| 1. |
- Naghavi, Mohsen, et al.
(author)
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Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013
- 2015
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In: The Lancet. - 1474-547X .- 0140-6736. ; 385:9963, s. 117-171
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Journal article (peer-reviewed)abstract
- Background Up-to-date evidence on levels and trends for age-sex-specifi c all-cause and cause-specifi c mortality is essential for the formation of global, regional, and national health policies. In the Global Burden of Disease Study 2013 (GBD 2013) we estimated yearly deaths for 188 countries between 1990, and 2013. We used the results to assess whether there is epidemiological convergence across countries. Methods We estimated age-sex-specifi c all-cause mortality using the GBD 2010 methods with some refinements to improve accuracy applied to an updated database of vital registration, survey, and census data. We generally estimated cause of death as in the GBD 2010. Key improvements included the addition of more recent vital registration data for 72 countries, an updated verbal autopsy literature review, two new and detailed data systems for China, and more detail for Mexico, UK, Turkey, and Russia. We improved statistical models for garbage code redistribution. We used six different modelling strategies across the 240 causes; cause of death ensemble modelling (CODEm) was the dominant strategy for causes with sufficient information. Trends for Alzheimer's disease and other dementias were informed by meta-regression of prevalence studies. For pathogen-specifi c causes of diarrhoea and lower respiratory infections we used a counterfactual approach. We computed two measures of convergence (inequality) across countries: the average relative difference across all pairs of countries (Gini coefficient) and the average absolute difference across countries. To summarise broad findings, we used multiple decrement life-tables to decompose probabilities of death from birth to exact age 15 years, from exact age 15 years to exact age 50 years, and from exact age 50 years to exact age 75 years, and life expectancy at birth into major causes. For all quantities reported, we computed 95% uncertainty intervals (UIs). We constrained cause-specific fractions within each age-sex-country-year group to sum to all-cause mortality based on draws from the uncertainty distributions. Findings Global life expectancy for both sexes increased from 65.3 years (UI 65.0-65.6) in 1990, to 71.5 years (UI 71.0-71.9) in 2013, while the number of deaths increased from 47.5 million (UI 46.8-48.2) to 54.9 million (UI 53.6-56.3) over the same interval. Global progress masked variation by age and sex: for children, average absolute diff erences between countries decreased but relative diff erences increased. For women aged 25-39 years and older than 75 years and for men aged 20-49 years and 65 years and older, both absolute and relative diff erences increased. Decomposition of global and regional life expectancy showed the prominent role of reductions in age-standardised death rates for cardiovascular diseases and cancers in high-income regions, and reductions in child deaths from diarrhoea, lower respiratory infections, and neonatal causes in low-income regions. HIV/AIDS reduced life expectancy in southern sub-Saharan Africa. For most communicable causes of death both numbers of deaths and age-standardised death rates fell whereas for most non-communicable causes, demographic shifts have increased numbers of deaths but decreased age-standardised death rates. Global deaths from injury increased by 10.7%, from 4.3 million deaths in 1990 to 4.8 million in 2013; but age-standardised rates declined over the same period by 21%. For some causes of more than 100 000 deaths per year in 2013, age-standardised death rates increased between 1990 and 2013, including HIV/AIDS, pancreatic cancer, atrial fibrillation and flutter, drug use disorders, diabetes, chronic kidney disease, and sickle-cell anaemias. Diarrhoeal diseases, lower respiratory infections, neonatal causes, and malaria are still in the top five causes of death in children younger than 5 years. The most important pathogens are rotavirus for diarrhoea and pneumococcus for lower respiratory infections. Country-specific probabilities of death over three phases of life were substantially varied between and within regions. Interpretation For most countries, the general pattern of reductions in age-sex specifi c mortality has been associated with a progressive shift towards a larger share of the remaining deaths caused by non-communicable disease and injuries. Assessing epidemiological convergence across countries depends on whether an absolute or relative measure of inequality is used. Nevertheless, age-standardised death rates for seven substantial causes are increasing, suggesting the potential for reversals in some countries. Important gaps exist in the empirical data for cause of death estimates for some countries; for example, no national data for India are available for the past decade.
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| 2. |
- Thompson, Paul M., et al.
