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Chytrid fungi distribution and co-occurrence with diatoms correlate with sea ice melt in the Arctic Ocean
No full textGlobal warming is rapidly altering physicochemical attributes of Arctic waters. These changes are predicted to alter microbial networks, potentially perturbing wider community functions including parasite infections and saprotrophic recycling of biogeochemical compounds. Specifically, the interaction between autotrophic phytoplankton and heterotrophic fungi e.g. chytrids (fungi with swimming tails) requires further analysis. Here, we investigate the diversity and distribution patterns of fungi in relation to abiotic variables during one record sea ice minimum in 2012 and explore co-occurrence of chytrids with diatoms, key primary producers in these changing environments. We show that chytrid fungi are primarily encountered at sites influenced by sea ice melt. Furthermore, chytrid representation positively correlates with sea ice-associated diatoms such as Fragilariopsis or Nitzschia. Our findings identify a potential future scenario where chytrid representation within these communities increases as a consequence of ice retreat, further altering community structure through perturbation of parasitic or saprotrophic interaction networks
Single cell assays for quantifying MRNA and protein during cystic fibrosis gene therapy trials
No full textTherapeutic senescence via GPCR activation in synovial fibroblasts facilitates resolution of arthritis
No full textRheumatoid arthritis affects individuals commonly during the most productive years of adulthood. Poor response rates and high costs associated with treatment mandate the search for new therapies. Here we show that targeting a specific G-protein coupled receptor promotes senescence in synovial fibroblasts, enabling amelioration of joint inflammation. Following activation of the melanocortin type 1 receptor (MC1), synovial fibroblasts acquire a senescence phenotype characterized by arrested proliferation, metabolic re-programming and marked gene alteration resembling the remodeling phase of wound healing, with increased matrix metalloproteinase expression and reduced collagen production. This biological response is attained by selective agonism of MC1, not shared by non-selective ligands, and dependent on downstream ERK1/2 phosphorylation. In vivo, activation of MC1 leads to anti-arthritic effects associated with induction of senescence in the synovial tissue and cartilage protection. Altogether, selective activation of MC1 is a viable strategy to induce cellular senescence, affording a distinct way to control joint inflammation and arthritis
Catalysis by the JmjC histone demethylase KDM4A integrates substrate dynamics, correlated motions and molecular orbital control
No full textThe Nε-methyl lysine status of histones is important in the regulation of eukaryotic transcription. The Fe(II) and 2-oxoglutarate (2OG) -dependent JmjC domain enzymes are the largest family of histone Nε-methyl lysine demethylases (KDMs). The human KDM4 subfamily of JmjC KDMs is linked with multiple cancers and some of its members are medicinal chemistry targets. We describe the use of combined molecular dynamics (MD) and Quantum Mechanical/Molecular Mechanical (QM/MM) methods to study the mechanism of KDM4A, which catalyzes demethylation of both tri- and di-methylated forms of histone H3 at K9 and K36. The results show that the oxygen activation at the active site of KDM4A is optimized towards the generation of the reactive Fe(IV)-oxo intermediate. Factors including the substrate binding mode, correlated motions of the protein and histone substrates, and molecular orbital control synergistically contribute to the reactivity of the Fe(IV)-oxo intermediate. In silico substitutions were performed to investigate the roles of residues (Lys241, Tyr177, and Asn290) in substrate orientation. The Lys241Ala substitution abolishes activity due to altered substrate orientation consistent with reported experimental studies. Calculations with a macrocyclic peptide substrate analogue reveal that induced conformational changes/correlated motions in KDM4A are sequence-specific in a manner that influences substrate binding affinity. Second sphere residues, such as Ser288 and Thr289, may contribute to KDM4A catalysis by correlated motions with active site residues. Residues that stabilize key intermediates, and which are predicted to be involved in correlated motions with other residues in the second sphere and beyond, are shown to be different in KDM4A compared to those in another JmjC KDM (PHF8), which acts on H3K9 di- and mono-methylated forms, suggesting that allosteric type inhibition is of interest from the perspective of developing selective JmjC KDM inhibitors
Three key considerations for biodiversity conservation in multilateral agreements
No full textIt is nearly three decades since the world recognized the need for a global multilateral treaty aiming to address accelerating biodiversity loss. However, biodiversity continues to decline at a concerning rate. Drawing on lessons from the implementation of the current strategic plan of the Convention on Biological Diversity and the 2010 Aichi Targets, we highlight three interlinked core areas, which require attention and improvement in the development of the post‐2020 Biodiversity Framework under the Convention on Biological Diversity. They are: (1) developing robust theories of change which define agreed, adaptive plans for achieving targets; (2) using models to evaluate assumptions and effectiveness of different plans and targets; and (3) identifying the common but differentiated responsibilities of different actors/states/countries within these plans. We demonstrate how future multilateral agreements must not focus only on what needs to be done but also on how it should be done, using measurable steps, which make sense at the scales at which biodiversity change happens
A human surfactant B deficiency air-liquid interface cell culture model suitable for gene therapy applications
No full textSurfactant protein B (SPB) deficiency is a severe monogenic interstitial lung disorder that leads to loss of life in infants as a result of alveolar collapse and respiratory distress syndrome. The development and assessment of curative therapies for the deficiency are limited by the general lack of well-characterized and physiologically relevant in vitro models of human lung parenchyma. Here, we describe a new human surfactant air-liquid interface (SALI) culture model based on H441 cells, which successfully recapitulates the key characteristics of human alveolar cells in primary culture as evidenced by RNA and protein expression of alveolar cell markers. SALI cultures were able to develop stratified cellular layers with functional barrier properties that are stable for at least 28 days after air-lift. A SFTPB knockout model of SPB deficiency was generated via gene editing of SALI cultures. The SFTPB-edited SALI cultures lost expression of SPB completely and showed weaker functional barrier properties. We were able to correct this phenotype via delivery of a lentiviral vector pseudotyped with Sendai virus glycoproteins F/HN expressing SPB. We believe that SALI cultures can serve as an important in vitro research tool to study human alveolar epithelium, especially for the development of advanced therapy medicinal products targeting monogenic disorders
Physical activity in a pandemic: a new treatment target for psychological therapy
No full textThe COVID-19 pandemic and its management are placing significant new strains on people's well-being, particularly those with pre-existing mental health conditions. Physical activity has been shown to improve mental as well as physical health. Increasing activity levels should be prioritized as a treatment target, especially when the barriers to exercise are greater than ever. Promoting physical activity has not traditionally been the remit of psychologists. Yet psychological theory and therapeutic techniques can be readily applied to address physical inactivity. We present theoretical perspectives and therapy techniques relating to (1) beliefs about physical activity, (2) motivation to be physically active, and (3) the sense of reward achieved through being physically active. We outline strategies to initiate and maintain physical activity during the COVID-19 pandemic, thereby benefitting mental and physical health. COVID-19 is demanding rapid and substantial change across the whole health care system. Psychological therapists can respond creatively by addressing physical activity, a treatable clinical target which delivers both mental and physical health benefits.
