bluuebunny/crossref_metadata_2025_split huggingface dataset:
Diabetic cats have decreased gut microbial diversity and a lack of butyrate producing bacteria
Authors: Kieler Ida Nordang , Osto Melania , Hugentobler Leoni , Puetz Lara , Gilbert M. Thomas P. , Hansen Torben , Pedersen Oluf , Reusch Claudia E. , Zini Eric , Lutz Thomas A. , Bjørnvad Charlotte Reinhard 
Published: March 2019

AbstractObesity and inactivity are major risk factors of feline diabetes mellitus (FDM) and human type II diabetes mellitus (T2DM). In recent years, changes in the gut microbiota have been suggested as a contributing factor to T2DM. Whether the gut microbiota (GM) composition plays a role in FDM remains unknown. The aim of the current study was firstly a cross-sectional comparison of the GM of diabetic cats, to that of lean, and of obese/overweight non-diabetic cats of a similar age. Specifically, fecal samples from 82 privately-owned cats from Denmark and Switzerland were sequenced using 16S rRNA gene amplicon metabarcoding. Secondly dietary intervention data was generated, by obtaining additional samples from a subset of cats after placing them on a high-protein diet for four weeks. The GM diversity of diabetic cats was lower than that of lean cats in the cross-sectional study, and lower compared to lean and to overweight/obese cats after diet intervention. Diabetic cats also exhibited fewer Anaerotruncus, Dialister, and unknown Ruminococcaceae than lean cats. Serum fructosamine levels correlated negatively with Prevotellaceae abundance and positively with Enterobacteriaceae abundance. In summary the intestinal microbiota of diabetic cats was characterized by decreased GM diversity and loss of butyrate producing bacterial genera.
A Systems Vaccinology Approach Reveals the Mechanisms of Immunogenic Responses to Hantavax Vaccination in Humans
Authors: Khan Adnan , Shin Ok Sarah , Na Jinhyuk , Kim Jae Kwan , Seong Rak-Kyun , Park Man-Seong , Noh Ji Yun , Song Joon Young , Cheong Hee Jin , Park Youngja Hwang , Kim Woo Joo 
Published: March 2019

AbstractHantavax is an inactivated vaccine for hemorrhagic fever with renal syndrome (HFRS). The immunogenic responses have not been elucidated yet. Here we conducted a cohort study in which 20 healthy subjects were administered four doses of Hantavax during 13-months period. Pre- and post- vaccinated peripheral blood mononuclear cells (PBMCs) and sera were analysed by transcriptomic and metabolomic profilings, respectively. Based on neutralizing antibody titers, subjects were subsequently classified into three groups; non responders (NRs), low responders (LRs) and high responders (HRs). Post vaccination differentially expressed genes (DEGs) associated with innate immunity and cytokine pathways were highly upregulated. DEG analysis revealed a significant induction of CD69 expression in the HRs. High resolution metabolomics (HRM) analysis showed that correlated to the antibody response, cholesteryl nitrolinoleate, octanoyl-carnitine, tyrosine, ubiquinone-9, and benzoate were significantly elevated in HRs, while chenodeoxycholic acid and methyl palmitate were upregulated in NRs and LRs, compared with HRs. Additionally, gene-metabolite interaction revealed upregulated gene-metabolite couplings in, folate biosynthesis, nicotinate and nicotinamide, arachidonic acid, thiamine and pyrimidine metabolism in a dose dependent manner in HR group. Collectively, our data provide new insight into the underlying mechanisms of the Hantavax-mediated immunogenicity in humans.
Multivariate profiling of African green monkey and rhesus macaque T lymphocytes
Authors: Hassan Wail M. , Burton Gregory F. , Pinter Gabriella A. , Lauko Istvan G. , Mahdi Nader N. , Johnson Mackenzie E. 
Published: March 2019

