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.
We report a GWAS of alcohol dependence (AD) in European-American (EA) and African-American (AA) populations, with replication in independent samples of EAs, AAs and Germans. Our sample for discovery ...and replication was 16 087 subjects, the largest sample for AD GWAS to date. Numerous genome-wide significant (GWS) associations were identified, many novel. Most associations were population specific, but in several cases were GWS in EAs and AAs for different SNPs at the same locus,showing biological convergence across populations. We confirmed well-known risk loci mapped to alcohol-metabolizing enzyme genes, notably ADH1B (EAs: Arg48His, P=1.17 × 10(-31); AAs: Arg369Cys, P=6.33 × 10(-17)) and ADH1C in AAs (Thr151Thr, P=4.94 × 10(-10)), and identified novel risk loci mapping to the ADH gene cluster on chromosome 4 and extending centromerically beyond it to include GWS associations at LOC100507053 in AAs (P=2.63 × 10(-11)), PDLIM5 in EAs (P=2.01 × 10(-8)), and METAP in AAs (P=3.35 × 10(-8)). We also identified a novel GWS association (1.17 × 10(-10)) mapped to chromosome 2 at rs1437396, between MTIF2 and CCDC88A, across all of the EA and AA cohorts, with supportive gene expression evidence, and population-specific GWS for markers on chromosomes 5, 9 and 19. Several of the novel associations implicate direct involvement of, or interaction with, genes previously identified as schizophrenia risk loci. Confirmation of known AD risk loci supports the overall validity of the study; the novel loci are worthy of genetic and biological follow-up. The findings support a convergence of risk genes (but not necessarily risk alleles) between populations, and, to a lesser extent, between psychiatric traits.
We report measurements of ambient amines and ammonia with a fast response chemical ionization mass spectrometer (CIMS) in a southeastern US forest and a moderately polluted midwestern site during the ...summer. At the forest site, mostly C3-amines (from pptv to tens of pptv) and ammonia (up to 2 ppbv) were detected, and they both showed temperature dependencies. Aerosol-phase amines measured thermal-desorption chemical ionization mass spectrometer (TDCIMS) showed a higher mass fraction in the evening with cooler temperatures and lower in the afternoon with warmer temperatures, a trend opposite to the gas-phase amines. Concentrations of aerosol-phase primary amines measured with Fourier transform infrared spectroscopy (FTIR) from micron and submicron particles were 2 orders of magnitude higher than the gas-phase amines. These results indicate that gas to particle conversion is one of the major processes that control the ambient amine concentrations at this forest site. Temperature dependencies of C3-amines and ammonia also imply reversible processes of evaporation of these nitrogen-containing compounds from soil surfaces in daytime and deposition to soil surfaces at nighttime. During the transported biomass burning plume events, various amines (C1-C6) appeared at the pptv level, indicating that biomass burning is a substantial source of amines in the southeastern US. At the moderately polluted Kent site, there were higher concentrations of C1- to C6-amines (pptv to tens of pptv) and ammonia (up to 6 ppbv). C1- to C3-amines and ammonia were well correlated with the ambient temperature. C4- to C6-amines showed frequent spikes during the nighttime, suggesting that they were emitted from local sources. These abundant amines and ammonia may in part explain the frequent new particle formation events reported from Kent. Higher amine concentrations measured at the polluted site than at the rural forested site highlight the importance of constraining anthropogenic emission sources of amines.
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.
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.
This paper is the second in a pair of papers presenting data release 1 (DR1) of the Herschel Astrophysical Terahertz Large Area Survey (H-ATLAS), the largest single open-time key project carried out ...with the Herschel
Space Observatory. The H-ATLAS is a wide-area imaging survey carried out in five photometric bands at 100, 160, 250, 350 and 500 μm covering a total area of 600 deg2. In this paper, we describe the identification of optical counterparts to submillimetre sources in DR1, comprising an area of 161 deg2 over three equatorial fields of roughly 12 × 4.5 deg centred at 9h, 12h and 14
${^{\rm h}_{.}}$
5, respectively. Of all the H-ATLAS fields, the equatorial regions benefit from the greatest overlap with current multi-wavelength surveys spanning ultraviolet (UV) to mid-infrared regimes, as well as extensive spectroscopic coverage. We use a likelihood ratio technique to identify Sloan Digital Sky Survey counterparts at r < 22.4 for 250-μm-selected sources detected at ≥4σ (≈28 mJy). We find ‘reliable’ counterparts (reliability R ≥ 0.8) for 44 835 sources (39 per cent), with an estimated completeness of 73.0 per cent and contamination rate of 4.7 per cent. Using redshifts and multi-wavelength photometry from GAMA and other public catalogues, we show that H-ATLAS-selected galaxies at z < 0.5 span a wide range of optical colours, total infrared (IR) luminosities and IR/UV ratios, with no strong disposition towards mid-IR-classified active galactic nuclei in comparison with optical selection. The data described herein, together with all maps and catalogues described in the companion paper, are available from the H-ATLAS website at www.h-atlas.org.
