Altered Ratios of Beta-Endorphin : Beta-Lipotropin Released from Anterior Lobe Corticotropes with Increased Secretory Drive. I. Effects of Diminished Glucocorticoid Secretion

Previous studies have demonstrated that acute stress or ovine corticotropin-releasing hormone (oCRH) in vivo , or oCRH in vitro , stimulates release of Β-endorphin over Β-lipotropin from anterior pituitary corticotropes. This occurs despite the predominance of Β-lipotropin in corticotrope peptide stores. In vitro studies with primary anterior pituitary cultures suggested that chronic exposure to oCRH results in a shift towards more Β-lipotropin secretion into the media than with short-term exposure. The current studies explored whether increased secretory drive in vivo results in a similar shift towards more Β-lipotropin. We used removal of glucocorticoids by adrenalectomy or metyrapone blockade of corticosterone synthesis, to stimulate endogenous secretion of CRH and vasopressin. Both treatments resulted in shifts of the ratio of Β-endorphin: Β-lipotropin in plasma of experimental animals in comparison to the sham-treated control rats. In vitro testing with oCRH of anterior lobe cultures from adrenalectomized or metyrapone-treated rats demonstrated similar effects of these treatments on the ratio of Β-endorphin : Β-lipotropin. These changes occurred despite similar ratios of Β-endorphin : Β-lipotropin in anterior pituitary peptide stores.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75388/1/j.1365-2826.1993.tb00370.x.pd

TurbEFA: an interdisciplinary effort to investigate the turbulent flow across a forest clearing

the atmosphere within turbulence closure models is mainly limited by a realistic three-dimensional (3D) representation of the vegetation architecture. Within this contribution we present a method to record the 3D vegetation structure and to use this information to derive model parameters that are suitable for numerical flow models. A mixed conifer forest stand around a clearing was scanned and represented by a dense 3D point cloud applying a terrestrial laser scanner. Thus, the plant area density (PAD) with a resolution of one cubic meter was provided for analysis and for numerical simulations. Multi-level high-frequency wind velocity measurements were recorded simultaneously by 27 ultrasonic anemometers on 4 towers for a period of one year. The relationship between wind speed, Reynolds stress and PAD was investigated and a parametrization of the drag coefficient CD by the PAD is suggested. The derived 3D vegetation model and a simpler model (based on classical forest assessments of the site) were applied in a boundary layer model (BLM) and in large-eddy simulations (LES). The spatial development of the turbulent flow over the clearing is further demonstrated by the results of a wind tunnel experiment. The project showed, that the simulation results were improved significantly by the usage of realistic vegetation models. 3D simulations are necessary to depict the influence of heterogeneous canopies on the turbulent flow. Whereas we found limits for the mapping of the vegetation structure within the wind tunnel, there is a considerable potential for numerical simulations. The field measurements and the LES gave new insight into the turbulent flow in the vicinity and across the clearing. The results show that the zones of intensive turbulence development can not be restricted to the locations found in previous studies with more idealized canopies

Localization of the peptidylglycine α-amidating monooxygenase gene ( Pam ) introduces a region of homology between human Chromosome 5q and mouse Chromosome 1

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47008/1/335_2004_Article_BF00426085.pd

The role of immune checkpoint inhibitors in clinical practice: an analysis of the treatment patterns, survival and toxicity rates by sex.

PURPOSE Our aim is to describe the role of immune checkpoint inhibitors (ICI) in clinical practice by providing the patient and tumor characteristics as well as survival and toxicity rates by sex. METHODS We used electronic health records to identify patients treated at the Cancer Center of the University Hospital Bern, Switzerland between January 1, 2017 and June 16, 2021. RESULTS We identified 5109 patients, 689 of whom (13.5%) received at least one dose of ICI. The fraction of patients who were prescribed ICI increased from 8.6% in 2017 to 22.9% in 2021. ICI represented 13.2% of the anticancer treatments in 2017 and increased to 28.2% in 2021. The majority of patients were male (68.7%), who were older than the female patients (median age 67 vs. 61 years). Over time, adjuvant and first line treatments increased for both sexes. Lung cancer and melanoma were the most common cancer types in males and females. The incidence of irAEs was higher among females (38.4% vs. 28.1%) and lead more often to treatment discontination in females than in males (21.1% vs. 16.8%). Independent of sex, the occurrence of irAEs was associated with greater median overall survival (OS, not reached vs. 1.1 years). Female patients had a longer median OS than males (1.9 vs. 1.5 years). CONCLUSIONS ICI play an increasingly important role in oncology. irAEs are more frequent in female patients and are associated with a longer OS. More research is needed to understand the association between patient sex and toxicity and survival

