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Whether attempting to meet accreditation curricular standards or not, undergraduate rehabilitation programs retain great flexibility within their curriculum. This malleability allows for courses and content specifically tailored to the local labor market and student characteristics and interests. This study sought to explore the similarities and differences within required coursework between undergraduate rehabilitation education programs across the United States, establishing what is universal to rehabilitation programs and those content areas or programmatic characteristics that distinguish one from another. A total of 40 programs were identified and 34 programs were included in the study. Although there was consistency within the coursework in some expected areas (most notably employment, case management, and interviewing skills), the versatility in other areas and program characteristics demonstrate the flexibility and uniqueness possible within this discipline and educational level. Results and recommendations for stakeholders and researchers are outlined.

OBJECTIVE: Non-alcoholic fatty liver disease (NAFLD) is an increasingly common condition in children characterized by insulin resistance and altered lipid metabolism. Affected patients are at increased risk of cardiovascular disease (CVD) and children with NAFLD are likely to be at risk of premature cardiac events. Evaluation of the plasma lipid profile of children with NAFLD offers the opportunity to investigate these perturbations and understand how closely they mimic the changes seen in adults with cardiometabolic disease.METHODS: We performed untargeted liquid chromatography mass spectrometry (LC-MS) plasma lipidomics on 287 children: 19 lean controls, 146 from an obese cohort, and 122 NAFLD cases who had undergone liver biopsy. Associations between lipid species and liver histology were assessed using regression adjusted for age and sex. Results were then replicated using data from 9,500 adults with metabolic phenotyping.RESULTS: More severe paediatric NAFLD was associated with lower levels of long chain, polyunsaturated phosphatidylcholines (PC) and triglycerides (TG). Similar trends in PC and TG chain length and saturation were seen in adults with hepatic steatosis. However, many of the specific lipids associated with NAFLD differed between children and adults. Five lipids replicated in adults (including PC(36:4)) have been directly linked to death and cardiometabolic disease, as well as indirectly via genetic variants.CONCLUSION: These findings suggest that, whilst similar pathways of lipid metabolism are perturbed in paediatric NAFLD as in cardiometabolic disease in adults, the specific lipid signature in children is different.

Fructose intake has increased substantially throughout the developed world and is associated with obesity, type 2 diabetes and non-alcoholic fatty liver disease. Currently, our understanding of the metabolic and mechanistic implications for immune cells, such as monocytes and macrophages, exposed to elevated levels of dietary fructose is limited. Here, we show that fructose reprograms cellular metabolic pathways to favour glutaminolysis and oxidative metabolism, which are required to support increased inflammatory cytokine production in both LPS-treated human monocytes and mouse macrophages. A fructose-dependent increase in mTORC1 activity drives translation of pro-inflammatory cytokines in response to LPS. LPS-stimulated monocytes treated with fructose rely heavily on oxidative metabolism and have reduced flexibility in response to both glycolytic and mitochondrial inhibition, suggesting glycolysis and oxidative metabolism are inextricably coupled in these cells. The physiological implications of fructose exposure are demonstrated in a model of LPS-induced systemic inflammation, with mice exposed to fructose having increased levels of circulating IL-1β after LPS challenge. Taken together, our work underpins a pro-inflammatory role for dietary fructose in LPS-stimulated mononuclear phagocytes which occurs at the expense of metabolic flexibility., Myeloid cells are able to utilize a variety of monosaccharides from our diet, including fructose. Here the authors show that when monocytes are reliant on fructose as a carbon energy source they are reprogrammed towards oxidative metabolism, glutamine anaplerosis and a pro-inflammatory phenotype owing to excess pro-inflammatory cytokine production.

