bluuebunny/crossref_metadata_2025 huggingface dataset:
Generation and characterization of a novel knockin minipig model of Hutchinson-Gilford progeria syndrome
Authors: Dorado Beatriz , Pløen Gro Grunnet , Barettino Ana , Macías Alvaro , Gonzalo Pilar , Andrés-Manzano María Jesús , González-Gómez Cristina , Galán-Arriola Carlos , Alfonso José Manuel , Lobo Manuel , López-Martín Gonzalo J. , Molina Antonio , Sánchez-Sánchez Raúl , Gadea Joaquín , Sánchez-González Javier , Liu Ying , Callesen Henrik , Filgueiras-Rama David , Ibáñez Borja , Sørensen Charlotte Brandt , Andrés Vicente
Published: March 2019

Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare genetic disorder for which no cure exists. The disease is characterized by premature aging and inevitable death in adolescence due to cardiovascular complications. Most HGPS patients carry a heterozygous de novo LMNA c.1824C > T mutation, which provokes the expression of a dominant-negative mutant protein called progerin. Therapies proven effective in HGPS-like mouse models have yielded only modest benefit in HGPS clinical trials. To overcome the gap between HGPS mouse models and patients, we have generated by CRISPR-Cas9 gene editing the first large animal model for HGPS, a knockin heterozygous LMNA c.1824C > T Yucatan minipig. Like HGPS patients, HGPS minipigs endogenously co-express progerin and normal lamin A/C, and exhibit severe growth retardation, lipodystrophy, skin and bone alterations, cardiovascular disease, and die around puberty. Remarkably, the HGPS minipigs recapitulate critical cardiovascular alterations seen in patients, such as left ventricular diastolic dysfunction, altered cardiac electrical activity, and loss of vascular smooth muscle cells. Our analysis also revealed reduced myocardial perfusion due to microvascular damage and myocardial interstitial fibrosis, previously undescribed readouts potentially useful for monitoring disease progression in patients. The HGPS minipigs provide an appropriate preclinical model in which to test human-size interventional devices and optimize candidate therapies before advancing to clinical trials, thus accelerating the development of effective applications for HGPS patients.
MiR-125a enhances self-renewal, lifespan, and migration of murine hematopoietic stem and progenitor cell clones
Authors: Wojtowicz Edyta Ewa , Broekhuis Mathilde Johanna Christina , Weersing Ellen , Dinitzen Alexander , Verovskaya Evgenia , Ausema Albertina , Ritsema Martha , Zwart Erik , de Haan Gerald , Bystrykh Leonid V.
Published: March 2019

Expansion of hematopoietic stem cells (HSCs) is a ‘holy grail’ of regenerative medicine, as successful stem cell transplantations depend on the number and quality of infused HSCs. Although many attempts have been pursued to either chemically or genetically increase HSC numbers, neither clonal analysis of these expanded cells nor their ability to support mature blood lineages has been demonstrated. Here we show that miR-125a, at the single cell level, can expand murine long-term repopulating HSCs. In addition, miR-125a increases clone longevity, clone size and clonal contribution to hematopoiesis. Unexpectedly, we found that miR-125a expanded HSCs clones were highly homogenously distributed across multiple anatomical sites. Interestingly, these miR-125a overexpressing cells had enhanced mobility and were more frequently detected in the spleen. Our study reveals a novel, cell-intrinsically controlled mechanism by which HSC migration is regulated.
Retraction Note: Auraptenol attenuates vincristine-induced mechanical hyperalgesia through serotonin 5-HT1A receptors
Authors: Wang Yunfei , Cao Shu-e , Tian Jianmin , Liu Guozhe , Zhang Xiaoran , Li Pingfa
Published: March 2019

This paper has been retracted.
The proton pumping bo oxidase from Vitreoscilla
Authors: Graf Simone , Brzezinski Peter , von Ballmoos Christoph
Published: March 2019

