bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of excessive autophagy and mitophagy mediates neuroprotective effects of URB597 against chronic cerebral hypoperfusion
Authors: Su Shao-Hua , Wu Yi-Fang , Wang Da-Peng , Hai Jian 
Published: June 2018

AbstractURB597 (URB) has therapeutic potential for treating chronic cerebral hypoperfusion (CCH)-induced neuronal death. The present study investigated the protective effects of URB on autopahgy and mitophagy in a CCH model as well as the underlying mechanisms. The ultrastructural changes were examined by electron microscopy. The mitochondrial membrane potential was assessed by immunofluorescence. The expressions of autophagy-related proteins (beclin-1, p62, and LC3), lysosome-related proteins (CTSD and LAMP1), and mitophagy-related proteins (BNIP3, cyt C and parkin) were evaluated by western blotting, and the interaction of beclin-1 and Bcl-2 were determined by immunoprecipitation. CCH significantly decreased the protein expression of p62, CTSD, and LAMP1 and increased the protein expression of beclin-1, parkin, and BNIP3, the LC3-II to LC3-I ratio, and the release of cyt C from mitochondria to cytoplasm. Furthermore, CCH induced the accumulation of ubiquitinated proteins in PSDs. However, URB significantly reversed these results. Besides, URB significantly inhibited the beclin-1 from beclin-1/Bcl-2 complex to whole-cell lysates. The above results indicate that URB could inhibit impaired autophagy degradation and the disruption of beclin-1/Bcl-2 complex and subsequently cut off BNIP3-cyt C- and parkin-required mitophagy, finally preventing the abnormal excessive autophagy and mitophagy. These findings provide new insights that URB is a promising agent for therapeutic management of CCH.
Epidermal-specific deletion of TC-PTP promotes UVB-induced epidermal cell survival through the regulation of Flk-1/JNK signaling
Authors: Baek Minwoo , Kim Mihwa , Lim Jae Sung , Morales Liza D. , Hernandez Joselin , Mummidi Srinivas , Williams-Blangero Sarah , Jang Ik-Soon , Tsin Andrew T. , Kim Dae Joon 
Published: June 2018

AbstractUVB exposure can contribute to the development of skin cancer by modulating protein tyrosine kinase (PTK) signaling. It has been suggested that UVB radiation increases the ligand-dependent activation of PTKs and induces PTP inactivation. Our recent studies have shown that T-cell protein tyrosine phosphatase (TC-PTP) attenuates skin carcinogenesis induced by chemical regimens, which indicates its critical role in the prevention of skin cancer. In the current work, we report that TC-PTP increases keratinocyte susceptibility to UVB-induced apoptosis via the downregulation of Flk-1/JNK signaling. We showed that loss of TC-PTP led to resistance to UVB-induced apoptosis in vivo epidermis. We established immortalized primary keratinocytes (IPKs) from epidermal-specific TC-PTP-deficient (K14Cre.Ptpn2fl/fl) mice. Immortalized TC-PTP-deficient keratinocytes (TC-PTP/KO IPKs) showed increased cell survival against UVB-induced apoptosis which was concomitant with a UVB-mediated increase in Flk-1 phosphorylation, especially on tyrosine residue 1173. Inhibition of Flk-1 by either its specific inhibitors or siRNA in TC-PTP/KO IPKs reversed this effect and significantly increased cell death after UVB irradiation in comparison with untreated TC-PTP/KO IPKs. Immunoprecipitation analysis using the TC-PTP substrate-trapping mutant TCPTP-D182A indicated that TC-PTP directly interacts with Flk-1 to dephosphorylate it and their interaction was stimulated by UVB. Following UVB-mediated Flk-1 activation, the level of JNK phosphorylation was also significantly increased in TC-PTP/KO IPKs compared to control IPKs. Similar to our results with Flk-1, treatment of TC-PTP/KO IPKs with the JNK inhibitor SP600125 significantly increased apoptosis after UVB irradiation, confirming that the effect of TC-PTP on UVB-mediated apoptosis is regulated by Flk-1/JNK signaling. Western blot analysis showed that both phosphorylated Flk-1 and phosphorylated JNK were significantly increased in the epidermis of TC-PTP-deficient mice compared to control mice following UVB. Our results suggest that TC-PTP plays a protective role against UVB-induced keratinocyte cell damage by promoting apoptosis via negative regulation of Flk-1/JNK survival signaling.
Glutamate as a potential “survival factor” in an in vitro model of neuronal hypoxia/reoxygenation injury: leading role of the Na+/Ca2+ exchanger
Authors: Piccirillo Silvia , Castaldo Pasqualina , Macrì Maria Loredana , Amoroso Salvatore , Magi Simona 
Published: June 2018

