bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modeling circadian regulation of ovulation timing: age-related disruption of estrous cyclicity
Authors: Ohara Takayuki , Nakamura Takahiro J. , Nakamura Wataru , Tokuda Isao T. 
Published: October 2020

AbstractThe circadian clocks within the hypothalamic–pituitary–gonadal axis control estrous cycles in female rodents. The suprachiasmatic nucleus (SCN), where the central clock is located, generates daily signals to trigger surge release of luteinizing hormone (LH), which in turn induces ovulation. It has been observed in aged rodents that output from the SCN such as neuronal firing activity is declined, and estrous cycles become irregular and finally stop. Circadian clock mutants display accelerated reproductive aging, suggesting the complicated interplay between the circadian system and the endocrine system. To investigate such circadian regulation of estrous cycles, we construct a mathematical model that describes dynamics of key hormones such as LH and of circadian clocks in the SCN and in the ovary, and simulate estrous cycles for various parameter values. Our simulation results demonstrate that reduction of the amplitude of the SCN signal, which is a symptom of aging, makes estrous cycles irregular. We also show that variation in the phase of the SCN signal and changes in the period of ovarian circadian clocks exacerbates the aging effect on estrous cyclicity. Our study suggests that misalignment between the SCN and ovarian circadian oscillations is one of the primary causes of the irregular estrous cycles.
ATP modulates SLC7A5 (LAT1) synergistically with cholesterol
Authors: Cosco Jessica , Scalise Mariafrancesca , Colas Claire , Galluccio Michele , Martini Riccardo , Rovella Filomena , Mazza Tiziano , Ecker Gerhard F. , Indiveri Cesare 
Published: October 2020

AbstractThe plasma membrane transporter hLAT1 is responsible for providing cells with essential amino acids. hLAT1 is over-expressed in virtually all human cancers making the protein a hot-spot in the fields of cancer and pharmacology research. However, regulatory aspects of hLAT1 biology are still poorly understood. A remarkable stimulation of transport activity was observed in the presence of physiological levels of cholesterol together with a selective increase of the affinity for the substrate on the internal site, suggesting a stabilization of the inward open conformation of hLAT1. A synergistic effect by ATP was also observed only in the presence of cholesterol. The same phenomenon was detected with the native protein. Altogether, the biochemical assays suggested that cholesterol and ATP binding sites are close to each other. The computational analysis identified two neighboring regions, one hydrophobic and one hydrophilic, to which cholesterol and ATP were docked, respectively. The computational data predicted interaction of the ϒ-phosphate of ATP with Lys 204, which was confirmed by site-directed mutagenesis. The hLAT1-K204Q mutant showed an impaired function and response to ATP. Interestingly, this residue is conserved in several members of the SLC7 family.
Receptor occupancy of dual glucagon-like peptide 1/glucagon receptor agonist SAR425899 in individuals with type 2 diabetes
Authors: Eriksson Olof , Haack Torsten , Hijazi Youssef , Teichert Lenore , Tavernier Veronique , Laitinen Iina , Berglund Jan Erik , Antoni Gunnar , Velikyan Irina , Johansson Lars , Pierrou Stefan , Wagner Michael , Tillner Joachim 
Published: October 2020

AbstractUnimolecular dual agonists for the glucagon-like peptide 1 receptor (GLP1R) and glucagon receptor (GCGR) are emerging as a potential new class of important therapeutics in type 2 diabetes (T2D). Reliable and quantitative assessments of in vivo occupancy on each receptor would improve the understanding of the efficacy of this class of drugs. In this study we investigated the target occupancy of the dual agonist SAR425899 at the GLP1R in pancreas and GCGR in liver by Positron Emission Tomography/Computed Tomography (PET/CT). Patients with T2D were examined by [68Ga]Ga-DO3A-Tuna-2 and [68Ga]Ga-DO3A-Exendin4 by PET, to assess the GCGR in liver and GLP1R in pancreas, respectively. Follow up PET examinations were performed after 17 (GCGR) and 20 (GLP-1R) days of treatment with SAR425899, to assess the occupancy at each receptor. Six out of 13 included patients prematurely discontinued the study due to adverse events. SAR425899 at a dose of 0.2 mg daily demonstrated an average GCGR occupancy of 11.2 ± 14.4% (SD) in N = 5 patients and a GLP1R occupancy of 49.9 ± 13.3%. Fasting Plasma Glucose levels (− 3.30 ± 1.14 mmol/L) and body weight (− 3.87 ± 0.87%) were lowered under treatment with SAR425899. In conclusion, SAR425899 demonstrated strong interactions at the GLP1R, but no clear occupancy at the GCGR. The study demonstrates that quantitative target engagement of dual agonists can be assessed by PET.
Nesfatin-1 and nesfatin-1-like peptide suppress growth hormone synthesis via the AC/PKA/CREB pathway in mammalian somatotrophs
Authors: Vélez Emilio J. , Unniappan Suraj 
Published: October 2020

