Discovery of Bright Variable X-ray Sources in NGC 1569 with Chandra

From the analysis of a ~100 ks Chandra observation of the dwarf starburst galaxy NGC 1569, we have found that the X-ray point sources, CXOU 043048.1+645050 and CXOU 043048.6+645058, showed significant time variability. During this observation, the X-ray flux of CXOU 043048.1+645050 increased by 10 times in only 2 x 10^4 s. Since the spectrum in its bright phase was fitted with a disk blackbody model with kT_in ~0.43 keV and the bolometric luminosity is L_bol ~10^38 ergs s^-1, this source is an X-ray binary with a stellar mass black-hole. Since the spectrum in its faint phase was also fitted with a disk blackbody model, the time variability can be explained by a change of the accretion rate onto the black hole. The other variable source, CXOU 043048.6+645058, had a flat spectrum with a photon index of ~1.6. This source may be an X-ray binary with an X-ray luminosity of several x 10^37 ergs s^-1. In addition, three other weak sources showed possible time variability. Taking all of the variability into account may suggest an abundant population of compact X-ray sources in NGC 1569.Comment: 15 pages including 4 Postscript figures; accepted for publication in ApJ

CD24 Is Not Required for Tumor Initiation and Growth in Murine Breast and Prostate Cancer Models

CD24 is a small, heavily glycosylated, GPI-linked membrane protein, whose expression has been associated with the tumorigenesis and progression of several types of cancer. Here, we studied the expression of CD24 in tumors of MMTV-PyMT, Apc1572/T+ and TRAMP genetic mouse models that spontaneously develop mammary or prostate carcinoma, respectively. We found that CD24 is expressed during tumor development in all three models. In MMTV-PyMT and Apc1572T/+ breast tumors, CD24 was strongly but heterogeneously expressed during early tumorigenesis, but decreased in more advanced stages, and accordingly was increased in poorly differentiated lesions compared with well differentiated lesions. In prostate tumors developing in TRAMP mice, CD24 expression was strong within hyperplastic lesions in comparison with non-hyperplastic regions, and heterogeneous CD24 expression was maintained in advanced prostate carcinomas. To investigate whether CD24 plays a functional role in tumorigenesis in these models, we crossed CD24 deficient mice with MMTV-PyMT, Apc1572T/+ and TRAMP mice, and assessed the influence of CD24 deficiency on tumor onset and tumor burden. We found that mice negative or positive for CD24 did not significantly differ in terms of tumor initiation and burden in the genetic tumor models tested, with the exception of Apc1572T/+ mice, in which lack of CD24 reduced the mammary tumor burden slightly but significantly. Together, our data suggest that while CD24 is distinctively expressed during the early development of murine mammary and prostate tumors, it is not essential for the formation of tumors developing in MMTV-PyMT, Apc1572T/+ and TRAMP mice

ZMYND10 Is Mutated in Primary Ciliary Dyskinesia and Interacts with LRRC6

Defects of motile cilia cause primary ciliary dyskinesia (PCD), characterized by recurrent respiratory infections and male infertility. Using whole-exome resequencing and high-throughput mutation analysis, we identified recessive biallelic mutations in ZMYND10 in 14 families and mutations in the recently identified LRRC6 in 13 families. We show that ZMYND10 and LRRC6 interact and that certain ZMYND10 and LRRC6 mutations abrogate the interaction between the LRRC6 CS domain and the ZMYND10 C-terminal domain. Additionally, ZMYND10 and LRRC6 colocalize with the centriole markers SAS6 and PCM1. Mutations in ZMYND10 result in the absence of the axonemal protein components DNAH5 and DNALI1 from respiratory cilia. Animal models support the association between ZMYND10 and human PCD, given that zmynd10 knockdown in zebrafish caused ciliary paralysis leading to cystic kidneys and otolith defects and that knockdown in Xenopus interfered with ciliogenesis. Our findings suggest that a cytoplasmic protein complex containing ZMYND10 and LRRC6 is necessary for motile ciliary function

