bluuebunny/crossref_metadata_2025 huggingface dataset:
Stress und Stressbewältigung
Authors: Petermann Franz
Published: September 2017

Zusammenfassung. In vielfältiger Weise können Stressoren (z.B. Arbeitsbelastungen, kritische und traumatisierende Ereignisse, Mobbing, psychische Erkrankungen der Eltern), unterschiedlich gut bewältigbare Anforderungen darstellen. Das Stressempfinden hängt entscheidend davon ab, wie man die eigenen Bewältigungskompetenzen einschätzt. Misslingt eine angemessene Stressbewältigung, dann führt chronischer Stress zu einem körperlichen, kognitiven und emotionalen Erschöpfungszustand, Depression und psychosomatischen Reaktionen.
Quality Assessment of Economic Evaluations of Suicide and Self-Harm Interventions
Authors: Bustamante Madsen Lizell , Eddleston Michael , Schultz Hansen Kristian , Konradsen Flemming
Published: September 2017

Abstract. Background: Death following self-harm constitutes a major global public health challenge and there is an urgent need for governments to implement cost-effective, national suicide prevention strategies. Aim: To conduct a systematic review and quality appraisal of the economic evaluations of interventions aimed at preventing suicidal behavior. Method: A systematic literature search was performed in several literature databases to identify relevant articles published from 2003 to 2016. Drummond's 10-item appraisal tool was used to assess the methodological quality of the included studies. Results: In total, 25 documents encompassing 30 economic evaluations were included in the review. Of the identified evaluations, 10 studies were found to be of poor quality, 14 were of average quality, and six studies were considered of good quality. The majority of evaluations found the interventions to be cost-effective. Limitations: Several limitations were identified and discussed in the article. Conclusion: A notable few economic evaluations were identified. The studies were diverse, primarily set in high-income countries, and often based on modeling, emphasizing the need for more primary research into the topic. The discussion of suicide and self-harm prevention should be as nuanced as possible, including health economics along with cultural, social, and political aspects.
Sensorimotor computation underlying phototaxis in zebrafish
Authors: Wolf Sébastien , Dubreuil Alexis M. , Bertoni Tommaso , Böhm Urs Lucas , Bormuth Volker , Candelier Raphaël , Karpenko Sophia , Hildebrand David G. C. , Bianco Isaac H. , Monasson Rémi , Debrégeas Georges
Published: September 2017

Animals continuously gather sensory cues to move towards favourable environments. Efficient goal-directed navigation requires sensory perception and motor commands to be intertwined in a feedback loop, yet the neural substrate underlying this sensorimotor task in the vertebrate brain remains elusive. Here, we combine virtual-reality behavioural assays, volumetric calcium imaging, optogenetic stimulation and circuit modelling to reveal the neural mechanisms through which a zebrafish performs phototaxis, i.e. actively orients towards a light source. Key to this process is a self-oscillating hindbrain population (HBO) that acts as a pacemaker for ocular saccades and controls the orientation of successive swim-bouts. It further integrates visual stimuli in a state-dependent manner, i.e. its response to visual inputs varies with the motor context, a mechanism that manifests itself in the phase-locked entrainment of the HBO by periodic stimuli. A rate model is developed that reproduces our observations and demonstrates how this sensorimotor processing eventually biases the animal trajectory towards bright regions.
Establishing multiple omics baselines for three Southeast Asian populations in the Singapore Integrative Omics Study
Authors: Saw Woei-Yuh , Tantoso Erwin , Begum Husna , Zhou Lihan , Zou Ruiyang , He Cheng , Chan Sze Ling , Tan Linda Wei-Lin , Wong Lai-Ping , Xu Wenting , Moong Don Kyin Nwe , Lim Yenly , Li Bowen , Pillai Nisha Esakimuthu , Peterson Trevor A. , Bielawny Tomasz , Meikle Peter J. , Mundra Piyushkumar A. , Lim Wei-Yen , Luo Ma , Chia Kee-Seng , Ong Rick Twee-Hee , Brunham Liam R. , Khor Chiea-Chuen , Too Heng Phon , Soong Richie , Wenk Markus R. , Little Peter , Teo Yik-Ying
Published: September 2017

The Singapore Integrative Omics Study provides valuable insights on establishing population reference measurement in 364 Chinese, Malay, and Indian individuals. These measurements include > 2.5 millions genetic variants, 21,649 transcripts expression, 282 lipid species quantification, and 284 clinical, lifestyle, and dietary variables. This concept paper introduces the depth of the data resource, and investigates the extent of ethnic variation at these omics and non-omics biomarkers. It is evident that there are specific biomarkers in each of these platforms to differentiate between the ethnicities, and intra-population analyses suggest that Chinese and Indians are the most biologically homogeneous and heterogeneous, respectively, of the three groups. Consistent patterns of correlations between lipid species also suggest the possibility of lipid tagging to simplify future lipidomics assays. The Singapore Integrative Omics Study is expected to allow the characterization of intra-omic and inter-omic correlations within and across all three ethnic groups through a systems biology approach.
A gateway towards non-collinear spin processing using three-atom magnets with strong substrate coupling
Authors: Hermenau J. , Ibañez-Azpiroz J. , Hübner Chr. , Sonntag A. , Baxevanis B. , Ton K. T. , Steinbrecher M. , Khajetoorians A. A. , dos Santos Dias M. , Blügel S. , Wiesendanger R. , Lounis S. , Wiebe J.
Published: September 2017