AbstractIn brain ischemia, reduction in oxygen and substrates affects mitochondrial respiratory chain and aerobic metabolism, culminating in ATP production impairment, ionic imbalance, and cell death. The restoration of blood flow and reoxygenation are frequently associated with exacerbation of tissue injury, giving rise to ischemia/reperfusion (I/R) injury. In this setting, the imbalance of brain bioenergetics induces important metabolic adaptations, including utilization of alternative energy sources, such as glutamate. Although glutamate has long been considered as a neurotoxin, it can also be used as intermediary metabolite for ATP synthesis, and both the Na+/Ca2+ exchanger (NCX) and the Na+-dependent excitatory amino-acid transporters (EAATs) are essential in this pathway. Here we analyzed the role of NCX in the potential of glutamate to improve metabolism and survival of neuronal cells subjected to hypoxia/reoxygenation (H/R). In SH-SY5Y neuroblastoma cells differentiated into a neuron-like state, H/R produced a significant cell damage, a decrease in ATP cellular content, and intracellular Ca2+ alterations. Exposure to glutamate at the onset of the reoxygenation phase attenuated H/R-induced cell damage and evoked a significant raise in intracellular ATP levels. Furthermore, we found that in H/R cells NCX reverse-mode activity was reduced, and that glutamate limited such reduction. All the effects induced by glutamate supplementation were lost when cells were transfected with small interfering RNA against NCX1 and EAAT3, suggesting the need of a specific functional interplay between these proteins for glutamate-induced protection. Collectively, our results revealed the potential beneficial effect of glutamate in an in vitro model of H/R injury and focused on the essential role exerted by NCX1. Although preliminary, these findings could be a starting point to further investigate in in vivo systems such protective effect in ischemic settings, shedding a new light on the classical view of glutamate as detrimental factor.
Activated platelets induce MLKL-driven neutrophil necroptosis and release of neutrophil extracellular traps in venous thrombosis
Authors: Nakazawa Daigo , Desai Jyaysi , Steiger Stefanie , Müller Susanne , Devarapu Satish Kumar , Mulay Shrikant R. , Iwakura Takamasa , Anders Hans-Joachim 
Published: June 2018