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

The Concise guide to pharmacology 2019/20: Ion channels

The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide represents approximately 400 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point‐in‐time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.14749. Ion channels are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein‐coupled receptors, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid‐2019, and supersedes data presented in the 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate

THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: Ion channels

The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point‐in‐time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15539. Ion channels are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein‐coupled receptors, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid‐2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate

The Concise Guide to PHARMACOLOGY 2023/24: Ion channels

The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and over 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (https://www.guidetopharmacology.org/), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point‐in‐time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.16178. Ion channels are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein‐coupled receptors, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid‐2023, and supersedes data presented in the 2021/22, 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate

Rare copy number variation in posttraumatic stress disorder

Posttraumatic stress disorder (PTSD) is a heritable (h2 = 24-71%) psychiatric illness. Copy number variation (CNV) is a form of rare genetic variation that has been implicated in the etiology of psychiatric disorders, but no large-scale investigation of CNV in PTSD has been performed. We present an association study of CNV burden and PTSD symptoms in a sample of 114,383 participants (13,036 cases and 101,347 controls) of European ancestry. CNVs were called using two calling algorithms and intersected to a consensus set. Quality control was performed to remove strong outlier samples. CNVs were examined for association with PTSD within each cohort using linear or logistic regression analysis adjusted for population structure and CNV quality metrics, then inverse variance weighted meta-analyzed across cohorts. We examined the genome-wide total span of CNVs, enrichment of CNVs within specified gene-sets, and CNVs overlapping individual genes and implicated neurodevelopmental regions. The total distance covered by deletions crossing over known neurodevelopmental CNV regions was significant (beta = 0.029, SE = 0.005, P = 6.3 × 10-8). The genome-wide neurodevelopmental CNV burden identified explains 0.034% of the variation in PTSD symptoms. The 15q11.2 BP1-BP2 microdeletion region was significantly associated with PTSD (beta = 0.0206, SE = 0.0056, P = 0.0002). No individual significant genes interrupted by CNV were identified. 22 gene pathways related to the function of the nervous system and brain were significant in pathway analysis (FDR q < 0.05), but these associations were not significant once NDD regions were removed. A larger sample size, better detection methods, and annotated resources of CNV are needed to explore this relationship further

Habituation of the Visually Evoked Potential and Its Vascular Response: Implications for Neurovascular Coupling in the Healthy Adult