TurbEFA: Ein interdisziplinärer Ansatz zur Untersuchung der turbulenten Strömung an einer Waldlichtung

Waldökosysteme spielen eine bedeutende Rolle in der Interaktion zwischen Landoberfläche und Atmosphäre. Ein besseres Verständnis der Austauschprozesse ist unter anderem notwendig für eine Einschätzung der Absorption und Emission von Spurenstoffen (z.B. CO2) und der Risiken von Waldschäden durch Wind, Frost und Dürre. Heutige Studien zur Rolle von terrestrischen Ökosystemen im Wasser- und Kohlenstoffkreislauf basieren auf langfristigen Messungen des Energie- und Massenaustausches zwischen Vegetation und Atmosphäre durch die Eddy-Kovarianz Methode (Goulden et al. 1996). Mehr als 500 Standorte weltweit sind derzeit in FLUXNET organisiert, einem internationalen Netzwerk (Baldocchi et al. 2001) zur kontinuierliche Messungen des Stoff- und Energieaustausches nach standardisierten Methoden (Aubinet et al. 2000). Der Austausch von Waldökosystemen wird dabei an einem Messturm durch eine Punktmessung über dem Bestand bestimmt, die eine bestimmte häufig komplexe Quellfläche repräsentiert. Mehr als drei Dekaden der Forschung in Feldexperimenten und Modellierung haben gezeigt, dass verbleibende Unsicherheiten vor allem durch räumliche Inhomogenität des Austausches begründet sind. Insbesondere fehlen Ansätze für eine geeignete Parametrisierung dieser Inhomogenitäten in numerischen Modellen

Probing the Production of Amidated Peptides following Genetic and Dietary Copper Manipulations

Amidated neuropeptides play essential roles throughout the nervous and endocrine systems. Mice lacking peptidylglycine α-amidating monooxygenase (PAM), the only enzyme capable of producing amidated peptides, are not viable. In the amidation reaction, the reactant (glycine-extended peptide) is converted into a reaction intermediate (hydroxyglycine-extended peptide) by the copper-dependent peptidylglycine-α-hydroxylating monooxygenase (PHM) domain of PAM. The hydroxyglycine-extended peptide is then converted into amidated product by the peptidyl-α-hydroxyglycine α-amidating lyase (PAL) domain of PAM. PHM and PAL are stitched together in vertebrates, but separated in some invertebrates such as Drosophila and Hydra. In addition to its luminal catalytic domains, PAM includes a cytosolic domain that can enter the nucleus following release from the membrane by γ-secretase. In this work, several glycine- and hydroxyglycine-extended peptides as well as amidated peptides were qualitatively and quantitatively assessed from pituitaries of wild-type mice and mice with a single copy of the Pam gene (PAM+/−) via liquid chromatography-mass spectrometry-based methods. We provide the first evidence for the presence of a peptidyl-α-hydroxyglycine in vivo, indicating that the reaction intermediate becomes free and is not handed directly from PHM to PAL in vertebrates. Wild-type mice fed a copper deficient diet and PAM+/− mice exhibit similar behavioral deficits. While glycine-extended reaction intermediates accumulated in the PAM+/− mice and reflected dietary copper availability, amidated products were far more prevalent under the conditions examined, suggesting that the behavioral deficits observed do not simply reflect a lack of amidated peptides

HOIL-1L Interacting Protein (HOIP) as an NF-κB Regulating Component of the CD40 Signaling Complex