A cluster of a few magnetic atoms on the surface of a nonmagnetic substrate is one suitable realization of a bit for spin-based information technology. The prevalent approach to achieve magnetic stability is decoupling the cluster spin from substrate conduction electrons in order to suppress destabilizing spin-flips. However, this route entails less flexibility in tailoring the coupling between the bits needed for spin-processing. Here, we use a spin-resolved scanning tunneling microscope to write, read, and store spin information for hours in clusters of three atoms strongly coupled to a substrate featuring a cloud of non-collinearly polarized host atoms, a so-called non-collinear giant moment cluster. The giant moment cluster can be driven into a Kondo screened state by simply moving one of its atoms to a different site. Using the exceptional atomic tunability of the non-collinear substrate mediated Dzyaloshinskii–Moriya interaction, we propose a logical scheme for a four-state memory.
Taking the pulse of Mars via dating of a plume-fed volcano
Authors: Cohen Benjamin E. , Mark Darren F. , Cassata William S. , Lee Martin R. , Tomkinson Tim , Smith Caroline L.
Published: September 2017

Mars hosts the solar system’s largest volcanoes. Although their size and impact crater density indicate continued activity over billions of years, their formation rates are poorly understood. Here we quantify the growth rate of a Martian volcano by40Ar/39Ar and cosmogenic exposure dating of six nakhlites, meteorites that were ejected from Mars by a single impact event at 10.7 ± 0.8 Ma (2σ). We find that the nakhlites sample a layered volcanic sequence with at least four discrete eruptive events spanning 93 ± 12 Ma (1416 ± 7 Ma to 1322 ± 10 Ma (2σ)). A non-radiogenic trapped40Ar/36Ar value of 1511 ± 74 (2σ) provides a precise and robust constraint for the mid-Amazonian Martian atmosphere. Our data show that the nakhlite-source volcano grew at a rate of ca. 0.4–0.7 m Ma−1—three orders of magnitude slower than comparable volcanoes on Earth, and necessitating that Mars was far more volcanically active earlier in its history.
Archaean and Proterozoic diamond growth from contrasting styles of large-scale magmatism
Authors: Koornneef Janne M. , Gress Michael U. , Chinn Ingrid L. , Jelsma Hielke A. , Harris Jeff W. , Davies Gareth R.
Published: September 2017

Precise dating of diamond growth is required to understand the interior workings of the early Earth and the deep carbon cycle. Here we report Sm-Nd isotope data from 26 individual garnet inclusions from 26 harzburgitic diamonds from Venetia, South Africa. Garnet inclusions and host diamonds comprise two compositional suites formed under markedly different conditions and define two isochrons, one Archaean (2.95 Ga) and one Proterozoic (1.15 Ga). The Archaean diamond suite formed from relatively cool fluid-dominated metasomatism during rifting of the southern shelf of the Zimbabwe Craton. The 1.8 billion years younger Proterozoic diamond suite formed by melt-dominated metasomatism related to the 1.1 Ga Umkondo Large Igneous Province. The results demonstrate that resolving the time of diamond growth events requires dating of individual inclusions, and that there was a major change in the magmatic processes responsible for harzburgitic diamond formation beneath Venetia from the Archaean to the Proterozoic.
Excitation of coupled spin–orbit dynamics in cobalt oxide by femtosecond laser pulses
Authors: Satoh Takuya , Iida Ryugo , Higuchi Takuya , Fujii Yasuhiro , Koreeda Akitoshi , Ueda Hiroaki , Shimura Tsutomu , Kuroda Kazuo , Butrim V. I. , Ivanov B. A.
Published: September 2017

Ultrafast control of magnets using femtosecond light pulses attracts interest regarding applications and fundamental physics of magnetism. Antiferromagnets are promising materials with magnon frequencies extending into the terahertz range. Visible or near-infrared light interacts mainly with the electronic orbital angular momentum. In many magnets, however, in particular with iron-group ions, the orbital momentum is almost quenched by the crystal field. Thus, the interaction of magnons with light is hampered, because it is only mediated by weak unquenching of the orbital momentum by spin–orbit interactions. Here we report all-optical excitation of magnons with frequencies up to 9 THz in antiferromagnetic CoO with an unquenched orbital momentum. In CoO, magnon modes are coupled oscillations of spin and orbital momenta with comparable amplitudes. We demonstrate excitations of magnon modes by directly coupling light with electronic orbital angular momentum, providing possibilities to develop magneto-optical devices operating at several terahertz with high output-to-input ratio.
Aromatic side-chain conformational switch on the surface of the RNA Recognition Motif enables RNA discrimination
Authors: Diarra dit Konté Nana , Krepl Miroslav , Damberger Fred F. , Ripin Nina , Duss Olivier , Šponer Jiří , Allain Frédéric H.-T.
Published: September 2017

The cyclooxygenase-2 is a pro-inflammatory and cancer marker, whose mRNA stability and translation is regulated by the CUG-binding protein 2 interacting with AU-rich sequences in the 3′ untranslated region. Here, we present the solution NMR structure of CUG-binding protein 2 RRM3 in complex with 5′-UUUAA-3′ originating from the COX-2 3′-UTR. We show that RRM3 uses the same binding surface and protein moieties to interact with AU- and UG-rich RNA motifs, binding with low and high affinity, respectively. Using NMR spectroscopy, isothermal titration calorimetry and molecular dynamics simulations, we demonstrate that distinct sub-states characterized by different aromatic side-chain conformations at the RNA-binding surface allow for high- or low-affinity binding with functional implications. This study highlights a mechanism for RNA discrimination possibly common to multiple RRMs as several prominent members display a similar rearrangement of aromatic residues upon binding their targets.
Application of bio-orthogonal proteome labeling to cell transplantation and heterochronic parabiosis
Authors: Liu Yan , Conboy Michael J. , Mehdipour Melod , Liu Yutong , Tran Thanhtra P. , Blotnick Aaron , Rajan Prasanna , Santos Thalie Cavalcante , Conboy Irina M.
Published: September 2017

