bluuebunny/crossref_metadata_2025 huggingface dataset:
SOCS2 is part of a highly prognostic 4-gene signature in AML and promotes disease aggressiveness
Authors: Nguyen Chi Huu , Glüxam Tobias , Schlerka Angela , Bauer Katharina , Grandits Alexander M. , Hackl Hubert , Dovey Oliver , Zöchbauer-Müller Sabine , Cooper Jonathan L. , Vassiliou George S. , Stoiber Dagmar , Wieser Rotraud , Heller Gerwin
Published: June 2019

Acute myeloid leukemia (AML) is a heterogeneous disease with respect to its genetic and molecular basis and to patients´ outcome. Clinical, cytogenetic, and mutational data are used to classify patients into risk groups with different survival, however, within-group heterogeneity is still an issue. Here, we used a robust likelihood-based survival modeling approach and publicly available gene expression data to identify a minimal number of genes whose combined expression values were prognostic of overall survival. The resulting gene expression signature (4-GES) consisted of 4 genes (SOCS2, IL2RA, NPDC1, PHGDH), predicted patient survival as an independent prognostic parameter in several cohorts of AML patients (total, 1272 patients), and further refined prognostication based on the European Leukemia Net classification. An oncogenic role of the top scoring gene in this signature, SOCS2, was investigated using MLL-AF9 and Flt3-ITD/NPM1c driven mouse models of AML. SOCS2 promoted leukemogenesis as well as the abundance, quiescence, and activity of AML stem cells. Overall, the 4-GES represents a highly discriminating prognostic parameter in AML, whose clinical applicability is greatly enhanced by its small number of genes. The newly established role of SOCS2 in leukemia aggressiveness and stemness raises the possibility that the signature might even be exploitable therapeutically.
Analysis of Side-band Inequivalence
Authors: Khorasani Sina
Published: June 2019

Frequency shifts of red- and blue-scattered (Stokes/anti-Stokes) side-bands in quantum optomechanics are shown to be counter-intuitively inequal, resulting in an unexpected symmetry breaking. This difference is referred to as Side-band Inequivalenve (SI), which normally leans towards red, and being a nonlinear effect it depends on optical power or intracavity photon number. Also there exists a maximum attainable SI at an optimal operation point. The mathematical method employed here is a combination of operator algebra equipped with harmonic balance, which allows a clear understanding of the associated nonlinear process. This reveals the existence of three distinct operation regimes in terms of pump power, two of which have immeasurably small SI. Compelling evidence from various experiments sharing similar interaction Hamiltonians, including quantum optomechanics, ion/Paul traps, electrooptic modulation, Brillouin scattering, and Raman scattering unambiguously confirm existence of a previously unnoticed SI.
Stacking sequence variations in vaterite resolved by precession electron diffraction tomography using a unified superspace model
Authors: Steciuk Gwladys , Palatinus Lukáš , Rohlíček Jan , Ouhenia Salim , Chateigner Daniel
Published: June 2019

As a metastable phase, vaterite is involved in the first step of crystallization of several carbonate-forming systems including the two stable polymorphs calcite and aragonite. Its complete structural determination would consequently shed important light to understand scaling formation and biomineralization processes. While vaterite’s hexagonal substructure (a0 ~ 4.1 Å and c0 ~ 8.5 Å) and the organization of the carbonate groups within a single layer is known, conflicting interpretations regarding the stacking sequence remain and preclude the complete understanding of the structure. To resolve the ambiguities, we performed precession electron diffraction tomography (PEDT) to collect single crystal data from 100 K to the ambient temperature. The structure was solved ab initio and described over all the temperature range using a unified modulated structure model in the superspace group C12/c1(α0γ)00 with a = a0 = 4.086(3) Å, b = $$\sqrt{{\bf{3}}}$$

3

a0 = 7.089(9) Å, c = c0 = 8.439(9) Å, α = β = γ = 90° and q = $$\tfrac{{\bf{2}}}{{\bf{3}}}$$

2
3

a* + γc*. At 100 K the model presents a pure 4-layer stacking sequence with γ = $$\tfrac{{\bf{1}}}{{\bf{2}}}$$

1
2

whereas at the ambient temperature, ordered stacking faults are introduced leading to γ < $$\tfrac{{\bf{1}}}{{\bf{2}}}$$

1
2

. The model was refined against PEDT data using the dynamical refinement procedure including modulation and twinning as well as against x-ray powder data by the Rietveld refinement.
RETRACTED ARTICLE: Oscillations of the baseline of solar magnetic field and solar
irradiance on a millennial timescale
Authors: Zharkova V. V. , Shepherd S. J. , Zharkov S. I. , Popova E.
Published: June 2019