AbstractNesfatin-1 (NESF) and NESF-like peptide (NLP), encoded in nucleobindin 2 and 1 (NUCB2 and NUCB1), respectively, are orphan ligands and metabolic factors. We hypothesized that NESF and NLP suppress growth hormone (GH) synthesis, and aimed to determine whether mammalian somatotrophs are a source and site of action of these peptides. Using immortalized rat somatotrophs (GH3 cells), NUCB expression was determined by qPCR, immunofluorescence and Western blot. NESF and NLP binding to GH3 cells was tested using fluorescence imaging. Both time- and concentration-dependent studies were performed to test whether NESF and NLP affect GH. Moreover, the ability of these peptides to modulate the effects of ghrelin, and cell-signaling pathways were studied. GH3 cells express NUCB mRNAs and protein. Labeled NESF and NLP bind to the surface of GH3 cells, and incubation with either NESF or NLP decreased GH mRNA and protein expression, downregulated pit-1 mRNA, and blocked the GH stimulatory effects of ghrelin. Pre-incubation with either of these peptides reduced CREB phosphorylation by an AC-activator, but not when PKA was directly activated by a cAMP analog. Our results indicate that rat somatotrophs are a source of NUCBs, and that NESF and NLP downregulate GH synthesis through the AC/PKA/CREB signaling pathway.
Poor numerical performance of guppies tested in a Skinner box
Authors: Gatto Elia , Testolin Alberto , Bisazza Angelo , Zorzi Marco , Lucon-Xiccato Tyrone 
Published: October 2020

AbstractWe tested the hypothesis that part of the gap in numerical competence between fish and warm-blooded vertebrates might be related to the more efficient procedures (e.g. automated conditioning chambers) used to investigate the former and could be filled by adopting an adapted version of the Skinner box in fish. We trained guppies in a visual numerosity discrimination task, featuring two difficulty levels (3 vs. 5 and 3 vs. 4) and three conditions of congruency between numerical and non-numerical cues. Unexpectedly, guppies trained with the automated device showed a much worse performance compared to previous investigations employing more “ecological” procedures. Statistical analysis indicated that the guppies overall chose the correct stimulus more often than chance; however, their average accuracy did not exceed 60% correct responses. Learning measured as performance improvement over training was significant only for the stimuli with larger numerical difference. Additionally, the target numerosity was selected more often than chance level only for the set of stimuli in which area and number were fully congruent. Re-analysis of prior studies indicate that the gap between training with the Skinner box and with a naturalistic setting was present only for numerical discriminations, but not for colour and shape discriminations. We suggest that applying automated conditioning chambers to fish might increase cognitive load and therefore interfere with achievement of numerosity discriminations.
Highly sensitive optical ion sensor with ionic liquid-based colorimetric membrane/photonic crystal hybrid structure
Authors: Kawasaki Daiki , Oishi Ryoutarou , Kobayashi Nao , Mizuta Tatsumi , Sueyoshi Kenji , Hisamoto Hideaki , Endo Tatsuro 
Published: October 2020

AbstractAn ionic liquid-based thin (~ 1 µm) colorimetric membrane (CM) is a key nano-tool for optical ion sensing, and a two-dimensional photonic crystal slab (PCS) is an important nano-platform for ultimate light control. For highly sensitive optical ion sensing, this report proposes a hybrid of these two optical nano-elements, namely, a CM/PCS hybrid. This structure was successfully fabricated by a simple and rapid process using nanoimprinting and spin-coating, which enabled control of the CM thickness. Optical characterization of the hybrid structure was conducted by optical measurement and simulation of the reflection spectrum, indicating that the light confined in the holes of the PCS was drastically absorbed by the CM when the spectrum overlapped with the absorption spectrum of the CM. This optical property obtained by the hybridization of CM and PCS enabled drastic improvement in the absorption sensitivity in Ca ion sensing, by ca. 78 times compared to that without PCS. Experimental and simulated investigation of the relation between the CM thickness and absorption sensitivity enhancement suggested that the controlled light in the PCS enhanced the absorption cross-section of the dye molecules within the CM based on the enhanced local density of states. This highly sensitive optical ion sensor is expected to be applied for micro-scale bio-analysis like cell-dynamics based on reflectometric Ca ion detection.
Low cost Ti–Si intermetallic compound membrane with nano-pores synthesized by in-situ reactive sintering process
Authors: Liu Zhongjun , Liu Zhuomeng , Ji Shuai , Wang Gaosong 
Published: October 2020