Studies of heterochronic parabiosis demonstrated that with age, the composition of the circulatory milieu changes in ways that broadly inhibit tissue regenerative capacity. In addition, local tissue niches have age-specific influences on their resident stem cells. Here we use bio-orthogonal proteome labeling for detecting in vivo proteins present only in transplanted myoblasts, but not in host tissue, and proteins exclusive to one young mouse and transferred during parabiosis to its old partner. We use a transgenic mouse strain that ubiquitously expresses a modified tRNA methionine synthase, metRS, which preferentially incorporates the methionine surrogate azido-nor-leucine (ANL) into newly generated proteins. Using click chemistry and a modified antibody array to detect ANL-labeled proteins, we identify several ‘young’ systemic factors in old regenerating muscle of the heterochronic parabiotic partners. Our approach enables the selective profiling of mammalian proteomes in mixed biological environments such as cell and tissue transplantation, apheresis or parabiosis.
Short-channel field-effect transistors with 9-atom and 13-atom wide graphene nanoribbons
Authors: Llinas Juan Pablo , Fairbrother Andrew , Borin Barin Gabriela , Shi Wu , Lee Kyunghoon , Wu Shuang , Yong Choi Byung , Braganza Rohit , Lear Jordan , Kau Nicholas , Choi Wonwoo , Chen Chen , Pedramrazi Zahra , Dumslaff Tim , Narita Akimitsu , Feng Xinliang , Müllen Klaus , Fischer Felix , Zettl Alex , Ruffieux Pascal , Yablonovitch Eli , Crommie Michael , Fasel Roman , Bokor Jeffrey
Published: September 2017

Bottom-up synthesized graphene nanoribbons and graphene nanoribbon heterostructures have promising electronic properties for high-performance field-effect transistors and ultra-low power devices such as tunneling field-effect transistors. However, the short length and wide band gap of these graphene nanoribbons have prevented the fabrication of devices with the desired performance and switching behavior. Here, by fabricating short channel (Lch ~ 20 nm) devices with a thin, high-κ gate dielectric and a 9-atom wide (0.95 nm) armchair graphene nanoribbon as the channel material, we demonstrate field-effect transistors with high on-current (Ion > 1 μA at Vd = −1 V) and high Ion/Ioff ~ 105 at room temperature. We find that the performance of these devices is limited by tunneling through the Schottky barrier at the contacts and we observe an increase in the transparency of the barrier by increasing the gate field near the contacts. Our results thus demonstrate successful fabrication of high-performance short-channel field-effect transistors with bottom-up synthesized armchair graphene nanoribbons.
PD-L1 is an activation-independent marker of brown adipocytes
Authors: Ingram Jessica R. , Dougan Michael , Rashidian Mohammad , Knoll Marko , Keliher Edmund J. , Garrett Sarah , Garforth Scott , Blomberg Olga S. , Espinosa Camilo , Bhan Atul , Almo Steven C. , Weissleder Ralph , Lodish Harvey , Dougan Stephanie K. , Ploegh Hidde L.
Published: September 2017

Programmed death ligand 1 (PD-L1) is expressed on a number of immune and cancer cells, where it can downregulate antitumor immune responses. Its expression has been linked to metabolic changes in these cells. Here we develop a radiolabeled camelid single-domain antibody (anti-PD-L1 VHH) to track PD-L1 expression by immuno-positron emission tomography (PET). PET-CT imaging shows a robust and specific PD-L1 signal in brown adipose tissue (BAT). We confirm expression of PD-L1 on brown adipocytes and demonstrate that signal intensity does not change in response to cold exposure or β-adrenergic activation. This is the first robust method of visualizing murine brown fat independent of its activation state.
Characterization of Soft Amyloid Cores in Human Prion-Like Proteins
Authors: Batlle Cristina , de Groot Natalia Sanchez , Iglesias Valentin , Navarro Susanna , Ventura Salvador
Published: September 2017

Prion-like behaviour is attracting much attention due to the growing evidences that amyloid-like self-assembly may reach beyond neurodegeneration and be a conserved functional mechanism. The best characterized functional prions correspond to a subset of yeast proteins involved in translation or transcription. Their conformational promiscuity is encoded in Prion Forming Domains (PFDs), usually long and intrinsically disordered protein segments of low complexity. The compositional bias of these regions seems to be important for the transition between soluble and amyloid-like states. We have proposed that the presence of cryptic soft amyloid cores embedded in yeast PFDs can also be important for their assembly and demonstrated their existence and self-propagating abilities. Here, we used an orthogonal approach in the search of human domains that share yeast PFDs compositional bias and exhibit a predicted nucleating core, identifying 535 prion-like candidates. We selected seven proteins involved in transcriptional or translational regulation and associated to disease to characterize the properties of their amyloid cores. All of them self-assemble spontaneously into amyloid-like structures able to propagate their polymeric state. This provides support for the presence of short sequences able to trigger conformational conversion in prion-like human proteins, potentially regulating their functionality.
A non-transcriptional role for the glucocorticoid receptor in mediating the cell stress response
Authors: Ptushkina Marina , Poolman Toryn , Iqbal Mudassar , Ashe Mark , Petersen Janni , Woodburn Joanna , Rattray Magnus , Whetton Anthony , Ray David
Published: September 2017