Recently discovered long-term oscillations of the solar background
magnetic field associated with double dynamo waves generated in inner and outer
layers of the Sun indicate that the solar activity is heading in the next three
decades (2019–2055) to a Modern grand minimum similar to Maunder one. On the other
hand, a reconstruction of solar total irradiance suggests that since the Maunder
minimum there is an increase in the cycle-averaged total solar irradiance (TSI) by a
value of about 1–1.5 Wm−2 closely correlated with an increase
of the baseline (average) terrestrial temperature. In order to understand these two
opposite trends, we calculated the double dynamo summary curve of magnetic field
variations backward one hundred thousand years allowing us to confirm strong
oscillations of solar activity in regular (11 year) and recently reported grand
(350–400 year) solar cycles caused by actions of the double solar dynamo. In
addition, oscillations of the baseline (zero-line) of magnetic field with a period
of 1950 ± 95 years (a super-grand cycle) are discovered by applying a running
averaging filter to suppress large-scale oscillations of 11 year cycles. Latest
minimum of the baseline oscillations is found to coincide with the grand solar
minimum (the Maunder minimum) occurred before the current super-grand cycle start.
Since then the baseline magnitude became slowly increasing towards its maximum at
2600 to be followed by its decrease and minimum at ~3700. These oscillations of the
baseline solar magnetic field are found associated with a long-term solar inertial
motion about the barycenter of the solar system and closely linked to an increase of
solar irradiance and terrestrial temperature in the past two centuries. This trend
is anticipated to continue in the next six centuries that can lead to a further
natural increase of the terrestrial temperature by more than 2.5 °C by 2600.
HER3 targeting potentiates growth suppressive effects of the PI3K inhibitor BYL719 in pre-clinical models of head and neck squamous cell carcinoma
Authors: Meister Kara S. , Godse Neal R. , Khan Nayel I. , Hedberg Matthew L. , Kemp Carolyn , Kulkarni Sucheta , Alvarado Diego , LaVallee Theresa , Kim Seungwon , Grandis Jennifer R. , Duvvuri Umamaheswar
Published: June 2019

BYL719 is a PI3K inhibitor that has demonstrated efficacy in the treatment of head and neck squamous cell carcinoma. BYL719 exerts its therapeutic effect by suppressing AKT and other proliferative signaling mechanisms. Despite PI3K inhibition and AKT suppression, residual activity of protein S6, a core marker of proliferative activation, has been observed. HER3, either via dimerization or activation by its ligand neurgeulin (NRG), is known to activate PI3K. Thus, we hypothesized that co-targeting HER3 and PI3K would lead to greater suppression of the PI3K-AKT signaling pathway and greater tumor suppression than with BYL719 alone. We investigated biochemical expression and activation of the HER3-PI3K-AKT-S6 pathway in HNSCC cell lines and patient-derived xenografts (PDXs). Antitumor effects of HER3 and PI3K inhibitors alone and in combination were evaluated in cell culture and murine models. Treatment of HNSCC cell lines with BYL719 significantly reduced AKT activation and suppressed tumor growth. However, S6 was persistently activated despite suppression of AKT. Combination treatment with KTN3379, a monoclonal antibody targeted against HER3, and BYL719 led to enhanced suppression of in vitro and in vivo cancer growth and durable suppression of AKT and S6. Therefore, inhibition of HER3 with KTN3379 enhanced the effects of PI3K inhibition in pre-clinical HNSCC models. These data support co-targeting HER3 and PI3K for the treatment of HSNCC.
Risk of osteoporosis in patients with chronic inflammatory neuropathy- a population-based cohort study
Authors: Kim Seung Woo , Kim Eun Hwa , Lee Jinae , Choi Young-Chul , Kim Seung Min , Shin Ha Young
Published: June 2019

The risk of osteoporosis in patients with chronic inflammatory neuropathy (CIN) has not been evaluated in detail. We conducted a population-based case-control study nested in a retrospective cohort to analyze osteoporosis risk among patients with CIN using a nationwide database. Patients with CIN based on the Korean Classification of Disease diagnostic code were included and were matched to controls. A Cox proportional hazards regression model was used to evaluate the effect of CIN on osteoporosis. After propensity score matching, 585 CIN patients and 585 controls were selected. Patients with CIN had an increased osteoporosis risk (hazard ratio [HR] = 2.293, 95% confidence interval [CI] 1.460–3.601) compared with controls. The osteoporosis risk was higher among male patients with CIN than among male controls (HR = 5.404, 95% CI 2.252–12.969), while there were no significant differences among women. Among the CIN patients, the average daily dose of corticosteroids was higher in those who developed osteoporosis (19.6 mg [10.8–49.3]) than those who did not (16.2 mg [7.2–29.1], p = 0.001). The osteoporosis risk among CIN patients is higher than among controls. High risk of osteoporosis in male patients may indicate that osteoporosis in CIN patients results from the disease itself or related treatments.
Multiple Sclerosis patients carry an increased burden of exceedingly rare genetic variants in the inflammasome regulatory genes
Authors: Vidmar Lovro , Maver Ales , Drulović Jelena , Sepčić Juraj , Novaković Ivana , Ristič Smiljana , Šega Saša , Peterlin Borut
Published: June 2019

The role of rare genetic variation and the innate immune system in the etiology of multiple sclerosis (MS) is being increasingly recognized. Recently, we described several rare variants in the NLRP1 gene, presumably conveying an increased risk for familial MS. In the present study we aimed to assess rare genetic variation in the inflammasome regulatory network. We performed whole exome sequencing of 319 probands, comprising patients with familial MS, sporadic MS and control subjects. 62 genes involved in the NLRP1/NLRP3 inflammasome regulation were screened for potentially pathogenic rare genetic variation. Aggregate mutational burden was analyzed, considering the variants’ predicted pathogenicity and frequency in the general population. We demonstrate an increased (p = 0.00004) variant burden among MS patients which was most pronounced for the exceedingly rare variants with high predicted pathogenicity. These variants were found in inflammasome genes (NLRP1/3, CASP1), genes mediating inflammasome inactivation via auto and mitophagy (RIPK2, MEFV), and genes involved in response to infection with DNA viruses (POLR3A, DHX58, IFIH1) and to type-1 interferons (TYK2, PTPRC). In conclusion, we present new evidence supporting the importance of rare genetic variation in the inflammasome signaling pathway and its regulation via autophagy and interferon-β to the etiology of MS.
Differential expression profiling of long non-coding RNA GAS5 and miR-126-3p in human cancer cells in response to sorafenib
Authors: Faranda Teresa , Grossi Ilaria , Manganelli Michele , Marchina Eleonora , Baiocchi Gianluca , Portolani Nazario , Crosatti Marialuisa , De Petro Giuseppina , Salvi Alessandro
Published: June 2019

