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Sterile inflammation after myocardial infarction is classically credited to myeloid cells interacting with dead cell debris in the infarct zone1,2. Here we show that cardiomyocytes are the dominant initiators of a previously undescribed type I interferon response in the infarct borderzone. Using spatial transcriptomics analysis in mice and humans, we find that myocardial infarction induces colonies of interferon-induced cells (IFNICs) expressing interferon-stimulated genes decorating the borderzone, where cardiomyocytes experience mechanical stress, nuclear rupture and escape of chromosomal DNA. Cardiomyocyte-selective deletion of Irf3 abrogated IFNIC colonies, whereas mice lacking Irf3 in fibroblasts, macrophages, neutrophils or endothelial cells, Ccr2-deficient mice or plasmacytoid-dendritic-cell-depleted mice did not. Interferons blunted the protective matricellular programs and contractile function of borderzone fibroblasts, and increased vulnerability to pathological remodelling. In mice that died after myocardial infarction, IFNIC colonies were immediately adjacent to sites of ventricular rupture, while mice lacking IFNICs were protected from rupture and exhibited improved survival3. Together, these results reveal a pathological borderzone niche characterized by a cardiomyocyte-initiated innate immune response. We suggest that selective inhibition of IRF3 activation in non-immune cells could limit ischaemic cardiomyopathy while avoiding broad immunosuppression.

Background: Hereditary transthyretin amyloidosis (ATTRv) is associated with polyneuropathy, cardiomyopathy, or both. The effects of eplontersen on cardiac structure and function were assessed., Methods and Results: NEURO-TTRansform was an open-label trial involving 144 adults with ATTRv polyneuropathy (49 patients [34%] with cardiomyopathy) receiving eplontersen throughout and compared with a historical placebo group (n = 60; 30 patients [50%] with cardiomyopathy) from the NEURO-TTR trial at week 65. Treatment effect (eplontersen vs placebo), presented as mean difference (95% confidence interval) was analyzed after adjusting for age, sex, region, baseline value, ATTRv disease stage, previous ATTRv treatment, and V30M transthyretin variant. There were notable differences at baseline between the eplontersen group and historical placebo. In the cardiomyopathy subgroup, 65 weeks of eplontersen treatment was associated with improvement from baseline relative to placebo in left ventricular ejection fraction of 4.3% (95% confidence interval 1.40-21.01; P = .049) and stroke volume 10.64 mL (95% confidence interval 3.99-17.29; P = .002) while the remainder of echocardiographic parameters remained stable., Conclusions: Eplontersen was associated with stable or improved measures of cardiac structure and function vs historical placebo in patients with ATTRv polyneuropathy and cardiomyopathy. Further investigation into eplontersen's effect on transthyretin amyloid cardiomyopathy is being conducted in the CARDIO-TTRansform trial., (Copyright © 2023. Published by Elsevier Inc.)

Virulent infectious agents such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and methicillin-resistant Staphylococcus aureus (MRSA) induce tissue damage that recruits neutrophils, monocyte, and macrophages, leading to T cell exhaustion, fibrosis, vascular leak, epithelial cell depletion, and fatal organ damage. Neutrophils, monocytes, and macrophages recruited to pathogen-infected lungs, including SARS-CoV-2-infected lungs, express phosphatidylinositol 3-kinase gamma (PI3Kγ), a signaling protein that coordinates both granulocyte and monocyte trafficking to diseased tissues and immune-suppressive, profibrotic transcription in myeloid cells. PI3Kγ deletion and inhibition with the clinical PI3Kγ inhibitor eganelisib promoted survival in models of infectious diseases, including SARS-CoV-2 and MRSA, by suppressing inflammation, vascular leak, organ damage, and cytokine storm. These results demonstrate essential roles for PI3Kγ in inflammatory lung disease and support the potential use of PI3Kγ inhibitors to suppress inflammation in severe infectious diseases.

Oocytes are among the longest-lived cells in the body and need to preserve their cytoplasm to support proper embryonic development. Protein aggregation is a major threat for intracellular homeostasis in long-lived cells. How oocytes cope with protein aggregation during their extended life is unknown. Here, we find that mouse oocytes accumulate protein aggregates in specialized compartments that we named endolysosomal vesicular assemblies (ELVAs). Combining live-cell imaging, electron microscopy, and proteomics, we found that ELVAs are non-membrane-bound compartments composed of endolysosomes, autophagosomes, and proteasomes held together by a protein matrix formed by RUFY1. Functional assays revealed that in immature oocytes, ELVAs sequester aggregated proteins, including TDP-43, and degrade them upon oocyte maturation. Inhibiting degradative activity in ELVAs leads to the accumulation of protein aggregates in the embryo and is detrimental for embryo survival. Thus, ELVAs represent a strategy to safeguard protein homeostasis in long-lived cells., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

SARS-CoV-2 infection-induced aggravation of host innate immune response not only causes tissue damage and multiorgan failure in COVID-19 patients but also induces host genome damage and activates DNA damage response pathways. To test whether the compromised DNA repair capacity of individuals modulates the severity of COVID-19 infection, we analyze DNA repair gene expression in publicly available patient datasets and observe a lower level of the DNA glycosylase NEIL2 in the lungs of severely infected COVID-19 patients. This observation of lower NEIL2 levels is further validated in infected patients, hamsters and ACE2 receptor-expressing human A549 (A549-ACE2) cells. Furthermore, delivery of recombinant NEIL2 in A549-ACE2 cells shows decreased expression of proinflammatory genes and viral E-gene, as well as lowers the yield of viral progeny compared to mock-treated cells. Mechanistically, NEIL2 cooperatively binds to the 5'-UTR of SARS-CoV-2 genomic RNA to block viral protein synthesis. Collectively, these data strongly suggest that the maintenance of basal NEIL2 levels is critical for the protective response of hosts to viral infection and disease., (© 2023. The Author(s).)

