bluuebunny/crossref_metadata_2025 huggingface dataset:
Seasonal and Interannual Variations in Nitrogen Availability and Particle Export in the Northwestern North Pacific Subtropical Gyre
Authors: Mino Y. , Sukigara C. , Honda M. C. , Kawakami H. , Wakita M. , Sasaoka K. , Yoshikawa C. , Abe O. , Kaiser J. , Kimoto K. , Kitamura M. , Fujiki T. , Matsumoto K. , Saino T.
Published: April 2020

Time series of particulate nitrogen isotope delta (PN‐δ15N) and flux of trapped particles at 200 m were determined in the northwestern North Pacific subtropical gyre between 2010 and 2014 in order to examine temporal variations in mixed layer nitrate availability and downward particle export. Lower PN‐δ15N (<4‰) seen every winter corresponded to convective nitrate supply triggering phytoplankton blooms. Greater particle fluxes were associated with higher CaCO3 concentrations (mass fraction >50%), implying that new nitrogen supply stimulated predominantly coccolithophore growth and downward transport of coccoliths. Even in the stratified summer of 2011, a δ15N drop associated with a spike in particulate flux was found and was attributed to the uplift of nitrate‐rich deep waters due to a mesoscale cyclonic eddy passing the mooring station. Total nitrate input sustains 86–93% of annual new production in this region while nitrogen fixation accounts for the rest. Trapped particles also showed that the winter δ15N decrease appeared earlier in the 2011–2012 blooms than those in 2013–2014, coinciding with 8% higher CaCO3 concentrations and a 40% lower particulate organic carbon to inorganic carbon export ratio, R(POC:PIC). This reflected stronger convective mixing and hence larger nutrient supply in 2011–2012, caused by larger ocean heat loss related to winter monsoon intensity. Such interannual change of winter R(POC:PIC) can affect CO2 uptake rate in the northwestern North Pacific subtropical gyre where anthropogenic CO2 accumulates in subtropical mode waters.
Decadal Wintertime Temperature Changes in East Asia During 1958–2001 and the Contributions of Internal Variability and External Forcing
Authors: Luo M. , Feng J.M. , Xu Z.F. , Chen L. , Wang J. , Wang Y.L. , Lin S. , Zhong L.H.
Published: April 2020

The winter temperature in East Asia from 1958 to 2001 has shown an obvious warming trend superposed with a large amplitude of decadal oscillations. To separate the relative contributions of external forcing and internal variability to the decadal change in winter temperature, we propose a method which combines reanalysis data, global atmosphere‐ocean coupled model outputs, and regional climate model. The results show that the weakening of the East Asian winter monsoon accounts for warming trend in the south Mongolia, the southeastern coast of Asia, and the adjacent seas to a large extent. In contrast, radiative forcing causes the warming trend in middle and high latitudes. The increasing concentration of aerosols could have resulted in local cooling in some areas. The winter temperature shows a decadal oscillation of 0.6 °C at a time scale of 8–20 a, which is mainly due to the oscillation of the Siberian‐Mongolia High and volcanic activities. The amplitude of temperature oscillations caused by volcanic activities was one third of that induced by the Siberian‐Mongolia High.
Temporal‐Geochemical Evolution of the Persani Volcanic Field, Eastern Transylvanian Basin (Romania): Implications for Slab Rollback Beneath the SE Carpathians
Authors: Ducea Mihai N. , Barla Anca , Stoica Adriana M. , Panaiotu Cristian , Petrescu Lucian
Published: April 2020

The Quaternary Persani volcanic field (PVF) consists of alkali basalts formed in an extensional basin at the SE end of the Transylvanian basin, near an important anomaly in the European mantle, the Vrancea slab, a seismically active near‐vertical lithospheric fragment of debated origin. The PVF is the only basaltic field regionally, has been studied geochemically in the past, and is also known for the presence of abundant mantle xenoliths. Here, we describe new geochemical data on rocks recently dated by Ar‐Ar chronometry and show that while we can reproduce virtually all previous results, there is a clear temporal evolution of the magmatic system. There is an increase of over 80°C in temperatures determined by the Si activity thermometer, from 1,300°C to 1,380°C during the ~0.5‐Myr duration of volcanic activity, which is accompanied by several coherent trends in geochemistry, among which the decrease of Zn/Fe and 87Sr/86Sr ratios over time. Earlier, higher Zn/Fe ratios are indicative of a pyroxenite/eclogite‐dominated source, which gradually changed to a peridotite‐dominated source. These characteristics are typical of a dynamic mantle in which vertical mantle lithosphere tectonics, either due to slab rollback or mantle dripping plays a role and are not consistent with simple decompression melting of asthenosphere. Synchronous adakitic rocks found about 25–30 km east of PVF are presumed to be slab melts and are consistent with the Vrancea slab rollback as the trigger for mantle melting responsible for the PVF.
Improving SWE Estimation With Data Assimilation: The Influence of Snow Depth Observation Timing and Uncertainty
Authors: Smyth Eric J. , Raleigh Mark S. , Small Eric E.
Published: April 2020

