Chronically stressed or stress-preconditioned neurons fail to maintain stress granule assembly

Dysregulation of stress granules (SGs) and their resident proteins contributes to pathogenesis of a number of (neuro)degenerative diseases. Phosphorylation of eIF2α is an event integrating different types of cellular stress and it is required for SG assembly. Phosphorylated eIF2α (p-eIF2α) is upregulated in the nervous system in some neurodegenerative conditions. We found that increasing p-eIF2α level by proteasomal inhibition in cultured cells, including mouse and human neurons, prior to a SG-inducing stress (‘stress preconditioning’), limits their ability to maintain SG assembly. This is due to upregulation of PP1 phosphatase regulatory subunits GADD34 and/or CReP in preconditioned cells and early decline of p-eIF2α levels during subsequent acute stress. In two model systems with constitutively upregulated p-eIF2α, mouse embryonic fibroblasts lacking CReP and brain neurons of tau transgenic mice, SG formation was also impaired. Thus neurons enduring chronic stress or primed by a transient mild stress fail to maintain p-eIF2α levels following subsequent acute stress, which would compromise protective function of SGs. Our findings provide experimental evidence on possible loss of function for SGs in certain neurodegenerative diseases

The evolution of the cluster optical galaxy luminosity function between z=0.4 and 0.9 in the DAFT/FADA survey

We compute optical galaxy luminosity functions (GLFs) in the B, V, R, and I rest-frame bands for one of the largest medium-to-high-redshift (0.4 < z < 0.9) cluster samples to date in order to probe the abundance of faint galaxies in clusters. We also study how the GLFs depend on cluster redshift, mass, and substructure, and compare the GLFs of clusters with those of the field. We separately investigate the GLFs of blue and red-sequence (RS) galaxies to understand the evolution of different cluster populations. We find that the shapes of our GLFs are similar for the B, V, R, and I bands with a drop at the red GLF faint end that is more pronounced at high-redshift: alpha(red) ~ -0.5 at 0.40 0.1 at 0.65 < z < 0.90. The blue GLFs have a steeper faint end (alpha(blue) ~ -1.6) than the red GLFs, that appears to be independent of redshift. For the full cluster sample, blue and red GLFs intersect at M(V) = -20, M(R) = -20.5, and M(I) = -20.3. A study of how galaxy types evolve with redshift shows that late type galaxies appear to become early types between z ~ 0.9 and today. Finally, the faint ends of the red GLFs of more massive clusters appear to be richer than less massive clusters, which is more typical of the lower redshift behaviour. Our results indicate that our clusters form at redshifts higher than z = 0.9 from galaxy structures that already have an established red sequence. Late type galaxies then appear to evolve into early types, enriching the red-sequence between this redshift and today. This effect is consistent with the evolution of the faint end slope of the red-sequence and the galaxy type evolution that we find. Finally, faint galaxies accreted from the field environment at all redshifts might have replaced the blue late type galaxies that converted into early types, explaining the lack of evolution in the faint end slopes of the blue GLFs.Comment: accepted for publication in A&

Hippocampal tau oligomerization early in tau pathology coincides with a transient alteration of mitochondrial homeostasis and DNA repair in a mouse model of tauopathy

International audienceInsoluble intracellular aggregation of tau proteins into filaments and neurodegeneration are histopathological hallmarks of Alzheimer disease (AD) and other tauopathies. Recently, prefibrillar, soluble, oligomeric tau intermediates have emerged as relevant pathological tau species; however, the molecular mechanisms of neuronal responses to tau oligomers are not fully understood. Here, we show that hippocampal neurons in six-month-old transgenic mouse model of tauopathy, THY-Tau22, are enriched with oligomeric tau, contain elongated mitochondria, and display cellular stress, but no overt cytotoxicity compared to the control mice. The levels of several key mitochondrial proteins were markedly different between the THY-Tau22 and control mice hippocampi including the mitochondrial SIRT3, PINK1, ANT1 and the fission protein DRP1. DNA base excision repair (BER) is the primary defense system against oxidative DNA damage and it was elevated in six-month-old transgenic mice. DNA polymerase β, the key BER DNA polymerase, was enriched in the cytoplasm of hippocampal neurons in six-month-old transgenic mice and localized with and within mitochondria. Polβ also co-localized with mitochondria in human AD brains in neurons containing oligomeric tau. Most of these altered mitochondrial and DNA repair events were specific to the transgenic mice at 6 months of age and were not different from control mice at 12 months of age when tau pathology reaches its maximum and oligomeric forms of tau are no longer detectable. In summary, our data suggests that we have identified key cellular stress responses at early stages of tau pathology to preserve neuronal integrity and to promote survival. To our knowledge, this work provides the first description of multiple stress responses involving mitochondrial homeostasis and BER early during the progression of tau pathology, and represents an important advance in the etiopathogenesis of tauopathies

Quality indicators for patients with traumatic brain injury in European intensive care units

Background: The aim of this study is to validate a previously published consensus-based quality indicator set for the management of patients with traumatic brain injury (TBI) at intensive care units (ICUs) in Europe and to study its potential for quality measur