Background: Revascularization of left main coronary artery (LMCA) stenosis is mostly based on angiography. Indices based on angiography might increase accuracy of the decision, although they have been scarcely used in LMCA. The objective of this study is to study the diagnostic agreement of QFR (quantitative flow ratio) with wire-based fractional flow reserve (FFR) in LMCA lesions and to compare with visual severity assessment., Methods: In a series of patients with invasive FFR assessment of intermediate LMCA stenoses we retrospectively compared the measured value of QFR with that of FFR and the estimate of significance from angiography., Results: 107 QFR studies were included. The QFR intra-observer and inter-observer agreement was 87% and 82% respectively. The mean QFR-FFR difference was 0.047 ± 0.05 with a concordance of 90.7%, sensitivity 88.1%, specificity 92.3%, positive predictive value 88.1% and negative predictive value 92.3%. All these values were superior to those observed with the visual estimation which showed an intra- and inter-observer agreement of 73% and 72% respectively, besides 78% with the FFR value. The low diagnostic performance of the visual estimation and the acceptable performance of the QFR index measurement were observed in all subgroups analysed., Conclusions: QFR allows an acceptable estimate of the FFR obtained with intracoronary pressure guidewire in intermediate LMCA lesions, and clearly superior to the assessment based on angiography alone. The decision to revascularize patients with moderate LMCA lesions should not be based solely on the degree of angiographic stenosis., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: The relationship between body size and cardiovascular events is complex. This study utilized the ADVANCE (Assessing Diagnostic Value of Noninvasive FFR CT in Coronary Care) Registry to investigate the association between body mass index (BMI), coronary artery disease (CAD), and clinical outcomes., Methods: The ADVANCE registry enrolled patients undergoing evaluation for clinically suspected CAD who had >30% stenosis on cardiac computed tomography angiography. Patients were stratified by BMI: normal <25 kg/m 2 , overweight 25-29.9 kg/m 2 , and obese ≥30 kg/m 2 . Baseline characteristics, cardiac computed tomography angiography and computed tomography fractional flow reserve (FFR CT ), were compared across BMI groups. Adjusted Cox proportional hazards models assessed the association between BMI and outcomes., Results: Among 5014 patients, 2166 (43.2%) had a normal BMI, 1883 (37.6%) were overweight, and 965 (19.2%) were obese. Patients with obesity were younger and more likely to have comorbidities, including diabetes and hypertension (all P <0.001), but were less likely to have obstructive coronary stenosis (65.2% obese, 72.2% overweight, and 73.2% normal BMI; P <0.001). However, the rate of hemodynamic significance, as indicated by a positive FFR CT , was similar across BMI categories (63.4% obese, 66.1% overweight, and 67.8% normal BMI; P =0.07). Additionally, patients with obesity had a lower coronary volume-to-myocardial mass ratio compared with patients who were overweight or had normal BMI (obese BMI, 23.7; overweight BMI, 24.8; and normal BMI, 26.3; P <0.001). After adjustment, the risk of major adverse cardiovascular events was similar regardless of BMI (all P >0.05)., Conclusions: Patients with obesity in the ADVANCE registry were less likely to have anatomically obstructive CAD by cardiac computed tomography angiography but had a similar degree of physiologically significant CAD by FFR CT and similar rates of adverse events. An exclusively anatomic assessment of CAD in patients with obesity may underestimate the burden of physiologically significant disease that is potentially due to a significantly lower volume-to-myocardial mass ratio., Competing Interests: Disclosures Dr Lowenstern reports consulting for Edwards Lifesciences. Dr Takagi reports speaking fees from HeartFlow Japan GK and consulting fee from HeartFlow Inc. Dr Koweek reports a research grant from HeartFlow. Dr Douglas reports a research grant from HeartFlow. Dr Pontone reports grants from GE Healthcare and HeartFlow and personal fees from GE, Bracco, and Medtronic. Dr Berman reports research support from HeartFlow. Dr de Bruyne reports grants from Abbott, St Jude Medical, and Medtronic, and other support from St Jude Medical, Boston Scientific, Opsens, Omega Pharma, Siemens, Edwards, GE, Sanofi, HeartFlow, and Bayer. Dr Bax reports grants from Boston Scientific, Medtronic, Biotronik, and Edwards Lifesciences. T. Akasaka reports grants from Daiichi-Sankyo, St. Jude Medical Japan, Boehringer Ingelheim Japan, Bayer, Pfizer Inc, Foundation for Biomedical Research and Innovation, Otsuka Pharmaceutical Co, Astellas Pharma, Terumo, Abbott Vascular Japan, Goodman Co, and Boston Scientific Japan and has served as a consultant for Daiichi-Sankyo, St. Jude Medical Japan, Boehringer Ingelheim Japan, Bayer, Pfizer Inc, Otsuka Pharmaceutical Co, Astellas Pharma Inc, Terumo, Abbott Vascular Japan, Goodman Co, Boston Scientific Japan, and HeartFlow Japan. Dr Nieman reports support from the National Institutes of Health (NIH R01–HL141712; NIH R01–HL146754) and reports unrestricted institutional research support from Siemens Healthineers, Bayer, HeartFlow Inc, Novartis unrelated to this work, consulting for Siemens Medical Solutions USA, and equity in Lumen Therapeutics. Dr Rogers reports receiving salary and equity in HeartFlow and is a full-time employee of HeartFlow; Dr Fairbairn is on the speaker’s bureau for HeartFlow. S. Mullen reports being an employee of and owning equity in HeartFlow. Dr Norgaard reports an unrestricted institutional research grant from HeartFlow Inc. Dr Patel reports research grants from Bayer, Janssen, HeartFlow, Novartis, the National Heart, Lung, and Blood Institute, and the Advisory Board/Consulting for Bayer, Janssen, HeartFlow, and Novartis. Dr Leipsic reports being a consultant and having stock options for Circle CVI and HeartFlow. The other authors report no conflicts.

Oocytes spend the majority of their lifetime in a primordial state. The cellular and molecular biology of primordial oocytes is largely unexplored; yet, it is necessary to study them to understand the mechanisms through which oocytes maintain cellular fitness for decades, and why they eventually fail with age. Here, we develop enabling methods for live-imaging-based comparative characterization of Xenopus, mouse and human primordial oocytes. We show that primordial oocytes in all three vertebrate species contain active mitochondria, Golgi and lysosomes. We further demonstrate that human and Xenopus oocytes have a Balbiani body characterized by a dense accumulation of mitochondria in their cytoplasm. However, despite previous reports, we did not find a Balbiani body in mouse oocytes. Instead, we demonstrate that what was previously used as a marker for the Balbiani body in mouse primordial oocytes is in fact a ring-shaped Golgi that is not functionally associated with oocyte dormancy. This study provides the first insights into the organization of the cytoplasm in mammalian primordial oocytes, and clarifies the relative advantages and limitations of choosing different model organisms for studying oocyte dormancy., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2022. Published by The Company of Biologists Ltd.)

The border zone (BZ) of the infarcted heart is a geographically complex and biologically enigmatic interface separating poorly perfused infarct zones (IZs) from remote zones (RZs). The cellular and molecular mechanisms of myocardial BZs are not well understood because microdissection inevitably combines them with uncontrolled amounts of RZs and IZs. Here, we use single-cell/nucleus RNA sequencing, spatial transcriptomics and multiplexed RNA fluorescence in situ hybridization to redefine the BZ based on cardiomyocyte transcriptomes. BZ1 ( Nppa + Xirp2 - ) forms a hundreds-of-micrometer-thick layer of morphologically intact cells adjacent to RZs that are detectable within an hour of injury. Meanwhile, BZ2 ( Nppa + Xirp2 + ) forms a near-single-cell-thick layer of morphologically distorted cardiomyocytes at the IZ edge that colocalize with matricellular protein-expressing myofibroblasts and express predominantly mechanotransduction genes. Surprisingly, mechanical injury alone is sufficient to induce BZ genes. We propose a 'loss of neighbor' hypothesis to explain how ischemic cell death mechanically destabilizes the BZ to induce its transcriptional response., Competing Interests: Competing interests F.S. is a cofounder and has an equity interest in Papillon Therapeutics; he is a consultant and has equity interest and a research grant from LEXEO Therapeutics. The other authors declare no competing interests.

Exposure to adverse childhood experiences or early life stress experiences (ELSs) increase the risk of non-adaptive behaviors and psychopathology in adulthood. Environmental enrichment (EE) has been proposed to minimize these effects. The vast number of methodological variations in animal studies underscores the lack of systematicity in the studies and the need for a detailed understanding of how enrichment interacts with other variables. Here we evaluate the effects of environmental enrichment in male and female Wistar rats exposed to adverse early life experiences (prenatal, postnatal, and combined) on emotional (elevated plus maze), social (social interaction chamber), memory (Morris water maze) and flexibility tasks. Our results-collected from PND 51 to 64-confirmed: 1) the positive effect of environmental enrichment (PND 28-49) on anxiety-like behaviors in animals submitted to ELSs. These effects depended on type of experience and type of enrichment: foraging enrichment reduced anxiety-like behaviors in animals with prenatal and postnatal stress but increased them in animals without ELSs. This effect was sex-dependent: females showed lower anxiety compared to males. Our data also indicated that females exposed to prenatal and postnatal stress had lower anxious responses than males in the same conditions; 2) no differences were found for social interactions; 3) concerning memory, there was a significant interaction between the three factors: A significant interaction for males with prenatal stress was observed for foraging enrichment, while physical enrichment was positive for males with postnatal stress; d) regarding cognitive flexibility, a positive effect of EE was found in animals exposed to adverse ELSs: animals with combined stress and exposed to physical enrichment showed a higher index of cognitive flexibility than those not exposed to enrichment. Yet, within animals with no EE, those exposed to combined stress showed lower flexibility than those exposed to both prenatal stress and no stress. On the other hand, animals with prenatal stress and exposed to foraging-type enrichment showed lower cognitive flexibility than those with no EE. The prenatal stress-inducing conditions used here 5) did not induced fetal or maternal problems and 6) did not induced changes in the volume of the dentate gyrus of the hippocampus., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Corredor, Duran, Herrera-Isaza, Forero, Quintanilla, Gomez, Martínez and Cardenas.)