(author)
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The ENIGMA Consortium : large-scale collaborative analyses of neuroimaging and genetic data
- 2014
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In: BRAIN IMAGING BEHAV. - : Springer Science and Business Media LLC. - 1931-7557 .- 1931-7565. ; 8:2, s. 153-182
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Journal article (peer-reviewed)abstract
- The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA's first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. We review the current progress of the ENIGMA Consortium, along with challenges and unexpected discoveries made on the way.
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| 3. |
- Toivainen Eloff, Sanne, et al.
(author)
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Different mechanisms underlie compulsive alcohol self-administration in male and female rats
- 2024
-
In: Biology of Sex Differences. - : BMC. - 2042-6410. ; 15:1
-
Journal article (peer-reviewed)abstract
- BackgroundSex is an important factor in the progression and treatment of alcohol addiction, and therapeutic approaches may have to be tailored to potential sex differences. This highlights the importance of understanding sex differences in behaviors that reflect key elements of clinical alcohol addiction, such as continued use despite negative consequences ("compulsive use"). Studies in experimental animals can help provide an understanding of the role sex plays to influence these behaviors.MethodsLarge populations of genetically heterogeneous male and female Wistar rats were tested in an established model of compulsive alcohol self-administration, operationalized as alcohol responding despite contingent foot shock punishment. We also tested baseline (fixed ratio, unpunished) operant alcohol self-administration, motivation to self-administer alcohol (progressive ratio), and temporal discounting for alcohol reward. In search of predictors of compulsivity, animals were screened for novelty-induced place preference, anxiety-like behavior, pain sensitivity and corticosterone levels. The estrous cycle was monitored throughout the study.ResultsUnpunished self-administration of alcohol did not differ between males and females when alcohol intake was corrected for body weight. Overall, females showed higher levels of compulsive responding for alcohol. Compulsive response rates showed bimodal distributions in male but not in female rats when intermediate shock intensities were used (0.2 and 0.25 mA); at higher shock intensities, responding was uniformly suppressed in both males and females. We also found less steep discounting in females when alcohol was devalued by delaying its delivery. Males exhibited a stronger motivation to obtain alcohol under unpunished conditions, while females showed higher corticosterone levels at baseline. Factor analysis showed that an underlying dimension related to stress and pain predicted compulsivity in females, while compulsivity in males was predicted by a reward factor. We did not find differences in alcohol-related behaviors throughout the various stages of the estrous cycle.ConclusionsOur results suggest that mechanisms promoting compulsivity, a key feature of alcohol addiction, likely differ between males and females. This underscores the importance of considering sex as a biological variable in both preclinical and clinical research, and has potential treatment implications in alcohol addiction. Sex plays an important role in the progression and treatment of alcohol addiction. While men show a higher prevalence of alcohol addiction, women are more susceptible to the adverse effects of excessive alcohol consumption. Additionally, women often rely on heavy drinking as a maladaptive coping mechanism to alleviate stress and anxiety, driven by negative affect. On the other hand, men are more likely to report heavy drinking and relapse in response to positive emotions and social influences. These sex-based differences underline the importance of understanding how vulnerability to alcohol addiction and its treatment varies in males and females.We used genetically heterogeneous rats to explore the behavioral traits that contribute to compulsivity, a key clinical feature of alcohol addiction. We found that motivation to self-administer alcohol was higher in males, while females showed higher compulsive alcohol self-administration. In males, motivation to self-administer alcohol showed a significant correlation with compulsivity, while in females compulsivity was predicted by higher basal corticosterone levels.These findings underlie the importance of sex-specific factors in compulsive alcohol self-administration, with potential prevention and treatment implications in alcohol addiction. Male rats showed a higher motivation to obtain alcohol.Females showed higher levels of compulsive responding for alcohol and a less steep discounting when alcohol was devalued by delaying its delivery.In males compulsivity was predicted by a reward factor, while in females by stress-pain factors.
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| 4. |
- Aiuppa, Sandro, et al.
