bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oceanic Processes in Ocean Temperature Products Key to a Realistic Presentation of Positive Indian Ocean Dipole Nonlinearity
Authors: Yang Kai , Cai Wenju , Huang Gang , Wang Guojian , Ng Benjamin , Li Shujun 
Published: August 2020

AbstractA positive Indian Ocean Dipole (pIOD) refers to a sea surface temperature anomaly pattern with cold anomalies in the equatorial eastern Indian Ocean and warm anomalies in the west, leading to floods in the eastern African countries and droughts and bushfires in Indonesia and Australia. The pIOD displays strong inter‐event differences, ranging from an extreme event dominated by westward‐extended strong cold anomalies along the equator, to a moderate event with weakened cooling confined to region off Sumatra‐Java. Representation of the extreme pIOD varies vastly across ocean temperature products. Here we show that products generated in a system explicitly involving subsurface oceanic processes capture the nonlinear dynamics of the extreme pIOD, i.e., the equatorial nonlinear zonal and vertical advection, and systematically produce a more realistic extreme pIOD. Thus, our study identifies ocean temperature products that are more suitable for studying extreme pIOD and its climatic impacts.
Ionospheric Planetary Wave Activity and Its Role in Equatorial Spread F Day‐to‐Day Variability
Authors: Manju G. , Aswathy R. P. 
Published: August 2020

AbstractA comprehensive analysis on the ionospheric planetary wave activity is undertaken using 8 years of ionosonde data at Trivandrum (8.5°N, 77°E), a dip equatorial station. The study reveals that the dominant planetary wave is of 16‐day type and its strength is maximum in winter solstice/autumnal equinox and minimum in summer solstice in high solar activity conditions. In low solar activity years planetary wave activity strength is more or less comparable in vernal equinox, autumnal equinox, and winter solstice, while it is observed to be least in summer solstice. Further, the planetary wave activity shows direct correlation with solar activity for the different seasons. Thermosphere Ionosphere Mesosphere Energetics and Dynamics (TIMED) satellite observations of off‐equatorial E‐region zonal winds confirm the fact that they are strong westward in high solar activity years compared to low solar activity years. The strong westward winds aid the upward propagation of westward propagating planetary waves in high solar activity years. Planetary waves reaching the off‐equatorial E‐region modulate the equatorial F‐region via the coupling along the magnetic field lines. The role of planetary waves in modulating the pre‐reversal enhancement, equatorial spread F duration, and its spread range on a day‐to‐day basis is brought out quantitatively for both high and low solar activity conditions. The study emphasizes the importance of ionospheric planetary wave studies for the prediction of equatorial spread F characteristics.
Dynamics of Energetic Electrons in the Slot Region During Geomagnetically Quiet Times: Losses Due to Wave‐Particle Interactions Versus a Source From Cosmic Ray Albedo Neutron Decay (CRAND)
Authors: Xiang Zheng , Li Xinlin , Ni Binbin , Temerin M. A. , Zhao Hong , Zhang Kun , Khoo Leng Ying 
Published: August 2020

AbstractEarth's slot region, lying between the outer and inner radiation belts, has been identified as due to a balance between inward radial diffusion and pitch angle (PA) scattering induced by waves. However, recent satellite observations and modeling studies indicate that cosmic ray albedo neutron decay (CRAND) may also play a significant role in energetic electron dynamics in the slot region. In this study, using a drift‐diffusion‐source model, we investigate the relative contribution of all significant waves and CRAND to the dynamics of energetic electrons in the slot region during July 2014, an extended period of quiet geomagnetic activity. The bounce‐averaged PA diffusion coefficients from three types of waves (hiss, lightning‐generated whistlers [LGW], and very low frequency [VLF] transmitters) are calculated based on quasi‐linear theory, while the CRAND source follows the results in Xiang et al. (2019, https://doi.org/10.1029/2018GL081730). The simulation results indicate that both LGW and VLF transmitter waves can enhance loss and weaken the top hat PA distribution induced by hiss waves. For 470 keV electrons at L = 2.5, simulation results without CRAND show a much quicker decrease than observations from the Van Allen Probes. After including CRAND, simulated electron flux variations reproduce satellite observations, suggesting that CRAND is an important source for hundreds of keV electrons in the slot region during quiet times. The balance between the CRAND source and loss due to wave‐particle interactions provides a lower limit to relativistic electron fluxes in the slot region, which can act as an important reference point for instrument calibration when a true background level is warranted.
Dysregulation of oxytocin and dopamine in the corticostriatal circuitry in bipolar II disorder
Authors: Wei Shyh-Yuh , Tseng Huai-Hsuan , Chang Hui Hua , Lu Tsung-Hua , Chang Wei Hung , Chiu Nan Tsing , Yang Yen Kuang , Chen Po See 
Published: August 2020

