Abstract
Mobile medical imaging devices are invaluable for clinical diagnostic purposes both in and outside healthcare institutions. Among the various imaging modalities, only a few are readily ...portable. Magnetic resonance imaging (MRI), the gold standard for numerous healthcare conditions, does not traditionally belong to this group. Recently, low-field MRI technology companies have demonstrated the first decisive steps towards portability within medical facilities and vehicles. However, these scanners’ weight and dimensions are incompatible with more demanding use cases such as in remote and developing regions, sports facilities and events, medical and military camps, or home healthcare. Here we present in vivo images taken with a light, small footprint, low-field extremity MRI scanner outside the controlled environment provided by medical facilities. To demonstrate the true portability of the system and benchmark its performance in various relevant scenarios, we have acquired images of a volunteer’s knee in: (i) an MRI physics laboratory; (ii) an office room; (iii) outside a campus building, connected to a nearby power outlet; (iv) in open air, powered from a small fuel-based generator; and (v) at the volunteer’s home. All images have been acquired within clinically viable times, and signal-to-noise ratios and tissue contrast suffice for 2D and 3D reconstructions with diagnostic value. Furthermore, the volunteer carries a fixation metallic implant screwed to the femur, which leads to strong artifacts in standard clinical systems but appears sharp in our low-field acquisitions. Altogether, this work opens a path towards highly accessible MRI under circumstances previously unrealistic.
During the last decades, climate and land use changes led to an increased prevalence of megafires in Mediterranean-type climate regions (MCRs). Here, we argue that current wildfire management ...policies in MCRs are destined to fail. Focused on fire suppression, these policies largely ignore ongoing climate warming and landscape-scale buildup of fuels. The result is a 'firefighting trap' that contributes to ongoing fuel accumulation precluding suppression under extreme fire weather, and resulting in more severe and larger fires. We believe that a 'business as usual' approach to wildfire in MCRs will not solve the fire problem, and recommend that policy and expenditures be rebalanced between suppression and mitigation of the negative impacts of fire. This requires a paradigm shift: policy effectiveness should not be primarily measured as a function of area burned (as it usually is), but rather as a function of avoided socio-ecological damage and loss.
Background
Healthcare workers are a key occupational group at risk for suicidal thoughts and behaviors (STB). We investigated the prevalence and correlates of STB among hospital workers during the ...first wave of the Spain COVID‐19 outbreak (March–July 2020).
Methods
Data come from the baseline assessment of a cohort of Spanish hospital workers (n = 5450), recruited from 10 hospitals just after the height of the coronavirus disease 2019 (COVID‐19) outbreak (May 5–July 23, 2020). Web‐based self‐report surveys assessed 30‐day STB, individual characteristics, and potentially modifiable contextual factors related to hospital workers' work and financial situation.
Results
Thirty‐day STB prevalence was estimated at 8.4% (4.9% passive ideation only, 3.5% active ideation with or without a plan or attempt). A total of n = 6 professionals attempted suicide in the past 30 days. In adjusted models, 30‐day STB remained significantly associated with pre‐pandemic lifetime mood (odds ratio OR = 2.92) and anxiety disorder (OR = 1.90). Significant modifiable factors included a perceived lack of coordination, communication, personnel, or supervision at work (population‐attributable risk proportion PARP = 50.5%), and financial stress (PARP = 44.1%).
Conclusions and Relevance
Thirty‐day STB among hospital workers during the first wave of the Spain COVID‐19 outbreak was high. Hospital preparedness for virus outbreaks should be increased, and strong governmental policy response is needed to increase financial security among hospital workers.
Magnetic Resonance Imaging (MRI) of hard biological tissues is challenging due to the fleeting lifetime and low strength of their response to resonant stimuli, especially at low magnetic fields. ...Consequently, the impact of MRI on some medical applications, such as dentistry, continues to be limited. Here, we present three-dimensional reconstructions of ex-vivo human teeth, as well as a rabbit head and part of a cow femur, all obtained at a field strength of 260 mT. These images are the first featuring soft and hard tissues simultaneously at sub-Tesla fields, and they have been acquired in a home-made, special-purpose, pre-medical MRI scanner designed with the goal of demonstrating dental imaging at low field settings. We encode spatial information with two pulse sequences: Pointwise-Encoding Time reduction with Radial Acquisition and a new sequence we have called Double Radial Non-Stop Spin Echo, which we find to perform better than the former. For image reconstruction we employ Algebraic Reconstruction Techniques (ART) as well as standard Fourier methods. An analysis of the resulting images shows that ART reconstructions exhibit a higher signal-to-noise ratio with a more homogeneous noise distribution.