Changing care pathways and between-center practice variations in intensive care for traumatic brain injury across Europe

Purpose: To describe ICU stay, selected management aspects, and outcome of Intensive Care Unit (ICU) patients with traumatic brain injury (TBI) in Europe, and to quantify variation across centers. Methods: This is a prospective observational multicenter study conducted across 18 countries in Europe and Israel. Admission characteristics, clinical data, and outcome were described at patient- and center levels. Between-center variation in the total ICU population was quantified with the median odds ratio (MOR), with correction for case-mix and random variation between centers. Results: A total of 2138 patients were admitted to the ICU, with median age of 49 years; 36% of which were mild TBI (Glasgow Coma Scale; GCS 13–15). Within, 72 h 636 (30%) were discharged and 128 (6%) died. Early deaths and long-stay patients (> 72 h) had more severe injuries based on the GCS and neuroimaging characteristics, compared with short-stay patients. Long-stay patients received more monitoring and were treated at higher intensity, and experienced worse 6-month outcome compared to short-stay patients. Between-center variations were prominent in the proportion of short-stay patients (MOR = 2.3, p < 0.001), use of intracranial pressure (ICP) monitoring (MOR = 2.5, p < 0.001) and aggressive treatme

PDRs4All: A JWST Early Release Science Program on Radiative Feedback from Massive Stars

22 pags., 8 figs., 1 tab.Massive stars disrupt their natal molecular cloud material through radiative and mechanical feedback processes. These processes have profound effects on the evolution of interstellar matter in our Galaxy and throughout the universe, from the era of vigorous star formation at redshifts of 1-3 to the present day. The dominant feedback processes can be probed by observations of the Photo-Dissociation Regions (PDRs) where the far-ultraviolet photons of massive stars create warm regions of gas and dust in the neutral atomic and molecular gas. PDR emission provides a unique tool to study in detail the physical and chemical processes that are relevant for most of the mass in inter-and circumstellar media including diffuse clouds, proto-planetary disks, and molecular cloud surfaces, globules, planetary nebulae, and star-forming regions. PDR emission dominates the infrared (IR) spectra of star-forming galaxies. Most of the Galactic and extragalactic observations obtained with the James Webb Space Telescope (JWST) will therefore arise in PDR emission. In this paper we present an Early Release Science program using the MIRI, NIRSpec, and NIRCam instruments dedicated to the observations of an emblematic and nearby PDR: the Orion Bar. These early JWST observations will provide template data sets designed to identify key PDR characteristics in JWST observations. These data will serve to benchmark PDR models and extend them into the JWST era. We also present the Science-Enabling products that we will provide to the community. These template data sets and Science-Enabling products will guide the preparation of future proposals on star-forming regions in our Galaxy and beyond and will facilitate data analysis and interpretation of forthcoming JWST observations.Support for JWST-ERS program ID 1288 was provided through grants from the STScI under NASA contract NAS5-03127 to STScI (K.G., D.V.D.P., M.R.), Univ. of Maryland (M.W., M.P.), Univ. of Michigan (E.B., F.A.), and Univ. of Toledo (T.S.-Y.L.). O.B. and E.H. are supported by the Programme National “Physique et Chimie du Milieu Interstellaire” (PCMI) of CNRS/INSU with INC/INP co-funded by CEA and CNES, and through APR grants 6315 and 6410 provided by CNES. E. P. and J.C. acknowledge support from the National Science and Engineering Council of Canada (NSERC) Discovery Grant program (RGPIN-2020-06434 and RGPIN-2021-04197 respectively). E.P. acknowledges support from a Western Strategic Support Accelerator Grant (ROLA ID 0000050636). J.R.G. and S.C. thank the Spanish MCINN for funding support under grant PID2019-106110GB-I00. Work by M.R. and Y.O. is carried out within the Collaborative Research Centre 956, subproject C1, funded by the Deutsche Forschungsgemeinschaft (DFG)—project ID 184018867. T.O. acknowledges support from JSPS Bilateral Program, grant No. 120219939. M.P. and M.W. acknowledge support from NASA Astrophysics Data Analysis Program award #80NSSC19K0573. C.B. is grateful for an appointment at NASA Ames Research Center through the San José State University Research Foundation (NNX17AJ88A) and acknowledges support from the Internal Scientist Funding Model (ISFM) Directed Work Package at NASA Ames titled: “Laboratory Astrophysics—The NASA Ames PAH IR Spectroscopic Database.”Peer reviewe

Use and impact of high intensity treatments in patients with traumatic brain injury across Europe: a CENTER-TBI analysis