All muscle contraction occurs due to the cyclical interaction between sarcomeric thin and thick filament proteins within the myocyte. The thin filament consists of the proteins actin, tropomyosin, Troponin C, Troponin I, and Troponin T. Mutations in these proteins can result in various forms of cardiomyopathy, including hypertrophic, restrictive, and dilated phenotypes and account for as many as 30% of all cases of inherited cardiomyopathy. There is significant evidence that thin filament mutations contribute to dysregulation of Ca 2+ within the sarcomere and may have a distinct pathomechanism of disease from cardiomyopathy associated with thick filament mutations. A number of distinct clinical findings appear to be correlated with thin-filament mutations: greater degrees of restrictive cardiomyopathy and relatively less left ventricular (LV) hypertrophy and LV outflow tract obstruction than that seen with thick filament mutations, increased morbidity associated with heart failure, increased arrhythmia burden and potentially higher mortality. Most therapies that improve outcomes in heart failure blunt the neurohormonal pathways involved in cardiac remodeling, while most therapies for hypertrophic cardiomyopathy involve use of negative inotropes to reduce LV hypertrophy or septal reduction therapies to reduce LV outflow tract obstruction. None of these therapies directly address the underlying sarcomeric dysfunction associated with thin-filament mutations. With mounting evidence that thin filament cardiomyopathies occur through a distinct mechanism, there is need for therapies targeting the unique, underlying mechanisms tailored for each patient depending on a given mutation., Competing Interests: JD reports personal fees from Lexeo during the conduct of the review. EA reports personal fees from Abiomed, Novartis, Abbott, non-financial support from Astra Zeneca, personal fees from Ionis Pharmaceuticals, Sana Biotechnology, Medtronic, other from Rocket Pharmaceuticals, Papillon Therapeutics, ResQ Pharmaceuticals, personal fees from Lexeo Pharmaceuticals, Cytokinetics, Endotronics, and during the conduct of the review. MM was employed by Providence Health. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Keyt, Duran, Bui, Chen, Miyamoto, Silva Enciso, Tardiff and Adler.)

There is a great need for non-invasive tools that inform of an early molecular response to cancer therapeutic treatment. Here, we tested the hypothesis that proteolytically resistant proteins could be candidate circulating tumor biomarkers for cancer therapy. Proteins resistant to proteolysis are drastically under-sampled by current proteomic workflows. These proteins could be reliable sensors for the response to therapy since they are likely to stay longer in circulation. We selected manganese superoxide dismutase (SOD2), a mitochondrial redox enzyme, from a screening of proteolytic resistant proteins in breast cancer (BC). First, we confirmed the robustness of SOD2 and determined that its proteolytic resistance is mediated by its quaternary protein structure. We also proved that the release of SOD2 upon chemotherapy treatment correlates with cell death in BC cells. Then, after confirming that SOD2 is very stable in human serum, we sought to measure its circulating levels in a cohort of BC patients undergoing neoadjuvant therapy. The results showed that circulating levels of SOD2 increased when patients responded to the treatment according to the tumor shrinkage during neoadjuvant chemotherapy. Therefore, the measurement of SOD2 levels in plasma could improve the non-invasive monitoring of the therapeutic treatment in breast cancer patients. The identification of circulating biomarkers linked to the tumor cell death induced by treatment could be useful for monitoring the action of the large number of cancer drugs currently used in clinics. We envision that our approach could help uncover candidate tumor biomarkers to measure a tumor's response to cancer therapy in real time by sampling the tumor throughout the course of treatment.

Oocytes form before birth and remain viable for several decades before fertilization 1 . Although poor oocyte quality accounts for most female fertility problems, little is known about how oocytes maintain cellular fitness, or why their quality eventually declines with age 2 . Reactive oxygen species (ROS) produced as by-products of mitochondrial activity are associated with lower rates of fertilization and embryo survival 3-5 . Yet, how healthy oocytes balance essential mitochondrial activity with the production of ROS is unknown. Here we show that oocytes evade ROS by remodelling the mitochondrial electron transport chain through elimination of complex I. Combining live-cell imaging and proteomics in human and Xenopus oocytes, we find that early oocytes exhibit greatly reduced levels of complex I. This is accompanied by a highly active mitochondrial unfolded protein response, which is indicative of an imbalanced electron transport chain. Biochemical and functional assays confirm that complex I is neither assembled nor active in early oocytes. Thus, we report a physiological cell type without complex I in animals. Our findings also clarify why patients with complex-I-related hereditary mitochondrial diseases do not experience subfertility. Complex I suppression represents an evolutionarily conserved strategy that allows longevity while maintaining biological activity in long-lived oocytes., (© 2022. The Author(s).)

Purpose of Review: The advent of induced pluripotent stem cells (iPSC) has paved the way for new in vitro models of human cardiomyopathy. Herein, we will review existing models of disease as well as strengths and limitations of the system., Recent Findings: Preclinical studies have now demonstrated that iPSCs generated from patients with both acquired or heritable genetic diseases retain properties of the disease in vitro and can be used as a model to study novel therapeutics. iPSCs can be differentiated in vitro into the cardiomyocyte lineage into cells resembling adult ventricular myocytes that retain properties of cardiovascular disease from their respective donor. iPSC pluripotency allows for them to be frozen, stored, and continually used to generate iPSC-derived myocytes for future experiments without need for invasive procedures or repeat myocyte isolations to obtain animal or human cardiac tissues. While not without their limitations, iPSC models offer new ways for studying patient-specific cardiomyopathies. iPSCs offer a high-throughput avenue for drug development, modeling of disease pathophysiology in vitro, and enabling experimental repair strategies without need for invasive procedures to obtain cardiac tissues., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Multiple psychological treatments for emotional disorders have been developed and implemented, improving the quality of life of individuals. Nevertheless, relapse and poor response to psychotherapy are common. This article argues that a greater understanding of both the psychological and neurobiological mechanisms of change in psychotherapy is essential to improve treatment for emotional disorders. It aims to demonstrate how an understanding of these mechanisms provides a basis for (i) reconceptualizing some mental disorders, (ii) refining and establishing the evidence for existing therapeutic techniques and (iii) designing new techniques that precisely target the processes that maintain these disorders. Possible future directions for researchers and practitioners working at the intersection of neuropsychology and clinical psychology are discussed., (© 2022 John Wiley & Sons, Ltd.)