The cytochrome bo3 quinol oxidase from Vitreoscilla (vbo3) catalyses oxidation of ubiquinol and reduction of O2 to H2O. Data from earlier studies suggested that the free energy released in this reaction is used to pump sodium ions instead of protons across a membrane. Here, we have studied the functional properties of heterologously expressed vbo3 with a variety of methods. (i) Following oxygen consumption with a Clark-type electrode, we did not observe a measurable effect of Na+ on the oxidase activity of purified vbo3 solubilized in detergent or reconstituted in liposomes. (ii) Using fluorescent dyes, we find that vbo3 does not pump Na+ ions, but H+ across the membrane, and that H+-pumping is not influenced by the presence of Na+. (iii) Using an oxygen pulse method, it was found that 2 H+/e− are ejected from proteoliposomes, in agreement with the values found for the H+-pumping bo3 oxidase of Escherichia coli (ecbo3). This coincides with the interpretation that 1 H+/e− is pumped across the membrane and 1 H+/e− is released during quinol oxidation. (iv) When the electron transfer kinetics of vbo3 upon reaction with oxygen were followed in single turnover experiments, a similar sequence of reaction steps was observed as reported for the E. coli enzyme and none of these reactions was notably affected by the presence of Na+. Overall the data show that vbo3 is a proton pumping terminal oxidase, behaving similarly to the Escherichia coli bo3 quinol oxidase.
miRNA profiling of urinary exosomes to assess the progression of acute kidney injury
Authors: Sonoda Hiroko , Lee Byung Rho , Park Ki-Hoon , Nihalani Deepak , Yoon Je-Hyun , Ikeda Masahiro , Kwon Sang-Ho
Published: March 2019

Because exosomes have gained attention as a source of biomarkers, we investigated if miRNAs in exosomes (exo-miRs) can report the disease progression of organ injury. Using rat renal ischemia-reperfusion injury (IRI) as a model of acute kidney injury (AKI), we determined temporally-released exo-miRs in urine during IRI and found that these exo-miRs could reliably mirror the progression of AKI. From the longitudinal measurements of miRNA expression in kidney and urine, we found that release of exo- miRs was a regulated sorting process. In the injury state, miR-16, miR-24, and miR-200c were increased in the urine. Interestingly, expression of target mRNAs of these exo-miRs was significantly altered in renal medulla. Next, in the early recovery state, exo-miRs (miR-9a, miR-141, miR-200a, miR-200c, miR-429), which share Zeb1/2 as a common target mRNA, were upregulated together, indicating that they reflect TGF-β-associated renal fibrosis. Finally, release of exo-miRs (miR-125a, miR-351) was regulated by TGF-β1 and was able to differentiate the sham and IRI even after the injured kidneys were recovered. Altogether, these data indicate that exo-miRs released in renal IRI are associated with TGF-β signaling. Temporal release of exo-miRs which share targets might be a regulatory mechanism to control the progression of AKI.
Social frame and tax compliance modulate electrophysiological and autonomic responses following tax-related decisions
Authors: Balconi Michela , Crivelli Davide , Castiglioni Cinzia , Lozza Edoardo
Published: March 2019

Given the intrinsic complexity of cognitive and affective processes affecting how people reason about taxes and their decisions to be compliant with such social duty, we aimed at exploring those latent processes by combining the analysis of their central and peripheral physiological correlates. We asked participants to make realistic economic decisions concerning tax-payment and manipulated the social vs. individual decisional frame. In addition, we took into account the potential role of tax-compliance trait. Thirty self-employed professionals took part in the study and completed a public good game while their autonomic (skin conductance – SC – and heart rate – HR) and neural brain (electroencephalography – EEG) activities were recorded. The analysis of physiological responses during the feedback phase – where participants could be presented or not with a fiscal audit – highlighted: (i) increased tonic SC levels and theta activity in the social condition than in the individual one; (ii) increased HR values when a fiscal audit did not take place, especially in participants who presented an enforced tax-compliance trait. Present findings support the idea that classic economic theories of tax behaviour developed under the assumption that taxpayers act as rational and individualist agents do not provide a comprehensive account for the decision-making process. They add to available evidence highlighting the contribution of psychological and social-affective variables to individuals’ decision-making processes to pay or evade taxes and to their appraisal of the consequences of such choice, as suggested by the ‘slippery slope’ framework.
Effect of graphene substrate type on formation of Bi2Se3 nanoplates
Authors: Andzane Jana , Britala Liga , Kauranens Edijs , Neciporenko Aleksandrs , Baitimirova Margarita , Lara-Avila Samuel , Kubatkin Sergey , Bechelany Mikhael , Erts Donats
Published: March 2019

