bluuebunny/crossref_metadata_2025 huggingface dataset:
In vitroandin vivo antibacterial activities of rhizophora man-gle l. against helicobacter pylori. chemical compounds elucida-tion
Authors: Luz MarÃ­a SÃ¡nchez Perera , MarÃ­a Rosario Morales Espinosa , Guillermo Delgado Lamas , Sergio De MendonÃ§a , Diego Miguel Cortes , Rafael RamÃ­rez Miranda
Published: March 2017

Rhizophora mangle L. is a vegetal species widely distributed in Cuba and other Caribbean countries with ethno- pharmacology relevance and preview reports as antiulcer and wound healing properties. The present work describes the in vitro and in vivo antibacterial activities of dried aqueous extract of bark and polyphenol fractions from R. mangle against Helicobacter pylori and the identification of new compounds in the active extracts. Minimum inhibitory concentration (MIC) and Minimum bactericide concentration (MBC) were evaluated against reference and clinical Helicobacter pylori strains with total extract, High Molecular Weight and Low Molecular Weight fractions isolated from total extract. Positive active fractions in vitro tests were evaluated in vivo using H. pylori C57BL/6 mice. Fractionation, isolation and structural elucidation of the compounds on High Molecular Weigh fraction and on Low Molecular Weight fraction were made using Chromatography methods and Mass and H+NMR spectrometry. Total aqueous extract from bark of R. mangle and some fraction shown promissory antibacterial activity on in vitro and in vivo models. It was isolated and identified proantocyanidin, catechin and epicatechin derivates, cyanidin and other compounds in this promissory extract. These results appoint to total extract with a promissory active principle in the development of phytodrug with antibacterial effect and as proton pump inhibitor by the treatment of gastroduodenal ulcer.
Die neue Zeitenwende in den internationalen Beziehungen – Konsequenzen für deutsche und europäische Politik
Authors: Krause Joachim
Published: March 2017

Kurzfassung:

Die internationalen Beziehungen machen derzeit einen fundamentalen Wandel durch, der Ähnlichkeiten mit früheren wechselhaften Perioden der Geschichte aufweist. Oft gingen diese Perioden in Krieg und Instabilität über, wenn es nicht gelang, neue politische Ordnungsmuster zu verankern. Die derzeitige Phase ist gekennzeichnet durch den Zerfall einer unter Bedingungen westlicher Hegemonie gestalteten internationalen Ordnung, die droht in eine Phase der Anarchie überzugehen. Die Ursachen dafür dürften in Folgewirkungen der Globalisierung und anderer Elemente der liberalen Ordnung zu suchen sein, die bislang zu wenig Beachtung fanden.
Innenpolitische Determinanten der Putinschen Außenpolitik
Authors: Adomeit Hannes
Published: March 2017

Kurzfassung:

Die konfrontative russische Außenpolitik wird oft als Reaktion auf angebliche Fehler des Westens gesehen. Tatsächlich sind es hauptsächlich innere Faktoren, die das russische Außenverhalten bestimmen. Im Wesentlichen wird das außenpolitische Verhalten Russlands aus der Krise des von Putin geschaffenen Regierungssystems (einer korrupten, anti-liberalen und undemokratischen Machtvertikale) erklärbar. Dieses System tendiert dazu, innere Stabilisierung durch das Schüren von äußeren Konflikten zu suchen und dabei die Lösung der zentralen wirtschaftlichen und gesellschaftlichen Probleme zu vernachlässigen. Zeitweilig wurde dieses Machtsystem auch innerhalb der russischen Machtelite als dysfunktional für die wirtschaftliche Modernisierung und damit als existenzgefährdend für das Land angesehen. Die von Präsident Dmitri Medwedew eingeleitete Modernisierungspartnerschaft mit dem Westen sollte diese Defizite abbauen, ist aber heute gescheitert.
Grundzüge einer neuen NATO-Strategie
Authors: Kamp Karl-Heinz
Published: March 2017

Kurzfassung:

Angesichts der fundamentalen Veränderungen in den vergangenen Jahren kommt die NATO nicht umhin, ihre strategischen Grundlagen an die Realitäten einer Welt anzupassen, in der es darum geht sich auch auf reale Bedrohungen (Art. 5) einzustellen. Die Verständigung auf neue Kernaufgaben wird kein einfaches Unterfangen sein, weil die Mitgliedstaaten von unterschiedlichen Gefahren in unterschiedlicher Weise betroffen sind. Die Erfahrungen mit dem Strategischen Konzept von 2010 haben allerdings gezeigt, dass nicht nur der Diskussionsprozess einen Wert in sich darstellt, sondern auch trotz unterschiedlicher Positionen Konsens in substanziellen Fragen gefunden werden kann. Sich einer strategischen Debatte aus Furcht vor sichtbarem Dissens zu verweigern, ist keine Option für ein Bündnis, das sich gerade durch die Kontroverse um Mittel und Ziele immer wieder an neue Herausforderungen angepasst hat.
Strategic Foresight – Die Zukunft antizipieren
Authors: Klüfers Philipp , Masala Carlo , Tepel Tim , Tsetsos Konstantinos
Published: March 2017