PRACTITIONER POINTS:
- Physical activity is essential for our mental and physical health. - Yet COVID-19 presents novel barriers to physical activity. - Psychological theory and techniques to address beliefs, motivation, and reward can be applied to increase physical activity during COVID-19. - Physical activity is an important clinical target to sustain and improve mental health, especially in the current pandemic
Sleep and intrusive memories immediately after a traumatic event in emergency department patients
No full textStudy objectives
Intrusive memories of psychological trauma are a core clinical feature of posttraumatic stress disorder (PTSD), and in the early period post-trauma may be a potential target for early intervention. Disrupted sleep in the weeks post-trauma is associated with later PTSD. The impact of sleep and intrusive memories immediately post-trauma, and their relation to later PTSD, is unknown. This study assessed the relationship between sleep duration on the first night following a real-life traumatic event and intrusive memories in the subsequent week, and how these might relate to PTSD symptoms at 2 months.
Methods
Patients (n = 87) recruited in the emergency department completed a sleep and intrusive memory diary from the day of their trauma and for the subsequent week, with optional actigraphy. PTSD, anxiety, and depression symptoms were assessed at 1 week and 2 months.
Results
A U-shaped relationship was observed between sleep duration on the first night and intrusive memories over the subsequent week: sleeping “too little” or “too much” was associated with more intrusive memories. Individuals who met Clinician-Administered PTSD Scale (CAPS) criteria for PTSD at 2 months had three times more intrusive memories in the first week immediately post-trauma than those who did not (M = 28.20 vs 9.96). Post hoc analysis showed that the absence of intrusive memories in the first week post-trauma was only observed in those who did not meet CAPS criteria for PTSD at 2 months.
Conclusions
Monitoring intrusive memories and sleep in the first week post-trauma, using a simple diary, may help identify individuals more vulnerable to later psychopathology
Ancient life and moving fluids
No full textOver 3.7 billion years of Earth history, life has evolved complex adaptations to help navigate and interact with the fluid environment. Consequently, fluid dynamics has become a powerful tool for studying ancient fossils, providing insights into the palaeobiology and palaeoecology of extinct organisms from across the tree of life. In recent years, this approach has been extended to the Ediacara biota, an enigmatic assemblage of Neoproterozoic soft‐bodied organisms that represent the first major radiation of macroscopic eukaryotes. Reconstructing the ways in which Ediacaran organisms interacted with the fluids provides new insights into how these organisms fed, moved, and interacted within communities. Here, we provide an in‐depth review of fluid physics aimed at palaeobiologists, in which we dispel misconceptions related to the Reynolds number and associated flow conditions, and specify the governing equations of fluid dynamics. We then review recent advances in Ediacaran palaeobiology resulting from the application of computational fluid dynamics (CFD). We provide a worked example and account of best practice in CFD analyses of fossils, including the first large eddy simulation (LES) experiment performed on extinct organisms. Lastly, we identify key questions, barriers, and emerging techniques in fluid dynamics, which will not only allow us to understand the earliest animal ecosystems better, but will also help to develop new palaeobiological tools for studying ancient life
Identifying drivers of forest resilience in long-term records from the Neotropics
No full textHere we use 30 long-term, high-resolution palaeoecological records from Mexico, Central and South America to address two hypotheses regarding possible drivers of resilience in tropical forests as measured in terms of recovery rates from previous disturbances. First, we hypothesise that faster recovery rates are associated with regions of higher biodiversity, as suggested by the insurance hypothesis. And second, that resilience is due to intrinsic abiotic factors that are location specific, thus regions presently displaying resilience in terms of persistence to current climatic disturbances should also show higher recovery rates in the past. To test these hypotheses, we applied a threshold approach to identify past disturbances to forests within each sequence. We then compared the recovery rates to these events with pollen richness before the event. We also compared recovery rates of each site with a measure of present resilience in the region as demonstrated by measuring global vegetation persistence to climatic perturbations using satellite imagery. Preliminary results indeed show a positive relationship between pre-disturbance taxonomic richness and faster recovery rates. However, there is less evidence to support the concept that resilience is intrinsic to a region; patterns of resilience apparent in ecosystems presently are not necessarily conservative through time