Knowledge of nucleation and further growth of Bi2Se3 nanoplates on different substrates is crucial for obtaining ultrathin nanostructures and films of this material by physical vapour deposition technique. In this work, Bi2Se3 nanoplates were deposited under the same experimental conditions on different types of graphene substrates (as-transferred and post-annealed chemical vapour deposition grown monolayer graphene, monolayer graphene grown on silicon carbide substrate). Dimensions of the nanoplates deposited on graphene substrates were compared with the dimensions of the nanoplates deposited on mechanically exfoliated mica and highly ordered pyrolytic graphite flakes used as reference substrates. The influence of different graphene substrates on nucleation and further lateral and vertical growth of the Bi2Se3 nanoplates is analysed. Possibility to obtain ultrathin Bi2Se3 thin films on these substrates is evaluated. Between the substrates considered in this work, graphene grown on silicon carbide is found to be the most promising substrate for obtaining of 1–5 nm thick Bi2Se3 films.
The WNT/β-catenin signaling inhibitor XAV939 enhances the elimination of LNCaP and PC-3 prostate cancer cells by prostate cancer patient lymphocytes in vitro
Authors: Stakheev Dmitry , Taborska Pavla , Strizova Zuzana , Podrazil Michal , Bartunkova Jirina , Smrz Daniel
Published: March 2019

Upregulated Wnt/β-catenin signaling is associated with increased cancer cell resistance and cancer cell-elicited immunosuppression. In non-neoplastic immune cells, upregulated Wnt/β-catenin is, however, associated with either immunosuppression or immunostimulation. Therefore, it is difficult to predict the therapeutic impact inhibitors of Wnt/β-catenin signaling will have when combined with cancer immunotherapy. Here, we evaluated the benefit(s) of the Wnt/β-catenin signaling inhibitor XAV939 in the in vitro elimination of LNCaP prostate cancer cells when cocultured with lymphocytes from patients with localized biochemically recurrent prostate cancer (BRPCa). We found that 5 µM XAV939 inhibited β-catenin translocation to the nucleus in LNCaP cells and CD4+ BRPCa lymphocytes without affecting their proliferation and viability. Preconditioning BRPCa lymphocytes with 5 µM XAV939 accelerated the elimination of LNCaP cells during the coculturing. However, during subsequent re-coculturing with fresh LNCaP cells, BRPCa lymphocytes were no longer able to eliminate LNCaP cells unless coculturing and re-coculturing were performed in the presence of 5 µM XAV939. Comparable results were obtained for PC-3 prostate cancer cells. These findings provide a rationale for combining cell-based immunotherapy of PCa with inhibitors of Wnt/β-catenin signaling.
Response of the daily transpiration of a larch plantation to variation in potential evaporation, leaf area index and soil moisture
Authors: Wang Yunni , Cao Gongxiang , Wang Yanhui , Webb Ashley A. , Yu Pengtao , Wang Xiaojiang
Published: March 2019

