Personalized medicine : the impact on chemistry

An effective strategy for personalized medicine requires a major conceptual change in the development and application of therapeutics. In this article, we argue that further advances in this field should be made with reference to another conceptual shift, that of network pharmacology. We examine the intersection of personalized medicine and network pharmacology to identify strategies for the development of personalized therapies that are fully informed by network pharmacology concepts. This provides a framework for discussion of the impact personalized medicine will have on chemistry in terms of drug discovery, formulation and delivery, the adaptations and changes in ideology required and the contribution chemistry is already making. New ways of conceptualizing chemistry’s relationship with medicine will lead to new approaches to drug discovery and hold promise of delivering safer and more effective therapies

Does repetitive task training improve functional activity after stroke? A Cochrane systematic review and meta-analysis.

Repetitive task training resulted in modest improvement across a range of lower limb outcome measures, but not upper limb outcome measures. Training may be sufficient to have a small impact on activities of daily living. Interventions involving elements of repetition and task training are diverse and difficult to classify: the results presented are specific to trials where both elements are clearly present in the intervention, without major confounding by other potential mechanisms of action

Unwind: Interactive Fish Straightening

The ScanAllFish project is a large-scale effort to scan all the world's 33,100 known species of fishes. It has already generated thousands of volumetric CT scans of fish species which are available on open access platforms such as the Open Science Framework. To achieve a scanning rate required for a project of this magnitude, many specimens are grouped together into a single tube and scanned all at once. The resulting data contain many fish which are often bent and twisted to fit into the scanner. Our system, Unwind, is a novel interactive visualization and processing tool which extracts, unbends, and untwists volumetric images of fish with minimal user interaction. Our approach enables scientists to interactively unwarp these volumes to remove the undesired torque and bending using a piecewise-linear skeleton extracted by averaging isosurfaces of a harmonic function connecting the head and tail of each fish. The result is a volumetric dataset of a individual, straight fish in a canonical pose defined by the marine biologist expert user. We have developed Unwind in collaboration with a team of marine biologists: Our system has been deployed in their labs, and is presently being used for dataset construction, biomechanical analysis, and the generation of figures for scientific publication

The Enteropathogenic E. coli Effector EspF Targets and Disrupts the Nucleolus by a Process Regulated by Mitochondrial Dysfunction

The nucleolus is a multifunctional structure within the nucleus of eukaryotic cells and is the primary site of ribosome biogenesis. Almost all viruses target and disrupt the nucleolus—a feature exclusive to this pathogen group. Here, using a combination of bio-imaging, genetic and biochemical analyses, we demonstrate that the enteropathogenic E. coli (EPEC) effector protein EspF specifically targets the nucleolus and disrupts a subset of nucleolar factors. Driven by a defined N-terminal nucleolar targeting domain, EspF causes the complete loss from the nucleolus of nucleolin, the most abundant nucleolar protein. We also show that other bacterial species disrupt the nucleolus, dependent on their ability to deliver effector proteins into the host cell. Moreover, we uncover a novel regulatory mechanism whereby nucleolar targeting by EspF is strictly controlled by EPEC's manipulation of host mitochondria. Collectively, this work reveals that the nucleolus may be a common feature of bacterial pathogenesis and demonstrates that a bacterial pathogen has evolved a highly sophisticated mechanism to enable spatio-temporal control over its virulence proteins

Methanogen activity and microbial diversity in Gulf of Cádiz mud volcano sediments

The Gulf of Cádiz is a tectonically active continental margin with over sixty mud volcanoes (MV) documented, some associated with active methane (CH4) seepage. However, the role of prokaryotes in influencing this CH4 release is largely unknown. In two expeditions (MSM1-3 and JC10) seven Gulf of Cádiz MVs (Porto, Bonjardim, Carlos Ribeiro, Captain Arutyunov, Darwin, Meknes, and Mercator) were analyzed for microbial diversity, geochemistry, and methanogenic activity, plus substrate amended slurries also measured potential methanogenesis and anaerobic oxidation of methane (AOM). Prokaryotic populations and activities were variable in these MV sediments reflecting the geochemical heterogeneity within and between them. There were also marked differences between many MV and their reference sites. Overall direct cell numbers below the SMTZ (0.2–0.5 mbsf) were much lower than the general global depth distribution and equivalent to cell numbers from below 100 mbsf. Methanogenesis from methyl compounds, especially methylamine, were much higher than the usually dominant substrates H2/CO2 or acetate. Also, CH4 production occurred in 50% of methylated substrate slurries and only methylotrophic CH4 production occurred at all seven MV sites. These slurries were dominated by Methanococcoides methanogens (resulting in pure cultures), and prokaryotes found in other MV sediments. AOM occurred in some slurries, particularly, those from Captain Arutyunov, Mercator and Carlos Ribeiro MVs. Archaeal diversity at MV sites showed the presence of both methanogens and ANME (Methanosarcinales, Methanococcoides, and ANME-1) related sequences, and bacterial diversity was higher than archaeal diversity, dominated by members of the Atribacterota, Chloroflexota, Pseudomonadota, Planctomycetota, Bacillota, and Ca. “Aminicenantes.” Further work is essential to determine the full contribution of Gulf of Cádiz mud volcanoes to the global methane and carbon cycles

Effects of Exercise and Sertraline on Measures of Coronary Heart Disease Risk in Patients With Major Depression: Results From the SMILE-II Randomized Clinical Trial

To assess the effects of supervised and home-based aerobic exercise training, and antidepressant pharmacotherapy (sertraline) on coronary heart disease (CHD) risk factors in a sample of participants with major depressive disorder (MDD)

