bluuebunny/crossref_metadata_2025_split huggingface dataset:
A 3D Empirical Model of Electron Density Based on CSES Radio Occultation Measurements
Authors: Huang He , Lin Jian , Xu Song , Le Huijun , Guo Feng , Zeren Zhima , Liu Libo , Shen Xuhui 
Published: April 2022

AbstractChina Seismo‐Electromagnetic Satellite (CSES) was successfully launched in February 2018. About 280 thousand ionospheric radio occultation (RO) electron density profiles (EDP) have been accumulated till the end of 2020. The CSES is a Sun‐synchronous orbit satellite with descending and ascending nodes around 14:00 and 02:00 LT, respectively, at the height of 507 km. Thus, most of the RO EDP concentrate on these two local time bins. First, we constructed empirical NmF2, hmF2, and Hm models at two local time windows 14:00 and 02:00 LT, respectively. The three models describe that NmF2, hmF2, and Hm vary with solar activity, season, longitude, and latitude. Through the comparison with CSES observations, the NmF2, hmF2, and Hm models could reproduce the physical characteristics rather well. Then, according to Chapman profile function, a EDP model was reconstructed based on the NmF2, hmF2, and Hm models, named CSES_Ne‐Profile Model. To evaluate the model performance, we simulated the COSMIC‐2 observations by CSES_Ne‐Profile Model and international reference ionosphere (IRI) model respectively. The results show that CSES_Ne‐Profile Model precedes the IRI model. Additionally, our model captures the merging phenomenon of the two peaks of equatorial ionospheric anomaly, which is missed by IRI. Further, CSES_NePrf model is a useful tool to provide the quiet background for case studies and joint studies with other payloads onboard CSES.
Statistical Survey of Arase Satellite Data Sets in Conjunction With the Finnish Riometer Network
Authors: Thomas Neethal , Kero Antti , Miyoshi Yoshizumi , Shiokawa Kazuo , Hyötylä Miikka , Raita Tero , Kasahara Yoshiya , Shinohara Iku , Matsuda Shoya , Nakamura Satoko , Kasahara Satoshi , Yokota Shoichiro , Keika Kunihiro , Hori Tomoaki , Mitani Takefumi , Takashima Takeshi , Asamura Kazushi , Kazama Yoichi , Wang Shiang‐Yu , Jun C.‐W. , Higashio Nana 
Published: April 2022

AbstractDuring disturbed geomagnetic conditions, the energetic particles in the inner magnetosphere are known to undergo precipitation loss due to interaction with various plasma waves. This study, investigates the energetic particle precipitation events statistically using coordinate observations from the ground riometer network and the inner‐magnetospheric satellite mission, Arase. We have compared cosmic noise absorption (CNA) data obtained from the Finnish ground riometer network located in the auroral/sub‐auroral latitudes with the comprehensive data set of omnidirectional electron/proton flux and plasma waves in ELF/VLF frequency range from the Arase satellite during the overpass intervals. The study period includes one and a half years of data between March 2017 and September 2018 covering Arase conjunctions with the riometer stations from all magnetic local time sectors. The relation between the plasma flux/waves observed at the satellite with the riometer absorptions are investigated statistically for CNA (absorption >0.5 dB) and non‐CNA (absorption <0.5 dB) cases separately. During CNA events, Arase observed elevated electron flux in the medium energy range (2–100 keV), and plasma wave activity in the whistler‐mode frequency range (0.5–3 kHz) of the spectra. Our study provides an estimate of the statistical dependence of the electron flux and plasma wave observations at Arase with the ground reality of actual precipitation.
Versatile chip-based nanoscopy becomes ready for histopathology assessment
Authors: Lopez-Garcia Martin 
Published: April 2022