Strategische Vorausschau wird zunehmend in Politik und Wirtschaft nachgefragt. Der Beitrag liefert einen Überblick über die gängigsten Methoden dieser Form der Zukunftsanalyse. Die Autoren konzentrieren sich dabei auf methodische Anforderungen, die Kategorisierung unterschiedlicher methodischer Ansätze, die Bewertung von deren Stärken und Schwächen sowie die Identifikation relevanter Anwendungsfelder. Zudem widmen sie sich der Problematik der Ableitung von Handlungsempfehlungen und diskutieren die Sinnhaftigkeit strategischer Vorausschau zur Entscheidungsunterstützung.
Russia changes the game: Bilanz der russischen Militärintervention in Syrien
Authors: Bino Tomisha , Krause Joachim
Published: March 2017

Kurzfassung:

Die seit Herbst 2015 laufende russische Militärintervention in Syrien hat nicht nur die Lage vor Ort verändert, sondern auch die strategische Lage im Nahen und Mittleren Osten auf den Kopf gestellt. Russland hat demonstriert, dass es im östlichen Mittelmeerraum über militärische Handlungsfähigkeit verfügt. Mit ihrer zögerlichen Haltung hat die Regierung in Washington Russland einWindow of Opportunityeröffnet. Die Russen im Nachhinein zu einer Aufgabe ihres Einsatzes zu zwingen, ist für die USA kaum möglich, es sei denn sie sind zu einer massiven Eskalation bereit. Die Intervention hat das scheinbar unvermeidliche Ende des Assad-Regimes abwenden können und hat das Bündnis zwischen Russland und dem Iran gestärkt, was innerhalb der sunnitischen arabischen Welt zu großer Besorgnis beiträgt.
‘The Times They are a Changin' – Fundamental Structural Change in International Relations as a Challenge for Germany and Europe
Authors: Krause Joachim
Published: March 2017

The international system is going through a period of fundamental change, which has similarities with earlier periods in history. Such periods of change might usher into war and instability if it turned out to be impossible to arrive at a new international order. The current period of change is characterized by the collapse of a liberal international order, which was established under conditions of Western hegemony. The coming anarchy is the consequence of unforeseen structural changes wrought about by globalization and other developments associated with the global spread of the liberal order.
Invisible minimalism
Authors: Falcato Ana
Published: March 2017

This essay attempts a rapprochement between Kent Bach’s view on semantic minimalism and the most radical version of contextualism about language on offer: Charles Travis’s occasion-sensitivity. Despite common assumptions held by defenders of semantic literalism – which cast Bach’s proposal as a form of contextualism – Bach rejects all conceivable forms of contextualism. In this paper, I argue that in spite of his systematic rejection of contextualism, Bach’s position bears a striking resemblance to Travis’s occasion-sensitivity. Further, when analyzed in light of the conceptual framework developed by Travis, Bach’s strand of minimalism can be shown to contain a deep-rooted conceptual inconsistency to the extent that he aims to ascribe “pure semantic content” to a linguistic entity that is necessarily pragmatic.
Representing ordinary people: experiential interview fragments in CCTV News
Authors: Feng Debing
Published: March 2017

The television news interview has been widely studied in the field of Conversation Analysis. Few researchers, however, have paid attention to the interview fragments that often occur in news bulletin programs. This article applies Conversation Analysis and the notion of recontextualization to the analysis of experiential interview fragments deployed in CCTV News. It is shown that this type of fragments enjoys a relatively fixed sequence structure: introduction–fragment, where the fragment consists of (question+) answer turns. The introduction may be designed to raise a question, offer background information or summarize key points. The fragment itself, unlike a complete interview, is often selected and designed to achieve particular communicative purposes. In CCTV News, for example, the fragments tend to be employed to represent ordinary people’s experience, beneficiary identity and positive image, among others.
Who is the victim? When the addresser of the echoed utterance and the target of the irony differ
Authors: Hirsch Galia
Published: March 2017

The goal of this contribution is to explore the relationship between the target of certain ironic instances and the source of their echoic mentions (Sperber and Wilson, “Irony and the use-mention distinction,” in Peter Cole’s
Patient participation in action: patients’ interactional initiatives during interdisciplinary goal-setting meetings in a rehabilitation clinic
Authors: Keel Sara , Schoeb Veronika
Published: March 2017

Clinical guidelines require the patient’s participation in the entire rehabilitation process, including discharge planning. However, very little is known about how this institutional requirement is actually dealt with in everyday clinical practice. Adopting a conversation analytic approach, our paper tackles the matter, looking at situations in which patients achieve interactional initiatives within interdisciplinary entry meetings (IEMs) at a rehabilitation clinic in German-speaking Switzerland. Based on audio-visual recordings of 11 IEMs, whose central aim is to formulate patients’ rehabilitation goals and to plan their discharge, the paper offers a detailed analysis of two conversational environments in which patients accomplish initiatives: incipient disagreement among the interdisciplinary team and difficulties faced by the professionals in moving towards the formulation of a goal. In both situations, the progress of the activity is at stake. Moreover, the analysis reveals the interactive and stepwise accomplishment of patients’ initiatives. Our paper argues that shedding light on how patients’ initiatives are interactively implemented makes it possible to discuss how issues of epistemic rights and entitlement to participate are locally negotiated. In the final discussion, the paper raises the question of how patients’ competence in intervening in the goal-formulation activity can be taken into account in clinical guidelines on patient participation.
A rose is more than a rose … the diatextual constitution of subjects and objects
Authors: Mininni Giuseppe , Manuti Amelia
Published: March 2017

