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"Smith, Benjamin"
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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
CD22 blockade restores homeostatic microglial phagocytosis in ageing brains
Microglia maintain homeostasis in the central nervous system through phagocytic clearance of protein aggregates and cellular debris. This function deteriorates during ageing and neurodegenerative disease, concomitant with cognitive decline. However, the mechanisms of impaired microglial homeostatic function and the cognitive effects of restoring this function remain unknown. We combined CRISPR–Cas9 knockout screens with RNA sequencing analysis to discover age-related genetic modifiers of microglial phagocytosis. These screens identified CD22, a canonical B cell receptor, as a negative regulator of phagocytosis that is upregulated on aged microglia. CD22 mediates the anti-phagocytic effect of α2,6-linked sialic acid, and inhibition of CD22 promotes the clearance of myelin debris, amyloid-β oligomers and α-synuclein fibrils in vivo. Long-term central nervous system delivery of an antibody that blocks CD22 function reprograms microglia towards a homeostatic transcriptional state and improves cognitive function in aged mice. These findings elucidate a mechanism of age-related microglial impairment and a strategy to restore homeostasis in the ageing brain.
CD22 inhibits microglial phagocytosis in the ageing brain, and treatment with a CD22-blocking antibody restores microglial homeostasis and cognitive function in ageing mice.
Journal Article
Chronic obstructive pulmonary disease
Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity, mortality, and health-care use worldwide. COPD is caused by exposure to inhaled noxious particles, notably tobacco smoke and pollutants. However, the broad range of factors that increase the risk of development and progression of COPD throughout the life course are increasingly being recognised. Innovations in omics and imaging techniques have provided greater insight into disease pathobiology, which might result in advances in COPD prevention, diagnosis, and treatment. Although few novel treatments have been approved for COPD in the past 5 years, advances have been made in targeting existing therapies to specific subpopulations using new biomarker-based strategies. Additionally, COVID-19 has undeniably affected individuals with COPD, who are not only at higher risk for severe disease manifestations than healthy individuals but also negatively affected by interruptions in health-care delivery and social isolation. This Seminar reviews COPD with an emphasis on recent advances in epidemiology, pathophysiology, imaging, diagnosis, and treatment.
Journal Article
Incidence and prevalence of patellofemoral pain: A systematic review and meta-analysis
Patellofemoral pain is considered one of the most common forms of knee pain, affecting adults, adolescents, and physically active populations. Inconsistencies in reported incidence and prevalence exist and in relation to the allocation of healthcare and research funding, there is a clear need to accurately understand the epidemiology of patellofemoral pain.
An electronic database search was conducted, as well as grey literature databases, from inception to June 2017. Two authors independently selected studies, extracted data and appraised methodological quality. If heterogeneous, data were analysed descriptively. Where studies were homogeneous, data were pooled through a meta-analysis.
23 studies were included. Annual prevalence for patellofemoral pain in the general population was reported as 22.7%, and adolescents as 28.9%. Incidence rates in military recruits ranged from 9.7-571.4/1,000 person-years, amateur runners in the general population at 1080.5/1,000 person-years and adolescents amateur athletes 5.1%-14.9% over 1 season. One study reported point prevalence within military populations as 13.5%. The pooled estimate for point prevalence in adolescents was 7.2% (95% Confidence Interval: 6.3%-8.3%), and in female only adolescent athletes was 22.7% (95% Confidence Interval 17.4%-28.0%).
This review demonstrates high incidence and prevalence levels for patellofemoral pain. Within the context of this, and poor long term prognosis and high disability levels, PFP should be an urgent research priority.
CRD42016038870.
Journal Article
Marine Ice Sheet Collapse Potentially Under Way for the Thwaites Glacier Basin, West Antarctica
Resting atop a deep marine basin, the West Antarctic Ice Sheet has long been considered prone to instability. Using a numerical model, we investigated the sensitivity of Thwaites Glacier to ocean melt and whether its unstable retreat is already under way. Our model reproduces observed losses when forced with ocean melt comparable to estimates. Simulated losses are moderate (<0.25 mm per year at sea level) over the 21st century but generally increase thereafter. Except possibly for the lowest-melt scenario, the simulations indicate that early-stage collapse has begun. Less certain is the time scale, with the onset of rapid (>1 mm per year of sea-level rise) collapse in the different simulations within the range of 200 to 900 years.
Journal Article