AbstractThe oxytocin (OXT) and dopamine systems synergistically facilitate striatal reactivity. Abnormal striatal activation has repeatedly been observed in patients with bipolar disorder (BD); however, such abnormality remains unclear in BD II. Here we aimed to investigate whether the corticostriatal connectivity was altered and the possible relationships among corticostriatal connectivity, OXT, and dopamine systems in BD II. Twenty-five BD II patients, as defined by the DSM-V, and 29 healthy controls (HC) were enrolled in this study. Plasma OXT was measured and striatal dopamine transporter (DAT) availability was assessed using [99mTc]TRODAT-1 single-photon emission computed tomography (SPECT). Brain network functional connectivity (FC) was measured during the resting-state using functional magnetic resonance imaging, and the dorsal caudate (DC) was selected as the seed region. The results showed that the OXT level was significantly lower in the BD II patients, while the striatal DAT availability was not significantly different between the BD II and HC groups. The BD II patients exhibited significantly lower FC between the DC and the executive control network (dorsolateral prefrontal, anterior cingulate cortex, and posterior parietal cortex) as compared with the HC. Only observed in HC, the DC-posterior parietal cortex FC was negatively correlated with the OXT level and striatal DAT availability. Our findings in the HC support a model in which the OXT and dopamine systems act in tandem to regulate corticostriatal circuitry, while the synergistic interaction was perturbed in BD II. Taken together, these results implied a maladaptive neuroplasticity in BD II.
Perceptions of genetic testing in patients with hereditary chronic pancreatitis and their families: a qualitative triangulation
Authors: Müller Regina , Aghdassi Ali A. , Kruse Judith , Lerch Markus M. , Simon Peter , Salloch Sabine 
Published: August 2020

AbstractHereditary chronic pancreatitis (HCP) is a genetically determined condition characterized by intermittent acute episodes of pancreatitis and long-term impairment of the exocrine and endocrine pancreatic functions. Genetic test results can have substantial psychological and social consequences for the individuals tested and their families. Nevertheless, little is known so far about the subjective experience of individuals genetically tested for HCP. This qualitative study examines the viewpoints of HCP patients and their relatives in order to identify the psychosocial and ethical implications related to genetic testing within families. Semi-structured qualitative individual interviews and a focus group with HCP patients and their family members were conducted. Data were audio-recorded, transcribed verbatim and analysed using qualitative content analysis. A total of 28 individuals were enrolled in the study: 24 individuals (17 patients, 7 relatives) were interviewed in semi-structured one-on-one interviews and 4 individuals (2 patients, 2 life partners) participated in the focus group. Emerging topics covered (1) genetic testing in childhood, (2) genetic testing within the family and (3) family planning. The study reveals that genetic testing for HCP has a wide influence in familial contexts and is accompanied by normative issues, such as autonomy, reproductive decisions and sharing of information within the family. The results raise the awareness of the complexity of family contexts: familial relationships and dynamics can have great influence on the individual decisions related to genetic testing. Increased understanding of these relational contexts can help health professionals, for example, in counselling, to discuss genetic testing better with patients and families.
Targeted gene correction of human hematopoietic stem cells for the treatment of Wiskott - Aldrich Syndrome
Authors: Rai Rajeev , Romito Marianna , Rivers Elizabeth , Turchiano Giandomenico , Blattner Georges , Vetharoy Winston , Ladon Dariusz , Andrieux Geoffroy , Zhang Fang , Zinicola Marta , Leon-Rico Diego , Santilli Giorgia , Thrasher Adrian J. , Cavazza Alessia 
Published: August 2020

AbstractWiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency with severe platelet abnormalities and complex immunodeficiency. Although clinical gene therapy approaches using lentiviral vectors have produced encouraging results, full immune and platelet reconstitution is not always achieved. Here we show that a CRISPR/Cas9-based genome editing strategy allows the precise correction of WAS mutations in up to 60% of human hematopoietic stem and progenitor cells (HSPCs), without impairing cell viability and differentiation potential. Delivery of the editing reagents to WAS HSPCs led to full rescue of WASp expression and correction of functional defects in myeloid and lymphoid cells. Primary and secondary transplantation of corrected WAS HSPCs into immunodeficient mice showed persistence of edited cells for up to 26 weeks and efficient targeting of long-term repopulating stem cells. Finally, no major genotoxicity was associated with the gene editing process, paving the way for an alternative, yet highly efficient and safe therapy.
A fluorogenic cyclic peptide for imaging and quantification of drug-induced apoptosis
Authors: Barth Nicole D. , Subiros-Funosas Ramon , Mendive-Tapia Lorena , Duffin Rodger , Shields Mario A. , Cartwright Jennifer A. , Henriques Sónia Troeira , Sot Jesus , Goñi Felix M. , Lavilla Rodolfo , Marwick John A. , Vermeren Sonja , Rossi Adriano G. , Egeblad Mikala , Dransfield Ian , Vendrell Marc 
Published: August 2020

AbstractProgrammed cell death or apoptosis is a central biological process that is dysregulated in many diseases, including inflammatory conditions and cancer. The detection and quantification of apoptotic cells in vivo is hampered by the need for fixatives or washing steps for non-fluorogenic reagents, and by the low levels of free calcium in diseased tissues that restrict the use of annexins. In this manuscript, we report the rational design of a highly stable fluorogenic peptide (termedApo-15) that selectively stains apoptotic cells in vitro and in vivo in a calcium-independent manner and under wash-free conditions. Furthermore, using a combination of chemical and biophysical methods, we identify phosphatidylserine as a molecular target ofApo-15. We demonstrate thatApo-15can be used for the quantification and imaging of drug-induced apoptosis in preclinical mouse models, thus creating opportunities for assessing the in vivo efficacy of anti-inflammatory and anti-cancer therapeutics.
High throughput error corrected Nanopore single cell transcriptome sequencing
Authors: Lebrigand Kevin , Magnone Virginie , Barbry Pascal , Waldmann Rainer 
Published: August 2020

AbstractDroplet-based high throughput single cell sequencing techniques tremendously advanced our insight into cell-to-cell heterogeneity. However, those approaches only allow analysis of one extremity of the transcript after short read sequencing. In consequence, information on splicing and sequence heterogeneity is lost. To overcome this limitation, several approaches that use long-read sequencing were introduced recently. Yet, those techniques are limited by low sequencing depth and/or lacking or inaccurate assignment of unique molecular identifiers (UMIs), which are critical for elimination of PCR bias and artifacts. We introduce ScNaUmi-seq, an approach that combines the high throughput of Oxford Nanopore sequencing with an accurate cell barcode and UMI assignment strategy. UMI guided error correction allows to generate high accuracy full length sequence information with the 10x Genomics single cell isolation system at high sequencing depths. We analyzed transcript isoform diversity in embryonic mouse brain and show that ScNaUmi-seq allows defining splicing and SNVs (RNA editing) at a single cell level.
ADP-dependent glucokinase as a novel onco-target for haematological malignancies
Authors: Tandon Amol , Birkenhagen Jana , Nagalla Deepthi , Kölker Stefan , Sauer Sven Wolfgang 
Published: August 2020

AbstractWarburg effect or aerobic glycolysis provides selective growth advantage to aggressive cancers. However, targeting oncogenic regulators of Warburg effect has always been challenging owing to the wide spectrum of roles of these molecules in multitude of cells. In this study, we present ADP-dependent glucokinase (ADPGK) as a novel glucose sensor and a potential onco-target in specifically high-proliferating cells in Burkitt’s lymphoma (BL). Previously, we had shownADPGKto play a major role in T-cell activation and induction of Warburg effect. We now reportADPGKknock-out Ramos BL cells display abated in vitro and in vivo tumour aggressiveness, via tumour-macrophage co-culture, migration and Zebrafish xenograft studies. We observed perturbed glycolysis and visibly reduced markers of Warburg effect inADPGKknock-out cells, finally leading to apoptosis. We found repression ofMYCproto-oncogene, and up to four-fold reduction in accumulated mutations in translocatedMYCin knock-out cells, signifying a successful targeting of the malignancy. Further, the activation induced differentiation capability of knock-out cells was impaired, owing to the inability to cope up with increased energy demands. The effects amplified greatly upon stimulation-based proliferation, thus providing a novel Burkitt’s lymphoma targeting mechanism originating from metabolic catastrophe induced in the cells by removal ofADPGK.
Hepatocellular carcinoma-derived high mobility group box 1 triggers M2 macrophage polarization via a TLR2/NOX2/autophagy axis
Authors: Shiau Dong-Jer , Kuo Wan-Ting , Davuluri Goutham Venkata Naga , Shieh Chi-Chang , Tsai Pei-Jane , Chen Chien-Chin , Lin Yee-Shin , Wu Yi-Zhen , Hsiao Yu-Peng , Chang Chih-Peng 
Published: August 2020

