Disruption of beta cell acetyl-CoA carboxylase-1 in mice impairs insulin secretion and beta cell mass

Aims/hypothesis: Pancreatic beta cells secrete insulin to maintain glucose homeostasis, and beta cell failure is a hallmark of type 2 diabetes. Glucose triggers insulin secretion in beta cells via oxidative mitochondrial pathways. However, it also feeds mitochondrial anaplerotic pathways, driving citrate export and cytosolic malonyl-CoA production by the acetyl-CoA carboxylase 1 (ACC1) enzyme. This pathway has been proposed as an alternative glucose-sensing mechanism, supported mainly by in vitro data. Here, we sought to address the role of the beta cell ACC1-coupled pathway in insulin secretion and glucose homeostasis in vivo. Methods: Acaca, encoding ACC1 (the principal ACC isoform in islets), was deleted in beta cells of mice using the Cre/loxP system. Acaca floxed mice were crossed with Ins2cre mice (βACC1KO; life-long beta cell gene deletion) or Pdx1creER mice (tmx-βACC1KO; inducible gene deletion in adult beta cells). Beta cell function was assessed using in vivo metabolic physiology and ex vivo islet experiments. Beta cell mass was analysed using histological techniques. Results: βACC1KO and tmx-βACC1KO mice were glucose intolerant and had defective insulin secretion in vivo. Isolated islet studies identified impaired insulin secretion from beta cells, independent of changes in the abundance of neutral lipids previously implicated as amplification signals. Pancreatic morphometry unexpectedly revealed reduced beta cell size in βACC1KO mice but not in tmx-βACC1KO mice, with decreased levels of proteins involved in the mechanistic target of rapamycin kinase (mTOR)-dependent protein translation pathway underpinning this effect. Conclusions/interpretation: Our study demonstrates that the beta cell ACC1-coupled pathway is critical for insulin secretion in vivo and ex vivo and that it is indispensable for glucose homeostasis. We further reveal a role for ACC1 in controlling beta cell growth prior to adulthood.</p

Neural Processing of Respiratory Sensations when Breathing Becomes More Difficult and Unpleasant

The accurate perception of respiratory sensations is important for the successful management and treatment of respiratory diseases. Previous studies demonstrated that external stimuli such as affective pictures and distracting films can impact the perception and neural processing of respiratory sensations. This study examined the neural processing of respiratory sensations when breathing as an internal stimulus is manipulated and becomes more difficult and unpleasant. Sustained breathing through an inspiratory resistive load was used to increase perceived breathing difficulty in 12 female individuals without respiratory disease. Using high-density EEG, respiratory-related evoked potentials (RREP) to short inspiratory occlusions were recorded at early versus late time points of sustained loaded breathing. Ratings of perceived intensity and unpleasantness of breathing difficulty showed an increase from early to late time points of loaded breathing (p < 0.01 and p < 0.05, respectively). This was paralleled by significant increases in the magnitudes of RREP components N1, P2, and P3 (p < 0.01, p < 0.05, and p < 0.05, respectively). The present results demonstrate increases in the neural processing of respiratory sensations when breathing becomes more difficult and unpleasant. This might reflect a protective neural mechanism allowing effective response behavior when air supply is at risk

Long-term outcome of patients undergoing liver transplantation for mixed hepatocellular carcinoma and cholangiocarcinoma: an analysis of the UNOS database

AbstractBackgroundMixed hepatocellular and cholangiocarcinoma (HCC-CC) have been associated with a poor prognosis after liver transplantation (LT). We aimed to evaluate long-term outcomes in patients undergoing LT for HCC-CC versus patients with hepatocellular carcinoma (HCC) or cholangiocarcinoma (CC).MethodsRetrospective analysis of the United Network for Organ Sharing (UNOS) database from 1994–2013. Overall survival (OS) in patients with HCC-CC, HCC, and CC, were compared.ResultsWe identified 4049 patients transplanted for primary malignancy (94 HCC-CC; 3515 HCC; 440 CC). Mean age of patients with HCC-CC was 57 ± 10 years, and 77% were male. MELD score did not differ among the groups (p = 0.637). Hepatitis C virus was the most common secondary diagnosis within the HCC-CC (44%) and HCC (36%) cohorts, with primary sclerosing cholangitis in the CC (16%) cohort. OS rates at 1, 3 and 5 years for HCC-CC (82%, 47%, 40%) were similar to CC (79%, 58%, 47%), but significantly worse than HCC (86%, 72%, and 62% p = 0.002).DiscussionPatients undergoing LT for HCC had significantly better survival compared to those transplanted for HCC-CC and CC. LT for mixed HCC-CC confers a survival rate similar to selected patients with CC. Efforts should be made to identify HCC-CC patients preoperatively