AbstractVenous thromboembolic (VTE) disease, often manifesting as deep vein thrombosis or pulmonary embolism, involves clot formation consisting of blood cells and platelets locked in plasma protein and chromatin networks. The latter derives from neutrophil extracellular traps released by dying neutrophils; however, the molecular mechanisms of neutrophil death in VTE remains unknown. We speculated that mixed lineage kinase-like (MLKL)-driven neutrophil necroptosis contributes to VTE. Indeed, human inferior venous cava thrombus material stained positive for phosphorylated MLKL, the activated version of MLKL that executes necroptotic cell death. In mice, MLKL immunostaining showed co-localization of MLKL with citrullinated histone H3, a marker of neutrophil extracellular trap (NET) formation. These data provide indirect support for a role of MLKL-mediated necroptosis. As a functional proof, both the stabilizer of receptor-interacting protein kinase-1 (RIPK1) and necroptosis inhibitor necrostatin-1s as well as genetic deficiency of MLKL partially prevented clot formation upon inferior vena cava ligation in mice. In both experiments terminal deoxynucleotidyl transferase dUTP nick-end labeling, RIPK3, and citrullinated histone H3+ areas were markedly reduced within the remnant thrombus. In vitro, thrombin-activated platelets induced cell death and NET formation in human neutrophils, which was inhibited by necrostatin-1s treatment. Necrostatin-1s and necrosulfonamide also inhibited neutrophil–platelet aggregate formation induced by tumor necrosis factor-α but had no effect on platelet activation itself. We conclude that in VTE, activated platelets, and possibly other triggers, induce neutrophil necroptosis, a process contributing to clot formation by releasing chromatin in the extracellular space.
Rapid transport of deformation-tuned nanoparticles across biological hydrogels and cellular barriers
Authors: Yu Miaorong , Xu Lu , Tian Falin , Su Qian , Zheng Nan , Yang Yiwei , Wang Jiuling , Wang Aohua , Zhu Chunliu , Guo Shiyan , Zhang XinXin , Gan Yong , Shi Xinghua , Gao Huajian 
Published: June 2018

AbstractTo optimally penetrate biological hydrogels such as mucus and the tumor interstitial matrix, nanoparticles (NPs) require physicochemical properties that would typically preclude cellular uptake, resulting in inefficient drug delivery. Here, we demonstrate that (poly(lactic-co-glycolic acid) (PLGA) core)-(lipid shell) NPs with moderate rigidity display enhanced diffusivity through mucus compared with some synthetic mucus penetration particles (MPPs), achieving a mucosal and tumor penetrating capability superior to that of both their soft and hard counterparts. Orally administered semi-elastic NPs efficiently overcome multiple intestinal barriers, and result in increased bioavailability of doxorubicin (Dox) (up to 8 fold) compared to Dox solution. Molecular dynamics simulations and super-resolution microscopy reveal that the semi-elastic NPs deform into ellipsoids, which enables rotation-facilitated penetration. In contrast, rigid NPs cannot deform, and overly soft NPs are impeded by interactions with the hydrogel network. Modifying particle rigidity may improve the efficacy of NP-based drugs, and can be applicable to other barriers.
Glucose starvation induces LKB1-AMPK-mediated MMP-9 expression in cancer cells
Authors: Endo Hitoshi , Owada Satoshi , Inagaki Yutaka , Shida Yukari , Tatemichi Masayuki 
Published: June 2018

AbstractCancer cells utilise the glycolytic pathway to support their rapid growth and proliferation. Since cells in most solid tumours are subjected to severe microenvironmental stresses including low nutrient and oxygen availability, such cancer cells must develop mechanisms to overcome these unfavourable growth conditions by metabolic adaptation. Although the liver kinase B1 (LKB1)-adenosine monophosphate-activated kinase (AMPK) signalling pathway plays a pivotal role in maintaining energy homeostasis under conditions of metabolic stress, the role of LKB1-AMPK signalling in aiding cancer cell survival and in malignant tumours has not yet been fully elucidated. We show that glucose starvation promotes cancer cell invasiveness and migration through LKB1-AMPK-regulated MMP-9 expression. Most intriguingly, triggering the LKB1-AMPK signalling pathway by glucose starvation-induced oxidative stress facilitates selective autophagy, which in turn enhances Keap1 degradation and the subsequent activation of Nrf2. Following this, Nrf2 regulates the transactivation of MMP-9 via Nrf2 binding sites in the promoter region of the MMP-9 gene. These mechanisms also contribute to the suppression of excessive oxidative stress under glucose starvation, and protect against cell death. Our data clearly shows that LKB1-AMPK signalling not only maintains energy and oxidative stress homeostasis, but could also promote cancer progression during metabolic stress conditions by MMP-9 induction.
An exciton-polariton bolometer for terahertz radiation detection
Authors: Paschos G. G. , Liew T. C. H. , Hatzopoulos Z. , Kavokin A. V. , Savvidis P. G. , Deligeorgis G. 
Published: June 2018

