The effect of fructose feeding on intestinal triacylglycerol production and de novo fatty acid synthesis in humans

A high fructose intake exacerbates postprandial plasma triacylglycerol (TAG) concentration, an independent risk factor for cardiovascular disease, although it is unclear whether this is due to increased production or impaired clearance of triacylglycerol (TAG)-rich lipoproteins. We determined the in vivo acute effect of fructose on postprandial intestinal and hepatic lipoprotein TAG kinetics and de novo lipogenesis (DNL). Five overweight men were studied twice, 4 weeks apart. They consumed hourly mixed-nutrient drinks that were high-fructose (30% energy) or low-fructose (<2% energy) for 11 hours. Oral 2H2O was administered to measure fasting and postprandial DNL. Postprandial chylomicron (CM)-TAG and very low-density lipoprotein (VLDL)-TAG kinetics were measured with an intravenous bolus of [2H5]-glycerol. CM and VLDL were separated by their apolipoprotein B content using antibodies. Plasma TAG (P<0.005) and VLDL-TAG (P=0.003) were greater, and CM-TAG production rate (PR, P=0.046) and CM-TAG fractional catabolic rate (FCR, P=0.073) lower when high-fructose was consumed, with no differences in VLDL-TAG kinetics. Insulin was lower (P=0.005) and apoB48 (P=0.039), apoB100 (P=0.013) and NEFA (P=0.013) were higher after high-fructose. Postprandial hepatic fractional DNL was higher than intestinal fractional DNL with high-fructose (P=0.043) and low-fructose (P=0.043). Fructose consumption had no effect on the rate of intestinal or hepatic DNL. We provide the first measurement of the rate of intestinal DNL in humans. Lower CM-TAG PR and CM-TAG FCR with high-fructose consumption suggests lower clearance of CM, rather than elevated production, may contribute to elevated plasma TAG, possibly due to lower insulin-mediated stimulation of lipoprotein lipase

Novel Schizophrenia Risk Gene TCF4 Influences Verbal Learning and Memory Functioning in Schizophrenia Patients

Background: Recently, a role of the transcription factor 4 (TCF4) gene in schizophrenia has been reported in a large genome-wide association study. It has been hypothesized that TCF4 affects normal brain development and TCF4 has been related to different forms of neurodevelopmental disorders. Schizophrenia patients exhibit strong impairments of verbal declarative memory (VDM) functions. Thus, we hypothesized that the disease-associated C allele of the rs9960767 polymorphism of the TCF4 gene led to impaired VDM functioning in schizophrenia patients. Method: The TCF4 variant was genotyped in 401 schizophrenia patients. VDM functioning was measured using the Rey Auditory Verbal Learning Test (RAVLT). Results: Carriers of the C allele were less impaired in recognition compared to those carrying the AA genotype (13.76 vs. 13.06; p = 0.049). Moreover, a trend toward higher scores in patients with the risk allele was found for delayed recall (10.24 vs. 9.41; p = 0.088). The TCF4 genotype did not influence intelligence or RAVLT immediate recall or total verbal learning. Conclusion: VDM function is influenced by the TCF4 gene in schizophrenia patients. However, the elevated risk for schizophrenia is not conferred by TCF4-mediated VDM impairment. Copyright (C) 2011 S. Karger AG, Base

A Narrative Review of Chronic Kidney Disease in Clinical Practice: Current Challenges and Future Perspectives

Chronic kidney disease (CKD) is a complex disease which affects approximately 13% of the world's population. Over time, CKD can cause renal dysfunction and progression to end-stage kidney disease and cardiovascular disease. Complications associated with CKD may contribute to the acceleration of disease progression and the risk of cardiovascular-related morbidities. Early CKD is asymptomatic, and symptoms only present at later stages when complications of the disease arise, such as a decline in kidney function and the presence of other comorbidities associated with the disease. In advanced stages of the disease, when kidney function is significantly impaired, patients can only be treated with dialysis or a transplant. With limited treatment options available, an increasing prevalence of both the elderly population and comorbidities associated with the disease, the prevalence of CKD is set to rise. This review discusses the current challenges and the unmet patient need in CKD