Snow depth observations can be leveraged with data assimilation (DA) to improve estimation of snow density and snow water equivalent (SWE). A key consideration for mission and campaign design is how snow depth retrieval characteristics (including observation timing/frequency and sampling error) influence SWE accuracy and uncertainty in a DA framework. To quantify these effects, we implement a particle filter (PF) assimilation technique to assimilate depth and validate this approach against observed snow density and SWE at 49 snow telemetry sites across 9 years. We sample from continuous in situ snow depth records to test a range of measurement timing and sampling error scenarios representative of remote sensing capabilities. Assimilation reduces density bias by over 40% and SWE bias by over 70% across climate zones and in both wet and dry years. There is little incremental benefit to SWE accuracy when assimilating more than one depth observation near peak accumulation. SWE estimates are less sensitive to observation timing than sampling error. Alternatively, more frequent depth observations improve melt‐out date timing and reduce SWE uncertainty, a key consideration when evaluating the operational utility of DA. In matching depth observations, the PF mostly acts to increase model precipitation inputs, while not systematically shifting other parameter values or forcings across the climate zones represented with the study sites. This demonstrates that precipitation is the largest source of model error. With DA, density errors are still nontrivial (above 10%), illuminating the need for further improvements to modeled density to estimate SWE within specified error limits.
An Element of Randomness in Modeling Arctic Ice Cover
Authors: Stanley Sarah
Published: April 2020

Incorporating random variation of temperature, humidity, and wind offers a computationally cheap alternative to improving resolution in an Earth system model when predicting when Arctic sea ice will disappear.
Chirality-assisted lateral momentum transfer for bidirectional enantioselective separation
Authors: Shi Yuzhi , Zhu Tongtong , Zhang Tianhang , Mazzulla Alfredo , Tsai Din Ping , Ding Weiqiang , Liu Ai Qun , Cipparrone Gabriella , Sáenz Juan José , Qiu Cheng-Wei
Published: April 2020

Lateral optical forces induced by linearly polarized laser beams have been predicted to deflect dipolar particles with opposite chiralities toward opposite transversal directions. These “chirality-dependent” forces can offer new possibilities for passive all-optical enantioselective sorting of chiral particles, which is essential to the nanoscience and drug industries. However, previous chiral sorting experiments focused on large particles with diameters in the geometrical-optics regime. Here, we demonstrate, for the first time, the robust sorting of Mie (size ~ wavelength) chiral particles with different handedness at an air–water interface using optical lateral forces induced by a single linearly polarized laser beam. The nontrivial physical interactions underlying these chirality-dependent forces distinctly differ from those predicted for dipolar or geometrical-optics particles. The lateral forces emerge from a complex interplay between the light polarization, lateral momentum enhancement, and out-of-plane light refraction at the particle-water interface. The sign of the lateral force could be reversed by changing the particle size, incident angle, and polarization of the obliquely incident light.
PD-L1 is a direct target of cancer-FOXP3 in pancreatic ductal adenocarcinoma (PDAC), and combined immunotherapy with antibodies against PD-L1 and CCL5 is effective in the treatment of PDAC
Authors: Wang Xiuchao , Li Xin , Wei Xunbin , Jiang Haiping , Lan Chungen , Yang Shengyu , Wang Han , Yang Yanhui , Tian Caijuan , Xu Zanmei , Zhang Jiangyan , Hao Jihui , Ren He
Published: April 2020

High expression of PD-L1 marks the poor prognosis of pancreatic ductal adenocarcinomas (PDAC). However, the regulatory mechanism of PD-L1 remains elusive. We recently reported that cancer Forkhead box protein 3 (Cancer-FOXP3 or C-FOXP3) promoted immune evasion of PDAC by recruiting Treg cells into PDAC via upregulation of CCL5. In this study, we confirmed that PD-L1 was overexpressed in PDAC samples from two independent cohorts of patients with radical resection. Moreover, C-FOXP3 was colocalized and correlated with the expression of PD-L1 in tumor cells at the mRNA and protein levels, and this finding was confirmed by the The Cancer Genome Atlas (TCGA) database. Chromatin immunoprecipitation (ChIP) revealed that C-FOXP3 directly bound to the promoter region of PD-L1 in pancreatic cancer cells. Furthermore, overexpression of C-FOXP3 activated the luciferase reporter gene under the control of the PD-L1 promoter. However, mutation of the binding motif-a completely reversed the luciferase activity. In addition, C-FOXP3-induced upregulation of PD-L1 effectively inhibited the activity of CD8+ T cells. Based on our recent finding that the CCL-5 antibody achieved a better response to PDAC models with high C-FOXP3 levels, we further demonstrated that the PD-L1 antibody strengthened the antitumor effect of CCL-5 blockade in xenograft and orthotopic mouse models with high C-FOXP3 levels. In conclusion, C-FOXP3 directly activates PD-L1 and represents a core transcription factor that mediates the immune escape of PDAC. Combined blockade of PD-L1 and CCL-5 may provide an effective therapy for patients with PDAC that have high C-FOXP3 levels.
A novel homozygous missense SLC25A20 mutation in three CACT-deficient patients: clinical and autopsy data
Authors: Chinen Yasutsugu , Yanagi Kumiko , Nakamura Sadao , Nakayama Noriko , Kamiya Motoko , Nakayashiro Mami , Kaname Tadashi , Naritomi Kenji , Nakanishi Koichi
Published: April 2020