AbstractWe experimentally investigate the feasibility of a bolometric device based on exciton-polaritons. Initial measurements presented in this work show that heating – via thermal expansion and bandgap renormalization – modifies the exciton-polariton propagation wavevector making exciton-polaritons propagation remarkably sensitive to thermal variations. By theoretical simulations we predict that using a single layer graphene absorbing layer, a THz bolometric sensor can be realized by a simple exciton-polariton ring interferometer device. The predicted sensitivity is comparable to presently existing THz bolometric devices with the convenience of being a device that inherently produces an optical signal output.
Graphene oxide polarizes iNKT cells for production of TGFβ and attenuates inflammation in an iNKT cell-mediated sepsis model
Authors: Lee Sung Won , Park Hyun Jung , Van Kaer Luc , Hong Suklyun , Hong Seokmann 
Published: June 2018

AbstractGraphene oxide (GO) modulates the functions of antigen-presenting cells including dendritic cells (DCs). Although carbon nanotubes affect expression of the MHC class I-like CD1d molecule, whether GO can influence immune responses of CD1d-dependent invariant natural killer T (iNKT) cells remains unclear. Here, we investigated the impact of GO on inflammatory responses mediated by α-galactosylceramide (α-GalCer), an iNKT cell agonist. We found that in vivo GO treatment substantially inhibited the capacity of α-GalCer to induce the iNKT cell-mediated trans-activation of and cytokine production by innate and innate-like cells, including DCs, macrophages, NK cells, and γδ T cells. Such effects of GO on α-GalCer-induced inflammatory responses closely correlated with iNKT cell polarization towards TGFβ production, which also explains the capacity of GO to expand regulatory T cells. Interestingly, the absence of TLR4, a receptor for GO, failed to downregulate, and instead partially enhanced the anti-inflammatory activity of GO against α-GalCer-elicited responses, implying negative effects of TLR4 signaling on the anti-inflammatory properties of GO. By employing an α-GalCer-induced sepsis model, we further demonstrated that GO treatment significantly protected mice from α-GalCer-induced lethality. Taken together, we provide strong evidence that GO holds promise as an adjuvant to modulate iNKT cell responses for immunotherapy.
Identification of genes underlying the enhancement of immunity by a formula of lentinan, pachymaran and tremelia polysaccharides in immunosuppressive mice
Authors: Luo Xia , Huang Shaowei , Luo Shuang , Liao Haifeng , Wang Yuanyuan , Deng Xiangliang , Ma Fangli , Ma Chung Wah , Zhou Lian 
Published: June 2018

AbstractThe efficacy of polysaccharides is widespread, especially in immune regulation. However, the genetic basis of the changes in polysaccharides regulating immunity is unclear. To obtain genome-wide insights into transcriptome changes and regulatory networks, we designed a polysaccharide formula, comprising lentinan, pachymaran and tremelia, to increase the availability of their optimized active sites. In this case, we focused on a model of immunosuppression to investigate genes by digital gene expression (DGE) tag profiling in T and B cells. These genes were further validated by qRT-PCR and Western blot experiments. Consequently, polysaccharide formula treatment helped to recover the expression of immune-related genes, including CADM1, CCR2, IGLL1, LIGP1, and FCGR3, FCGR2 in B cells, as well as S100A8, S100A9, ChIL3, MMP8 and IFITM3 in T cells. These results suggest that treatment with polysaccharides improves the immunity of immunosuppressive mice by regulating genes associated with T and B cell functions.
Direct evidence of a low barrier hydrogen bond in the catalytic triad of a Serine protease
Authors: Agback Peter , Agback Tatiana 
Published: June 2018