This paper integrates contributions coming from psychology with a phenomenological and semiotic perspective and focuses on the relationship of reciprocal constitution between “Subject” and “Object.” This relationship is evoked through radically different concepts such as the notions of “experience,” “consciousness” and “embodiment,” focusing attention on “discourse” as a macro-procedure generating the mutual link between Subject and Object. Therefore, the relationship between subject and object is identifiable through the text, namely “diatext.” It will be further argued that human beings act as “diatexters” of their existence in the world. Accordingly, psycho-discursive practices have the performative power to constitute both objects and subjects because they offer a creative solution by interlacing the “Body-Mind-Problem” to the “Mind-Culture-Problem.” In detail, the discursive resource granted by metaphors may be recognized as a modelling matrix embodying thought, as the interweaving of conceptual fields and as reasoning processes.
Different sensitivities of photosystem II in green algae and cyanobacteria to phenylurea and phenol-type herbicides: effect on electron donor side
Authors: Yotsova Ekaterina K. , Stefanov Martin A. , Dobrikova Anelia G. , Apostolova Emilia L.
Published: March 2017

The effects of short-term treatment with phenylurea (DCMU, isoproturon) and phenol-type (ioxynil) herbicides on the green alga Chlorella kessleri and the cyanobacterium Synechocystis salina with different organizations of photosystem II (PSII) were investigated using pulse amplitude modulated (PAM) chlorophyll fluorescence and photosynthetic oxygen evolution measured by polarographic oxygen electrodes (Clark-type and Joliot-type). The photosynthetic oxygen evolution showed stronger inhibition than the PSII photochemistry. The effects of the studied herbicides on both algal and cyanobacterial cells decreased in the following order: DCMU>isoproturon>ioxynil. Furthermore, we observed that the number of blocked PSII centers increased significantly after DCMU treatment (204–250 times) and slightly after ioxynil treatment (19–35 times) in comparison with the control cells. This study suggests that the herbicides affect not only the acceptor side but also the donor side of PSII by modifications of the Mn cluster of the oxygen-evolving complex. We propose that one of the reasons for the different PSII inhibitions caused by herbicides is their influence, in different extents, on the kinetic parameters of the oxygen-evolving reactions (the initial S0−S1 state distribution, the number of blocked centers SB, the turnover time of Si states, misses and double hits). The relationship between the herbicide-induced inhibition and the changes in the kinetic parameters is discussed.
Parallel Specification of Visuomotor Feedback Gains during Bimanual Reaching to Independent Goals
Authors: de Brouwer Anouk J. , Jarvis Tayler , Gallivan Jason P. , Flanagan J. Randall
Published: March 2017

During goal-directed reaching, rapid visuomotor feedback processes enable the human motor system to quickly correct for errors in the trajectory of the hand that arise from motor noise and, in some cases, external perturbations. To date, these visuomotor responses, the gain of which is sensitive to features of the task and environment, have primarily been examined in the context of unimanual reaching movements toward a single target. However, many natural tasks involve moving both hands together, often to separate targets, such that errors can occur in parallel and at different spatial locations. Here, we examined the resource capacity of automatic visuomotor corrective mechanisms by comparing feedback gains during bimanual reaches, toward two targets, to feedback gains during unimanual reaches toward single targets. To investigate the sensitivity of the feedback gains and their relation to visual-spatial processing, we manipulated the widths of the targets and participants’ gaze location. We found that the gain of corrective responses to cursor displacements, while strongly modulated by target width and gaze position, were only slightly reduced during bimanual control. Our results show that automatic visuomotor corrective mechanisms can efficiently operate in parallel across multiple spatial locations.
Inhibition of L-Type Ca2+Channels by TRPC1-STIM1 Complex Is Essential for the Protection of Dopaminergic Neurons
Authors: Sun Yuyang , Zhang Haopeng , Selvaraj Senthil , Sukumaran Pramod , Lei Saobo , Birnbaumer Lutz , Singh Brij B.
Published: March 2017

Loss of dopaminergic (DA) neurons leads to Parkinson's disease; however, the mechanism(s) for the vulnerability of DA neurons is(are) not fully understood. We demonstrate that TRPC1 regulates the L-type Ca2+channel that contributes to the rhythmic activity of adult DA neurons in the substantia nigra region. Store depletion that activates TRPC1, via STIM1, inhibits the frequency and amplitude of the rhythmic activity in DA neurons of wild-type, but not in TRPC1−/−, mice. Similarly, TRPC1−/−substantia nigra neurons showed increased L-type Ca2+currents, decreased stimulation-dependent STIM1-Cav1.3 interaction, and decreased DA neurons. L-type Ca2+currents and the open channel probability of Cav1.3 channels were also reduced upon TRPC1 activation, whereas increased Cav1.3 currents were observed upon STIM1 or TRPC1 silencing. Increased interaction between Cav1.3-TRPC1-STIM1 was observed upon store depletion and the loss of either TRPC1 or STIM1 led to DA cell death, which was prevented by inhibiting L-type Ca2+channels. Neurotoxins that mimic Parkinson's disease increased Cav1.3 function, decreased TRPC1 expression, inhibited Tg-mediated STIM1-Cav1.3 interaction, and induced caspase activation. Importantly, restoration of TRPC1 expression not only inhibited Cav1.3 function but increased cell survival. Together, we provide evidence that TRPC1 suppresses Cav1.3 activity by providing an STIM1-based scaffold, which is essential for DA neuron survival.

