bluuebunny/crossref_metadata_2025 huggingface dataset:
PIM kinases mediate resistance of glioblastoma cells to TRAIL by a p62/SQSTM1-dependent mechanism
Authors: Serrano-Saenz Santiago , Palacios Carmen , Delgado-Bellido Daniel , López-Jiménez Laura , Garcia-Diaz Angel , Soto-Serrano Yolanda , Casal J. Ignacio , Bartolomé Rubén A. , Fernández-Luna José Luis , López-Rivas Abelardo , Oliver F. Javier
Published: February 2019

Glioblastoma (GBM) is the most common and aggressive brain tumor and is associated with poor prognosis. GBM cells are frequently resistant to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and finding new combinatorial therapies to sensitize glioma cells to TRAIL remains an important challenge. PIM kinases are serine/threonine kinases that promote cell survival and proliferation and are highly expressed in different tumors. In this work, we studied the role of PIM kinases as regulators of TRAIL sensitivity in GBM cells. Remarkably, PIM inhibition or knockdown facilitated activation by TRAIL of a TRAIL-R2/DR5-mediated and mitochondria-operated apoptotic pathway in TRAIL-resistant GBM cells. The sensitizing effect of PIM knockdown on TRAIL-induced apoptosis was mediated by enhanced caspase-8 recruitment to and activation at the death-inducing signaling complex (DISC). Interestingly, TRAIL-induced internalization of TRAIL-R2/DR5 was significantly reduced in PIM knockdown cells. Phospho-proteome profiling revealed a decreased phosphorylation of p62/SQSTM1 after PIM knockdown. Our results also showed an interaction between p62/SQSTM1 and the DISC that was reverted after PIM knockdown. In line with this, p62/SQSTM1 ablation increased TRAIL-R2/DR5 levels and facilitated TRAIL-induced caspase-8 activation, revealing an inhibitory role of p62/SQSTM1 in TRAIL-mediated apoptosis in GBM. Conversely, upregulation of TRAIL-R2/DR5 upon PIM inhibition and apoptosis induced by the combination of PIM inhibitor and TRAIL were abrogated by a constitutively phosphorylated p62/SQSTM1S332E mutant. Globally, our data represent the first evidence that PIM kinases regulate TRAIL-induced apoptosis in GBM and identify a specific role of p62/SQSTM1Ser332 phosphorylation in the regulation of the extrinsic apoptosis pathway activated by TRAIL.
Chemerin reverses neurological impairments and ameliorates neuronal apoptosis through ChemR23/CAMKK2/AMPK pathway in neonatal hypoxic–ischemic encephalopathy
Authors: Zhang Yixin , Xu Ningbo , Ding Yan , Doycheva Desislava Met , Zhang Yiting , Li Qian , Flores Jerry , Haghighiabyaneh Mina , Tang Jiping , Zhang John H.
Published: February 2019

Hypoxic–ischemic encephalopathy (HIE) is a devastating neurological event that contributes to the prolonged neurodevelopmental consequences in infants. Therapeutic strategies focused on attenuating neuronal apoptosis in the penumbra appears to be promising. Given the increasingly recognized neuroprotective roles of adipokines in HIE, we investigated the potential anti-apoptotic roles of a novel member of adipokines, Chemerin, in an experimental model of HIE. In the present study, 10-day-old rat pups underwent right common carotid artery ligation followed by 2.5 h hypoxia. At 1 h post hypoxia, pups were intranasally administered with human recombinant chemerin (rh-chemerin). Here, we showed that rh-chemerin prevented the neuronal apoptosis and degeneration as evidenced by the decreased expression of the pro-apoptotic markers, cleaved caspase 3 and Bax, as well as the numbers of Fluoro-Jade C and TUNEL-positive neurons. Furthermore, rh-Chemerin reversed neurological and morphological impairments induced by hypoxia–ischemia in neonatal rats at 24 h and 4 weeks after HIE. In addition, chemerin-mediated neuronal survival correlated with the elevation of chemerin receptor 23 (chemR23), phosphorylated calmodulin-dependent protein kinase kinase 2 (CAMKK2), as well as phosphorylated adenosine monophosphate-activated protein kinase (AMPK). Specific inhibition of chemR23, CAMKK2, and AMPK abolished the anti-apoptotic effects of rh-chemerin at 24 h after HIE, demonstrating that rh-chemerin ameliorated neuronal apoptosis partially via activating chemR23/CAMKK2/AMPK signaling pathway. Neuronal apoptosis is a well-established contributing factor of pathological changes and the neurological impairment after HIE. These results revealed mechanisms of neuroprotection by rh-chemerin, and indicated that activation of chemR23 might be harnessed to protect from neuronal apoptosis in HIE.
Pigment epithelium-derived factor mediates retinal ganglion cell neuroprotection by suppression of caspase-2
Authors: Vigneswara Vasanthy , Ahmed Zubair
Published: February 2019