The Observations and Modeling of the Green Ocean Amazon (GoAmazon2014/5) Experiment was carried out in the environs of Manaus, Brazil, in the central region of the Amazon basin for 2 years from ...1 January 2014 through 31 December 2015. The experiment focused on the complex interactions among vegetation, atmospheric chemistry, and aerosol production on the one hand and their connections to aerosols, clouds, and precipitation on the other. The objective was to understand and quantify these linked processes, first under natural conditions to obtain a baseline and second when altered by the effects of human activities. To this end, the pollution plume from the Manaus metropolis, superimposed on the background conditions of the central Amazon basin, served as a natural laboratory. The present paper, as the introduction to the special issue of GoAmazon2014/5, presents the context and motivation of the GoAmazon2014/5 Experiment. The nine research sites, including the characteristics and instrumentation of each site, are presented. The sites range from time point zero (T0) upwind of the pollution, to T1 in the midst of the pollution, to T2 just downwind of the pollution, to T3 furthest downwind of the pollution (70 km). In addition to the ground sites, a low-altitude G-159 Gulfstream I (G-1) observed the atmospheric boundary layer and low clouds, and a high-altitude Gulfstream G550 (HALO) operated in the free troposphere. During the 2-year experiment, two Intensive Operating Periods (IOP1 and IOP2) also took place that included additional specialized research instrumentation at the ground sites as well as flights of the two aircraft. GoAmazon2014/5 IOP1 was carried out from 1 February to 31 March 2014 in the wet season. GoAmazon2014/5 IOP2 was conducted from 15 August to 15 October 2014 in the dry season. The G-1 aircraft flew during both IOP1 and IOP2, and the HALO aircraft flew during IOP2. In the context of the Amazon basin, the two IOPs also correspond to the clean and biomass burning seasons, respectively. The Manaus plume is present year-round, and it is transported by prevailing northeasterly and easterly winds in the wet and dry seasons, respectively. This introduction also organizes information relevant to many papers in the special issue. Information is provided on the vehicle fleet, power plants, and industrial activities of Manaus. The mesoscale and synoptic meteorologies relevant to the two IOPs are presented. Regional and long-range transport of emissions during the two IOPs is discussed based on satellite observations across South America and Africa. Fire locations throughout the airshed are detailed. In conjunction with the context and motivation of GoAmazon2014/5 as presented in this introduction, research articles including thematic overview articles are anticipated in this special issue to describe the detailed results and findings of the GoAmazon2014/5 Experiment.
Key points
Blood glucose is an important fuel for endurance exercise. It can be derived from ingested carbohydrate, stored liver glycogen and newly synthesized glucose (gluconeogenesis).
We ...hypothesized that athletes habitually following a low carbohydrate high fat (LCHF) diet would have higher rates of gluconeogenesis during exercise compared to those who follow a mixed macronutrient diet.
We used stable isotope tracers to study glucose production kinetics during a 2 h ride in cyclists habituated to either a LCHF or mixed macronutrient diet.
The LCHF cyclists had lower rates of total glucose production and hepatic glycogenolysis but similar rates of gluconeogenesis compared to those on the mixed diet.
The LCHF cyclists did not compensate for reduced dietary carbohydrate availability by increasing glucose synthesis during exercise but rather adapted by altering whole body substrate utilization.