SIGNIFICANCE STATEMENTCa2+entry serves critical cellular functions in virtually every cell type, and appropriate regulation of Ca2+in neurons is essential for proper function. In Parkinson's disease, DA neurons are specifically degenerated, but the mechanism is not known. Unlike other neurons, DA neurons depend on Cav1.3 channels for their rhythmic activity. Our studies show that, in normal conditions, the pacemaking activity in DA neurons is inhibited by the TRPC1-STIM1 complex. Neurotoxins that mimic Parkinson's disease target TRPC1 expression, which leads to an abnormal increase in Cav1.3 activity, thereby causing degeneration of DA neurons. These findings link TRPC1 to Cav1.3 regulation and provide important indications about how disrupting Ca2+balance could have a direct implication in the treatment of Parkinson's patients.
EphA4 Regulates Neuroblast and Astrocyte Organization in a Neurogenic Niche
Authors: Todd Krysti L. , Baker Kasey L. , Eastman Matthew B. , Kolling Frederick W. , Trausch Alexandra G. , Nelson Craig E. , Conover Joanne C.
Published: March 2017

Significant migration cues are required to guide and contain newly generated rodent subventricular zone (SVZ) neuroblasts as they transit along the lateral ventricles and then through the anterior forebrain to their ultimate site of differentiation in the olfactory bulbs (OBs). These cues enforce strict neuroblast spatial boundaries within the dense astroglial meshwork of the SVZ and rostral migratory stream (RMS), yet are permissive to large-scale neuroblast migration. Therefore, the molecular mechanisms that define these cues and control dynamic interactions between migratory neuroblasts and surrounding astrocytes are of particular interest. We found that deletion of EphA4 and specifically ablation of EphA4 kinase activity resulted in misaligned neuroblasts and disorganized astrocytes in the RMS/SVZ, linking EphA4 forward signaling to SVZ and RMS spatial organization, orientation, and regulation. In addition, within a 3 week period, there was a significant reduction in the number of neuroblasts that reached the OB and integrated into the periglomerular layer, revealing a crucial role for EphA4 in facilitating efficient neuroblast migration to the OB. Single-cell analysis revealed thatEPHA4and itsEFNbinding partners are expressed by subpopulations of neuroblasts and astrocytes within the SVZ/RMS/OB system resulting in a cell-specific mosaic, suggesting complex EphA4 signaling involving both homotypic and heterotypic cell–cell interactions. Together, our studies reveal a novel molecular mechanism involving EphA4 signaling that functions in stem cell niche organization and ultimately neuroblast migration in the anterior forebrain.

SIGNIFICANCE STATEMENTThe subventricular zone neurogenic stem cell niche generates highly migratory neuroblasts that transit the anterior forebrain along a defined pathway to the olfactory bulb. Postnatal and adult brain organization dictates strict adherence to a narrow migration corridor. Subventricular zone neuroblasts are aligned in tightly bundled chains within a meshwork of astrocytes; however, the cell–cell cues that organize this unique, cell-dense migration pathway are largely unknown. Our studies show that forward signaling through the EphA4 tyrosine kinase receptor, mediated by ephrins expressed by subpopulations of neuroblasts and astrocytes, is required for compact, directional organization of neuroblasts and astrocytes within the pathway and efficient transit of neuroblasts through the anterior forebrain to the olfactory bulb.
Locomotion Induces Stimulus-Specific Response Enhancement in Adult Visual Cortex
Authors: Kaneko Megumi , Fu Yu , Stryker Michael P.
Published: March 2017

The responses of neurons in the visual cortex (V1) of adult mammals have long been thought to be stable over long periods. Here, we investigated whether repeated exposure to specific stimuli would enhance V1 visual responses in mice using intrinsic signal imaging through the intact skull and two-photon imaging of calcium signals in single neurons. Mice ran on Styrofoam balls floating on air while viewing one of three different, high-contrast visual stimuli. V1 responses to the stimuli that were viewed by the animal were specifically enhanced, while responses to other stimuli were unaffected. Similar exposure in stationary mice or in mice in which NMDA receptors were partially blocked did not significantly enhance responses. These findings indicate that stimulus-specific plasticity in the adult visual cortex depends on concurrent locomotion, presumably as a result of the high-gain state of the visual cortex induced by locomotion.

SIGNIFICANCE STATEMENTWe report a rapid and persistent increase in visual cortical responses to visual stimuli presented during locomotion in intact mice. We first used a method that is completely noninvasive to image intrinsic signals through the intact skull. We then measured the same effects on single neurons using two-photon calcium imaging and found that the increase in response to a particular stimulus produced by locomotion depends on how well the neuron is initially driven by the stimulus. To our knowledge, this is the first time such enhancement has been described in single neurons or using noninvasive measurements.
Uncoupling of neurogenesis and differentiation during retinal development
Authors: Engerer Peter , Suzuki Sachihiro C , Yoshimatsu Takeshi , Chapouton Prisca , Obeng Nancy , Odermatt Benjamin , Williams Philip R , Misgeld Thomas , Godinho Leanne
Published: March 2017