Regulation of neutrophil senescence by microRNAs

Neutrophils are rapidly recruited to sites of tissue injury or infection, where they protect against invading pathogens. Neutrophil functions are limited by a process of neutrophil senescence, which renders the cells unable to respond to chemoattractants, carry out respiratory burst, or degranulate. In parallel, aged neutrophils also undergo spontaneous apoptosis, which can be delayed by factors such as GMCSF. This is then followed by their subsequent removal by phagocytic cells such as macrophages, thereby preventing unwanted inflammation and tissue damage. Neutrophils translate mRNA to make new proteins that are important in maintaining functional longevity. We therefore hypothesised that neutrophil functions and lifespan might be regulated by microRNAs expressed within human neutrophils. Total RNA from highly purified neutrophils was prepared and subjected to microarray analysis using the Agilent human miRNA microarray V3. We found human neutrophils expressed a selected repertoire of 148 microRNAs and that 6 of these were significantly upregulated after a period of 4 hours in culture, at a time when the contribution of apoptosis is negligible. A list of predicted targets for these 6 microRNAs was generated from http://mirecords.biolead.org and compared to mRNA species downregulated over time, revealing 83 genes targeted by at least 2 out of the 6 regulated microRNAs. Pathway analysis of genes containing binding sites for these microRNAs identified the following pathways: chemokine and cytokine signalling, Ras pathway, and regulation of the actin cytoskeleton. Our data suggest that microRNAs may play a role in the regulation of neutrophil senescence and further suggest that manipulation of microRNAs might represent an area of future therapeutic interest for the treatment of inflammatory disease

BMI and HbA1c are metabolic markers for pancreatic cancer: matched case-control study using a UK primary care database

Background Weight loss, hyperglycaemia and diabetes are known features of pancreatic cancer. We quantified the timing and the amount of changes in body mass index (BMI) and glycated haemoglobin (HbA1c), and their association with pancreatic cancer from five years before diagnosis. Methods A matched case-control study was undertaken within 590 primary care practices in England, United Kingdom. 8,777 patients diagnosed with pancreatic cancer (cases) between 1st January 2007 and 31st August 2020 were matched to 34,979 controls by age, gender and diabetes. Longitudinal trends in BMI and HbA1c were visualised. Odds ratios adjusted for demographic and lifestyle factors (aOR) and 95% confidence intervals (CI) were calculated with conditional logistic regression. Subgroup analyses were undertaken according to the diabetes status. Results Changes in BMI and HbA1c observed for cases on longitudinal plots started one and two years (respectively) before diagnosis. In the year before diagnosis, a 1 kg/m2 decrease in BMI between cases and controls was associated with aOR for pancreatic cancer of 1.05 (95% CI 1.05 to 1.06), and a 1 mmol/mol increase in HbA1c was associated with aOR of 1.06 (1.06 to 1.07). ORs remained statistically significant (p < 0.001) for 2 years before pancreatic cancer diagnosis for BMI and 3 years for HbA1c. Subgroup analysis revealed that the decrease in BMI was associated with a higher pancreatic cancer risk for people with diabetes than for people without (aORs 1.08, 1.06 to 1.09 versus 1.04, 1.03 to 1.05), but the increase in HbA1c was associated with a higher risk for people without diabetes than for people with diabetes (aORs 1.09, 1.07 to 1.11 versus 1.04, 1.03 to 1.04). Conclusions The statistically significant changes in weight and glycaemic control started three years before pancreatic cancer diagnosis but varied according to the diabetes status. The information from this study could be used to detect pancreatic cancer earlier than is currently achieved. However, regular BMI and HbA1c measurements are required to facilitate future research and implementation in clinical practice

Diabetes foot complications and standardized mortality rate in type 2 diabetes

Aim: To quantify the impact of foot complications on mortality outcomes in people with type 2 diabetes (T2D), and how routinely measured factors might modulate that risk. Materials and Methods: Data for individuals with T2D for 2010-2020, from the Salford Integrated Care Record (Salford, UK), were extracted for laboratory and clinical data, and deaths. Annual expected deaths were taken from Office of National Statistics mortality data. An index of multiple deprivation (IMD) adjusted the standardized mortality ratio (SMR_IMD). Life years lost per death (LYLD) was estimated from the difference between expected and actual deaths. Results: A total of 11 806 T2D patients were included, with 5583 new diagnoses and 3921 deaths during 2010-2020. The number of expected deaths was 2135; after IMD adjustment, there were 2595 expected deaths. Therefore, excess deaths numbered 1326 (SMR_IMD 1.51). No foot complications were evident in n = 9857. This group had an SMR_IMD of 1.13 and 2.74 LYLD. In total, 2979 patients had any foot complication recorded. In this group, the SMD_IMR was 2.29; of these, 2555 (75%) had only one foot complication. Patients with a foot complication showed little difference in percentage HbA1c more than 58 mmol/mol. In multivariate analysis, for those with a foot complication and an albumin-to-creatinine ratio of more than 3 mg/mmol, the odds ratio (OR) for death was 1.93, and for an estimated glomerular filtration rate of less than 60 mL/min/1.73m2, the OR for death was 1.92. Conclusions: Patients with T2D but without a foot complication have an SMR_IMD that is only slightly higher than that of the general population. Those diagnosed with a foot complication have a mortality risk that is double that of those without T2D

