Detection of cellular senescence is important not only in the study of senescence in various biological systems, but also in various practical applications such as image-guided surgical removal of ...senescent cells, as well as the monitoring of drug-responsiveness during cancer therapies. Due to the lack of suitable imaging probes for senescence detection, particularly in living subjects, we have developed an activatable near-infrared (NIR) molecular probe with far-red excitation, NIR emission, and high "turn-on" ratio upon senescence-associated β-galactosidase (SABG) activation. We present here the first successful demonstration of NIR imaging of DNA damage-induced senescence both in vitro and in human tumor xenograft models.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Heparanase (HPA) is a critical enzyme involved in the remodeling of the extracellular matrix (ECM), and its elevated expression has been linked with diseases such as various types of cancer and ...inflammation. The detection of heparanase enzymatic activity holds tremendous value in the study of the cellular microenvironment, and search of molecular therapeutics targeting heparanase, however, no structurally defined probes are available for the detection of heparanase activity. Here we present the development of the first ultrasensitive fluorogenic small-molecule probe for heparanase enzymatic activity
via
tuning the electronic effect of the substrate. The probe exhibits a 756-fold fluorescence turn-on response in the presence of human heparanase, allowing one-step detection of heparanase activity in real-time with a picomolar detection limit. The high sensitivity and robustness of the probe are exemplified in a high-throughput screening assay for heparanase inhibitors.
Heparanase, a critical enzyme involved in the remodeling of the extracellular matrix, activates a disaccharide probe
HADP
to give a strong fluorescence signal.
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IJS, KILJ, NUK, UL, UM, UPUK
The incidence of inflammatory bowel disease (IBD) is increasing internationally, particularly in nations with historically low rates. Previous reports of the epidemiology of pediatric-onset IBD ...identified a paucity of data. We systematically reviewed the global trends in incidence and prevalence of IBD diagnosed in individuals <21 years old over the first 2 decades of the 21st century.
We systematically reviewed studies indexed in MEDLINE, EMBASE, Airiti Library, and SciELO from January 2010 to February 2020 to identify population-based studies reporting the incidence and/or prevalence of IBD, Crohn’s disease, ulcerative colitis, and/or IBD-unclassified. Data from studies published before 2000 were derived from a previously published systematic review. We described the geographic distribution and trends in children of all ages and limiting to very early onset (VEO) IBD.
A total of 131 studies from 48 countries were included. The incidence and prevalence of pediatric-onset IBD is highest in Northern Europe and North America and lowest in Southern Europe, Asia, and the Middle East. Among studies evaluating trends over time, most (31 of 37, 84%) studies reported significant increases in incidence and all (7 of 7) reported significant increases in prevalence. Data on the incidence and prevalence of VEO-IBD are limited to countries with historically high rates of IBD. Time trends in the incidence of VEO-IBD were visually heterogeneous.
Rates of pediatric-onset IBD continue to rise around the world and data are emerging from regions where it was not previously reported; however, there remains a paucity of data on VEO-IBD and on pediatric IBD from developing and recently developed countries.
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Inflammatory bowel disease is becoming increasingly common in children around the world. However, there are still many countries where estimates of the number of children diagnosed with inflammatory bowel disease are not available.
Radium isotopes are produced in sediments via the decay of thorium isotopes and are generally soluble in seawater. As such, isotopes of the radium quartet (224Ra, 223Ra, 228Ra, 226Ra) have been used ...as tracers of ocean boundary inputs and mixing processes. We measured radium isotopes on the US GEOTRACES North Atlantic cruises in 2010 and 2011, which crossed a number of key ocean boundary features including the Mediterranean outflow, the Mauritanian upwelling and oxygen minimum zones (OMZ) along western Africa, a hydrothermal plume over the mid-Atlantic Ridge (MAR), and the broad continental margin of the north-eastern United States. Radium isotope features at these locations are discussed in the context of their potential to quantify fluxes of trace elements and isotopes (TEIs) from common sources. Notable observations include: (1) a Mediterranean outflow spreading rate of 0.52–0.60cm/s derived from 228Ra, (2) evidence of substantial sediment–water interaction in the benthic boundary layer along the OMZ, (3) decoupling between 223Ra and the other Ra isotope sources over the MAR, and (4) significant continental inputs (e.g. submarine groundwater discharge—SGD) in the western Atlantic. Lastly, 228Ra inventories have remained constant over the past 30years, which suggests that SGD is steady-state for the North Atlantic on decadal time scales.
