Challenges in Characterizing the Environmental Fate and Effects of Carbon Nanotubes and Inorganic Nanomaterials in Aquatic Systems

The current lack of commonly used protocols for dispersion, characterization, and aquatic toxicity testing of nanomaterials (NMs) has resulted in inconsistent results, which make meaningful comparisons difficult. The need for standardized sample preparation procedures that allow the reproducible generation of relevant test conditions remains a key challenge for studies of the environmental fate and aquatic toxicity of NMs. Together with the further development of optimized and cost-effective analytical techniques for physicochemical characterization that depend on reproducible sample preparation, such methods have the potential to overcome the current uncertainties with regard to NM dispersion properties, effective dose, and particle dissolution. In this review, recent data available on the challenges are summarized, especially those associated with preparing and quantifying NM dispersions, determining NM uptake and accumulation in aquatic organisms, and the transformation of organic and inorganic NM in aquatic species. Additional limitations and challenges that are specific to certain types of NMs are highlighted. The release of highly persistent carbon nanotubes (CNTs) from nanocomposites is determined to be a potential source of environmental contamination. Furthermore, the role of NM dissolution and the contribution of ions versus particles to NM toxicity are discussed. A phenomenon of particular relevance for the environment is photoactivation of NMs. This is elucidated with regard to its consequences in complex aquatic ecosystems. Widespread implementation of standardized protocols alongside the consideration of phenomena associated with different life cycle stages of industrial products is crucial to the future establishment of NM environmental risk assessment.publishedVersio

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

No interactions between previously associated 2-hour glucose gene variants and physical activity or BMI on 2-hour glucose levels.

Gene-lifestyle interactions have been suggested to contribute to the development of type 2 diabetes. Glucose levels 2 h after a standard 75-g glucose challenge are used to diagnose diabetes and are associated with both genetic and lifestyle factors. However, whether these factors interact to determine 2-h glucose levels is unknown. We meta-analyzed single nucleotide polymorphism (SNP) × BMI and SNP × physical activity (PA) interaction regression models for five SNPs previously associated with 2-h glucose levels from up to 22 studies comprising 54,884 individuals without diabetes. PA levels were dichotomized, with individuals below the first quintile classified as inactive (20%) and the remainder as active (80%). BMI was considered a continuous trait. Inactive individuals had higher 2-h glucose levels than active individuals (β = 0.22 mmol/L [95% CI 0.13-0.31], P = 1.63 × 10(-6)). All SNPs were associated with 2-h glucose (β = 0.06-0.12 mmol/allele, P ≤ 1.53 × 10(-7)), but no significant interactions were found with PA (P > 0.18) or BMI (P ≥ 0.04). In this large study of gene-lifestyle interaction, we observed no interactions between genetic and lifestyle factors, both of which were associated with 2-h glucose. It is perhaps unlikely that top loci from genome-wide association studies will exhibit strong subgroup-specific effects, and may not, therefore, make the best candidates for the study of interactions

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

A genome-wide association search for type 2 diabetes genes in African Americans.

African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations

Assessment of pyloric sphincter physiology after Ivor-Lewis esophagectomy using an endoluminal functional lumen imaging probe

Objective of the study The most common functional complication after Ivor-Lewis esophagectomy is the delayed emptying of the gastric conduit (DGCE) for which several diagnostic tools are available, e.g. chest X-ray, upper esophagogastroduodenoscopy (EGD) and water-soluble contrast radiogram. However, none of these diagnostic tools evaluate the pylorus itself. Our study demonstrates the successful measurement of pyloric distensibility in patients with DGCE after esophagectomy and in those without it. Methods and procedures Between May 2021 and October 2021, we performed a retrospective single-centre study of all patients who had an oncological Ivor-Lewis esophagectomy and underwent our post-surgery follow-up programme with surveillance endoscopies and computed tomography scans. EndoFlip (TM) was used to perform measurements of the pylorus under endoscopic control, and distensibility was measured at 40 ml, 45 ml and 50 ml balloon filling. Results We included 70 patients, and EndoFlip (TM) measurement was feasible in all patients. Successful application of EndoFlip (TM) was achieved in all interventions (n = 70, 100%). 51 patients showed a normal postoperative course, whereas 19 patients suffered from DGCE. Distensibility proved to be smaller in patients with symptoms of DGCE compared to asymptomatic patients. For 40 ml, 45 ml and 50 ml, the mean distensibility was 6.4 vs 10.1, 5.7 vs 7.9 and 4.5 vs 6.3 mm(2)/mmHg. The differences were significant for all three balloon fillings. No severe EndoFlip (TM) treatment-related adverse events occurred. Conclusion Measurement with EndoFlip (TM) is a safe and technically feasible endoscopic option for measuring the distensibility of the pylorus. Our study shows that the distensibility in asymptomatic patients after esophagectomy is significantly higher than that in patients suffering from DGCE. However, more studies need to be conducted to demonstrate the general use of EndoFlip (TM) measurement of the pylorus after esophagectomy