AbstractNanoscopy is a mature technology used routinely in life science to obtain images well below the optical diffraction limit. But the use of nanoscopy in histopathology assessment is very limited mostly due to the low throughput of traditional nanoscopic techniques. So far, Chip-nanoscopy, nanoscopy in which sample illumination is performed by an integrated photonic chip instead of bulk optics, has been shown to provide an enhanced field of view and throughput for cell biology. Now, a new development shows that chip-nanoscopy also offers interesting progress for the study of histological samples offering a complementary technique to electron microscopy for histopathology assessment.
Genome-wide association analyses of symptom severity among clozapine-treated patients with schizophrenia spectrum disorders
Authors: Okhuijsen-Pfeifer C. , van der Horst M. Z. , Bousman C. A. , Lin B. , van Eijk K. R. , Ripke S. , Ayhan Y. , Babaoglu M. O. , Bak M. , Alink W. , van Beek H. , Beld E. , Bouhuis A. , Edlinger M. , Erdogan I. M. , Ertuğrul A. , Yoca G. , Everall I. P. , Görlitz T. ,   GROUP (Genetic Risk and Outcome of Psychosis) investigators, van Amelsvoort T. , Bartels-Velthuis A. A. , Bruggeman R. , Cahn W. , Guloksuz S. , de Haan L. , Kahn R. S. , Schirmbeck F. , Simons C. J. P. , van Os J. , Alizadeh B. Z. , Luykx J. J. , Rutten B. P. F. , van Winkel R. , Grootens K. P. , Gutwinski S. , Hallikainen T. , Jeger-Land E. , de Koning M. , Lähteenvuo M. , Legge S. E. , Leucht S. , Morgenroth C. , Müderrisoğlu A. , Narang A. , Pantelis C. , Pardiñas A. F. , Oviedo-Salcedo T. , Schneider-Thoma J. , Schreiter S. , Repo-Tiihonen E. , Tuppurainen H. , Veereschild M. , Veerman S. , de Vos M. , Wagner E. , Cohen D. , Bogers J. P. A. M. , Walters J. T. R. , Yağcıoğlu A. E. Anil , Tiihonen J. , Hasan A. , Luykx J. J. 
Published: April 2022

AbstractClozapine is the most effective antipsychotic for patients with treatment-resistant schizophrenia. However, response is highly variable and possible genetic underpinnings of this variability remain unknown. Here, we performed polygenic risk score (PRS) analyses to estimate the amount of variance in symptom severity among clozapine-treated patients explained by PRSs (R2) and examined the association between symptom severity and genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activity. Genome-wide association (GWA) analyses were performed to explore loci associated with symptom severity. A multicenter cohort of 804 patients (after quality control N = 684) with schizophrenia spectrum disorder treated with clozapine were cross-sectionally assessed using the Positive and Negative Syndrome Scale and/or the Clinical Global Impression-Severity (CGI-S) scale. GWA and PRS regression analyses were conducted. Genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activities were calculated. Schizophrenia-PRS was most significantly and positively associated with low symptom severity (p = 1.03 × 10−3; R2 = 1.85). Cross-disorder-PRS was also positively associated with lower CGI-S score (p = 0.01; R2 = 0.81). Compared to the lowest tertile, patients in the highest schizophrenia-PRS tertile had 1.94 times (p = 6.84×10−4) increased probability of low symptom severity. Higher genotype-predicted CYP2C19 enzyme activity was independently associated with lower symptom severity (p = 8.44×10−3). While no locus surpassed the genome-wide significance threshold, rs1923778 within NFIB showed a suggestive association (p = 3.78×10−7) with symptom severity. We show that high schizophrenia-PRS and genotype-predicted CYP2C19 enzyme activity are independently associated with lower symptom severity among individuals treated with clozapine. Our findings open avenues for future pharmacogenomic projects investigating the potential of PRS and genotype-predicted CYP-activity in schizophrenia.
Beyond antipsychotics: a twenty-first century update for preclinical development of schizophrenia therapeutics
Authors: Spark Daisy L. , Fornito Alex , Langmead Christopher J. , Stewart Gregory D. 
Published: April 2022

AbstractDespite 50+ years of drug discovery, current antipsychotics have limited efficacy against negative and cognitive symptoms of schizophrenia, and are ineffective—with the exception of clozapine—against any symptom domain for patients who are treatment resistant. Novel therapeutics with diverse non-dopamine D2 receptor targets have been explored extensively in clinical trials, yet often fail due to a lack of efficacy despite showing promise in preclinical development. This lack of translation between preclinical and clinical efficacy suggests a systematic failure in current methods that determine efficacy in preclinical rodent models. In this review, we critically evaluate rodent models and behavioural tests used to determine preclinical efficacy, and look to clinical research to provide a roadmap for developing improved translational measures. We highlight the dependence of preclinical models and tests on dopamine-centric theories of dysfunction and how this has contributed towards a self-reinforcing loop away from clinically meaningful predictions of efficacy. We review recent clinical findings of distinct dopamine-mediated dysfunction of corticostriatal circuits in patients with treatment-resistant vs. non-treatment-resistant schizophrenia and suggest criteria for establishing rodent models to reflect such differences, with a focus on objective, translational measures. Finally, we review current schizophrenia drug discovery and propose a framework where preclinical models are validated against objective, clinically informed measures and preclinical tests of efficacy map onto those used clinically.
Gut microbiota and voluntary alcohol consumption
Authors: Segovia-Rodríguez L. , Echeverry-Alzate V. , Rincón-Pérez I. , Calleja-Conde J. , Bühler K. M. , Giné E. , Albert J. , Hinojosa J. A. , Huertas E. , Gómez-Gallego F. , Bressa C. , Rodríguez de Fonseca F. , López-Moreno J. A. 
Published: April 2022