The limited availability of human kidney biopsies to study acute kidney injury (AKI) has restricted the development of effective therapies for this condition. Here, we validate the use of deceased transplant organ donor kidneys to study human AKI and characterized the multi-omics and immune landscape of human AKI kidneys. We demonstrate that changes in kidney injury and inflammatory markers following AKI in deceased transplant donors are similar to that of mouse kidney ischemia-reperfusion injury. Integrated transcriptomic and metabolomic analysis of human kidneys shows upregulated renal arachidonic acid metabolism following AKI, a pathway speculated to be linked to the ceramide accumulation detected in these kidneys. Markers of T and B lymphocytes, and macrophages were upregulated in AKI kidneys. Interestingly, we show upregulated renal cytoplasmic phospholipase A2 (cPLA2) levels in AKI kidneys, and the inhibition of this enzyme reduced injury and inflammation in vitro, findings that have potentially important therapeutic implications.

S‐layers are paracrystalline proteinaceous lattices that surround prokaryotic cells, forming a critical interface between the cells and their extracellular environment. Here, we report the discovery of a novel S‐layer protein present in the Gram‐negative marine organism, Pseudoalteromonas tunicata D2. An uncharacterized protein (EAR28894) was identified as the most abundant protein in planktonic cultures and biofilms. Bioinformatic methods predicted a beta‐helical structure for EAR28894 similar to the Caulobacter S‐layer protein, RsaA, despite sharing less than 20% sequence identity. Transmission electron microscopy revealed that purified EAR28894 protein assembled into paracrystalline sheets with a unique square lattice symmetry and a unit cell spacing of ~9.1 nm. An S‐layer was found surrounding the outer membrane in wild‐type cells and completely removed from cells in an EAR28894 deletion mutant. S‐layer material also appeared to be “shed” from wild‐type cells and was highly abundant in the extracellular matrix where it is associated with outer membrane vesicles and other matrix components. EAR28894 and its homologs form a new family of S‐layer proteins that are widely distributed in Gammaproteobacteria including species of Pseudoalteromonas and Vibrio, and found exclusively in marine metagenomes. We propose the name Slr4 for this novel protein family., The S‐layer is the outermost protein layer surrounding bacterial cells. We discovered a new family of S‐layer proteins in marine bacteria that forms a paracrystalline square lattice surrounding cells. In addition, the S‐layer was found surrounding extracellular components in biofilms, suggesting that it may provide physical protection not only to cells but also to extracellular structures.

The underlying models of lithium-ion batteries are spatiotemporal and, therefore, consist of partial differential equations (PDEs), as they have to capture spatiotemporal electrochemical mechanisms. As parametric uncertainty increases, often PDE models become inadequate as modeling errors due to parameter uncertainty are much larger than those due to model reduction to ordinary differential equations (ODEs). In this paper, we focus on a linear ODE model derived from the PDE combined with algebraic nonlinearities to carry out parameter identification. The ODE model captures the diffusion dynamics while the nonlinearities capture the overpotential and open-circuit potential aspects. The parameter identification method consists of a matrix-regressor adaptive observer, whose regressors are composed using both the states of the linear dynamic model and suitably constructed basis functions of the algebraic nonlinearities. Under conditions of persistent excitation, the parameter and state estimation errors are shown to converge to zero if the overpotential is known, and to a compact set if the overpotential is unknown. A PDE-based single-particle model is used as the truth model to evaluate the accuracy of the proposed adaptive observer. It is shown that the adaptive observer is able to carry out fast estimation of internal states for a battery management system, such as the state of charge and state of health, under a range of operating conditions.

Maternal obesity during pregnancy has immediate and long-term detrimental effects on the offspring heart. In this study, we characterized the cardiac and circulatory lipid profiles in late gestation E18.5 fetuses of diet-induced obese pregnant mice and established the changes in lipid abundance and fetal cardiac transcriptomics. We used untargeted and targeted lipidomics and transcriptomics to define changes in the serum and cardiac lipid composition and fatty acid metabolism in male and female fetuses. From these analyses we observed: (1) maternal obesity affects the maternal and fetal serum lipidome distinctly; (2) female fetal heart lipidomes are more sensitive to maternal obesity than males; (3) changes in lipid supply might contribute to early expression of lipolytic genes in mouse hearts exposed to maternal obesity. These results highlight the existence of sexually dimorphic responses of the fetal heart to the same in utero obesogenic environment and identify lipids species that might mediate programming of cardiovascular health., MRC Metabolic Diseases Unit [MRC_MC_UU_00014/4] Cambridge Home and EU Student Scholarship British Heart Foundation studentship [FS/12/64/30001] II was supported by a British Heart Foundation studentship [FS/18/56/35177]