AbstractIn many human cancers, including hepatocellular carcinoma (HCC), high density of infiltrating tumor-associated macrophages (TAM) is associated with poor prognosis. Most TAMs express a M2 phenotype subsequently supporting tumor growth. How tumor cells polarize these TAMs to a pro-tumor M2 phenotype is still poorly understood. Our previous studies have revealed that a Toll-like receptor 2 (TLR2)-dependent autophagy triggered by hepatoma-derived factors down-regulates NF-κB p65 and drives M2 macrophage differentiation. However, the underlying mechanisms and potential hepatoma-derived TLR2 ligands are not clear. Here, we provide evidence to reveal that NADPH oxidase 2 (NOX2)-dependent reactive oxygen species (ROS) generation is crucial for HCC-induced autophagy, NF-κB p65 down-regulation and M2 phenotype polarization in primary macrophages. This NOX2-generated ROS production in abolished in TLR2-deficient macrophages. HCC-derived or recombinant high-mobility group box 1 (HMGB1) is able to trigger this TLR2-mediated M2 macrophage polarization. Blockage of HMGB1 and ROS by inhibitors, ethyl pyruvate and N-acetylcysteine amide, respectively, significantly reduces both M2 macrophage accumulation and liver nodule formation in HCC-bearing mice. Our findings uncover a HMGB1/TLR2/NOX2/autophagy axis to trigger M2 macrophage polarization in HCC that can be considered as a novel therapeutic target for treating HCC.
Chemical p38 MAP kinase inhibition constrains tissue inflammation and improves antibiotic activity in Mycobacterium tuberculosis-infected mice
Authors: Hölscher Christoph , Gräb Jessica , Hölscher Alexandra , Müller Annie Linnea , Schäfer Stephan C. , Rybniker Jan 
Published: August 2020

AbstractHost-modulating therapies have become an important focus in the development of novel concepts for improved management of tuberculosis (TB). Previous in vitro studies revealed that the p38 MAP kinase signaling pathway coordinates several inflammatory and stress responses in Mycobacterium tuberculosis (Mtb)-infected host cells. Here we extend these findings and show that in vivo treatment of Mtb-infected C57BL/6 mice with doramapimod, a p38 MAP-kinase inhibitor, results in reduced inflammation, granuloma formation and lung pathology. Moreover, doramapimod, together with standard antibiotic treatment, significantly reduced lung and spleen mycobacterial loads compared to antibiotic treatment alone. Our in vivo data suggest the opportunity to repurpose p38 MAPK inhibitors for adjunct host directed therapies. We also provide first data on safety of p38 MAPK inhibition which is of relevance for future application of these substances in inflammatory diseases and concomitant TB.
Metabolites profiling and pharmacokinetics of troxipide and its pharmacodynamics in rats with gastric ulcer
Authors: Guo Hongbin , Chen Baohua , Yan Zihan , Gao Jian , Tang Jiamei , Zhou Chengyan 
Published: August 2020

AbstractTroxipide is widely used to treat gastric ulcer (GU) in the clinic. However, a lack of systematic metabolic, pharmacokinetic and pharmacological studies limits its clinical use. This study aimed to firstly explore the metabolic, pharmacokinetic and pharmacological mechanisms of troxipide in rats with GU compared to normal control (NC) rats. First, metabolic study was perormed by a highly selective, high-resolution mass spectrometry method. A total of 45 metabolites, including 9 phase I metabolites and 36 phase II metabolites, were identified based on MS/MS spectra. Subsequently, the pharmacokinetics results suggested that the Cmax, Ka, t1/2, AUC(0−t) and AUC(0−∞) of troxipide were significantly increased in rats with GU compared with NC rats. The Vz, K10 and absolute bioavailability of troxipide were obviously decreased in rats with GU compared with NC rats, and its tissue distribution (in the liver, lung and kidney) was significantly different between the two groups of rats. Additionally, the pharmacodynamic results suggested that the levels of biochemical factors (IL-17, IL-6, TNF-α, IFN-γ, AP-1, MTL, GAS, and PG-II) were significantly increased, the PG-Ӏ level was obviously decreased, and the protein expression levels of HSP-90, C-Cas-3 and C-PARP-1 were markedly increased in rats with GU compared with NC rats. The above results suggested that the therapeutic mechanisms underlying the metabolic, pharmacokinetic and pharmacological properties of troxipide in vivo in rats deserve further attention based on the importance of troxipide in the treatment of GU in this study, and these mechanisms could be targets for future studies.
The preclinical amyloid sensitive composite to determine subtle cognitive differences in preclinical Alzheimer’s disease
Authors: Hahn Alice , Kim Young Ju , Kim Hee Jin , Jang Hyemin , Cho Hanna , Choi Seong Hye , Kim Byeong C. , Park Kyung Won , Na Duk L. , Chin Juhee , Seo Sang Won 
Published: August 2020