Retinal ganglion cells (RGCs) undergo rapid cell death by apoptosis after injury but can be rescued by suppression of caspase-2 (CASP2) using an siRNA to CASP2 (siCASP2). Pigment epithelium-derived factor (PEDF), has neuroprotective and anti-angiogenic functions and protects RGC from death. The purpose of this study was to investigate if suppression of CASP2 is a possible mechanism of neuroprotection by PEDF in RGC. Adult rat retinal cells were treated in vitro with sub-optimal and optimal concentrations of siCASP2 and PEDF and levels of CASP2 mRNA and RGC survival were then quantified. Optic nerve crush (ONC) injury followed by intravitreal injections of siCASP2 or PEDF and eye drops of PEDF-34 were also used to determine CASP2 mRNA and protein reduction. Results showed that PEDF and PEDF-34 significantly suppressed CASP2 mRNA in culture, by 1.85- and 3.04-fold, respectively, and increased RGC survival by 63.2 ± 3.8% and 81.9 ± 6.6%, respectively compared to cells grown in Neurobasal-A alone. RGC survival was significantly reduced in glial proliferation inhibited and purified RGC cultures suggesting that some of the effects of PEDF were glia-mediated. In addition, intravitreal injection of PEDF and eye drops of PEDF-34 after ONC also suppressed CASP2 mRNA levels by 1.82- and 3.89-fold and cleaved caspase-2 (C-CASP2) protein levels by 4.98- and 8.93-fold compared to ONC + PBS vehicle groups, respectively, without affecting other executioner caspases. Treatment of retinal cultures with PEDF and PEDF-34 promoted the secretion of neurotrophic factors (NTF) into the culture media, of which brain-derived neurotrophic factor (BDNF) caused the greatest reduction in CASP2 mRNA and C-CASP2 protein. The neuroprotective effects of PEDF were blocked by a polyclonal antibody and PEDF suppressed key elements in the apoptotic pathway. In conclusion, this study shows that some of the RGC neuroprotective effects of PEDF is regulated through suppression of CASP2 and downstream apoptotic signalling molecules.
Single-molecule sequencing detection of N6-methyladenine in microbial reference materials
Authors: McIntyre Alexa B. R. , Alexander Noah , Grigorev Kirill , Bezdan Daniela , Sichtig Heike , Chiu Charles Y. , Mason Christopher E.
Published: February 2019

The DNA base modification N6-methyladenine (m6A) is involved in many pathways related to the survival of bacteria and their interactions with hosts. Nanopore sequencing offers a new, portable method to detect base modifications. Here, we show that a neural network can improve m6A detection at trained sequence contexts compared to previously published methods using deviations between measured and expected current values as each adenine travels through a pore. The model, implemented as the mCaller software package, can be extended to detect known or confirm suspected methyltransferase target motifs based on predictions of methylation at untrained contexts. We use PacBio, Oxford Nanopore, methylated DNA immunoprecipitation sequencing (MeDIP-seq), and whole-genome bisulfite sequencing data to generate and orthogonally validate methylomes for eight microbial reference species. These well-characterized microbial references can serve as controls in the development and evaluation of future methods for the identification of base modifications from single-molecule sequencing data.
SMARCA4 loss is synthetic lethal with CDK4/6 inhibition in non-small cell lung cancer
Authors: Xue Yibo , Meehan Brian , Fu Zheng , Wang Xue Qing D. , Fiset Pierre Olivier , Rieker Ralf , Levins Cameron , Kong Tim , Zhu Xianbing , Morin Geneviève , Skerritt Lashanda , Herpel Esther , Venneti Sriram , Martinez Daniel , Judkins Alexander R. , Jung Sungmi , Camilleri-Broet Sophie , Gonzalez Anne V. , Guiot Marie-Christine , Lockwood William W. , Spicer Jonathan D. , Agaimy Abbas , Pastor William A. , Dostie Josée , Rak Janusz , Foulkes William D. , Huang Sidong
Published: February 2019

Tumor suppressor SMARCA4 (BRG1), a key SWI/SNF chromatin remodeling gene, is frequently inactivated in cancers and is not directly druggable. We recently uncovered that SMARCA4 loss in an ovarian cancer subtype causes cyclin D1 deficiency leading to susceptibility to CDK4/6 inhibition. Here, we show that this vulnerability is conserved in non-small cell lung cancer (NSCLC), where SMARCA4 loss also results in reduced cyclin D1 expression and selective sensitivity to CDK4/6 inhibitors. In addition, SMARCA2, another SWI/SNF subunit lost in a subset of NSCLCs, also regulates cyclin D1 and drug response when SMARCA4 is absent. Mechanistically, SMARCA4/2 loss reduces cyclin D1 expression by a combination of restricting CCND1 chromatin accessibility and suppressing c-Jun, a transcription activator of CCND1. Furthermore, SMARCA4 loss is synthetic lethal with CDK4/6 inhibition both in vitro and in vivo, suggesting that FDA-approved CDK4/6 inhibitors could be effective to treat this significant subgroup of NSCLCs.
Just add sugar for carbohydrate induced self-assembly of curcumin
Authors: Wong Sandy , Zhao Jiacheng , Cao Cheng , Wong Chin Ken , Kuchel Rhiannon P. , De Luca Sergio , Hook James M. , Garvey Christopher J. , Smith Sean , Ho Junming , Stenzel Martina H.
Published: February 2019

In nature, self-assembly processes based on amphiphilic molecules play an integral part in the design of structures of higher order such as cells. Among them, amphiphilic glycoproteins or glycolipids take on a pivotal role due to their bioactivity. Here we show that sugars, in particular, fructose, are capable of directing the self-assembly of highly insoluble curcumin resulting in the formation of well-defined capsules based on non-covalent forces. Simply by mixing an aqueous solution of fructose and curcumin in an open vessel leads to the generation of capsules with sizes ranging between 100 and 150 nm independent of the initial concentrations used. Our results demonstrate that hydrogen bonding displayed by fructose can induce the self-assembly of hydrophobic molecules such as curcumin into well-ordered structures, and serving as a simple and virtually instantaneous way of making nanoparticles from curcumin in water with the potential for template polymerization and nanocarriers.
Pioneer axons employ Cajal’s battering ram to enter the spinal cord
Authors: Nichols Ev L. , Smith Cody J.
Published: February 2019

