bluuebunny/crossref_metadata_2025 huggingface dataset:
The Effect of Solar Wind Mach Numbers on the Occurrence Rate of Flux Transfer Events at the Dayside Magnetopause
Authors: Chen C. , Sun T. R. , Wang C. , Huang Z. H. , Tang B. B. , Guo X. C.
Published: April 2019

Although many works have investigated the occurrence rate of flux transfer events (FTEs) under different upstream conditions, the relation between the upstream Mach number and the occurrence rate of FTEs remains unclear. By using global magnetohydrodynamics simulations, we study the occurrence rate of FTEs under different upstream Alvénic Mach numbers (MA). A recently developed method is used to identify the FTEs throughout the dayside magnetopause. It shows that the occurrence rate of FTEs decreases with increasing value of MA. We suggest that the magnetosheath β, which increases with increasing MA, plays an important role in the process of reconnection and thus affects the occurrence rate of FTEs. As the solar wind MA increases with increasing distance from the Sun, we speculate that the planet with a larger heliocentric distance may have less FTEs because of the increasing value of upstream MA.
Crustal Extension and Graben Formation by Fault Slip‐Associated Pore Opening, Kyushu, Japan
Authors: Wang Zhi , Fukao Yoshio , Miyakawa Ayumu , Hasegawa Akira , Takei Yasuko
Published: April 2019

Crustal extension in graben takes place by normal (+strike‐slip) faulting, yet the physical processes involved are poorly understood. A series of shallow large earthquakes struck the Kumamoto area of Kyushu, Japan, in 2016. The Mw7.0 main shock was a slip along the southern boundary of the Beppu‐Shimabara Graben, where NS‐extensional crustal deformation is now taking place. We conducted a tomographic inversion for crustal P and S velocities and Poisson's ratio (Vp, Vs, and σ) in Kyushu. The most outstanding feature in this region is a Beppu‐Shimabara Graben‐parallel belt of low Vp and Vs anomalies at depths of the upper crust. We find that within the belt dVs/Vs ≈ dVp/Vp (<0) in marked contrast to relations in other low‐velocity regions where |dVs/Vs| > |dVp/Vp|. This observation can be interpreted as due to water‐saturated, oblate‐spheroid pores with either of two very different geometries: one almost round pore and the other very flat pore. We calculate 3‐D density anomaly distributions and 2‐D gravity anomaly profiles for these two pore models. The gravity anomaly map calculated for spherical pores shows a significant negative anomaly belt that spatially agrees with observed Bouguer anomaly map. The spatial agreement is very poor if pores are modeled as flat. This and extensive seismicity within Beppu‐Shimabara Graben imply significance of fault‐associated round pore formation in the process of graben opening. Seismic tomography combined with gravity and poroeasticty analyses can constrain the crack/pore state of extensionally deforming crust.
Global Distribution of the Solar Wind Flux and Velocity From SOHO/SWAN During SC‐23 and SC‐24
Authors: Koutroumpa D. , Quémerais E. , Ferron S. , Schmidt W.
Published: April 2019

We analyze SOHO (SOlar Heliospheric Observatory)/SWAN (Solar Wind ANisotropy) hydrogen Lyman‐α data collected between 1996 and 2018 to derive the solar wind latitudinal distribution over time. Full‐sky interplanetary Lyman‐α maps are inverted to derive the total hydrogen ionization rate latitude profiles, normalized to proton charge‐exchange and photoionization. Using Interplanetary Scintillation velocities to calculate the velocity‐dependent charge‐exchange cross‐sections, we produce the solar wind flux latitudinal profiles. Finally, we compute solar wind velocity latitude profiles, based on the dynamic pressure and energy flux conservation (calculated from OMNI data) over latitude. SWAN reproduces the Interplanetary Scintillation velocity profiles up to at least ±60°, and also agrees with Ulysses in situ measurements for solar minimum periods in 1996–1997 and 2007. During solar maximum, discrepancies are more frequent because in situ data reflect local solar wind conditions, while SWAN data reflect global conditions in the heliosphere.
The mevalonate coordinates energy input and cell proliferation
Authors: Gong Li , Xiao Yi , Xia Fan , Wu Pei , Zhao Tingting , Xie Shulin , Wang Ran , Wen Qiaocheng , Zhou Wensu , Xu Huilan , Zhu Lingyan , Zheng Zeqi , Yang Tianlun , Chen Zihua , Duan Qiong
Published: April 2019

The mevalonate pathway is known for the synthesis of cholesterol, but recent studies have reported that it also controls Hippo signaling, which is critical for the regulation of organ size and tumorigenesis. Here, we discover that the suppression of the mevalonate pathway inhibits the growth and proliferation of colon cancer cell lines. The results of transcriptomic and proteomic assays suggested that the mevalonate pathway controls multiple signaling pathways relevant to cell proliferation, and the results were further confirmed using western blot, PCR, and immunofluorescence assays. As cell proliferation is an energy-consuming process, we postulate that the mevalonate pathway may also control nutrient uptake to coordinate the processes of energy supply and cell proliferation. Here, we found that lovastatin, a mevalonate pathway inhibitor, suppresses glucose and amino acid uptake and lactate acid production. More importantly, mevalonic acid itself is sufficient to promote glucose uptake by colon cancer cells. In addition, we found that colon cancer tissues displayed a higher expression of mevalonate pathway enzymes, which may promote cell growth and stimulate energy uptake. Together, our findings establish the mevalonate pathway as a critical regulator in coordinating energy input and cell proliferation.
Minocycline mitigates the effect of neonatal hypoxic insult on human brain organoids
Authors: Boisvert Erin M. , Means Robert E. , Michaud Michael , Madri Joseph A. , Katz Samuel G.
Published: April 2019