The tumor necrosis factor receptor (TNFR) superfamily mediates signals critical for regulation of the immune system. One family member, CD40, is important for the efficient activation of antibody-producing B cells and other antigen-presenting cells. The molecules and mechanisms that mediate CD40 signaling are only partially characterized. Proteins known to interact with the cytoplasmic domain of CD40 include members of the TNF receptor-associated factor (TRAF) family, which regulate signaling and serve as links to other signaling molecules. To identify additional proteins important for CD40 signaling, we used a combined stimulation/immunoprecipitation procedure to isolate CD40 signaling complexes from B cells and characterized the associated proteins by mass spectrometry. In addition to known CD40-interacting proteins, we detected SMAC/DIABLO, HTRA2/Omi, and HOIP/RNF31/PAUL/ZIBRA. We found that these previously unknown CD40-interacting partners were recruited in a TRAF2-dependent manner. HOIP is a ubiquitin ligase capable of mediating NF-κB activation through the ubiquitin-dependent activation of IKKγ. We found that a mutant HOIP molecule engineered to lack ubiquitin ligase activity inhibited the CD40-mediated activation of NF-κB. Together, our results demonstrate a powerful approach for the identification of signaling molecules associated with cell surface receptors and indicate an important role for the ubiquitin ligase activity of HOIP in proximal CD40 signaling

POMC: The Physiological Power of Hormone Processing.

Pro-opiomelanocortin (POMC) is the archetypal polypeptide precursor of hormones and neuropeptides. In this review, we examine the variability in the individual peptides produced in different tissues and the impact of the simultaneous presence of their precursors or fragments. We also discuss the problems inherent in accurately measuring which of the precursors and their derived peptides are present in biological samples. We address how not being able to measure all the combinations of precursors and fragments quantitatively has affected our understanding of the pathophysiology associated with POMC processing. To understand how different ratios of peptides arise, we describe the role of the pro-hormone convertases (PCs) and their tissue specificities and consider the cellular processing pathways which enable regulated secretion of different peptides that play crucial roles in integrating a range of vital physiological functions. In the pituitary, correct processing of POMC peptides is essential to maintain the hypothalamic-pituitary-adrenal axis, and this processing can be disrupted in POMC-expressing tumors. In hypothalamic neurons expressing POMC, abnormalities in processing critically impact on the regulation of appetite, energy homeostasis, and body composition. More work is needed to understand whether expression of the POMC gene in a tissue equates to release of bioactive peptides. We suggest that this comprehensive view of POMC processing, with a focus on gaining a better understanding of the combination of peptides produced and their relative bioactivity, is a necessity for all involved in studying this fascinating physiological regulatory phenomenon

Characterization of the Conus bullatus genome and its venom-duct transcriptome

<p>Abstract</p> <p>Background</p> <p>The venomous marine gastropods, cone snails (genus <it>Conus</it>), inject prey with a lethal cocktail of conopeptides, small cysteine-rich peptides, each with a high affinity for its molecular target, generally an ion channel, receptor or transporter. Over the last decade, conopeptides have proven indispensable reagents for the study of vertebrate neurotransmission. <it>Conus bullatus </it>belongs to a clade of <it>Conus </it>species called <it>Textilia</it>, whose pharmacology is still poorly characterized. Thus the genomics analyses presented here provide the first step toward a better understanding the enigmatic <it>Textilia </it>clade.</p> <p>Results</p> <p>We have carried out a sequencing survey of the <it>Conus bullatus </it>genome and venom-duct transcriptome. We find that conopeptides are highly expressed within the venom-duct, and describe an <it>in silico </it>pipeline for their discovery and characterization using RNA-seq data. We have also carried out low-coverage shotgun sequencing of the genome, and have used these data to determine its size, genome-wide base composition, simple repeat, and mobile element densities.</p> <p>Conclusions</p> <p>Our results provide the first global view of venom-duct transcription in any cone snail. A notable feature of <it>Conus bullatus </it>venoms is the breadth of A-superfamily peptides expressed in the venom duct, which are unprecedented in their structural diversity. We also find SNP rates within conopeptides are higher compared to the remainder of <it>C. bullatus </it>transcriptome, consistent with the hypothesis that conopeptides are under diversifying selection.</p