The ALS/FTD-related C9orf72 hexanucleotide repeat expansion forms RNA condensates through multimolecular G-quadruplexes

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases that exist on a clinico-pathogenetic spectrum, designated ALS/FTD. The most common genetic cause of ALS/FTD is expansion of the intronic hexanucleotide repeat (GGGGCC)n in C9orf72. Here, we investigate the formation of nucleic acid secondary structures in these expansion repeats, and their role in generating condensates characteristic of ALS/FTD. We observe significant aggregation of the hexanucleotide sequence (GGGGCC)n, which we associate to the formation of multimolecular G-quadruplexes (mG4s) by using a range of biophysical techniques. Exposing the condensates to G4-unfolding conditions leads to prompt disassembly, highlighting the key role of mG4-formation in the condensation process. We further validate the biological relevance of our findings by detecting an increased prevalence of G4-structures in C9orf72 mutant human motor neurons when compared to healthy motor neurons by staining with a G4-selective fluorescent probe, revealing signal in putative condensates. Our findings strongly suggest that RNA G-rich repetitive sequences can form protein-free condensates sustained by multimolecular G-quadruplexes, highlighting their potential relevance as therapeutic targets for C9orf72 mutation-related ALS/FTD

A multiple spacecraft detection of the 2 April 2022 M-class flare and filament eruption during the first close Solar Orbiter perihelion

CONTEXT: The Solar Orbiter mission completed its first remote-sensing observation windows in the spring of 2022. On 2 April 2022, an M-class flare followed by a filament eruption was seen both by the instruments on board the mission and from several observatories in Earth’s orbit, providing an unprecedented view of a flaring region with a large range of observations. AIMS: We aim to understand the nature of the flaring and filament eruption events via the analysis of the available dataset. The complexity of the observed features is compared with the predictions given by the standard flare model in 3D. METHOD: In this paper, we use the observations from a multi-view dataset, which includes extreme ultraviolet (EUV) imaging to spectroscopy and magnetic field measurements. These data come from the Interface Region Imaging Spectrograph, the Solar Dynamics Observatory, Hinode, as well as several instruments on Solar Orbiter. RESULTS: The large temporal coverage of the region allows us to analyse the whole sequence of the filament eruption starting with its pre-eruptive state. Information given by spectropolarimetry from SDO/HMI and Solar Orbiter PHI/HRT shows that a parasitic polarity emerging underneath the filament is responsible for bringing the flux rope to an unstable state. As the flux rope erupts, Hinode EIS captures blue-shifted emission in the transition region and coronal lines in the northern leg of the flux rope prior to the flare peak. This may be revealing the unwinding of one of the flux rope legs. At the same time, Solar Orbiter SPICE captures the whole region, complementing the Doppler diagnostics of the filament eruption. Analyses of the formation and evolution of a complex set of flare ribbons and loops, of the hard and soft X-ray emissions with STIX, show that the parasitic emerging bipole plays an important role in the evolution of the flaring region. CONCLUSIONS: The extensive dataset covering this M-class flare event demonstrates how important multiple viewpoints and varied observations are in order to understand the complexity of flaring regions. While the analysed data are overall consistent with the standard flare model, the present particular magnetic configuration shows that surrounding magnetic activity such as nearby emergence needs to be taken into account to fully understand the processes at work. This filament eruption is the first to be covered from different angles by spectroscopic instruments, and provides an unprecedented diagnostic of the multi-thermal structures present before and during the flare. This complete dataset of an eruptive event showcases the capabilities of coordinated observations with the Solar Orbiter mission

Nitrogen uptake and internal recycling in Zostera marina exposed to oyster farming: eelgrass potential as a natural biofilter

Oyster farming in estuaries and coastal lagoons frequently overlaps with the distribution of seagrass meadows, yet there are few studies on how this aquaculture practice affects seagrass physiology. We compared in situ nitrogen uptake and the productivity of Zostera marina shoots growing near off-bottom longlines and at a site not affected by oyster farming in San Quintin Bay, a coastal lagoon in Baja California, Mexico. We used benthic chambers to measure leaf NH4 (+) uptake capacities by pulse labeling with (NH4)-N-15 (+) and plant photosynthesis and respiration. The internal N-15 resorption/recycling was measured in shoots 2 weeks after incubations. The natural isotopic composition of eelgrass tissues and vegetative descriptors were also examined. Plants growing at the oyster farming site showed a higher leaf NH4 (+) uptake rate (33.1 mmol NH4 (+) m(-2) day(-1)) relative to those not exposed to oyster cultures (25.6 mmol NH4 (+) m(-2) day(-1)). We calculated that an eelgrass meadow of 15-16 ha (which represents only about 3-4 % of the subtidal eelgrass meadow cover in the western arm of the lagoon) can potentially incorporate the total amount of NH4 (+) excreted by oysters (similar to 5.2 x 10(6) mmol NH4 (+) day(-1)). This highlights the potential of eelgrass to act as a natural biofilter for the NH4 (+) produced by oyster farming. Shoots exposed to oysters were more efficient in re-utilizing the internal N-15 into the growth of new leaf tissues or to translocate it to belowground tissues. Photosynthetic rates were greater in shoots exposed to oysters, which is consistent with higher NH4 (+) uptake and less negative delta C-13 values. Vegetative production (shoot size, leaf growth) was also higher in these shoots. Aboveground/belowground biomass ratio was lower in eelgrass beds not directly influenced by oyster farms, likely related to the higher investment in belowground biomass to incorporate sedimentary nutrients