Funder: Foundation for Liver Research, Funder: Royal Society and a CAMS-UK fellowship, The metabolic syndrome (MetS) is a cluster of cardiovascular risk factors characterised by central obesity, atherogenic dyslipidaemia, and changes in the circulating lipidome; the underlying mechanisms that lead to this lipid remodelling have only been partially elucidated. This study used an integrated "omics" approach (untargeted whole serum lipidomics, targeted proteomics, and lipoprotein lipidomics) to study lipoprotein remodelling and HDL composition in subjects with central obesity diagnosed with MetS (vs. controls). Compared with healthy subjects, MetS patients showed higher free fatty acids, diglycerides, phosphatidylcholines, and triglycerides, particularly those enriched in products of de novo lipogenesis. On the other hand, the "lysophosphatidylcholines to phosphatidylcholines" and "cholesteryl ester to free cholesterol" ratios were reduced, pointing to a lower activity of lecithin cholesterol acyltransferase (LCAT) in MetS; LCAT activity (directly measured and predicted by lipidomic ratios) was positively correlated with high-density lipoprotein cholesterol (HDL-C) and negatively correlated with body mass index (BMI) and insulin resistance. Moreover, many phosphatidylcholines and sphingomyelins were significantly lower in the HDL of MetS patients and strongly correlated with BMI and clinical metabolic parameters. These results suggest that MetS is associated with an impairment of phospholipid metabolism in HDL, partially led by LCAT, and associated with obesity and underlying insulin resistance. This study proposes a candidate strategy to use integrated "omics" approaches to gain mechanistic insights into lipoprotein remodelling, thus deepening the knowledge regarding the molecular basis of the association between MetS and atherosclerosis.

Hypoxic-ischemic encephalopathy (HIE) is associated with perinatal brain injury, which may lead to disability or death. As the brain is a lipid-rich organ, various lipid species can be significantly impacted by HIE and these correlate with specific changes to the lipidomic profile in the circulation. Objective: To investigate the peripheral blood lipidomic signature in dried blood spots (DBS) from newborns with HIE. Using univariate analysis, multivariate analysis and sPLS-DA modelling, we show that newborns with moderate-severe HIE (n = 46) who underwent therapeutic hypothermia (TH) displayed a robust peripheral blood lipidomic signature comprising 29 lipid species in four lipid classes; namely phosphatidylcholine (PC), lysophosphatidylcholine (LPC), triglyceride (TG) and sphingomyelin (SM) when compared with newborns with mild HIE (n = 18). In sPLS-DA modelling, the three most discriminant lipid species were TG 50:3, TG 54:5, and PC 36:5. We report a reduction in plasma TG and SM and an increase in plasma PC and LPC species during the course of TH in newborns with moderate-severe HIE, compared to a single specimen from newborns with mild HIE. These findings may guide the research in nutrition-based intervention strategies after HIE in synergy with TH to enhance neuroprotection., NIHR Cambridge Biomedical Research Centre (146281) & Biotechnology and Biological Sciences Research Council (BB/P028195/1)

Pregnancy is characterised by metabolic changes that occur to support the growth and development of the fetus over the course of gestation. These metabolic changes can be classified into two distinct phases: an initial anabolic phase to prepare an adequate store of substrates and energy which are then broken down and used during a catabolic phase to meet the energetic demands of the mother, placenta and fetus. Dynamic readjustment of immune homeostasis is also a feature of pregnancy and is likely linked to the changes in energy substrate utilisation at this time. As cellular metabolism is increasingly recognised as a key determinant of immune cell phenotype and function, we consider how changes in maternal metabolism might contribute to T cell plasticity during pregnancy.