AbstractA low cost Ti–Si intermetallic compound membrane with nano-pores was successfully prepared by an in-situ reactive sintering process. The all synthesized membrane shows the presence of Ti, Ti5Si3, TiSi and TiO2 phases, and the Ti:Si atomic ratio of membrane is about 1.9. Two different synthesized granule configuration zones on membrane are observed. Membrane synthesized on the surface of Ti particles contains the mean sizes of both 631 nm nano-particles and 238 nm nano-pores, which is considerably different from that of membrane growing on top of the micro-pores of Ti matrix, 238 nm nano-particles and 80 nm nano-pores, respectively.
Estimating soil water retention for wide ranges of pressure head and bulk density based on a fractional bulk density concept
Authors: Sun Huihui , Lee Jaehoon , Chen Xijuan , Zhuang Jie 
Published: October 2020

AbstractSoil water retention determines plant water availability and contaminant transport processes in the subsurface environment. However, it is usually difficult to measure soil water retention characteristics. In this study, an analytical model based on a fractional bulk density (FBD) concept was presented for estimating soil water retention curves. The concept allows partitioning of soil pore space according to the relative contribution of certain size fractions of particles to the change in total pore space. The input parameters of the model are particle size distribution (PSD), bulk density, and residual water content at water pressure head of 15,000 cm. The model was tested on 30 sets of water retention data obtained from various types of soils that cover wide ranges of soil texture from clay to sand and soil bulk density from 0.33 g/cm3 to 1.65 g/cm3. Results showed that the FBD model was effective for all soil textures and bulk densities. The estimation was more sensitive to the changes in soil bulk density and residual water content than PSD parameters. The proposed model provides an easy way to evaluate the impacts of soil bulk density on water conservation in soils that are manipulated by mechanical operation.
The impact of cultivation systems on the nutritional and phytochemical content, and microbiological contamination of highbush blueberry
Authors: Ochmian Ireneusz , Błaszak Magdalena , Lachowicz Sabina , Piwowarczyk Renata 
Published: October 2020

AbstractThe aim of this study was to compare the nutritional and use value of berries grown in organic and conventional systems. The polyphenol content, fruit colour and firmness, and yeast, mould, and mycotoxin contents were assessed in blueberry fruit freshly harvested and stored for 8 weeks in controlled conditions (CA: CO2-12%; O2-1.5%, temperature 1.5 °C). The Shannon–Wiener diversity index was comparable in both systems and was lower for mould in organic fruit than in conventional fruit. Mycotoxins (deoxynivalenol, zearalenone) were found only in organic fruits. The optimal mineral content and pH of the soil allowed the cultivation of blueberry in accordance with organic standards. The storage of highbush blueberry fruit in CA cold storage for 8 weeks resulted in a slight deterioration in fruit quality and polyphenol content. The lower nutritional value of these fruits is compensated by the lack of pesticides and artificial fertilizers residues. The use of fungicides in conventional cultivation reduces the population of sensitive fungi and therefore reduces the contamination of fruits with mycotoxins.
Common evolutionary features of the envelope glycoprotein of HIV-1 in patients belonging to a transmission chain
Authors: Beretta Maxime , Migraine Julie , Moreau Alain , Essat Asma , Goujard Cécile , Chaix Marie-Laure , Drouin Aurélie , Bouvin-Pley Mélanie , Meyer Laurence , Barin Francis , Braibant Martine 
Published: October 2020

AbstractThe diversity of the HIV-1 envelope glycoproteins (Env) is largely a consequence of the pressure exerted by the adaptive immune response to infection. While it was generally assumed that the neutralizing antibody (NAb) response depended mainly on the infected individual, the concept that virus-related factors could be important in inducing this response has recently emerged. Here, we analyzed the influence of the infecting viral strain in shaping NAb responses in four HIV-1 infected subjects belonging to a transmission chain. We also explored the impact of NAb responses on the functional evolution of the viral quasispecies. The four patients developed a strong autologous neutralizing antibody response that drove viral escape and coincided with a parallel evolution of their infecting quasispecies towards increasing infectious properties, increasing susceptibility to T20 and increasing resistance to both CD4 analogs and V3 loop-directed NAbs. This evolution was associated with identical Env sequence changes at several positions in the V3 loop, the fusion peptide and the HR2 domain of gp41. The common evolutionary pattern of Env in different hosts suggests that the capacity of a given Env to adapt to changing environments may be restricted by functional constraints that limit its evolutionary landscape.
P1-Bypass: Ist die autologe Vene noch indiziert? – Pro
Authors: Rantner Barbara 
Published: October 2020

