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Targeting common disease pathomechanisms to treat amyotrophic lateral sclerosis
Get PDFThe motor neuron disease amyotrophic lateral sclerosis (ALS) is a devastating condition with limited treatment options. The past few years have witnessed a ramping up of translational ALS research, offering the prospect of disease-modifying therapies. Although breakthroughs using gene-targeted approaches have shown potential to treat patients with specific disease-causing mutations, the applicability of such therapies remains restricted to a minority of individuals. Therapies targeting more general mechanisms that underlie motor neuron pathology in ALS are therefore of considerable interest. ALS pathology is associated with disruption to a complex array of key cellular pathways, including RNA processing, proteostasis, metabolism and inflammation. This Review details attempts to restore cellular homeostasis by targeting these pathways in order to develop effective, broadly-applicable ALS therapeutics
Osteology and functional morphology of a transitional pterosaur Dearc sgiathanach from the Middle Jurassic (Bathonian) of Scotland
No full textPterosaurs were the first vertebrates to evolve active flight. The lack of many well-preserved pterosaur fossils limits our understanding of the functional anatomy and behavior of these flight pioneers, particularly from their early history (Triassic to Middle Jurassic). Here we describe in detail the osteology of an exceptionally preserved Middle Jurassic pterosaur, the holotype of Dearc sgiathanach from the Isle of Skye, Scotland. We identify new autapomorphies of the flight apparatus (humerus and sternum), which further support the distinctiveness of Dearc compared with other early-diverging pterosaurs and describe features, such as the vertebral morphology, shared with later-diverging pterosaurs that probably developed convergently to support a large body size or as a sign of modular evolution. We used extant phylogenetic bracketing to infer the principal cranial and antebrachial musculature, indicating that Dearc had large and anteriorly placed palatal musculature that compensated for weak temporal jaw adductors and wing musculature suggestive of flight style reliant on powerful adduction and protraction of the humerus. Comparisons with other pterosaurs revealed that non-pterodactyloids such as Dearc, despite their overall conservative bauplans, adapted various flight and feeding styles. The osteology and myology of Dearc are indicative of a large predator that flew and hunted above lagoons and nearshore environments of the Middle Jurassic
Genetically Predicted IL-18 Inhibition and Risk of Cardiovascular Events: A Mendelian Randomization Study
Get PDFTransitivity and couple relationship satisfaction:Sharing and visiting friends and family make the difference
Get PDFThis study focused on the relationship between couple relationship satisfaction and the transitivity of ties with family and friends within couples, that is, the tendency of partners to share friends and family. Transitivity was measured using three indicators: 1) the proportion of shared friends (friendship network overlap), 2) the frequency of contact each partner has with their own and their partner’s friends and family, and 3) whether social visits to friends and family are made with or without the partner (togetherness). This study used data from the MOSAiCH survey, which included 1,320 partnered individuals residing in Switzerland. The link between the transitivity of ties with family and friends within couples and couple relationship satisfaction was estimated using structural equation modelling. The results revealed that transitivity was consistently informed by the three selected indicators (overlap, frequency, and togetherness) and that transitivity positively contributed to couple relationship satisfaction. Furthermore, transitivity explained couple relationship satisfaction more than the partner’s level of education, nationality, or the duration of the couple relationship. By emphasizing the role and importance of visits performed jointly by both members of the couple, this study shares an original insight and a better understanding of the ways in which marital satisfaction varies
Humility and the sacred in One Health
Get PDFThe secularisation of education has led to the progressive sequestration of the sacred to its present ghetto on the margins of Western mental life. This means that that which is of the highest possible value is no longer central to our lives and we are left struggling to assert the dignity and respect owed to the living. Abraham Heschel asserted that mankind will not perish for want of information but only for want of appreciation. Such appreciative respect is the uncommon ground we need to somehow reclaim. To do so, however, requires us to learn to shift our source of attention and turn to the I-Thou, thereby exploring what Buber has described as genuine dialogue. This presentation will provide insights into these deep listening practices, drawing on learning from five years of teaching on the Innovative Approaches to Health Challenges Across Disciplines postgraduate course offered to students on the MSc in One Health. A fundamental starting point for this course is humility. This can be viewed as a suspending of judgement, a willingness to listen and a move into curiosity. It can involve a sacred pause, a slowing down and a modulation of the nervous system to allow us to become more receptive. In deepening this attentiveness, a shift from curiosity into wonder becomes possible. The I-Thou turn involves a shift in which we listen not from the head but from the heart. Cynicism is suspended and compassionate listening invited in. Such listening is predicated on humility and this presentation will therefore emphasise this as a starting point that allows us to recover the uncommon ground that is the field of possibility and where playfulness and hope for emergent futures can be co-created. This includes the possibility of re-sacralising our relationships with ourselves, each other and the more-than-human world
Trans-ancestry genome-wide study of depression identifies 697 associations implicating cell types and pharmacotherapies