Tree transpiration (T) is a major water budget component and varies widely due to the integrated effects of many environmental and vegetation factors. This study aimed to separate, quantify, and then integrate the effects of the main individual factors, to improve water use estimation and manage the hydrological impacts of forests. A field study was conducted at 3 plots of larch (Larix principis-rupprechtii) plantation in the semi-humid area of the Liupan Mountains, northwest China. The main influencing factors were the atmospheric evaporative demand expressed by potential evapotranspiration (PET), the soil water availability expressed by volumetric soil moisture (VSM) within the 0–100 cm layer, and the canopy transpiration capacity expressed by forest canopy leaf area index (LAI). The daily stand T was estimated through the up-scaling of sap-flow data from sampled trees. It displayed a high degree of scattering in response to PET, VSM and LAI, with an average of 0.76 mm·day−1 and range of 0.01–1.71 mm·day−1 in the growing season of 2014. Using upper boundary lines of measured data, the response tendency of T to each factor and corresponding function type were determined. The T increases firstly rapidly with rising PET, VSM and LAI, then gradually and tends to be stable when the threshold of PET (3.80 mm·day−1), VSM (0.28 m3·m−3) and LAI (3.7) is reached. The T response follows a quadratic equation for PET and saturated exponential function for VSM and LAI. These individual factor functions were coupled to form a general daily T model which was then fitted using measured data as: T = (0.793PET − 0.078PET2)·(1 − exp(−0.272LAI))·(1 − exp(−9.965VSM)). It can well explain the daily T variation of all 3 plots (R2 = 0.86–0.91), and thus can be used to predict the response of daily T of larch stands to changes in both environmental and canopy conditions.
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

Obesity 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

Hantavax 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

The 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

Outer 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

Spinobulbar 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

In 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

Several 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

Changes 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

Host-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

The 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

The 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

Procalcitonin (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

Emerging 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

Trees 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.
Dysregulated Redox Regulation Contributes to Nuclear EGFR Localization and Pathogenicity in Lung Cancer
Authors: Little Andrew C. , Hristova Milena , van Lith Loes , Schiffers Caspar , Dustin Christopher M. , Habibovic Aida , Danyal Karamatullah , Heppner David E. , Lin Miao-Chong J. , van der Velden Jos , Janssen-Heininger Yvonne M. , van der Vliet Albert
Published: March 2019

Lung cancers are frequently characterized by inappropriate activation of epidermal growth factor receptor (EGFR)-dependent signaling and epigenetic silencing of the NADPH oxidase (NOX) enzyme DUOX1, both potentially contributing to worse prognosis. Based on previous findings linking DUOX1 with redox-dependent EGFR activation, the present studies were designed to evaluate whether DUOX1 silencing in lung cancers may be responsible for altered EGFR regulation. In contrast to normal epithelial cells, EGF stimulation of lung cancer cell lines that lack DUOX1 promotes EGF-induced EGFR internalization and nuclear localization, associated with induction of EGFR-regulated genes and related tumorigenic outcomes. Each of these outcomes could be reversed by overexpression of DUOX1 or enhanced by shRNA-dependent DUOX1 silencing. EGF-induced nuclear EGFR localization in DUOX1-deficient lung cancer cells was associated with altered dynamics of cysteine oxidation of EGFR, and an overall reduction of EGFR cysteines. These various outcomes could also be attenuated by silencing of glutathione S-transferase P1 (GSTP1), a mediator of metabolic alterations and drug resistance in various cancers, and a regulator of cysteine oxidation. Collectively, our findings indicate DUOX1 deficiency in lung cancers promotes dysregulated EGFR signaling and enhanced GSTP1-mediated turnover of EGFR cysteine oxidation, which result in enhanced nuclear EGFR localization and tumorigenic properties.
Impact of predictive medicine on therapeutic decision making: a randomized controlled trial in congenital heart disease
Authors: Naci Huseyin , Salcher-Konrad Maximilian , Mcguire Alistair , Berger Felix , Kuehne Titus , Goubergrits Leonid , Muthurangu Vivek , Wilson Ben , Kelm Marcus
Published: March 2019