AbstractThe complexity of immune responses limits the usefulness of univariate methods in answering complex immunology questions. To demonstrate the utility of a multivariate approach, we employ such approach to compare T cells of African green monkeys (AGMs) and rhesus macaques (RMs). Among the most prominent distinguishing features we found were lower CD3 and higher CD28 surface expression in AGMs compared to RMs. Afterin vitrostimulation, a larger proportion of AGM T cells secreted cytokines, especially those producing more than one cytokine (i.e. multifunctional cells). To find out whether multifunctional responses associate with protection in other species, we compared T cells of cynomolgus macaques (CMs) infected with wild-type Simian Immunodeficiency Virus (SIV) to those of CMs infected (vaccinated) with a replication-defective virus. Wild-type SIV infection in macaques leads to simian Acquired Immunodeficiency Syndrome (AIDS), which does not happen in animals previously vaccinated with a replication-defective virus. Interestingly, afterin vitrostimulation, multifunctional cells were more abundant among T cells of vaccinated CMs. Our results propose T-cell multifunctionality as a potentially useful marker of immunity, although additional verification is needed. Finally, we hope our multivariate model and its associated validation methods will inform future studies in the field of immunology.
Sulfate depletion triggers overproduction of phospholipids and the release of outer membrane vesicles by Neisseria meningitidis
Authors: Gerritzen Matthias J. H. , Martens Dirk E. , Uittenbogaard Joost P. , Wijffels René H. , Stork Michiel 
Published: March 2019

AbstractOuter membrane vesicles (OMVs) produced by bacteria are interesting vaccine candidates. OMVs are nanoparticles that contain many immunogenic components, are self-adjuvating, and non-replicative. Despite recent insights in the biogenesis of OMVs, there is no consensus on a conserved mechanism of OMV release and the OMV yield from bacterial cultures remains low. For Neisseria meningitidis, a Gram-negative human pathogen causing meningitis and sepsis, a feasible OMV production method based on triggering OMV release by cysteine depletion has been described. In this study, we investigated the mechanism behind this external trigger for OMV release to improve the production process. Since enhanced OMV release upon cysteine depletion was associated with oxidative stress and redox responses, we investigate the influence of more oxidized sulfur sources on OMV release. We show that N. meningitidis grows similarly on sulfate, the most oxidized sulfur source, and OMV release is triggered by sulfur depletion in general. Sulfate depletion induced increased release of OMVs over cysteine depletion. Proteomics showed that sulfur depletion resulted in oxidative stress responses and upregulated phospholipid and LPS biosynthesis. Furthermore, OMVs produced by sulfur depletion were enriched in phospholipids. Mechanistically, we hypothesize that sulfur depletion results in overproduction of phospholipids causing increased bulging of the outer membrane and subsequent OMV release.
Muscle contractility in spinobulbar muscular atrophy
Authors: Dahlqvist Julia R. , Oestergaard Sofie T. , Poulsen Nanna S. , Knak Kirsten Lykke , Thomsen Carsten , Vissing John 
Published: March 2019

AbstractSpinobulbar muscular atrophy (SBMA) is caused by a trinucleotide repeat expansion in the androgen receptor gene on the X chromosome. There is a toxic effect of the mutant receptor on muscle and neurons resulting in muscle weakness and atrophy. The weakness can be explained by wasting due to loss of muscle cells, but it is unknown whether weakness also relates to poor muscle contractility of the remaining musculature. In this study, we investigated the muscle contractility in SBMA. We used stationary dynamometry and quantitative MRI to assess muscle strength and absolute and fat-free, cross-sectional areas. Specific muscle force (strength per cross-sectional area) and contractility (strength per fat-free cross-sectional area) were compared with healthy controls and their relation to walking distance and disease severity was investigated. Specific force was reduced by 14–49% in SBMA patients compared to healthy controls. Contractility was reduced by 22–39% in elbow flexion, knee extension, ankle dorsi- and plantarflexion in SBMA patients. The contractility decreased with increasing muscle fat content in muscles with affected contractility in SBMA. The decreased muscle contractility in SBMA may relate to motor neuron degeneration and changed fibre type distribution and muscle architecture.
Parkinson’s Disease is Associated with Dysregulations of a Dopamine-Modulated Gene Network Relevant to Sleep and Affective Neurobehaviors in the Striatum
Authors: Jiang Peng , Scarpa Joseph R. , Gao Vance D. , Vitaterna Martha Hotz , Kasarskis Andrew , Turek Fred W. 
Published: March 2019