Carnitine-acylcarnitine translocase (CACT) deficiency is a fatty acid ß-oxidation disorder of the carnitine shuttle in mitochondria, with a high mortality rate in childhood. We evaluated three patients, including two siblings, with neonatal-onset CACT deficiency and revealed identical homozygous missense mutations of p.Arg275Gln within the SLC25A20 gene. One patient died from hypoglycemia and arrhythmia at 26 months; his pathological autopsy revealed increased and enlarged mitochondria in the heart but not in the liver.
Author Correction: Exploring use of unsupervised clustering to associate signaling profiles of GPCR ligands to clinical response
Authors: Benredjem Besma , Gallion Jonathan , Pelletier Dennis , Dallaire Paul , Charbonneau Johanie , Cawkill Darren , Nagi Karim , Gosink Mark , Lukasheva Viktoryia , Jenkinson Stephen , Ren Yong , Somps Christopher , Murat Brigitte , Van Der Westhuizen Emma , Le Gouill Christian , Lichtarge Olivier , Schmidt Anne , Bouvier Michel , Pineyro Graciela
Published: April 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
The effect of optimistic expectancies on attention bias: Neural and behavioral correlates
Authors: Singh Laura , Schüpbach Laurent , Moser Dominik A. , Wiest Roland , Hermans Erno J. , Aue Tatjana
Published: April 2020

Optimism bias and positive attention bias are important features of healthy information processing. Recent findings suggest dynamic bidirectional optimism-attention interactions, but the underlying neural mechanisms remain to be identified. The current functional magnetic resonance imaging (fMRI) study, therefore, investigated the neural mechanisms underlying causal effects of optimistic expectancies on attention. We hypothesized that expectancies guide attention to confirmatory evidence in the environment, with enhanced salience and executive control network (SN/ECN) activity for unexpected information. Moreover, based on previous findings, we anticipated optimistic expectancies to more strongly impact attention and SN/ECN activity than pessimistic expectancies. Expectancies were induced with visual cues in 50 participants; subsequent attention to reward and punishment was assessed in a visual search task. As hypothesized, cues shortened reaction times to expected information, and unexpected information enhanced SN/ECN activity. Notably, these effects were stronger for optimistic than pessimistic expectancy cues. Our findings suggest that optimistic expectancies involve particularly strong predictions of reward, causing automatic guidance of attention to reward and great surprise about unexpected punishment. Such great surprise may be counteracted by visual avoidance of the punishing evidence, as revealed by prior evidence, thereby reducing the need to update (over)optimistic reward expectancies.
Measurement and prediction on thermal conductivity of fused quartz
Authors: Zhang Xin Rui , Kong Gang Qiang , Wang Le Hua , Xu Xiao Liang
Published: April 2020

Thermal conductivity of soil is a basic physical property related to heat conduction, and also is one of parameters widely applied in geotechnical engineering. The effect of gradation on the thermal conductivity of fused quartz was analyzed by thermal needle tests. The different particle size with the same uniformity coefficient (Cu = 3.2) and different uniformity coefficient for the same particle size (0.10~1.00 mm) were considered in this study. It shows that the thermal conductivity of fused quartz decreases with the decreasing of the mean particle size and with the increasing of the porosity. Simple modified methods to estimate the value of thermal conductivity are proposed, and had been demonstrated successfully by conducting fused quartz, carbonate sand and Ottawa sand.
Role of aldehyde dehydrogenases, alcohol dehydrogenase 1B genotype, alcohol consumption, and their combination in breast cancer in East-Asian women
Authors: Park Boyoung , Kim Ji-Hyun , Lee Eun Sook , Jung So-Youn , Lee See Youn , Kang Han-Sung , Lee Eun-Gyeong , Han Jai Hong
Published: April 2020

The associations between genetic polymorphisms in ADH1B (rs1229984) and ALDH2 (rs671), alcohol consumption, the effect of a combination of the two polymorphisms, and breast cancer risk were studied in a population of East-Asian women. In this study, 623 breast cancer cases and 1845 controls, aged 40 or above, were included. The association between ALDH2 polymorphism and breast cancer risk was validated in 2143 breast cancer cases and 3977 controls. Alcohol consumption increased the risk of breast cancer regardless of ADH1B and ALDH2 genotypes. The rs671 polymorphism of ALDH2 was independently associated with increased breast cancer risk (OR = 1.27, 95% CI = 1.02–1.58 per increment of A). The ADH1B rs1229984 polymorphism, and combined effects of the rs671 and rs1229984 polymorphisms, did not reveal any significant association with breast cancer. Stratification by menopausal status revealed that rs671 gene polymorphisms were significantly associated with breast cancer only in postmenopausal women (OR = 1.45, 95% CI = 1.03–2.05 per increment of A). This is the first study to demonstrate an independent association between ALDH2 gene variants and breast cancer in Asian women. Further studies are warranted to further elucidate the etiology of breast cancer as it relates to alcohol consumption in Asian women.
Influence of genetic factors in elbow tendon pathology: a case-control study
Authors: Alakhdar Mohmara Yasser , Cook Jill , Benítez-Martínez Josep C. , McPeek Emily R. , Aguilar Antonio Alberola , Olivas Emilio Soria , Hernandez-Sanchez Sergio
Published: April 2020