Computational modelling has made significant progress towards clinical application in recent years. In addition to providing detailed diagnostic data, these methods have the potential to simulate patient-specific interventions and to predict their outcome. Our objective was to evaluate to which extent patient-specific modelling influences treatment decisions in coarctation of the aorta (CoA), a common congenital heart disease. We selected three cases with CoA, two of which had borderline indications for intervention according to current clinical guidelines. The third case was not indicated for intervention according to guidelines. For each case, we generated two separate datasets. First dataset included conventional diagnostic parameters (echocardiography and magnetic resonance imaging). In the second, we added modelled parameters (pressure fields). For the two cases with borderline indications for intervention, the second dataset also included pressure fields after virtual stenting simulations. All parameters were computed by modelling methods that were previously validated. In an online-administered, invitation-only survey, we randomized 178 paediatric cardiologists to view either conventional (control) or add-on modelling (experimental) datasets. Primary endpoint was the proportion of participants recommending different therapeutic options: (1) surgery or catheter lab (collectively, “intervention”) or (2) no intervention (follow-up with or without medication). Availability of data from computational predictive modelling influenced therapeutic decision making in two of three cases. There was a statistically significant association between group assignment and the recommendation of an intervention for one borderline case and one non-borderline case: 94.3% vs. 72.2% (RR: 1.31, 95% CI: 1.14–1.50, p = 0.00) and 18.8% vs. 5.1% (RR: 3.09, 95% CI: 1.17–8.18, p = 0.01) of participants in the experimental and control groups respectively recommended an intervention. For the remaining case, there was no difference between the experimental and control group and the majority of participants recommended intervention. In sub-group analyses, findings were not affected by the experience level of participating cardiologists. Despite existing clinical guidelines, the therapy recommendations of the participating physicians were heterogeneous. Validated patient-specific computational modelling has the potential to influence treatment decisions. Future studies in broader areas are needed to evaluate whether differences in decisions result in improved outcomes (Trial Registration: NCT02700737).
Engineering of a keto acid reductase through reconstructing the substrate binding pocket to improve its activity
Authors: Wang Di-Chen , Li Heng , Xia Shu-Ning , Xue Ya-Ping , Zheng Yu-Guo
Published: March 2019

Enzyme–substrate docking-guided point mutation of the substrate-binding pocket to generate mutant L244G/A250G/L245R with superior activity in the synthesis of (R)-2-hydroxy-4-phenylbutyric acid.
Multi-gram scale synthesis of a bleomycin (BLM) carbohydrate moiety: exploring the antitumor beneficial effect of BLM disaccharide attached to 10-hydroxycamptothecine (10-HCPT)
Authors: Li MaoLin , Huang Weiping , Jiang Zhilin , Shi Yonghui , Yuan Sisi , Fu Kaishuo , Chen YongJun , Zhou Li , Zhou Wen
Published: March 2019

An efficient multi-gram synthesis of bleomycin disaccharide has been developed, and its conjugate with 10-HCPT displayed obvious selectivity, clearly indicating the potential of bleomycin disaccharide in solving the targeted therapy of cytotoxic drugs.
Preparation of a magnetic mesoporous Fe3O4–Pd@TiO2 photocatalyst for the efficient selective reduction of aromatic cyanides
Authors: Zhao Ziming , Long Yu , Luo Sha , Wu Wei , Ma Jiantai
Published: March 2019

Fe3O4–Pd@TiO2 exhibited extremely superior photocatalytic activity for the selective reduction of aromatic cyanides to aromatic primary amines.
Hyperfine coupling and slow magnetic relaxation in isotopically enriched DyIII mononuclear single-molecule magnets
Authors: Flores Gonzalez Jessica , Pointillart Fabrice , Cador Olivier
Published: March 2019

On the role of hyperfine coupling constant on the relaxation time of single-molecule magnets.
Target DNA mutagenesis-based fluorescence assessment of off-target activity of the CRISPR-Cas9 system
Authors: Wang Dan , Niu Cuili , Han Jingxin , Ma Dejun , Xi Zhen
Published: March 2019

Fluorescence assessment of off-target activity of Cas9 nuclease using an engineered dual-luciferase reporter in living cells.
Efficient removal of sulfamerazine (SMR) by ozonation in acetic acid solution after enrichment SMR from water using granular activated carbon
Authors: Yao Youru , Mi Na , Zhu Yongqing , Yin Li , Zhang Yong , Li Shiyin
Published: March 2019