Long non-coding RNAs (lncRNAs) and microRNAs are involved in numerous physio-pathological conditions included cancer. To better understand the molecular mechanism of the oral antitumor multikinase inhibitor sorafenib, we profiled the expression of a panel of lncRNAs and miRNAs by qPCR array in a sorafenib-treated hepatocellular carcinoma (HCC) cell line. Among the most affected ncRNAs, we found that sorafenib mediated the dysregulation of the lncRNAs GAS5, HOTTIP and HOXA-AS2 and the miR-126-3p, in a panel of human cancer cell lines (HCC, renal and breast carcinomas). By luciferase gene reporter assay, we discovered that GAS5 may act as a sponge for miR-126-3p in HCC cells. The expression level of GAS5 and miR-126-3p was verified in human liquid and/or solid biopsies from HCC patients. miR-126-3p expression in HCC tissues was decreased respect to their correspondent peritumoral tissues. The levels of plasmatic circulating miR-126-3p and GAS5 were significantly higher and lower in HCC patients compared to healthy subjects, respectively. This study highlighted the capability of sorafenib to modulate the expression of a wide range of ncRNAs and specifically, GAS5 and miR-126-3p were involved in the response to sorafenib of different cancer cell types.
Brain wave classification using long short-term memory network based OPTICAL predictor
Authors: Kumar Shiu , Sharma Alok , Tsunoda Tatsuhiko
Published: June 2019

Brain-computer interface (BCI) systems having the ability to classify brain waves with greater accuracy are highly desirable. To this end, a number of techniques have been proposed aiming to be able to classify brain waves with high accuracy. However, the ability to classify brain waves and its implementation in real-time is still limited. In this study, we introduce a novel scheme for classifying motor imagery (MI) tasks using electroencephalography (EEG) signal that can be implemented in real-time having high classification accuracy between different MI tasks. We propose a new predictor, OPTICAL, that uses a combination of common spatial pattern (CSP) and long short-term memory (LSTM) network for obtaining improved MI EEG signal classification. A sliding window approach is proposed to obtain the time-series input from the spatially filtered data, which becomes input to the LSTM network. Moreover, instead of using LSTM directly for classification, we use regression based output of the LSTM network as one of the features for classification. On the other hand, linear discriminant analysis (LDA) is used to reduce the dimensionality of the CSP variance based features. The features in the reduced dimensional plane after performing LDA are used as input to the support vector machine (SVM) classifier together with the regression based feature obtained from the LSTM network. The regression based feature further boosts the performance of the proposed OPTICAL predictor. OPTICAL showed significant improvement in the ability to accurately classify left and right-hand MI tasks on two publically available datasets. The improvements in the average misclassification rates are 3.09% and 2.07% for BCI Competition IV Dataset I and GigaDB dataset, respectively. The Matlab code is available at https://github.com/ShiuKumar/OPTICAL.
Design of Scalable Optical Decoder based on Hexagonal Plasmonic Modes induced on Topological Insulator Surface States
Authors: Srivastava Siddharth , Jain Priyanshu , Maiti Tanmoy
Published: June 2019

In the present work, optical decoder based on hexagonal plasmonic lens encrypted on topological insulator is designed. Using Finite Difference Time Domain (FDTD) simulation we have shown 2D optical lattice of scalar vortices in hexagonal plasmonic lens using surface states of topological insulator (Bi1.5Sb0.5Te1.8Se1.2). To ensure feasible and flexible physical dimensions, scaling of the optical device is proposed via increasing area density of vortices. This is numerically obtained by changing radius of hexagonal lens or decreasing incident wavelength. Using these scalable optical vortex lattices, a device scheme is proposed for storing or decoding information. Advantage of scaling in optical devices without any additional processing step shows the promise of this technology for future devices. Simulation results are further validated by detailed theoretical calculation of electric field intensity and phase distribution.
3DμF - Interactive Design Environment for Continuous Flow Microfluidic Devices
Authors: Sanka Radhakrishna , Lippai Joshua , Samarasekera Dinithi , Nemsick Sarah , Densmore Douglas
Published: June 2019

The design of microfluidic Lab on a Chip (LoC) systems is an onerous task requiring specialized skills in fluid dynamics, mechanical design drafting, and manufacturing. Engineers face significant challenges during the labor-intensive process of designing microfluidic devices, with very few specialized tools that help automate the process. Typical design iterations require the engineer to research the architecture, manually draft the device layout, optimize for manufacturing processes, and manually calculate and program the valve sequences that operate the microfluidic device. The problem compounds when engineers not only have to test the functionality of the chip but are also expected to optimize them for the robust execution of biological assays. In this paper, we present an interactive tool for designing continuous flow microfluidic devices. 3DμF is the first completely open source interactive microfluidic system designer that readily supports state of the art design automation algorithms. Through various case studies, we show 3DμF can be used to reproduce designs from literature, provide metrics for evaluating microfluidic design complexity and showcase how 3DμF is a platform for integrating a wide assortment of engineering techniques used in the design of microfluidic devices as a part of the standard design workflow.
Screening of Candida albicans GRACE library revealed a unique pattern of biofilm formation under repression of the essential gene ILS1
Authors: Costa Anna Carolina Borges Pereira , Omran Raha Parvizi , Correia-Mesquita Tuana Oliveira , Dumeaux Vanessa , Whiteway Malcolm
Published: June 2019