Background: Acute myocarditis (AM) is thought to be a rare cardiovascular complication of COVID-19, although minimal data are available beyond case reports. We aim to report the prevalence, baseline characteristics, in-hospital management, and outcomes for patients with COVID-19-associated AM on the basis of a retrospective cohort from 23 hospitals in the United States and Europe., Methods: A total of 112 patients with suspected AM from 56 963 hospitalized patients with COVID-19 were evaluated between February 1, 2020, and April 30, 2021. Inclusion criteria were hospitalization for COVID-19 and a diagnosis of AM on the basis of endomyocardial biopsy or increased troponin level plus typical signs of AM on cardiac magnetic resonance imaging. We identified 97 patients with possible AM, and among them, 54 patients with definite/probable AM supported by endomyocardial biopsy in 17 (31.5%) patients or magnetic resonance imaging in 50 (92.6%). We analyzed patient characteristics, treatments, and outcomes among all COVID-19-associated AM., Results: AM prevalence among hospitalized patients with COVID-19 was 2.4 per 1000 hospitalizations considering definite/probable and 4.1 per 1000 considering also possible AM. The median age of definite/probable cases was 38 years, and 38.9% were female. On admission, chest pain and dyspnea were the most frequent symptoms (55.5% and 53.7%, respectively). Thirty-one cases (57.4%) occurred in the absence of COVID-19-associated pneumonia. Twenty-one (38.9%) had a fulminant presentation requiring inotropic support or temporary mechanical circulatory support. The composite of in-hospital mortality or temporary mechanical circulatory support occurred in 20.4%. At 120 days, estimated mortality was 6.6%, 15.1% in patients with associated pneumonia versus 0% in patients without pneumonia ( P =0.044). During hospitalization, left ventricular ejection fraction, assessed by echocardiography, improved from a median of 40% on admission to 55% at discharge (n=47; P <0.0001) similarly in patients with or without pneumonia. Corticosteroids were frequently administered (55.5%)., Conclusions: AM occurrence is estimated between 2.4 and 4.1 out of 1000 patients hospitalized for COVID-19. The majority of AM occurs in the absence of pneumonia and is often complicated by hemodynamic instability. AM is a rare complication in patients hospitalized for COVID-19, with an outcome that differs on the basis of the presence of concomitant pneumonia.

Although increased neuropeptides are often detected in lungs that exhibit respiratory distress, whether they contribute to the condition is unknown. Here, we show in a mouse model of neuroendocrine cell hyperplasia of infancy, a pediatric disease with increased pulmonary neuroendocrine cells (PNECs), excess PNEC-derived neuropeptides are responsible for pulmonary manifestations including hypoxemia. In mouse postnatal lung, prolonged signaling from elevated neuropeptides such as calcitonin gene-related peptide (CGRP) activate receptors enriched on endothelial cells, leading to reduced cellular junction gene expression, increased endothelium permeability, excess lung fluid, and hypoxemia. Excess fluid and hypoxemia were effectively attenuated by either prevention of PNEC formation, inactivation of CGRP gene, endothelium-specific inactivation of CGRP receptor gene, or treatment with CGRP receptor antagonist. Neuropeptides were increased in human lung diseases with excess fluid such as acute respiratory distress syndrome. Our findings suggest that restricting neuropeptide function may limit fluid and improve gas exchange in these conditions., Competing Interests: Declaration of interests X.S. is a member of the advisory board for Developmental Cell. J.X., L.R.Y., and X.S. have one related Patent Cooperation Treaty (PCT) application approved by World Intellectual Property Organization (WIPO) with number WO2020252368., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Immunosuppressed heart transplant (HT) recipients are thought to be at higher risk of infection and mortality from SARS-CoV-2 infection coronavirus disease 2019 (COVID-19); however, evidence guiding management of HT patients are limited. Retrospective search of electronic health records from February 2020 to February 2021, identified 28 HT recipients out of 400 followed by UC San Diego who tested positive for SARS-CoV-2. Patient demographics, COVID-19 directed therapies, hospital course and outcomes were compared to control HT recipients who tested negative for SARS-CoV-2 during the same period (n = 80). Among 28 HT recipients who tested positive for SARS-CoV-2, 15 were admitted to the hospital and 13 were monitored closely as outpatients. Among inpatients, five developed severe illness and two died (7% mortality). Nine patients were treated with remdesivir, and four received dexamethasone and remdesivir. Two outpatients received neutralizing monoclonal antibody therapy and one outpatient received dexamethasone for persistent dyspnea. Immunosuppressed HT recipients, especially Hispanic patients and patients with higher body mass index, were at greater risk of infection and mortality from COVID-19 than the general population. Use of remdesivir and dexamethasone may have improved outcomes in our HT recipients compared to HT recipients at other centers., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Patients with end-stage heart failure are at high risk for sudden cardiac death. However, implantable cardioverter-defibrillator (ICD) is not routinely implanted given the high competing risk of pump failure. A unique population worth separate consideration are patients with end-stage heart failure awaiting heart transplantation, as prolonged survival improves the chances of receiving transplant., Objective: To compare clinical outcomes of heart failure patients with and without an ICD awaiting heart transplant., Methods: We performed an extensive literature search and systematic review of studies that compared end-stage heart failure patients with and without an ICD awaiting heart transplantation. We separately assessed the rates of total mortality, sudden cardiac death, nonsudden cardiac death, and heart transplantation. Risk ratio (RR) and 95% confidence intervals were measured using the Mantel-Haenszel method. The random effects model was used owing to heterogeneity across study cohorts., Results: Ten studies with a total of 36,112 patients were included. A total of 62.5% of patients had an ICD implanted. Patients with an ICD had decreased total mortality (RR 0.60, 95% CI 0.51-0.71, P  < .00001) and sudden cardiac death (RR 0.27, 95% CI 0.11-0.66, P  = .004) and increased rates of heart transplantation (RR 1.09, 95% CI 1.05-1.14, P < .0001). There was no difference in prevalence of nonsudden cardiac death (RR 0.68, 95% CI 0.44-1.04, P = .07)., Conclusion: ICD implantation is associated with improved outcomes in patients awaiting heart transplant, characterized by decreased total mortality and sudden cardiac death as well as higher rates of heart transplantation., (© 2021 Heart Rhythm Society. Published by Elsevier Inc.)

Background: In the last decade, pharmacological strategies targeting reconsolidation after memory retrieval have shown promising efforts to attenuate persistent memories and overcome fear recovery. However, most reconsolidation inhibiting agents have not been approved for human testing. While non-invasive neuromodulation can be considered an alternative approach to pharmacological treatments, there is a lack of evidence about the efficacy of these technologies when modifying memory traces via reactivation/reconsolidation mechanism., Objective: In this study, we evaluate the effect of cathodal (c-tDCS) and anodal (a-DCS) transcranial direct current stimulation applied after memory reactivation and extinction in rats., Methods: Male Wistar rats were randomly assigned into three groups: one sham group, one anodal tDCS group, and one cathodal tDCS group (500 μA, 20 min). Reconsolidation and extinction of fear memories were evaluated using a contextual fear conditioning., Results: Our results showed that c-tDCS and a-tDCS after memory reactivation can attenuate mild fear memories. However, only c-tDCS stimulation prevented both fear expression under strong fear learning and fear recovery after a reinstatement protocol without modification of learning rate or extinction retrieval. Nevertheless, the remote memories were resistant to modification through this type of neuromodulation. Our results are discussed considering the interaction between intrinsic excitability promoted by learning and memory retrieval and the electric field applied during tDCS., Conclusion: These results point out some of the boundary conditions influencing the efficacy of tDCS in fear attenuation and open new ways for the development of noninvasive interventions aimed to control fear-related disorders via reconsolidation., (Copyright © 2021. Published by Elsevier Ltd.)

