•Mitochondrial dysfunction is one of the earliest pathophysiological events in amyotrophic lateral sclerosis (ALS).•ALS-associated mutant proteins accumulate in mitochondria and cause mitochondrial ...damage.•ALS-associated mitochondrial dysfunction occurs at multiple levels.•ALS affects mitochondrial respiration and ATP production, calcium handling, dynamics, and apoptotic signalling.
Mitochondria are unique organelles that are essential for a variety of cellular processes including energy metabolism, calcium homeostasis, lipid biosynthesis, and apoptosis. Mitochondrial dysfunction is a prevalent feature of many neurodegenerative diseases including motor neuron disorders such as amyotrophic lateral sclerosis (ALS). Disruption of mitochondrial structure, dynamics, bioenergetics and calcium buffering has been extensively reported in ALS patients and model systems and has been suggested to be directly involved in disease pathogenesis. Here we review the alterations in mitochondrial parameters in ALS and examine the common pathways to dysfunction.
Although the social identity model of collective action (SIMCA) demonstrates that identity, efficacy, and injustice are key correlates of collective action, longitudinal tests of these causal ...assumptions are absent from the literature. Moreover, most collective action research focuses on disadvantaged groups’ responses to injustice, with few studies examining what motivates advantaged groups to protest. We address these oversights using nationally representative longitudinal panel data to investigate SIMCA among members of disadvantaged (N = 2,574) and advantaged (N = 13,367) groups. As hypothesized, identity predicted increases in injustice, efficacy, and collective action support over time. In turn, injustice (but not efficacy) mediated the longitudinal association between identity and collective action support. Notably, results were largely consistent across disadvantaged and advantaged groups. Thus, we provide the first demonstration that identity temporally precedes collective action across objectively disadvantaged and advantaged groups, but identify complexities regarding the role of efficacy in protest.
B-mode ultrasound is often used to quantify muscle architecture during movements. Our objectives were to
) systematically review the reliability of fascicle length (FL) and pennation angles (PA) ...measured using ultrasound during movements involving voluntary contractions;
) systematically review the methods used in studies reporting reliability, discuss associated challenges, and provide recommendations to improve the reliability and validity of dynamic ultrasound measurements; and
) provide an overview of computational approaches for quantifying fascicle architecture, their validity, agreement with manual quantification of fascicle architecture, and advantages and drawbacks. Three databases were searched until June 2019. Studies among healthy human individuals aged 17-85 yr that investigated the reliability of FL or PA in lower-extremity muscles during isoinertial movements and that were written in English were included. Thirty studies (
= 340 participants) were included for reliability analyses. Between-session reliability as measured by coefficient of multiple correlations (CMC), and coefficient of variation (CV) was FL CMC: 0.89-0.96; CV: 8.3% and PA CMC: 0.87-0.90; CV: 4.5-9.6%. Within-session reliability was FL CMC: 0.82-0.99; CV: 0.0-6.7% and PA CMC: 0.91; CV: 0.0-15.0%. Manual analysis reliability was FL CMC: 0.89-0.96; CV: 0.0-15.9%; PA CMC: 0.84-0.90; and CV: 2.0-9.8%. Computational analysis FL CMC was 0.82-0.99, and PA CV was 14.0-15.0%. Eighteen computational approaches were identified, and these generally showed high agreement with manual analysis and high validity compared with phantoms or synthetic images. B-mode ultrasound is a reliable method to quantify fascicle architecture during movement. Additionally, computational approaches can provide a reliable and valid estimation of fascicle architecture.
Microglia and astrocytes play essential roles in the central nervous system contributing to many functions including homeostasis, immune response, blood-brain barrier maintenance and synaptic ...support. Evidence has emerged from experimental models of glial communication that microglia and astrocytes influence and coordinate each other and their effects on the brain environment. However, due to the difference in glial cells between humans and rodents, it is essential to confirm the relevance of these findings in human brains. Here, we aim to review the current knowledge on microglia-astrocyte crosstalk in humans, exploring novel methodological techniques used in health and disease conditions. This will include an in-depth look at cell culture and iPSCs,
studies, imaging and fluid biomarkers, genetics and transcriptomic data. In this review, we will discuss the advantages and limitations of these methods, highlighting the understanding these methods have brought the field on these cells communicative abilities, and the knowledge gaps that remain.
We report the encapsulation of the hydrophilic model molecule calcein in the Zr-based MOF UiO-66, followed by amorphization of the framework by ball-milling. We show controlled release of calcein ...over more than 30 days, compared with the 2 day release period from crystalline UiO-66.