Candida albicans biofilm formation is governed by a regulatory circuit comprising nine transcription factors which control a network of target genes. However, there are still unknown genes contributing to biofilm features. Thus, the GRACE library was screened to identify genes involved in mature biofilm development. Twenty-nine conditional mutants were selected for a second screening revealing three groups of genes: twenty- two conditional mutants were defective for normal growth and unable to form biofilms; six strains, conditionally defective in genes ARC40, ARC35, ORF19.2438, SKP1, ERG6, and ADE5,7 that are likely essential or involved in general cell processes, grew normally as free-floating cells but produced less biofilm; finally, the conditional strain for a putative essential isoleucyl- tRNA synthetase gene, ILS1, was unable to grow as yeast-phase cells but was capable of producing a tridimensional biofilm structure in spite of reduced metabolic activity. This unique biofilm still relied on the classical biofilm genes, while it differentially induced groups of genes involved in adhesion, protein synthesis, cell wall organization, and protein folding. Although the conditional mutant repressed genes annotated for morphology and homeostasis processes affecting morphology and metabolism, the dynamic cell growth enabled the formation of a complex biofilm community independent of ILS1.
Self-compensation in chlorine-doped CdTe
Authors: Orellana Walter , Menéndez-Proupin Eduardo , Flores Mauricio A.
Published: June 2019

Defect energetics, charge transition levels, and electronic band structures of several Cl-related complexes in CdTe are studied using density-functional theory calculations. We investigate substitutional chlorine (ClTe and ClCd) and complexes formed by ClTe with the cadmium vacancy (ClTe-VCd and 2ClTe-VCd) and the TeCd antisite (ClTe-TeCd). Our calculations show that none of the complexes studied induce deep levels in the CdTe band gap. Moreover, we find that ClTe-VCd and ClTe are the most stable Cl-related centers in n-type and p-type CdTe, under Te-rich growth conditions, showing shallow donor and acceptor properties, respectively. This result suggests that the experimentally-observed Fermi level pinning near midgap would be originated in self-compensation. We also find that the formation of the ClTe-TeCd complex passivates the deep level associated to the Te antisite in neutral charge state.
Negative Capacitance as Universal Digital and Analog Performance Booster for Complementary MOS Transistors
Authors: Saeidi Ali , Jazaeri Farzan , Stolichnov Igor , Enz Christian C. , Ionescu Adrian M.
Published: June 2019

Boltzmann electron energy distribution poses a fundamental limit to lowering the energy dissipation of conventional MOS devices, a minimum increase of the gate voltage, i.e. 60 mV, is required for a 10-fold increase in drain-to-source current at 300 K. Negative Capacitance (NC) in ferroelectric materials is proposed in order to address this physical limitation of CMOS technology. A polarization destabilization in ferroelectrics causes an effective negative permittivity, resulting in a differential voltage amplification and a reduced subthreshold swing when integrated into the gate stack of a transistor. The novelty and universality of this approach relate to the fact that the gate stack is not anymore a passive part of the transistor and contributes to signal amplification. In this paper, we experimentally validate NC as a universal performance booster: (i) for complementary MOSFETs, of both n- and p-type in an advanced CMOS technology node, and, (ii) for both digital and analog significant enhancements of key figures of merit for information processing (subthreshold swing, overdrive, and current efficiency factor). Accordingly, a sub-thermal swing down to 10 mV/decade together with an enhanced current efficiency factor up to 105 V−1 is obtained in both n- and p-type MOSFETs at room temperature by exploiting a PZT capacitor as the NC booster. As a result of the subthreshold swing reduction and overdrive improvement observed by NC, the required supply voltage to provide the same on-current is reduced by approximately 50%.
Engineering mouse cationic trypsinogen for rapid and selective activation by cathepsin B
Authors: Demcsák Alexandra , Geisz Andrea , Sahin-Tóth Miklós
Published: June 2019

Intra-pancreatic activation of trypsin is an early event in pancreatitis. Trypsinogen can be activated to trypsin either through autoactivation (trypsin-mediated trypsinogen activation) or by the lysosomal protease cathepsin B (CTSB). Experimental separation of CTSB-mediated activation from autoactivation in mice is possible through knocking in mutations that render trypsinogen sensitive to CTSB but resistant to trypsin. Here we present biochemical studies on novel mouse cationic trypsinogen (isoform T7) mutants engineered for selective CTSB activation. First, we demonstrated that mutation K24G, which alters the activation site Lys in T7 trypsinogen, abolished autoactivation while activation by CTSB was stimulated 4-fold at pH 4.0. Interestingly, CTSB-mediated activation of the K24G mutant became more sensitive to inhibition by increasing pH. Next, Ala-scanning of the five Asp residues preceding the activation site Lys revealed that mutation D22A accelerated CTSB-mediated activation by 2-fold. Finally, combination of mutations D22A and K24G resulted in a trypsinogen mutant that exhibited 14-fold increased activation by CTSB and normal pH sensitivity. We conclude that we successfully engineered a mouse T7 trypsinogen mutant (D22A,K24G), which is robustly activated by CTSB but cannot undergo autoactivation. These studies set the stage for the generation of a preclinical mouse model of CTSB-dependent pancreatitis.
A novel potent autophagy inhibitor ECDD-S27 targets vacuolar ATPase and inhibits cancer cell survival
Authors: Paha Jiraporn , Kanjanasirirat Phongthon , Munyoo Bamroong , Tuchinda Patoomratana , Suvannang Naravut , Nantasenamat Chanin , Boonyarattanakalin Kanokthip , Kittakoop Prasat , Srikor Sirawit , Kongklad Gunganist , Rangkasenee Noppawan , Hongeng Suradej , Utaisincharoen Pongsak , Borwornpinyo Suparerk , Ponpuak Marisa
Published: June 2019