(author)
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Tracking formation of a lava lake from ground and space: Masaya volcano (Nicaragua), 2015-2017
- 2018
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In: Geochemistry, Geophysics, Geosystems. - 1525-2027. ; 19:2, s. 496-515
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Journal article (peer-reviewed)abstract
- A vigorously degassing lava lake appeared inside the Santiago pit crater of Masaya volcano (Nicaragua) in December 2015, after years of degassing with no (or minor) incandescence. Here, we present an unprecedented-long (3 years) and continuous volcanic gas record that instrumentally characterizes the (re)activation of the lava-lake. Our results show that, before appearance of the lake, the volcanic gas plume composition became unusually CO2-rich, as testified by high CO2/SO2 ratios (mean, 12.2±6.3) and low H2O/CO2 ratios (mean, 2.3±1.3). The volcanic CO2 flux also peaked in November 2015 (mean, 81.3±40.6 kg/s; maximum, 247 kg/s). Using results of magma degassing models and budgets, we interpret this elevated CO2 degassing as sourced by degassing of a volatile-rich fast-convecting (3.6-5.2 m3·s-1) magma, supplying CO2-rich gas bubbles from minimum equivalent depths of 0.36-1.4 km. We propose this elevated gas bubbles supply destabilized the shallow (<1 km) Masaya magma reservoir, leading to upward migration of vesicular (buoyant) resident magma, and ultimately to (re)formation of the lava lake. At onset of lava lake activity on 11 December 2015 (constrained by satellite-based (MODIS) thermal observations), the gas emissions transitioned to more SO2-rich composition, and the SO2 flux increased by a factor ~40 % (11.4±5.2 kg/s) relative to background degassing (8.0 kg/s), confirming faster than normal (4.4 vs. ~3 m3·s-1) shallow magma convection. Elevated shallow magma circulation is also supported by gradual increase in irradiated thermal energy, captured by MODIS, from which we calculate that 0.4-0.8 m3·s-1 of magma have been surface-emplaced since December 2015.
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| 5. |
- Barchiesi, Riccardo, 1989-, et al.
(author)
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An epigenetic mechanism for over-consolidation of fear memories
- 2022
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In: Molecular Psychiatry. - : Springer Nature. - 1359-4184 .- 1476-5578. ; 27:12, s. 4893-4904
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Journal article (peer-reviewed)abstract
- Excessive fear is a hallmark of anxiety disorders, a major cause of disease burden worldwide. Substantial evidence supports a role of prefrontal cortex-amygdala circuits in the regulation of fear and anxiety, but the molecular mechanisms that regulate their activity remain poorly understood. Here, we show that downregulation of the histone methyltransferase PRDM2 in the dorsomedial prefrontal cortex enhances fear expression by modulating fear memory consolidation. We further show that Prdm2 knock-down (KD) in neurons that project from the dorsomedial prefrontal cortex to the basolateral amygdala (dmPFC-BLA) promotes increased fear expression. Prdm2 KD in the dmPFC-BLA circuit also resulted in increased expression of genes involved in synaptogenesis, suggesting that Prdm2 KD modulates consolidation of conditioned fear by modifying synaptic strength at dmPFC-BLA projection targets. Consistent with an enhanced synaptic efficacy, we found that dmPFC Prdm2 KD increased glutamatergic release probability in the BLA and increased the activity of BLA neurons in response to fear-associated cues. Together, our findings provide a new molecular mechanism for excessive fear responses, wherein PRDM2 modulates the dmPFC -BLA circuit through specific transcriptomic changes.
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| 6. |
- Barchiesi, Riccardo, et al.
(author)
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Stress-induced escalation of alcohol self-administration, anxiety-like behavior, and elevated amygdala Avp expression in a susceptible subpopulation of rats
- 2021
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In: Addiction Biology. - : Wiley. - 1355-6215 .- 1369-1600. ; 26:5
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Journal article (peer-reviewed)abstract
- Comorbidity between alcohol use and anxiety disorders is associated with more severe symptoms and poorer treatment outcomes than either of the conditions alone. There is a well-known link between stress and the development of these disorders, with post-traumatic stress disorder as a prototypic example. Post-traumatic stress disorder can arise as a consequence of experiencing traumatic events firsthand and also after witnessing them. Here, we used a model of social defeat and witness stress in rats, to study shared mechanisms of stress-induced anxiety-like behavior and escalated alcohol self-administration. Similar to what is observed clinically, we found considerable individual differences in susceptibility and resilience to the stress. Both among defeated and witness rats, we found a subpopulation in which exposure was followed by emergence of increased anxiety-like behavior and escalation of alcohol self-administration. We then profiled gene expression in tissue from the amygdala, a key brain region in the regulation of stress, alcohol use, and anxiety disorders. When comparing "comorbid" and resilient socially defeated rats, we identified a strong upregulation of vasopressin and oxytocin, and this correlated positively with the magnitude of the alcohol self-administration and anxiety-like behavior. A similar trend was observed in comorbid witness rats. Together, our findings provide novel insights into molecular mechanisms underpinning the comorbidity of escalated alcohol self-administration and anxiety-like behavior.
