Grand challenges in cell death and survival: apoptosis vs. necroptosis

Cell death is, perhaps paradoxically, essential for life. This is particularly so for multicellular organisms, where cell death plays crucial roles in regulating embryonic development, tissue homeostasis, immune function, tumor suppression, and infection resistance. Much of what is known about cell death has been developed through studies in the last two decades, an era that has witnessed an explosion of publication in the area of programmed cell death (PCD). In this Grand Challenges monograph, I provide a short background on what we've learned thus far. I will then highlight areas that are likely to be of strong focus in the future, focusing primarily on distinct forms of PCD including caspase-dependent apoptosis, programmed necrosis/necroptosis, and autophagic cell death. The relevance of these cell death pathways to disease is described, and the potential that manipulation of these pathways may be the key to treating such diseases is considered. My intent is not to provide an encyclopedic review of the field, a task that would likely fill many volumes. Instead, I wish to highlight areas that are likely to be relevant to our mission as we christen a new Frontiers Specialty area, Frontiers in Cell Death and Survival

Neural precursor cells derived from induced pluripotent stem cells exhibit reduced susceptibility to infection with a neurotropic coronavirus.

The present study examines the susceptibility of mouse induced pluripotent stem cell-derived neural precursor cells (iPSC-NPCs) to infection with the neurotropic JHM strain of mouse hepatitis virus (JHMV). Similar to NPCs derived from striatum of day 1 postnatal GFP-transgenic mice (GFP-NPCs), iPSC-derived NPCs (iPSC-NPCs) are able to differentiate into terminal neural cell types and express MHC class I and II in response to IFN-γ treatment. However, in contrast to postnatally-derived NPCs, iPSC-NPCs express low levels of carcinoembryonic antigen-cell adhesion molecule 1a (CEACAM1a), the surface receptor for JHMV, and are less susceptible to infection and virus-induced cytopathic effects. The relevance of this in terms of therapeutic application of NPCs resistant to viral infection is discussed

Explaining trends in alcohol-related harms in Scotland 1991–2011 (II): policy, social norms, the alcohol market, clinical changes and a synthesis

Objective: To provide a basis for evaluating post-2007 alcohol policy in Scotland, this paper tests the extent to which pre-2007 policy, the alcohol market, culture or clinical changes might explain differences in the magnitude and trends in alcohol-related mortality outcomes in Scotland compared to England & Wales (E&W). Study design: Rapid literature reviews, descriptive analysis of routine data and narrative synthesis. Methods: We assessed the impact of pre-2007 Scottish policy and policy in the comparison areas in relation to the literature on effective alcohol policy. Rapid literature reviews were conducted to assess cultural changes and the potential role of substitution effects between alcohol and illicit drugs. The availability of alcohol was assessed by examining the trends in the number of alcohol outlets over time. The impact of clinical changes was assessed in consultation with key informants. The impact of all the identified factors were then summarised and synthesised narratively. Results: The companion paper showed that part of the rise and fall in alcohol-related mortality in Scotland, and part of the differing trend to E&W, were predicted by a model linking income trends and alcohol-related mortality. Lagged effects from historical deindustrialisation and socio-economic changes exposures also remain plausible from the available data. This paper shows that policy differences or changes prior to 2007 are unlikely to have been important in explaining the trends. There is some evidence that aspects of alcohol culture in Scotland may be different (more concentrated and home drinking) but it seems unlikely that this has been an important driver of the trends or the differences with E&W other than through interaction with changing incomes and lagged socio-economic effects. Substitution effects with illicit drugs and clinical changes are unlikely to have substantially changed alcohol-related harms: however, the increase in alcohol availability across the UK is likely to partly explain the rise in alcohol-related mortality during the 1990s. Conclusions: Future policy should ensure that alcohol affordability and availability, as well as socio-economic inequality, are reduced, in order to maintain downward trends in alcohol-related mortality in Scotland

