Interleukin-1ß activates a short STAT-3 isoform in clonal insulin-secreting cells

Abstract Interleukin-1ß (IL-1ß) is a potent inflammatory cytokine involved in type 1 diabetes and acts through defined IL-1ß signaling pathways. In the present work we describe induction of DNA binding activity to signal transducer and activator of transcription (STAT) in response to IL-1ß in clonal insulin-secreting cells. Moreover, IL-1ß activates a short isoform of STAT-3 that potently stimulates transcription. Immunopre- cipitation studies reveal an interaction between the activated STAT-3 and the IL-1 receptor accessory protein indicating an association between the two signaling pathways. This may be a novel point of transduction cross talk and an additional mechanism utilised by IL-1ß in the pancreatic ß-cell during the process of type 1 diabetes. z 1999 Federation of European Biochemical Societies

Leptin signalling in pancreatic islets and clonal insulin-secreting cells

Leptin is a cytokine secreted from adipose tissue at a rate commensurate with the size of the body's fat stores. In addition to its anorectic and thermogenic central actions, leptin is known to act on peripheral tissues, including the pancreatic ß-cell where it inhibits insulin secretion and reduces insulin transcript levels. However, the role of leptin signalling through its full-length receptor, OB-Rb, in the ß-cell remains unclear. In the present study, we show that leptin activates a signal transducer and activator of transcription (STAT)3 signalling mechanism in pancreatic islets and in a rat model of the pancreatic ß-cell, RINm5F. Leptin induced DNA binding to a STAT consensus oligonucleotide and resulted in transcriptional activation from STAT reporter constructs in a manner consistent with STAT3 activation. Western blot analysis confirmed activation of STAT3 in RINm5F and isolated rat islets. Conditions that mimic increased metabolic activity resulted in attenuation of leptin-mediated STAT DNA binding but had no significant eVect on STAT3 tyrosine phosphorylation in RINm5F cells. In addition, leptin activated the mitogen activated protein (MAP) kinase pathway in RINm5F cells. The present study provides a framework for OB-Rb signalling mechanisms in the programming of the ß-cell by leptin and suggests that increased metabolic activity may modulate this function

Robo-AO Kepler Survey. V. the Effect of Physically Associated Stellar Companions on Planetary Systems

The Kepler light curves used to detect thousands of planetary candidates are susceptible to dilution due to blending with previously unknown nearby stars. With the automated laser adaptive optics instrument, Robo-AO, we have observed 620 nearby stars around 3857 planetary candidates host stars. Many of the nearby stars, however, are not bound to the KOI. We use galactic stellar models and the observed stellar density to estimate the number and properties of unbound stars. We estimate the spectral type and distance to 145 KOIs with nearby stars using multi-band observations from Robo-AO and Keck-AO. Most stars within 1″ of a Kepler planetary candidate are likely bound, in agreement with past studies. We use likely bound stars and the precise stellar parameters from the California Kepler Survey to search for correlations between stellar binarity and planetary properties. No significant difference between the binarity fraction of single and multiple-planet systems is found, and planet hosting stars follow similar binarity trends as field stars, many of which likely host their own non-aligned planets. We find that hot Jupiters are ∼4× more likely than other planets to reside in a binary star system. We correct the radius estimates of the planet candidates in characterized systems and find that for likely bound systems, the estimated planetary radii will increase on average by a factor of 1.77, if either star is equally likely to host the planet. Lastly, we find the planetary radius gap is robust to the impact of dilution

Robo-AO Kepler Survey. IV. the Effect of Nearby Stars on 3857 Planetary Candidate Systems

We present the overall statistical results from the Robo-AO Kepler planetary candidate survey, comprising of 3857 high-angular resolution observations of planetary candidate systems with Robo-AO, an automated laser adaptive optics system. These observations reveal previously unknown nearby stars blended with the planetary candidate host stars that alter the derived planetary radii or may be the source of an astrophysical false positive transit signal. In the first three papers in the survey, we detected 440 nearby stars around 3313 planetary candidate host stars. In this paper, we present observations of 532 planetary candidate host stars, detecting 94 companions around 88 stars; 84 of these companions have not previously been observed in high resolution. We also report 50 more-widely separated companions near 715 targets previously observed by Robo-AO. We derive corrected planetary radius estimates for the 814 planetary candidates in systems with a detected nearby star. If planetary candidates are equally likely to orbit the primary or secondary star, the radius estimates for planetary candidates in systems with likely bound nearby stars increase by a factor of 1.54, on average. We find that 35 previously believed rocky planet candidates are likely not rocky due to the presence of nearby stars. From the combined data sets from the complete Robo-AO KOI survey, we find that 14.5 - 0.5% of planetary candidate hosts have a nearby star with 4″, while 1.2% have two nearby stars, and 0.08% have three. We find that 16% of Earth-sized, 13% of Neptune-sized, 14% of Saturn-sized, and 19% of Jupiter-sized planet candidates have detected nearby stars

Transactive response DNA-binding protein-43 proteinopathy in oligodendrocytes revealed using an induced pluripotent stem cell model

Oligodendrocytes are implicated in amyotrophic lateral sclerosis pathogenesis and display transactive response DNA-binding protein-43 (TDP-43) pathological inclusions. To investigate the cell autonomous consequences of TDP-43 mutations on human oligodendrocytes, we generated oligodendrocytes from patient-derived induced pluripotent stem cell lines harbouring mutations in the TARDBP gene, namely G298S and M337V. Through a combination of immunocytochemistry, electrophysiological assessment via whole-cell patch clamping, and three-dimensional cultures, no differences in oligodendrocyte differentiation, maturation or myelination were identified. Furthermore, expression analysis for monocarboxylate transporter 1 (a lactate transporter) coupled with a glycolytic stress test showed no deficit in lactate export. However, using confocal microscopy, we report TDP-43 mutation-dependent pathological mis-accumulation of TDP-43. Furthermore, using in vitro patch-clamp recordings, we identified functional Ca2+-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor dysregulation in oligodendrocytes. Together, these findings establish a platform for further interrogation of the role of oligodendrocytes and cellular autonomy in TDP-43 proteinopathy

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

A Comprehensive Pan-Cancer Molecular Study of Gynecologic and Breast Cancers

We analyzed molecular data on 2,579 tumors from The Cancer Genome Atlas (TCGA) of four gynecological types plus breast. Our aims were to identify shared and unique molecular features, clinically significant subtypes, and potential therapeutic targets. We found 61 somatic copy-number alterations (SCNAs) and 46 significantly mutated genes (SMGs). Eleven SCNAs and 11 SMGs had not been identified in previous TCGA studies of the individual tumor types. We found functionally significant estrogen receptor-regulated long non-coding RNAs (lncRNAs) and gene/lncRNA interaction networks. Pathway analysis identified subtypes with high leukocyte infiltration, raising potential implications for immunotherapy. Using 16 key molecular features, we identified five prognostic subtypes and developed a decision tree that classified patients into the subtypes based on just six features that are assessable in clinical laboratories. By performing molecular analyses of 2,579 TCGA gynecological (OV, UCEC, CESC, and UCS) and breast tumors, Berger et al. identify five prognostic subtypes using 16 key molecular features and propose a decision tree based on six clinically assessable features that classifies patients into the subtypes