Sensory axons must traverse a spinal cord glia limitans to connect the brain with the periphery. The fundamental mechanism of how these axons enter the spinal cord is still debatable; both Ramon y Cajal’s battering ram hypothesis and a boundary cap model have been proposed. To distinguish between these hypotheses, we visualized the entry of pioneer axons into the dorsal root entry zone (DREZ) with time-lapse imaging in zebrafish. Here, we identify that DRG pioneer axons enter the DREZ before the arrival of neural crest cells at the DREZ. Instead, actin-rich invadopodia in the pioneer axon are necessary and sufficient for DREZ entry. Using photoactivable Rac1, we demonstrate cell-autonomous functioning of invasive structures in pioneer axon spinal entry. Together these data support the model that actin-rich invasion structures dynamically drive pioneer axon entry into the spinal cord, indicating that distinct pioneer and secondary events occur at the DREZ.
The meiotic TERB1-TERB2-MAJIN complex tethers telomeres to the nuclear envelope
Authors: Wang Yan , Chen Yanyan , Chen Juan , Wang Lijun , Nie Leitong , Long Juanjuan , Chang Haishuang , Wu Jian , Huang Chenhui , Lei Ming
Published: February 2019

During meiotic prophase I, telomeres attach to and move on the nuclear envelope (NE), regulating chromosome movement to promote homologous pairing. Meiosis-specific proteins TERB1, TERB2 and MAJIN play a key role in this process. Here, we report the crystal structures of human TERB1-TERB2 and TERB2-MAJIN subcomplexes. Specific disruption of the TERB1-TERB2 or the TERB2-MAJIN interaction in the mouse Terb2 gene abolishes the telomere attachment to the NE and causes aberrant homologous pairing and disordered synapsis. In addition, depletion of SUN1 also partially disrupts the telomere-NE connection. We propose that the telomere-TRF1-TERB1-TERB2-MAJIN-NE interaction network and the telomere-LINC complex connection are likely two separate but cooperative pathways to stably recruit telomeres to the NE in meiosis prophase I. Our work provides a molecular model of the connection between telomeres and the NE and reveals the correlation between aberrant synapsis and the defective telomere attachment to the NE.
Phosphoric acid-catalyzed atroposelective construction of axially chiral arylpyrroles
Authors: Zhang Lei , Xiang Shao-Hua , Wang Jun , Xiao Jian , Wang Jun-Qi , Tan Bin
Published: February 2019

Axially chiral arylpyrroles are key components of pharmaceuticals and natural products as well as chiral catalysts and ligands for asymmetric transformations. However, the catalytic enantioselective construction of optically active arylpyrroles remains a formidable challenge. Here we disclose a highly efficient strategy to access enantioenriched axially chiral arylpyrroles by means of organocatalytic atroposelective desymmetrization and kinetic resolution. Depending on the remote control of chiral catalyst, the arylpyrroles were obtained in high yields and excellent enantioselectivities under mild reaction conditions. This strategy tolerates a wide range of functional groups, providing a facile avenue to approach axially chiral arylpyrroles from simple and readily available starting materials. Selected arylpyrrole products proved to be efficient chiral ligands in asymmetric catalysis and also important precursors for further synthetic transformations into highly functionalized pyrroles with potential bioactivity, especially the axially chiral fully substituted arylpyrroles.
Ocean colour signature of climate change
Authors: Dutkiewicz Stephanie , Hickman Anna E. , Jahn Oliver , Henson Stephanie , Beaulieu Claudie , Monier Erwan
Published: February 2019

Monitoring changes in marine phytoplankton is important as they form the foundation of the marine food web and are crucial in the carbon cycle. Often Chlorophyll-a (Chl-a) is used to track changes in phytoplankton, since there are global, regular satellite-derived estimates. However, satellite sensors do not measure Chl-a directly. Instead, Chl-a is estimated from remote sensing reflectance (RRS): the ratio of upwelling radiance to the downwelling irradiance at the ocean’s surface. Using a model, we show that RRS in the blue-green spectrum is likely to have a stronger and earlier climate-change-driven signal than Chl-a. This is because RRS has lower natural variability and integrates not only changes to in-water Chl-a, but also alterations in other optically important constituents. Phytoplankton community structure, which strongly affects ocean optics, is likely to show one of the clearest and most rapid signatures of changes to the base of the marine ecosystem.
Combining attentional bias modification with dorsolateral prefrontal rTMS does not attenuate maladaptive attentional processing
Authors: Bovy Leonore , Möbius Martin , Dresler Martin , Fernández Guillén , Sanfey Alan , Becker Eni , Tendolkar Indira
Published: February 2019

High frequency repetitive Transcranial Magnetic Stimulation (rTMS) over the left dorsolateral prefrontal cortex (DLPFC) has been shown to reduce depressive symptoms and improve cognitive biases such as attentional bias. One promising technique that may complement rTMS treatment is attentional bias modification (ABM) training, given the similarity in modulating attentional bias and affecting neuronal activity. We tested whether the combination of rTMS treatment and ABM training in a single session would attenuate maladaptive attentional processing and improve mood in participants with subclinical depressive symptoms. To this end, 122 healthy participants were randomly assigned to one of four groups, receiving either a single rTMS treatment, a single ABM treatment, a combination of rTMS and ABM or a sham treatment. Of these 122 participants, 72 showed a heightened BDI-II score (between 9 and 25) and were included in our main analyses. In our subclinical (≥9 and ≤25 BDI-II) sample, a single combination treatment of rTMS and ABM training induced no significant changes in attentional bias, attentional control or mood, nor did rTMS alone affect attentional bias systematically. We discuss these null findings in light of the task specifics and relate them to the ongoing discussion on ABM training in depression.
The effect of ILs as co-salts in electrolytes for high voltage supercapacitors
Authors: Kwon Ha-Na , Jang Su-Jin , Kang Yun Chan , Roh Kwang Chul
Published: February 2019