Summary Background Cardiovascular risk factors are associated with an increased risk of dementia. We assessed whether a multidomain intervention targeting these factors can prevent dementia in a ...population of community-dwelling older people. Methods In this open-label, cluster-randomised controlled trial, we recruited individuals aged 70–78 years through participating general practices in the Netherlands. General practices within each health-care centre were randomly assigned (1:1), via a computer-generated randomisation sequence, to either a 6-year nurse-led, multidomain cardiovascular intervention or control (usual care). The primary outcomes were cumulative incidence of dementia and disability score (Academic Medical Center Linear Disability Score ALDS) at 6 years of follow-up. The main secondary outcomes were incident cardiovascular disease and mortality. Outcome assessors were masked to group assignment. Analyses included all participants with available outcome data. This trial is registered with ISRCTN, number ISRCTN29711771. Findings Between June 7, 2006, and March 12, 2009, 116 general practices (3526 participants) within 26 health-care centres were recruited and randomly assigned: 63 (1890 participants) were assigned to the intervention group and 53 (1636 participants) to the control group. Primary outcome data were obtained for 3454 (98%) participants; median follow-up was 6·7 years (21 341 person-years). Dementia developed in 121 (7%) of 1853 participants in the intervention group and in 112 (7%) of 1601 participants in the control group (hazard ratio HR 0·92, 95% CI 0·71–1·19; p=0·54). Mean ALDS scores measured during follow-up did not differ between groups (85·7 SD 6·8 in the intervention group and 85·7 7·1 in the control group; adjusted mean difference −0·02, 95% CI −0·38 to 0·42; p=0·93). 309 (16%) of 1885 participants died in the intervention group, compared with 269 (16%) of 1634 participants in the control group (HR 0·98, 95% CI 0·80–1·18; p=0·81). Incident cardiovascular disease did not differ between groups (273 19% of 1469 participants in the intervention group and 228 17% of 1307 participants in the control group; HR 1·06, 95% CI 0·86–1·31; p=0·57). Interpretation A nurse-led, multidomain intervention did not result in a reduced incidence of all-cause dementia in an unselected population of older people. This absence of effect might have been caused by modest baseline cardiovascular risks and high standards of usual care. Future studies should assess the efficacy of such interventions in selected populations. Funding Dutch Ministry of Health, Welfare and Sport; Dutch Innovation Fund of Collaborative Health Insurances; and Netherlands Organisation for Health Research and Development.
Social change movements may take years or decades to achieve their goals and thus require ongoing efforts from their supporters. We apply the insights of self-determination theory to examine ...sustained collective action over time. We expected that autonomous motivation, but not controlled motivation, would predict sustained action. We also examine whether autonomous motivation shapes and is shaped by social identification as a supporter of the cause. Longitudinal data were collected from supporters of global poverty reduction (N = 263) at two timepoints 1 year apart. Using latent change score modeling, we found that increases in autonomous motivation positively predicted increases in opinion-based group identification, which in turn predicted increases in self-reported collective action. Controlled motivation (Time 1) negatively predicted changes in action. We concluded that autonomous motivation predicts sustained action over time, while promoting controlled motives for action may backfire because it may undermine identification with the cause.
Combinations of anti-cancer drugs can overcome resistance and provide new treatments
. The number of possible drug combinations vastly exceeds what could be tested clinically. Efforts to ...systematically identify active combinations and the tissues and molecular contexts in which they are most effective could accelerate the development of combination treatments. Here we evaluate the potency and efficacy of 2,025 clinically relevant two-drug combinations, generating a dataset encompassing 125 molecularly characterized breast, colorectal and pancreatic cancer cell lines. We show that synergy between drugs is rare and highly context-dependent, and that combinations of targeted agents are most likely to be synergistic. We incorporate multi-omic molecular features to identify combination biomarkers and specify synergistic drug combinations and their active contexts, including in basal-like breast cancer, and microsatellite-stable or KRAS-mutant colon cancer. Our results show that irinotecan and CHEK1 inhibition have synergistic effects in microsatellite-stable or KRAS-TP53 double-mutant colon cancer cells, leading to apoptosis and suppression of tumour xenograft growth. This study identifies clinically relevant effective drug combinations in distinct molecular subpopulations and is a resource to guide rational efforts to develop combinatorial drug treatments.
Over the last quarter of a century, social psychological research on collective action has grown exponentially and progressed through four distinct phases. While the first phase showed that identity, ...efficacy, and injustice motivate the aggrieved to protest on behalf of their ingroup, the second phase acknowledged that protests could involve collaborations between the disadvantaged and their advantaged allies. The third phase of research examined reactionary movements by integrating ideology and acknowledging that advantaged groups can protest to protect or expand their privileged status. The research showcased in this special issue highlights a fourth phase of collective action by illustrating its dialectical nature and recognising the opposing agendas advanced by structurally disadvantaged and advantaged groups. We also advance a two‐dimensional taxonomy differentiating between the goals (Inclusive vs. Exclusive) and societal implications (Challenge vs. Defend the Status Quo) of collective action. In doing so, we provide some of the necessary conceptual and definitional foundations for the next generation of research on collective action and social change.
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