Neonatal hypoxic injury (NHI) is a devastating cause of disease that affects >60% of babies born with a very low birth weight, resulting in significant morbidity and mortality, including life-long neurological consequences such as seizures, cerebral palsy, and intellectual disability. Hypoxic injury results in increased neuronal death, which disrupts normal brain development. Although animal model systems have been useful to study the effects of NHI, they do not fully represent the uniqueness and complexities of the human brain. To better understand the effects of hypoxia on human brain development, we have generated a brain organoid protocol and evaluated these cells over the course of 6 months. As anticipated, the expression of a forebrain marker, FOXG1, increased and then remained expressed over time, while there was a transition in the expression of the deep-layer (TBR1) and upper-layer (SATB2) cortical markers. In addition, ventral genes (Eng1 and Nkx2.1) as well as markers of specialized nonneuronal cells (Olig2 and GFAP) also increased at later time points. We next tested the development of our in vitro cerebral organoid model at different oxygen concentrations and found that hypoxia repressed gene markers for forebrain, oligodendrocytes, glial cells, and cortical layers, as well as genes important for the migration of cortical neurons. In contrast, ventral markers were either unaffected or even increased in expression with hypoxic insult. Interestingly, the negative effect of hypoxia on the dorsal brain genes as well as oligodendrocytes, and neuronal progenitors could be mitigated by the use of minocycline, an FDA-approved small molecule. Taken together, we have generated a unique and relevant in vitro human brain model system to study diseases such as NHI as well as their potential treatments. Using this system, we have shown the efficacy of minocycline for human NHI.
Akt inhibitor SC66 promotes cell sensitivity to cisplatin in chemoresistant ovarian cancer cells through inhibition of COL11A1 expression
Authors: Wu Yi-Hui , Huang Yu-Fang , Chen Chien-Chin , Chou Cheng-Yang
Published: April 2019

We studied Akt inhibition using SC66 in a NOD-SCID xenograft mouse model and a panel of eight ovarian cancer cell lines. Elevated phospho-Akt levels in cancerous tissue were associated with short progression-free survival and overall survival. Cell sensitivity to SC66 was inversely correlated with phospho-Akt and COL11A1 expression levels, as well as resistance to cisplatin or paclitaxel. SC66 inhibited phosphorylation of Akt and its downstream effectors 4EBP1 and p70S6 kinase. SC66 also attenuated expression of TWIST1 and Mcl-1, factors important in cell invasiveness and anti-apoptosis, respectively. SC66-sensitized chemoresistant cells to cisplatin and paclitaxel treatment, and promoted apoptosis. In addition, SC66 inhibited COL11A1 expression via decreased binding of CCAAT/enhancer-binding protein beta (c/EBPβ), reducing chemoresistance and decreasing binding of nuclear transcription factor Y (NF-YA) to COL11A1. A mouse xenograft experiment demonstrated that SC66 treatment caused a reduction in tumor formation and enhanced the therapeutic efficacy of cisplatin. This study demonstrates the role of Akt in ovarian tumor progression and chemoresistance, and supports the application of SC66 as a therapy for ovarian cancer.
IBTK contributes to B-cell lymphomagenesis in Eμ-myc transgenic mice conferring resistance to apoptosis
Authors: Vecchio Eleonora , Golino Gaetanina , Pisano Antonio , Albano Francesco , Falcone Cristina , Ceglia Simona , Iaccino Enrico , Mimmi Selena , Fiume Giuseppe , Giurato Giorgio , Britti Domenico , Scala Giuseppe , Quinto Ileana
Published: April 2019

Increasing evidence supports the involvement of IBTK in cell survival and tumor growth. Previously, we have shown that IBTK RNA interference affects the wide genome expression and RNA splicing in cell-type specific manner. Further, the expression of IBTK gene progressively increases from indolent to aggressive stage of chronic lymphocytic leukemia and decreases in disease remission after therapy. However, the role of IBTK in tumorigenesis has not been elucidated. Here, we report that loss of the murine Ibtk gene raises survival and delays tumor onset in Eμ-myc transgenic mice, a preclinical model of Myc-driven lymphoma. In particular, we found that the number of pre-cancerous B cells of bone marrow and spleen is reduced in Ibtk−/−Eμ-myc mice owing to impaired viability and increased apoptosis, as measured by Annexin V binding, Caspase 3/7 cleavage assays and cell cycle profile analysis. Instead, the proliferation rate of pre-cancerous B cells is unaffected by the loss of Ibtk. We observed a direct correlation between Ibtk and myc expression and demonstrated a Myc-dependent regulation of Ibtk expression in murine B cells, human hematopoietic and nonhematopoietic cell lines by analysis of ChIP-seq data. By tet-repressible Myc system, we confirmed a Myc-dependent expression of IBTK in human B cells. Further, we showed that Ibtk loss affected the main apoptotic pathways dependent on Myc overexpression in pre-cancerous Eμ-myc mice, in particular, MCL-1 and p53. Of note, we found that loss of IBTK impaired cell cycle and increased apoptosis also in a human epithelial cell line, HeLa cells, in Myc-independent manner. Taken together, these results suggest that Ibtk sustains the oncogenic activity of Myc by inhibiting apoptosis of murine pre-cancerous B cells, as a cell-specific mechanism. Our findings could be relevant for the development of IBTK inhibitors sensitizing tumor cells to apoptosis.
CXCR7 signaling promotes breast cancer survival in response to mesenchymal stromal stem cell-derived factors
Authors: Al-toub Mashael , Almohawes Mohammad , Vishnubalaji Radhakrishnan , Alfayez Musaad , Aldahmash Abdullah , Kassem Moustapha , Alajez Nehad M.
Published: April 2019