Resilient trees for urban environments: The importance of intraspecific variation

Societal Impact Statement: Trees in urban environments provide us with shade, heat mitigation, flood abatement, noise and pollution reduction, pollination, beauty, and much more. However, many of these benefits are strongly connected to tree size and vitality, with larger, healthier trees providing ecosystem services more effectively, which means that selecting the right tree for site and function is crucial in order to gain all benefits from our urban trees. Summary: Trees play a major role in the Earth's biogeochemical processes, influencing soil production, hydrological, nutrient and carbon cycles, and the global climate. They store about 50% of the world's terrestrial carbon stocks, and provide habitats for a wide range of other species, supporting at least half of the Earth's known terrestrial plants and animals. Trees are not only found in forests and other natural ecosystems, but also in urban environments. Most of the human population is concentrated in cities, towns and villages, so urban trees are critical to meet on‐going and future social, economic and environmental challenges. However, many urban tree populations are strongly challenged by a changing climate, outbreaks of pests and pathogens and an urban development with increasingly dense cities and a high proportion of impermeable surface materials. The importance of intraspecific variation needs to be better acknowledged in this context, since poor matching of trees and the local climate and growing conditions can lead to extensive loss of valuable trees. By using the right genetic plant material for the challenging urban environments, a more resilient tree population with a greater diversity and higher capacity for delivering ecosystem services can be gained. Here, we wish to discuss the need to consider intraspecific variation when planning resilient tree populations for urban environments and how seed banks and botanical garden play important roles in efforts to improve the matching of genetic plant material for future environmental challenges. Strategies to enrich urban tree diversity and increase resilience are outlined

Comparison of cellular responses to TGF-β1 and BMP-2 between healthy and torn tendons

Background: Tendons heal by fibrotic repair, increasing the likelihood of reinjury. Animal tendon injury and overuse models have identified transforming growth factor beta (TGF-β) and bone morphogenetic proteins (BMPs) as growth factors actively involved in the development of fibrosis, by mediating extracellular matrix synthesis and cell differentiation. Purpose: To understand how TGF-β and BMPs contribute to fibrotic processes using tendon-derived cells isolated from healthy and diseased human tendons. Study Design: Controlled laboratory study. Methods: Tendon-derived cells were isolated from patients with a chronic rotator cuff tendon tear (large to massive, diseased) and healthy hamstring tendons of patients undergoing anterior cruciate ligament repair. Isolated cells were incubated with TGF-β1 (10 ng/mL) or BMP-2 (100 ng/mL) for 3 days. Gene expression was measured by real-time quantitative polymerase chain reaction. Cell signaling pathway activation was determined by Western blotting. Results: TGF-β1 treatment induced ACAN mRNA expression in both cell types but less in the diseased compared with healthy cells (P < .05). BMP-2 treatment induced BGN mRNA expression in healthy but not diseased cells (P < .01). In the diseased cells, TGF-β1 treatment induced increased ACTA2 mRNA expression (P < .01) and increased small mothers against decapentaplegic (SMAD) signaling (P < .05) compared with those of healthy cells. Moreover, BMP-2 treatment induced ACTA2 mRNA expression in the diseased cells only (P < .05). Conclusion: Diseased tendon–derived cells show reduced expression of the proteoglycans aggrecan and biglycan in response to TGF-β1 and BMP-2 treatments. These same treatments induced enhanced fibrotic differentiation and canonical SMAD cell signaling in diseased compared with healthy cells. Clinical Relevance: Findings from this study suggest that diseased tendon–derived cells respond differently than healthy cells in the presence of TGF-β1 and BMP-2. The altered responses of diseased cells may influence fibrotic repair processes during tendon healing

Using botanic gardens and arboreta to help identify urban trees for the future

Societal Impact StatementDiversification of urban forests is essential to enhance their resilience to future biotic threats as well as those posed by a changing climate. Arboreta and botanic gardens host a wide range of plant material that can be evaluated to inform tree selection policy. This study demonstrates that plant functional traits, such as the water potential at leaf turgor loss, can be highly instructive when developing evidence-based recommendations for urban environments. However, if botanic collections are to fulfil a critical role in understanding plant response to environment, they should not be managed solely as visitor attractions but must have scientific objectives at the forefront of management policy.SummaryArboreta and botanic gardens host a multitude of species that can be utilized in research focused on improving diversity within urban forests. Higher tree species diversity will enhance the resilience of urban forests to abiotic and biotic threats and help deliver strategies that foster sustainable communities. Consequently, this study aims to demonstrate the value of botanic collections as a resource for research into tree species selection for more resilient urban landscapes. As water stress is a major constraint for trees in urban environments, understanding the drought tolerance of species is essential for urban tree selection. This study evaluates a key functional trait relating to drought tolerance. Using vapor pressure osmometry, the water potential at leaf turgor loss was evaluated for 96 species using plant material from seven botanic collections in North America and Europe. Leaf turgor loss contrasted widely in the temperate deciduous trees evaluated and, in summer, ranged from -1.7 MPa to -3.9 MPa. Significant differences in drought tolerance were also apparent across genera and closely related cultivars. Osmotic adjustment was shown to be a major physiological factor driving leaf turgor loss. A meta-analysis also demonstrated that leaf turgor loss was closely related to a drought-tolerance scale based on observations of tree performance under drought. Arboreta and botanic collections can play a vital role in the evaluation of plant material for urban environments, provided they are curated with scientific objectives at the forefront of management policy and are not managed purely as visitor attractions