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| 7. |
- Battista, Simone, et al.
(author)
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Which lecturers’ characteristics facilitate the learning process? A qualitative study on students’ perceptions in the rehabilitation sciences
- 2023
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In: BMC Medical Education. - 1472-6920. ; 23, s. 1-10
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Journal article (peer-reviewed)abstract
- Background: In education, lecturers play a crucial role in facilitating students’ learning process. However, only a few studies explored which lecturers’ characteristics can facilitate this process in higher education for rehabilitation healthcare professionals. Starting from students’ perspectives, our qualitative study investigated the lecturers’ characteristics that facilitate students’ learning process in the rehabilitation sciences. Methods: A qualitative interview study. We enrolled students attending the 2nd year of the Master of Science (MSc) degree in ‘Rehabilitation Sciences of Healthcare Professions’. Different themes were generated following a ‘Reflexive Thematic Analysis’. Results: Thirteen students completed the interviews. From their analysis, we generated five themes. Specifically, a lecturer that facilitates students’ learning process should be: 1) ‘A Performer who Interacts with the Classroom’, 2) A Flexible Planner who Adopts Innovative Teaching Skills’, 3) ‘A Motivator who Embraces Transformational Leadership’, 4) ‘A Facilitator Who Encourages a Constructive Learning Context’ and 5) ‘A Coach who Devises Strategies to Reach Shared Learning Goals’. Conclusions: The results of this study underscore the importance for lecturers in rehabilitation to cultivate a diverse set of skills drawn from the arts and performance, education, team building and leadership to facilitate students’ learning process. By developing these skills, lecturers can design lessons that are worth attending not only for their relevant content but also for their value in human experience.
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| 8. |
- Chapman, Henry N, et al.
(author)
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Femtosecond X-ray protein nanocrystallography.
- 2011
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In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 470:7332, s. 73-7
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Journal article (peer-reviewed)abstract
- X-ray crystallography provides the vast majority of macromolecular structures, but the success of the method relies on growing crystals of sufficient size. In conventional measurements, the necessary increase in X-ray dose to record data from crystals that are too small leads to extensive damage before a diffraction signal can be recorded. It is particularly challenging to obtain large, well-diffracting crystals of membrane proteins, for which fewer than 300 unique structures have been determined despite their importance in all living cells. Here we present a method for structure determination where single-crystal X-ray diffraction 'snapshots' are collected from a fully hydrated stream of nanocrystals using femtosecond pulses from a hard-X-ray free-electron laser, the Linac Coherent Light Source. We prove this concept with nanocrystals of photosystem I, one of the largest membrane protein complexes. More than 3,000,000 diffraction patterns were collected in this study, and a three-dimensional data set was assembled from individual photosystem I nanocrystals (∼200nm to 2μm in size). We mitigate the problem of radiation damage in crystallography by using pulses briefer than the timescale of most damage processes. This offers a new approach to structure determination of macromolecules that do not yield crystals of sufficient size for studies using conventional radiation sources or are particularly sensitive to radiation damage.
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| 9. |
- Domi, Esi, et al.
(author)
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Activation of GABA(B) receptors in central amygdala attenuates activity of PKC delta plus neurons and suppresses punishment-resistant alcohol self-administration in rats
- 2023
-
In: Neuropsychopharmacology. - : SPRINGERNATURE. - 0893-133X .- 1740-634X. ; 48, s. 1386-1395
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Journal article (peer-reviewed)abstract
- Alcohol use despite negative consequences is a core phenomenon of alcohol addiction. We recently used alcohol self-administration that is resistant to footshock punishment as a model of this behavior, and found that activity of PKC delta + GABAergic neurons in the central amygdala (CeA) is a determinant of individual susceptibility for punishment resistance. In the present study, we examined whether activation of GABA(B) receptors in CeA can attenuate the activity of PKC delta + neurons in this region, and whether this will result in suppression of punishment- resistant alcohol self-administration in the minority of rats that show this behavior. Systemic administration of the clinically approved GABA(B) agonist baclofen (1 and 3 mg/kg) dose- dependently reduced punishment-resistant alcohol self-administration. Bilateral microinjections of baclofen into CeA (64 ng in 0.3 mu l/side) reduced the activity of PKC delta + neurons, as measured by Fos expression. This manipulation also selectively suppressed punished alcohol self-administration in punishment-resistant rats. Expression analysis indicated that virtually all CeA PKC delta + neurons express the GABA(B) receptor. Using in vitro electrophysiology, we found that baclofen induced hyperpolarization of CeA neurons, reducing their firing rate in response to depolarizing current injections. Together, our findings provide a potential mechanism that contributes to the clinical efficacy of baclofen in alcohol addiction. Therapeutic use of baclofen itself is limited by problems of tolerance and need for dose escalation. Our findings support a mechanistic rationale for developing novel, improved alcohol addiction medications that target GABA(B) receptors, and that lack these limitations, such as e.g., GABA(B) positive allosteric modulators (PAM:s).