A Role for FADD in T Cell Activation and Development

AbstractFADD is a cytoplasmic adapter molecule that links the family of death receptors to the activation of caspases during apoptosis. We have produced transgenic mice expressing a dominantly interfering mutant of FADD, lacking the caspase-dimerizing death effector domain, as well as mice overexpressing the poxvirus serpin, CrmA, an inhibitor of caspases downstream of FADD. While thymocytes from either line of mice were completely protected from CD95-dependent cytotoxicity, neither transgene afforded protection from apoptosis induced during thymocyte selection and neither led to the lymphoproliferative disorders associated with deficiencies in CD95. However, in FADD dominant negative (FADDdd) mice, early thymocyte development was retarded and peripheral lymphocyte pools were devoid of normal populations of T cells. We show that thymocytes and peripheral T cells from FADDdd display signaling anomalies, implying that FADD plays a previously uncharacterized role in T cell development and activation

Improving the efficiency of electrochemical CO2 reduction using immobilized manganese complexes

Immobilization of [Mn(bpy)(CO)3Br], (1) and [Mn(bpy(tBu)2)(CO)3Br] (2, where (bpy(tBu)2) = 4,4′-di-tert-butyl-2,2′-bipyridine) in Nafion/multi-walled carbon nanotubes (MWCNT) on glassy carbon yielded highly active electrodes for the reduction of CO2 to CO in aqueous solutions at pH 7. Films incorporating 2 have significantly improved selectivity towards CO2, with CO : H2 ∼ 1 at −1.4 V vs. SCE, exceeding that for the previously reported 1/MWCNT/Nafion electrode. Furthermore, we report the synthesis and subsequent electrochemical characterization of two new substituted Mn(i) bipyridine complexes, [Mn(bpy(COOH)2)(CO)3Br] (3) and [Mn(bpy(OH)2)(CO)3Br] (4) (where (bpy(COOH)2) = 4,4′-di-carboxy-2,2′-bipyridine and (bpy(OH)2) = 4,4′-di-hydroxy-2,2′-bipyridine). Both 3 and 4 were found to have some activity towards CO2 in acetonitrile solutions; however once immobilized in Nafion membranes CO2 reduction was found to not occur at significant levels.</p

The young age of the extremely metal-deficient blue compact dwarf galaxy SBS 1415+437

We use Multiple Mirror Telescope (MMT) spectrophotometry and Hubble Space Telescope (HST) Faint Object Spectrograph (FOS) spectra and Wide Field and Planetary Camera 2 (WFPC2) V and I images to study the properties and evolutionary status of the nearby (D = 11.4 Mpc) extremely metal-deficient blue compact dwarf (BCD) galaxy SBS 1415+437=CG 389. The oxygen abundance in the galaxy is 12+log(O/H)=7.60+/-0.01 or Zsun/21. The helium mass fraction in SBS 1415+437 is Y=0.246+/-0.004 which agrees with the primordial helium abundance determined by Izotov & Thuan using a much larger sample of BCDs. The alpha-elements-to-oxygen abundance ratios (Ne/O, S/O, Ar/O) are in very good agreement with the mean values for other metal-deficient BCDs and are consistent with the scenario that these elements are made in massive stars. The Fe/O abundance ratio is ~2 times smaller than the solar ratio. The Si/O ratio is close to the solar value, implying that silicon is not significantly depleted into dust grains. The values of the N/O and C/O ratios imply that intermediate-mass stars have not had time to evolve in SBS 1415+437 and release their nucleosynthesis products and that both N and C in the BCD have been made by massive stars only. This sets an upper limit of ~100 Myr on the age of SBS 1415+437. The (V-I) color of the low-surface-brightness component of the galaxy is blue (<0.4 mag) indicative of a very young underlying stellar population. The (V-I) - I color-magnitude diagrams of the resolved stellar populations in different regions of SBS 1415+437 suggest propagating star formation from the NE side of the galaxy to the SW. All regions in SBS 1415+437 possess very blue spectral energy distributions (SED). We find that the ages of the stellar populations in SBS 1415+437 to range from a few Myr to 100 Myr.Comment: 25 pages, 12 PS and 5 JPG figures, to appear in Ap

