Survey and alignment of the synchrotron SIS18

Mesenteric fat belongs to visceral fat. An increased deposition of mesenteric fat contributes to obesity associated complications such as type 2 diabetes and cardiovascular diseases. We have investigated the therapeutic effects of bardoxolone methyl (BARD) on mesenteric adipose tissue of mice fed a high-fat diet (HFD). Male C57BL/6J mice were administered oral BARD during HFD feeding (HFD/BARD), only fed a high-fat diet (HFD), or fed low-fat diet (LFD) for 21 weeks. Histology and immunohistochemistry were used to analyse mesenteric morphology and macrophages, while Western blot was used to assess the expression of inflammatory, oxidative stress, and energy expenditure proteins. Supplementation of drinking water with BARD prevented mesenteric fat deposition, as determined by a reduction in large adipocytes. BARD prevented inflammation as there were fewer inflammatory macrophages and reduced proinflammatory cytokines (interleukin-1 beta and tumour necrosis factor alpha). BARD reduced the activation of extracellular signal-regulated kinase (ERK) and Akt, suggesting an antioxidative stress effect. BARD upregulates energy expenditure proteins, judged by the increased activity of tyrosine hydroxylase (TH) and AMP-activated protein kinase (AMPK) and increased peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), and uncoupling protein 2 (UCP2) proteins. Overall, BARD induces preventive effect in HFD mice through regulation of mesenteric adipose tissue

Bardoxolone methyl prevents the development and progression of cardiac and renal pathophysiologies in mice fed a high-fat diet

Obesity caused by the consumption of a high-fat (HF) diet is a major risk factor for the development of associated complications, such as heart and kidney failure. A semi-synthetic triterpenoid, bardoxolone methyl (BM) was administrated to mice fed a HF diet for 21 weeks to determine if it would prevent the development of obesity-associated cardiac and renal pathophysiologies. Twelve week old male C57BL/6J mice were fed a lab chow (LC), HF (40% fat), or a HF diet supplemented with 10 mg/kg/day BM in drinking water. After 21 weeks, the left ventricles of hearts and cortex of kidneys of mice were collected for analysis. Histological analysis revealed that BM prevented HF diet-induced development of structural changes in the heart and kidneys. BM prevented HF diet-induced decreases in myocyte number in cardiac tissue, although this treatment also elevated cardiac endothelin signalling molecules. In the kidneys, BM administration prevented HF diet-induced renal corpuscle hypertrophy and attenuated endothelin signalling. Furthermore, in both the hearts and kidneys of mice fed a HF diet, BM administration prevented HF diet-induced increases in fat accumulation, macrophage infiltration and tumour necrosis factor alpha (TNFα) gene expression. These findings suggest that BM prevents HF diet-induced developments of cardiac and renal pathophysiologies in mice fed a chronic HF diet by preventing inflammation. Moreover, these results suggest that BM has the potential as a therapeutic for preventing obesity-induced cardiac and renal pathophysiologies

Radio Continuum and Star Formation in CO-rich Early Type Galaxies

In this paper we present new high resolution VLA 1.4 GHz radio continuum observations of five FIR bright CO-rich early-type galaxies and two dwarf early-type galaxies. The position on the radio-FIR correlation combined with striking agreements in morphology between high resolution CO and radio maps show that the radio continuum is associated with star formation in at least four of the eight galaxies. The average star formation rate for the sample galaxies detected in radio is approximately 2 solar masses per year. There is no evidence of a luminous AGN in any of our sample galaxies. We estimate Toomre Q values and find that the gas disks may well be gravitationally unstable, consistent with the above evidence for star formation activity. The radio continuum emission thus corroborates other recent suggestions that star formation in early type galaxies may not be uncommon.Comment: 21 pages, 7 figures, to be published in the Astronomical Journa

Bardoxolone methyl: a potential therapeutic for the prevention of anti-psychotic drug-induced obesity?

Abstract of a presentation

Clinical and genetic characterization of AP4B1-associated SPG47.