Understanding viral tropism is an essential step toward reducing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission, decreasing mortality from coronavirus disease 2019 (COVID-19) and limiting opportunities for mutant strains to arise. Currently, little is known about the extent to which distinct tissue sites in the human head and neck region and proximal respiratory tract selectively permit SARS-CoV-2 infection and replication. In this translational study, we discover key variabilities in expression of angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2), essential SARS-CoV-2 entry factors, among the mucosal tissues of the human proximal airways. We show that SARS-CoV-2 infection is present in all examined head and neck tissues, with a notable tropism for the nasal cavity and tracheal mucosa. Finally, we uncover an association between smoking and higher SARS-CoV-2 viral infection in the human proximal airway, which may explain the increased susceptibility of smokers to developing severe COVID-19. This is at least partially explained by differences in interferon (IFN)-β1 levels between smokers and non-smokers., Competing Interests: I.T.L. is currently an employee and shareholder of Moderna, although this work was conducted prior to/independent of his employment. I.T.L. had also received research support unrelated to this study from Genentech (Roche). Moderna did not fund or participate in this study in any form., (© 2021.)

The Air Force Research Laboratory's Sensors Directorate has multiple missions, including the development of next generation infrared sensors. These sensors reflect advancements in both academic and research communities, as well as requirements flow-down from operators. There has been a multitude of developments over the past decade in each community. However, there has also been consilience that low-cost infrared sensing will be necessary for the Air Force. This paradigm stands in contrast to the current generation of high performance infrared sensors, i.e., cryogenically cooled, hybridized HgCdTe, InSb, and III/V strained layer superlattices. The Sensors Directorate currently has a multi-pronged approach to low-cost infrared sensing to meet this paradigm shift, including research in silicides, SiGeSn, and lead salts. Each of these approaches highlights our integration of materials, devices, and characterization.

Novel coronavirus disease 2019 (COVID-19) severity is highly variable, with pediatric patients typically experiencing less severe infection than adults and especially the elderly. The basis for this difference is unclear. We find that mRNA and protein expression of angiotensin-converting enzyme 2 (ACE2), the cell entry receptor for the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes COVID-19, increases with advancing age in distal lung epithelial cells. However, in humans, ACE2 expression exhibits high levels of intra- and interindividual heterogeneity. Further, cells infected with SARS-CoV-2 experience endoplasmic reticulum stress, triggering an unfolded protein response and caspase-mediated apoptosis, a natural host defense system that halts virion production. Apoptosis of infected cells can be selectively induced by treatment with apoptosis-modulating BH3 mimetic drugs. Notably, epithelial cells within young lungs and airways are more primed to undergo apoptosis than those in adults, which may naturally hinder virion production and support milder COVID-19 severity., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Background : The epidemiological situation generated by COVID-19 has cast into sharp relief the delicate balance between public health priorities and the economy, with businesses obliged to toe the line between employee health and continued production. In an effort to detect as many cases as possible, isolate contacts, cut transmission chains, and limit the spread of the virus in the workplace, mass testing strategies have been implemented in both public health and industrial contexts to minimize the risk of disruption in activity. Objective : To evaluate the economic impact of the mass workplace testing strategy as carried out by a large automotive company in Catalonia in terms of health and healthcare resource savings. Methodology : Analysis of health costs and impacts based on the estimation of the mortality and morbidity avoided because of screening, and the resulting savings in healthcare costs. Results : The economic impact of the mass workplace testing strategies (using both PCR and RAT tests) was approximately €10.44 per test performed or €5575.49 per positive detected; 38% of this figure corresponds to savings derived from better use of health resources (hospital beds, ICU beds, and follow-up of infected cases), while the remaining 62% corresponds to improved health rates due to the avoided morbidity and mortality. In scenarios with higher positivity rates and a greater impact of the infection on health and the use of health resources, these results could be up to ten times higher (€130.24 per test performed or €69,565.59 per positive detected). Conclusion : In the context of COVID-19, preventive actions carried out by the private sector to safeguard industrial production also have concomitant public benefits in the form of savings in healthcare costs. Thus, governmental bodies need to recognize the value of implementing such strategies in private settings and facilitate them through, for example, subsidies.

It is widely discussed in the literature that a problem of reduction of thermal noise of mid-wave and long-wave infrared (MWIR and LWIR) cameras and focal plane arrays (FPAs) can be solved by using light-concentrating structures. The idea is to reduce the area and, consequently, the thermal noise of photodetectors, while still providing a good collection of photons on photodetector mesas that can help to increase the operating temperature of FPAs. It is shown that this approach can be realized using microconical Si light concentrators with (111) oriented sidewalls, which can be mass-produced by anisotropic wet etching of Si (100) wafers. The design is performed by numerical modeling in a mesoscale regime when the microcones are sufficiently large (several MWIR wavelengths) to resonantly trap photons, but still too small to apply geometrical optics or other simplified approaches. Three methods of integration Si microcone arrays with the focal plane arrays are proposed and studied: (i) inverted microcones fabricated in a Si slab, which can be heterogeneously integrated with the front illuminated FPA photodetectors made from high quantum efficiency materials to provide resonant power enhancement factors (PEF) up to 10 with angle-of-view (AOV) up to 10°; (ii) inverted microcones, which can be monolithically integrated with metal-Si Schottky barrier photodetectors to provide resonant PEFs up to 25 and AOVs up to 30° for both polarizations of incident plane waves; and iii) regular microcones, which can be monolithically integrated with near-surface photodetectors to provide a non-resonant power concentration on compact photodetectors with large AOVs. It is demonstrated that inverted microcones allow the realization of multispectral imaging with ∼100 nm bands and large AOVs for both polarizations. In contrast, the regular microcones operate similar to single-pass optical components (such as dielectric microspheres), producing sharply focused photonic nanojets.

In vitro experiments have shown that GRASP65 (GORASP1) and GRASP55 (GORASP2) proteins function in stacking Golgi cisternae. However, in vivo depletion of GORASPs in metazoans has given equivocal results. We have generated a mouse lacking both GORASPs and find that Golgi cisternae remained stacked. However, the stacks are disconnected laterally from each other, and the cisternal cross-sectional diameters are significantly reduced compared with their normal counterparts. These data support earlier findings on the role of GORASPs in linking stacks, and we suggest that unlinking of stacks likely affects dynamic control of COPI budding and vesicle fusion at the rims. The net result is that cisternal cores remain stacked, but cisternal diameter is reduced by rim consumption., (© 2020 Grond et al.)