ER-mitochondria signaling in Parkinson's disease Gómez-Suaga, Patricia; Bravo-San Pedro, José M; González-Polo, Rosa A ...
Cell death & disease,
03/2018, Letnik:
9, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Mitochondria form close physical contacts with a specialized domain of the endoplasmic reticulum (ER), known as the mitochondria-associated membrane (MAM). This association constitutes a key ...signaling hub to regulate several fundamental cellular processes. Alterations in ER-mitochondria signaling have pleiotropic effects on a variety of intracellular events resulting in mitochondrial damage, Ca
dyshomeostasis, ER stress and defects in lipid metabolism and autophagy. Intriguingly, many of these cellular processes are perturbed in neurodegenerative diseases. Furthermore, increasing evidence highlights that ER-mitochondria signaling contributes to these diseases, including Parkinson's disease (PD). PD is the second most common neurodegenerative disorder, for which effective mechanism-based treatments remain elusive. Several PD-related proteins localize at mitochondria or MAM and have been shown to participate in ER-mitochondria signaling regulation. Likewise, PD-related mutations have been shown to damage this signaling. Could ER-mitochondria associations be the link between pathogenic mechanisms involved in PD, providing a common mechanism? Would this provide a pharmacological target for treating this devastating disease? In this review, we aim to summarize the current knowledge of ER-mitochondria signaling and the recent evidence concerning damage to this signaling in PD.
Sorafenib is the unique accepted molecular targeted drug for the treatment of patients in advanced stage of hepatocellular carcinoma. The current study evaluated cell signaling regulation of ...endoplasmic reticulum (ER) stress, c‐Jun‐N‐terminal kinase (JNK), Akt, and 5′AMP‐activated protein kinase (AMPK) leading to autophagy and apoptosis induced by sorafenib. Sorafenib induced early (3–12 hr) ER stress characterized by an increase of Ser51P‐eIF2α/eIF2α, C/EBP homologous protein (CHOP), IRE1α, and sXBP1, but a decrease of activating transcription factor 6 expression, overall temporally associated with the increase of Thr183,Tyr185P‐JNK1/2/JNK1/2, Thr172P‐AMPKα, Ser413P‐Foxo3a, Thr308P‐AKt/AKt and Thr32P‐Foxo3a/Foxo3a ratios, and reduction of Ser2481P‐mammalian target of rapamycin (mTOR)/mTOR and protein translation. This pattern was related to a transient increase of tBid, Bim
EL, Beclin‐1, Bcl‐xL, Bcl‐2, autophagy markers, and reduction of myeloid cell leukemia‐1 (Mcl‐1) expression. The progressive increase of CHOP expression, and reduction of Thr308P‐AKt/AKt and Ser473P‐AKt/AKt ratios were associated with the reduction of autophagic flux and an additional upregulation of Bim
EL expression and caspase‐3 activity (24 hr). Small interfering‐RNA (si‐RNA) assays showed that Bim, but not Bak and Bax, was involved in the induction of caspase‐3 in sorafenib‐treated HepG2 cells. Sorafenib increased autophagic and apoptotic markers in tumor‐derived xenograft model. In conclusion, the early sorafenib‐induced ER stress and regulation of JNK and AMPK‐dependent signaling were related to the induction of survival autophagic process. The sustained drug treatment induced a progressive increase of ER stress and PERK‐CHOP‐dependent rise of Bim
EL, which was associated with the shift from autophagy to apoptosis. The kinetic of Bim
EL expression profile might also be related to the tight balance between AKt‐ and AMPK‐related signaling leading to Foxo3a‐dependent BIM
EL upregulation.
The early sorafenib‐induced endoplasmic reticulum (ER) stress and regulation of JNK and AMPK‐dependent signaling were related to the induction of survival autophagic process. The sustained drug treatment induced a progressive increase of ER stress and PERK‐CHOP‐dependent rise of BimEL, which was associated with the shift from autophagy to apoptosis.