ZusammenfassungIn der endovaskulären Ära wird die Indikation zur supragenualen Bypassanlage bei Patientinnen und Patienten mit längerstreckigen Pathologien der A. femoralis superficialis insgesamt nur mehr selten gestellt. Wenn die Entscheidung zur chirurgischen Sanierung des Gefäßproblems gefallen ist, muss die Wahl des Bypassmaterials getroffen werden. In diesem Artikel soll die Evidenz für die femoropopliteale Bypassanlage oberhalb des Knies (P1-Bypass) mittels autologer Vene dargestellt und ein klares Pro für den Venenbypass ausgesprochen werden.
Multimodale Therapie primärer, nicht metastasierter retroperitonealer Sarkome
Authors: Ptok Henry , Schalk Enrico , Hass Peter , Heinze Constanze , Brunner Thomas , Croner Roland S. 
Published: October 2020

ZusammenfassungWeichteilsarkome sind eine heterogene Gruppe von Tumoren mesenchymalen Ursprungs, die teilweise ein sehr unterschiedliches biologisches Verhalten zeigen. Retroperitoneale Weichteilsarkome (RSTS) machen 10 – 15% aller Weichteilsarkome aus. Behandlungsempfehlungen für RSTS basieren auf vorrangig retrospektiven Analysen mit geringer Evidenz, die in dieser Übersichtsarbeit dargestellt werden. Zentraler Pfeiler in der Behandlung des lokalisierten, nicht metastasierten RSTS ist die chirurgische Resektion im Sinne einer Kompartment-Resektion. Ziel ist dabei immer die allseitig vollständige Tumorentfernung mit mikroskopisch freien Resektionsrändern. Ist das Erreichen dieses Behandlungsziels mit der alleinigen Kompartment-Resektion fraglich oder besteht eine hohe Wahrscheinlichkeit für eine lokale Tumorrekurrenz bei high-grade Sarkomen, so sollte eine neoadjuvante Bestrahlung, gegebenenfalls mit intraoperativem Boost, im Rahmen eines multimodalen Therapieansatzes durchgeführt
werden. Die in Analogie zu den Extremitätensarkomen zu favorisierende Anthrazyklin-basierte Chemotherapie hat ihren Stellenwert vorrangig in der Adjuvanz. Auch wenn ein onkologischer Vorteil durch eine adjuvante Chemotherapie für RSTS bisher nicht nachgewiesen ist, sollte bei high-grade Sarkomen die Indikation diskutiert werden. In Kenntnis der unterschiedlichen Krankheitsverläufe werden zunehmend an die unterschiedlichen histologischen Subtypen adaptierte Therapiekonzepte diskutiert und in Studien untersucht. Valide Empfehlungen lassen sich jedoch bisher nicht ableiten. Die Behandlung von RSTS-Patienten wie überhaupt von Patienten mit Sarkomen in Zentren mit entsprechender Expertise ist mit einer signifikanten Verbesserung der Prognose assoziiert und ist unbedingt anzustreben.
Stadt vs. Land: Eine Querschnittsstudie zu Arbeitszufriedenheit und –belastung von jungen Ärzten in Sachsen
Authors: Jung Franziska Ulrike , Röhr Susanne , Deutsch Tobias , Riedel-Heller Steffi G. 
Published: October 2020

Zusammenfassung
Einleitung Ärztemangel und eine damit verbundene Unterversorgung der Patienten bedroht besonders ländliche, strukturschwache Regionen. Bisherige Studien konzentrieren sich auf Faktoren, die die Niederlassungsentscheidung auf dem Land begünstigen oder verhindern. Über Faktoren wie Arbeitszufriedenheit und Arbeitsbelastung und geografisch bedingte Unterschiede in Deutschland ist bisher wenig bekannt.
Methode Ziel der Studie war es diese Faktoren einem detaillierten Stadt-Land-Vergleich mittels einer sekundären Analyse von Surveydaten zu unterziehen.
Ergebnisse Hierfür konnten Daten von 1813 in Sachsen praktizierenden Ärzten (25–40 Jahre), welche postalisch kontaktiert wurden, analysiert werden.
Schlussfolgerung Die Ergebnisse zeigen, dass sich hinsichtlich der Arbeitszufriedenheit lediglich akzentuierte Unterschiede feststellen lassen. In Bezug auf Arbeitsbelastung lassen sich keine signifikanten Unterschiede zwischen Ärzten, die auf dem Land oder in der Stadt tätig sind, finden.
Kombinierte Immuncheckpoint-Inhibition bei inoperablem Gingivamelanom
Authors: Neumann M. , Ruppel E. , Unger S. , Zah A. , Ludwig-Peitsch W. K. 
Published: October 2020