The hereditary spastic paraplegias (HSPs) are a heterogeneous group of disorders characterized by degeneration of the corticospinal and spinocerebellar tracts leading to progressive spasticity. One subtype, spastic paraplegia type 47 (SPG47 or HSP-AP4B1), is due to bi-allelic loss-of-function mutations in the AP4B1 gene. AP4B1 is a subunit of the adapter protein complex 4 (AP-4), a heterotetrameric protein complex that regulates the transport of membrane proteins. Since 2011, 11 individuals from six families with AP4B1 mutations have been reported, nine of whom had homozygous mutations and were from consanguineous families. Here we report eight patients with AP4B1-associated SPG47, the majority born to non-consanguineous parents and carrying compound heterozygous mutations. Core clinical features in this cohort and previously published patients include neonatal hypotonia that progresses to spasticity, early onset developmental delay with prominent motor delay and severely impaired or absent speech development, episodes of stereotypic laughter, seizures including frequent febrile seizures, thinning of the corpus callosum, and delayed myelination/white matter loss. Given that some of the features of AP-4 deficiency overlap with those of cerebral palsy, and the discovery of the disorder in non-consanguineous populations, we believe that AP-4 deficiency may be more common than previously appreciated

Developing standardized patient-based cases for communication training: lessons learned from training residents to communicate diagnostic uncertainty.

Health professions education has benefitted from standardized patient (SP) programs to develop and refine communication and interpersonal skills in trainees. Effective case design is essential to ensure an SP encounter successfully meets learning objectives that are focused on communication skills. Creative, well-designed case scenarios offer learners the opportunity to engage in complex patient encounters, while challenging them to address the personal and emotional contexts in which their patients are situated. Therefore, prior to considering the practical execution of the patient encounter, educators will first need a clear and structured strategy for writing, organizing, and developing cases. The authors reflect on lessons learned in developing standardized patient-based cases to train learners to communicate to patients during times of diagnostic uncertainty, and provide suggestions to develop a set of simulation cases that are both standardized and diverse. Key steps and workflow processes that can assist educators with case design are introduced. The authors review the need to increase awareness of and mitigate existing norms and implicit biases, while maximizing variation in patient diversity. Opportunities to leverage the breadth of emotional dispositions of the SP and the affective domain of a clinical encounter are also discussed as a means to guide future case development and maximize the value of a case for its respective learning outcomes

Development and validation of a comprehensive genomic diagnostic tool for myeloid malignancies.

The diagnosis of hematologic malignancies relies on multidisciplinary workflows involving morphology, flow cytometry, cytogenetic, and molecular genetic analyses. Advances in cancer genomics have identified numerous recurrent mutations with clear prognostic and/or therapeutic significance to different cancers. In myeloid malignancies, there is a clinical imperative to test for such mutations in mainstream diagnosis; however, progress toward this has been slow and piecemeal. Here we describe Karyogene, an integrated targeted resequencing/analytical platform that detects nucleotide substitutions, insertions/deletions, chromosomal translocations, copy number abnormalities, and zygosity changes in a single assay. We validate the approach against 62 acute myeloid leukemia, 50 myelodysplastic syndrome, and 40 blood DNA samples from individuals without evidence of clonal blood disorders. We demonstrate robust detection of sequence changes in 49 genes, including difficult-to-detect mutations such as FLT3 internal-tandem and mixed-lineage leukemia (MLL) partial-tandem duplications, and clinically significant chromosomal rearrangements including MLL translocations to known and unknown partners, identifying the novel fusion gene MLL-DIAPH2 in the process. Additionally, we identify most significant chromosomal gains and losses, and several copy neutral loss-of-heterozygosity mutations at a genome-wide level, including previously unreported changes such as homozygosity for DNMT3A R882 mutations. Karyogene represents a dependable genomic diagnosis platform for translational research and for the clinical management of myeloid malignancies, which can be readily adapted for use in other cancers

Capture of MicroRNA–Bound mRNAs Identifies the Tumor Suppressor miR-34a as a Regulator of Growth Factor Signaling