AbstractAlcohol is part of the usual diet of millions of individuals worldwide. However, not all individuals who drink alcohol experience the same effects, nor will everyone develop an alcohol use disorder. Here we propose that the intestinal microbiota (IMB) helps explain the different consumption patterns of alcohol among individuals. 507 humans participated in this study and alcohol consumption and IMB composition were analyzed. On the other hand, in 80 adult male Wistar rats, behavioral tests, alcohol intoxication, fecal transplantation, administration of antibiotics and collection of fecal samples were performed. For identification and relative quantification of bacterial taxa was used the bacterial 16 S ribosomal RNA gene. In humans, we found that heavy episodic drinking is associated with a specific stool type phenotype (type 1, according to Bristol Stool Scale;p < 0.05) and with an increase in the abundance ofActinobacteria(p < 0.05). Next, using rats, we demonstrate that the transfer of IMB from alcohol-intoxicated animals causes an increase in voluntary alcohol consumption in transplant-recipient animals (p < 0.001). The relative quantification data indicate that the genusPorphyromonascould be associated with the effect on voluntary alcohol consumption. We also show that gut microbiota depletion by antibiotics administration causes a reduction in alcohol consumption (p < 0.001) and altered the relative abundance of relevant phyla such asFirmicutes,BacteroidetesorCyanobacteria(p < 0.05), among others. Benjamini–Hochberg false discovery rate (FDR) correction was performed for multiple comparisons. These studies reveal some of the consequences of alcohol on the IMB and provide evidence that manipulation of IMB may alter voluntary alcohol consumption.
SorCS3 promotes the internalization of p75NTR to inhibit GBM progression
Authors: Zhang Yanqiu , Li Yue , Fan Yuhua , Zhang Xiaoyuan , Tang Zhihong , Qi Jing , Zhao Baoshan , Li Fuyuan , Chen Xiaofeng , Liang Huan , Xu Haiyan , Li Dongliang 
Published: April 2022

AbstractGlioblastoma (GBM) is a fatal malignancy caused by dysregulation of cellular signal transduction. Internalization plays a key role in maintaining signalling balance. Previous reports showed that Sortilin related VPS10 domain containing receptor 3 (SorCS3) has the ability to regulate internalization. However, the impacts of SorCS3 on the biological processes involved in GBM have not yet been reported. In this study, we investigated the bio-function of SorCS3 in GBM. We found that SorCS3 was significantly downregulated in GBM. In addition, low expression level of SorCS3 predicted poor prognoses in patients with GBM. Here, we proved that SorCS3 suppressed cell invasion and proliferation mainly via NGF/p75NTR pathway in GBM. We found that SorCS3 co-localized with p75NTR in GBM cells and regulated the p75NTR protein level by promoting trafficking of the endosomal to the lysosome. Immunofluorescence (IF) and Co-Immunoprecipitation (Co-IP) detection confirmed that SorCS3 bound to p75NTR, which subsequently increased the internalization of p75NTR, and then transported p75NTR to the lysosome for degradation, ultimately contributing to inhibit of glioma progression. Taken together, our work suggests that SorCS3 is a marker of promising prognosis in GBM patients and suggests that SorCS3 regulates internalization, which plays a pivotal role in inhibiting glioma progression.
N6-isopentenyladenosine induces cell death through necroptosis in human glioblastoma cells
Authors: Pagano Cristina , Navarra Giovanna , Coppola Laura , Avilia Giorgio , Pastorino Olga , Della Monica Rosa , Buonaiuto Michela , Torelli Giovanni , Caiazzo Pasquale , Bifulco Maurizio , Laezza Chiara 
Published: April 2022