Conventionally, neuronal development is regarded to follow a stereotypic sequence of neurogenesis, migration, and differentiation. We demonstrate that this notion is not a general principle of neuronal development by documenting the timing of mitosis in relation to multiple differentiation events for bipolar cells (BCs) in the zebrafish retina using in vivo imaging. We found that BC progenitors undergo terminal neurogenic divisions while in markedly disparate stages of neuronal differentiation. Remarkably, the differentiation state of individual BC progenitors at mitosis is not arbitrary but matches the differentiation state of post‐mitotic BCs in their surround. By experimentally shifting the relative timing of progenitor division and differentiation, we provide evidence that neurogenesis and differentiation can occur independently of each other. We propose that the uncoupling of neurogenesis and differentiation could provide neurogenic programs with flexibility, while allowing for synchronous neuronal development within a continuously expanding cell pool.
The linear ubiquitin chain assembly complex regulates TRAIL‐induced gene activation and cell death
Authors: Lafont Elodie , Kantari‐Mimoun Chahrazade , Draber Peter , De Miguel Diego , Hartwig Torsten , Reichert Matthias , Kupka Sebastian , Shimizu Yutaka , Taraborrelli Lucia , Spit Maureen , Sprick Martin R , Walczak Henning
Published: March 2017

The linear ubiquitin chain assembly complex (LUBAC) is the only known E3 ubiquitin ligase which catalyses the generation of linear ubiquitin linkages de novo. LUBAC is a crucial component of various immune receptor signalling pathways. Here, we show that LUBAC forms part of the TRAIL‐R‐associated complex I as well as of the cytoplasmic TRAIL‐induced complex II. In both of these complexes, HOIP limits caspase‐8 activity and, consequently, apoptosis whilst being itself cleaved in a caspase‐8‐dependent manner. Yet, by limiting the formation of a RIPK1/RIPK3/MLKL‐containing complex, LUBAC also restricts TRAIL‐induced necroptosis. We identify RIPK1 and caspase‐8 as linearly ubiquitinated targets of LUBAC following TRAIL stimulation. Contrary to its role in preventing TRAIL‐induced RIPK1‐independent apoptosis, HOIP presence, but not its activity, is required for preventing necroptosis. By promoting recruitment of the IKK complex to complex I, LUBAC also promotes TRAIL‐induced activation of NF‐κB and, consequently, the production of cytokines, downstream of FADD, caspase‐8 and cIAP1/2. Hence, LUBAC controls the TRAIL signalling outcome from complex I and II, two platforms which both trigger cell death and gene activation.
Mortality in Graves’ orbitopathy is increased and influenced by gender, age and pre-existing morbidity: a nationwide Danish register study
Authors: Schwensen Charlotte F , Brandt Frans , Hegedüs Laszlo , Brix Thomas H
Published: March 2017

Introduction

It is unclear whether the excess mortality associated with Graves’ disease differs between individuals with Graves’ orbitopathy (GO) or without (GD).

Subjects and methods

A nationwide, register-based cohort study in which all adult Danes diagnosed with GD (n = 28 461) and GO (n = 3965) between 1995 and 2012 were matched for age and gender with four control subjects. Median follow-up time was 7.9 years (range 0–17.5). Mortality risk in GO patients compared to the control population and compared to GD patients was calculated using Cox regression analyses, adjusting for pre-existing morbidity using the Charlson score.

Results

Adjusted mortality in Graves’ disease overall (GD + GO) was significantly increased compared to that in the background population (HR = 1.18 (95% confidence interval: 1.15–1.21)). In GD and GO separately, adjusted mortality was also significantly higher than that in their respective control populations (HR: 1.19 (1.16–1.22) and HR: 1.23 (1.12–1.35) respectively). However, mortality in GO compared to that in GD was decreased (HR: 0.64 (0.59–0.69)), although this difference attenuated after adjustment for pre-existing morbidity, age and gender. Both GD and GO males had a significantly higher mortality than those in females. For GO, but not for GD, mortality risk was the highest in the youngest and decreased with increasing age.

Conclusions

GD and GO were associated with increased mortality, especially in males. In GO, but not in GD patients, there was an inverse relationship between age and mortality. Surprisingly, and in need of further study, mortality was not higher in GO than that in GD individuals.
DIAGNOSIS OF ENDOCRINE DISEASE: Expanding the cause of hypopituitarism
Authors: Pekic Sandra , Popovic Vera
Published: March 2017

Hypopituitarism is defined as one or more pituitary hormone deficits due to a lesion in the hypothalamic–pituitary region. By far, the most common cause of hypopituitarism associated with a sellar mass is a pituitary adenoma. A high index of suspicion is required for diagnosing hypopituitarism in several other conditions such as other massess in the sellar and parasellar region, brain damage caused by radiation and by traumatic brain injury, vascular lesions, infiltrative/immunological/inflammatory diseases (lymphocytic hypophysitis, sarcoidosis and hemochromatosis), infectious diseases and genetic disorders. Hypopituitarism may be permanent and progressive with sequential pattern of hormone deficiencies (radiation-induced hypopituitarism) or transient after traumatic brain injury with possible recovery occurring years from the initial event. In recent years, there is increased reporting of less common and less reported causes of hypopituitarism with its delayed diagnosis. The aim of this review is to summarize the published data and to allow earlier identification of populations at risk of hypopituitarism as optimal hormonal replacement may significantly improve their quality of life and life expectancy.
Impaired adipose expansion caused by liver X receptor activation is associated with insulin resistance in mice fed a high-fat diet
Authors: Dong Yueting , Xu Zhiye , Zhang Ziyi , Yin Xueyao , Lin Xihua , Li Hong , Zheng Fenping
Published: March 2017