Autophagy is a conserved lysosomal-dependent cellular degradation process and its dysregulation has been linked to numerous diseases including neurodegeneration, infectious diseases, and cancer. Modulation of autophagy is therefore considered as an attractive target for disease intervention. We carried out a high-content image analysis screen of natural product-derived compounds to discover novel autophagy modulating molecules. Our screen identified ECDD-S27 as the most effective compound for increasing the number of autophagic vacuoles inside cells. The structure of ECDD-S27 revealed that it is a derivative of cleistanthin A, a natural arylnaphthalene lignan glycoside found in plants. ECDD-S27 increases the number of autophagic vacuoles by inhibiting the autophagic flux and is able to restrict the survival of different cancer cells at low nanomolar concentrations. Molecular docking and SERS analysis showed that ECDD-S27 may potentially target the V-ATPase. Upon treatment of various cancer cells with ECDD-S27, the V-ATPase activity is potently inhibited thereby resulting in the loss of lysosomal acidification. Taken together, these data indicated that ECDD-S27 retards the autophagy pathway by targeting the V-ATPase and inhibits cancer cell survival. The observed antitumor activity without cytotoxicity to normal cells suggests the therapeutic potential warranting further studies on lead optimization of the compound for cancer treatment.
The extracellular matrix proteoglycan lumican improves survival and counteracts cardiac dilatation and failure in mice subjected to pressure overload
Authors: Mohammadzadeh Naiyereh , Lunde Ida G. , Andenæs Kine , Strand Mari E. , Aronsen Jan Magnus , Skrbic Biljana , Marstein Henriette S. , Bandlien Caroline , Nygård Ståle , Gorham Joshua , Sjaastad Ivar , Chakravarti Shukti , Christensen Geir , Engebretsen Kristin V. T. , Tønnessen Theis
Published: June 2019

Left ventricular (LV) dilatation is a key step in transition to heart failure (HF) in response to pressure overload. Cardiac extracellular matrix (ECM) contains fibrillar collagens and proteoglycans, important for maintaining tissue integrity. Alterations in collagen production and cross-linking are associated with cardiac LV dilatation and HF. Lumican (LUM) is a collagen binding proteoglycan with increased expression in hearts of patients and mice with HF, however, its role in cardiac function remains poorly understood. To examine the role of LUM in pressure overload induced cardiac remodeling, we subjected LUM knock-out (LUMKO) mice to aortic banding (AB) and treated cultured cardiac fibroblasts (CFB) with LUM. LUMKO mice exhibited increased mortality 1–14 days post-AB. Echocardiography revealed increased LV dilatation, altered hypertrophic remodeling and exacerbated contractile dysfunction in surviving LUMKO 1–10w post-AB. LUMKO hearts showed reduced collagen expression and cross-linking post-AB. Transcriptional profiling of LUMKO hearts by RNA sequencing revealed 714 differentially expressed transcripts, with enrichment of cardiotoxicity, ECM and inflammatory pathways. CFB treated with LUM showed increased mRNAs for markers of myofibroblast differentiation, proliferation and expression of ECM molecules important for fibrosis, including collagens and collagen cross-linking enzyme lysyl oxidase. In conclusion, we report the novel finding that lack of LUM attenuates collagen cross-linking in the pressure-overloaded heart, leading to increased mortality, dilatation and contractile dysfunction in mice.
Deep transcriptome analysis using RNA-Seq suggests novel insights into molecular aspects of fat-tail metabolism in sheep
Authors: Bakhtiarizadeh Mohammad Reza , Salehi Abdolreza , Alamouti Ali A. , Abdollahi-Arpanahi Rostam , Salami Seyed Alireza
Published: June 2019

Fat-tail content of sheep breeds is varied and the molecular mechanisms regulating fat-tail development have not been well characterized. Aiming at better identifying the important candidate genes and their functional pathways contributing to fat deposition in the tail, a comparative transcriptome analysis was performed between fat- (Lori-Bakhtiari) and thin-tailed (Zel) Iranian sheep breeds using RNA-seq. The experiment was conducted on six male lambs (three lambs per each breed) at seven months of age. Four different combinations of aligners and statistical methods including Hisat2 + edgeR, Hisat2 + DESeq2, STAR + edgeR and STAR + DESeq2 were used to identify the differentially expressed genes (DEGs). The DEGs were selected for functional enrichment analysis and protein-protein interaction (PPI) network construction. Module analysis was also conducted to mine the functional sub-networks from the PPI network. In total, 264 genes including 80 up- and 184 down-regulated genes were identified as DEGs. The RNA-Seq results were validated by Q-RT-PCR. Functional analysis of DEGs and the module analysis of PPI network demonstrated that in addition to pathways affecting lipid metabolism, a series of enriched functional terms related to “response to interleukin”, “MAPK signaling pathways”, “Wnt signaling pathway”, “ECM-receptor interaction”, “regulation of actin cytoskeleton”, and “response to cAMP” might contribute to the deposition of fat in tails of sheep. Overall results using RNA-Seq analysis characterized important candidate genes involved in the fatty acid metabolism and regulation of fat deposition, suggesting novel insights into molecular aspects of fat-tail metabolism in sheep. Selected DEGs should be further investigated as potential markers associated with the fat-tail development in sheep breeds.
Scheelite type Sr1−xBaxWO4 (x = 0.1, 0.2, 0.3) for possible application in Solid Oxide Fuel Cell electrolytes
Authors: Afif Ahmed , Zaini Juliana , Rahman Seikh Mohammad Habibur , Eriksson Sten , Islam Md Aminul , Azad Abul Kalam
Published: June 2019