BACKGROUND AND AIMS NAFLD is a growing public health burden. However, the pathogenesis of NAFLD has not yet been fully elucidated, and the importance of genetic factors has only recently been appreciated. Genomic studies have revealed a strong association between NAFLD progression and the I148M variant in patatin-like phospholipase domain-containing protein 3 (PNPLA3). Nonetheless, very little is known about the mechanisms by which this gene and its variants can influence disease development. To investigate these mechanisms, we have developed an in vitro model that takes advantage of the unique properties of human-induced pluripotent stem cells (hiPSCs) and the CRISPR/CAS9 gene editing technology. APPROACH AND RESULTS We used isogenic hiPSC lines with either a knockout (PNPLA3KO ) of the PNPLA3 gene or with the I148M variant (PNPLA3I148M ) to model PNPLA3-associated NAFLD. The resulting hiPSCs were differentiated into hepatocytes, treated with either unsaturated or saturated free fatty acids to induce NAFLD-like phenotypes, and characterized by various functional, transcriptomic, and lipidomic assays. PNPLA3KO hepatocytes showed higher lipid accumulation as well as an altered pattern of response to lipid-induced stress. Interestingly, loss of PNPLA3 also caused a reduction in xenobiotic metabolism and predisposed PNPLA3KO cells to be more susceptible to ethanol-induced and methotrexate-induced toxicity. The PNPLA3I148M cells exhibited an intermediate phenotype between the wild-type and PNPLA3KO cells. CONCLUSIONS Together, these results indicate that the I148M variant induces a loss of function predisposing to steatosis and increased susceptibility to hepatotoxins.

Fetal sex differences play an important role in the pathophysiology of several placenta-related pregnancy complications. We previously reported that the maternal circulating level of a polyamine metabolite was altered in a fetal sex-specific manner, and was associated with pre-eclampsia and fetal growth restriction. Here we show that placental polyamine metabolism is altered in these disorders and that polyamines influence widespread changes in gene expression by regulating the availability of acetyl-CoA which is necessary for histone acetylation. Sex differences in polyamine metabolism are associated with escape from X chromosome inactivation of the gene encoding the enzyme spermine synthase in female placentas, as evidenced by biallelic expression of the gene in female trophoblasts. Polyamine depletion in primary human trophoblasts impairs glycolysis and mitochondrial metabolism resulting in decreased availability of acetyl-CoA and global histone hypoacetylation, in a sex-dependent manner. Chromatin-immunoprecipitation sequencing and RNA–sequencing identifies downregulation of progesterone biosynthetic pathways as a key target and polyamine depletion reduced progesterone release in male trophoblasts. Collectively, these findings suggest that polyamines regulate placental endocrine function through metabolic regulation of gene expression, and that sex differences in polyamine metabolism due to XCI escape may buffer the effects of placental dysfunction in pregnancy disorders.