Crystal constructions in Number Theory

Weyl group multiple Dirichlet series and metaplectic Whittaker functions can be described in terms of crystal graphs. We present crystals as parameterized by Littelmann patterns and we give a survey of purely combinatorial constructions of prime power coefficients of Weyl group multiple Dirichlet series and metaplectic Whittaker functions using the language of crystal graphs. We explore how the branching structure of crystals manifests in these constructions, and how it allows access to some intricate objects in number theory and related open questions using tools of algebraic combinatorics

Proceedings of a membrane update symposium: advancements, scientific insights, and future trends for dialysis membranes for enhanced clinical outcomes in end stage kidney disease patients

Purpose of symposium: From September 6 – 8 2022, the Life/2022 Membrane Symposium was held in Frankfurt, Germany, and transmitted live to a worldwide internet audience. The event was part of the Life/Nephrology Campus initiative, a continuous educational platform for the nephrology community to expand knowledge and share expertise on contemporary topics in chronic kidney disease. We describe recent questions and advances in the field, and we underline challenges in the care of dialysis patients and opportunities for integration of new findings into clinical practice to improve patient outcomes in end stage kidney disease patients. Topics: Most patients with kidney failure are on maintenance hemodialysis (MHD). The scientific program of the symposium was developed around topics about the role, functional determinants, technical aspects, limitations, and clinical implications of membranes presently in use. International experts with clinical or technical expertise as well as scientific recognition within the nephrology community were asked to prepare their presentations based on their own experiences, perceptions, opinions, and sources of information. The symposium devoted a major portion to discussing novel approaches for improving membranes and treatment quality, including updates on innovative concepts that may could potentially transform the landscape of kidney replacement therapy for chronic kidney disease patients in the future. Implications: The intent was to provide insights into current attention points for healthcare professionals new to the field of MHD, and to test a unique forum for continuing medical education integrating physician and patient experiences to promote changes in clinical practice. Furthermore, the symposium premiered a specifically developed mixed reality holographic 3D model to demonstrate recent dialyzer innovation diminishing protein fouling on membrane surfaces. As a continuous online educational platform for scientific exchange, this Life/2022 event provided online learning opportunities with on-demand content, with all symposium lectures freely available on nephrologycampus.com

Lymphoid aggregates that resemble tertiary lymphoid organs define a specific pathological subset in metal-on-metal hip replacements

Aseptic lymphocyte-dominated vasculitis-associated lesion (ALVAL) has been used to describe the histological lesion associated with metal-on-metal (M-M) bearings. We tested the hypothesis that the lymphoid aggregates, associated with ALVAL lesions resemble tertiary lymphoid organs (TLOs). Histopathological changes were examined in the periprosthetic tissue of 62 M-M hip replacements requiring revision surgery, with particular emphasis on the characteristics and pattern of the lymphocytic infiltrate. Immunofluorescence and immunohistochemistry were used to study the classical features of TLOs in cases where large organized lymphoid follicles were present. Synchrotron X-ray fluorescence (XRF) measurements were undertaken to detect localisation of implant derived ions/particles within the samples. Based on type of lymphocytic infiltrates, three different categories were recognised; diffuse aggregates (51%), T cell aggregates (20%), and organised lymphoid aggregates (29%). Further investigation of tissues with organised lymphoid aggregates showed that these tissues recapitulate many of the features of TLOs with T cells and B cells organised into discrete areas, the presence of follicular dendritic cells, acquisition of high endothelial venule like phenotype by blood vessels, expression of lymphoid chemokines and the presence of plasma cells. Co-localisation of implant-derived metals with lymphoid aggregates was observed. These findings suggest that in addition to the well described general foreign body reaction mediated by macrophages and a T cell mediated type IV hypersensitivity response, an under-recognized immunological reaction to metal wear debris involving B cells and the formation of tertiary lymphoid organs occurs in a distinct subset of patients with M-M implants

