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.
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.
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.
That natural resources can be a curse as well as a blessing is almost a truism in political analysis. In many late-developing countries, the "resource curse" theory predicts, the exploitation of ...valuable resources will not result in stable, prosperous states but rather in their opposite. Petroleum deposits, for example, may generate so much income that rulers will have little need to establish efficient, tax-extracting bureaucracies, leading to shallow, poorly functioning administrations that remain at the mercy of the world market for oil. Alternatively, resources may be geographically concentrated, thereby intensifying regional, ethnic, or other divisive tensions.
InHard Times in the Land of Plenty, Benjamin Smith deciphers the paradox of the resource curse and questions its inevitability through an innovative comparison of the experiences of Iran and Indonesia. These two populous, oil-rich countries saw profoundly different changes in their fortunes in the period 1960-1980. Focusing on the roles of state actors and organized opposition in using oil revenues, Smith finds that the effects of oil wealth on politics and on regime durability vary according to the circumstances under which oil exports became a major part of a country's economy. The presence of natural resources is, he argues, a political opportunity rather than simply a structural variable.
Drawing on extensive primary research in Iran and Indonesia and quantitative research on nineteen other oil-rich developing countries, Smith challenges us to reconsider resource wealth in late-developing countries, not as a simple curse or blessing, but instead as a tremendously flexible source of both political resources and potential complications.
Chronic obstructive pulmonary disease Christenson, Stephanie A; Smith, Benjamin M; Bafadhel, Mona ...
The Lancet (British edition),
06/2022, Letnik:
399, Številka:
10342
Journal Article
Recenzirano
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.
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.
This article examines contrasting claims made by scholars of oil and politics that oil wealth either tends (1) to undermine regime durability or (2) to enhance it. Using cross-sectional time-series ...data from 107 developing states between 1960 and 1999, I test the effects of oil wealth on regime failure, political protests, and civil war. I find that oil wealth is robustly associated with increased regime durability, even when controlling for repression, and with lower likelihoods of civil war and antistate protest. I also find that neither the boom nor bust periods exerted any significant effect on regime durability in the states most dependent on exports, even while those states saw more protests during the bust. In short, oil wealth has generally increased the durability of regimes, and repression does not account for this effect. Future research focused on the origins of robust coalitions in oil-rich states is most likely to provide fruitful explanations to this puzzle.
Three-Dimensional Speckle Tracking of the Right Ventricle Smith, Benjamin C.F., MSc; Dobson, Gary, MDCM, MSc; Dawson, David, MSc ...
Journal of the American College of Cardiology,
07/2014, Letnik:
64, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Abstract Background Quantitative assessment of right ventricular (RV) systolic function largely depends on right ventricular ejection fraction (RVEF). Three-dimensional speckle tracking (3D-ST) has ...been used extensively to quantify left ventricular function, but its value for RV assessment has not been established. Objectives This study sought to prospectively assess whether 3D-ST would be a reliable method for assessing RV systolic function and whether strain values were associated with survival. Methods Comprehensive 2-dimensional echocardiographic assessment, 3D-ST of the RV free wall, and measurement of RVEF was performed in 97 consecutive patients with established pulmonary hypertension (PHT) (RVEF 31.4 ± 9.6%, right ventricular systolic pressure RVSP 76.5 ± 26.2 mm Hg) and 60 healthy volunteers (RVEF 43.8 ± 9.4%, RVSP 25.9 ± 4.3 mm Hg). Results Area strain (AS) (−24.3 ± 7.3 vs. −30.8 ± 7.2; p < 0.001), radial strain (23.2 ± 14.4 vs. 34.9 ± 18.2; p < 0.001), longitudinal strain (LS) (−15.5 ± 3.8 vs. −17.9 ± 4.4; p = 0.001), and circumferential strain (CS) (−12.2 ± 4.5 vs. −15.7 ± 6.1; p < 0.001) were all reduced in patients with PHT, compared with normal individuals. AS and CS strongly correlated to RVEF (r = 0.851, r = −0.711; p < 0.001). Systolic dyssynchrony index was greater in PHT (0.14 ± 0.06 vs. 0.11 ± 0.07; p = 0.003) and correlated to RVEF (r = −0.563, p < 0.001). AS (hazard ratio HR: 3.49; 95% confidence interval CI: 1.21 to 7.07; p = 0.017), CS (HR: 4.17; 95% CI: 1.93 to 12.97; p < 0.001), LS (HR: 7.63; 95% CI: 1.76 to 10.27; p = 0.001), and RVEF (HR: 2.43; 95 CI: 1.00 to 5.92; p = 0.050) were significant determinants of all-cause mortality. Only AS (p = 0.029) and age (p = 0.087) were predictive of death after logistic regression analysis. Conclusions PHT patients have reduced RV strain patterns and more dyssynchronous ventricles compared with controls, which was relatable to clinical outcomes. AS best correlated with RVEF and provides prognostic information independent of other variables.
Glycans modify lipids and proteins to mediate inter- and intramolecular interactions across all domains of life. RNA is not thought to be a major target of glycosylation. Here, we challenge this view ...with evidence that mammals use RNA as a third scaffold for glycosylation. Using a battery of chemical and biochemical approaches, we found that conserved small noncoding RNAs bear sialylated glycans. These “glycoRNAs” were present in multiple cell types and mammalian species, in cultured cells, and in vivo. GlycoRNA assembly depends on canonical N-glycan biosynthetic machinery and results in structures enriched in sialic acid and fucose. Analysis of living cells revealed that the majority of glycoRNAs were present on the cell surface and can interact with anti-dsRNA antibodies and members of the Siglec receptor family. Collectively, these findings suggest the existence of a direct interface between RNA biology and glycobiology, and an expanded role for RNA in extracellular biology.
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•Synthetic, clickable sugars that label glycoproteins and glycolipids also label RNAs•RNA-glycan conjugates, glycoRNAs, are conserved, small, noncoding RNAs•GlycoRNAs possess N-glycans that are highly sialylated and fucosylated•GlycoRNAs are displayed on the cell surface and can bind Siglec receptors
Identification of stable mammalian RNAs decorated with glycan structures opens up a new dimension for regulatory control of RNA localization and function by post-transcriptional modification.
The disialoganglioside GD2 is overexpressed on several solid tumors, and monoclonal antibodies targeting GD2 have substantially improved outcomes for children with high-risk neuroblastoma. However, ...approximately 40% of patients with neuroblastoma still relapse, and anti-GD2 has not mediated significant clinical activity in any other GD2
malignancy. Macrophages are important mediators of anti-tumor immunity, but tumors resist macrophage phagocytosis through expression of the checkpoint molecule CD47, a so-called 'Don't eat me' signal. In this study, we establish potent synergy for the combination of anti-GD2 and anti-CD47 in syngeneic and xenograft mouse models of neuroblastoma, where the combination eradicates tumors, as well as osteosarcoma and small-cell lung cancer, where the combination significantly reduces tumor burden and extends survival. This synergy is driven by two GD2-specific factors that reorient the balance of macrophage activity. Ligation of GD2 on tumor cells (a) causes upregulation of surface calreticulin, a pro-phagocytic 'Eat me' signal that primes cells for removal and (b) interrupts the interaction of GD2 with its newly identified ligand, the inhibitory immunoreceptor Siglec-7. This work credentials the combination of anti-GD2 and anti-CD47 for clinical translation and suggests that CD47 blockade will be most efficacious in combination with monoclonal antibodies that alter additional pro- and anti-phagocytic signals within the tumor microenvironment.
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