AbstractIn addition to the characteristic motor symptoms, Parkinson’s disease (PD) often involves a constellation of sleep and mood symptoms. However, the mechanisms underlying these comorbidities are largely unknown. We have previously reconstructed gene networks in the striatum of a population of (C57BL/6J x A/J) F2 mice and associated the networks to sleep and affective phenotypes, providing a resource for integrated analyses to investigate perturbed sleep and affective functions at the gene network level. Combining this resource with PD-relevant transcriptomic datasets from humans and mice, we identified four networks that showed elevated gene expression in PD patients, including a circadian clock and mitotic network that was altered similarly in mouse models of PD. We then utilized multiple types of omics data from public databases and linked this gene network to postsynaptic dopamine signaling in the striatum, CDK1-modulated transcriptional regulation, and the genetic susceptibility of PD. These findings suggest that dopamine deficiency, a key aspect of PD pathology, perturbs a circadian/mitotic gene network in striatal neurons. Since the normal functions of this network were relevant to sleep and affective behaviors, these findings implicate that dysregulation of functional gene networks may be involved in the emergence of non-motor symptoms in PD. Our analyses present a framework for integrating multi-omics data from diverse sources in mice and humans to reveal insights into comorbid symptoms of complex diseases.
Amelioration of diabetic nephropathy by SGLT2 inhibitors independent of its glucose-lowering effect: A possible role of SGLT2 in mesangial cells
Authors: Maki Toshinobu , Maeno Sayaka , Maeda Yasutaka , Yamato Mayumi , Sonoda Noriyuki , Ogawa Yoshihiro , Wakisaka Masanori , Inoguchi Toyoshi 
Published: March 2019

AbstractSeveral clinical studies have shown the beneficial effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on diabetic nephropathy. The underlying mechanisms are not fully understood. We found that administration of canagliflozin at a low dose (0.01 mg/kg/day) did not affect either blood glucose levels or glycosuria, but it improved albuminuria and mesangial expansion in db/db mice to a similar extent as at a high dose (3.0 mg/kg/day) that lowered blood glucose levels. This indicated the existence of a tubular SGLT2-independent reno-protective mechanism. Here we focused on the potential role of SGLT2 in mesangial cells (MCs). Western blot analysis revealed the expression of SGLT2 in cultured mouse MCs. Exposure of MCs to high glucose levels for 72 h significantly increased the expression of SGLT2. Canagliflozin or ipragliflozin (both 100 nM) treatment inhibited glucose consumption in the medium under high-glucose conditions but not under normal-glucose conditions. Furthermore, canagliflozin inhibited high-glucose-induced activation of the protein kinase C (PKC)-NAD(P)H oxidase pathway and increases in reactive oxygen species (ROS) production. Thus, the inhibition of mesangial SGLT2 may cause an inhibition of PKC activation and ROS overproduction in diabetic nephropathy, and this may at least in part account for the reno-protective effect of SGLT2 inhibitors.
Implications of variable late Cenozoic surface uplift across the Peruvian central Andes
Authors: Sundell Kurt E. , Saylor Joel E. , Lapen Thomas J. , Horton Brian K. 
Published: March 2019

AbstractChanges in Earth’s surface elevation can be linked to the geodynamic processes that drive surface uplift, which in turn modulate regional climate patterns. We document hydrogen isotopic compositions of hydrated volcanic glasses and modern stream waters to determine late Cenozoic surface uplift across the Peruvian central Andes. Modern water isotopic compositions reproduce mean catchment elevations to a precision better than ±500 m (1σ). Glass isotopic data show a spatiotemporally variable transition from isotopically heavy to isotopically light compositions. The latter are consistent with modern water on the plateau. When interpreted in the context of published paleoelevation estimates and independent geological information, the isotopic data indicate that elevation rapidly increased by 2–2.5 km from 20–17 Ma in the central Western Cordillera, and from 15–10 Ma in the southern Western Cordillera and Altiplano; these patterns are consistent with foundering of mantle lithosphere via Rayleigh-Taylor instability. The Eastern Cordillera was slowly elevated 1.5–2 km between 25 and 10 Ma, a rate consistent with crustal shortening as the dominant driver of surface uplift. The Ayacucho region attained modern elevation by ~22 Ma. The timing of orographic development across southern Peru is consistent with the early Miocene onset and middle Miocene intensification of hyperarid conditions along the central Andean Pacific coast.
Host-directed kinase inhibitors act as novel therapies against intracellular Staphylococcus aureus
Authors: Bravo-Santano Natalia , Stölting Helen , Cooper Frederic , Bileckaja Narina , Majstorovic Andrea , Ihle Nadine , Mateos Luis M. , Calle Yolanda , Behrends Volker , Letek Michal 
Published: March 2019