Elbow tendinopathy is a common pathology of the upper extremity that impacts both athletes and workers. Some research has examined the genetic component as a risk factor for tendinopathy, mainly in the lower limbs. A case-control study was designed to test for a relationship between certain collagen gene single nucleotide polymorphisms (SNPs) and elbow tendon pathology. A sample of 137 young adult athletes whose sports participation involves loading of the upper limb were examined for the presence of structural abnormalities indicative of pathology in the tendons of the lateral and medial elbow using ultrasound imaging and genotyped for the following SNPs: COL5A1 rs12722, COL11A1 rs3753841, COL11A1 rs1676486, and COL11A2 rs1799907. Anthropometric measurements and data on participants’ elbow pain and dysfunction were collected using the Disabilities of the Arm, Shoulder and Hand and the Mayo Clinic Performance Index for the Elbow questionnaires. Results showed that participants in the structural abnormality group had significantly higher scores in pain and dysfunction. A significant relationship between COL11A1 rs3753841 genotype and elbow tendon pathology was found (p = 0.024), with the CT variant associated with increased risk of pathology.
Modified Drude model for small gold nanoparticles surface plasmon resonance based on the role of classical confinement
Authors: Kheirandish Asef , Sepehri Javan Nasser , Mohammadzadeh Hosein
Published: April 2020

In this paper, we study the effect of restoration force caused by the limited size of a small metallic nanoparticle (MNP) on its linear response to the electric field of incident light. In a semi-classical phenomenological Drude-like model for small MNP, we consider restoration force caused by the displacement of conduction electrons with respect to the ionic positive background taking into account a free coefficient as a function of diameter of nanoparticle (NP) in the force term obtained by the idealistic Thomson model in order to adjust the classical approach. All important mechanisms of the energy dissipation such as electron-electron, electron-phonon and electron-NP surface scatterings and radiation are included in the model. In addition a correction term added to the damping factor of mentioned mechanisms in order to rectify the deficiencies of theoretical approaches. For determining the free parameters of model, the experimental data of extinction cross section of gold NPs with different sizes doped in the glass host medium are used and a good agreement between experimental data and results of our model is observed. It is shown that by decreasing the diameter of NP, the restoration force becomes larger and classical confinement effect becomes more dominant in the interaction. According to experimental data, the best fitted parameter for the coefficient of restoration force is a third order negative powers function of diameter. The fitted function for the correction damping factor is proportional to the inverse squared wavelength and third order power series of NP diameter. Based on the model parameters, the real and imaginary parts of permittivity for different sizes of gold NPs are presented and it is seen that the imaginary part is more sensitive to the diameter variations. Increase in the NP diameter causes increase in the real part of permittivity (which is negative) and decrease in the imaginary part.
Author Correction: Noninvasive Electroencephalogram Based Control of a Robotic Arm for Reach and Grasp Tasks
Authors: Meng Jianjun , Zhang Shuying , Beyko Angeliki , Olsoe Jaron , Baxter Bryan , He Bin
Published: April 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Efficient Drug Screening and Nephrotoxicity Assessment on Co-culture Microfluidic Kidney Chip
Authors: Yin Lei , Du Guanru , Zhang Bing , Zhang Hongbo , Yin Ruixue , Zhang Wenjun , Yang Shih-Mo
Published: April 2020

The function and susceptibility of various drugs are tested with renal proximal tubular epithelial cells; yet, replicating the morphology and kidneys function using the currently available in vitro models remains difficult. To overcome this difficulty, in the study presented in this paper, a device and a three-layer microfluidic chip were developed, which provides a simulated environment for kidney organs. This device includes two parts: (1) microfluidic drug concentration gradient generator and (2) a flow-temperature controlled platform for culturing of kidney cells. In chip study, renal proximal tubular epithelial cells (RPTECs) and peritubular capillary endothelial cells (PCECs) were screened with the drugs to assess the drug-induced nephrotoxicity. Unlike cells cultured in petri dishes, cells cultured in the microfluidic device exhibited higher performance in terms of both cell growth and drug nephrotoxicity evaluation. It is worth mentioning that a significant decrease in cisplatin-induced nephrotoxicity was found because of the intervention of cimetidine in the microfluidic device. In conclusion, the different in the cell performance between the microfluidic device and the petri dishes demonstrates the physiological relevance of the nephrotoxicity screening technology along with the microfluidic device developed in this study. Furthermore, this technology can also facilitate the development of reliable kidney drugs and serve as a useful and efficient test-bed for further investigation of the drug nephrotoxicity evaluation.
Founder BRCA1/BRCA2/PALB2 pathogenic variants in French-Canadian breast cancer cases and controls
Authors: Behl Supriya , Hamel Nancy , de Ladurantaye Manon , Lepage Stéphanie , Lapointe Réjean , Mes-Masson Anne-Marie , Foulkes William D.
Published: April 2020