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| 10. |
- Lguensat, Asmae, 1993-, et al.
(author)
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Animal Models Used to Study Alcohol Use Disorder
- 2023
-
In: Alcohol and Alcohol-related Diseases. - Cham : Springer Nature. - 9783031324826 ; , s. 665-685
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Book chapter (peer-reviewed)abstract
- For ethical and technical reasons, research in humans has some limitations and requires the support of animal models. Numerous animal models have been developed over the years to study alcohol consumption and model alcohol-related behaviors in several species, including non-human primates, rodents and more recently zebrafish, fruit flies and C. elegans. In this chapter, we provide an overview of the most commonly used animal models of alcohol use disorder (AUD) and discuss their pros and cons. We classify animal models of AUD into two main categories, operant and non-operant paradigms, which covers behavioral procedures developed to model several aspects of human addiction, including primary alcohol reinforcement, physical dependence, loss of control over alcohol intake, progressive choice of alcohol over healthy rewards and relapse. Finally, we will conclude and discuss about other important aspects of human addiction, including interindividual differences, sex differences and social factors, that need to be incorporated into preclinical models of AUD to improve their translational value.
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| 11. |
- Peltier, Aline, et al.
(author)
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Volcano Crisis Management at Piton de la Fournaise (La Reunion) during the COVID-19 Lockdown
- 2021
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In: Seismological Research Letters. - : Seismological Society of America (SSA). - 1938-2057 .- 0895-0695. ; 92:1, s. 38-52
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Journal article (peer-reviewed)abstract
- In March 2020, the coronavirus disease 2019 outbreak was declared a pandemic by the World Health Organization and became a global health crisis. Authorities worldwide implemented lockdowns to restrict travel and social exchanges in a global effort to counter the pandemic. In France, and in French overseas departments, the lockdown was effective from 17 March to 11 May 2020. It was in this context that the 2-6 April 2020 eruption of Piton de la Fournaise (La Reunion Island, Indian Ocean) took place. Upon the announcement of the lockdown in France, a reduced activity plan was set up by the Institut de Physique du Globe de Paris, which manages the Observatoire Volcanologique du Piton de la Fournaise (OVPF). The aim was to (1) maintain remote monitoring operations by teleworking and (2) authorize fieldwork only for critical reasons, such as serious breakdowns of stations or transmission relays. This eruption provided an opportunity for the observatory to validate its capacity to manage a volcanic crisis with 100% remotely operated monitoring networks. We thus present the longand short-term precursors to the eruption, and the evolution of the eruption recorded using the real-time monitoring data as communicated to the stakeholders. The data were from both continuously recording and transmitting field instruments as well as satellites. The volcano observatory staff remotely managed the volcano crisis with the various stakeholders based only on these remotely functioning networks. Monitoring duties were also assured in the absence of ad hoc field investigation of the eruption by observatory staff or face-to-face communications. The density and reliability of the OVPF networks, combined with satellite observations, allowed for trustworthy instrument-based monitoring of the eruption and continuity of the OVPF duties in issuing regular updates of volcanic activity in the context of a double crisis: volcanic and health.
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| 12. |
- Seibert, M. Marvin, et al.
