this paper will assess how the position of global political elites towards the protests in Egypt possibly opened up the editorial space within the news coverage of the revolution for the anti-Mubarak opposition movement to emerge as the dominant voice within the reporting.

The activation of mixed lineage kinase-like (MLKL) by receptor-interacting protein kinase-3 (RIPK3) results in plasma membrane (PM) disruption and a form of regulated necrosis, called necroptosis. Here, we showthat, during necroptosis, MLKL-dependent calcium (Ca2+) influx and phosphatidylserine (PS) exposure on the outer leaflet of the plasma membrane preceded loss of PM integrity. Activation of MLKL results in the generation of broken, PM "bubbles'' with exposed PS that are released from the surface of the otherwise intact cell. The ESCRT-III machinery is required for formation of these bubbles and acts to sustain survival of the cell when MLKL activation is limited or reversed. Under conditions of necroptotic cell death, ESCRT-III controls the duration of plasma membrane integrity. As a consequence of the action of ESCRT-III, cells undergoing necroptosis can express chemokines and other regulatory molecules and promote antigenic cross-priming of CD8(+) T cells.

OBJECTIVEPediatric dermatology appointment wait times often exceed several months. We evaluated the usability, acceptability, and clinical impact of a store-and-forward teledermatology mobile application (app) linking families with pediatric dermatologists.METHODSParents of children age 6 weeks to 17 years or individuals 18-21 years old were invited (by e-mail or referral) to participate in this single group, prospective study. Within the app, users photographed the skin condition, answered questions, and submitted their case for review. One pediatric dermatologist viewed cases, diagnosed conditions, and provided instructions and prescriptions. User surveys immediately following app use and 1 week later, supplemented by electronic logs, assessed usability, acceptability, and impact.RESULTSOne hundred ninety-seven parents and one adolescent submitted cases within 39 days of invitation. App users were more likely to be white than those in the population invited (67% vs. 34%, p < 0.001) and their children were slightly younger (mean 7.3 vs. 9.0 years, p < 0.001). A majority, 83% found the app easy to use, 97% felt that submitting a case took "the right amount of time," 87% were satisfied, and 93% would use the app again. Prescription receipt was associated with increased app satisfaction (p = 0.008). The median user received a response in 2.8 h (interquartile range 1.1-6.4). Had the app been unavailable, 44% reported that they would have waited for primary care, 32% for a dermatology appointment, and 7% would have gone to an urgent care clinic.CONCLUSIONSA mobile health app allowing families to directly consult a pediatric dermatologist was usable, acceptable, and expedited care.

Apoptosis is a form of active cell death engaged by developmental cues as well as many different cellular stresses in which the dying cell essentially 'packages' itself for removal. The process of apoptotic cell death, as defined at the molecular level, is unique to the Metazoa (animals). Yet active cell death exists in non-animal organisms, and in some cases molecules involved in such death show some sequence similarities to those involved in apoptosis, leading to extensive speculation regarding the evolution of apoptosis. Here, we examine such speculation from the perspective of the functional properties of molecules of the mitochondrial apoptotic cell death pathway. We suggest scenarios for the evolution of one pathway of apoptosis, the mitochondrial pathway, and consider how they might be tested. We conclude with a 'Just So Story' of how the mitochondrial pathway of apoptosis might have evolved during eukaryotic evolution.