Ionic liquids (ILs) which have electrical stability are attractive materials to enhance the potential window of electrolyte. According to the potential window is extended, available voltage for supercapacitor is broaden. In this study, the addition of ILs which is 1-ethyl-3-methylimidazolium tetrafluoroborate (EMIBF4) and 1-ethyl-3-methylimidazolium bis(trifluoromethylesulfonyl) imide (EMITFSI) as co-salts, to a supercapacitor electrolyte increases the ionic conductivity and stability of it due to inhibition of electrolyte decomposition. As a result, the electrochemical stability potential windows (ESPWs) of supercapacitor is improved and the supercapacitor exhibited increased cycling stability. The loss of specific capacitance upon addition of 7 wt% EMIBF4 or EMITFSI to the electrolyte was 2.5% and 8.7%, respectively, after 10,000 cycles at 3.5 V, compared to the specific capacitance of the initial discharge.
Inferring Gene Regulatory Networks from a Population of Yeast Segregants
Authors: Chen Chen , Zhang Dabao , Hazbun Tony R. , Zhang Min
Published: February 2019

Constructing gene regulatory networks is crucial to unraveling the genetic architecture of complex traits and to understanding the mechanisms of diseases. On the basis of gene expression and single nucleotide polymorphism data in the yeast, Saccharomyces cerevisiae, we constructed gene regulatory networks using a two-stage penalized least squares method. A large system of structural equations via optimal prediction of a set of surrogate variables was established at the first stage, followed by consistent selection of regulatory effects at the second stage. Using this approach, we identified subnetworks that were enriched in gene ontology categories, revealing directional regulatory mechanisms controlling these biological pathways. Our mapping and analysis of expression-based quantitative trait loci uncovered a known alteration of gene expression within a biological pathway that results in regulatory effects on companion pathway genes in the phosphocholine network. In addition, we identify nodes in these gene ontology-enriched subnetworks that are coordinately controlled by transcription factors driven by trans-acting expression quantitative trait loci. Altogether, the integration of documented transcription factor regulatory associations with subnetworks defined by a system of structural equations using quantitative trait loci data is an effective means to delineate the transcriptional control of biological pathways.
Limiting the Spectral Diffusion of Nano-Scale Light Emitters using the Purcell effect in a Photonic-Confined Environment
Authors: Lyasota A. , Jarlov C. , Rudra A. , Dwir B. , Kapon E.
Published: February 2019

Partial suppression of the spectral diffusion of quantum dot (QD) excitons tuned to resonance of a nano-photonic cavity is reported. The suppression is caused by the Purcell enhancement of the QD-exciton recombination rate, which alters the rate of charging of the solid-state environment by the QD itself. The effect can be used to spectrally-stabilize solid-state emitters of single photons and other non-classical states of light.
Lignocellulose utilization and bacterial communities of millet straw based mushroom (Agaricus bisporus) production
Authors: Zhang Hao-Lin , Wei Jin-Kang , Wang Qing-Hui , Yang Rui , Gao Xiao-Jing , Sang Yu-Xi , Cai Pan-Pan , Zhang Guo-Qing , Chen Qing-Jun
Published: February 2019

Agaricus bisporus is in general cultivated on wheat and rice straw in China. However, millet straw is a potential alternative resource for Agaricus bisporus cultivation, but this has hardly been studied. In the present study, the feasibility of millet straw based mushroom production was analyzed by three successive trials. Mature compost demonstrated high quality with total nitrogen, pH, and C/N ratio of 2.0%, 7.5, and 18:1 respectively, which was suitable for mushroom mycelia growth. During composting, 47–50% of cellulose, 63–65% of hemicellulose, and 8–17% lignin were degraded, while 22–27% of cellulose, 14–16% of hemicellulose, and 15–21% of lignin were consumed by A. bisporus mycelia during cultivation. The highest FPUase and CMCase were observed during mushroom flushes. Endo-xylanase had the key role in hemicellulose degradation with high enzyme activity during cultivation stages. Laccase participated in lignin degradation with the highest enzyme activity in Pinning stage followed by a sharp decline at the first flush. Yield was up to 20 kg/m2, as this is similar to growth on wheat straw, this shows that millet straw is an effective resource for mushroom cultivation. Actinobacteria, Bacteroidetes, Chloroflexi, Deinococcus-Thermus, Firmicutes, and Proteobacteria were the dominant phyla, based on 16S rRNA gene sequencing during composting. The key environmental factors dominating bacterial communities of the samples were determined to be pH value, cellulose content, and hemicellulose content for prewetting and premixed phase of basic mixture (P0); moisture content for phase I (PI); and nitrogen content, lignin content, and ash content for phase II (PII), respectively.
Performance of Trichogramma pretiosum Riley (Hymenoptera: Trichogrammatidae) on eggs of Helicoverpa armigera (Hübner) (Lepidoptera: Noctuidae)
Authors: Laurentis Valéria Lucas , Ramalho Dagmara Gomes , Santos Nathália Alves , Carvalho Vanessa Fabíola Pereira , Vacari Alessandra Marieli , De Bortoli Sergio Antonio , Veneziani Rodrigo Cassio Sola , da Costa Inácio Gabriel , Dami Bruno Gomes
Published: February 2019