(author)
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Single mimivirus particles intercepted and imaged with an X-ray laser
- 2011
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 470:7332, s. 78-81
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Journal article (peer-reviewed)abstract
- X-ray lasers offer new capabilities in understanding the structure of biological systems, complex materials and matter under extreme conditions(1-4). Very short and extremely bright, coherent X-ray pulses can be used to outrun key damage processes and obtain a single diffraction pattern from a large macromolecule, a virus or a cell before the sample explodes and turns into plasma(1). The continuous diffraction pattern of non-crystalline objects permits oversampling and direct phase retrieval(2). Here we show that high-quality diffraction data can be obtained with a single X-ray pulse from a noncrystalline biological sample, a single mimivirus particle, which was injected into the pulsed beam of a hard-X-ray free-electron laser, the Linac Coherent Light Source(5). Calculations indicate that the energy deposited into the virus by the pulse heated the particle to over 100,000 K after the pulse had left the sample. The reconstructed exit wavefront (image) yielded 32-nm full-period resolution in a single exposure and showed no measurable damage. The reconstruction indicates inhomogeneous arrangement of dense material inside the virion. We expect that significantly higher resolutions will be achieved in such experiments with shorter and brighter photon pulses focused to a smaller area. The resolution in such experiments can be further extended for samples available in multiple identical copies.
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| 13. |
- Swift, Imogen J, et al.
(author)
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A systematic review of progranulin concentrations in biofluids in over 7,000 people-assessing the pathogenicity of GRN mutations and other influencing factors.
- 2024
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In: Alzheimer's Research & Therapy. - 1758-9193. ; 16:1
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Journal article (peer-reviewed)abstract
- Pathogenic heterozygous mutations in the progranulin gene (GRN) are a key cause of frontotemporal dementia (FTD), leading to significantly reduced biofluid concentrations of the progranulin protein (PGRN). This has led to a number of ongoing therapeutic trials aiming to treat this form of FTD by increasing PGRN levels in mutation carriers. However, we currently lack a complete understanding of factors that affect PGRN levels and potential variation in measurement methods. Here, we aimed to address this gap in knowledge by systematically reviewing published literature on biofluid PGRN concentrations.Published data including biofluid PGRN concentration, age, sex, diagnosis and GRN mutation were collected for 7071 individuals from 75 publications. The majority of analyses (72%) had focused on plasma PGRN concentrations, with many of these (56%) measured with a single assay type (Adipogen) and so the influence of mutation type, age at onset, sex, and diagnosis were investigated in this subset of the data.We established a plasma PGRN concentration cut-off between pathogenic mutation carriers and non-carriers of 74.8ng/mL using the Adipogen assay based on 3301 individuals, with a CSF concentration cut-off of 3.43ng/mL. Plasma PGRN concentration varied by GRN mutation type as well as by clinical diagnosis in those without a GRN mutation. Plasma PGRN concentration was significantly higher in women than men in GRN mutation carriers (p=0.007) with a trend in non-carriers (p=0.062), and there was a significant but weak positive correlation with age in both GRN mutation carriers and non-carriers. No significant association was seen with weight or with TMEM106B rs1990622 genotype. However, higher plasma PGRN levels were seen in those with the GRN rs5848 CC genotype in both GRN mutation carriers and non-carriers.These results further support the usefulness of PGRN concentration for the identification of the large majority of pathogenic mutations in the GRN gene. Furthermore, these results highlight the importance of considering additional factors, such as mutation type, sex and age when interpreting PGRN concentrations. This will be particularly important as we enter the era of trials for progranulin-associated FTD.
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| 14. |
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| 15. |
- Wang, Sheng, et al.
(author)
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De Novo Sequence and Copy Number Variants Are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis
- 2018
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In: Cell Reports. - : CELL PRESS. - 2211-1247. ; 24:13, s. 3441-
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Journal article (peer-reviewed)abstract
- We previously established the contribution of de novo damaging sequence variants to Tourette disorder (TD) through whole-exome sequencing of 511 trios. Here, we sequence an additional 291 TD trios and analyze the combined set of 802 trios. We observe an overrepresentation of de novo damaging variants in simplex, but not multiplex, families; we identify a high-confidence TD risk gene, CELSR3 (cadherin EGF LAG seven-pass G-type receptor 3); we find that the genes mutated in TD patients are enriched for those related to cell polarity, suggesting a common pathway underlying pathobiology; and we confirm a statistically significant excess of de novo copy number variants in TD. Finally, we identify significant overlap of de novo sequence variants between TD and obsessive-compulsive disorder and de novo copy number variants between TD and autism spectrum disorder, consistent with shared genetic risk.
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