Inherited germline pathogenic variants are responsible for ~5% of breast cancer globally. Through rapid expansion and isolation since immigration in the early 17th century, French Canadians are a relatively genetically homogenous founder population and therefore represent a unique demographic for genetic contributions to disease. To date, twenty variants in BRCA1, BRCA2, and PALB2 that predispose families to breast and ovarian cancer have been identified as recurring in the French-Canadian founder population. Our objective was to evaluate the clinical efficacy and validity of targeted genetic testing for these variants in Montreal French Canadians. A total of 555 breast cancer cases unselected for family history or age of diagnosis were genotyped, along with 1940 controls without a personal or family history of cancer. A Sequenom genotyping assay identified a pathogenic variant in 0.2% (5 of 1940) of cancer-free controls, and 3.8% (21/555) of breast cancer cases. Almost 10% (12/113) of early onset cases were heterozygous for founder BRCA1 or BRCA2 pathogenic variant. Of twenty variants tested, only seven were identified in this study. The option of providing this test as population-based screening is discussed.
Reproducibility of flutter-range vibrotactile detection and discrimination thresholds
Authors: Mikkelsen Mark , He Jason , Tommerdahl Mark , Edden Richard A. E. , Mostofsky Stewart H. , Puts Nicolaas A. J.
Published: April 2020

Somatosensory processing can be probed empirically through vibrotactile psychophysical experiments. Psychophysical approaches are valuable for investigating both normal and abnormal tactile function in healthy and clinical populations. To date, the test-retest reliability of vibrotactile detection and discrimination thresholds has yet to be established. This study sought to assess the reproducibility of vibrotactile detection and discrimination thresholds in human adults using an established vibrotactile psychophysical battery. Fifteen healthy adults underwent three repeat sessions of an eleven-task battery that measured a range of vibrotactile measures, including reaction time, detection threshold, amplitude and frequency discrimination, and temporal order judgement. Coefficients of variation and intraclass correlation coefficients (ICCs) were calculated for the measures in each task. Linear mixed-effects models were used to test for length and training effects and differences between tasks within the same domain. Reaction times were shown to be the most reproducible (ICC: ~0.9) followed by detection thresholds (ICC: ~0.7). Frequency discrimination thresholds were the least reproducible (ICC: ~0.3). As reported in prior studies, significant differences in measures between related tasks were also found, demonstrating the reproducibility of task-related effects. These findings show that vibrotactile detection and discrimination thresholds are reliable, further supporting the use of psychophysical experiments to probe tactile function.
Preserving Airway Smooth Muscle Contraction in Precision-Cut Lung Slices
Authors: Li Guang , Cohen Jonathan A. , Martines Carolina , Ram-Mohan Sumati , Brain Joseph D. , Krishnan Ramaswamy , Ai Xingbin , Bai Yan
Published: April 2020

Precision-cut lung slices (PCLS) are ideal for measuring small airway contraction. However, these measurements are currently limited to acute exposure scenarios that typically last a few minutes to a few hours. Using an insulin-supplemented culture medium, we prolong the small airway contractility in mouse PCLS for up to two weeks. Compared to conventional culture medium, insulin-supplemented culture medium provides no additional benefit in preserving cellular viability or airway structure. However, it protects the airway smooth muscle (ASM) against a loss of smooth muscle myosin heavy chain (SMMHC) expression. We elucidate the significance of this new culture medium for chronic disease modeling of IL-13-induced airway hyper-responsiveness.
X-ray irradiated cultures of mouse cortical neural stem/progenitor cells recover cell viability and proliferation with dose-dependent kinetics
Authors: Licursi Valerio , Anzellotti Silvia , Favaro Jessica , Sineri Serena , Carucci Nicoletta , Cundari Enrico , Fiore Mario , Guarguaglini Giulia , Pippa Simone , Nisi Paola S. , Vernì Fiammetta , Biagioni Stefano , Cacci Emanuele , Amendola Roberto , Lupo Giuseppe , Negri Rodolfo
Published: April 2020

Exposure of the developing or adult brain to ionizing radiation (IR) can cause cognitive impairment and/or brain cancer, by targeting neural stem/progenitor cells (NSPCs). IR effects on NSPCs include transient cell cycle arrest, permanent cell cycle exit/differentiation, or cell death, depending on the experimental conditions. In vivo studies suggest that brain age influences NSPC response to IR, but whether this is due to intrinsic NSPC changes or to niche environment modifications remains unclear. Here, we describe the dose-dependent, time-dependent effects of X-ray IR in NSPC cultures derived from the mouse foetal cerebral cortex. We show that, although cortical NSPCs are resistant to low/moderate IR doses, high level IR exposure causes cell death, accumulation of DNA double-strand breaks, activation of p53-related molecular pathways and cell cycle alterations. Irradiated NSPC cultures transiently upregulate differentiation markers, but recover control levels of proliferation, viability and gene expression in the second week post-irradiation. These results are consistent with previously described in vivo effects of IR in the developing mouse cortex, and distinct from those observed in adult NSPC niches or in vitro adult NSPC cultures, suggesting that intrinsic differences in NSPCs of different origins might determine, at least in part, their response to IR.
Oligomeric amyloid-β induces early and widespread changes to the proteome in human iPSC-derived neurons
Authors: Sackmann Christopher , Hallbeck Martin
Published: April 2020