Aims: Patients hospitalized for heart failure (HF) are at increased risk for events post-discharge. Mineralocorticoid receptor antagonists (MRAs) improve the clinical course of patients with HF with reduced ejection fraction. We assessed MRA use in high-risk patients following an HF hospitalization to determine rate of MRA prescription, likelihood of drug continuation post-discharge, reasons for discontinuation, and association between MRA maintenance and outcomes., Methods and Results: Patients admitted to our hospital system between 2011 and 2013 were identified retrospectively through automated search of electronic medical records for appropriate ICD 9 and 10 codes. Patients with left ventricular ejection fraction <40%, New York Heart Association class III-IV symptoms, >1 year of follow-up and no contraindication to MRA use were included. Of 271 patients meeting inclusion criteria, 105 (38.7%) were prescribed an MRA on discharge from index admission. Over a median follow-up of 3.12 ± 0.09 years, 70 (66.7%) continued MRA therapy, while 35 (33.3%) discontinued MRA therapy. Hyperkalemia, which occurred in 43 of the 105 patients (40.1%), was the most frequent cause of MRA discontinuation. Patients who maintained MRA therapy had significantly less all-cause, cardiovascular, and HF hospitalizations and significantly better survival compared with those who discontinued drug., Conclusions: A minority of HF with reduced ejection fraction patients who were eligible for an MRA received them following HF hospitalization and nearly a third of them discontinued drug. Patients who discontinued an MRA were more likely to be hospitalized or die during follow-up. These findings indicate a need for better strategies to increase MRA prescription and maintain therapy following a hospitalization for HF., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Spontaneous coronary artery dissection (SCAD) is a relatively rare cause of acute coronary syndrome historically thought to primarily affect young, healthy women. The lack of multicenter collaborative research efforts has made it challenging to identify the precise etiology and pathological mechanisms underlying SCAD. However, there are many similarities in the patient demographics, clinical presentations, and predisposing stressors between SCAD and takotsubo syndrome (TTS)., Objectives: The aim of this observational study was to examine the coronary and left ventriculographic features of patients with angiographically confirmed SCAD and determine the prevalence of concomitant TTS., Methods: In this observational study, patients with angiographically confirmed SCAD were identified from the Massachusetts General Hospital SCAD registry. The coronary angiograms with simultaneous left ventriculograms (LVG) were carefully analyzed by an independent and blinded angiographic core laboratory., Results: From our analysis of patients with SCAD who also underwent a LVG at time of coronary angiography, we identified a high prevalence of SCAD and concomitant TTS., Conclusions: Therefore, we present TTS as a plausible mechanistic etiology for SCAD in some patients. In light of this finding as well as the many similarities between SCAD and TTS, clinicians should be vigilant about the potential concomitant presence of these two entities. Additional future investigations further exploring the clinical implications of the association between SCAD and TTS are warranted., (© 2019 Wiley Periodicals, Inc.)

Spontaneous coronary artery dissection (SCAD) is increasingly being recognized. However, data supporting diagnosis and management are scarce. We analyze a contemporary and comprehensive SCAD registry to advance the understanding of SCAD risk factors, angiographic appearance, and gender differences. This is a retrospective analysis of a prospectively populated database of SCAD patients seen at the Massachusetts General Hospital (MGH) between June 2013 and October 2017. Core laboratory analysis of both coronary angiograms and computerized tomographic (CT) angiography of the extracoronary vessels was performed. Of the 113 patients, 87% were female and mean age was 47 ± 10 years. Traditional cardiovascular risk factors including hypertension, hyperlipidemia, and smoking were present in 27%, 14%, and 22% of patients. Among females, 14%, 8%, and 9% had a history of gestational hypertension, pre-eclampsia, and gestational diabetes, respectively. Fifteen percent had used fertility treatment and 47% of postmenopausal women had used hormone replacement therapy. Angiography showed multivessel SCAD in 42%, severe coronary artery tortuosity in 59%, and extracoronary vascular abnormalities in 100% of patients with complete CT angiographic imaging. Gender differences revealed a self-reported depression and anxiety prevalence of 20% and 32%, respectively, in women compared with 0% in men. Type 1 SCAD was more commonly diagnosed in men than women (71% vs 29%, p <0.01). In conclusion, we highlight under-recognized features of SCAD including (1) relation with pregnancy complications and exposure to hormonal therapy; (2) diffuse, multivessel process in tortuous coronaries on a background of extracoronary arterial abnormalities; and (3) gender differences highlighting the role of mental health as well as potential underdiagnoses in men., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Amphiphilic alkoxybenzonitriles (ABNs) of varying chain length are studied at the solution/graphite interface to analyze dynamics of assembly. Competitive self-assembly between ABNs and alkanoic acid solvent is shown by scanning tunneling microscopy (STM) to be controlled by concentration and molecular size. Molecular dynamics (MD) simulations reveal key roles of the sub-nanosecond fundamental steps of desorption, adsorption, and on-surface motion. We discovered asymmetry in desorption-adsorption steps. Desorption starting from alkyl chain detachment from the surface is favored due to dynamic occlusion by neighbouring chains. Even though the nitrile head has a strong solvent affinity, it more frequently re-adsorbs following a detachment event.

After local transient fluctuations are dissipated, in an energy transfer process, a system evolves to a state where the energy density field varies slowly in time relative to the dynamics of atomic collisions and vibrations. Furthermore, the energy density field remains strongly coupled to the atomic scale processes (collisions and vibrations), and it can serve as the basis of a multiscale theory of energy transfer. Here, a method is introduced to capture the long scale energy density variations as they coevolve with the atomistic state in a way that yields insights into the basic physics and implies an efficient algorithm for energy transfer simulations. The approach is developed based on the N-atom Liouville equation and an interatomic force field and avoids the need for conjectured phenomenological equations for energy transfer and other processes. The theory is demonstrated for sodium chloride and silicon dioxide nanoparticles immersed in a water bath via molecular dynamics simulations of the energy transfer between a nanoparticle and its aqueous host fluid. The energy density field is computed for different sets of symmetric grid densities, and the multiscale theory holds when slowly varying energy densities at the nodes are obtained. Results strongly depend on grid density and nanoparticle constituent material. A nonuniform temperature distribution, larger thermal fluctuations in the nanoparticle than in the bath, and enhancement of fluctuations at the surface, which are expressed due to the atomic nature of the systems, are captured by this method rather than by phenomenological continuum energy transfer models.

The natriuretic peptides play a vital role in normal physiology and as counter-regulatory hormones in heart failure (HF). Clinical assessment of their levels (for B-type natriuretic peptide [BNP], N-terminal proBNP, and the midregion of N-terminal pro-atrial natriuretic peptide) have become valuable tools in diagnosing patients with HF as well as risk stratifying and guiding therapy. Their roles have further expanded beyond HF to other cardiovascular conditions and for risk stratification in asymptomatic individuals. Understanding the clinical use of these hormones is vital to achieving their full potential., (Published by Elsevier Inc.)

The nutrient starvation-specific unconventional secretion of Acb1 in Saccharomyces cerevisiae requires ESCRT-I, -II, and -III and Grh1. In this study, we report that another signal sequence lacking cytoplasmic protein, superoxide dismutase 1 (SOD1), and its mutant form linked to amyotrophic lateral sclerosis (ALS), is also secreted by yeast upon nutrient starvation in a Grh1- and ESCRT-I-, -II-, and -III-dependent process. Our analyses reveal that a conserved diacidic motif (Asp-Glu) in these proteins is necessary for their export. Importantly, secretion of wild-type human SOD1 and the ALS-linked mutant in human cells also require the diacidic residues. Altogether, these findings reveal information encoded within the cytoplasmic proteins required for their unconventional secretion and provide a means to unravel the significance of the cytoplasmic versus the secreted form of mutant SOD1 in the pathology of ALS. We also propose how cells, based on a signal-induced change in cytoplasmic physiology, select a small pool of a subset of cytoplasmic proteins for unconventional secretion., (© 2017 Cruz-Garcia et al.)

Preeclampsia (PE) is a major complication of pregnancy in which the placenta is known to have shallow implantation into the uterine decidua. Studies have implicated soluble fms-like tyrosine kinase-1 (sFlt1), a soluble vascular endothelial growth factor (VEGF) receptor protein, in the pathogenesis of PE. sFlt1 has the ability to bind to and neutralize the angiogenic functions of VEGF and placental growth factor (PlGF). The presence of sFlt1 and its action in the endometrium is yet to be determined. We hypothesize that endometrial stromal cells (ESC) at the maternal-fetal interface may play a role in sFlt-1 regulation during pregnancy. In this study, we seek to understand the dynamic regulation of sFlt1 production in primary human ESC as a result of hormone stimulation and withdrawal. To mimic a biphasic menstrual cycle, ESC were treated with cAMP to induce endometrial decidualization that occurs during the luteal secretory phase, followed by cAMP withdrawal reflecting the follicular proliferative phase. Here, we present data to show that (1) ESC produce detectable amounts of sFlt1, (2) sFlt1 expression is turned off during decidualization at both the protein and RNA level (3) ESC decidualization and resulting sFlt1 expression are reversible phenomenon, and (4) Decidualization markers prolactin (PRL) and VEGF expressions in ESC are negatively correlated with sFlt1. These findings may have important implications in diseases such as PE that involve abnormal decidualization, implantation and angiogenesis at the maternal-fetal interface.