Polycrystalline scheelite type Sr1−xBaxWO4 (x = 0.1, 0.2 & 0.3) materials were synthesized by the solid state sintering method and studied with respect to phase stability and ionic conductivity under condition of technological relevance for SOFC applications. All compounds crystallized in the single phase of tetragonal scheelite structure with the space group of I41/a. Room temperature X-ray diffraction and subsequent Rietveld analysis confirms its symmetry, space group and structural parameters. SEM illustrates the highly dense compounds. Significant mass change was observed to prove the proton uptake at higher temperature by TG-DSC. All compound shows lower conductivity compared to the traditional BCZY perovskite structured materials. SBW with x = 0.3 exhibit the highest ionic conductivity among all compounds under wet argon condition which is 1.9 × 10−6 S cm−1 at 1000 °C. Since this scheelite type compounds show significant conductivity, the new series of SBW could serve in IT-SOFC as proton conducting electrolyte.
Seebeck-voltage-triggered self-biased photoelectrochemical water splitting using HfOx/SiOx bi-layer protected Si photocathodes
Authors: Jung Jin-Young , Woong Kim Dae , Kim Dong-Hyung , Joo Park Tae , Wehrspohn Ralf B. , Lee Jung-Ho
Published: June 2019

The use of a photoelectrochemical device is an efficient method of converting solar energy into hydrogen fuel via water splitting reactions. One of the best photoelectrode materials is Si, which absorbs a broad wavelength range of incident light and produces a high photocurrent level (~44 mA·cm−2). However, the maximum photovoltage that can be generated in single-junction Si devices (~0.75 V) is much lower than the voltage required for a water splitting reaction (>1.6 V). In addition, the Si surface is electrochemically oxidized or reduced when it comes into direct contact with the aqueous electrolyte. Here, we propose the hybridization of the photoelectrochemical device with a thermoelectric device, where the Seebeck voltage generated by the thermal energy triggers the self-biased water splitting reaction without compromising the photocurrent level at 42 mA cm−2. In this hybrid device p-Si, where the surface is protected by HfOx/SiOx bilayers, is used as a photocathode. The HfOx exhibits high corrosion resistance and protection ability, thereby ensuring stability. On applying the Seebeck voltage, the tunneling barrier of HfOx is placed at a negligible energy level in the electron transfer from Si to the electrolyte, showing charge transfer kinetics independent of the HfOx thickness. These findings serve as a proof-of-concept of the stable and high-efficiency production of hydrogen fuel by the photoelectrochemical-thermoelectric hybrid devices.
Precipitation extremes and depth-duration-frequency under internal climate variability
Authors: Bhatia Udit , Ganguly Auroop Ratan
Published: June 2019

Natural climate variability, captured through multiple initial condition ensembles, may be comparable to the variability caused by knowledge gaps in future emissions trajectories and in the physical science basis, especially at adaptation-relevant scales and projection horizons. The relations to chaos theory, including sensitivity to initial conditions, have caused the resulting variability in projections to be viewed as the irreducible uncertainty component of climate. The multiplier effect of ensembles from emissions-trajectories, multiple-models and initial-conditions contribute to the challenge. We show that ignoring this variability results in underestimation of precipitation extremes return periods leading to maladaptation. However, we show that concatenating initial-condition ensembles results in reduction of hydroclimate uncertainty. We show how this reduced uncertainty in precipitation extremes percolates to adaptation-relevant-Depth-Duration Frequency curves. Hence, generation of additional initial condition ensembles therefore no longer needs to be viewed as an uncertainty explosion problem but as a solution that can lead to uncertainty reduction in assessment of extremes.
Discovery of Biomarker Panels for Neural Dysfunction in Inborn Errors of Amino Acid Metabolism
Authors: Castells Alba-Aina , Gueraldi Daniela , Balada Rafel , Tristán-Noguero Alba , Cortès-Saladelafont Elisenda , Ramos Federico , Meavilla Silvia , De Los Santos Mariela , Garcia-Volpe Camila , Colomé Roser , Couce Maria Luz , Sierra Cristina , Ormazábal Aida , Batllori Marta , Artuch Rafael , Armstrong Judith , Alcántara Soledad , Garcia-Cazorla Àngels
Published: June 2019

Patients with inborn errors of amino acid metabolism frequently show neuropsychiatric symptoms despite accurate metabolic control. This study aimed to gain insight into the underlying mechanisms of neural dysfunction. Here we analyzed the expression of brain-derived neurotrophic factor (BDNF) and 10 genes required for correct brain functioning in plasma and blood of patients with Urea Cycle Disorders (UCD), Maple Syrup Urine Disease (MSUD) and controls. Receiver-operating characteristic (ROC) analysis was used to evaluate sensitivity and specificity of potential biomarkers. CACNA2D2 (α2δ2 subunit of voltage-gated calcium channels) and MECP2 (methyl-CpG binding protein 2) mRNA and protein showed an excellent neural function biomarker signature (AUC ≥ 0,925) for recognition of MSUD. THBS3 (thrombospondin 3) mRNA and AABA gave a very good biomarker signature (AUC 0,911) for executive-attention deficits. THBS3, LIN28A mRNA, and alanine showed a perfect biomarker signature (AUC 1) for behavioral and mood disorders. Finally, a panel of BDNF protein and at least two large neural AAs showed a perfect biomarker signature (AUC 1) for recognition of psychomotor delay, pointing to excessive protein restriction as central causative of psychomotor delay. To conclude, our study has identified promising biomarker panels for neural function evaluation, providing a base for future studies with larger samples.
Blockade of microglial Cav1.2 Ca2+ channel exacerbates the symptoms in a Parkinson’s disease model
Authors: Wang Xinshuang , Saegusa Hironao , Huntula Soontaraporn , Tanabe Tsutomu
Published: June 2019