The interaction between cancer cells and molecular cues provided by tumor stromal cells plays a crucial role in cancer growth and progression. We have recently reported that the outcome of interaction between tumor cells and stromal cells is dependent on the gene expression signature of tumor cells. In the current study, we observed that several cancer cell lines, e.g., MCF7 breast cancer line, exhibited growth advantage when cultured in the presence of conditioned media (CM) derived from human bone marrow stromal stem cells (hBMSCs). Regarding the underlying molecular mechanism, we have identified CXCR7 as highly expressed by MCF7 cells and that it mediated the enhanced growth in response to hBMSC CM. Regarding the clinical relevance, we found an inverse correlation between the level of tumor gene expression of CXCR7 in bladder, breast, cervical, kidney, liver, lung, pancreatic, stomach, and uterine cancers, and patients’ overall survival. Interestingly, significant positive correlation between CXCR7 and CXCL12 gene expression (Pearson = 0.3, p = 2.0 × 10–16) was observed in breast cancer patients, suggesting a biological role for the CXCR7/CXCL12 genetic circuit in breast cancer biology. Our data provide insight into the molecular mechanisms by which stromal-derived microenvironmental cues mediate CXCR7 signaling and growth enhancement of breast cancer cells. Therapeutic targeting of this circuit might provide novel therapeutic opportunity for breast cancer.
Anomalous Nernst effect beyond the magnetization scaling relation in the ferromagnetic Heusler compound Co2MnGa
Authors: Guin Satya N. , Manna Kaustuv , Noky Jonathan , Watzman Sarah J. , Fu Chenguang , Kumar Nitesh , Schnelle Walter , Shekhar Chandra , Sun Yan , Gooth Johannes , Felser Claudia
Published: April 2019

Applying a temperature gradient in a magnetic material generates a voltage that is perpendicular to both the heat flow and the magnetization. This phenomenon is the anomalous Nernst effect (ANE), which was long thought to be proportional to the value of the magnetization. However, more generally, the ANE has been predicted to originate from a net Berry curvature of all bands near the Fermi level (EF). Subsequently, a large anomalous Nernst thermopower ($${\boldsymbol{S}}_{{\boldsymbol{yx}}}^{\boldsymbol{A}}$$

S

yx

A

) has recently been observed in topological materials with no net magnetization but a large net Berry curvature [Ωn(k)] around EF. These experiments clearly fall outside the scope of the conventional magnetization model of the ANE, but a significant question remains. Can the value of the ANE in topological ferromagnets exceed the highest values observed in conventional ferromagnets? Here, we report a remarkably high $${\boldsymbol{S}}_{{\boldsymbol{yx}}}^{\boldsymbol{A}}$$

S

yx

A

-value of ~6.0 µV K−1 in the ferromagnetic topological Heusler compound Co2MnGa at room temperature, which is approximately seven times larger than any anomalous Nernst thermopower value ever reported for a conventional ferromagnet. Combined electrical, thermoelectric, and first-principles calculations reveal that this high-value of the ANE arises from a large net Berry curvature near the Fermi level associated with nodal lines and Weyl points.
Analysis of oral microbiota in patients with obstructive sleep apnea-associated hypertension
Authors: Ko Chih-Yuan , Hu An-Ke , Chou Dylan , Huang Li-Mei , Su Huan-Zhang , Yan Fu-Rong , Zhang Xiao-Bin , Zhang Hua-Ping , Zeng Yi-Ming
Published: April 2019

Obstructive sleep apnea–hypopnea syndrome (OSAHS) is an independent risk factor for hypertension (HTN). The oral microbiota plays a pathophysiological role in cardiovascular diseases; however, there are few reports directly investigating and identifying the organisms involved in OSAHS-related HTN. Therefore, this study aimed to identify those organisms. We obtained 139 oral samples and determined the microbiome composition using pyrosequencing and bioinformatic analyses of the 16S rRNA. We examined the fasting levels of cytokines and homocysteine in all participants and analyzed the correlations between the oral microbiota and homocysteine levels. We determined the molecular mechanism underlying HTN by investigating the genetic composition of the strains in the blood. We detected higher relative abundances of Porphyromonas and Aggregatibacter and elevated proinflammatory cytokines in patients with OSAHS of varying severity compared with individuals without OSAHS; however, the two organisms were not measured in the blood samples from all participants. High levels of specific Porphyromonas bacteria were detected in patients with OSAHS with and without HTN, whereas the relative abundance of Aggregatibacter was negatively correlated with the homocysteine level. The receiver operating characteristic curve analysis of controls and patients with OSAHS resulted in area under the curve values of 0.759 and 0.641 for patients with OSAHS with or without HTN, respectively. We found that the predictive function of oral microbiota was different in patients with OSAHS with and without HTN. However, there was no direct invasion by the two organisms causing endothelial cell injury, leading to speculation regarding the other mechanisms that may lead to HTN. Elucidating the differences in the oral microbiome will help us understand the pathogenesis of OSAHS-related HTN.
Microtubule end conversion mediated by motors and diffusing proteins with no intrinsic microtubule end-binding activity
Authors: Chakraborty Manas , Tarasovetc Ekaterina V. , Zaytsev Anatoly V. , Godzi Maxim , Figueiredo Ana C. , Ataullakhanov Fazly I. , Grishchuk Ekaterina L.
Published: April 2019