YB-1 Interferes with TNFα-TNFR Binding and Modulates Progranulin-Mediated Inhibition of TNFα Signaling.

Inflammation and an influx of macrophages are common elements in many diseases. Among pro-inflammatory cytokines, tumor necrosis factor α (TNFα) plays a central role by amplifying the cytokine network. Progranulin (PGRN) is a growth factor that binds to TNF receptors and interferes with TNFα-mediated signaling. Extracellular PGRN is processed into granulins by proteases released from immune cells. PGRN exerts anti-inflammatory effects, whereas granulins are pro-inflammatory. The factors coordinating these ambivalent functions remain unclear. In our study, we identify Y-box binding protein-1 (YB-1) as a candidate for this immune-modulating activity. Using a yeast-2-hybrid assay with YB-1 protein as bait, clones encoding for progranulin were selected using stringent criteria for strong interaction. We demonstrate that at physiological concentrations, YB-1 interferes with the binding of TNFα to its receptors in a dose-dependent manner using a flow cytometry-based binding assay. We show that YB-1 in combination with progranulin interferes with TNFα-mediated signaling, supporting the functionality with an NF-κB luciferase reporter assay. Together, we show that YB-1 displays immunomodulating functions by affecting the binding of TNFα to its receptors and influencing TNFα-mediated signaling via its interaction with progranulin

YB-1 Interferes with TNF–TNFR Binding and Modulates Progranulin-Mediated Inhibition of TNF Signaling

Inflammation and an influx of macrophages are common elements in many diseases. Among pro-inflammatory cytokines, tumor necrosis factor (TNF) plays a central role by amplifying the cytokine network. Progranulin (PGRN) is a growth factor that binds to TNF receptors and interferes with TNF-mediated signaling. Extracellular PGRN is processed into granulins by proteases released from immune cells. PGRN exerts anti-inflammatory effects, whereas granulins are pro-inflammatory. The factors coordinating these ambivalent functions remain unclear. In our study, we identify Y-box binding protein-1 (YB-1) as a candidate for this immune-modulating activity. Using a yeast-2-hybrid assay with YB-1 protein as bait, clones encoding for progranulin were selected using stringent criteria for strong interaction. We demonstrate that at physiological concentrations, YB-1 interferes with the binding of TNF to its receptors in a dose-dependent manner using a flow cytometry-based binding assay. We show that YB-1 in combination with progranulin interferes with TNF-mediated signaling, supporting the functionality with an NF-B luciferase reporter assay. Together, we show that YB-1 displays immunomodulating functions by affecting the binding of TNF to its receptors and influencing TNF-mediated signaling via its interaction with progranulin

YB-1 Interferes with TNF–TNFR Binding and Modulates Progranulin-Mediated Inhibition of TNF Signaling

Inflammation and an influx of macrophages are common elements in many diseases. Among pro-inflammatory cytokines, tumor necrosis factor (TNF) plays a central role by amplifying the cytokine network. Progranulin (PGRN) is a growth factor that binds to TNF receptors and interferes with TNF-mediated signaling. Extracellular PGRN is processed into granulins by proteases released from immune cells. PGRN exerts anti-inflammatory effects, whereas granulins are pro-inflammatory. The factors coordinating these ambivalent functions remain unclear. In our study, we identify Y-box binding protein-1 (YB-1) as a candidate for this immune-modulating activity. Using a yeast-2-hybrid assay with YB-1 protein as bait, clones encoding for progranulin were selected using stringent criteria for strong interaction. We demonstrate that at physiological concentrations, YB-1 interferes with the binding of TNF to its receptors in a dose-dependent manner using a flow cytometry-based binding assay. We show that YB-1 in combination with progranulin interferes with TNF-mediated signaling, supporting the functionality with an NF-B luciferase reporter assay. Together, we show that YB-1 displays immunomodulating functions by affecting the binding of TNF to its receptors and influencing TNF-mediated signaling via its interaction with progranulin