AbstractTargeting necroptosis is considered a promising therapeutic strategy in cancer, including Glioblastoma Multiforme (GBM), one of the most lethal brain tumors. Necroptosis is a mechanism of programmed cell death overcoming the apoptosis resistance mechanism underlying GBM tumorigenesis and malignant progression. N6-isopentenyladenosine (iPA), adenosine modified with isoprenoid derivative, displays antitumor activity in different cancer models. In previous studies, we demonstrated that iPA interferes with EGFR signaling reducing glioma cell viability. Here, we show that iPA induces necroptosis in glioblastoma cell lines and in primary cells established from tumor explants, without affecting the viability of non-cancerous brain cell lines, (Normal Human Astrocyte). The activation of RIP1, RIP3, and MLKL and the upregulation of necrosome formation were increased upon iPA treatment while caspase-3, caspase-8, and PARP were not activated in GBM cells. Co-treatment with specific necroptosis inhibitor necrostatin-1 (Nec-1) or Necrosulfonamide (NSA) prevented cell death caused by iPA treatment while the general caspase inhibitor Z-VAD-fluoromethylketone (z-VAD-fmk) did not elicit any effect, suggesting that this molecule induces caspase-independent necroptosis. These results suggest that iPA treatment can be able to bypass the apoptosis resistance mechanism in glioblastoma thereby offering higher therapeutic efficacy.
Inhibition of BKCa channels protects neonatal hearts against myocardial ischemia and reperfusion injury
Authors: Sanghvi Shridhar , Szteyn Kalina , Ponnalagu Devasena , Sridharan Divya , Lam Alexander , Hansra Inderjot , Chaudhury Ankur , Majumdar Uddalak , Kohut Andrew R. , Gururaja Rao Shubha , Khan Mahmood , Garg Vidu , Singh Harpreet 
Published: April 2022

AbstractBKCa channels are large-conductance calcium and voltage-activated potassium channels that are heterogeneously expressed in a wide array of cells. Activation of BKCa channels present in mitochondria of adult ventricular cardiomyocytes is implicated in cardioprotection against ischemia-reperfusion (IR) injury. However, the BKCa channel’s activity has never been detected in the plasma membrane of adult ventricular cardiomyocytes. In this study, we report the presence of the BKCa channel in the plasma membrane and mitochondria of neonatal murine and rodent cardiomyocytes, which protects the heart on inhibition but not activation. Furthermore, K+ currents measured in neonatal cardiomyocyte (NCM) was sensitive to iberiotoxin (IbTx), suggesting the presence of BKCa channels in the plasma membrane. Neonatal hearts subjected to IR when post-conditioned with NS1619 during reoxygenation increased the myocardial infarction whereas IbTx reduced the infarct size. In agreement, isolated NCM also presented increased apoptosis on treatment with NS1619 during hypoxia and reoxygenation, whereas IbTx reduced TUNEL-positive cells. In NCMs, activation of BKCa channels increased the intracellular reactive oxygen species post HR injury. Electrophysiological characterization of NCMs indicated that NS1619 increased the beat period, field, and action potential duration, and decreased the conduction velocity and spike amplitude. In contrast, IbTx had no impact on the electrophysiological properties of NCMs. Taken together, our data established that inhibition of plasma membrane BKCa channels in the NCM protects neonatal heart/cardiomyocytes from IR injury. Furthermore, the functional disparity observed towards the cardioprotective activity of BKCa channels in adults compared to neonatal heart could be attributed to their differential localization.
CHMP2A regulates tumor sensitivity to natural killer cell-mediated cytotoxicity
Authors: Bernareggi Davide , Xie Qi , Prager Briana C. , Yun Jiyoung , Cruz Luisjesus S. , Pham Timothy V. , Kim William , Lee Xiqing , Coffey Michael , Zalfa Cristina , Azmoon Pardis , Zhu Huang , Tamayo Pablo , Rich Jeremy N. , Kaufman Dan S. 
Published: April 2022

AbstractNatural killer (NK) cells are known to mediate killing of various cancer types, but tumor cells can develop resistance mechanisms to escape NK cell-mediated killing. Here, we use a “two cell type” whole genome CRISPR-Cas9 screening system to discover key regulators of tumor sensitivity and resistance to NK cell-mediated cytotoxicity in human glioblastoma stem cells (GSC). We identify CHMP2A as a regulator of GSC resistance to NK cell-mediated cytotoxicity and we confirm these findings in a head and neck squamous cells carcinoma (HNSCC) model. We show that deletion of CHMP2A activates NF-κB in tumor cells to mediate increased chemokine secretion that promotes NK cell migration towards tumor cells. In the HNSCC model we demonstrate that CHMP2A mediates tumor resistance to NK cells via secretion of extracellular vesicles (EVs) that express MICA/B and TRAIL. These secreted ligands induce apoptosis of NK cells to inhibit their antitumor activity. To confirm these in vitro studies, we demonstrate that deletion of CHMP2A in CAL27 HNSCC cells leads to increased NK cell-mediated killing in a xenograft immunodeficient mouse model. These findings illustrate a mechanism of tumor immune escape through EVs secretion and identify inhibition of CHMP2A and related targets as opportunities to improve NK cell-mediated immunotherapy.
Host-guest liquid gating mechanism with specific recognition interface behavior for universal quantitative chemical detection
Authors: Wang Huimeng , Fan Yi , Hou Yaqi , Chen Baiyi , Lei Jinmei , Yu Shijie , Chen Xinyu , Hou Xu 
Published: April 2022