Rationale: Catecholamines increase cardiac contractility, but exposure to high concentrations or prolonged exposures can cause cardiac injury. A recent study demonstrated that a single subcutaneous injection of isoproterenol (ISO; 200 mg/kg) in mice causes acute myocyte death (8%-10%) with complete cardiac repair within a month. Cardiac regeneration was via endogenous cKit(+) cardiac stem cell-mediated new myocyte formation., Objective: Our goal was to validate this simple injury/regeneration system and use it to study the biology of newly forming adult cardiac myocytes., Methods and Results: C57BL/6 mice (n=173) were treated with single injections of vehicle, 200 or 300 mg/kg ISO, or 2 daily doses of 200 mg/kg ISO for 6 days. Echocardiography revealed transiently increased systolic function and unaltered diastolic function 1 day after single ISO injection. Single ISO injections also caused membrane injury in ≈10% of myocytes, but few of these myocytes appeared to be necrotic. Circulating troponin I levels after ISO were elevated, further documenting myocyte damage. However, myocyte apoptosis was not increased after ISO injury. Heart weight to body weight ratio and fibrosis were also not altered 28 days after ISO injection. Single- or multiple-dose ISO injury was not associated with an increase in the percentage of 5-ethynyl-2'-deoxyuridine-labeled myocytes. Furthermore, ISO injections did not increase new myocytes in cKit(+/Cre)×R-GFP transgenic mice., Conclusions: A single dose of ISO causes injury in ≈10% of the cardiomyocytes. However, most of these myocytes seem to recover and do not elicit cKit(+) cardiac stem cell-derived myocyte regeneration., (© 2016 American Heart Association, Inc.)

Objectives: In this study we sought to evaluate coverage and apposition of Synergy™ stent at 3 and 6 months after implantation., Background: The Pt-Cr everolimus-eluting stent with abluminal bioabsorbable polymer (Synergy™) is a new generation drug-eluting stent with features potentially favoring an early healing process which could make safe a shorter period of dual antiplatelet-therapy treatment., Methods: Prospective, two-centers study enrolling patients with similar lesions treated with Synergy™ stents undergoing examination with OCT at 3 and 6 months in the respective centers. Blinded analysis was done at a core lab. Co-primary endpoints were proportion of struts with coverage and with apposition at 3 and 6 months., Results: Finally, 22 patients (30 stents) in the 3 months group and 20 patients (30 stents) in the 6 months group were included. There were no significant differences between groups regarding clinical, angiographic measurements, and procedural data. The rate of strut coverage was 94.5% at 3 months and 96.6% at 6 months (P < 0.001), the rates of apposition were 93.8% and 96.2%, respectively, (P < 0.001), the proportion of uncovered but apposed struts was 2.5% and 1.9% (P = 0.03) and the proportion of uncovered and malapposed struts was 3% and 1.8%, respectively (P < 0.001). The maximal area of malapposition related with uncovered struts was 0.43 ± 0.4 mm(2) at 3 months and 0.14 ± 0.2 mm(2) at 6 months (P = 0.001)., Conclusions: The everolimus-eluting stent with absorbable polymer, Synergy™, is associated to a high degree of intimal coverage and apposition at 3 months after implantation with additional increase at 6 months. © 2015 Wiley Periodicals, Inc., (© 2015 Wiley Periodicals, Inc.)

Carbon nanotubes are being considered for the design of drug delivery systems (DDSs) due to their capacity to internalize molecules and control their release. However, for cellular uptake of drugs, this approach requires an active translocation pathway or a channel to transport the drug into the cell. To address this issue, it is suggested to use TRPV1 ion channels as a potential target for drug release by nano-DDSs since these channels are overexpressed in cancer cells and allow the permeation of large cationic molecules. Considering these facts, this work presents three studies using molecular dynamics simulations of a human TRPV1 (hTRPV1) channel built here. The purpose of these simulations is to study the interaction between a single-wall carbon nanotube (SWCNT) and hTRPV1, and the diffusion of doxorubicin (DOX) across hTRPV1 and across a POPC lipid membrane. The first study shows an attractive potential between the SWCNT surface and hTRPV1, tilting the adsorbed SWCNT. The second study shows low diffusion probability of DOX across the open hTRPV1 due to a high free energy barrier. Although, the potential energy between DOX and hTRPV1 reveals an attractive interaction while DOX is inside hTRPV1. These results suggest that if the channel is dilated, then DOX diffusion could occur. The third study shows a lower free energy barrier for DOX across the lipid membrane than for DOX across hTRPV1. Taking into account the results obtained, it is feasible to design novel nano-DDSs based on SWCNTs to accomplish controlled drug release into cells using as translocation pathway, the hTRPV1 ion channel.

Determination of fundamental mechanisms of disease often hinges on histopathology visualization and quantitative image analysis. Currently, the analysis of multi-channel fluorescence tissue images is primarily achieved by manual measurements of tissue cellular content and sub-cellular compartments. Since the current manual methodology for image analysis is a tedious and subjective approach, there is clearly a need for an automated analytical technique to process large-scale image datasets. Here, we introduce Nuquantus (Nuclei quantification utility software) - a novel machine learning-based analytical method, which identifies, quantifies and classifies nuclei based on cells of interest in composite fluorescent tissue images, in which cell borders are not visible. Nuquantus is an adaptive framework that learns the morphological attributes of intact tissue in the presence of anatomical variability and pathological processes. Nuquantus allowed us to robustly perform quantitative image analysis on remodeling cardiac tissue after myocardial infarction. Nuquantus reliably classifies cardiomyocyte versus non-cardiomyocyte nuclei and detects cell proliferation, as well as cell death in different cell classes. Broadly, Nuquantus provides innovative computerized methodology to analyze complex tissue images that significantly facilitates image analysis and minimizes human bias.