Adverse effect of increased left ventricular wall thickness on five year outcomes of patients with negative dobutamine stress

<p>Abstract</p> <p>Background</p> <p>To determine if patients without dobutamine induced left ventricular wall motion abnormalities (WMA) but an increased LV end-diastolic wall thickness (EDWT) exhibit a favorable cardiac prognosis.</p> <p>Results</p> <p>Between 1999 and 2001, 175 patients underwent a dobutamine stress cardiovascular magnetic resonance (DCMR) procedure utilizing gradient-echo cines. Participants had a LV ejection fraction >55% without evidence of an inducible WMA during peak dobutamine/atropine stress. After an average of 5.5 years, all participants were contacted and medical records were reviewed to determine the post-DCMR occurrence of cardiac death, myocardial infarction (MI), and unstable angina (USA) or congestive heart failure (CHF) warranting hospitalization.</p> <p>In a multivariate analysis, that took into account Framingham and other risk factors associated with cardiac events, a cine gradient-echo derived LV EDWT ≥12 mm was associated independently with an increase in cardiac death and MI (HR 6.0, p = 0.0016), and the combined end point of MI, cardiac death, and USA or CHF warranting hospitalization (HR 3.0, p = 0.0005).</p> <p>Conclusion</p> <p>Similar to echocardiography, CMR measures of increased LV wall thickness should be considered a risk factor for cardiac events in individuals receiving negative reports of inducible ischemia after dobutamine stress. Additional prognostic studies of the importance of LV wall thickness and mass measured with steady-state free precession techniques are warranted.</p

Identification and proteomic profiling of exosomes in human cerebrospinal fluid

<p>Abstract</p> <p>Background</p> <p>Exosomes are released from multiple cell types, contain protein and RNA species, and have been exploited as a novel reservoir for disease biomarker discovery. They can transfer information between cells and may cause pathology, for example, a role for exosomes has been proposed in the pathophysiology of Alzheimer's disease. Although studied in several biofluids, exosomes have not been extensively studied in the cerebrospinal fluid (CSF) from humans. The objective of this study was to determine: 1) whether human CSF contains exosomes and 2) the variability in exosomal protein content across individuals.</p> <p>Methods</p> <p>CSF was collected from 5 study participants undergoing thoraco-abdominal aortic aneurysm repair (around 200 - 500 ml per participant) and low-density membrane vesicles were concentrated by ultracentrifugation. The presence of exosomes was determined by western blot for marker proteins, isopycnic centrifugation on a sucrose step gradient and transmission electron microscopy with immuno-labelling. Whole protein profiling was performed using Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR).</p> <p>Results</p> <p>Flotillin 1 and tumor susceptibility gene 101 (TSG101), two exosomal marker proteins, were identified in the ultracentrifugation pellet using western blot. These markers localized to a density consistent with exosomes following isopycnic centrifugation. Transmission electron microscopy visualized structures consistent with exosomes in size and appearance that labelled positive for flotillin 1. Therefore, the pellet that resulted from ultracentrifugation of human CSF contained exosomes. FT-ICR profiling of this pellet was performed and 84-161 ions were detected per study participant. Around one third of these ions were only present in a single study participant and one third were detected in all five. With regard to ion quantity, the median coefficient of variation was 81% for ions detected in two or more samples.</p> <p>Conclusions</p> <p>Exosomes were identified in human CSF and their proteome is a potential new reservoir for biomarker discovery in neurological disorders such as Alzheimer's disease. However, techniques used to concentrate exosomes from CSF need refinement to reduce variability. In this study we used relatively large starting volumes of human CSF, future studies will focus on exosome isolation from smaller 'real life' clinical samples; a key challenge in the development of exosomes as translational tools.</p