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The clinical impact of glycobiology: targeting selectins, Siglecs and mammalian glycans
Carbohydrates — namely glycans — decorate every cell in the human body and most secreted proteins. Advances in genomics, glycoproteomics and tools from chemical biology have made glycobiology more tractable and understandable. Dysregulated glycosylation plays a major role in disease processes from immune evasion to cognition, sparking research that aims to target glycans for therapeutic benefit. The field is now poised for a boom in drug development. As a harbinger of this activity, glycobiology has already produced several drugs that have improved human health or are currently being translated to the clinic. Focusing on three areas — selectins, Siglecs and glycan-targeted antibodies — this Review aims to tell the stories behind therapies inspired by glycans and to outline how the lessons learned from these approaches are paving the way for future glycobiology-focused therapeutics.Numerous proteins and lipids are covered in glycans, which affects the way these molecules interact. In this Review, Smith and Bertozzi discuss therapies targeting proteins that recognize glycosylation, namely the selectins and Siglecs, as well as glycan-targeted antibodies that have entered the clinic or are in development. They provide their perspectives on the future of glycobiology.
Journal Article
Homocysteine-Lowering by B Vitamins Slows the Rate of Accelerated Brain Atrophy in Mild Cognitive Impairment: A Randomized Controlled Trial
An increased rate of brain atrophy is often observed in older subjects, in particular those who suffer from cognitive decline. Homocysteine is a risk factor for brain atrophy, cognitive impairment and dementia. Plasma concentrations of homocysteine can be lowered by dietary administration of B vitamins.
To determine whether supplementation with B vitamins that lower levels of plasma total homocysteine can slow the rate of brain atrophy in subjects with mild cognitive impairment in a randomised controlled trial (VITACOG, ISRCTN 94410159).
Single-center, randomized, double-blind controlled trial of high-dose folic acid, vitamins B(6) and B(12) in 271 individuals (of 646 screened) over 70 y old with mild cognitive impairment. A subset (187) volunteered to have cranial MRI scans at the start and finish of the study. Participants were randomly assigned to two groups of equal size, one treated with folic acid (0.8 mg/d), vitamin B(12) (0.5 mg/d) and vitamin B(6) (20 mg/d), the other with placebo; treatment was for 24 months. The main outcome measure was the change in the rate of atrophy of the whole brain assessed by serial volumetric MRI scans.
A total of 168 participants (85 in active treatment group; 83 receiving placebo) completed the MRI section of the trial. The mean rate of brain atrophy per year was 0.76% [95% CI, 0.63-0.90] in the active treatment group and 1.08% [0.94-1.22] in the placebo group (P = 0.001). The treatment response was related to baseline homocysteine levels: the rate of atrophy in participants with homocysteine >13 µmol/L was 53% lower in the active treatment group (P = 0.001). A greater rate of atrophy was associated with a lower final cognitive test scores. There was no difference in serious adverse events according to treatment category.
The accelerated rate of brain atrophy in elderly with mild cognitive impairment can be slowed by treatment with homocysteine-lowering B vitamins. Sixteen percent of those over 70 y old have mild cognitive impairment and half of these develop Alzheimer's disease. Since accelerated brain atrophy is a characteristic of subjects with mild cognitive impairment who convert to Alzheimer's disease, trials are needed to see if the same treatment will delay the development of Alzheimer's disease.
Controlled-Trials.com ISRCTN94410159.
Journal Article
Isolation, quarantine, social distancing and community containment: pivotal role for old-style public health measures in the novel coronavirus (2019-nCoV) outbreak
Public health measures were decisive in controlling the SARS epidemic in 2003. Isolation is the separation of ill persons from non-infected persons. Quarantine is movement restriction, often with fever surveillance, of contacts when it is not evident whether they have been infected but are not yet symptomatic or have not been infected. Community containment includes measures that range from increasing social distancing to community-wide quarantine. Whether these measures will be sufficient to control 2019-nCoV depends on addressing some unanswered questions.
Journal Article
River god
\"Ancient Egypt. Land of the Pharaohs. The Valley of the Kings lies ravaged by the war, drained of its lifeblood as weak men inherit the cherished crown. In the city of Thebes, at the Festival of Osiris, loyal subjects of the Pharaoh gather to pay homage to their leader. But Taita - a wise and formidably gifted eunuch slave - sees him only as a symbol of a kingdom's fading glory. Beside Taita stand his protégés: Lostris, daughter of Lord Intef, beautiful beyond her years ; and Tanus, proud young army officer, who has vowed to avenge the death - at Intef's and - of his father, and seize Lostris as his prize. Together they share a dream-to restore the majesty of the true Pharaoh of Pharaohs on the glittering banks of the Nile.\"--Page 4 of cover.
Book
Constructing a broadly inclusive seed plant phylogeny
Premise of the Study Large phylogenies can help shed light on macroevolutionary patterns that inform our understanding of fundamental processes that shape the tree of life. These phylogenies also serve as tools that facilitate other systematic, evolutionary, and ecological analyses. Here we combine genetic data from public repositories (GenBank) with phylogenetic data (Open Tree of Life project) to construct a dated phylogeny for seed plants. Methods We conducted a hierarchical clustering analysis of publicly available molecular data for major clades within the Spermatophyta. We constructed phylogenies of major clades, estimated divergence times, and incorporated data from the Open Tree of Life project, resulting in a seed plant phylogeny. We estimated diversification rates, excluding those taxa without molecular data. We also summarized topological uncertainty and data overlap for each major clade. Key Results The trees constructed for Spermatophyta consisted of 79,881 and 353,185 terminal taxa; the latter included the Open Tree of Life taxa for which we could not include molecular data from GenBank. The diversification analyses demonstrated nested patterns of rate shifts throughout the phylogeny. Data overlap and inference uncertainty show significant variation throughout and demonstrate the continued need for data collection across seed plants. Conclusions This study demonstrates a means for combining available resources to construct a dated phylogeny for plants. However, this approach is an early step and more developments are needed to add data, better incorporating underlying uncertainty, and improve resolution. The methods discussed here can also be applied to other major clades in the tree of life.
Journal Article
Exercise metabolism and adaptation in skeletal muscle
Viewing metabolism through the lens of exercise biology has proven an accessible and practical strategy to gain new insights into local and systemic metabolic regulation. Recent methodological developments have advanced understanding of the central role of skeletal muscle in many exercise-associated health benefits and have uncovered the molecular underpinnings driving adaptive responses to training regimens. In this Review, we provide a contemporary view of the metabolic flexibility and functional plasticity of skeletal muscle in response to exercise. First, we provide background on the macrostructure and ultrastructure of skeletal muscle fibres, highlighting the current understanding of sarcomeric networks and mitochondrial subpopulations. Next, we discuss acute exercise skeletal muscle metabolism and the signalling, transcriptional and epigenetic regulation of adaptations to exercise training. We address knowledge gaps throughout and propose future directions for the field. This Review contextualizes recent research of skeletal muscle exercise metabolism, framing further advances and translation into practice.Skeletal muscles show high metabolic flexibility and functional plasticity in their response to different exercise modalities. Recent findings have advanced our understanding of signalling, transcriptional and epigenetic mechanisms that regulate muscle adaptation to exercise and their impact on muscle physiology.
Journal Article