Abstract: Purpose: To study variation in, and clinical impact of high Therapy Intensity Level (TIL) treatments for elevated intracranial pressure (ICP) in patients with traumatic brain injury (TBI) across European Intensive Care Units (ICUs). Methods: We studied high TIL treatments (metabolic suppression, hypothermia (< 35 °C), intensive hyperventilation (PaCO2 < 4 kPa), and secondary decompressive craniectomy) in patients receiving ICP monitoring in the ICU stratum of the CENTER-TBI study. A random effect logistic regression model was used to determine between-centre variation in their use. A propensity score-matched model was used to study the impact on outcome (6-months Glasgow Outcome Score-extended (GOSE)), whilst adjusting for case-mix severity, signs of brain herniation on imaging, and ICP. Results: 313 of 758 patients from 52 European centres (41%) received at least one high TIL treatment with significant variation between centres (median odds ratio = 2.26). Patients often transiently received high TIL therapies without escalation from lower tier treatments. 38% of patients with high TIL treatment had favourable outcomes (GOSE ≥ 5). The use of high TIL treatment was not significantly associated with worse outcome (285 matched pairs, OR 1.4, 95% CI [1.0–2.0]). However, a sensitivity analysis excluding high TIL treatments at day 1 or use of metabolic suppression at any day did reveal a statistically significant association with worse outcome. Conclusion: Substantial between-centre variation in use of high TIL treatments for TBI was found and treatment escalation to higher TIL treatments were often not preceded by more conventional lower TIL treatments. The significant association between high TIL treatments after day 1 and worse outcomes may reflect aggressive use or unmeasured confounders or inappropriate escalation strategies. Take home message: Substantial variation was found in the use of highly intensive ICP-lowering treatments across European ICUs and a stepwise escalation strategy from lower to higher intensity level therapy is often lacking. Further research is necessary to study the impact of high therapy intensity treatments. Trial registration: The core study was registered with ClinicalTrials.gov, number NCT02210221, registered 08/06/2014, https://clinicaltrials.gov/ct2/show/NCT02210221?id=NCT02210221&draw=1&rank=1 and with Resource Identification Portal (RRID: SCR_015582)

Quality indicators for patients with traumatic brain injury in European intensive care units: a CENTER-TBI study

Abstract: Background: The aim of this study is to validate a previously published consensus-based quality indicator set for the management of patients with traumatic brain injury (TBI) at intensive care units (ICUs) in Europe and to study its potential for quality measurement and improvement. Methods: Our analysis was based on 2006 adult patients admitted to 54 ICUs between 2014 and 2018, enrolled in the CENTER-TBI study. Indicator scores were calculated as percentage adherence for structure and process indicators and as event rates or median scores for outcome indicators. Feasibility was quantified by the completeness of the variables. Discriminability was determined by the between-centre variation, estimated with a random effect regression model adjusted for case-mix severity and quantified by the median odds ratio (MOR). Statistical uncertainty of outcome indicators was determined by the median number of events per centre, using a cut-off of 10. Results: A total of 26/42 indicators could be calculated from the CENTER-TBI database. Most quality indicators proved feasible to obtain with more than 70% completeness. Sub-optimal adherence was found for most quality indicators, ranging from 26 to 93% and 20 to 99% for structure and process indicators. Significant (p < 0.001) between-centre variation was found in seven process and five outcome indicators with MORs ranging from 1.51 to 4.14. Statistical uncertainty of outcome indicators was generally high; five out of seven had less than 10 events per centre. Conclusions: Overall, nine structures, five processes, but none of the outcome indicators showed potential for quality improvement purposes for TBI patients in the ICU. Future research should focus on implementation efforts and continuous reevaluation of quality indicators. Trial registration: The core study was registered with ClinicalTrials.gov, number NCT02210221, registered on August 06, 2014, with Resource Identification Portal (RRID: SCR_015582)

Changing care pathways and between-center practice variations in intensive care for traumatic brain injury across Europe: a CENTER-TBI analysis

Abstract: Purpose: To describe ICU stay, selected management aspects, and outcome of Intensive Care Unit (ICU) patients with traumatic brain injury (TBI) in Europe, and to quantify variation across centers. Methods: This is a prospective observational multicenter study conducted across 18 countries in Europe and Israel. Admission characteristics, clinical data, and outcome were described at patient- and center levels. Between-center variation in the total ICU population was quantified with the median odds ratio (MOR), with correction for case-mix and random variation between centers. Results: A total of 2138 patients were admitted to the ICU, with median age of 49 years; 36% of which were mild TBI (Glasgow Coma Scale; GCS 13–15). Within, 72 h 636 (30%) were discharged and 128 (6%) died. Early deaths and long-stay patients (> 72 h) had more severe injuries based on the GCS and neuroimaging characteristics, compared with short-stay patients. Long-stay patients received more monitoring and were treated at higher intensity, and experienced worse 6-month outcome compared to short-stay patients. Between-center variations were prominent in the proportion of short-stay patients (MOR = 2.3, p < 0.001), use of intracranial pressure (ICP) monitoring (MOR = 2.5, p < 0.001) and aggressive treatments (MOR = 2.9, p < 0.001); and smaller in 6-month outcome (MOR = 1.2, p = 0.01). Conclusions: Half of contemporary TBI patients at the ICU have mild to moderate head injury. Substantial between-center variations exist in ICU stay and treatment policies, and less so in outcome. It remains unclear whether admission of short-stay patients represents appropriate prudence or inappropriate use of clinical resources