AbstractHost-directed therapeutics are a promising anti-infective strategy against intracellular bacterial pathogens. Repurposing host-targeted drugs approved by the FDA in the US, the MHRA in the UK and/or regulatory equivalents in other countries, is particularly interesting because these drugs are commercially available, safe doses are documented and they have been already approved for other clinical purposes. In this study, we aimed to identify novel therapies against intracellular Staphylococcus aureus, an opportunistic pathogen that is able to exploit host molecular and metabolic pathways to support its own intracellular survival. We screened 133 host-targeting drugs and found three host-directed tyrosine kinase inhibitors (Ibrutinib, Dasatinib and Crizotinib) that substantially impaired intracellular bacterial survival. We found that Ibrutinib significantly increased host cell viability after S. aureus infection via inhibition of cell invasion and intracellular bacterial proliferation. Using phosphoproteomics data, we propose a putative mechanism of action of Ibrutinib involving several host factors, including EPHA2, C-JUN and NWASP. We confirmed the importance of EPHA2 for staphylococcal infection in an EPHA2-knock-out cell line. Our study serves as an important example of feasibility for identifying host-directed therapeutics as candidates for repurposing.
Modulation of feedback processing by social context in social anxiety disorder (SAD)–an event-related potentials (ERPs) study
Authors: Voegler Rolf , Peterburs Jutta , Bellebaum Christian , Straube Thomas 
Published: March 2019

AbstractThe ability to learn from feedback, especially under social scrutiny, is an essential prerequisite for successful interaction with the environment. Patients suffering from social anxiety disorder (SAD) have been proposed to show altered processing of and learning from feedback, especially depending on social context. However, the neural basis and behavioral consequences of altered reinforcement learning in SAD are not clear yet. In the present event-related potentials (ERPs) study, 34 SAD patients and 30 healthy control subjects (HC) performed an adapted version of a probabilistic feedback learning task in two distinct social conditions. In the observation condition, participants were observed by a confederate; in the control condition, they performed the task without being observed. Patients as compared to healthy controls experienced more subjective discomfort under social observation. Moreover, they showed better learning from negative feedback in the control condition, but reduced learning from negative feedback in the observation condition. This effect correlated with reduced differentiation of positive and negative feedback in the time range of the feedback-related negativity (FRN) under high action-feedback contingency. In addition, SAD patients demonstrated increased FRN amplitudes in the first half of the observation condition, in particular to positive feedback. The present results demonstrate that processing of and learning from feedback are altered in SAD, especially under social scrutiny. In particular, it appears that SAD patients do not process positive information adequately on the neural level, which may impair their ability to differentiate between negative and positive outcomes.
Effect of Spheroidal Age on Sorafenib Diffusivity and Toxicity in a 3D HepG2 Spheroid Model
Authors: Eilenberger Christoph , Rothbauer Mario , Ehmoser Eva-Kathrin , Ertl Peter , Küpcü Seta 
Published: March 2019

AbstractThe enhanced predictive power of 3D multi-cellular spheroids in comparison to conventional monolayer cultures makes them a promising drug screening tool. However, clinical translation for pharmacology and toxicology is lagging its technological progression. Even though spheroids show a biological complexity resembling native tissue, standardization and validation of drug screening protocols are influenced by continuously changing physiological parameters during spheroid formation. Such cellular heterogeneities impede the comparability of drug efficacy studies and toxicological screenings. In this paper, we demonstrated that aside from already well-established physiological parameters, spheroidal age is an additional critical parameter that impacts drug diffusivity and toxicity in 3D cell culture models. HepG2 spheroids were generated and maintained on a self-assembled ultra-low attachment nanobiointerface and characterized regarding time-dependent changes in morphology, functionality as well as anti-cancer drug resistance. We demonstrated that spheroidal aging directly influences drug response due to the evolution of spheroid micro-structure and organo-typic functions, that alter inward diffusion, thus drug uptake.
Association between acute kidney injury and serum procalcitonin levels and their diagnostic usefulness in critically ill patients
Authors: Chun Kayeong , Chung Wookyung , Kim Ae Jin , Kim Hyunsook , Ro Han , Chang Jae Hyun , Lee Hyun Hee , Jung Ji Yong 
Published: March 2019