Accurate chromosome segregation relies on microtubule end conversion, the ill-understood ability of kinetochores to transit from lateral microtubule attachment to durable association with dynamic microtubule plus-ends. The molecular requirements for this conversion and the underlying biophysical mechanisms are elusive. We reconstituted end conversion in vitro using two kinetochore components: the plus end–directed kinesin CENP-E and microtubule-binding Ndc80 complex, combined on the surface of a microbead. The primary role of CENP-E is to ensure close proximity between Ndc80 complexes and the microtubule plus-end, whereas Ndc80 complexes provide lasting microtubule association by diffusing on the microtubule wall near its tip. Together, these proteins mediate robust plus-end coupling during several rounds of microtubule dynamics, in the absence of any specialized tip-binding or regulatory proteins. Using a Brownian dynamics model, we show that end conversion is an emergent property of multimolecular ensembles of microtubule wall-binding proteins with finely tuned force-dependent motility characteristics.
Hybrid longitudinal-transverse phonon polaritons
Authors: Gubbin Christopher R. , Berte Rodrigo , Meeker Michael A. , Giles Alexander J. , Ellis Chase T. , Tischler Joseph G. , Wheeler Virginia D. , Maier Stefan A. , Caldwell Joshua D. , De Liberato Simone
Published: April 2019

Phonon polaritons, hybrid light-matter quasiparticles resulting from strong coupling of the electromagnetic field with the lattice vibrations of polar crystals are a promising platform for mid-infrared photonics but for the moment there has been no proposal allowing for their electrical pumping. Electrical currents in fact mainly generate longitudinal optical phonons, while only transverse ones participate in the creation of phonon polaritons. We demonstrate how to exploit long-cell polytypes of silicon carbide to achieve strong coupling between transverse phonon polaritons and zone-folded longitudinal optical phonons. We develop a microscopic theory predicting the existence of the resulting hybrid longitudinal-transverse excitations. We then provide an experimental observation by tuning the resonance of a nanopillar array through the folded longitudinal optical mode, obtaining a clear spectral anti-crossing. The hybridisation of phonon polaritons with longitudinal phonons could represent an important step toward the development of phonon polariton-based electrically pumped mid-infrared emitters.
Defining the genetic and evolutionary architecture of alternative splicing in response to infection
Authors: Rotival Maxime , Quach Hélène , Quintana-Murci Lluis
Published: April 2019

Host and environmental factors contribute to variation in human immune responses, yet the genetic and evolutionary drivers of alternative splicing in response to infection remain largely uncharacterised. Leveraging 970 RNA-sequencing profiles of resting and stimulated monocytes from 200 individuals of African- and European-descent, we show that immune activation elicits a marked remodelling of the isoform repertoire, while increasing the levels of erroneous splicing. We identify 1,464 loci associated with variation in isoform usage (sQTLs), 9% of them being stimulation-specific, which are enriched in disease-related loci. Furthermore, we detect a longstanding increased plasticity of immune gene splicing, and show that positive selection and Neanderthal introgression have both contributed to diversify the splicing landscape of human populations. Together, these findings suggest that differential isoform usage has been an important substrate of innovation in the long-term evolution of immune responses and a more recent vehicle of population local adaptation.
Closing the gap between atomic-scale lattice deformations and continuum elasticity
Authors: Salvalaglio Marco , Voigt Axel , Elder Ken R.
Published: April 2019

Crystal lattice deformations can be described microscopically by explicitly accounting for the position of atoms or macroscopically by continuum elasticity. In this work, we report on the description of continuous elastic fields derived from an atomistic representation of crystalline structures that also include features typical of the microscopic scale. Analytic expressions for strain components are obtained from the complex amplitudes of the Fourier modes representing periodic lattice positions, which can be generally provided by atomistic modeling or experiments. The magnitude and phase of these amplitudes, together with the continuous description of strains, are able to characterize crystal rotations, lattice deformations, and dislocations. Moreover, combined with the so-called amplitude expansion of the phase-field crystal model, they provide a suitable tool for bridging microscopic to macroscopic scales. This study enables the in-depth analysis of elasticity effects for macroscale and mesoscale systems taking microscopic details into account.
Crowdsourced MRI quality metrics and expert quality annotations for training of humans and machines
Authors: Esteban Oscar , Blair Ross W. , Nielson Dylan M. , Varada Jan C. , Marrett Sean , Thomas Adam G. , Poldrack Russell A. , Gorgolewski Krzysztof J.
Published: April 2019

The neuroimaging community is steering towards increasingly large sample sizes, which are highly heterogeneous because they can only be acquired by multi-site consortia. The visual assessment of every imaging scan is a necessary quality control step, yet arduous and time-consuming. A sizeable body of evidence shows that images of low quality are a source of variability that may be comparable to the effect size under study. We present the MRIQC Web-API, an open crowdsourced database that collects image quality metrics extracted from MR images and corresponding manual assessments by experts. The database is rapidly growing, and currently contains over 100,000 records of image quality metrics of functional and anatomical MRIs of the human brain, and over 200 expert ratings. The resource is designed for researchers to share image quality metrics and annotations that can readily be reused in training human experts and machine learning algorithms. The ultimate goal of the database is to allow the development of fully automated quality control tools that outperform expert ratings in identifying subpar images.
Power of Ensemble Diversity and Randomization for Energy Aggregation
Authors: Métivier David , Luchnikov Ilia , Chertkov Michael
Published: April 2019