The glucocorticoid receptor (GR) is essential for the stress response in mammals. We investigated potential non-transcriptional roles of GR in cellular stress response using fission yeast as a model.We surprisingly discovered marked heat stress resistance in yeast ectopically expressing human GR, which required expression of both the N-terminal transactivation domain, and the C-terminal ligand binding domain, but not the DNA-binding domain of the GR. This effect was not affected by GR ligand exposure, and occurred without significant GR nuclear accumulation. Mechanistically, the GR survival effect required Hsp104, and, indeed, GR expression increased Hsp104 expression. Proteomic analysis revealed GR binding to translasome components, including eIF3, a known partner for Sty1, a pattern of protein interaction which we confirmed using yeast two-hybrid studies.Taken together, we find evidence for a novel pathway conferring stress resistance in yeast that can be activated by the human GR, acting by protein-protein mechanisms in the cytoplasm. This suggests that in organisms where GR is natively expressed, GR likely contributes to stress responses through non-transcriptional mechanisms in addition to its well-established transcriptional responses.
Directional beaming of light from a subwavelength metal slit with phase-gradient metasurfaces
Authors: Zhu Hua , Yin Xiang , Chen Lin , Li Xun
Published: September 2017

In this article, we demonstrate directional beaming of light from a metal nanoslit surrounded with phase-gradient metasurfaces on both sides. Distinct from the grating-based beaming structures, here the momentum mismatch between the surface wave and radiation wave is overcome by the phase-gradient metasurfaces. The deviation angle of the directional beam can be flexibly adjusted by appropriately arranging the phase-gradient of metasurfaces on each side of the nanoslit. The metasurface-based beaming structures also present the ability to operate with high diffraction efficiency and small divergence angle, implying various potential applications in nanophotonics.
Field-cycling NMR with high-resolution detection under magic-angle spinning: determination of field-window for nuclear hyperpolarization in a photosynthetic reaction center
Authors: Gräsing Daniel , Bielytskyi Pavlo , Céspedes-Camacho Isaac F. , Alia A. , Marquardsen Thorsten , Engelke Frank , Matysik Jörg
Published: September 2017

Several parameters in NMR depend on the magnetic field strength. Field-cycling NMR is an elegant way to explore the field dependence of these properties. The technique is well developed for solution state and in relaxometry. Here, a shuttle system with magic-angle spinning (MAS) detection is presented to allow for field-dependent studies on solids. The function of this system is demonstrated by exploring the magnetic field dependence of the solid-state photochemically induced nuclear polarization (photo-CIDNP) effect. The effect allows for strong nuclear spin-hyperpolarization in light-induced spin-correlated radical pairs (SCRPs) under solid-state conditions. To this end, 13C MAS NMR is applied to a photosynthetic reaction center (RC) of the purple bacterium Rhodobacter (R.) sphaeroides wildtype (WT). For induction of the effect in the stray field of the magnet and its subsequent observation at 9.4 T under MAS NMR conditions, the sample is shuttled by the use of an aerodynamically driven sample transfer technique. In the RC, we observe the effect down to 0.25 T allowing to determine the window for the occurrence of the effect to be between about 0.2 and 20 T.
Antibacterial and immunomodulatory activities of insect defensins-DLP2 and DLP4 against multidrug-resistant Staphylococcus aureus
Authors: Li Zhanzhan , Mao Ruoyu , Teng Da , Hao Ya , Chen Huixian , Wang Xiumin , Wang Xiao , Yang Na , Wang Jianhua
Published: September 2017

Methicillin-resistant Staphylococcus aureus (MRSA), are the most frequent cause of sepsis, which urgently demanding new drugs for treating infection. Two homologous insect CSαβ peptides-DLP2 and DLP4 from Hermetia illucens were firstly expressed in Pichia pastoris, with the yields of 873.5 and 801.3 mg/l, respectively. DLP2 and DLP4 displayed potent antimicrobial activity against Gram-positive bacteria especially MRSA and had greater potency, faster killing, and a longer postantibiotic effect than vancomycin. A 30-d serial passage of MRSA in the presence of DLP2/DLP4 failed to produce resistant mutants. Macromolecular synthesis showed that DLP2/DLP4 inhibited multi-macromolecular synthesis especially for RNA. Flow cytometry and electron microscopy results showed that the cell cycle was arrested at R-phase; the cytoplasmic membrane and cell wall were broken by DLP2/DLP4; mesosome-like structures were observed in MRSA. At the doses of 3‒7.5 mg/kg DLP2 or DLP4, the survival of mice challenged with MRSA were 80‒100%. DLP2 and DLP4 reduced the bacterial translocation burden over 95% in spleen and kidneys; reduced serum pro-inflammatory cytokines levels; promoted anti-inflammatory cytokines levels; and ameliorated lung and spleen injury. These data suggest that DLP2 and DLP4 may be excellent candidates for novel antimicrobial peptides against staphylococcal infections.
Silent Sentence Completion Shows Superiority Localizing Wernicke’s Area and Activation Patterns of Distinct Language Paradigms Correlate with Genomics: Prospective Study
Authors: Salek Kamel El , Hassan Islam S. , Kotrotsou Aikaterini , Abrol Srishti , Faro Scott H. , Mohamed Feroze B. , Zinn Pascal O. , Wei Wei , Li Nan , Kumar Ashok J. , Weinberg Jeffrey S. , Wefel Jeffrey S. , Kesler Shelli R. , Liu Ho-Ling Anthony , Hou Ping , Stafford R. Jason , Prabhu Sujit , Sawaya Raymond , Colen Rivka R.
Published: September 2017