AbstractProcalcitonin (PCT) is a useful marker for the diagnosis of systemic inflammatory response syndrome. In addition, PCT is affected by renal function. However, few studies have investigated the relationship between PCT and the development of acute kidney injury (AKI). Hence, we investigated whether serum PCT levels at the time of admission were associated with the development of AKI and clinical outcomes. A total of 790 patients in whom PCT was measured on admission to the intensive care unit (ICU) were analyzed retrospectively. We attempted to investigate whether serum PCT levels measured at the time of admission could be used as a risk factor for the development of AKI in septic and nonseptic patients or as a risk factor for all-cause mortality, and diagnostic usefulness of PCT was further assessed. Serum PCT levels were significantly higher in patients with AKI than in those without AKI (P < 0.001). After multivariable adjustment for clinical factors, laboratory findings, and comorbidities, PCT as a continuous variable showed a significant association with AKI (OR 1.006, 95% CI [1.000–1.011]; P = 0.035). However, PCT was not effective in predicting mortality. The cut-off value of PCT for the prediction of AKI incidence was calculated to be 0.315 ng/ml, with sensitivity and specificity of 60.9% and 56.9%, respectively. The odds ratios (ORs) from an equation adjusted for optimum thresholds of PCT levels for developing AKI with and without sepsis were 2.422 (1.222–4.802, P = 0.011) and 1.798 (1.101–2.937, P = 0.019), respectively. However, there were no absolute differences between the pre- and posttest probabilities after including the PCT value for AKI development. This study suggests that the PCT value was higher in AKI patients than in non-AKI patients, but PCT measurement at the time of admission did not improve the prediction model for AKI.
Hygiene and biosecurity protocols reduce infection prevalence but do not improve fledging success in an endangered parrot
Authors: Fogell Deborah J. , Groombridge Jim J. , Tollington Simon , Canessa Stefano , Henshaw Sion , Zuel Nicolas , Jones Carl G. , Greenwood Andrew , Ewen John G. 
Published: March 2019

AbstractEmerging Infectious Diseases (EIDs) are recognised as global extinction drivers of threatened species. Unfortunately, biodiversity managers have few tested solutions to manage them when often the desperate need for solutions necessitates a response. Here we testin situbiosecurity protocols to assess the efficacy of managing Psittacine beak and feather disease (PBFD), one of the most common and emergent viral diseases in wild parrots (Psittaciformes) that is currently affecting numerous threatened species globally. In response to an outbreak of PBFD in Mauritius “echo” parakeets (Psittacula eques), managers implemented a set of biosecurity protocols to limit transmission and impact of Beak and feather disease virus (BFDV). Here we used a reciprocal design experiment on the wild population to test whether BFDV management reduced viral prevalence and viral load, and improved nestling body condition and fledge success. Whilst management reduced the probability of nestling infection by approximately 11% there was no observed impact on BFDV load and nestling body condition. In contrast to expectations there was lower fledge success in nests with added BFDV biosecurity (83% in untreated vs. 79% in treated nests). Our results clearly illustrate that management for wildlife conservation should be critically evaluated through targeted monitoring and experimental manipulation, and this evaluation should always focus on the fundamental objective of conservation.
Tree ring phototropism and implications for the rotation of the North China Block
Authors: Jiang Zikun , Liu Benpei , Wang Yongdong , Huang Min , Kapitany Tom , Tian Ning , Cao Yong , Lu Yuanzheng , Deng Shenghui 
Published: March 2019

AbstractTrees grow towards the sunlight via a process of phototropism. The trunk phototropism processes are frequently observed in Northern Hemisphere from high latitude to at least the Tropic of Cancer region, and also occur in some in situ preserved vertical petrified woods in various geological ages. However, such evidence is still very limited and poorly known in fossil record; and the relationship between tree ring phototropism and rotation of tectonic blocks is unclear. Here we report the eccentricities of living and fossil trees as a proxy to determine geological block rotation at the same latitudes within the North China Block. The dominant eccentricity of living trees is southwest 219° ± 5°. By contrast, standing in situ fossil trunks in the Mid-Late Jurassic Tiaojishan Formation and the Late Jurassic Tuchengzi Formation had average eccentricities of 237° and 233.5°, respectively. These differences shed light on the palaeogeographical changes, indicating that the North China Block rotated clockwise from the Late Jurassic to the present day. This result is largely coincident with the palaeomagnetic results, indicating that the North China Block rotated clockwise by 26.5° ± 5.5° since the Middle to Late Jurassic transition.