Liver X receptors (LXR) are deemed as potential drug targets for atherosclerosis, whereas a role in adipose tissue expansion and its relation to insulin sensitivity remains unclear. To assess the metabolic effects of LXR activation by the dual LXRα/β agonist T0901317, C57BL/6 mice fed a high-fat diet (HFD) were treated with T0901317 (30 mg/kg once daily by intraperitoneal injection) for 3 weeks. Differentiated 3T3-L1 adipocytes were used for analysing the effect of T0901317 on glucose uptake. The following results were obtained from this study. T0901317 reduced fat mass, accompanied by a massive fatty liver and lower serum adipokine levels in HFD mice. Increased adipocyte apoptosis was found in epididymal fat of T0901317-treated HFD mice. In addition, T0901317 treatment promoted basal lipolysis, but blunted the anti-lipolytic action of insulin. Furthermore, LXR activation antagonised PPARγ target genes in epididymal fat and PPARγ-PPRE-binding activity in 3T3-L1 adipocytes. Although the glucose tolerance was comparable to that in HFD mice, the insulin response during IPGTT was significantly higher and the insulin tolerance was significantly impaired in T0901317-treated HFD mice, indicating decreased insulin sensitivity by T0901317 administration, and which was further supported by impaired insulin signalling found in epididymal fat and decreased insulin-induced glucose uptake in 3T3-L1 adipocytes by T0901317 administration. In conclusion, these findings reveal that LXR activation impairs adipose expansion by increasing adipocyte apoptosis, lipolysis and antagonising PPARγ-mediated transcriptional activity, which contributes to decreased insulin sensitivity in whole body. The potential of LXR activation being a therapeutic target for atherosclerosis might be limited by the possibility of exacerbating insulin resistance.
Maternal metabolic stress may affect oviduct gatekeeper function
Authors: Jordaens L , Van Hoeck V , Maillo V , Gutierrez-Adan A , Marei W F A , Vlaeminck B , Thys S , Sturmey R G , Bols P E J , Leroy J L M R
Published: March 2017

We hypothesized that elevated non-esterified fatty acids (NEFA) modify in vitro bovine oviduct epithelial cell (BOEC) metabolism and barrier function. Hereto, BOECs were studied in a polarized system with 24-h treatments at Day 9: (1) control (0 µM NEFA + 0% EtOH), (2) solvent control (0 µM NEFA + 0.45% EtOH), (3) basal NEFA (720 µM NEFA + 0.45% EtOH in the basal compartment) and (4) apical NEFA (720 µM NEFA + 0.45% EtOH in the apical compartment). FITC-albumin was used for monolayer permeability assessment and related to transepithelial electric resistance (TER). Fatty acid (FA), glucose, lactate and pyruvate concentrations were measured in spent medium. Intracellular lipid droplets (LD) and FA uptake were studied using Bodipy 493/503 and immunolabelling of FA transporters (FAT/CD36, FABP3 and CAV1). BOEC-mRNA was retrieved for qRT-PCR. Results revealed that apical NEFA reduced relative TER increase (46.85%) during treatment and increased FITC–albumin flux (27.59%) compared to other treatments. In basal NEFA, FAs were transferred to the apical compartment as free FAs: mostly palmitic and oleic acid increased respectively 56.0 and 33.5% of initial FA concentrations. Apical NEFA allowed no FA transfer, but induced LD accumulation and upregulated FA transporter expression (↑CD36, ↑FABP3 and ↑CAV1). Gene expression in apical NEFA indicated increased anti-apoptotic (↑BCL2) and anti-oxidative (↑SOD1) capacity, upregulated lipid metabolism (↑CPT1, ↑ACSL1 and ↓ACACA) and FA uptake (↑CAV1). All treatments had similar carbohydrate metabolism and oviduct function-specific gene expression (OVGP1, ESR1 and FOXJ1). Overall, elevated NEFAs affected BOEC metabolism and barrier function differently depending on NEFA exposure side. Data substantiate the concept of the oviduct as a gatekeeper that may actively alter early embryonic developmental conditions.
Doxorubicin and vincristine affect undifferentiated rat spermatogonia
Authors: Beaud Hermance , van Pelt Ans , Delbes Geraldine
Published: March 2017

Anticancer drugs, such as alkylating agents, can affect male fertility by targeting the DNA of proliferative spermatogonial stem cells (SSC). Therefore, to reduce such side effects, other chemotherapeutics are used. However, less is known about their potential genotoxicity on SSC. Moreover, DNA repair mechanisms in SSC are poorly understood. To model treatments deprived of alkylating agents that are commonly used in cancer treatment, we tested the impact of exposure to doxorubicin and vincristine, alone or in combination (MIX), on a rat spermatogonial cell line with SSC characteristics (GC-6spg). Vincristine alone induced a cell cycle arrest and cell death without genotoxic impact. On the other hand, doxorubicin and the MIX induced a dose-dependent cell death. More importantly, doxorubicin and the MIX induced DNA breaks, measured by the COMET assay, at a non-cytotoxic dose. To elucidate which DNA repair pathway is activated in spermatogonia after exposure to doxorubicin, we screened the expression of 75 genes implicated in DNA repair. Interestingly, all were expressed constitutively in GC-6spg, suggesting great potential to respond to genotoxic stress. Doxorubicin treatments affected the expression of 16 genes (>1.5 fold change;P < 0.05) involved in cell cycle, base/nucleotide excision repair, homologous recombination and non-homologous end joining (NHEJ). The significant increase in CDKN1A and XRCC1 suggest a cell cycle arrest and implies an alternative NHEJ pathway in response to doxorubicin-induced DNA breaks. Together, our results support the idea that undifferentiated spermatogonia have the ability to respond to DNA injury from chemotherapeutic compounds and escape DNA break accumulation.
A Whole-Transcriptome Approach to Evaluating Reference Genes for Quantitative Gene Expression Studies: A Case Study in Mimulus
Authors: Stanton Kimmy A , Edger Patrick P , Puzey Joshua R , Kinser Taliesin , Cheng Philip , Vernon Daniel M , Forsthoefel Nancy R , Cooley Arielle M
Published: March 2017