Helicoverpa armigera (Hübner) (Lepidoptera: Noctuidae) is a polyphagous pest with a wide geographic distribution. This pest first arrived in Brazil in 2013, and since then studies on possible control methods for it have been necessary. A possible method for the control of H. armigera is using the egg parasitoid Trichogramma pretiosum Riley (Hymenoptera: Trichogrammatidae). Therefore, the objective of this study was to evaluate the performance of T. pretiosum on H. armigera eggs, which are known to represent suitable hosts for the development of this parasitoid species in the laboratory. Parasitism and emergence rates and the duration of the egg-to-adult period of T. pretiosum were investigated following 24- and 48-h exposures of this parasitoid to H. armigera and Corcyra cephalonica (Stainton) (Lepidoptera: Pyralidae) eggs. The longevity of offspring after the 24-h exposure was studied, as well as the frequency of parasitism and emergence, host preference, and the emergence of offspring from eggs of different ages or oviposited by lepidopterans on different days. Parasitism was 14.4 and 34.9% more frequent on C. cephalonica than on H. armigera after 24 and 48 h of exposure, respectively. In C. cephalonica, parasitism was 27.2% higher after 48 h. Parasitism was more frequent on C. cephalonica eggs collected on the second day of oviposition (76.2%), and on H. armigera on the third day of oviposition (71.1%). Parasitism frequency was lower on 2-day-old C. cephalonica eggs (63.3%) and on 3-day-old H. armigera eggs (41.3%). When tested with a chance of choice between hosts, T. pretiosum preferred H. armigera, while in the test with no chance of choice there was no difference in preference. Thus, T. pretiosum may be considered a tool for the Integrated Pest Management (IPM) of H. armigera.
Visit-to-visit HbA1c and glucose variability and the risks of macrovascular and microvascular events in the general population
Authors: Jang Ji-Yong , Moon Shinje , Cho Sungsoo , Cho Kyoo Ho , Oh Chang-Myung
Published: February 2019

This study evaluate association between glycemic variability and adverse vascular events in nondiabetic middle-aged adults. From 10,020 Ansung-Ansan cohort, Korean Genome, and Epidemiology Study (KoGES) data. 6,462 nondiabetic adults aged <65 years was analyzed. The mean and coefficient of variation (CV) of all biannually recorded HbA1c, fasting blood glucose(FBG), and post 2 hr blood glucose (PBG) were calculated and divided into 3 groups based on tertile of CV at each measurement, respectively. Primary endpoint was composite of Macro (composite of Coronary artery disease, Myocardial infarction, Congestive heart failure or Stroke) and Microvascular event (Creatine Clearance <60 ml/min/1.73 m2). The participants (mean age: 50 years, 50% men) were followed for a median of 9.9 (9.1–10.0) years. The high HbA1c-CV tertile (odds ratio 1.30; 1.01–1.66) was independent risk factor for microvascular events. In contrast, high FBG-CV tertile (2.32; 1.30–4.12) and PBG-CV (1.85; 1.05–3.26) was for macrovascular events. In this 10-year prespective cohort study, higher HbA1c-CV tertile was associated with higher composite of macro- and microvascular events and independent risk factor in non-DM middle-aged participants. In addition, higher tertile of FBG-CV and PBG-CV were risk factors for macrovascular events.
Millennial and orbital scale variability of the South American Monsoon during the penultimate glacial period
Authors: Burns Stephen J. , Welsh Lisa Kanner , Scroxton Nick , Cheng Hai , Edwards R. Lawrence
Published: February 2019

The presence of large, rapid climate oscillations is the most prominent feature of the Earth’s last glacial period. These oscillations are observed throughout the Northern Hemisphere and into the Southern Hemisphere tropics. Whether similar oscillations are typical of prior glacial periods, however, has not been well established. Here, we present results of a study of the South American Summer Monsoon system that covers nearly the entire penultimate glacial period, from 195 to 135 ky BP. We use a well-dated, high-resolution (~50 y) time series of oxygen isotopes to show that the precession of the earth’s orbit is the primary control on monsoon intensity. After removing the precession signal we observe millennial oscillations that are very similar in amplitude and structure to the Dansgaard/Oeschger cycles of the last interglacial and that match well a synthetic reconstruction of millennial variability. Time series analyses shows that the most prominent of the observed cycles occur at considerably longer frequency (~3500 y) that the Dansgaard/Oeschger cycles from Marine Isotope Stages 2–4.
Critical synchronization and 1/f noise in inhibitory/excitatory rich-club neural networks
Authors: Aguilar-Velázquez Daniel , Guzmán-Vargas Lev
Published: February 2019

In recent years, diverse studies have reported that different brain regions, which are internally densely connected, are also highly connected to each other. This configuration seems to play a key role in integrating and interchanging information between brain areas. Also, changes in the rich-club connectivity and the shift from inhibitory to excitatory behavior of hub neurons have been associated with several diseases. However, there is not a clear understanding about the role of the proportion of inhibitory/excitatory hub neurons, the dynamic consequences of rich-club disconnection, and hub inhibitory/excitatory shifts. Here, we study the synchronization and temporal correlations in the neural Izhikevich model, which comprises excitatory and inhibitory neurons located in a scale-free hierarchical network with rich-club connectivity. We evaluated the temporal autocorrelations and global synchronization dynamics displayed by the system in terms of rich-club connectivity and hub inhibitory/excitatory population. We evaluated the synchrony between pairs of sets of neurons by means of the global lability synchronization, based on the rate of change in the total number of synchronized signals. The results show that for a wide range of excitatory/inhibitory hub ratios the network displays 1/f dynamics with critical synchronization that is concordant with numerous health brain registers, while a network configuration with a vast majority of excitatory hubs mostly exhibits short-term autocorrelations with numerous large avalanches. Furthermore, rich-club connectivity promotes the increase of the global lability of synchrony and the temporal persistence of the system.
Methylglyoxal down-regulates the expression of cell cycle associated genes and activates the p53 pathway in human umbilical vein endothelial cells
Authors: Braun Jana D. , Pastene Diego O. , Breedijk Annette , Rodriguez Angelica , Hofmann Björn B. , Sticht Carsten , von Ochsenstein Elke , Allgayer Heike , van den Born Jacob , Bakker Stephan , Hauske Sibylle J. , Krämer Bernhard K. , Yard Benito A. , Albrecht Thomas
Published: February 2019