Isolated hydrogen atoms absorbed on graphene are predicted to induce magnetic moments. Here we demonstrate that the adsorption of a single hydrogen atom on graphene induces a magnetic moment ...characterized by a ~20–millielectron volt spin-split state at the Fermi energy. Our scanning tunneling microscopy (STM) experiments, complemented by first-principles calculations, show that such a spin-polarized state is essentially localized on the carbon sublattice opposite to the one where the hydrogen atom is chemisorbed. This atomically modulated spin texture, which extends several nanometers away from the hydrogen atom, drives the direct coupling between the magnetic moments at unusually long distances. By using the STM tip to manipulate hydrogen atoms with atomic precision, it is possible to tailor the magnetism of selected graphene regions.
Although oxidative stress is fundamental to the etiopathology of Parkinson disease, the signaling molecules involved in transduction after oxidant exposure to cell death are ill-defined, thus making ...it difficult to identify molecular targets of therapeutic relevance. We have addressed this question in human dopaminergic neuroblastoma SH-SY5Y cells exposed to the parkinsonian toxin paraquat (PQ). This toxin elicited a dose-dependent increase in reactive oxygen species and cell death that correlated with activation of ASK1 and the stress kinases p38 and JNK. The relevance of these kinases in channeling PQ neurotoxicity was demonstrated with the use of interference RNA for ASK1 and two well-established pharmaceutical inhibitors for JNK and p38. The toxic effect of PQ was substantially attenuated by preincubation with vitamin E, blocking ASK1 pathways and preventing oxidative stress and cell death. In a search for a physiological pathway that might counterbalance PQ-induced ASK1 activation, we analyzed the role of the transcription factor Nrf2, master regulator of redox homeostasis, and its target thioredoxin (Trx), which binds and inhibits ASK1. Trx levels were undetectable in Nrf2-deficient mouse embryo fibroblasts (MEFs), whereas they were constitutively high in Keap1-deficient MEFs as well as in SH-SY5Y cells treated with sulforaphane (SFN). Consistent with these data, Nrf2-deficient MEFs were more sensitive and Keap1-deficient MEFs and SH-SY5Y cells incubated with SFN were more resistant to PQ-induced cell death. This study identifies ASK1/JNK and ASK1/p38 as two critical pathways involved in the activation of cell death under oxidative stress conditions and identifies the Nrf2/Trx axis as a new target to block these pathways and protect from oxidant exposure such as that found in Parkinson and other neurodegenerative diseases.
The ability of cyclodextrin‐based polycationic cluster to undergo reversible DNA condensation and release in a physiologically useful pH window has been finely tuned by the installation of a capping ...xylylene moiety at the secondary face of the cyclooligosaccharide. This strategy can be exploited advantageously in the design of self‐assembling nonviral gene‐delivery systems from molecular entities.
Programming self‐assembly: pH‐Sensitive, hierarchical self‐assembly of cyclodextrin‐based polycationic clusters and DNA was programmed by the installation of a xylylene moiety at the secondary face of the cyclooligosaccharide. At neutral pH dimer formation facilitates DNA condensation, whereas at acidic pH electrostatic repulsions promote disassembly of the nanocomplexes and DNA release. This can be exploited advantageously in the design of nonviral gene delivery systems (see figure).
Parkinson’s disease (PD) is a chronic and progressive neurodegenerative disorder. While most PD cases are idiopathic, the known genetic causes of PD are useful to understand common disease ...mechanisms. Recent data suggests that autophagy is regulated by protein acetylation mediated by histone acetyltransferase (HAT) and histone deacetylase (HDAC) activities. The changes in histone acetylation reported to be involved in PD pathogenesis have prompted this investigation of protein acetylation and HAT and HDAC activities in both idiopathic PD and G2019S
leucine-rich repeat kinase 2
(LRRK2) cell cultures. Fibroblasts from PD patients (with or without the G2019S
LRRK2
mutation) and control subjects were used to assess the different phenotypes between idiopathic and genetic PD. G2019S
LRRK2
mutation displays increased mitophagy due to the activation of class III HDACs whereas idiopathic PD exhibits downregulation of clearance of defective mitochondria. This reduction of mitophagy is accompanied by more reactive oxygen species (ROS). In parallel, the acetylation protein levels of idiopathic and genetic individuals are different due to an upregulation in class I and II HDACs. Despite this upregulation, the total HDAC activity is decreased in idiopathic PD and the total HAT activity does not significantly vary. Mitophagy upregulation is beneficial for reducing the ROS-induced harm in genetic PD. The defective mitophagy in idiopathic PD is inherent to the decrease in class III HDACs. Thus, there is an imbalance between total HATs and HDACs activities in idiopathic PD, which increases cell death. The inhibition of HATs in idiopathic PD cells displays a cytoprotective effect.
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