We study an ensemble of diverse (inhomogeneous) thermostatically controlled loads aggregated to provide the demand response (DR) services in a district-level energy system. Each load in the ensemble is assumed to be equipped with a random number generator switching heating/cooling on or off with a Poisson rate, r, when the load leaves the comfort zone. Ensemble diversity is modeled through inhomogeneity/disorder in the deterministic dynamics of loads. Approached from the standpoint of statistical physics, the ensemble represents a non-equilibrium system driven away from its natural steady state by the DR. The ability of the ensemble to recover by mixing faster to the steady state after its DR’s use is advantageous. The trade-off between the level of the aggregator’s control, commanding the devices to lower the rate r, and the phase-space-oscillatory deterministic dynamics is analyzed. Then, we study the effect of the load diversity, investigating four different disorder probability distributions (DPDs) ranging from the case of the Gaussian DPD to the case of the uniform with finite support DPD. We show that stronger regularity of the DPD results in faster mixing, which is similar to the Landau damping in plasma physics. Our theoretical analysis is supported by extensive numerical validation.
TGFβ2-induced senescence during early inner ear development
Authors: Gibaja Alejandro , Aburto María R. , Pulido Sara , Collado Manuel , Hurle Juan M. , Varela-Nieto Isabel , Magariños Marta
Published: April 2019

Embryonic development requires the coordinated regulation of apoptosis, survival, autophagy, proliferation and differentiation programs. Senescence has recently joined the cellular processes required to master development, in addition to its well-described roles in cancer and ageing. Here, we show that senescent cells are present in a highly regulated temporal pattern in the developing vertebrate inner ear, first, surrounding the otic pore and, later, in the otocyst at the endolymphatic duct. Cellular senescence is associated with areas of increased apoptosis and reduced proliferation consistent with the induction of the process when the endolymphatic duct is being formed. Modulation of senescence disrupts otic vesicle morphology. Transforming growth factor beta (TGFβ) signaling interacts with signaling pathways elicited by insulin-like growth factor type 1 (IGF-1) to jointly coordinate cellular dynamics required for morphogenesis and differentiation. Taken together, these results show that senescence is a natural occurring process essential for early inner ear development.
Shift in soil organic carbon and nitrogen pools in different reclaimed lands following intensive coastal reclamation on the coasts of eastern China
Authors: Yang Wen , Xia Lu , Zhu Zhihong , Jiang Lifen , Cheng Xiaoli , An Shuqing
Published: April 2019

The impacts of coastal reclamation on carbon (C) and nitrogen (N) sinks of coastal wetlands remain unclearly understood. This study was conducted to investigate the alterations of soil organic C and N (SOC and SON) pools following conversion of Phragmites australis salt marsh into fishpond, wheat and rapeseed fields and town construction land through reclamation along Jiangsu coast in eastern China. Coastal reclamation significantly increased stocks of soil total, labile and recalcitrant organic C and N (SLOC, SLON, SROC, and SRON), and concentrations of water-soluble organic C (WSOC), microbial biomass C and N (SMBC and SMBN), cumulative CO2-C mineralization (MINC) following conversion of P. australis salt marsh into fishpond, wheat and rapeseed fields. However, coastal reclamation reduced SOC, SLOC, SROC, SRON, WSOC, SMBC, SMBN, and MINC following conversion of P. australis salt marsh into town construction land. Our results suggest that coastal reclamation affects C and N sinks of coastal wetlands by changing SOC and SON pools size, stability and dynamics changes following conversion of P. australis salt marsh into other land use types. This finding were primarily attributed to alterations in quantity and quality of exogenous materials returning the soil, and soil physiochemical properties as affected by coastal reclamation.
STING agonists activate latently infected cells and enhance SIV-specific responses ex vivo in naturally SIV controlled cynomolgus macaques
Authors: Yamamoto Takuya , Kanuma Tomohiro , Takahama Shokichi , Okamura Tomotaka , Moriishi Eiko , Ishii Ken J. , Terahara Kazutaka , Yasutomi Yasuhiro
Published: April 2019

To achieve a functional cure for HIV, treatment regimens that eradicate latently HIV-infected cells must be established. For this, many groups have attempted to reactivate latently-infected cells to induce cytopathic effects and/or elicit cytotoxic T lymphocyte (CTL)/NK cell-mediated immune responses to kill these cells. We believe that not only the reactivation of latently-infected cells, but also the induction of strong CTL responses, would be required for this. Here, we used typical immune activators that target pattern recognition receptors (PRRs). For our experimental model, we identified eight SIV-infected cynomolgus monkeys that became natural controllers of viremia. Although plasma viral loads were undetectable, we could measure SIV-DNA by qPCR in peripheral blood mononuclear cells (PBMCs). Using these PBMCs, we screened 10 distinct PRR ligands to measure IFN-α and IFN-γ production. Among these, STING ligands, cGAMP and c-di-AMP, and the TLR7/8 agonist R848 markedly increased cytokine levels. Both R848 and STING ligands could reactivate latently-infected cells in both cynomolgus monkeys and human PBMCs in vitro. Furthermore, c-di-AMP increased the frequency of SIV Gag-specific CD8+ T cells including polyfunctional CD8+ T cells, as compared to that in untreated control or R848-treated cells. Together, STING ligands might be candidates for HIV treatment.
Diagnostic value of procalcitonin, C-reactive protein and lactate dehydrogenase in paediatric malignant solid tumour concurrent with infection and tumour progression
Authors: Li Fan , Zhang Weiling , Hu Huimin , Zhang Yi , Huang Dongsheng
Published: April 2019