Maternal obesity is a global problem that increases the risk of short- and long-term adverse outcomes for mother and child, many of which are linked to gestational diabetes mellitus. Effective treatments are essential to prevent the transmission of poor metabolic health from mother to child. Metformin is an effective glucose lowering drug commonly used to treat gestational diabetes mellitus; however, its wider effects on maternal and fetal health are poorly explored. In this study we used a mouse (C57Bl6/J) model of diet-induced (high sugar/high fat) maternal obesity to explore the impact of metformin on maternal and feto-placental health. Metformin (300 mg kg-1 day-1 ) was given to obese females via the diet and was shown to achieve clinically relevant concentrations in maternal serum (1669 ± 568 nM in late pregnancy). Obese dams developed glucose intolerance during pregnancy and had reduced uterine artery compliance. Metformin treatment of obese dams improved maternal glucose tolerance, reduced maternal fat mass and restored uterine artery function. Placental efficiency was reduced in obese dams, with increased calcification and reduced labyrinthine area. Consequently, fetuses from obese dams weighed less (P < 0.001) at the end of gestation. Despite normalisation of maternal parameters, metformin did not correct placental structure or fetal growth restriction. Metformin levels were substantial in the placenta and fetal circulation (109.7 ± 125.4 nmol g-1 in the placenta and 2063 ± 2327 nM in fetal plasma). These findings reveal the distinct effects of metformin administration during pregnancy on mother and fetus and highlight the complex balance of risk vs. benefits that are weighed in obstetric medical treatments. KEY POINTS: Maternal obesity and gestational diabetes mellitus have detrimental short- and long-term effects for mother and child. Metformin is commonly used to treat gestational diabetes mellitus in many populations worldwide but the effects on fetus and placenta are unknown. In a mouse model of diet-induced obesity and glucose intolerance in pregnancy we show reduced uterine artery compliance, placental structural changes and reduced fetal growth. Metformin treatment improved maternal metabolic health and uterine artery compliance but did not rescue obesity-induced changes in the fetus or placenta. Metformin crossed the placenta into the fetal circulation and entered fetal tissue. Metformin has beneficial effects on maternal health beyond glycaemic control. However, despite improvements in maternal physiology, metformin did not prevent fetal growth restriction or placental ageing. The high uptake of metformin into the placental and fetal circulation highlights the potential for direct immediate effects of metformin on the fetus with possible long-term consequences postnatally.

Identifying optimal locations for new facilities is a common, yet paramount, task in fields as diverse as communications (e.g., cell phone towers) to business (e.g., store locations). Problematically, identifying optimal locations is computationally expensive. In this paper, we propose a novel algorithm to solve the facility localization problem based on a parallelizable discrete approximation of a Voronoi diagram, rather than previously considered exact Voronoi diagram calculations. The growth in execution time across increasing numbers of facilities and increasing geographic planes are empirically analyzed. Finally, the execution time of sequential and parallel implementations is compared across a variety of two-dimensional problem sizes illustrating substantial speedup.

Maternal obesity during pregnancy has immediate and long-term detrimental effects on the offspring heart. In this study, we characterized the cardiac and circulatory lipid profiles in fetuses of diet-induced obese pregnant mice and established the changes in lipid abundance and fetal cardiac transcriptomics. We used untargeted and targeted lipidomics and transcriptomics to define changes in the serum and cardiac lipid composition and fatty acid metabolism in male and female fetuses. From these analyses we observed: (1) maternal obesity affects the maternal and fetal serum lipidome distinctly; (2) female heart lipidomes are more sensitive to maternal obesity than male fetuses; (3) changes in lipid supply might contribute to early expression of lipolytic genes in mouse hearts exposed to maternal obesity. These results highlight the existence of sexually dimorphic responses of the fetal heart to the same in utero obesogenic environment and identify lipids species that might mediate programming of cardiovascular health.

Even though metformin is widely used to treat type2 diabetes, reducing glycaemia and body weight, the mechanisms of action are still elusive. Recent studies have identified the gastrointestinal tract as an important site of action. Here we used intestinal organoids to explore the effects of metformin on intestinal cell physiology. Bulk RNA-sequencing analysis identified changes in hexose metabolism pathways, particularly glycolytic genes. Metformin increased expression of Slc2a1 (GLUT1), decreased expression of Slc2a2 (GLUT2) and Slc5a1 (SGLT1) whilst increasing GLUT-dependent glucose uptake and glycolytic rate as observed by live cell imaging of genetically encoded metabolite sensors and measurement of oxygen consumption and extracellular acidification rates. Metformin caused mitochondrial dysfunction and metformin’s effects on 2D-cultures were phenocopied by treatment with rotenone and antimycin-A, including upregulation of GDF15 expression, previously linked to metformin dependent weight loss. Gene expression changes elicited by metformin were replicated in 3D apical-out organoids and distal small intestines of metformin treated mice. We conclude that metformin affects glucose uptake, glycolysis and GDF-15 secretion, likely downstream of the observed mitochondrial dysfunction. This may explain the effects of metformin on intestinal glucose utilisation and food balance.