A simple biochemical method to isolate mRNAs pulled down with a transfected, biotinylated microRNA was used to identify direct target genes of miR-34a, a tumor suppressor gene. The method reidentified most of the known miR-34a regulated genes expressed in K562 and HCT116 cancer cell lines. Transcripts for 982 genes were enriched in the pull-down with miR-34a in both cell lines. Despite this large number, validation experiments suggested that ∼90% of the genes identified in both cell lines can be directly regulated by miR-34a. Thus miR-34a is capable of regulating hundreds of genes. The transcripts pulled down with miR-34a were highly enriched for their roles in growth factor signaling and cell cycle progression. These genes form a dense network of interacting gene products that regulate multiple signal transduction pathways that orchestrate the proliferative response to external growth stimuli. Multiple candidate miR-34a–regulated genes participate in RAS-RAF-MAPK signaling. Ectopic miR-34a expression reduced basal ERK and AKT phosphorylation and enhanced sensitivity to serum growth factor withdrawal, while cells genetically deficient in miR-34a were less sensitive. Fourteen new direct targets of miR-34a were experimentally validated, including genes that participate in growth factor signaling (ARAF and PIK3R2) as well as genes that regulate cell cycle progression at various phases of the cell cycle (cyclins D3 and G2, MCM2 and MCM5, PLK1 and SMAD4). Thus miR-34a tempers the proliferative and pro-survival effect of growth factor stimulation by interfering with growth factor signal transduction and downstream pathways required for cell division

Science and Technology of Future Light Sources

Many of the important challenges facing humanity, including developing alternative sources of energy and improving health, are being addressed by advances that demand the improved understanding and control of matter. While the visualization, exploration, and manipulation of macroscopic matter have long been technological goals, scientific developments in the twentieth century have focused attention on understanding matter on the atomic scale through the underlying framework of quantum mechanics. Of special interest is matter that consists of natural or artificial nanoscale building blocks defined either by atomic structural arrangements or by electron or spin formations created by collective correlation effects The essence of the challenge to the scientific community has been expressed in five grand challenges for directing matter and energy recently formulated by the Basic Energy Sciences Advisory Committee [1]. These challenges focus on increasing our understanding of, and ultimately control of, matter at the level of atoms, electrons. and spins, as illustrated in Figure 1.1, and serve the entire range of science from advanced materials to life sciences. Meeting these challenges will require new tools that extend our reach into regions of higher spatial, temporal, and energy resolution. X-rays with energies above 10 keV offer capabilities extending beyond the nanoworld shown in Figure 1.1 due to their ability to penetrate into optically opaque or thick objects. This opens the door to combining atomic level information from scattering studies with 3D information on longer length scales from real space imaging with a resolution approaching 1 nm. The investigation of multiple length scales is important in hierarchical structures, providing knowledge about function of living organisms, the atomistic origin of materials failure, the optimization of industrial synthesis, or the working of devices. Since the fundamental interaction that holds matter together is of electromagnetic origin, it is intuitively clear that electromagnetic radiation is the critical tool in the study of material properties. On the level of atoms, electrons, and spins, x-rays have proved especially valuable. Future advanced x-ray sources and instrumentation will extend the power of x-ray methods to reach greater spatial resolution, increased sensitivity, and unexplored temporal domains. The purpose of this document is threefold: (1) summarize scientific opportunities that are beyond the reach of today's x-ray sources and instrumentation; (2) summarize the requirements for advanced x-ray sources and instrumentation needed to realize these scientific opportunities, as well as potential methods of achieving them; and (3) outline the R&D required to establish the technical feasibility of these advanced x-ray sources and instrumentation

Integration of spatial and single-cell transcriptomics localizes epithelial cell–immune cross-talk in kidney injury

Single-cell sequencing studies have characterized the transcriptomic signature of cell types within the kidney. However, the spatial distribution of acute kidney injury (AKI) is regional and affects cells heterogeneously. We first optimized coordination of spatial transcriptomics and single-nuclear sequencing data sets, mapping 30 dominant cell types to a human nephrectomy. The predicted cell-type spots corresponded with the underlying histopathology. To study the implications of AKI on transcript expression, we then characterized the spatial transcriptomic signature of 2 murine AKI models: ischemia/reperfusion injury (IRI) and cecal ligation puncture (CLP). Localized regions of reduced overall expression were associated with injury pathways. Using single-cell sequencing, we deconvoluted the signature of each spatial transcriptomic spot, identifying patterns of colocalization between immune and epithelial cells. Neutrophils infiltrated the renal medulla in the ischemia model. Atf3 was identified as a chemotactic factor in S3 proximal tubules. In the CLP model, infiltrating macrophages dominated the outer cortical signature, and Mdk was identified as a corresponding chemotactic factor. The regional distribution of these immune cells was validated with multiplexed CO-Detection by indEXing (CODEX) immunofluorescence. Spatial transcriptomic sequencing complemented single-cell sequencing by uncovering mechanisms driving immune cell infiltration and detection of relevant cell subpopulations