Endogenous glucose production (EGP) occurs via hepatic glycogenolysis (GLY) and gluconeogenesis (GNG) and plays an important role in maintaining euglycaemia. Rates of GLY and GNG increase during exercise in athletes following a mixed macronutrient diet; however, these processes have not been investigated in athletes following a low carbohydrate high fat (LCHF) diet. Therefore, we studied seven well‐trained male cyclists that were habituated to either a LCHF (7% carbohydrate, 72% fat, 21% protein) or a mixed diet (51% carbohydrate, 33% fat, 16% protein) for longer than 8 months. After an overnight fast, participants performed a 2 h laboratory ride at 72% of maximal oxygen consumption. Glucose kinetics were measured at rest and during the final 30 min of exercise by infusion of 6,6‐2H2‐glucose and the ingestion of 2H2O tracers. Rates of EGP and GLY both at rest and during exercise were significantly lower in the LCHF group than the mixed diet group (Exercise EGP: LCHF, 6.0 ± 0.9 mg kg−1 min−1, Mixed, 7.8 ± 1.1 mg kg−1 min−1, P < 0.01; Exercise GLY: LCHF, 3.2 ± 0.7 mg kg−1 min−1, Mixed, 5.3 ± 0.9 mg kg−1 min−1, P < 0.01). Conversely, no difference was detected in rates of GNG between groups at rest or during exercise (Exercise: LCHF, 2.8 ± 0.4 mg kg−1 min−1, Mixed, 2.5 ± 0.3 mg kg−1 min−1, P = 0.15). We conclude that athletes on a LCHF diet do not compensate for reduced glucose availability via higher rates of glucose synthesis compared to athletes on a mixed diet. Instead, GNG remains relatively stable, whereas glucose oxidation and GLY are influenced by dietary factors.
Key points
Blood glucose is an important fuel for endurance exercise. It can be derived from ingested carbohydrate, stored liver glycogen and newly synthesized glucose (gluconeogenesis).
We hypothesized that athletes habitually following a low carbohydrate high fat (LCHF) diet would have higher rates of gluconeogenesis during exercise compared to those who follow a mixed macronutrient diet.
We used stable isotope tracers to study glucose production kinetics during a 2 h ride in cyclists habituated to either a LCHF or mixed macronutrient diet.
The LCHF cyclists had lower rates of total glucose production and hepatic glycogenolysis but similar rates of gluconeogenesis compared to those on the mixed diet.
The LCHF cyclists did not compensate for reduced dietary carbohydrate availability by increasing glucose synthesis during exercise but rather adapted by altering whole body substrate utilization.
Introduction Synthetic biology, as a research field, brings together molecular life scientists, computational biologists, and social scientists to (re)engineer biological systems toward societally ...desired goals. Alongside furthering their academic development, students participating in the competition develop a range of soft skills, including team organization, project management, scientific communication, fund raising, and advertising. Over the last decade, at WUR, we have led teams that have researched methods to, for example, protect banana trees from infection (http://2014.igem.org/Team:Wageningen_UR), solve colony collapse disorder of bee hives (http://2016.igem.org/Team:Wageningen_UR), develop on-the-spot blood diagnostic tools (https://2017.igem.org/Team:Wageningen_UR), eradicate widespread plant pathogens (https://2019.igem.org/Team:Wageningen_UR), and tackle gas emissions from cattle (https://2021.igem.org/Team:Wageningen_UR). Individual supervisors and team advisors need not be experts of all fields—life sciences, mathematic/statistical modeling, computer science, or social science—but, rather, the aim should be to create a coaching group that can provide support in each domain.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Benzodiazepines, often used to treat anxiety, insomnia, and other conditions, are prescribed more frequently to women than men, and emergency department visits and overdose deaths involving ...benzodiazepines have increased significantly among women in recent years. This study describes characteristics and trends associated with benzodiazepine exposures among women of reproductive age (15–49 years old) that were reported to United States poison control centers from 2004 through 2018. The National Poison Data System recorded 258,370 first-ranked benzodiazepine exposures among women 15–49 years old during the study period. More than one-half (56.9%) of exposures involved a single-substance and one-third (34.0%) occurred among women 20–29 years old. The majority were categorized as “intentional, suspected suicide” (73.2%) or “intentional” (12.9%). Exposures frequently resulted in admission to a psychiatric facility (20.6%), critical care unit (18.1%), or non-critical care unit (9.3%). Twenty percent of cases resulted in a serious medical outcome, including 205 deaths. The substantial percentage of benzodiazepine exposures among women of reproductive age that were intentional and associated with suicide attempts or suicide deaths indicate that increased prevention efforts are needed to address this issue.
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