Contains fulltext : 232477.pdf (Publisher’s version ) (Open Access) Tissue-resident macrophages are required for homeostasis, but also contribute to tissue dysfunction in pathophysiological states. The sympathetic neurotransmitter norepinephrine (NE) induces an anti-inflammatory and tissue-reparative phenotype in macrophages. As NE has a well-established role in promoting triglyceride lipolysis in adipocytes, and macrophages accumulate triglyceride droplets in various physiological and disease states, we investigated the effect of NE on primary mouse bone marrow-derived macrophage triglyceride metabolism. Surprisingly, our data show that in contrast to the canonical role of NE in stimulating lipolysis, NE acting via beta2-adrenergic receptors (B2ARs) in macrophages promotes extracellular fatty acid uptake and their storage as triglycerides and reduces free fatty acid release from triglyceride-laden macrophages. We demonstrate that these responses are mediated by a B2AR activation-dependent increase in Hilpda and Dgat1 gene expression and activity. We further show that B2AR activation favors the storage of extracellular polyunsaturated fatty acids. Finally, we present evidence that macrophages isolated from hearts after myocardial injury, for which survival critically depends on leukocyte B2ARs, have a transcriptional signature indicative of a transient triglyceride accumulation. Overall, we describe a novel and unexpected role of NE in promoting triglyceride storage in macrophages that could have potential implications in multiple diseases.

RNA interference (RNAi) is a gene regulatory mechanism based on RNA-RNA interaction conserved through eukaryotes. Surprisingly, many animals can take-up human-made double stranded RNA (dsRNA) from the environment to initiate RNAi suggesting a mechanism for dsRNA-based information exchange between organisms and their environment. However, no naturally occurring example has been identified since the discovery of the phenomenon 22 years ago. Therefore it remains enigmatic why animals are able to take up dsRNA. Here, we explore other possible functions by performing phenotypic studies of dsRNA uptake deficient sid-2 mutants in Caenorhabditis elegans. We find that SID-2 does not have a nutritional role in feeding experiments using genetic sensitized mutants. Furthermore, we use robot assisted imaging to show that sid-2 mutants accelerate growth rate and, by maternal contribution, body length at hatching. Finally, we perform transcriptome and lipidome analysis showing that sid-2 has no effect on energy storage lipids, but affects signalling lipids and the embryo transcriptome. Overall, these results suggest that sid-2 has mild effects on development and is unlikely functioning in the nutritional uptake of dsRNA. These findings broaden our understanding of the biological role of SID-2 and motivate studies identifying the role of environmental dsRNA uptake.

Background & aimsGenome-wide association studies in adults have identified variants in HSD17B13 and MARC1 as protective against NAFLD. It is not known if they are similarly protective in children and, more generally, whether the peri-portal inflammation of pediatric NAFLD and lobular inflammation seen in adults share common genetic influences. Therefore, we aimed to: establish if these variants are associated with NAFLD in children, and to investigate the function of these variants in hepatic metabolism using metabolomics.Methods960 children (590 with NAFLD, 394 with liver histology) were genotyped for rs72613567T>TA in HSD17B13, rs2642438G>A in MARC1. Genotype-histology associations were tested using ordinal regression. Untargeted hepatic proteomics and plasma lipidomics were performed in a subset of samples. In silico tools were used to model the effect of rs2642438G>A (p.Ala165Thr) on MARC1.Resultsrs72613567T>TA in HSD17B13 was associated with lower odds of NAFLD diagnosis (OR 0.7 (95%CI 0.6-0.9) and lower grade of portal inflammation (PA in MARC1 was associated with lower grade of hepatic steatosis (P=0.02). Proteomics found reduced expression of HSD17B13 in carriers of the protective allele, whereas MARC1 levels were not affected by genotype. Both variants showed downregulation of hepatic fibrotic pathways, upregulation of retinol metabolism and perturbation of phospholipid species. Modelling suggests that p.Ala165Thr would disrupt the stability and metal-binding of MARC1.ConclusionsThere are shared genetic mechanisms between pediatric and adult NAFLD, despite their differences in histology. MARC1 and HSD17B13 are involved in phospholipid metabolism and suppress fibrosis in NAFLD.