ZusammenfassungSchleimhautmelanome sind seltene Formen von Melanomen mit einer ungünstigen Prognose. Bei Fehlen von therapierelevanten Mutationen und Inoperabilität stellt die Therapie mit Immuncheckpoint-Inhibitoren eine aussichtsreiche Option dar. Die Kombination aus dem PD-1-Antikörper Nivolumab und dem CTLA4-Antikörper Ipilimumab ist effektiver, jedoch auch erheblich toxischer als die Monotherapie mit PD-1-Antikörpern. Wir berichten über eine 57-jährige Patientin mit einem lymphogen metastasierten inoperablen Gingivamelanom im Stadium IIID, die mit einer Kombination aus Nivolumab und Ipilimumab behandelt wurde und hierunter multiple autoimmunvermittelte Nebenwirkungen einschließlich eines Schubs einer rheumatoiden Arthritis, einer Autoimmunkolitis, einer Autoimmunthyreoiditis und einer Autoimmunhepatitis entwickelte. Diese konnten mithilfe von systemischen Steroiden und symptomatischer Therapie beherrscht werden und es konnte eine anhaltende partielle Remission bei guter Lebensqualität erzielt werden. Unser Fall liefert ein Beispiel für den erfolgreichen Einsatz von Immuncheckpoint-Inhibitoren bei seltenen Melanom-Entitäten, veranschaulicht jedoch auch die Bedeutung von intensivem Monitoring besonders bei Patienten mit zugrunde liegenden Autoimmunerkrankungen.
Evaluation and Docking Study of Pyrazine Containing 1, 3, 4-Oxadiazoles Clubbed with Substituted Azetidin-2-one: A New Class of Potential Antimicrobial and Antitubercular
Authors: Das Rina , Mehta Dinesh Kumar 
Published: October 2020

Abstract
Background Tuberculosis (TB) caused by Mycobacterium tuberculosis is one of the main killers of people all over the world. The major hurdles with existing therapy are the lengthy regimen and appearance of multi drug resistant (MDR) and extensively drug resistant (XDR) strains of M.tuberculosis.
Aims The present work was aimed to synthesize and determine antitubercular and antimicrobial potential of some novel 3-chloro-4-aryl-1-[4-(5-pyrazin-2-yl[1,3,4]oxadiazole-2-ylmethoxy)-phenyl]-azetidin-2-one derivatives 7(a-h) from pyrazinoic acid as precursor, which is a well-established antitubercular agent. Here we report the synthesis of a new class of heterocyclic molecules in which pyrazine, 1, 3, 4-oxadiazole and azetidinone moieties were present in one frame work.
Methods Pyrazinoic acid (1) was esterified first (2) followed by amination to produce hydrazide (3) which was refluxed with POCl3 to obtain 2-chloromethyl-5pyrazino-1, 3, 4-oxadiazole (4). This was then further reacted with 4-amino phenol to obtain 4-[5-pyrazino-1, 3, 4-oxadiazol-2-yl-methoxy]-phenyl amine (5) which on condensation with various aromatic aldehydes afforded a series Schiff’s bases 6(a-h). Dehydrative annulations of 6(a-h) in the presence of chloroacetyl chloride and triethylamine yielded 3-chloro-4-aryl-1-[4-(5-pyrazin-2-yl-[1, 3, 4]oxadiazole-2-ylmethoxy)-phenyl]-azetidin-2-one derivatives 7(a-h). Antibacterial, antifungal and antitubercular potential of all the synthesized compounds were assessed. Docking study was performed using the software VLife Engine tools of Vlifemds 4.6 on the protein lumazine synthase of M. tuberculosis (PDB entry code 2C92).
Results The present studies demonstrated that synthesized oxadiazole derivatives have good antimicrobial activity against the various microorganisms. Among the synthesized derivative, 7b and 7g were found to be prominent compounds which have potential antibacterial, antifungal and antitubercular activity (with MIC 3.12 µg/ml and high dock score ranging from −59.0 to −54.0) against Mycobacterium tuberculosis.
Conclusions Derivatives 7b and 7g would be effective lead candidates for tuberculosis therapy.