AbstractRecently, the focus of Alzheimer’s disease (AD) research has shifted from the clinical stage to the preclinical stage. We, therefore, aimed to develop a cognitive composite score that can detect the subtle cognitive differences between the amyloid positive (Aβ+) and negative (Aβ−) status in cognitively normal (CN) participants. A total of 423 CN participants with Aβ positron emission tomography images were recruited. The multiple-indicators multiple-causes model found the latent mean difference between the Aβ+ and Aβ− groups in the domains of verbal memory, visual memory, and executive functions. The multivariate analysis of covariance (MANCOVA) showed that the Aβ+ group performed worse in tests related to the verbal and visual delayed recall, semantic verbal fluency, and inhibition of cognitive inference within the three cognitive domains. The Preclinical Amyloid Sensitive Composite (PASC) model we developed using the result of MANCOVA and the MMSE presented a good fit with the data. The accuracy of the PASC score when applied with age, sex, education, and APOE ε4 for distinguishing between Aβ+ and Aβ− was adequate (AUC = 0.764; 95% CI = 0.667–0.860) in the external validation set (N = 179). We conclude that the PASC can eventually contribute to facilitating more prevention trials in preclinical AD.
Dysregulation of ghrelin in diabetes impairs the vascular reparative response to hindlimb ischemia in a mouse model; clinical relevance to peripheral artery disease
Authors: Neale Joshua P. H. , Pearson James T. , Thomas Kate N. , Tsuchimochi Hirotsugu , Hosoda Hiroshi , Kojima Masayasu , Sato Takahiro , Jones Gregory T. , Denny Adam P. , Daniels Lorna J. , Chandrasekera Dhananjie , Liu Ping , van Rij Andre M. , Katare Rajesh , Schwenke Daryl O. 
Published: August 2020

AbstractType 2 diabetes is a prominent risk factor for peripheral artery disease (PAD). Yet, the mechanistic link between diabetes and PAD remains unclear. This study proposes that dysregulation of the endogenous hormone ghrelin, a potent modulator of vascular function, underpins the causal link between diabetes and PAD. Moreover, this study aimed to demonstrate the therapeutic potential of exogenous ghrelin in a diabetic mouse model of PAD. Standard ELISA analysis was used to quantify and compare circulating levels of ghrelin between (i) human diabetic patients with or without PAD (clinic) and (ii) db/db diabetic and non-diabetic mice (lab). Db/db mice underwent unilateral hindlimb ischaemia (HLI) for 14 days and treated with or without exogenous ghrelin (150 µg/kg/day.) Subsequently vascular reparation, angiogenesis, hindlimb perfusion, structure and function were assessed using laser Doppler imaging, micro-CT, microangiography, and protein and micro-RNA (miRNA) analysis. We further examined hindlimb perfusion recovery of ghrelin KO mice to determine whether an impaired vascular response to HLI is linked to ghrelin dysregulation in diabetes. Patients with PAD, with or without diabetes, had significantly lower circulating levels of endogenous ghrelin, compared to healthy individuals. Diabetic db/db mice had ghrelin levels that were only 7% of non-diabetic mice. The vascular reparative capacity of diabetic db/db mice in response to HLI was impaired compared to non-diabetic mice and, importantly, comparable to ghrelin KO mice. Daily therapeutic treatment of db/db mice with ghrelin for 14 days post HLI, stimulated angiogenesis, and improved skeletal muscle architecture and cell survival, which was associated with an increase in pro-angiogenic miRNAs-126 and -132. These findings unmask an important role for endogenous ghrelin in vascular repair following limb ischemia, which appears to be downregulated in diabetic patients. Moreover, these results implicate exogenous ghrelin as a potential novel therapy to enhance perfusion in patients with lower limb PAD, especially in diabetics.