Infection is a fatal complication in cancer patients that sometimes is not distinguished from tumour progression. We compared the diagnostic value of procalcitonin (PCT), C-reactive protein (CRP) and lactate dehydrogenase (LDH) in paediatric malignant solid tumour concurrent with infection and tumour progression. The 152 children enrolled were divided into infection and control groups. Each group was divided further into stable and progression groups. An intergroup comparison was made in terms of serum PCT, CRP and LDH in all children. PCT, CRP and LDH levels were significantly higher in the infection than in the control groups (P < 0.05). Among the controls, PCT, CRP and LDH levels were significantly higher in the progression than in the stable groups (P < 0.05). In diagnosing infection, the sensitivity and specificity of PCT and CRP at the cutoff values of 0.296 ng/mL and 28.13 mg/L were relatively better than those at 0.5 ng/mL and 10 mg/L, respectively. LDH had the highest correlation with tumour progression, whereas PCT had the lowest (LDH, r = 0.684; CRP, r = 0.570; PCT, r = 0.322). Thus, PCT has the highest value in diagnosing infection and is less susceptible to tumour progression than CRP. LDH has obvious advantages in judging tumour progression.
Methionine Oxidation Changes the Mechanism of Aβ Peptide Binding to the DMPC Bilayer
Authors: Lockhart Christopher , Smith Amy K. , Klimov Dmitri K.
Published: April 2019

Using all-atom explicit solvent replica exchange molecular dynamics simulations with solute tempering, we study the effect of methionine oxidation on Aβ10–40 peptide binding to the zwitterionic DMPC bilayer. By comparing oxidized and reduced peptides, we identified changes in the binding mechanism caused by this modification. First, Met35 oxidation unravels C-terminal helix in the bound peptides. Second, oxidation destabilizes intrapeptide interactions and expands bound peptides. We explain these outcomes by the loss of amphiphilic character of the C-terminal helix due to oxidation. Third, oxidation “polarizes” Aβ binding to the DMPC bilayer by strengthening the interactions of the C-terminus with lipids while largely releasing the rest of the peptide from bilayer. Fourth, in contrast to the wild-type peptide, oxidized Aβ induces significantly smaller bilayer thinning and drop in lipid density within the binding footprint. These observations are the consequence of mixing oxidized peptide amino acids with lipids promoted by enhanced Aβ conformational fluctuations. Fifth, methionine oxidation reduces the affinity of Aβ binding to the DMPC bilayer by disrupting favorable intrapeptide interactions upon binding, which offset the gains from better hydration. Reduced binding affinity of the oxidized Aβ may represent the molecular basis for its reduced cytotoxicity.
Itaconic acid inhibits growth of a pathogenic marine Vibrio strain: A metabolomics approach
Authors: Nguyen Thao Van , Alfaro Andrea C. , Young Tim , Green Saras , Zarate Erica , Merien Fabrice
Published: April 2019

The antimicrobial role of itaconic acid (ITA) has been recently discovered in mammalian cells. In our previous studies, we discovered that marine molluscs biosynthesise substantial quantities of ITA when exposed to marine pathogens, but its antimicrobial function to Vibrio bacteria is currently unknown. Thus, in this study, we used an untargeted gas chromatography–mass spectrometry (GC-MS) platform to identify metabolic changes of Vibrio sp. DO1 (V. corallyliticus/neptunius-like isolate) caused by ITA exposure. Vibrio sp. DO1 was cultured in Luria-Bertani broth supplemented with 3 mM sodium acetate and with different concentrations of ITA (0, 3 and 6 mM) for 24 h. The results showed that ITA completely inhibited Vibrio sp. growth at 6 mM and partially inhibited the bacterial growth at 3 mM. A principal component analysis (PCA) revealed a clear separation between metabolite profiles of Vibrio sp. DO1 in the 3 mM ITA treatment and the control, which were different in 25 metabolites. Among the altered metabolites, the accumulation of glyoxylic acid and other metabolites in glyoxylate cycle (cis-aconitic acid, isocitric acid and fumaric acid) together with the increase of isocitrate lyase (ICL) activity in the 3 mM ITA treatment compared to the control suggest that ITA inhibited Vibrio sp. growth via disruption of central carbon metabolism.
Spin-polarized localization in a magnetized chain
Authors: Benini Leonardo , Mukherjee Amrita , Chakrabarti Arunava , Römer Rudolf A.
Published: April 2019

We investigate a simple tight-binding Hamiltonian to understand the stability of spin-polarized transport of states with an arbitrary spin content in the presence of disorder. The general spin state is made to pass through a linear chain of magnetic atoms, and the localization lengths are computed. Depending on the value of spin, the chain of magnetic atoms unravels a hidden transverse dimensionality that can be exploited to engineer energy regimes where only a selected spin state is allowed to retain large localization lengths. We carry out a numerical anmalysis to understand the roles played by the spin projections in different energy regimes of the spectrum. For this purpose, we introduce a new measure, dubbed spin-resolved localization length. We study uncorrelated disorder in the potential profile offered by the magnetic substrate or in the orientations of the magnetic moments concerning a given direction in space. Our results show that the spin filtering effect is robust against weak disorder and hence the proposed system should be a good candidate model for experimental realizations of spin-selective transport devices.
Causal Interactions in Human Amygdala Cortical Networks across the Lifespan
Authors: Jiang Yuhao , Tian Yin , Wang Zhongyan
Published: April 2019