AbstractSerine proteases are one of the largest groups of enzymes, found in both eukaryotes and prokaryotes, and are responsible for many different functions. The detailed information about the hydrogen-bonds in the catalytic triad (Asp…His…Ser) of these enzymes is of importance in order to fully understand the mechanism of action. The aspartate of the triad is hydrogen bonded to the histidine but the exact nature of this bond has been under discussion for some time. It is either a common short ionic hydrogen bond (SIHB) or a delocalized low barrier hydrogen bond (LBHB) were the hydrogen bond is shorter. So far, the evidence for LBHB in proteins have not been conclusive. Here we show clear NMR evidence that LBHB does exist in NS3, a serine protease from Dengue. The one bond coupling constant between the hydrogen and nitrogen was shown to be only 52 Hz instead of the usual 90 Hz. This together with a 1H chemical shift of 19.93 ppm is evidence that the hydrogen bond distance between His and Asp is shorter than for SIHB. Our result clearly shows the existence of LBHB and will help in understanding the mechanism of the catalytic triad in the important group of serine proteases.
Monomolecular tetrahelix of polyguanine with a strictly defined folding pattern
Authors: Kankia Besik 
Published: June 2018

AbstractThe G3TG3TG3TG3 (G3T) sequence folds into a monomolecular quadruplex with all-parallel G3 segments connected to each other by chain-reversal loops. The homopolymer consisting of n number of G3T domains directly conjugated to each other folds into an uninterrupted and unusually stable polymer, tetrahelical monomolecular DNA (tmDNA). It was demonstrated that the tmDNA architecture has strong potential in nanotechnologies as highly programmable building material, high affinity coupler and the driving force for endergonic reactions. Here, we explore capability of analogous DNA sequences (i.e., monomolecular quadruplexes with G2 or G4 segments) to construct tmDNA architecture. The study demonstrates that tmDNA can have only one building pattern based on a quadruplex domain with three G-tetrads and single-nucleotide loops, G3N (N = G, A, C and T); all other domains demonstrate antiparallel topologies unsuitable for tmDNA. The present study also suggests that polyguanine is capable of tmDNA formation with strictly defined building pattern; G3 segments connected to each other by chain-reversal G-loops. These findings can have significant impact on (i) DNA nanotechnologies; (ii) structure prediction of G-rich sequences of genome; and (iii) modeling of abiogenesis.
Evaluation of Linguistic Markers of Word-Finding Difficulty and Cognition in Parkinson's Disease
Authors: Smith Kara M. , Ash Sharon , Xie Sharon X. , Grossman Murray 
Published: June 2018

Purpose
Early cognitive symptoms such as word-finding difficulty (WFD) in daily conversation are common in Parkinson's disease (PD), but studies have been limited by a lack of feasible, quantitative measures. Linguistic analysis, focused on pauses in speech, may yield markers of impairment of cognition and communication in PD. The objective of this study was to evaluate the relationship of linguistic markers in semistructured speech to WFD symptoms and cognitive function in PD.

Method
Speech recordings of description of the Cookie Theft picture in 53 patients with PD without dementia and 23 elderly controls were analyzed with Praat software. Montreal Cognitive Assessment (MoCA; Nasreddine et al., 2005), category naming fluency, and confrontation naming tests were administered. Questionnaires rating WFD symptoms and cognitive instrumental activities of daily living were completed. We determined the relationships between (a) pause length and location, (b) MoCA score, and (c) WFD symptoms, using Pearson's correlations and multivariate regression models.

Results

Compared with controls, patients with PD had more pauses within utterances as well as fewer words per minute and a lower percentage of well-formed sentences. Pauses within utterances differed significantly between PD–mild cognitive impairment and normal cognition (
p
< .001). Words per minute and percentage of well-formed sentences were predictive of MoCA in multivariate regression models. Pauses before verbs were associated with patient-reported severity of WFD symptoms (
p
= .006).

Conclusions
Linguistic markers including pauses within utterances distinguish patients with PD with mild cognitive symptoms from elderly controls. These markers are associated with global cognitive function before the onset of dementia. Pauses before verbs and grammatical markers may index early cognitive symptoms such as WFD that may interfere with functional communication.