Cav1.2 channels are an L-type voltage-dependent Ca2+channel, which is specifically blocked by calcium antagonists. Voltage-dependent Ca2+channels are generally considered to be functional only in excitable cells like neurons and muscle cells, but recently they have been reported to also be functional in non-excitable cells like microglia, which are key players in the innate immune system and have been shown to be involved in the pathophysiology of Parkinson’s disease. Here, we show that Cav1.2 channels are expressed in microglia, and that calcium antagonists enhanced theneuroinflammatoryM1 transition and inhibitedneuroprotectiveM2 transition of microgliain vitro. Moreover, intensive degeneration of dopaminergic neurons and accompanying behavioural deficits were observed in microglia-specific Cav1.2 knockdown mice intoxicated with MPTP, a neurotoxin that induces Parkinson’s disease-like symptoms, suggesting detrimental effects of microglial Cav1.2 blockade on Parkinson’s disease. Therefore, microglial Cav1.2 channel may have neuroprotective roles under physiological conditions and may also contribute to recovery from disease conditions.
Weight Bearing Activities change the Pivot Position after Total Knee Arthroplasty
Authors: Moewis Philippe , Hommel Hagen , Trepczynski Adam , Krahl Leonie , von Roth Philipp , Duda Georg N.
Published: June 2019

The knee joint center of rotation is altered in the absence of the anterior cruciate ligament, which leads to substantially higher variance in kinematic patterns. To overcome this, total knee arthroplasty (TKA) designs with a high congruency in the lateral compartment have been proposed. The purpose of this study was to analyze the influence of a lateral pivot TKA-design on in-vivo knee joint kinematics. Tibiofemoral motion was retrospectively addressed in 10 patients during unloaded flexion-extension and loaded lunge using single plane fluoroscopy. During the unloaded flexion-extension movement, the lateral condyle remained almost stationary with little rollback at maximum flexion. The medial condyle exhibited anterior translation during the whole flexion cycle. During the loaded lunge movement, a higher degree of rollback compared to the unloaded activity was observed on the lateral condyle, whereas the medial condyle remained almost stationary. The results showed a clear lateral pivot during the unloaded activity, reflective of the implant’s geometric characteristics, and a change to a medial pivot and a higher lateral rollback during the weight-bearing conditions, revealing the impact of load and muscle force. It remains unclear if the kinematics with a lateral TKA design could be considered as physiological, due to the limited knowledge available on native knee joint kinematics.
Genome-wide association study identifies loci for arterial stiffness index in 127,121 UK Biobank participants
Authors: Fung Kenneth , Ramírez Julia , Warren Helen R. , Aung Nay , Lee Aaron M. , Tzanis Evan , Petersen Steffen E. , Munroe Patricia B.
Published: June 2019

Arterial stiffness index (ASI) is a non-invasive measure of arterial stiffness using infra-red finger sensors (photoplethysmography). It is a well-suited measure for large populations as it is relatively inexpensive to perform, and data can be acquired within seconds. These features raise interest in using ASI as a tool to estimate cardiovascular disease risk as prior work demonstrates increased arterial stiffness is associated with elevated systolic blood pressure, and ASI is predictive of cardiovascular disease and mortality. We conducted genome-wide association studies (GWASs) for ASI in 127,121 UK Biobank participants of European-ancestry. Our primary analyses identified variants at four loci reaching genome-wide significance (P < 5 × 10−8): TEX41 (rs1006923; P = 5.3 × 10−12), FOXO1 (rs7331212; P = 2.2 × 10−11), C1orf21 (rs1930290, P = 1.1 × 10−8) and MRVI1 (rs10840457, P = 3.4 × 10−8). Gene-based testing revealed three significant genes, the most significant gene was COL4A2 (P = 1.41 × 10−8) encoding type IV collagen. Other candidate genes at associated loci were also involved in smooth muscle tone regulation. Our findings provide new information for understanding the development of arterial stiffness.
Characterization of metal binding of bifunctional kinase/phosphatase AceK and implication in activity modulation
Authors: Zhang Xiaoying , Shen Qingya , Lei Zhen , Wang Qianyi , Zheng Jimin , Jia Zongchao
Published: June 2019

A unique bifunctional enzyme, isocitrate dehydrogenase kinase/phosphatase (AceK) regulates isocitrate dehydrogenase (IDH) by phosphorylation and dephosphorylation in response to nutrient availability. Herein we report the crystal structure of AceK in complex with ADP and Mn2+ ions. Although the overall structure is similar to the previously reported structures which contain only one Mg2+ ion, surprisingly, two Mn2+ ions are found in the catalytic center of the AceK-Mn2+ structure. Our enzymatic assays demonstrate that AceK-Mn2+ showed higher phosphatase activity than AceK-Mg2+, whereas the kinase activity was relatively unaffected. We created mutants of AceK for all metal-coordinating residues. The phosphatase activities of these mutants were significantly impaired, suggesting the pivotal role of the binuclear (M1-M2) core in AceK phosphatase catalysis. Moreover, we have studied the interactions of Mn2+ and Mg2+ with wild-type and mutant AceK and found that the number of metal ions bound to AceK is in full agreement with the crystal structures. Combined with the enzymatic results, we demonstrate that AceK exhibits phosphatase activity in the presence of two, but not one, Mn2+ ions, similar to PPM phosphatases. Taken together, we suggest that metal ions help AceK to balance and fine tune its kinase and phosphatase activities.
Recombinant production of human α2-macroglobulin variants and interaction studies with recombinant G-related α2-macroglobulin binding protein and latent transforming growth factor-β2
Authors: Marino-Puertas Laura , del Amo-Maestro Laura , Taulés Marta , Gomis-Rüth F. Xavier , Goulas Theodoros
Published: June 2019