Preoperative mapping of language areas using fMRI greatly depends on the paradigms used, as different tasks harness distinct capabilities to activate speech processing areas. In this study, we compared the ability of 3 covert speech paradigms: Silent Sentence Completion (SSC), category naming (CAT) and verbal fluency (FAS), in localizing the Wernicke’s area and studied the association between genomic markers and functional activation. Fifteen right-handed healthy volunteers and 35 mixed-handed patients were included. We focused on the anatomical areas of posterosuperior, middle temporal and angular gyri corresponding to Wernicke’s area. Activity was deemed significant in a region of interest if P < 0.05. Association between fMRI activation and genomic mutation status was obtained. Results demonstrated SSC’s superiority at localizing Wernicke’s area. SSC demonstrated functional activity in 100% of cancer patients and healthy volunteers; which was significantly higher than those for FAS and CAT. Patients with 1p/19q non-co-deleted had higher extent of activation on SSC (P < 0.02). Those with IDH-1 wild-type were more likely to show no activity on CAT (P < 0.05). SSC is a robust paradigm for localizing Wernicke’s area, making it an important clinical tool for function-preserving surgeries. We also found a correlation between tumor genomics and functional activation, which deserves more comprehensive study.
Interference of stress with the somatotropic axis in pigs – lights on new biomarkers
Authors: Wirthgen Elisa , Kunze Martin , Goumon Sébastien , Walz Christina , Höflich Christine , Spitschak Marion , Brenmoehl Julia , Kanitz Ellen , Tuchscherer Margret , Otten Winfried , Gimsa Ulrike , Schön Peter , Manteuffel Christian , Tuchscherer Armin , Pfuhl Ralf , Metges Cornelia C. , Stabenow Bernd , Erdmann Sandra , Schluricke Kathleen , Faucitano Luigi , Hoeflich Andreas
Published: September 2017

The acceptance of animal products is increasingly associated with standardized animal welfare, which relates to appropriate animal husbandry from birth to slaughter. In particular, shipment to the slaughterhouse is considered as a critical process exposing the animals to a number of, in part severe, stressors. New biomarkers may be useful for the assessment of animal welfare. The IGF-system has been assessed in a commercial pig transport in conjunction with established markers of stress response. Furthermore, the effect of repeated restraint as an experimental model for repeated acute stress was investigated. During shipment from farm to slaughterhouse, plasma concentrations of IGFBP-3 and IGFBP-2 were significantly reduced (p < 0.01). After shipment, the plasma concentrations of IGFBP-5, glucocorticoids and IL-2 increased but decreased after lairage (p < 0.05) whereas IGF-1 decreased after shipment (p < 0.01). Repeated acute stress increased concentrations of IGFBP-3 and IGF-1 in exsanguination blood (p < 0.05). Differential IGF- signatures can indicate altered endocrine or metabolic control and thus contain complex animal-related information. The somatotropic axis may be of particular interest when established biomarkers such as cortisol, glucose, or lactate cannot be used for the assessment of animal stress or welfare.
Impact of mitochondrial nitrite reductase on hemodynamics and myocardial contractility
Authors: Dungel Peter , Penzenstadler Carina , Ashmwe Mostafa , Dumitrescu Sergiu , Stoegerer Tanja , Redl Heinz , Bahrami Soheyl , Kozlov Andrey V.
Published: September 2017

Inorganic nitrite (NO2−) can be reduced back to nitric oxide (NO) by several heme proteins called nitrite reductases (NR) which affect both the vascular tonus and hemodynamics. The objective of this study was to clarify the impact of several NRs on the regulation of hemodynamics, for which hemodynamic parameters such as heart rate, blood pressure, arterial stiffness, peripheral resistance and myocardial contractility were characterized by pulse wave analysis. We have demonstrated that NO2− reduced to NO in RBCs predominantly influences the heart rate, while myoglobin (Mb) and mitochondria-derived NO regulates arterial stiffness, peripheral resistance and myocardial contractility. Using ex vivo on-line NO-detection, we showed that Mb is the strongest NR occurring in heart, which operates sufficiently only at very low oxygen levels. In contrast, mitochondrial NR operates under both hypoxia and normoxia. Additional experiments with cardiomyocytes suggested that only mitochondria-derived generation of NO regulates cGMP levels mediating the contractility of cardiomyocytes. Our data suggest that a network of NRs is involved in NO2− mediated regulation of hemodynamics. Oxygen tension and hematocrit define the activity of specific NRs.
Demonstration and Analysis of the Suction Effect for Pumping Lymph from Tissue Beds at Subatmospheric Pressure
Authors: Jamalian Samira , Jafarnejad Mohammad , Zawieja Scott D. , Bertram Christopher D. , Gashev Anatoliy A. , Zawieja David C. , Davis Michael J. , Moore James E.
Published: September 2017

Many tissues exhibit subatmospheric interstitial pressures under normal physiologic conditions. The mechanisms by which the lymphatic system extracts fluid from these tissues against the overall pressure gradient are unknown. We address this important physiologic issue by combining experimental measurements of contractile function and pressure generation with a previously validated mathematical model. We provide definitive evidence for the existence of ‘suction pressure’ in collecting lymphatic vessels, which manifests as a transient drop in pressure downstream of the inlet valve following contraction. This suction opens the inlet valve and is required for filling in the presence of low upstream pressure. Positive transmural pressure is required for this suction, providing the energy required to reopen the vessel. Alternatively, external vessel tethering can serve the same purpose when the transmural pressure is negative. Suction is transmitted upstream, allowing fluid to be drawn in through initial lymphatics. Because suction plays a major role in fluid entry to the lymphatics and is affected by interstitial pressure, our results introduce the phenomenon as another important factor to consider in the study of lymphoedema and its treatment.
Correlation profiling of brain sub-cellular proteomes reveals co-assembly of synaptic proteins and subcellular distribution
Authors: Pandya Nikhil J. , Koopmans Frank , Slotman Johan A. , Paliukhovich Iryna , Houtsmuller Adriaan B. , Smit August B. , Li Ka Wan
Published: September 2017