AbstractUniversal visual quantitative chemical detection technology has emerged as an increasingly crucial tool for convenient testing with immediate results in the fields of environmental assessment, homeland security, clinical drug testing and health care, particularly in resource-limited settings. Here, we show a host-guest liquid gating mechanism to translate molecular interface recognition behavior into visually quantifiable detection signals. Quantitative chemical detection is achieved, which has obvious advantages for constructing a portable, affordable, on-site sensing platform to enable the visual quantitative testing of target molecules without optical/electrical equipment. Experiments and theoretical calculations confirm the specificity and scalability of the system. This mechanism can also be tailored by the rational design of host-guest complexes to quantitatively and visually detect various molecules. With the advantages of versatility and freedom from additional equipment, this detection mechanism has the potential to revolutionize environmental monitoring, food safety analysis, clinical drug testing, and more.
A genetic toolkit and gene switches to limit Mycoplasma growth for biosafety applications
Authors: Broto Alicia , Gaspari Erika , Miravet-Verde Samuel , dos Santos Vitor A. P. Martins , Isalan Mark 
Published: April 2022

AbstractMycoplasmas have exceptionally streamlined genomes and are strongly adapted to their many hosts, which provide them with essential nutrients. Owing to their relative genomic simplicity, Mycoplasmas have been used to develop chassis for biotechnological applications. However, the dearth of robust and precise toolkits for genomic manipulation and tight regulation has hindered any substantial advance. Herein we describe the construction of a robust genetic toolkit for M. pneumoniae, and its successful deployment to engineer synthetic gene switches that control and limit Mycoplasma growth, for biosafety containment applications. We found these synthetic gene circuits to be stable and robust in the long-term, in the context of a minimal cell. With this work, we lay a foundation to develop viable and robust biosafety systems to exploit a synthetic Mycoplasma chassis for live attenuated vectors for therapeutic applications.
Emergence and intensification of dairying in the Caucasus and Eurasian steppes
Authors: Scott Ashley , Reinhold Sabine , Hermes Taylor , Kalmykov Alexey A. , Belinskiy Andrey , Buzhilova Alexandra , Berezina Natalia , Kantorovich Anatoliy R. , Maslov Vladimir E. , Guliyev Farhad , Lyonnet Bertille , Gasimov Parviz , Jalilov Bakhtiyar , Eminli Jeyhun , Iskandarov Emil , Hammer Emily , Nugent Selin E. , Hagan Richard , Majander Kerttu , Onkamo Päivi , Nordqvist Kerkko , Shishlina Natalia , Kaverzneva Elena , Korolev Arkadiy I. , Khokhlov Aleksandr A. , Smolyaninov Roman V. , Sharapova Svetlana V. , Krause Rüdiger , Karapetian Marina , Stolarczyk Eliza , Krause Johannes , Hansen Svend , Haak Wolfgang , Warinner Christina 
Published: April 2022

AbstractArchaeological and archaeogenetic evidence points to the Pontic–Caspian steppe zone between the Caucasus and the Black Sea as the crucible from which the earliest steppe pastoralist societies arose and spread, ultimately influencing populations from Europe to Inner Asia. However, little is known about their economic foundations and the factors that may have contributed to their extensive mobility. Here, we investigate dietary proteins within the dental calculus proteomes of 45 individuals spanning the Neolithic to Greco-Roman periods in the Pontic–Caspian Steppe and neighbouring South Caucasus, Oka–Volga–Don and East Urals regions. We find that sheep dairying accompanies the earliest forms of Eneolithic pastoralism in the North Caucasus. During the fourth millennium bc, Maykop and early Yamnaya populations also focused dairying exclusively on sheep while reserving cattle for traction and other purposes. We observe a breakdown in livestock specialization and an economic diversification of dairy herds coinciding with aridification during the subsequent late Yamnaya and North Caucasus Culture phases, followed by severe climate deterioration during the Catacomb and Lola periods. The need for additional pastures to support these herds may have driven the heightened mobility of the Middle and Late Bronze Age periods. Following a hiatus of more than 500 years, the North Caucasian steppe was repopulated by Early Iron Age societies with a broad mobile dairy economy, including a new focus on horse milking.