Mortality in systemic lupus erythematosus in the United Kingdom 1999-2012

OBJECTIVES: To estimate the mortality associated with SLE during the period 1999-2012 by age, gender and region; and to ascertain the cause of death for people with SLE. METHODS: A retrospective cohort study using the UK Clinical Practice Research Datalink. Incident SLE cases diagnosed between 1999 and 2012 were matched by age, sex and practice to four controls. Age-, gender- and region-specific mortality rates were calculated per 1000 person-years and compared with control mortality rates using mortality rate ratios (MRRs). For individuals with linked Office of National Statistics data, cause of death was summarized by International Classification of Disease-10 chapter heading. RESULTS: Of 2740 incident cases, 227 died, giving a mortality rate of 15.84/1000 person-years (95% CI 13.91, 18.04). This was 67% higher than in controls (MRR 1.67, 95% CI 1.43, 1.94, P < 0.001). Men with SLE had higher rates of mortality than females with SLE. Compared with controls, the mortality rate for males with SLE was 1.80 times that of male controls (95% CI 1.32, 2.45, P < 0.001); for females the mortality rate was 1.64 times higher (95% CI 1.37, 1.96, P < 0.001). The age-specific mortality rates increased significantly with age; however, the MRR diminished from 3.81 (95% CI 1.43, 10.14) in those aged <40 years to 0.82 (95% CI 0.36, 1.83) in those 90 years. There was no significant difference in mortality between regions. Circulatory system disease and malignancy were the most frequent causes of death in both cases and controls. CONCLUSION: There remains an increased mortality for people with SLE compared with matched controls, particularly at younger ages

Genome analyses of the carboxydotrophic sulfate-reducers Desulfotomaculum nigrificans and Desulfotomaculum carboxydivorans and reclassification of Desulfotomaculum caboxydivorans as a later synonym of Desulfotomaculum nigrificans

Desulfotomaculum nigrificans and D. carboxydivorans are moderately thermophilic members of the polyphyletic spore-forming genus Desulfotomaculum in the family Peptococcaceae. They are phylogenetically very closely related and belong to 'subgroup a' of the Desulfotomaculum cluster 1. D. nigrificans and D. carboxydivorans have a similar growth substrate spectrum; they can grow with glucose and fructose as electron donors in the presence of sulfate. Additionally, both species are able to ferment fructose, although fermentation of glucose is only reported for D. carboxydivorans. D. nigrificans is able to grow with 20% carbon monoxide (CO) coupled to sulfate reduction, while D. carboxydivorans can grow at 100% CO with and without sulfate. Hydrogen is produced during growth with CO by D. carboxydivorans. Here we present a summary of the features of D. nigrificans and D. carboxydivorans together with the description of the complete genome sequencing and annotation of both strains. Moreover, we compared the genomes of both strains to reveal their differences. This comparison led us to propose a reclassification of D. carboxydivorans as a later heterotypic synonym of D. nigrificans.We would like to gratefully acknowledge the help of Christine Munk and Megan Lu for finishing the genome sequence (both at JGI). The work conducted by the U.S. Department of Energy Joint Genome Institute is supported by the Office of Science of the U.S. Department of Energy under Contract No. DE-AC02-05CH11231, and was also supported by grants CW-TOP 700.55.343 and ALW 819.02.014 of the Netherlands Science Foundation (NWO) and grant 323009 of the European Research Council

Re-evaluation of the mechanisms of dietary fibre and implications for macronutrient bioaccessibility, digestion and postprandial metabolism

The positive effects of dietary fibre on health are now widely recognised; however, our understanding of the mechanisms involved in producing such benefits remains unclear. There are even uncertainties about how dietary fibre in plant foods should be defined and analysed. This review attempts to clarify the confusion regarding the mechanisms of action of dietary fibre and deals with current knowledge on the wide variety of dietary fibre materials, comprising mainly of NSP that are not digested by enzymes of the gastrointestinal (GI) tract. These non-digestible materials range from intact cell walls of plant tissues to individual polysaccharide solutions often used in mechanistic studies. We discuss how the structure and properties of fibre are affected during food processing and how this can impact on nutrient digestibility. Dietary fibre can have multiple effects on GI function, including GI transit time and increased digesta viscosity, thereby affecting flow and mixing behaviour. Moreover, cell wall encapsulation influences macronutrient digestibility through limited access to digestive enzymes and/or substrate and product release. Moreover, encapsulation of starch can limit the extent of gelatinisation during hydrothermal processing of plant foods. Emphasis is placed on the effects of diverse forms of fibre on rates and extents of starch and lipid digestion, and how it is important that a better understanding of such interactions with respect to the physiology and biochemistry of digestion is needed. In conclusion, we point to areas of further investigation that are expected to contribute to realisation of the full potential of dietary fibre on health and well-being of humans