Protein correlation profiling might assist in defining co-assembled proteins and subcellular distribution. Here, we quantified the proteomes of five biochemically isolated mouse brain cellular sub-fractions, with emphasis on synaptic compartments, from three brain regions, hippocampus, cortex and cerebellum. We demonstrated the expected co-fractionation of canonical synaptic proteins belonging to the same functional groups. The enrichment profiles also suggested the presence of many novel pre- and post-synaptic proteins. Using super-resolution microscopy on primary neuronal culture we confirmed the postsynaptic localization of PLEKHA5 and ADGRA1. We further detected profound brain region specific differences in the extent of enrichment for some functionally associated proteins. This is exemplified by different AMPA receptor subunits and substantial differences in sub-fraction distribution of their potential interactors, which implicated the differences of AMPA receptor complex compositions. This resource aids the identification of proteins partners and subcellular distribution of synaptic proteins.
Formalin Fixation and Cryosectioning Cause Only Minimal Changes in Shape or Size of Ocular Tissues
Authors: Tran Huong , Jan Ning-Jiun , Hu Danielle , Voorhees Andrew , Schuman Joel S. , Smith Matthew A. , Wollstein Gadi , Sigal Ian A.
Published: September 2017

Advances in imaging have made it increasingly common to study soft tissues without first embedding them in plastic or paraffin and without using labels or stains. The process, however, usually still involves fixation and cryosectioning, which could deform the tissues. Our goal was to quantify the morphological changes of ocular tissues caused by formalin fixation and cryosectioning. From each of 6 porcine eyes, 4 regions were obtained: cornea, equatorial and posterior sclera, and posterior pole containing the optic nerve head. Samples were imaged using visible light microscopy fresh, 1-minute and 24-hours post-fixation, and post-cryosectioning. Effects were assessed by 14 parameters representing sample size and shape. Overall, formalin fixation and sectioning caused only minimal changes to the ocular tissues, with average percentage parameter differences of 0.1%, 1%, and 1.2% between fresh and post-fixing by 1 minute, 24 hours, and post-cryosectioning, respectively. Parameter changes were not directional, and were only weakly dependent on the duration of fixation and the region of the eye. These results demonstrate that formalin fixation and cryosectioning are good choices for studying ocular tissue morphology and structure, as they do not cause the large tissue shrinkage or distortions typically associated with other, more complicated, techniques.
Serum Uric Acid to Creatinine Ratio and Risk of Metabolic Syndrome in Saudi Type 2 Diabetic Patients
Authors: Al-Daghri Nasser M. , Al-Attas Omar S. , Wani Kaiser , Sabico Shaun , Alokail Majed S.
Published: September 2017

This study aimed to investigate whether uric acid to creatinine (UA/Cr) ratio is associated with higher risk of metabolic syndrome (MetS) and its components. 332 adult Saudi type 2 diabetes mellitus (T2DM) patients were divided into UA/Cr tertiles. Risk for full MetS was significantly highest in individuals that constitutes the uppermost serum UA/Cr tertile [Odds ratio (OR): 1.80, 95% confidence interval (CI): 1.0–3.3; p < 0.001) after adjustment for age, gender and BMI. Similarly, risk for individual components of MetS like central obesity, hypertriglyceridemia, low HDL-cholesterol and hypertension was significantly highest in this tertile with OR’s of 2.61 (1.2–5.6), 1.42 (0.7–2.3), 1.45 (0.7–2.8) and 1.16 (0.6–2.2) respectively (all p-values < 0.001) after adjustment for age, gender, BMI and other components of MetS. Furthermore, serum UA/Cr levels increased with increasing number of MetS components (mean values of 4.44, 4.49, 4.64, 4.89 and 4.91 respectively for 1,2,3,4 and 5 MetS components, p-values < 0.001 after adjusting for age, gender and BMI). Our data suggest that serum UA/Cr in T2DM patients is strongly associated with full MetS as well as its individual components. These findings are of considerable clinical importance as serum UA/Cr may be used as a marker in the pathogenesis of MetS.
Membrane particles generated from mesenchymal stromal cells modulate immune responses by selective targeting of pro-inflammatory monocytes
Authors: Gonçalves Fabiany da C. , Luk Franka , Korevaar Sander S. , Bouzid Rachid , Paz Ana H. , López-Iglesias Carmen , Baan Carla C. , Merino Ana , Hoogduijn Martin J.
Published: September 2017

Mesenchymal stromal cells (MSC) are a promising therapy for immunological disorders. However, culture expanded MSC are large and get trapped in the capillary networks of the lungs after intravenous infusion, where they have a short survival time. Hypothetically, living cells are a risk for tumor formation. To reduce risks associated with MSC infusion and improve the distribution in the body, we generated membrane particles (MP) of MSC and MSC stimulated with IFN-γ (MPγ). Tracking analysis and electron microscopy indicated that the average size of MP was 120 nm, and they showed a round shape. MP exhibited ATPase, nucleotidase and esterase activity, indicating they are enzymatically active. MP and MPγ did not physically interact with T cells and had no effect on CD4+ and CD8+ T cells proliferation. However, MP and MPγ selectively bound to monocytes and decreased the frequency of pro-inflammatory CD14+CD16+ monocytes by induction of selective apoptosis. MP and MPγ increased the percentage of CD90 positive monocytes, and MPγ but not MP increased the percentage of anti-inflammatory PD-L1 monocytes. MPγ increased mRNA expression of PD-L1 in monocytes. These data demonstrate that MP have immunomodulatory properties and have potential as a novel cell-free therapy for treatment of immunological disorders.
Evidence of auditory insensitivity to vocalization frequencies in two frogs
Authors: Goutte Sandra , Mason Matthew J. , Christensen-Dalsgaard Jakob , Montealegre-Z Fernando , Chivers Benedict D. , Sarria-S Fabio A. , Antoniazzi Marta M. , Jared Carlos , Almeida Sato Luciana , Felipe Toledo Luís
Published: September 2017