•Benthic radium isotope fluxes are highest beneath the west African upwelling zone.•Mediterranean outflow transport rate of 0.5–0.8cm/s quantified using 228Ra•Enhanced 223Ra fluxes from Mid-Atlantic Ridge sediments•Elevated radium isotopes observed in a neutrally buoyant hydrothermal plume•Atlantic Ocean submarine groundwater discharge is at steady-state over 40years.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Fecal calprotectin (FC) is increasingly used during the diagnosis of inflammatory bowel disease (IBD), outperforming blood markers during investigation in children. Tests that reduce endoscopy rates ...in children with suspected gut inflammation would be beneficial. We aimed to determine the usefulness of FC in children undergoing their primary investigation for suspected IBD by systematic review and meta-analysis.
An electronic search was performed with keywords relating to IBD and calprotectin in multiple electronic resources from 1946 to May 2012; a hand search was also performed. Inclusion criteria were studies that reported FC levels before the endoscopic investigation of IBD in patients less than 18 years old. Studies were evaluated using the Quality Assessment of Diagnostic Accuracy Studies tool, and a meta-analysis was performed using a hierarchical summary receiver operating curve model.
Eight papers met the inclusion criteria (six prospective and two retrospective case-control studies); methodological quality was determined in detail for each study. The 8 studies presented FC levels at presentation in 715 patients, 394 pediatric IBD patients, and 321 non-IBD controls. Pooled sensitivity and specificity for the diagnostic utility of FC during the investigation of suspected pediatric IBD were 0.978 (95% confidence interval (CI), 0.947-0.996) and 0.682 (95% CI, 0.502-0.863), respectively; the positive and negative likelihood ratios were 3.07 and 0.03, respectively.
FC has a high sensitivity and a modest specificity during the diagnosis of suspected pediatric IBD. Further work is required to determine the effect of FC levels on endoscopy rates and its role during the re-evaluation of those with confirmed disease.
Radium‐226(226Ra) and barium (Ba) exhibit similar chemical behaviors and distributions in the marine environment, serving as valuable tracers of water masses, ocean mixing, and productivity. Despite ...their similar distributions, these elements originate from distinct sources and undergo disparate biogeochemical cycles, which might complicate the use of these tracers. In this study, we investigate these processes by analyzing a full‐depth ocean section of 226Ra activities (T1/2 = 1,600 years) and barium concentrations obtained from samples collected along the US GEOTRACES GP15 Pacific Meridional Transect during September–November 2018, spanning from Alaska to Tahiti. We find that surface waters possess low levels of 226Ra and Ba due to export of sinking particulates, surpassing inputs from the continental margins. In contrast, deep waters have higher 226Ra activities and Ba concentrations due to inputs from particle regeneration and sedimentary sources, with 226Ra inputs primarily resulting from the decay of 230Th in sediments. Further, dissolved 226Ra and Ba exhibit a strong correlation along the GP15 section. To elucidate the drivers of the correlation, we used a water mass analysis, enabling us to quantify the influence of water mass mixing relative to non‐conservative processes. While a significant fraction of each element's distribution can be explained by conservative mixing, a considerable fraction cannot. The balance is driven using non‐conservative processes, such as sedimentary, rivers, or hydrothermal inputs, uptake and export by particles, and particle remineralization. Our study demonstrates the utility of 226Ra and Ba as valuable biogeochemical tracers for understanding ocean processes, while shedding light on conservative and myriad non‐conservative processes that shape their respective distributions.
Key Points
Water mass analysis shows significant shallow deficits and deep excesses of dissolved 226Ra and Ba in the Pacific Ocean along the GP15
Shallow deficits seem driven by BaSO4 precipitation, deep excesses reflect benthic inputs that are more significant for 226Ra than for Ba
Budgets suggest that regional barium fluxes nearly balance, and the Pacific is likely a significant source of radium‐226 to the global ocean
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Genetic association studies have identified 215 risk loci for inflammatory bowel disease, thereby uncovering fundamental aspects of its molecular biology. We performed a genome-wide association study ...of 25,305 individuals and conducted a meta-analysis with published summary statistics, yielding a total sample size of 59,957 subjects. We identified 25 new susceptibility loci, 3 of which contain integrin genes that encode proteins in pathways that have been identified as important therapeutic targets in inflammatory bowel disease. The associated variants are correlated with expression changes in response to immune stimulus at two of these genes (ITGA4 and ITGB8) and at previously implicated loci (ITGAL and ICAM1). In all four cases, the expression-increasing allele also increases disease risk. We also identified likely causal missense variants in a gene implicated in primary immune deficiency, PLCG2, and a negative regulator of inflammation, SLAMF8. Our results demonstrate that new associations at common variants continue to identify genes relevant to therapeutic target identification and prioritization.