Although methylglyoxal (MGO) has emerged as key mediator of diabetic microvascular complications, the influence of MGO on the vascular transcriptome has not thoroughly been assessed. Since diabetes is associated with low grade inflammation causing sustained nuclear factor-kappa B (NF-κB) activation, the current study addressed 1) to what extent MGO changes the transcriptome of human umbilical vein endothelial cells (HUVECs) exposed to an inflammatory milieu, 2) what are the dominant pathways by which these changes occur and 3) to what extent is this affected by carnosine, a putative scavenger of MGO. Microarray analysis revealed that exposure of HUVECs to high MGO concentrations significantly changes gene expression, characterized by prominent down-regulation of cell cycle associated genes and up-regulation of heme oxygenase-1 (HO-1). KEGG-based pathway analysis identified six significantly enriched pathways of which the p53 pathway was the most affected. No significant enrichment of inflammatory pathways was found, yet, MGO did inhibit VCAM-1 expression in Western blot analysis. Carnosine significantly counteracted MGO-mediated changes in a subset of differentially expressed genes. Collectively, our results suggest that MGO initiates distinct transcriptional changes in cell cycle/apoptosis genes, which may explain MGO toxicity at high concentrations. MGO did not augment TNF-α induced inflammation.
High doses of synthetic antioxidants induce premature senescence in cultivated mesenchymal stem cells
Authors: Kornienko Ju. S. , Smirnova I. S. , Pugovkina N. A. , Ivanova Ju. S. , Shilina M. A. , Grinchuk T. M. , Shatrova A. N. , Aksenov N. D. , Zenin V. V. , Nikolsky N. N. , Lyublinskaya O. G.
Published: February 2019

Stress-induced premature senescence program is known to be activated in cells by various genotoxic stressors, and oxidative stress is considered to be the main of those. To this end, many studies discover antioxidants as protective anti-aging agents. In the current study, we examined the effects of different antioxidants (Tempol, resveratrol, NAC, DPI) on the mesenchymal stem cells maintained in normal physiological conditions. We used high, but non-cytotoxic antioxidant doses which are widely used in laboratory practice to protect cells from oxidative damage. We show that these substances induce reversible block of cell proliferation and do not cause any genotoxic effects when applied to the quiescent cells. However, the same doses of the same substances, when applied to the proliferating cells, can induce irreversible cell cycle arrest, DNA strand breaks accumulation and DNA damage response activation. As a consequence, antioxidant-induced DNA damage results in the stress-induced premature senescence program activation. We conclude that high doses of antioxidants, when applied to the proliferating cells that maintain physiological levels of reactive oxygen species, can cause DNA damage and induce premature senescence which suggests to re-estimate believed unconditional anti-aging antioxidant properties.
Apolipoprotein A-I enhances insulin-dependent and insulin-independent glucose uptake by skeletal muscle
Authors: Tang Shudi , Tabet Fatiha , Cochran Blake J. , Cuesta Torres Luisa F. , Wu Ben J. , Barter Philip J. , Rye Kerry-Anne
Published: February 2019

Therapeutic interventions that increase plasma high density lipoprotein (HDL) and apolipoprotein (apo) A-I levels have been reported to reduce plasma glucose levels and attenuate insulin resistance. The present study asks if this is a direct effect of increased glucose uptake by skeletal muscle. Incubation of primary human skeletal muscle cells (HSKMCs) with apoA-I increased insulin-dependent and insulin–independent glucose uptake in a time- and concentration-dependent manner. The increased glucose uptake was accompanied by enhanced phosphorylation of the insulin receptor (IR), insulin receptor substrate-1 (IRS-1), the serine/threonine kinase Akt and Akt substrate of 160 kDa (AS160). Cell surface levels of the glucose transporter type 4, GLUT4, were also increased. The apoA-I-mediated increase in glucose uptake by HSKMCs was dependent on phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/Akt, the ATP binding cassette transporter A1 (ABCA1) and scavenger receptor class B type I (SR-B1). Taken together, these results establish that apoA-I increases glucose disposal in skeletal muscle by activating the IR/IRS-1/PI3K/Akt/AS160 signal transduction pathway. The findings suggest that therapeutic agents that increase apoA-I levels may improve glycemic control in people with type 2 diabetes.
Genetic polymorphisms associated with treatment failure and mortality in pediatric Pneumocystosis
Authors: Singh Yogita , Mirdha Bijay Ranjan , Guleria Randeep , Kabra Sushil K. , Mohan Anant , Chaudhry Rama , Kumar Lalit , Dwivedi Sada Nand , Agarwal Sanjay K.
Published: February 2019