Get PDFIn a genome-wide association study (GWAS) meta-analysis of 688,808 individuals with major depression (MD) and 4,364,225 controls from 29 countries across diverse and admixed ancestries, we identify 697 associations at 635 loci, 293 of which are novel. Using fine-mapping and functional tools, we find 308 high-confidence gene associations and enrichment of postsynaptic density and receptor clustering. A neural cell-type enrichment analysis utilizing single-cell data implicates excitatory, inhibitory, and medium spiny neurons and the involvement of amygdala neurons in both mouse and human single-cell analyses. The associations are enriched for antidepressant targets and provide potential repurposing opportunities. Polygenic scores trained using European or multi-ancestry data predicted MD status across all ancestries, explaining up to 5.8% of MD liability variance in Europeans. These findings advance our global understanding of MD and reveal biological targets that may be used to target and develop pharmacotherapies addressing the unmet need for effective treatment.</p
The dependence of shugoshin on Bub1-kinase activity is dispensable for the maintenance of spindle assembly checkpoint response in Cryptococcus neoformans
Get PDFDuring chromosome segregation, the spindle assembly checkpoint (SAC) detects errors in kinetochore-microtubule attachments. Timely activation and maintenance of the SAC until defects are corrected is essential for genome stability. Here, we show that shugoshin (Sgo1), a conserved tension-sensing protein, ensures the maintenance of SAC signals in response to unattached kinetochores during mitosis in a basidiomycete budding yeast Cryptococcus neoformans. Sgo1 maintains optimum levels of Aurora B kinase Ipl1 and protein phosphatase 1 (PP1) at kinetochores. The absence of Sgo1 results in the loss of Aurora B Ipl1 with a concomitant increase in PP1 levels at kinetochores. This leads to a premature reduction in the kinetochore-bound Bub1 levels and early termination of the SAC signals. Intriguingly, the kinase function of Bub1 is dispensable for shugoshin’s subcellular localization. Sgo1 is predominantly localized to spindle pole bodies (SPBs) and along the mitotic spindle with a minor pool at kinetochores. In the absence of proper kinetochore-microtubule attachments, Sgo1 reinforces the Aurora B kinase Ipl1-PP1 phosphatase balance, which is critical for prolonged maintenance of the SAC response.</p
Time to start taking time seriously: How to investigate unexpected biological rhythms within infectious disease research
Get PDFThe discovery of rhythmicity in host and pathogen activities dates back to the Hippocratic era, but the causes and consequences of these biological rhythms have remained poorly understood. Rhythms in infection phenotypes or traits are observed across taxonomically diverse hosts and pathogens, suggesting general evolutionary principles. Understanding these principles may enable rhythms to be leveraged in manners that improve drug and vaccine efficacy or disrupt pathogen timekeeping to reduce virulence and transmission. Explaining and exploiting rhythms in infections requires an integrative and multidisciplinary approach, which is a hallmark of research within chronobiology. Many researchers are welcomed into chronobiology from other fields after observing an unexpected rhythm or time-of-day effect in their data. Such findings can launch a rich new research topic, but engaging with the concepts, approaches, and dogma, in a new discipline can be daunting. Fortunately, chronobiology has well-developed frameworks for interrogating rhythms that can be readily applied in novel contexts. Here, we provide a “how to” guide for exploring unexpected daily rhythms in infectious disease research. We outline how to establish: if the rhythm is circadian, to what extent the host and pathogen are responsible, the relevance for host-pathogen interactions, and how to explore therapeutic potential
Effectiveness of psychological interventions in improving relationship functioning among couples coping with prostate cancer:A systematic review and meta-analysis
Get PDFObjective: There is an increasing amount of literature acknowledging the significance of addressing the psychosocial impact of prostate cancer (PCa) on couples' relationship functioning and well-being. However, research on developing and evaluating psychological interventions for individuals and couples coping with PCa remains limited. This systematic review aimed to critically evaluate and synthesise the effectiveness of psychological interventions in improving the relationship functioning of couples affected by PCa and to identify the moderating role of several methodological characteristics of intervention studies. Methods: Five databases MEDLINE, PsycINFO, Embase, Global Health, and Cochrane Library were searched up to September 2024. Twenty-three studies with randomised trials and a total sample size of 3333 participants were included. Random effects meta-analyses for relationship functioning, sensitivity analysis for outliers, and publication bias analysis were conducted. Results: The results showed that psychological interventions had a non-significant trivial effect (g = 0.06, p = 0.328) on improving relationship functioning among couples coping with PCa. Subgroup analyses identified two potential moderators: firstly, the intervention format (conjoint vs. individual; p = 0.005), and secondly, the intervention frequency (session number < 6 vs. session number ≥ 6; p = 0.004). Conclusions: The findings suggest that more high-quality intervention studies are needed to improve the relationship functioning of those affected by PCa, with screening processes to select more representative samples at entry. The implications for clinical practice highlight the need to tailor interventions to the specific needs of couples coping with PCa
Long-Range Vapour-Mediated Interactions between Adjacent Droplets
Get PDFDroplet motion can occur due to interaction with the surrounding vapor phase. We examined experimentally the motion of two adjacent droplets, either pure liquid or a binary mixture, without direct contact. A droplet is repelled or attracted by the (pinned) adjacent droplet, which acts as a vapor source, depending on its initial concentration as well as the composition in the vapor, even for a pure liquid. The observation is explained by a theoretical model that combines evaporation and adsorption processes, which unifies the mechanism for both directions of motion (attraction and repulsion) and, more importantly, for both binary mixtures and pure liquid droplets. Good agreement is achieved between the theoretical model and the experimental observations. A critical concentration is proposed to determine the transition between attractive and repulsive motion, this being a criterion to predict droplet motion.</p
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