GesamtdissertationModerne nicht-invasiv bildgebende Verfahren des Gehirns basieren auf dem Prinzip der neurovaskulären Kopplung, dem Phänomen, dass aktivierte Hirnareale aufgrund eines erhöhten Energieverbrauches stärker durchblutet werden. Wie die Übersetzung neuronaler Aktivität in die resultierende vaskuläre Antwort erfolgt, ist bislang nur unvollständig verstanden. Unter lang anhaltender Stimulation wurde eine Amplitudenreduktion der vaskulären Antwort beschrieben. Dies führte zu der Annahme, dass eine transiente „Entkopplung" zwischen neuronaler Aktivität und vaskulärem Signal auftrete, die aufgrund unterschiedlicher metabolischer Prozesse zu Beginn und im Verlauf der Stimulation erklärt wurden. Bisher ist jedoch ungeklärt, inwieweit dies allein auf metabolischen Umstellungen oder neuronalen und vaskulären Gewöhnungseffekten an den wiederkehrenden Reiz, im Sinne einer Habituation, beruht. In der vorliegenden Studie werden neuronale und vaskuläre Habituation unter visueller Stimulation (3 Hz Kontrastumkehr) simultan mittels Visuell Evozierten Potentialen (VEP) und Nahinfrarot-Spektroskopie (NIRS) untersucht. Habituationseffekte wurden auf zwei Zeitskalen untersucht. Innerhalb eines einminütigen Stimulationsblockes zeigte sich eine signifikante Reduktion der P100N135-Amplitude des VEPs in Korrelation mit einer Reduktion der vaskulären Parameter (Konzentrationsänderungen des oxygenierten und deoxygenierten Hämoglobins; [oxy-Hb] und [deoxy-Hb]). Über 13 sukzessive Stimulationsblöcke zeigte sich nur ein schwacher Trend hinsichtlich einer neuronalen Habituation ohne Relation zur vaskulären Antwort. Anhand der Ratio zwischen Veränderungen der P100N135-Amplitude des VEPs und der Konzentrationsänderungen der vaskulären Parameter ([oxy-Hb] und [deoxy-Hb]) innerhalb des einminütigen Stimulationsblockes konnte ein Kopplungsindex definiert werden. Es ergab sich ein Abfall des [deoxy-Hb] um 0,02 µM und ein Anstieg des [oxy-Hb] um 0,06 µM pro 1 µV Zunahme der P100N135-Amplitude. Dieser Kopplungsindex war sowohl für den Stimulations- als auch den Habituationseffekt konstant. Diese Ergebnisse unterstützen die Vorstellung eines linearen Verhältnisses der neurovaskulären Kopplung und sprechen gegen eine transiente Entkopplung neuronaler Aktivität und vaskulärer Antwort aufgrund metabolischer Umstellungen.Non-invasive imaging methods of the brain are based on the neurovascular coupling, the phenomenon of an increased regional blood flow of functionally activated brain regions due to an increased energy demand. There are, however, a number of unresolved questions, i.e. regarding the translation from the neuronal activation to the vascular response. For prolonged stimulations a reduction of the vascular response has been shown. This led to the assumption of an transient uncoupling of neuronal activity and vascular signal due to a shift from non-oxidative to oxidative metabolism. So far, it is unclear, whether these changes could also be explained by neuronal habituation that will be mirrored by the closely linked vascular response. In this study, visually evoked potentials (VEP) and cerebral oxygenation changes, as measured by near-infrared spectroscopy (NIRS), are assessed to elucidate the relation between electrophysiological and vascular responses to a checkerboard stimulus reversing at 3 Hz. Habituation of either response is analysed on two time scales. Within the 1-min stimulation period a significant decrease in P100N135-component amplitude was closely coupled to a significant decrease in the amplitude of the oxygenation parameters (concentration changes in oxygenated and deoxygenated haemoglobin, [oxy-Hb] and [deoxy-Hb]). The analysis across the 13 successive stimulation blocks yields a trend for a decrease in the VEP-components' amplitude, not reflected in the vascular response. When calculating a ratio between the amplitude of the P100N135-component and the concentration changes in the vascular parameters a "coupling index" of a 0,02 µM decrease in [deoxy-Hb] and an increase of 0,06 µM in [oxy-Hb] is found per 1 µV increase in the P100N135-component amplitude. The ratio is the same irrespective of its assessment from the stimulation effect or the habituation effect. These results support the notion that the coupling between neuronal activation and the vascular response exhibits linear aspects and thus might argue against a transient uncoupling of neuronal activity and vascular response due to oxidative metabolism

The pharmacological profile and clinical prospects of the oral 5-HT1F receptor agonist lasmiditan in the acute treatment of migraine

More than 20 years have passed without the launch of a new substance class for acute migraine therapy. Triptans were the latest class of substances which successfully passed all developmental stages with a significant antimigraine efficacy and a sufficient safety profile. New drugs with a better adverse event profile and at least similar efficacy are needed for migraine subjects who cannot tolerate triptans for attack treatment. Lasmiditan is a novel highly specific 5-HT 1F receptor agonist currently in clinical trials for acute migraine therapy and devoid of vasoconstriction in coronary arteries as determined in a surrogate assay. In both phase II randomized, placebo-controlled trials in acute migraine the primary endpoint was met. For the intravenous formulation a clear dose-dependent effect on headaches could be determined. Lasmiditan tablets in doses of 50–400 mg show significant headache relief after 2 hours compared with placebo and improved accompanying symptoms. This substance is chemically clearly different from other antimigraine drugs, which is also reflected by its dose-dependent adverse event profile chiefly including dizziness, vertigo, paresthesia and fatigue. Adverse events are usually linked to the central nervous system. Future phase III clinical trials with an active triptan comparator or in a preferential trial design will allow a better comparison of lasmiditan and triptans. They will also determine whether lasmiditan will become available to the migraine patient