Data on the genetic diversity of Pneumocystis jirovecii causing Pneumocystis pneumonia (PCP) among children are still limited, and there are no available data from the Indian subcontinent, particularly associations between genotypes and clinical characteristics. A total of 37 children (62 days-12 years [median 5.5 years]) were included in this study. Pneumocystis was diagnosed by microscopy using Grocott-Gomori methenamine silver stain in 12 cases and by nested PCR using mtLSUrRNA in 25 cases. Genotyping was performed using three different genes, mitochondrial large subunit ribosomal RNA (mtLSUrRNA), dihydropteroate synthase (DHPS) and dihydrofolate reductase (DHFR). mtLSUrRNA genotype 3 and novel mutations at the gene target DHFR (401 T > C) and DHPS 96/98 were frequently observed and clinically associated with severe PCP and treatment failure. Phylogenetic analyses revealed 13 unique sequence types (STs). Two STs (i) 3-DHFR 401 T > C-DHPS 96/98 – PJ1 and (ii) 3-DHFR 401 T > C-DHPS 96- PJ3 were significantly associated with treatment failure and high mortality among PCP-positive patients. In conclusion, the present study strongly suggests the emergence of virulent P. jirovecii strains or genetic polymorphisms, leading to treatment failure and high mortality. Our study is the first of its kind from the Indian subcontinent and has highlighted the genetic diversity of Pneumocystis jirovecii among children and their clinical outcomes. These findings emphasize the need to focus more on genotypes to better understand the epidemiology of Pneumocystis pneumonia.
Diverse hydrocarbon biosynthetic enzymes can substitute for olefin synthase in the cyanobacterium Synechococcus sp. PCC 7002
Authors: Knoot Cory J. , Pakrasi Himadri B.
Published: February 2019

Cyanobacteria are among only a few organisms that naturally synthesize long-chain alkane and alkene hydrocarbons. Cyanobacteria use one of two pathways to synthesize alka/enes, either acyl-ACP reductase (Aar) and aldehyde deformylating oxygenase (Ado) or olefin synthase (Ols). The genomes of cyanobacteria encode one of these pathways but never both, suggesting a mutual exclusivity. We studied hydrocarbon pathway compatibility using the model cyanobacterium Synechococcus sp. PCC 7002 (S7002) by co-expressing Ado/Aar and Ols and by entirely replacing Ols with three other types of hydrocarbon biosynthetic pathways. We find that Ado/Aar and Ols can co-exist and that slower growth occurs only when Ado/Aar are overexpressed at 38 °C. Furthermore, Ado/Aar and the non-cyanobacterial enzymes UndA and fatty acid photodecarboxylase are able to substitute for Ols in a knockout strain and conditionally rescue slow growth. Production of hydrocarbons by UndA in S7002 required a rational mutation to increase substrate range. Expression of the non-native enzymes in S7002 afforded unique hydrocarbon profiles and alka/enes not naturally produced by cyanobacteria. This suggests that the biosynthetic enzyme and the resulting types of hydrocarbons are not critical to supporting growth. Exchanging or mixing hydrocarbon pathways could enable production of novel types of CO2-derived hydrocarbons in cyanobacteria.
Telmisartan induces browning of fully differentiated white adipocytes via M2 macrophage polarization
Authors: Jeon Eun Jeong , Kim Dong Young , Lee Na Hyun , Choi Hye-Eun , Cheon Hyae Gyeong
Published: February 2019

Telmisartan is a well-known anti-hypertensive drug acting as an angiotensin 2 receptor blocker (ARB), but it also possesses partial PPARγ agonistic activity and induces insulin sensitivity. In the present study, we investigated the effects of telmisartan on macrophage polarization in association with its browning capacity, because PPARγ plays a key role in M2 polarization and in the browning of white adipocytes. Telmisartan induced M2 marker expression in murine macrophages concentration dependently, which was confirmed by flow cytometry. Both PPARγ and PPARδ activations appear to be responsible for telmisartan-induced M2 polarization. Telmisartan-treated conditioned medium (Tel-CM) of RAW264.7 cells and of bone marrow derived macrophages (BMDM) induced the expressions of browning markers in fully differentiated white adipocytes with reduced lipid droplets, and increased oxygen consumption rate and mitochondrial biogenesis. Levels of catecholamines (CA) released into the conditioned medium as well as intracellular tyrosine hydroxylase (TH) mRNAs were found to be increased by telmisartan, and browning effects of Tel-CM were lessened by β3 receptor antagonist (L-748,337), suggesting CA secreted into CM play a role in Tel-CM-induced adipocyte browning. Acute administration of telmisartan (2 weeks, p.o.) to C57BL/6J mice increased the expressions of browning markers and M2 markers in white adipose tissues, whereas macrophage depletion by clodronate liposome pretreatment attenuated the telmisartan-induced expressions of browning markers. Together, telmisartan was observed to induce the browning of fully differentiated white adipocytes, at least in part, via PPAR activation-mediated M2 polarization.
The reliability of estimating visual working memory capacity
Authors: Dai Mengnuo , Li Yanju , Gan Shuoqiu , Du Feng
Published: February 2019

The reliability of estimations of working memory capacity has not been thoroughly examined. The present study examined the test-retest reliability for working memory capacity as estimated in a lateralized change detection task, which is frequently used in studies involving electroencephalography. The test-retest correlations between K values for each set size in the two tests varied from 0.502 to 0.757, with test-retest correlations rising as set size increased. The results indicate that individual visual working memory capacity can be reliably estimated in a change detection task. Furthermore, test-retest reliability was higher when the two tests occurred at the same time of day than at different times of day.
Satisfaction with a digitally-enabled telephone health coaching intervention for people with non-diabetic hyperglycaemia
Authors: Coventry Peter , Bower Peter , Blakemore Amy , Baker Elizabeth , Hann Mark , Li Jinshuo , Paisley Angela , Gibson Martin
Published: February 2019