Alzheimer’s disease (AD) is the most common form of dementia globally and is characterized by aberrant accumulations of amyloid-beta (Aβ) and tau proteins. Oligomeric forms of these proteins are believed to be most relevant to disease progression, with oligomeric amyloid-β (oAβ) particularly implicated in AD. oAβ pathology spreads among interconnected brain regions, but how oAβ induces pathology in these previously unaffected neurons requires further study. Here, we use well characterized iPSC-derived human neurons to study the early changes to the proteome and phosphoproteome after 24 h exposure to oAβ 1-42. Using nLC-MS/MS and label-free quantification, we identified several proteins that are differentially regulated in response to acute oAβ challenge. At this early timepoint, oAβ induced the decrease of TDP-43, heterogeneous nuclear ribonucleoproteins (hnRNPs), and coatomer complex I (COPI) proteins. Conversely, increases were observed in 20 S proteasome subunits and vesicle associated proteins VAMP1/2, as well as the differential phosphorylation of tau at serine 208. These changes show that there are widespread alterations to the neuronal proteome within 24 h of oAβ uptake, including proteins previously not shown to be related to neurodegeneration. This study provides new targets for the further study of early mediators of AD pathogenesis.
CLEAR: A Holistic Figure-of-Merit for Post- and Predicting Electronic and Photonic-based Compute-system Evolution
Authors: Sun Shuai , Narayana Vikram K. , Miscuglio Mario , Kimerling Lionel C. , El-Ghazawi Tarek , Sorger Volker J.
Published: April 2020

Continuing demands for increased computing efficiency and communication bandwidth have pushed the current semiconductor technology to its limit. This led to novel technologies with the potential to outperform conventional electronic solutions such as photonic pre-processors or accelerators, electronic-photonic hybrid circuits, and neural networks. However, the efforts made to describe and predict the performance evolution of compute-performance fall short to accurately predict and thereby explain the actually observed development pace with time; that is all proposed metrics eventually deviate from their development trajectory after several years from when they were originally proposed. This discrepancy demands a figure-of-merit that includes a holistic set of driving forces of the compute-system evolution. Here we introduce the Capability-to-Latency-Energy-Amount-Resistance (CLEAR) metric encompassing synchronizing speed, energy efficiency, physical machine size scaling, and economic cost. We show that CLEAR is the only metric to accurately describe the historical compute-system development. We find that even across different technology options CLEAR matches the observed (post-diction) constant rate-of-growth, and also fits proposed future compute-system (prediction). Therefore, we propose CLEAR to serve as a guide to quantitatively predict required compute-system demands at a given time in the future.
Stability and anti-proliferative properties of biologically active compounds extracted from Cistus L. after sterilization treatments
Authors: Ammendola Mario , Haponska Monika , Balik Karolina , Modrakowska Paulina , Matulewicz Karolina , Kazmierski Lukasz , Lis Aleksandra , Kozlowska Justyna , Garcia-Valls Ricard , Giamberini Marta , Bajek Anna , Tylkowski Bartosz
Published: April 2020

The growing interest of oncologists in natural compounds such as polyphenols and flavonoids is encouraging the development of innovative and efficient carriers for the delivery of those drugs. This study examines carboxymethyl chitosan-based microcapsules created by spray drying as a method for delivering biologically active compounds isolated from the Cistus herb. Effects of sterilization and encapsulation on the polyphenol and flavonoid content of Cistus extract were investigated to optimize the production process. Furthermore, in vitro studies were carried out to examine the anticancer properties of sterilized polyphenols and flavonoids on glioblastoma cells isolated from oncological patients. Acquired results show high anticancer potential towards glioblastoma as well as low cytotoxicity towards non-cancer cell lines by the substances in question. Steam sterilization is shown to affect the content of biologically active compounds the least. We demonstrate that the investigated form of drug encapsulation is both efficient and potentially possible to scale up from the viewpoint of the pharmaceutical industry.
The first Q-Tube based high-pressure synthesis of anti-cancer active thiazolo[4,5-c]pyridazines via the [4 + 2] cyclocondensation of 3-oxo-2-arylhydrazonopropanals with 4-thiazolidinones
Authors: Ibrahim Hamada Mohamed , Behbehani Haider
Published: April 2020

A novel and efficient protocol for the synthesis of thiazolo[4,5-c]pyridazine derivatives was developed. The approach utilizes a high pressure Q-Tube reactor to promote cyclocondensation reactions between 3-oxo-2-arylhydrazonopropanals and 4-thiazolidinones. The process has a significantly high atom economy and a broad substrate scope, as well as being applicable to gram scale syntheses. The in vitro cytotoxic activities of the synthesized thiazolo[4,5-c]pyridazine derivatives were examined utilizing a MTT colorimetric assay with doxorubicin as a reference anti-cancer drug and three human cancer cell lines including HCT-116 (colon), MCF-7 (breast) and A549 (lung). The results show that thiazolopyridazines 7c, h, k and p have high cytotoxic activity against the MCF-7 cell line with respective IC50 values of 14.34, 10.39, 15.43 and 13.60 μM. Moreover, the thiazolopyridazine derivative 7s also show promising cytotoxic activity against the HCT-116 cell line with IC50 = 6.90 μM . Observations made in this effort serve as a basis for further investigations into the design and preparation of new anti-cancer drugs.
Genome wide association study of 40 clinical measurements in eight dog breeds
Authors: Momozawa Yukihide , Merveille Anne-Christine , Battaille Géraldine , Wiberg Maria , Koch Jørgen , Willesen Jakob Lundgren , Proschowsky Helle Friis , Gouni Vassiliki , Chetboul Valérie , Tiret Laurent , Fredholm Merete , Seppälä Eija H. , Lohi Hannes , Georges Michel , Lequarré Anne-Sophie
Published: April 2020