Motivations for innovation in the built environment: new directions for research

Innovation in the built environment involves multiple actors with diverse motivations. Policy-makers find it difficult to promote changes that require cooperation from these numerous and dispersed actors and to align their sometimes divergent interests. Established research traditions on the economics and management of innovation pay only limited attention to stakeholder choices, engagement and motivation. This paper reviews the insights that emerge as research in these traditions comes into contact with work on innovation from sociological and political perspectives. It contributes by highlighting growing areas of research on user involvement in complex innovation, collective action, distributed innovation and transition management. To differing extents, these provide approaches to incorporate the motivations of different actors into theoretical understanding. These indicate new directions for research that promise to enrich understanding of innovation

Shaping pedestrian movement through playful interventions in security planning: what do field surveys suggest?

© 2015 Taylor & Francis The control and shaping of pedestrian movement recurs as an aspect of security planning for crowded spaces. Using the concepts of triangulation, performance and flow, this paper presents a series of experiments designed to shape pedestrian movement patterns in public spaces in different spatial and operation contexts, by eliciting noticeable behaviours and disrupting routine use of space. The hypothesis investigated is that playful, non-obstructive interventions foster a positive social experience yet can be used to shape pedestrian movement. The interventions examined were around the themes of floor marking and mirrors. Analysis demonstrated that the interventions were able to create zones of attraction and exclusion, engage people’s curiosity and elicit playful actions. Habituation, goal-directed behaviour and the influence of increased cognitive load at personal level were all important factors responsible for reducing the level of engagement with an intervention. The results suggest that increased understanding between environmental and interpersonal stimuli and behavioural responses can provide guidance in using socially acceptable design interventions to influence use of space in different operational contexts, contributing to sustainable security

Epstein-Barr virus transcription factor Zta acts through distal regulatory elements to directly control cellular gene expression

Lytic replication of the human gamma herpes virus Epstein-Barr virus (EBV) is an essential prerequisite for the spread of the virus. Differential regulation of a limited number of cellular genes has been reported in B-cells during the viral lytic replication cycle. We asked whether a viral bZIP transcription factor, Zta (BZLF1, ZEBRA, EB1), drives some of these changes. Using genome-wide chromatin immunoprecipitation coupled to next-generation DNA sequencing (ChIP-seq) we established a map of Zta interactions across the human genome. Using sensitive transcriptome analyses we identified 2263 cellular genes whose expression is significantly changed during the EBV lytic replication cycle. Zta binds 278 of the regulated genes and the distribution of binding sites shows that Zta binds mostly to sites that are distal to transcription start sites. This differs from the prevailing view that Zta activates viral genes by binding exclusively at promoter elements. We show that a synthetic Zta binding element confers Zta regulation at a distance and that distal Zta binding sites from cellular genes can confer Zta-mediated regulation on a heterologous promoter. This leads us to propose that Zta directly reprograms the expression of cellular genes through distal elements

Frequency and properties of bars in cluster and field galaxies at intermediate redshifts

We present a study of large-scale bars in field and cluster environments out to redshifts of ~0.8 using a final sample of 945 moderately inclined disk galaxies drawn from the EDisCS project. We characterize bars and their host galaxies and look for relations between the presence of a bar and the properties of the underlying disk. We investigate whether the fraction and properties of bars in clusters are different from their counterparts in the field. The total optical bar fraction in the redshift range z=0.4-0.8 (median z=0.60), averaged over the entire sample, is 25% (20% for strong bars). For the cluster and field subsamples, we measure bar fractions of 24% and 29%, respectively. We find that bars in clusters are on average longer than in the field and preferentially found close to the cluster center, where the bar fraction is somewhat higher (~31%) than at larger distances (~18%). These findings however rely on a relatively small subsample and might be affected by small number statistics. In agreement with local studies, we find that disk-dominated galaxies have a higher optical bar fraction (~45%) than bulge-dominated galaxies (~15%). This result is based on Hubble types and effective radii and does not change with redshift. The latter finding implies that bar formation or dissolution is strongly connected to the emergence of the morphological structure of a disk and is typically accompanied by a transition in the Hubble type. (abridged)Comment: 17 pages, accepted for publication in A&