International evidence shows that lifestyle interventions can effectively reduce the risk of developing diabetes in people with non-diabetic hyperglycaemia (NDH). A candidate intervention that has potential to be rolled out at population level is health coaching. Digital interventions offer the means to potentially enhance user satisfaction with health coaching and improve efficiencies. We used a randomised controlled trial to test whether a digitally-enabled health coaching intervention that included an online dashboard and telephone health coaching improved user satisfaction and cost-efficiencies compared with a telephone only health coaching intervention. The primary outcome was satisfaction measured by Client Satisfaction Questionnaire (CSQ-8). 103 participants with NDH were allocated to the telephone coaching only intervention and 106 participants with NDH were allocated to the digital and telephone coaching intervention. In an intention-to-treat analysis satisfaction was higher in participants allocated to the digital and telephone coaching intervention than those allocated to the telephone only intervention, but the difference was not significant. There were no significant differences between the groups on secondary outcomes (HbA1c, BMI, activation, depression, self-management, health status). From a service commissioning perspective the mean incremental cost of the digitally-enabled intervention was £236 ($332; €270). Call times, including administration, were longer for participants allocated to the digitally-enabled intervention. The results show that user satisfaction with digitally-enabled intervention is broadly equivalent with that of telephone delivered interventions in the context of routinely delivered diabetes prevention programmes. There is scope for future work that assesses how economies of scale can be achieved at larger user bases.
Precision medicine and the cursed dimensions
Authors: Barbour Dennis L.
Published: February 2019

Our intuition regarding “average” is rooted in one-dimensional thinking, such as the distribution of height across a population. This intuition breaks down in higher dimensions when multiple measurements are combined: fewer individuals are close to average for many measurements simultaneously than for any single measurement alone. This phenomenon is known as the curse of dimensionality. In medicine, diagnostic sophistication generally increases through the addition of more predictive factors. Disease classes themselves become more dissimilar as a result, increasing the difficulty of incorporating (i.e., averaging) multiple patients into a single class for guiding treatment of new patients. Failure to consider the curse of dimensionality will ultimately lead to inherent limits on the degree to which precision medicine can extend the advances of evidence-based medicine for selecting suitable treatments. One strategy to compensate for the curse of dimensionality involves incorporating predictive observation models into the patient workup.
Regional protein expression in human Alzheimer’s brain correlates with disease severity
Authors: Xu Jingshu , Patassini Stefano , Rustogi Nitin , Riba-Garcia Isabel , Hale Benjamin D. , Phillips Alexander M , Waldvogel Henry , Haines Robert , Bradbury Phil , Stevens Adam , Faull Richard L. M. , Dowsey Andrew W. , Cooper Garth J. S. , Unwin Richard D.
Published: February 2019

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that currently affects 36 million people worldwide with no effective treatment available. Development of AD follows a distinctive pattern in the brain and is poorly modelled in animals. Therefore, it is vital to widen the spatial scope of the study of AD and prioritise the study of human brains. Here we show that functionally distinct human brain regions display varying and region-specific changes in protein expression. These changes provide insights into the progression of disease, novel AD-related pathways, the presence of a gradient of protein expression change from less to more affected regions and a possibly protective protein expression profile in the cerebellum. This spatial proteomics analysis provides a framework which can underpin current research and open new avenues to enhance molecular understanding of AD pathophysiology, provide new targets for intervention and broaden the conceptual frameworks for future AD research.
Frustrated spin order and stripe fluctuations in FeSe
Authors: Baum A. , Ruiz H. N. , Lazarević N. , Wang Yao , Böhm T. , Hosseinian Ahangharnejhad R. , Adelmann P. , Wolf T. , Popović Z. V. , Moritz B. , Devereaux T. P. , Hackl R.
Published: February 2019

The charge and spin dynamics of the structurally simplest iron-based superconductor, FeSe, may hold the key to understanding the physics of high temperature superconductors in general. Unlike the iron pnictides, FeSe lacks long range magnetic order in spite of a similar structural transition around 90 K. Here, we report results of Raman scattering experiments as a function of temperature and polarization and simulations based on exact diagonalization of a frustrated spin model. Both experiment and theory find a persistent low energy peak close to 500 cm−1 in B1g symmetry, which softens slightly around 100 K, that we assign to spin excitations. By comparing with results from neutron scattering, this study provides evidence for nearly frustrated stripe order in FeSe.
Organocatalyzed carboxylative cyclization of propargylic amides with atmospheric CO2 towards oxazolidine-2,4-diones
Authors: Zhou Hui , Mu Sen , Ren Bai-Hao , Zhang Rui , Lu Xiao-Bing
Published: February 2019

A facile and practical TBD-catalyzed carboxylative cyclization of propargylic amides with atmospheric CO2 has been developed for the formation of (Z) 5-alkylidene 1,3-oxazolidine-2,4-diones.
One-step fabrication of size-controllable nicotine containing core–shell structures
Authors: Hong Jeongmin , Guduru Rakesh , Khizroev Sakhrat , You Long
Published: February 2019

We report a one-step synthesis of a size-controllable nicotine-containing nanoparticles.
A Robust strategy enabling addressable porous 3D carbon-based functional nanomaterials in miniaturized systems
Authors: Wongkaew Nongnoot , Simsek Marcel , Arumugam Palaniappan , Behrent Arne , Berchmans Sheela , Baeumner Antje J.
Published: February 2019

Facile construction of high performance carbon nanofiber electrodes via electrospinning and one-step laser-induced carbonization for electrochemical sensors in miniaturized systems.
Penetration of nanoparticles across a lipid bilayer: effects of particle stiffness and surface hydrophobicity
Authors: Wang Shuo , Guo Hui , Li Yinfeng , Li Xuejin
Published: February 2019

Evolution of orientation angles during the penetration processes of nanoparticles with different surface hydrophobicities.
Creating a synthetic platform for the encapsulation of nanocrystals with covalently bound polymer shells
Authors: Koll Rieke , Fruhner Lisa Sarah , Heller Hauke , Allgaier Jürgen , Pyckhout-Hintzen Wim , Kruteva Margarita , Feoktystov Artem , Biehl Ralf , Förster Stephan , Weller Horst
Published: February 2019

Nanocrystal encapsulation with highly stable polymer shell for nanocomposite synthesis and detailed characterization with small angle scattering and electron microscopy.