Lipidomics is of increasing interest in studies of biological systems. However, high-throughput data collection and processing remains non-trivial, making assessment of phenotypes difficult. We describe a platform for surveying the lipid fraction for a range of tissues. These techniques are demonstrated on a set of seven different tissues (serum, brain, heart, kidney, adipose, liver, and vastus lateralis muscle) from post-weaning mouse dams that were either obese (> 12 g fat mass) or lean (

Non-alcoholic fatty liver disease (NAFLD) is an increasingly common condition in children and adults characterized by insulin resistance and altered lipid metabolism. Affected patients are at increased risk of cardiovascular disease (CVD) and children with NAFLD are likely to be at risk of premature cardiac events. Evaluation of the plasma lipid profile of children with NAFLD offers the opportunity to investigate these perturbations and understand how closely they mimic the changes seen in adults with cardiometabolic disease. We hypothesized that change in the concentration of lipid species in pediatric NAFLD would mimic the alterations known to be associated with CVD in adults (and be largely reflective of insulin resistance). Here, we performed untargeted liquid chromatography mass spectrometry (LC-MS) plasma lipidomics on 287 children: 19 lean controls, 146 from an obese cohort, and 122 NAFLD cases who had undergone liver biopsy. Associations between lipid species and liver histology were assessed using regression adjusted for age and sex. Results were then replicated using data from 9,500 adults with metabolic phenotyping. Phosphatidylcholine (PC) and triglyceride (TG) desaturation and chain length were inversely associated with histological severity of paediatric NAFLD. Nine lipids species (lyso-PC, PC, and TG classes) were also associated with hepatic steatosis and insulin resistance in an independent cohort of adults. Five of the 9 lipids replicated in the adults cohort (including PC(36:4)) have been directly linked to death and cardiometabolic disease in adults, as well as indirectly via genetic variants that influence the concentration of these species. Together, these findings suggest that lipid metabolism is altered in paediatric NAFLD in a similar way as in cardiometabolic disease in adults and it is therefore critical to alleviate insulin resistance in these children to mitigate their long-term morbidity.

Parental exposure to pathogens can prime offspring immunity in diverse organisms. The mechanisms by which this heritable priming occurs are largely unknown. Here we report that the soil bacteria Pseudomonas vranovensis is a natural pathogen of the nematode Caenorhabditis elegans and that parental exposure of animals to P. vranovensis promotes offspring resistance to infection. Furthermore, we demonstrate a multigenerational enhancement of progeny survival when three consecutive generations of animals are exposed to P. vranovensis. By investigating the mechanisms by which animals heritably adapt to P. vranovensis infection, we found that parental infection by P. vranovensis results in increased expression of the cysteine synthases cysl-1 and cysl-2 and the regulator of hypoxia inducible factor rhy-1 in progeny, and that these three genes are required for adaptation to P. vranovensis. These observations establish a CYSL-1, CYSL-2, and RHY-1 dependent mechanism by which animals heritably adapt to infection., Caenorhabditis elegans exhibits multigenerational adaptation to bacterial infection but the mechanisms remain unclear. Here, the authors show that C. elegans parental exposure to Pseudomonas vranovensis promotes offspring resistance to infection, a process mediated by the cysteine synthases CYSL-1 and CYSL-2.

Background:\ud Urothelial carcinomas of the upper urinary tract (UTUCs) are rare, with poorer stage-for-stage prognosis than urothelial carcinomas of the urinary bladder. No international consensus exists on the benefit of adjuvant chemotherapy for patients with UTUCs after nephroureterectomy with curative intent. The POUT (Peri-Operative chemotherapy versus sUrveillance in upper Tract urothelial cancer) trial aimed to assess the efficacy of systemic platinum-based chemotherapy in patients with UTUCs.\ud \ud Methods:\ud We did a phase 3, open-label, randomised controlled trial at 71 hospitals in the UK. We recruited patients with UTUC after nephroureterectomy staged as either pT2–T4 pN0–N3 M0 or pTany N1–3 M0. We randomly allocated participants centrally (1:1) to either surveillance or four 21-day cycles of chemotherapy, using a minimisation algorithm with a random element. Chemotherapy was either cisplatin (70 mg/m2) or carboplatin (area under the curve [AUC]4·5/AUC5, for glomerular filtration rate