The domestic dog represents an ideal model for identifying susceptibility genes, many of which are shared with humans. In this study, we investigated the genetic contribution to individual differences in 40 clinically important measurements by a genome-wide association study (GWAS) in a multinational cohort of 472 healthy dogs from eight breeds. Meta-analysis using the binary effects model after breed-specific GWAS, identified 13 genome-wide significant associations, three of them showed experimental-wide significant associations. We detected a signal at chromosome 13 for the serum concentration of alanine aminotransferase (ALT) in which we detected four breed-specific signals. A large proportion of the variance of ALT (18.1–47.7%) was explained by this locus. Similarly, a single SNP was also responsible for a large proportion of the variance (6.8–78.4%) for other measurements such as fructosamine, stress during physical exam, glucose, and morphometric measurements. The genetic contribution of single variant was much larger than in humans. These findings illustrate the importance of performing meta-analysis after breed-specific GWAS to reveal the genetic contribution to individual differences in clinically important measurements, which would lead to improvement of veterinary medicine.
Variations in cag pathogenicity island genes of Helicobacter pylori from Latin American groups may influence neoplastic progression to gastric cancer
Authors: Rizzato Cosmeri , Torres Javier , Obazee Ofure , Camorlinga-Ponce Margarita , Trujillo Esperanza , Stein Angelika , Mendez-Tenorio Alfonso , Bravo Maria Mercedes , Canzian Federico , Kato Ikuko
Published: April 2020

Helicobacter pylori (HP) colonizes the human stomach and induces acute gastritis, peptic ulcer disease, atrophic gastritis, and gastric adenocarcinoma. Increased virulence in HP isolates derives from harboring the cag (cytotoxin-associated genes) pathogenicity island (cagPAI). We analyzed the microvariants in cagPAI genes with the hypothesis that they may play an important role in determining HP virulence. We tested DNAs from cagA positive patients HP isolates; a total of 74 patients with chronic gastritis (CG, N = 37), intestinal metaplasia (IM, N = 21) or gastric cancer (GC, N = 16) from Mexico and Colombia. We selected 520 non-synonymous variants with at least 7.5% frequency in the original sequence outputs or with a minimum of 5 isolates with minor allele. After adjustment for multiple comparisons, no variants were statistically significantly associated with IM or GC. However, 19 non-synonymous showed conventional P-values < 0.05 comparing the frequency of the alleles between the isolates from subjects with gastritis and isolates from subjects with IM or GC; 12 of these showed a significant correlation with the severity of the disease. The present study revealed that several cagPAI genes from Latin American Western HP strains contains a number of non-synonymous variants in relatively high frequencies which could influence on the clinical outcome. However, none of the associations remained statistically significant after adjustment for multiple comparison.
Warm afterglow from the Toarcian Oceanic Anoxic Event drives the success of deep-adapted brachiopods
Authors: Ullmann C. V. , Boyle R. , Duarte L. V. , Hesselbo S. P. , Kasemann S. A. , Klein T. , Lenton T. M. , Piazza  V. , Aberhan M.
Published: April 2020

Many aspects of the supposed hyperthermal Toarcian Oceanic Anoxic Event (T-OAE, Early Jurassic, c. 182 Ma) are well understood but a lack of robust palaeotemperature data severely limits reconstruction of the processes that drove the T-OAE and associated environmental and biotic changes. New oxygen isotope data from calcite shells of the benthic fauna suggest that bottom water temperatures in the western Tethys were elevated by c. 3.5 °C through the entire T-OAE. Modelling supports the idea that widespread marine anoxia was induced by a greenhouse-driven weathering pulse, and is compatible with the OAE duration being extended by limitation of the global silicate weathering flux. In the western Tethys Ocean, the later part of the T-OAE is characterized by abundant occurrences of the brachiopod Soaresirhynchia, which exhibits characteristics of slow-growing, deep sea brachiopods. The unlikely success of Soaresirhynchia in a hyperthermal event is attributed here to low metabolic rate, which put it at an advantage over other species from shallow epicontinental environments with higher metabolic demand.
In-vitro analysis of free radical scavenging activities and suppression of LPS-induced ROS production in macrophage cells by Solanum sisymbriifolium extracts
Authors: More Garland K. , Makola Raymond T.
Published: April 2020