While quantitative PCR (qPCR) is widely recognized as being among the most accurate methods for quantifying gene expression, it is highly dependent on the use of reliable, stably expressed reference genes. With the increased availability of high-throughput methods for measuring gene expression, whole-transcriptome approaches may be increasingly utilized for reference gene selection and validation. In this study, RNA-seq was used to identify a set of novel qPCR reference genes and evaluate a panel of traditional “housekeeping” reference genes in two species of the evolutionary model plant genus Mimulus. More broadly, the methods proposed in this study can be used to harness the power of transcriptomes to identify appropriate reference genes for qPCR in any study organism, including emerging and nonmodel systems. We find that RNA-seq accurately estimates gene expression means in comparison to qPCR, and that expression means are robust to moderate environmental and genetic variation. However, measures of expression variability were only in agreement with qPCR for samples obtained from a shared environment. This result, along with transcriptome-wide comparisons, suggests that environmental changes have greater impacts on expression variability than on expression means. We discuss how this issue can be addressed through experimental design, and suggest that the ever-expanding pool of published transcriptomes represents a rich and low-cost resource for developing better reference genes for qPCR.
Planar Cell Polarity Effector Fritz Interacts with Dishevelled and Has Multiple Functions in Regulating PCP
Authors: Wang Ying , Naturale Victor F , Adler Paul N
Published: March 2017

The Planar cell Polarity Effector (PPE) genes inturned, fuzzy, and fritz are downstream components in the frizzled/starry night signaling pathway, and their function is instructed by upstream Planar Cell Polarity (PCP) core genes such as frizzled and dishevelled. PPE proteins accumulate asymmetrically in wing cells and function in a protein complex mediated by direct interactions between In and Frtz and In and Fy. How the PCP proteins instruct the accumulation of PPE protein is unknown. We found a likely direct interaction between Dishevelled and Fritz and Dishevelled and Fuzzy that could play a role in this. We previously found that mild overexpression of frtz rescued a weak in allele. To determine if this was due to extra Frtz stabilizing mutant In or due to Frtz being able to bypass the need for In we generate a precise deletion of the inturned gene (inPD). We found that mild overexpression of Fritz partially rescued inPD, indicating that fritz has In independent activity in PCP. Previous studies of PPE proteins used fixed tissues, and did not provide any insights into the dynamic properties of PPE proteins. We used CRISPR/Cas9 genome editing technology to edit the fritz gene to add a green fluorescent protein tag. fritzmNeonGreen provides complete rescue activity and works well for in vivo imaging. Our data showed that Fritz is very dynamic in epidermal cells and preferentially distributed to discrete membrane subdomains (“puncta”). Surprisingly, we found it in stripes in developing bristles.
Automated Phenotyping Indicates Pupal Size in Drosophila Is a Highly Heritable Trait with an Apparent Polygenic Basis
Authors: Reeves R Guy , Tautz Diethard
Published: March 2017

The intense focus on studying human height has done more than any other genetic analysis to advance our understanding of the heritability of highly complex phenotypes. Here, we describe in detail the properties of a previously unexplored trait in Drosophila melanogaster that shares many salient properties with human height. The total length of the pupal case varies between 2.8 and 3.9 mm among natural variants, and we report that it is among the most heritable traits reported in this species. We have developed a simple semiautomatic phenotyping system with which a single operator can reliably score >5000 individuals in a day. The precision of the automated system is 0.042 mm (± 0.030 SD). All phenotyped individuals are available to be mated in subsequent generations or uniquely archived for future molecular work. We report both broad sense and narrow sense heritability estimates for two biologically distinct data sets. Narrow sense heritability (h2) ranged from 0.44 to 0.50, and broad sense heritability (H2) ranged from 0.58 to 0.61. We present results for mapping the trait in 195 recombinant inbred lines, which suggests that there are no loci with >10% effect size in this panel. We propose that pupal size genetics in Drosophila could represent a model complex trait amenable to deep genetic dissection using the automated system described.
Dynamic Notch Signaling Specifies Each Cell Fate inDrosophilaSpermathecal Lineage
Authors: Shen Wei , Sun Jianjun
Published: March 2017

Spermathecae are glandular organs in the insect female reproductive tract that play essential roles in insect reproduction; however, the molecular mechanism involved in their development is largely unknown. Drosophila spermathecae consist of class-III secretory units, in which each secretory cell (SC) discharges its products to the central lumen through an end-apparatus and a canal. Secretory unit formation in Drosophila spermathecae utilizes a fixed cell lineage, in which each secretory unit precursor (SUP) divides to produce one pIIb cell and one pIIa cell. The former differentiates into an apical cell (AC), whereas the latter divides again to produce an SC and a basal cell (BC). It is unclear how each cell acquires its identity and contributes to secretory unit formation. Here, we demonstrate that Notch signaling is required and sufficient for the specification of lumen epithelial precursors (LEPs; vs. SUPs), pIIb (vs. pIIa), and SCs (vs. BCs) sequentially. To our surprise, Notch activation in LEPs and SCs apparently utilizes different ligand mechanisms. In addition, Notch signaling both suppresses and activates transcription factors Hindsight (Hnt) and Cut during spermathecal lineage specification, supporting the notion that Notch signaling can have opposite biological outcomes in different cellular environments. Furthermore, LEP-derived epithelial cells (ECs) and ACs show distinct cellular morphology and are essential for securing secretory units to the epithelial lumen. Our work demonstrates, for the first time, the dynamic role of Notch signaling in binary cell fate determination in Drosophila spermathecae and the role of ECs and ACs in secretory unit formation.
pnp4aIs the Causal Gene of the Medaka Iridophore Mutantguanineless
Authors: Kimura Tetsuaki , Takehana Yusuke , Naruse Kiyoshi
Published: March 2017