α2-Macroglobulins (α2Ms) regulate peptidases, hormones and cytokines. Mediated by peptidase cleavage, they transit between native, intact forms and activated, induced forms. α2Ms have been studied over decades using authentic material from primary sources, which was limited by sample heterogeneity and contaminants. Here, we developed high-yield expression systems based on transient transfection in Drosophila Schneider 2 and human Expi293F cells, which produced pure human α2M (hα2M) at ~1.0 and ~0.4 mg per liter of cell culture, respectively. In both cases, hα2M was mainly found in the induced form. Shorter hα2M variants encompassing N-/C-terminal parts were also expressed and yielded pure material at ~1.6/~1.3 and ~3.2/~4.6 mg per liter of insect or mammalian cell culture, respectively. We then analyzed the binding of recombinant and authentic hα2M to recombinant latent human transforming growth factor-β2 (pro-TGF-β2) and bacterial G-related α2M binding protein (GRAB) by surface plasmon resonance, multiple-angle laser light scattering, size-exclusion chromatography, fluorogenic labelling, gel electrophoresis and Western-blot analysis. Two GRAB molecules formed stable complexes of high affinity with native and induced authentic hα2M tetramers. The shorter recombinant hα2M variants interacted after preincubation only. In contrast, pro-TGF-β2 did not interact, probably owing to hindrance by the N-terminal latency-associated protein of the cytokine.
Current and future climatic regions favourable for a globally introduced wild carnivore, the raccoon Procyon lotor
Authors: Louppe Vivien , Leroy Boris , Herrel Anthony , Veron Géraldine
Published: June 2019

Invasive species are considered as one of the major threats to biodiversity and represent a major challenge in the conservation of natural ecosystems, in preventing damage to agricultural production, and human health risks. Environmental Niche Modelling has emerged as a powerful tool to predict the patterns of range expansion of non-native species and to direct effective strategies for managing biological invasions. The raccoon,Procyon lotor, is a wild mesocarnivore presenting a high adaptability and showing successful introduced populations worldwide. Here, we modelled the current and future climatically favourable areas for the raccoon using two protocols, based on data sets filtrated in geographic and environmental spaces. Projections from these models show extensive current favourable geographical areas covering extensive regions of temperate biomes. Moreover, predictions for 2050 reveals extensive new favourable areas north of the current favourable regions. However, the results of the two modeling approaches differ in the extent of predicted favourable spaces. Protocols using geographically filtered data present more conservative forecasts, while protocol using environmental filtration presents forecasts across greater areas. Given the biological characteristics and the ecological requirements of a generalist carnivore such as the raccoon, the latter forecasts appears more relevant and should be privileged in the development of conservation plans for ecosystems.
Transcriptome Analysis of Long-lived Drosophila melanogaster E(z) Mutants Sheds Light on the Molecular Mechanisms of Longevity
Authors: Moskalev Alexey A. , Shaposhnikov Mikhail V. , Zemskaya Nadezhda V. , Koval Liubov А. , Schegoleva Eugenia V. , Guvatova Zulfiya G. , Krasnov George S. , Solovev Ilya A. , Sheptyakov Maksim A. , Zhavoronkov Alex , Kudryavtseva Anna V.
Published: June 2019

The E(z) histone methyltransferase heterozygous mutation in Drosophila is known to increase lifespan and stress resistance. However, the longevity mechanisms of E(z) mutants have not been revealed. Using genome-wide transcriptome analysis, we demonstrated that lifespan extension, increase of resistance to hyperthermia, oxidative stress and endoplasmic reticulum stress, and fecundity enhancement in E(z) heterozygous mutants are accompanied by changes in the expression level of 239 genes (p < 0.05). Our results demonstrated sex-specific effects of E(z) mutation on gene expression, which, however, did not lead to differences in lifespan extension in both sexes. We observed that a mutation in an E(z) gene leads to perturbations in gene expression, most of which participates in metabolism, such as Carbohydrate metabolism, Lipid metabolism, Drug metabolism, Nucleotide metabolism. Age-dependent changes in the expression of genes involved in pathways related to immune response, cell cycle, and ribosome biogenesis were found.
Revealing higher than expected diversity of Harpacticoida (Crustacea:Copepoda) in the North Sea using MALDI-TOF MS and molecular barcoding
Authors: Rossel S. , Martínez Arbizu P.
Published: June 2019

The North Sea is one of the most extensively studied marine regions of the world. Hence, large amounts of molecular data for species identification are available in public repositories, and expectations to find numerous new species in this well-known region are rather low. However, molecular reference data for harpacticoid copepods from this area in particular but also for this group in general is scarce. By assessing COI barcodes and MALDI-TOF mass spectra for this group of small crustaceans, it was discovered that there is a huge unknown diversity in this area. In total, COI sequences for 548 specimens from 115 species of harpacticoid copepods are presented. Over 19% of these were new to science and ten MOTUs were found to be part of cryptic species complexes. MALDI-TOF mass spectra were assessed for 622 specimens from 75 species. Because results were in concordance with species delimitation by COI barcoding and also enabled recognition of possible cryptic species, the discriminative power of this technique for biodiversity assessments is highlighted. Findings imply, species diversity in this group may be largely underestimated and total species number can be expected to be much higher than previously assumed.