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IJS, NUK, SBMB, UL, UM, UPUK
IBD prevalence is estimated to be rising, but no detailed, recent UK data are available. The last reported prevalence estimate in the UK was 0.40% in 2003. We aimed to establish the current, and ...project future, prevalence in Lothian, Scotland.
We conducted an all-age multiparameter search strategy using inpatient IBD international classification of disease (ICD-10) coding (K50/51)(1997-2018), IBD pathology coding (1990-2018), primary and secondary care prescribing data (2009-2018) and a paediatric registry, (1997-2018) to identify 'possible' IBD cases up to 31/08/2018. Diagnoses were manually confirmed through electronic health record review as per Lennard-Jones/Porto criteria. Autoregressive integrated moving average (ARIMA) regression was applied to forecast prevalence to 01/08/2028.
In total, 24 601 possible IBD cases were identified of which 10 499 were true positives. The point prevalence for IBD in Lothian on 31/08/2018 was 784/100 000 (UC 432/100 000, Crohn's disease 284/100 000 and IBD unclassified (IBDU) 68/100 000). Capture-recapture methods identified an additional 427 'missed' cases (95% CI 383 to 477) resulting in a 'true' prevalence of 832/100 000 (95% CI 827 to 837).Prevalence increased by 4.3% per year between 2008 and 2018 (95% CI +3.7 to +4.9%, p<0.0001). ARIMA modelling projected a point prevalence on 01/08/2028 of 1.02% (95% CI 0.97% to 1.07%) that will affect an estimated 1.53% (95% CI 1.37% to 1.69%) of those >80 years of age.
We report a rigorously validated IBD cohort with all-age point prevalence on 31/08/2018 of 1 in 125, one of the highest worldwide.
Using radium (Ra) isotopes, we estimate that the average submarine groundwater discharge (SGD) flux (marine plus terrestrial groundwater) into the southwest Florida Shelf (SWFS) was 20 ± 10 × 10⁷ and ...18 ± 8 × 10⁷ m³ d−1 in July and October 2009, respectively. The terrestrial groundwater flux was the same order of magnitude as the local river discharge in July 2009. Shelf-water total alkalinity (TAlk) and dissolved inorganic carbon (DIC) concentrations could not be explained by river inputs alone, suggesting a groundwater source. We estimated SGD fluxes of TAlk and DIC using the SGD flux derived from a shelf-water 226Ra budget and TAlk and DIC concentration differences between the groundwater and seawater. These fluxes were also determined by the observed TAlk : 226Ra and DIC : 226Ra relationships in the shelf water, and the 226Ra flux sustained by SGD. These TAlk and DIC fluxes were 11–71 times more than the combined input of local rivers, suggesting that SGD was the dominant source of TAlk and DIC to the SWFS during 2009. SGD is an important component of the inorganic carbon budget for the coastal ocean.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NMLJ, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
•Both 239,240Pu and 137Cs remain elevated today at Bikini and Enewetak Atolls.•These sites remain a small long term source of Pu and Cs to the North Pacific.•About half of the Pu in the waters at ...Enewetak Lagoon originates near Runit Dome.•Only a small fraction of Pu and Cs from Runit Dome is delivered via groundwater.
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We made an assessment of the levels of radionuclides in the ocean waters, seafloor and groundwater at Bikini and Enewetak Atolls where the US conducted nuclear weapons tests in the 1940's and 50's. This included the first estimates of submarine groundwater discharge (SGD) derived from radium isotopes that can be used here to calculate radionuclide fluxes in to the lagoon waters. While there is significant variability between sites and sample types, levels of plutonium (239,240Pu) remain several orders of magnitude higher in lagoon seawater and sediments than what is found in rest of the world's oceans. In contrast, levels of cesium-137 (137Cs) while relatively elevated in brackish groundwater are only slightly higher in the lagoon water relative to North Pacific surface waters. Of special interest was the Runit dome, a nuclear waste repository created in the 1970's within the Enewetak Atoll. Low seawater ratios of 240Pu/239Pu suggest that this area is the source of about half of the Pu in the Enewetak lagoon water column, yet radium isotopes suggest that SGD from below the dome is not a significant Pu source. SGD fluxes of Pu and Cs at Bikini were also relatively low. Thus radioactivity associated with seafloor sediments remains the largest source and long term repository for radioactive contamination. Overall, Bikini and Enewetak Atolls are an ongoing source of Pu and Cs to the North Pacific, but at annual rates that are orders of magnitude smaller than delivered via close-in fallout to the same area.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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