The emergence and maintenance of animal communication systems requires the co-evolution of signal and receiver. Frogs and toads rely heavily on acoustic communication for coordinating reproduction and typically have ears tuned to the dominant frequency of their vocalizations, allowing discrimination from background noise and heterospecific calls. However, we present here evidence that two anurans, Brachycephalus ephippium and B. pitanga, are insensitive to the sound of their own calls. Both species produce advertisement calls outside their hearing sensitivity range and their inner ears are partly undeveloped, which accounts for their lack of high-frequency sensitivity. If unheard by the intended receivers, calls are not beneficial to the emitter and should be selected against because of the costs associated with signal production. We suggest that protection against predators conferred by their high toxicity might help to explain why calling has not yet disappeared, and that visual communication may have replaced auditory in these colourful, diurnal frogs.
Mucin 5B in saliva and serum of patients with oral lichen planus
Authors: Agha-Hosseini Farzaneh , Imanpour Mojtaba , Mirzaii-Dizgah Iraj , Moosavi Mahdieh-Sadat
Published: September 2017

Oral lichen planus (OLP) is among the most common oral diseases. Its etiopathogenesis has yet to be clearly identified. OLP patients complain of mouth dryness. This study aimed to assess the level of Mucin 5B in OLP patients with xerostomia. This study was conducted on 30 OLP patients and 30 healthy individuals. In addition to patient complaint of mouth dryness, xerostomia was assessed by tongue blade and lipstick tests. Stimulated and unstimulated saliva were collected in plastic vials by spitting method. Level of Mucin 5B was measured by ELISA. Unstimulated saliva flow was significantly lower in OLP patients (P = 0.0001). Stimulated saliva flow was not significantly different between the two groups (P > 0.05). Level of Mucin 5B in unstimulated saliva was significantly lower in OLP group (P = 0.0001) while it was not significantly different in stimulated saliva of the two groups (P > 0.05). Level of Mucin 5B was significantly higher in serum of OLP patients (P = 0.016). Both saliva flow and level of Mucin 5B decrease in OLP patients. Since Mucin 5B is effective for wetting and lubrication of the oral cavity, this result can suggest a possible reason for mouth dryness in OLP patients.
Novel scaffolds for inhibition of Cruzipain identified from high-throughput screening of anti-kinetoplastid chemical boxes
Authors: Salas-Sarduy Emir , Landaburu Lionel Urán , Karpiak Joel , Madauss Kevin P. , Cazzulo Juan José , Agüero Fernán , Alvarez Vanina Eder
Published: September 2017

American Trypanosomiasis or Chagas disease is a prevalent, neglected and serious debilitating illness caused by the kinetoplastid protozoan parasite Trypanosoma cruzi. The current chemotherapy is limited only to nifurtimox and benznidazole, two drugs that have poor efficacy in the chronic phase and are rather toxic. In this scenario, more efficacious and safer drugs, preferentially acting through a different mechanism of action and directed against novel targets, are particularly welcome. Cruzipain, the main papain-like cysteine peptidase of T. cruzi, is an important virulence factor and a chemotherapeutic target with excellent pre-clinical validation evidence. Here, we present the identification of new Cruzipain inhibitory scaffolds within the GlaxoSmithKline HAT (Human African Trypanosomiasis) and Chagas chemical boxes, two collections grouping 404 non-cytotoxic compounds with high antiparasitic potency, drug-likeness, structural diversity and scientific novelty. We have adapted a continuous enzymatic assay to a medium-throughput format and carried out a primary screening of both collections, followed by construction and analysis of dose-response curves of the most promising hits. Using the identified compounds as a starting point a substructure directed search against CHEMBL Database revealed plausible common scaffolds while docking experiments predicted binding poses and specific interactions between Cruzipain and the novel inhibitors.
Differential regulation of Effector and Regulatory T cell function by Blimp1
Authors: Bankoti Rashmi , Ogawa Chihiro , Nguyen Truc , Emadi Lena , Couse Michael , Salehi Soofia , Fan Xuemo , Dhall Deepti , Wang Yizhou , Brown Jordan , Funari Vincent , Tang Jie , Martins Gislâine A.
Published: September 2017

The transcriptional regulator Blimp1 plays crucial roles in controlling terminal differentiation in several lineages. In T cells, Blimp1 is expressed in both effector (Teff) and regulatory (Treg) cells, and mice with T cell-specific deletion of Blimp1 (Blimp1CKO mice) spontaneously develop severe intestinal inflammation, indicating a crucial role for Blimp1 in T cell homeostasis regulation. Blimp1 has been shown to function as a direct activator of the Il10 gene and although its requirement for IL10 expression has been demonstrated in both Treg and Teff cells under inflammatory conditions, the intrinsic requirement of Blimp1 for homeostatic maintenance of these T cell subsets had not been investigated. Using mice with Foxp3+ Treg-cell specific deletion of Blimp1 and other approaches, here we show that Foxp3+ Treg cell-intrinsic expression of Blimp1 is required to control Treg and Teff cells homeostasis but, unexpectedly, it is dispensable to prevent development of severe spontaneous intestinal inflammation. In addition, we show that Blimp1 controls common and unique aspects of Treg and Teff cell function by differentially regulating gene expression in these T cell subsets. These findings document previously unappreciated aspects of Blimp1’s role in T cell biology and shed light on the intricate mechanisms regulating Treg and Teff cell function.
Effects of ticagrelor in a mouse model of ischemic stroke
Authors: Yamauchi Keita , Imai Takahiko , Shimazawa Masamitsu , Iwama Toru , Hara Hideaki
Published: September 2017