There is growing evidence that the amygdala serves as the base for dealing with complex human social communication and emotion. Although amygdalar networks plays a central role in these functions, causality connectivity during the human lifespan between amygdalar subregions and their corresponding perception network (PerN), affiliation network (AffN) and aversion network (AveN) remain largely unclear. Granger causal analysis (GCA), an approach to assess directed functional interactions from time series data, was utilized to investigated effective connectivity between amygdalar subregions and their related networks as a function of age to reveal the maturation and degradation of neural circuits during development and ageing in the present study. For each human resting functional magnetic resonance imaging (fMRI) dataset, the amygdala was divided into three subareas, namely ventrolateral amygdala (VLA), medial amygdala (MedA) and dorsal amygdala (DorA), by using resting-state functional connectivity, from which the corresponding networks (PerN, AffN and AveN) were extracted. Subsequently, the GC interaction of the three amygdalar subregions and their associated networks during life were explored with a generalised linear model (GLM). We found that three causality flows significantly varied with age: the GC of VLA → PerN showed an inverted U-shaped trend with ageing; the GC of MedA→ AffN had a U-shaped trend with ageing; and the GC of DorA→ AveN decreased with ageing. Moreover, during ageing, the above GCs were significantly correlated with Social Responsiveness Scale (SRS) and State-Trait Anxiety Inventory (STAI) scores. In short, PerN, AffN and AveN associated with the amygdalar subregions separately presented different causality connectivity changes with ageing. These findings provide a strong constituent framework for normal and neurological diseases associated with social disorders to analyse the neural basis of social behaviour during life.
Delivery of pancreatic digestive enzymes into the gastrointestinal tract by pancreatic exocrine tissue transplant
Authors: Ito Kyoji , Matsuura Katsuhisa , Mihara Yuichiro , Sakamoto Yoshihiro , Hasegawa Kiyoshi , Kokudo Norihiro , Shimizu Tatsuya
Published: April 2019

Exocrine pancreatic insufficiency, caused by disease-induced loss of pancreatic exocrine cells, may be treated through regenerative stem cell technologies that facilitate the production of pancreatic exocrine cells from induced pluripotent stem cells (iPSCs). However, delivering the digestive enzymes produced in the transplanted cells to the gastrointestinal tract remains a challenge. To generate an allogenic transplantation rat model, minced pancreas was transplanted into the gastric submucosal space with ablation of muscularis mucosa. In the allogenic transplantation, transplanted pancreatic cells were engrafted. Elevated amylase was detected in gastric juice, while transplanted cells disappeared through auto-digestion when the muscularis mucosa was not eliminated. Human iPSCs were differentiated into pancreatic exocrine cells by stage-specific treatment with growth factors and chemical compounds, and the differentiated pancreatic cells were implanted into the gastric submucosal space of nude rats. The transplanted cells were engrafted, and amylase was detected in the gastric juice in some cases. These findings suggest that transplantation of pancreatic exocrine cells into the gastric submucosal space with muscularis mucosa elimination will contribute to a regenerative approach for pancreatic exocrine insufficiency.
PfMSA180 is a novel Plasmodium falciparum vaccine antigen that interacts with human erythrocyte integrin associated protein (CD47)
Authors: Nagaoka Hikaru , Sasaoka Chisa , Yuguchi Takaaki , Kanoi Bernard N. , Ito Daisuke , Morita Masayuki , Udomsangpetch Rachanee , Sattabongkot Jetsumon , Ishino Tomoko , Tsuboi Takafumi , Takashima Eizo
Published: April 2019

Malaria symptoms and pathology are initiated by invasion of host erythrocytes by Plasmodium merozoites in a complex process that involves interactions between parasite and host erythrocyte proteins. Erythrocyte invasion presents attractive targets for malaria vaccine and drug development. Recently it was observed that antibodies against PfMSA180 (PF3D7_1014100) are associated with protection from symptomatic malaria, suggesting that this protein is a target of naturally acquired protective antibodies. Here we characterize PfMSA180, a ~170 kDa merozoite surface antigen that is potentially involved in erythrocyte invasion. PfMSA180 synthesized by the wheat germ cell-free system was used to raise antibodies in rabbits. Growth inhibition assays revealed that parasite invasion is inhibited by antibodies to the PfMSA180 C-terminal region, which contains an erythrocyte-binding domain. Surface plasmon resonance analysis showed that PfMSA180 specifically interacts with human erythrocyte integrin associated protein (CD47), suggesting that PfMSA180 plays a role during merozoite invasion of erythrocytes. Polymorphism analysis revealed that pfmsa180 is highly conserved among field isolates. We show that naturally acquired PfMSA180-specific antibodies responses are associated with protective immunity in a malaria-exposed Thai population. In sum, the data presented here supports further evaluation of the conserved erythrocyte-binding C-terminal region of PfMSA180 as an asexual blood-stage malaria vaccine candidate.
CMR derived left ventricular septal convexity in carriers of the hypertrophic cardiomyopathy-causing MYBPC3-Q1061X mutation
Authors: Tarkiainen Mika , Sipola Petri , Jalanko Mikko , Heliö Tiina , Jääskeläinen Pertti , Kivelä Kati , Laine Mika , Lauerma Kirsi , Kuusisto Johanna
Published: April 2019