3D meso-scale modelling of concrete material in spall tests

Tensile strength is one of the key factors of concrete material that need be accurately defined in analysis of concrete structures subjected to high-speed impact loads. Dynamic tensile strength of concrete material is usually obtained by conducting laboratory tests such as direct tensile test, Brazilian splitting test and spall test. Concrete is a heterogeneous material with different components, but is conventionally assumed to be homogeneous, i.e., cement mortar only, in most previous experimental or numerical studies. The aggregates in concrete material are usually neglected owing to testing limitation and numerical simplification. It has been well acknowledged that neglecting coarse aggregates might not necessarily give accurate concrete dynamic material properties. In the present study, a 3D meso-scale model of concrete specimen with consideration of cement mortar and aggregates is developed to simulate spall tests and investigate the behaviour of concrete material under high strain rate. The commercial software LS-DYNA is used to perform the numerical simulations of spall tests. The mesh size sensitivity is examined by conducting mesh convergence tests. The reliability of the numerical model in simulating the spall tests is verified by comparing the numerical results with the experimental data from the literature. The influence of coarse aggregates on the experimental test results is studied. The wave attenuation in concrete specimen is analysed, and empirical equations are proposed for quick assessment of the test data to determine the true dynamic tensile strength of concrete material. The contributions of aggregates to dynamic strength in spall tests are quantified for modifying the test results based on mortar material in the literature

The Disabilities of the Arm, Shoulder and Hand Questionnaire (DASH) can measure the impairment, activity limitations and participation restriction constructs from the International Classification of Functioning, Disability and Health (ICF)

Background The International Classification of Functioning, Disability and Health (ICF) model of the consequences of disease identifies three health outcomes, impairment, activity limitations and participation restrictions. However, few orthopaedic health outcome measures were developed with reference to the ICF. This study examined the ability of a valid and frequently used measure of upper limb function, namely the Disabilities of the Arm, Shoulder and Hand Questionnaire (DASH), to operationalise the ICF. Methods Twenty-four judges used the method of Discriminant Content Validation to allocate the 38 items of the DASH to the theoretical definition of one or more ICF outcome. One-sample t-tests classified each item as measuring, impairment, activity limitations, participation restrictions, or a combination thereof. Results The DASH contains items able to measure each of the three ICF outcomes with discriminant validity. The DASH contains five pure impairment items, 19 pure activity limitations items and three participation restriction items. In addition, seven items measured both activity limitations and participation restrictions. Conclusions The DASH can measure the three health outcomes identified by the ICF. Consequently the DASH could be used to examine the impact of trauma and subsequent interventions on each health outcome in the absence of measurement confound

Ischemic preconditioning improves maximal performance in humans

Repeated episodes of ischemia followed by reperfusion, commonly referred to as ischemic preconditioning (IPC), represent an endogenous protective mechanism that delays cell injury. IPC also increases blood flow and improves endothelial function. We hypothesize that IPC will improve physical exercise performance and maximal oxygen consumption. The purpose of the study was to examine the effect of ischemic preconditioning in leg skeletal muscles on cycling exercise performance in healthy individuals. Fifteen healthy, well-trained subjects performed two incremental maximal exercise tests on a bicycle ergometer. Power output, oxygen consumption, ventilation, respiratory quotient, and heart rate were measured continuously. Blood pressure and blood lactate were measured before and after the test. One exercise test was performed after the application of ischemic preconditioning, using a protocol of three series of 5-min ischemia at both legs with resting periods of 5 min in between. The other maximal cycling test served as a control. Tests were conducted in counterbalanced order, at least 1 week apart, at the same time of the day. The repeated ischemic periods significantly increased maximal oxygen consumption from 56.8 to 58.4 ml/min per kg (P = 0.003). Maximal power output increased significantly from 366 to 372 W (P = 0.05). Ischemic preconditioning had no effect on ventilation, respiratory quotient, maximal heart rate, blood pressure or on blood lactate. Repeated short-term leg ischemia prior to an incremental bicycle exercise test improves maximal oxygen consumption by 3% and power output by 1.6%. This protocol, which is suggested to mimic the effects of ischemic preconditioning, may have important implications for exercise performance

Factors influencing success in quality-improvement collaboratives: development and psychometric testing of an instrument