Ticagrelor is a direct acting and reversibly binding P2Y12 antagonist approved for the prevention of thromboembolic events. Its potential benefits in ischemic stroke have not been investigated sufficiently. Mice were subjected to 2 hours of transient middle cerebral artery occlusion (MCAO). Mice were orally treated with ticagrelor (10 or 30 mg/kg), aspirin (60 mg/kg), or vehicle at 3 and 24 hours before MCAO and 0 and 6 hours after reperfusion. The infarct volume and neurological deficits 22 hours after reperfusion were evaluated. Cerebral blood flow (CBF) within 24 hours after MCAO was monitored. We performed western blotting and in vitro analysis using oxygen-glucose deprivation (OGD) stress in human brain microvessel endothelial cells (HBMVECs) to investigate the protective effects of ticagrelor. Ticagrelor (30 mg/kg) improved neurological deficits, reduced the infarct volume, and improved CBF. It promoted the phosphorylation of endothelial nitric oxide synthase (eNOS) and extracellular signal-regulated kinase 1/2 (ERK1/2) during the early phase after reperfusion. Increased phosphorylation of eNOS and ERK1/2 were also observed in HBMVECs after OGD stress. Ticagrelor attenuate ischemia reperfusion injury possibly via phosphorylation of eNOS and ERK1/2 in endothelial cells. This suggests that ticagrelor has neuroprotective effects via mechanisms other than its antiplatelet action.
Toward the identification of a type I toxin-antitoxin system in the plasmid DNA of dairy Lactobacillus rhamnosus
Authors: Folli Claudia , Levante Alessia , Percudani Riccardo , Amidani Davide , Bottazzi Stefania , Ferrari Alberto , Rivetti Claudio , Neviani Erasmo , Lazzi Camilla
Published: September 2017

Plasmids carry genes that give bacteria beneficial traits and allow them to survive in competitive environments. In many cases, they also harbor toxin-antitoxin (TA) systems necessary for plasmid maintenance. TA systems are generally characterized by a stable “toxin”, a protein or peptide capable of killing the cell upon plasmid loss and by an unstable “antitoxin”, a protein or a non-coding RNA that inhibits toxin activity. Here we report data toward the identification of a RNA-regulated TA system in the plasmid DNA of L. rhamnosus isolated from cheese. The proposed TA system comprises two convergently transcribed RNAs: a toxin RNA encoding a 29 amino acid peptide named Lpt and an antitoxin non-coding RNA. Both toxin and antitoxin RNAs resulted upregulated under conditions mimicking cheese ripening. The toxicity of the Lpt peptide was demonstrated in E. coli by cloning the Lpt ORF under the control of an inducible promoter. Bioinformatics screening of the bacterial nucleotide database, shows that regions homologous to the Lpt TA locus are widely distributed in the Lactobacillus genus, particularly within the L. casei group, suggesting a relevant role of TA systems in plasmid maintenance of cheese microbiota.
Absolute quantitation of disease protein biomarkers in a single LC-MS acquisition using apolipoprotein F as an example
Authors: Kumar Abhinav , Gangadharan Bevin , Cobbold Jeremy , Thursz Mark , Zitzmann Nicole
Published: September 2017

LC-MS and immunoassay can detect protein biomarkers. Immunoassays are more commonly used but can potentially be outperformed by LC-MS. These techniques have limitations including the necessity to generate separate calibration curves for each biomarker. We present a rapid mass spectrometry-based assay utilising a universal calibration curve. For the first time we analyse clinical samples using the HeavyPeptide IGNIS kit which establishes a 6-point calibration curve and determines the biomarker concentration in a single LC-MS acquisition. IGNIS was tested using apolipoprotein F (APO-F), a potential biomarker for non-alcoholic fatty liver disease (NAFLD). Human serum and IGNIS prime peptides were digested and the IGNIS assay was used to quantify APO-F in clinical samples. Digestion of IGNIS prime peptides was optimised using trypsin and SMART Digest™. IGNIS was 9 times faster than the conventional LC-MS method for determining the concentration of APO-F in serum. APO-F decreased across NAFLD stages. Inter/intra-day variation and stability post sample preparation for one of the peptides was ≤13% coefficient of variation (CV). SMART Digest™ enabled complete digestion in 30 minutes compared to 24 hours using in-solution trypsin digestion. We have optimised the IGNIS kit to quantify APO-F as a NAFLD biomarker in serum using a single LC-MS acquisition.
Deterministic optical polarisation in nitride quantum dots at thermoelectrically cooled temperatures
Authors: Wang Tong , Puchtler Tim J. , Patra Saroj K. , Zhu Tongtong , Jarman John C. , Oliver Rachel A. , Schulz Stefan , Taylor Robert A.
Published: September 2017

We report the successful realisation of intrinsic optical polarisation control by growth, in solid-state quantum dots in the thermoelectrically cooled temperature regime (≥200 K), using a non-polar InGaN system. With statistically significant experimental data from cryogenic to high temperatures, we show that the average polarisation degree of such a system remains constant at around 0.90, below 100 K, and decreases very slowly at higher temperatures until reaching 0.77 at 200 K, with an unchanged polarisation axis determined by the material crystallography. A combination of Fermi-Dirac statistics and k·p theory with consideration of quantum dot anisotropy allows us to elucidate the origin of the robust, almost temperature-insensitive polarisation properties of this system from a fundamental perspective, producing results in very good agreement with the experimental findings. This work demonstrates that optical polarisation control can be achieved in solid-state quantum dots at thermoelectrically cooled temperatures, thereby opening the possibility of polarisation-based quantum dot applications in on-chip conditions.