This manuscript has not been published before and is not currently being considered for publication elsewhere. Increased septal convexity of left ventricle has been described in subjects with hypertrophic cardiomyopathy (HCM) -causing mutations without left ventricular hypertrophy (LVH). Our objective was to study septal convexity by cardiac magnetic resonance (CMR) in subjects with the Finnish founder mutation Q1016X in the myosin-binding protein C gene (MYBPC3). Septal convexity was measured in end-diastolic 4-chamber CMR image in 67 study subjects (47 subjects with the MYBPC3-Q1061X mutation and 20 healthy relatives without the mutation). Septal convexity was significantly increased in subjects with the MYBPC3-Q1061X mutation and LVH (n = 32) compared to controls (11.4 ± 4.3 vs 2.7 ± 3.2 mm, P < 0.001). In mutation carriers without LVH, there was a trend for increased septal convexity compared to controls (4.9 ± 2.5 vs 2.7 ± 3.2 mm, P = 0.074). When indexed for BSA, septal convexity in mutation carriers without LVH was 2.8 ± 1.4 mm/m2 and 1.5 ± 1.6 mm/m2 in controls (P = 0.036). In all mutation carriers, septal convexity correlated significantly with body surface area, age, maximal LV wall thickness, LV mass, and late gadolinium enhancement. Subjects with the MYBPC3–Q10961X mutation have increased septal convexity irrespective of the presence of LVH. Septal convexity appears to reflect septal remodeling, and could be useful in recognizing LVH negative mutation carriers.
Comparative RNA sequencing reveals that HPV16 E6 abrogates the effect of E6*I on ROS metabolism
Authors: Paget-Bailly Philippe , Meznad Koceila , Bruyère Diane , Perrard Jérôme , Herfs Michael , Jung Alain C. , Mougin Christiane , Prétet Jean-Luc , Baguet Aurélie
Published: April 2019

High-risk Human Papillomavirus infections are responsible for anogenital and oropharyngeal cancers. Alternative splicing is an important mechanism controlling HPV16 gene expression. Modulation in the splice pattern leads to polycistronic HPV16 early transcripts encoding a full length E6 oncoprotein or truncated E6 proteins, commonly named E6*. Spliced E6*I transcripts are the most abundant RNAs produced in HPV-related cancers. To date, the biological function of the E6*I isoform remains controversial. In this study, we identified, by RNA sequencing, cellular targets deregulated by E6*I, among which genes related to ROS metabolism. Concomitantly, E6*I-overexpressing cells display high levels of ROS. However, co-overexpression of both E6 and E6*I has no effect on ROS production. In HPV16-infected cells expressing different E6/E6*I levels, we show that the newly identified targets CCL2 and RAC2 are increased by E6*I but decreased by E6 expression, suggesting that E6 abrogates the effect of E6*I. Taken together, these data support the idea that E6*I acts independently of E6 to increase ROS production and that E6 has the ability to counteract the effects of E6*I. This asks the question of how E6*I can be considered separately of E6 in the natural history of HPV16 infection.
MtGA2ox10 encoding C20-GA2-oxidase regulates rhizobial infection and nodule development in Medicago truncatula
Authors: Kim Goon-Bo , Son Seong-Uk , Yu Hee-Ju , Mun Jeong-Hwan
Published: April 2019

Gibberellin (GA) plays a controversial role in the legume-rhizobium symbiosis. Recent studies have shown that the GA level in legumes must be precisely controlled for successful rhizobial infection and nodule organogenesis. However, regulation of the GA level via catabolism in legume roots has not been reported to date. Here, we investigate a novel GA inactivating C20-GA2-oxidase gene MtGA2ox10 in Medicago truncatula. RNA sequencing analysis and quantitative polymerase chain reaction revealed that MtGA2ox10 was induced as early as 6 h post-inoculation (hpi) of rhizobia and reached peak transcript abundance at 12 hpi. Promoter::β-glucuronidase fusion showed that the promoter activity was localized in the root infection/differentiation zone during the early stage of rhizobial infection and in the vascular bundle of the mature nodule. The CRISPR/Cas9-mediated deletion mutation of MtGA2ox10 suppressed infection thread formation, which resulted in reduced development and retarded growth of nodules on the Agrobacterium rhizogenes-transformed roots. Over-expression of MtGA2ox10 in the stable transgenic plants caused dwarfism, which was rescued by GA3 application, and increased infection thread formation but inhibition of nodule development. We conclude that MtGA2ox10 plays an important role in the rhizobial infection and the development of root nodules through fine catabolic tuning of GA in M. truncatula.
The secreted Ly6/uPAR-related protein-1 suppresses neutrophil binding, chemotaxis, and transmigration through human umbilical vein endothelial cells
Authors: Swamynathan Sudha , Tiwari Anil , Loughner Chelsea L. , Gnalian John , Alexander Nicholas , Jhanji Vishal , Swamynathan Shivalingappa K.
Published: April 2019

The secreted Ly-6/uPAR Related Protein-1 (SLURP1) is an immunomodulatory protein that promotes corneal immune- and angiogenic-privilege. Here, we have examined the influence of SLURP1 on neutrophil-vascular endothelial cell interactions using human umbilical vein endothelial cells (HUVEC) and differentiated neutrophil-like HL-60 (dHL-60) cells, or primary human neutrophils. SLURP1 blocked the tumor necrosis factor-alpha (TNF-α)-activated dHL-60 cells (i) binding to TNF-α-activated HUVEC with a concurrent reduction in endothelial cell adhesion molecule E-selectin, (ii) transmigration through TNF-α-activated confluent HUVEC monolayer by stabilizing VE-cadherin and β-catenin on endothelial cell cytoplasmic membranes, (iii) chemotaxis towards chemoattractant formyl Met-Leu-Phe (fMLP) coupled with their decreased polarization, and (iv) TNF-α-stimulated matrix metalloproteinase-9 (MMP9) expression and activity. SLURP1 also suppressed the primary human neutrophil chemotaxis, and interaction with HUVEC. Furthermore, SLURP1 suppressed fMLP-induced phosphorylation of protein kinase-B (AKT) in dHL-60 cells. Collectively, these results provide evidence that SLURP1 suppresses neutrophil (i) docking on HUVEC cells by decreasing endothelial cell adhesion molecule E-Selectin production, (ii) transmigration through HUVEC monolayer by stabilizing endothelial cell membrane localization of VE-cadherin and β-catenin complex and promoting their barrier function, and (iii) chemotaxis by modulating their polarization and TNF-α-stimulated MMP9 production.