The endocannabinoid system (ECS) has a pivotal role in different cognitive functions such as learning and memory. Recent evidence confirm the involvement of the hippocampal CB1 receptors in the modulation of both memory extinction and reconsolidation processes in different brain areas, but few studies focused on the infralimbic cortex, another important cognitive area. Here, we infused the cannabinoid agonist CP55,940 either into the infralimbic cortex (IL) or the CA1 area of the dorsal hippocampus (HPC) of adult male Wistar rats immediately after a short (3min) reactivation session, known to labilize a previously consolidated memory trace in order to allow its reconsolidation with some modification. In both structures, the treatment was able to disrupt reconsolidation in a relatively long lasting way, reducing the freezing response. To our notice, this is the first demonstration of ECS involvement in reconsolidation in the Infralimbic Cortex. Despite poorly discriminative between CB1 and CB2 receptors, CP55,940 is a potent agent, and these results suggest that a similar CB1-dependent circuitry is at work both in HPC and in the IL during memory reconsolidation., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Animal models of fear extinction have an important clinical relevance to pharmacological and exposure-based therapies for anxiety disorders. Lesions of prefrontal structures impair fear extinction. On the other hand, d-cycloserine is able to enhance this process. We hypothesize that the integrity of cortical structures involved in inhibitory control of emotional responses is crucial for the facilitatory effects of d-cycloserine. Here, we showed that medial orbitofrontal cortex lesion prevents d-cycloserine enhancement of fear extinction. These preliminary results suggest that effects of pharmacological treatments could be dependent on cortical activity state to promote fear memory reduction., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Rationale: Adoptive transfer of multiple stem cell types has only had modest effects on the structure and function of failing human hearts. Despite increasing the use of stem cell therapies, consensus on the optimal stem cell type is not adequately defined. The modest cardiac repair and functional improvement in patients with cardiac disease warrants identification of a novel stem cell population that possesses properties that induce a more substantial improvement in patients with heart failure., Objective: To characterize and compare surface marker expression, proliferation, survival, migration, and differentiation capacity of cortical bone stem cells (CBSCs) relative to mesenchymal stem cells (MSCs) and cardiac-derived stem cells (CDCs), which have already been tested in early stage clinical trials., Methods and Results: CBSCs, MSCs, and CDCs were isolated from Gottingen miniswine or transgenic C57/BL6 mice expressing enhanced green fluorescent protein and were expanded in vitro. CBSCs possess a unique surface marker profile, including high expression of CD61 and integrin β4 versus CDCs and MSCs. In addition, CBSCs were morphologically distinct and showed enhanced proliferation capacity versus CDCs and MSCs. CBSCs had significantly better survival after exposure to an apoptotic stimuli when compared with MSCs. ATP and histamine induced a transient increase of intracellular Ca(2+) concentration in CBSCs versus CDCs and MSCs, which either respond to ATP or histamine only further documenting the differences between the 3 cell types., Conclusions: CBSCs are unique from CDCs and MSCs and possess enhanced proliferative, survival, and lineage commitment capacity that could account for the enhanced protective effects after cardiac injury., (© 2015 American Heart Association, Inc.)

Background: Cardiac- (CSC) and mesenchymal-derived (MSC) CD117+ isolated stem cells improve cardiac function after injury. However, no study has compared the therapeutic benefit of these cells when used autologously., Methods: MSCs and CSCs were isolated on day 0. Cardiomyopathy was induced (day 28) by infusion of L-isoproterenol (1,100 ug/kg/hour) from Alzet minipumps for 10 days. Bromodeoxyuridine (BrdU) was infused via minipumps (50 mg/mL) to identify proliferative cells during the injury phase. Following injury (day 38), autologous CSC (n = 7) and MSC (n = 4) were delivered by intracoronary injection. These animals were compared to those receiving sham injections by echocardiography, invasive hemodynamics, and immunohistochemistry., Results: Fractional shortening improved with CSC (26.9 ± 1.1% vs. 16.1 ± 0.2%, p = 0.01) and MSC (25.1 ± 0.2% vs. 12.1 ± 0.5%, p = 0.01) as compared to shams. MSC were superior to CSC in improving left ventricle end-diastolic (LVED) volume (37.7 ± 3.1% vs. 19.9 ± 9.4%, p = 0.03) and ejection fraction (27.7 ± 0.1% vs. 19.9 ± 0.4%, p = 0.02). LVED pressure was less in MSC (6.3 ± 1.3 mmHg) as compared to CSC (9.3 ± 0.7 mmHg) and sham (13.3 ± 0.7); p = 0.01. LV BrdU+ myocytes were higher in MSC (0.17 ± 0.03%) than CSC (0.09 ± 0.01%) and sham (0.06 ± 01%); p < 0.001., Conclusions: Both CD117+ isolated CSC and MSC therapy improve cardiac function and attenuate pathological remodeling. However, MSC appear to confer additional benefit., (© 2015 Wiley Periodicals, Inc.)

Memories can be destabilized by the reexposure to the training context, and may reconsolidate into a modified engram. Reconsolidation relies on some particular molecular mechanisms involving LVGCCs and GluN2B-containing NMDARs. In this study we investigate the interference caused by the presence of a distractor - a brief, unanticipated stimulus that impair a fear memory expression - during the reactivation session, and tested the hypothesis that this disruptive effect relies on a reconsolidation process. Rats previously trained in the contextual fear conditioning (CFC) were reactivated in the presence or absence of a distractor stimulus. In the test, groups reactivated in the original context with distractor displayed a reduction of the freezing response lasting up to 20 days. To check for the involvement of destabilization / reconsolidation mechanisms, we studied the effect of systemic nimodipine (a L-VGCC blocker) or intra-CA1 ifenprodil (a selective GluN2B/NMDAR antagonist) infused right before the reactivation session. Both treatments were able to prevent the disruptive effect of distraction. Ifenprodil results also bolstered the case for hippocampus as the putative brain structure hosting this phenomenon. Our results provide some evidence in support of a behavioral, non-invasive procedure that was able to disrupt an aversive memory in a long-lasting way.

Upon starvation, Grh1, a peripheral membrane protein located at endoplasmic reticulum (ER) exit sites and early Golgi in Saccharomyces cerevisiae under growth conditions, relocates to a compartment called compartment for unconventional protein secretion (CUPS). Here we report that CUPS lack Golgi enzymes, but contain the coat protein complex II (COPII) vesicle tethering protein Uso1 and the Golgi t-SNARE Sed5. Interestingly, CUPS biogenesis is independent of COPII- and COPI-mediated membrane transport. Pik1- and Sec7-mediated membrane export from the late Golgi is required for complete assembly of CUPS, and Vps34 is needed for their maintenance. CUPS formation is triggered by glucose, but not nitrogen starvation. Moreover, upon return to growth conditions, CUPS are absorbed into the ER, and not the vacuole. Altogether our findings indicate that CUPS are not specialized autophagosomes as suggested previously. We suggest that starvation triggers relocation of secretory and endosomal membranes, but not their enzymes, to generate CUPS to sort and secrete proteins that do not enter, or are not processed by enzymes of the ER-Golgi pathway of secretion., (© 2014 Cruz-Garcia et al.)

Rationale: Sorafenib is an effective treatment for renal cell carcinoma, but recent clinical reports have documented its cardiotoxicity through an unknown mechanism., Objective: Determining the mechanism of sorafenib-mediated cardiotoxicity., Methods and Results: Mice treated with sorafenib or vehicle for 3 weeks underwent induced myocardial infarction (MI) after 1 week of treatment. Sorafenib markedly decreased 2-week survival relative to vehicle-treated controls, but echocardiography at 1 and 2 weeks post MI detected no differences in cardiac function. Sorafenib-treated hearts had significantly smaller diastolic and systolic volumes and reduced heart weights. High doses of sorafenib induced necrotic death of isolated myocytes in vitro, but lower doses did not induce myocyte death or affect inotropy. Histological analysis documented increased myocyte cross-sectional area despite smaller heart sizes after sorafenib treatment, further suggesting myocyte loss. Sorafenib caused apoptotic cell death of cardiac- and bone-derived c-kit+ stem cells in vitro and decreased the number of BrdU+ (5-bromo-2'-deoxyuridine+) myocytes detected at the infarct border zone in fixed tissues. Sorafenib had no effect on infarct size, fibrosis, or post-MI neovascularization. When sorafenib-treated animals received metoprolol treatment post MI, the sorafenib-induced increase in post-MI mortality was eliminated, cardiac function was improved, and myocyte loss was ameliorated., Conclusions: Sorafenib cardiotoxicity results from myocyte necrosis rather than from any direct effect on myocyte function. Surviving myocytes undergo pathological hypertrophy. Inhibition of c-kit+ stem cell proliferation by inducing apoptosis exacerbates damage by decreasing endogenous cardiac repair. In the setting of MI, which also causes large-scale cell loss, sorafenib cardiotoxicity dramatically increases mortality., (© 2014 American Heart Association, Inc.)