Contains fulltext : 88630.pdf (publisher's version ) (Open Access)ABSTRACT: BACKGROUND: To increase the effectiveness of quality-improvement collaboratives (QICs), it is important to explore factors that potentially influence their outcomes. For this purpose, we have developed and tested the psychometric properties of an instrument that aims to identify the features that may enhance the quality and impact of collaborative quality-improvement approaches. The instrument can be used as a measurement instrument to retrospectively collect information about perceived determinants of success. In addition, it can be prospectively applied as a checklist to guide initiators, facilitators, and participants of QICs, with information about how to perform or participate in a collaborative with theoretically optimal chances of success. Such information can be used to improve collaboratives. METHODS: We developed an instrument with content validity based on literature and the opinions of QIC experts. We collected data from 144 healthcare professionals in 44 multidisciplinary improvement teams participating in two QICs and used exploratory factor analysis to assess the construct validity. We used Cronbach's alpha to ascertain the internal consistency. RESULTS: The 50-item instrument we developed reflected expert-opinion-based determinants of success in a QIC. We deleted nine items after item reduction. On the basis of the factor analysis results, one item was dropped, which resulted in a 40-item questionnaire. Exploratory factor analysis showed that a three-factor model provided the best fit. The components were labeled 'sufficient expert team support', 'effective multidisciplinary teamwork', and 'helpful collaborative processes'. Internal consistency reliability was excellent (alphas between .85 and .89). CONCLUSIONS: This newly developed instrument seems a promising tool for providing healthcare workers and policy makers with useful information about determinants of success in QICs. The psychometric properties of the instrument are satisfactory and warrant application either as an objective measure or as a checklist

Different regression equations relate age to the incidence of Lauren types 1 and 2 stomach cancer in the SEER database: these equations are unaffected by sex or race

BACKGROUND: Although impacts upon gastric cancer incidence of race, age, sex, and Lauren type have been individually explored, neither their importance when evaluated together nor the presence or absence of interactions among them have not been fully described. METHODS: This study, derived from SEER (Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute) data, analyzed the incidences of gastric cancer between the years 1992–2001. There were 7882 patients who had developed gastric cancer. The total denominator population was 145,155, 669 persons (68,395,787 for 1992–1996, 78,759,882 for 1997–2001). Patients with multiple tumors were evaluated as per the default of the SEER*Stat program. 160 age-, five year period (1992–1996 vs 1997–2001)-, sex-, race (Asian vs non-Asian)-, Lauren type- specific incidences were derived to form the stratified sample evaluated by linear regression. (160 groups = 2 five year periods × 2 race groups × 2 sexes × 2 Lauren types × 10 age groups.) Linear regression was used to analyze the importance of each of these explanatory variables and to see if there were interactions among the explanatory variables. RESULTS: Race, sex, age group, and Lauren type were found to be important explanatory variables, as were interactions between Lauren type and each of the other important explanatory variables. In the final model, the contribution of each explanatory variable was highly statistically significant (t > 5, d.f. 151, P < 0.00001). The regression equation for Lauren type 1 had different coefficients for the explanatory variables Race, Sex, and Age, than did the regression equation for Lauren type 2. CONCLUSION: The change of the incidence of stomach cancer with respect to age for Lauren type 1 stomach cancer differs from that for Lauren type 2 stomach cancers. The relationships between age and Lauren type do not differ across gender or race. The results support the notion that Lauren type 1 and Lauren type 2 gastric cancers have different etiologies and different patterns of progression from pre-cancer to cancer. The results should be validated by evaluation of other databases

World Heart Federation Roadmap on Atrial Fibrillation - A 2020 Update

The World Heart Federation (WHF) commenced a Roadmap initiative in 2015 to reduce the global burden of cardiovascular disease and resultant burgeoning of healthcare costs. Roadmaps provide a blueprint for implementation of priority solutions for the principal cardiovascular diseases leading to death and disability. Atrial fibrillation (AF) is one of these conditions and is an increasing problem due to ageing of the world’s population and an increase in cardiovascular risk factors that predispose to AF. The goal of the AF roadmap was to provide guidance on priority interventions that are feasible in multiple countries, and to identify roadblocks and potential strategies to overcome them. Since publication of the AF Roadmap in 2017, there have been many technological advances including devices and artificial intelligence for identification and prediction of unknown AF, better methods to achieve rhythm control, and widespread uptake of smartphones and apps that could facilitate new approaches to healthcare delivery and increasing community AF awareness. In addition, the World Health Organisation added the non-vitamin K antagonist oral anticoagulants (NOACs) to the Essential Medicines List, making it possible to increase advocacy for their widespread adoption as therapy to prevent stroke. These advances motivated the WHF to commission a 2020 AF Roadmap update. Three years after the original Roadmap publication, the identified barriers and solutions were judged still relevant, and progress has been slow. This 2020 Roadmap update reviews the significant changes since 2017 and identifies priority areas for achieving the goals of reducing death and disability related to AF, particularly targeted at low-middle income countries. These include advocacy to increase appreciation of the scope of the problem; plugging gaps in guideline management and prevention through physician education, increasing patient health literacy, and novel ways to increase access to integrated healthcare including mHealth and digital transformations; and greater emphasis on achieving practical solutions to national and regional entrenched barriers. Despite the advances reviewed in this update, the task will not be easy, but the health rewards of implementing solutions that are both innovative and practical will be great