Supplemental Material

https://doi.org/10.23641/asha.6615401
Suchtprobleme unter Flüchtlingen und Migranten in Griechenland
Authors: Nikolaou Kakia 
Published: June 2018

ZusammenfassungDer Flüchtlingsstatus verstärkt die Vulnerabilität höchst gefährdeter Menschen, die Pre-Migrations-Traumata und Post-Migrations-Stress ausgesetzt sind. Die Auswirkungen des Migrationsstresses spiegeln sich wieder in der Entwicklung von psychischen Störungen, besonders von posttraumatischen Stressstörungen, Angst und Depression, wodurch die Gefahr für Alkohol- und Drogenkonsum erhöht wird. In Griechenland kommen noch die Auswirkungen der ökonomischen und humanistischen Krise hinzu. Flüchtlinge auf den griechischen Inseln müssen sich an den Empfangs- und Identifizierungszentren einen komplizierten und langwierigen Prozess unterziehen, mit ungewissem Ausgang des Asylverfahrens. Die Kapazität des Fachpersonals öffentlicher Dienstleistungen ist aufgrund fehlender Arbeitskräfte und Finanzmittel unzureichend, bei gleichzeitiger Zunahme der Einweisungen und der Notfälle mit psychiatrischen Problemen. Es gibt kaum systematische Untersuchungen des Substanzgebrauchs unter Flüchtlingen in Griechenland, Erfahrungen und Informationen sind limitiert. Qualitative und empirische Daten mehrerer Träger sprechen aber für eine Zunahme des Phänomens. Es wird das Profil von jungen, untätigen, armen Männer beschrieben, gut informiert über die verfügbaren Drogenszenen, viele schon in ihrer Heimat Gebraucher, mit Alkohol, Cannabis und Opioiden als Hauptsubstanzen. Alle offiziellen Drogenhilfeträger, Präventionszentren und viele Nichtregierungsorganisationen versuchen gemeinsam ein Netzwerk zu errichten, welches auf psychosoziale Unterstützung, reibungslose Integration von Kindern und Jugendlichen und Früherkennung von Gebrauchern abzielt. Es müssen aber noch alle Drogengebraucher an den Empfangszentren registriert, ein interinstitutioneller Träger aufgebaut, psychiatrische Beurteilungs-und Behandlungsmöglichkeiten in den Empfangszentren implementiert und Überweisungen zu spezialisierten Trägern ermöglicht werden.
Expertentreffen COPD: Integriertes Patientenmanagement bei COPD
Authors: Jany B. , Bals R. , Buhr-Schinner H. , Dreher M. , Koczulla R. , Jany L. , Meyer A. , Randerath W. , Steinkamp G. 
Published: June 2018

ZusammenfassungDie Lebensqualität und Prognose der COPD-Patienten lässt trotz erheblich verbesserter medikamentöser Therapieoptionen weiterhin zu wünschen übrig. Ziel des Workshops war es, COPD-spezifische Hindernisse auf dem Weg zur verbesserten Betreuung der Patienten zu beschreiben. Dazu zählen der Sozial- und Bildungsstatus der COPD-Patienten sowie die gesellschaftliche Stigmatisierung der Erkrankung als selbstverschuldete „Raucherkrankheit“. Die strenge sektorale Trennung trägt zu Defiziten in der Betreuung bei. Im zweiten Teil des Workshops wurden Möglichkeiten der Verbesserung dargestellt. Die Nutzung IT-basierter Hilfsmittel, verbesserte Kommunikation zwischen Patienten und Therapeuten und zwischen den Sektoren des Gesundheitswesens, verbesserte Integration von Rehabilitation sowie durch Strategien des Selbstmanagements, sind solche Möglichkeiten. Als Schlussfolgerung konnte festgehalten werden, dass ein integriertes Patientenmanagement mit Einbeziehung multiprofessioneller Teams die Betreuungsqualität nachhaltig verbessern könnte.