See-through medaka lines are suitable for observing internal organs throughout life. They were bred by crossing multiple color mutants. However, some of the causal genes for these mutants have not been identified. The medaka has four pigment cell types: black melanophores, yellow xanthophores, white leucophores, and silvery iridophores. The causal genes of melanophore, xanthophore, and leucophore mutants have been elucidated, but the causal gene for the iridophore mutant remains unknown. Here, we describe the iridophore mutant, guanineless (gu), which exhibits a strong reduction in visible iridophores throughout its larval to adult stages. The gu locus was previously mapped to chromosome 5, but was located near the telomeric region, making it difficult to integrate into the chromosome. We sought the causal gene of gu using synteny analysis with the zebrafish genome and found a strong candidate, purine nucleoside phosphorylase 4a (pnp4a). Gene targeting and complementation testing showed that pnp4a is the causal gene of gu. This result will allow the establishment of inbred medaka strains or other useful strains with see-through phenotypes without major disruption in the genetic background of each strain.
A Pooled Sequencing Approach Identifies a Candidate Meiotic Driver inDrosophila
Authors: Wei Kevin H-C , Reddy Hemakumar M , Rathnam Chandramouli , Lee Jimin , Lin Deanna , Ji Shuqing , Mason James M , Clark Andrew G , Barbash Daniel A
Published: March 2017

Mendel’s Law of equal segregation states that each of the two alleles in a diploid organism has an equal probability of being transmitted into...

Meiotic drive occurs when a selfish element increases its transmission frequency above the Mendelian ratio by hijacking the asymmetric divisions of female meiosis. Meiotic drive causes genomic conflict and potentially has a major impact on genome evolution, but only a few drive loci of large effect have been described. New methods to reliably detect meiotic drive are therefore needed, particularly for discovering moderate-strength drivers that are likely to be more prevalent in natural populations than strong drivers. Here, we report an efficient method that uses sequencing of large pools of backcross (BC1) progeny to test for deviations from Mendelian segregation genome-wide with single-nucleotide polymorphisms (SNPs) that distinguish the parental strains. We show that meiotic drive can be detected by a characteristic pattern of decay in distortion of SNP frequencies, caused by recombination unlinking the driver from distal loci. We further show that control crosses allow allele-frequency distortion caused by meiotic drive to be distinguished from distortion resulting from developmental effects. We used this approach to test whether chromosomes with extreme telomere-length differences segregate at Mendelian ratios, as telomeric regions are a potential hotspot for meiotic drive due to their roles in meiotic segregation and multiple observations of high rates of telomere sequence evolution. Using four different pairings of long and short telomere strains, we find no evidence that extreme telomere-length variation causes meiotic drive in Drosophila. However, we identify one candidate meiotic driver in a centromere-linked region that shows an ∼8% increase in transmission frequency, corresponding to a ∼54:46 segregation ratio. Our results show that candidate meiotic drivers of moderate strength can be readily detected and localized in pools of BC1 progeny.
Germ Granules Prevent Accumulation of Somatic Transcripts in the AdultCaenorhabditis elegansGermline
Authors: Knutson Andrew Kekūpa’a , Egelhofer Thea , Rechtsteiner Andreas , Strome Susan
Published: March 2017

Germ granules are widely conserved, germ-cell-specific, ribonucleo protein organelles. In C. elegans, germ granules (P granules) are necessary for fertility...

The germ cells of multicellular organisms protect their developmental potential through specialized mechanisms. A shared feature of germ cells from worms to humans is the presence of nonmembrane-bound, ribonucleoprotein organelles called germ granules. Depletion of germ granules in Caenorhabditis elegans (i.e., P granules) leads to sterility and, in some germlines, expression of the neuronal transgene unc-119::gfp and the muscle myosin MYO-3. Thus, P granules are hypothesized to maintain germ cell totipotency by preventing somatic development, although the mechanism by which P granules carry out this function is unknown. In this study, we performed transcriptome and single molecule RNA-FISH analyses of dissected P granule-depleted gonads at different developmental stages. Our results demonstrate that P granules are necessary for adult germ cells to downregulate spermatogenesis RNAs and to prevent the accumulation of numerous soma-specific RNAs. P granule-depleted gonads that express the unc-119::gfp transgene also express many other genes involved in neuronal development and concomitantly lose expression of germ cell fate markers. Finally, we show that removal of either of two critical P-granule components, PGL-1 or GLH-1, is sufficient to cause germ cells to express UNC-119::GFP and MYO-3 and to display RNA accumulation defects similar to those observed after depletion of P granules. Our data identify P granules as critical modulators of the germline transcriptome and guardians of germ cell fate.