The current study aims to evaluate the antioxidant, cytotoxicity activities and suppression of LPS-induced oxidative stress production and characterization of phytochemicals in Solanum sisymbriifolium leaf extracts. The 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-azino-bis3-ethylbenzothiazoline-6-sulphonic acid (ABTS) radical scavenging activity of the leaves of S. sisymbriifolium extracted with solvents of various polarities viz. water: ethanol, ratio 50: 50; ethyl acetate and dichloromethane, was assessed. The cytotoxicity of the extracts was determined using the [3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide] (MTT) assay on RAW 264.7 macrophage (Murine) cells and real-time cell analysis (RTCA) xCELLigence system was used for determining cell viability. Cell-based detection of reactive oxygen species (ROS) was investigated utilizing a 2′,7′-Dichlorodihydrofluorescein diacetate (H2DCF-DA) assay. The DPPH and ABTS scavenging activity results of extracts revealed a dose-dependent response with significantly lower activity in both DPPH and ABTS. The superoxide dismutase (SOD) enzyme activity was then evaluated and extracts displayed a high SOD enzyme activity with 90–50% activity. Cytotoxicity results revealed that S. sisymbriifolium extracts were not toxic to RAW 264.7 macrophage cells at the tested concentrations. All three extracts decreased the production of ROS in macrophage cells. Phytochemical analysis using Fourier-transform infrared spectroscopy (FTIR) indicated the presence of metabolite functional groups which may be responsible for the antioxidant activity. The current study indicates that S. sisymbriifolium contains phytochemicals that scavenge free radicals, with less toxicity, and suppresses the LPS-induced ROS production in RAW 264.7 macrophage cells.
Enhancing Brain Retention of a KIF11 Inhibitor Significantly Improves its Efficacy in a Mouse Model of Glioblastoma
Authors: Gampa Gautham , Kenchappa Rajappa S. , Mohammad Afroz S. , Parrish Karen E. , Kim Minjee , Crish James F. , Luu Amanda , West Rita , Hinojosa Alfredo Quinones , Sarkaria Jann N. , Rosenfeld Steven S. , Elmquist William F.
Published: April 2020

Glioblastoma, the most lethal primary brain cancer, is extremely proliferative and invasive. Tumor cells at tumor/brain-interface often exist behind a functionally intact blood-brain barrier (BBB), and so are shielded from exposure to therapeutic drug concentrations. An ideal glioblastoma treatment needs to engage targets that drive proliferation as well as invasion, with brain penetrant therapies. One such target is the mitotic kinesin KIF11, which can be inhibited with ispinesib, a potent molecularly-targeted drug. Although, achieving durable brain exposures of ispinesib is critical for adequate tumor cell engagement during mitosis, when tumor cells are vulnerable, for efficacy. Our results demonstrate that the delivery of ispinesib is restricted by P-gp and Bcrp efflux at BBB. Thereby, ispinesib distribution is heterogeneous with concentrations substantially lower in invasive tumor rim (intact BBB) compared to glioblastoma core (disrupted BBB). We further find that elacridar—a P-gp and Bcrp inhibitor—improves brain accumulation of ispinesib, resulting in remarkably reduced tumor growth and extended survival in a rodent model of glioblastoma. Such observations show the benefits and feasibility of pairing a potentially ideal treatment with a compound that improves its brain accumulation, and supports use of this strategy in clinical exploration of cell cycle-targeting therapies in brain cancers.
Versatile Single-Element Ultrasound Imaging Platform using a Water-Proofed MEMS Scanner for Animals and Humans
Authors: Choi Seongwook , Kim Jin Young , Lim Hae Gyun , Baik Jin Woo , Kim Hyung Ham , Kim Chulhong
Published: April 2020

Single-element transducer based ultrasound (US) imaging offers a compact and affordable solution for high-frequency preclinical and clinical imaging because of its low cost, low complexity, and high spatial resolution compared to array-based US imaging. To achieve B-mode imaging, conventional approaches adapt mechanical linear or sector scanning methods. However, due to its low scanning speed, mechanical linear scanning cannot achieve acceptable temporal resolution for real-time imaging, and the sector scanning method requires specialized low-load transducers that are small and lightweight. Here, we present a novel single-element US imaging system based on an acoustic mirror scanning method. Instead of physically moving the US transducer, the acoustic path is quickly steered by a water-proofed microelectromechanical (MEMS) scanner, achieving real-time imaging. Taking advantage of the low-cost and compact MEMS scanner, we implemented both a tabletop system for in vivo small animal imaging and a handheld system for in vivo human imaging. Notably, in combination with mechanical raster scanning, we could acquire the volumetric US images in live animals. This versatile US imaging system can be potentially used for various preclinical and clinical applications, including echocardiography, ophthalmic imaging, and ultrasound-guided catheterization.
Exploring dynamic protein-protein interactions in cassava through the integrative interactome network
Authors: Thanasomboon Ratana , Kalapanulak Saowalak , Netrphan Supatcharee , Saithong Treenut
Published: April 2020

Protein-protein interactions (PPIs) play an essential role in cellular regulatory processes. Despite, in-depth studies to uncover the mystery of PPI-mediated regulations are still lacking. Here, an integrative interactome network (MePPI-Ux) was obtained by incorporating expression data into the improved genome-scale interactome network of cassava (MePPI-U). The MePPI-U, constructed by both interolog- and domain-based approaches, contained 3,638,916 interactions and 24,590 proteins (59% of proteins in the cassava AM560 genome version 6). After incorporating expression data as information of state, the MePPI-U rewired to represent condition-dependent PPIs (MePPI-Ux), enabling us to envisage dynamic PPIs (DPINs) that occur at specific conditions. The MePPI-Ux was exploited to demonstrate timely PPIs of cassava under various conditions, namely drought stress, brown streak virus (CBSV) infection, and starch biosynthesis in leaf/root tissues. MePPI-Uxdrought and MePPI-UxCBSV suggested involved PPIs in response to stress. MePPI-UxSB,leaf and MePPI-UxSB,root suggested the involvement of interactions among transcription factor proteins in modulating how leaf or root starch is synthesized. These findings deepened our knowledge of the regulatory roles of PPIs in cassava and would undeniably assist targeted breeding efforts to improve starch quality and quantity.