To understand the interaction between diet and health, biomarkers that accurately reflect consumption of foods of perceived health relevance are needed. The aim of this investigation was to use direct infusion-mass spectrometry (DI-MS) lipidomics to determine the effects of fish oil supplementation on lipid profiles of human adipose tissue. Adipose tissue samples from an n-3 polyunsaturated fatty acid (PUFA) supplementation study (n = 66) were analyzed to compare the pattern following supplementation equivalent to zero or four portions of oily fish per week. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were incorporated into highly unsaturated (≥5 double bonds) triglycerides (TGs), phosphocholines, and phosphoethanolamines as well as being detected directly as the nonesterified fatty acid forms. Multivariate statistics demonstrated that phospholipids were the most accurate and sensitive lipids for the assessing EPA and DHA incorporation into adipose tissue. Potential confounding factors (adiposity, age, and sex of the subject) were also considered in the analysis, and adiposity was also associated with an increase in highly unsaturated TGs as a result of incorporation of the n-6 PUFA arachidonic acid. DI-MS provides a high-throughput analysis of fatty acid status that can monitor oily fish consumption, suitable for use in cohort studies.

The convergence properties of adaptive systems in terms of excitation conditions on the regressor vector are well known. With persistent excitation of the regressor vector in model reference adaptive control the state error and the adaptation error are globally exponentially stable, or equivalently, exponentially stable in the large. When the excitation condition however is imposed on the reference input or the reference model state it is often incorrectly concluded that the persistent excitation in those signals also implies exponential stability in the large. The definition of persistent excitation is revisited so as to address some possible confusion in the adaptive control literature. It is then shown that persistent excitation of the reference model only implies local persistent excitation (weak persistent excitation). Weak persistent excitation of the regressor is still sufficient for uniform asymptotic stability in the large, but not exponential stability in the large. We show that there exists an infinite region in the state-space of adaptive systems where the state rate is bounded. This infinite region with finite rate of convergence is shown to exist not only in classic open-loop reference model adaptive systems, but also in a new class of closed-loop reference model adaptive systems., Comment: 22 pages, 5 figures

Summary Cells dynamically adjust organelle organization in response to growth and environmental cues. This requires regulation of synthesis of phospholipids, the building blocks of organelle membranes, or remodeling of their fatty-acyl (FA) composition. FAs are also the main components of triacyglycerols (TGs), which enable energy storage in lipid droplets. How cells coordinate FA metabolism with organelle biogenesis during cell growth remains unclear. Here, we show that Lro1, an acyltransferase that generates TGs from phospholipid-derived FAs in yeast, relocates from the endoplasmic reticulum to a subdomain of the inner nuclear membrane. Lro1 nuclear targeting is regulated by cell cycle and nutrient starvation signals and is inhibited when the nucleus expands. Lro1 is active at this nuclear subdomain, and its compartmentalization is critical for nuclear integrity. These data suggest that Lro1 nuclear targeting provides a site of TG synthesis, which is coupled with nuclear membrane remodeling., Graphical Abstract, Highlights • Nutrients regulate the phospholipid:diacylglycerol acyltransferase Lro1 • Lro1 targets the INM subdomain bordering the nucleolus • Lro1 is active at the INM and can sustain cell survival during starvation • Compartmentalized synthesis of nuclear TG is important for nuclear envelope integrity, Membrane phospholipids can be used as fatty acyl donors for the synthesis of triacylglycerols by enzymes called PDATs. Barbosa et al. present evidence that, in response to nutrient signals, the yeast PDAT Lro1 is active at the inner nuclear membrane, providing a link between organelle membrane remodeling and lipid storage.