Sulfamerazine (SMR) as a persistent organic pollutant in waste streams is of growing environmental concern.
Performance enhancement of a supercapacitor negative electrode based on loofah sponge derived oxygen rich carbon through encapsulation of MoO3 nanoflowers
Authors: Joshi Akanksha , Sahu Vikrant , Singh Gurmeet , Sharma Raj Kishore
Published: March 2019

Mutual capacitive and diffusive mechanisms enhancing the performance of a carbon based negative electrode.
Polyelectrolyte–micelle coacervates: intrapolymer-dominantvs.interpolymer-dominant association, solute uptake and rheological properties
Authors: Zhao Mengmeng , Wang Chao , Jiang Haowei , Dawadi Mahesh B. , Vogt Bryan D. , Modarelli David A. , Zacharia Nicole S.
Published: March 2019

Polyelectrolyte charge density, polyelectrolyte-to-surfactant ratio, and micelle species impact the coacervation of the weak polyelectrolyte branched polyethylenimine and oppositely charged micelles composed of SDS and/or poly(ethylene glycol) 4-nonylphenyl 3-sulfopropyl ether potassium salt (PENS).
Magnetically-actuated artificial cilium: a simple theoretical model
Authors: Meng Fanlong , Matsunaga Daiki , Yeomans Julia M. , Golestanian Ramin
Published: March 2019

We propose a theoretical model for a magnetically-actuated artificial cilium in a fluid environment and investigate its dynamical behaviour, using both analytical calculations and numerical simulations.
A monoclonal antibody-based immunosensor for the electrochemical detection of imidacloprid pesticide
Authors: Pérez-Fernández Beatriz , Mercader Josep V. , Checa-Orrego Brenda I. , de la Escosura-Muñiz Alfredo , Costa-García Agustín
Published: March 2019

Imidacloprid (IMD) is one of the most used pesticides worldwide as a systemic insecticide as well as for pest control and seed treatment.
DNA supersandwich assemblies as artificial receptors to mediate intracellular delivery of catalase for efficient ROS scavenging
Authors: Chen Qiaoshu , Zhou Shaohong , Li Chunying , Guo Qiuping , Yang Xiaohai , Huang Jin , Liu Jianbo , Wang Kemin
Published: March 2019

Aptamer–supersandwich nanostructures as artificial receptors to mediate catalase intracellular delivery with high transfection efficacy and a significant ROS scavenging ability.
Supramolecular strategy for smart windows
Authors: Wang Sai , Gao Wei , Hu Xiao-Yu , Shen Ying-Zhong , Wang Leyong
Published: March 2019

Supramolecular strategy-based materials are outlined and their applications for fabricating smart windows are summarized for future exploration of ideal smart windows.
Discrepancy between thermodynamic and kinetic stabilities of thetert-butanol hydrates and its implication for obtaining pharmaceutical powders by freeze-drying
Authors: Ogienko A. G. , Stoporev A. S. , Ogienko A. A. , Mel’gunov M. S. , Adamova T. P. , Yunoshev A. S. , Manakov A. Yu. , Boldyreva E. V.
Published: March 2019

The substitution of sublimed “H1 + Ih” for “H2 + Ih” leads to both a reduction of primary drying time and a significant increase in specific surface area of the trehalose freeze-dried cakes.
Nitrogen and phosphorous co-doped graphitic carbon encapsulated ultrafine OsP2 nanoparticles: a pH universal highly durable catalyst for hydrogen evolution reaction
Authors: Chakrabartty Sukanta , Barman Barun Kumar , Retna Raj C.
Published: March 2019

Synthesis of a high performance pH universal electrochemical hydrogen evolution catalyst based on OsP2.
Carbon quantum dots and carbon layer double protected cuprous oxide for efficient visible light CO2 reduction
Authors: Li Haitao , Deng Yadan , Liu Youdi , Zeng Xin , Wiley Dianne , Huang Jun
Published: March 2019

We designed a photocatalyst of carbon dots and carbon layer double-protected Cu2O which exhibited excellent performance in CO2 conversion.