bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association between temporal muscle thickness and clinical outcomes in patients with newly diagnosed glioblastoma
Authors: An Geon , Ahn Stephen , Park Jae-Sung , Jeun Sin-Soo , Hong Yong-Kil 
Published: July 2020

AbstractPurposeTemporal muscle thickness (TMT) has been suggested as a novel biomarker that can represent sarcopenia in head and neck malignancies. This study investigated the association of TMT with clinical outcomes in patients with newly diagnosed glioblastoma (GBM).Materials and MethodsUsing electronic medical records, all GBM patients between 2008 and 2018 at Seoul St. Mary’s Hospital were reviewed. Total 177 patients met our eligibility criteria.ResultsThe thinner group who had TMT less than the median showed shorter overall survival (OS) and progression-free survival (PFS) than the thicker group who had TMT more than median (OS; 11.0 versus 18.0 months, p < 0.001, and PFS; 6.0 versus 11.0 months, p < 0.001). In the multivariate analysis, the thinner group had negative associations with OS and PFS (OS; HR 2.63 (1.34-2.63), p < 0.001, and PFS; HR 2.21 (1.34-2.50), p = 0.002). We also performed propensity score matching between the thinner and thicker groups to minimize the potential bias. The thinner group showed shorter OS and PFS (OS; 13.5 versus 19.0 months, p = 0.006, and PFS; 6.5 versus 9.0 months, p = 0.028) and had negative associations with OS and PFS than the thicker group (OS; HR 1.90 (1.19-3.03), p = 0.008, and PFS; HR 1.70 (1.07-2.70), p = 0.026) in matched patients.ConclusionOur findings suggest that TMT can be a useful prognostic biomarker for clinical outcomes in GBM patients. Further preclinical and clinical studies could help elucidate this association of sarcopenia with clinical outcomes in GBM patients.
APOE-stratified genome-wide association study suggests potential novel genes for late-onset Alzheimer’s disease in East-Asian descent
Authors: Kang Sarang , Gim Jungsoo , Gunasekaran Tamil Iniyan , Choi Kyu Yeong , Lee Jang Jae , Seo Eun Hyun , Ko Pan-Woo , Chung Ji Yeon , Choi Seong-Min , Lee Young Min , Jeong Jee Hyang , Park Kyung Won , Song Min Kyung , Lee Ho-Won , Kim Ki Woong , Choi Seong Hye , Lee Dong Young , Kim Sang Yun , Kim Hoowon , Kim Byeong C. , Ikeuchi Takeshi , Lee Kun Ho 
Published: July 2020

ABSTRACTIn this study, we report two new possible susceptible genes for late-onset Alzheimer’s disease identified through an APOE-stratified genome-wide association analysis (GWAS) using East Asian samples. In the discovery phase, we performed a GWAS of Alzheimer’s disease in 2,291 Korean seniors from the Gwangju Alzheimer’s and Related Dementias (GARD) cohort study. A successive replication analysis with a Japanese sample of size 1,956 suggested three novel susceptible SNPs in two genes: LRIG1 and CACNA1A. This study demonstrates that the discovery of AD-associated variants can be accomplished in non-European ethnic groups with a more homogeneous genetic background using samples comprising fewer subjects.
Ultrametric model for covid-19 dynamics: an attempt to explain slow approaching herd immunity in Sweden
Authors: Khrennikov Andrei 
Published: July 2020

AbstractWe present a mathematical model of infection dynamics that might explain slower approaching the herd immunity during the covid-19 epidemy in Sweden than it was predicted by a variety of other models; see graphs Fig. 2. The new model takes into account the hierarchic structure of social clusters in the human society. We apply the well developed theory of random walk on the energy landscapes represented mathematically with ultrametric spaces. This theory was created for applications to spin glasses and protein dynamics. To move from one social cluster (valley) to another, the virus (its carrier) should cross a social barrier between them. The magnitude of a barrier depends on the number of social hierarchy’s levels composing this barrier. As the most appropriate for the recent situation in Sweden, we consider linearly increasing (with respect to hierarchy’s levels) barriers. This structure of barriers matches with a rather soft regulations imposed in Sweden in March 2020. In this model, the infection spreads rather easily inside a social cluster (say working collective), but jumps to other clusters are constrained by social barriers. This model’s feature matches with the real situation during the covid-19 epidemy, with its cluster spreading structure. Clusters need not be determined solely geographically, they are based on a number of hierarchically ordered social coordinates. The model differs crucially from the standard mathematical models of spread of disease, such as the SIR-model. In particular, our model describes such a specialty of spread of covid-19 virus as the presence of “super-spreaders” who by performing a kind of random walk on a hierarchic landscape of social clusters spreads infection. In future, this model will be completed by adding the SIR-type counterpart. But, the latter is not a specialty of covid-19 spreading.
Repurposed Drugs Block Toxin-Driven Platelet Clearance by the Hepatic Ashwell-Morell Receptor to ClearStaphylococcus aureusBacteremia
Authors: Sun Josh , Uchiyama Satoshi , Olson Joshua , Morodomi Yosuke , Cornax Ingrid , Ando Nao , Kohno Yohei , Kyaw May M. T. , Aguilar Bernice , Haste Nina M. , Kanaji Sachiko , Kanaji Taisuke , Rose Warren E. , Sakoulas George , Marth Jamey D. , Nizet Victor 
Published: July 2020

ABSTRACTStaphylococcus aureus(SA) bloodstream infections cause high morbidity and mortality (20-30%) despite modern supportive care. In a human bacteremia cohort, development of thrombocytopenia was correlated to increased mortality and increased α-toxin expression by the pathogen. Platelet-derived antibacterial peptides are important in bloodstream defense against SA, but α-toxin decreased platelet viability, induced platelet sialidase to cause desialylation of platelet glycoproteins, and accelerated platelet clearance by the hepatic Ashwell-Morell receptor (AMR). Ticagrelor (Brilinta®), a commonly prescribed P2Y12 receptor inhibitor used post-myocardial infarction, blocked α-toxin-mediated platelet injury and resulting thrombocytopenia, thus providing protection from lethal SA infection in a murine intravenous challenge model. Genetic deletion or pharmacological inhibition of AMR stabilized platelet counts and enhanced resistance to SA infection, and the anti-influenza sialidase inhibitor oseltamivir (Tamiflu®) provided similar therapeutic benefit. Thus a “toxin-platelet-AMR” regulatory pathway plays a critical role in the pathogenesis of SA bloodstream infection, and its elucidation provides proof-of-concept for repurposing two FDA-approved drugs as adjunctive therapies to improve patient outcomes.
AXL is a key factor for cell plasticity and promotes metastasis in pancreatic cancer
Authors: Du Wenting , Huang Huocong , Wang Zhaoning , Toombs Jason E. , Phinney Natalie Z. , Zhang Yuqing , Beg Muhammad S. , Wilkie Thomas M. , Lorens James B. , Brekken Rolf A. 
Published: July 2020

AbstractPancreatic ductal adenocarcinoma (PDA), a leading cause of cancer-related death in the US, has a high metastatic rate and is associated with persistent immune suppression. AXL, a member of the TAM (TYRO3, AXL, MERTK) receptor tyrosine kinase family, has been identified as a driver of metastasis and immune suppression in multiple cancer types. Here we use single cell RNA sequencing to reveal that AXL is expressed highly in tumor cells that have a mesenchymal-like phenotype and that AXL expression correlates with classic markers of mesenchymal tumor cells. We demonstrate thatAXL-deficiencyextends survival, reduces primary and metastatic burden and enhances sensitivity to gemcitabine in an autochthonous model of PDA. PDA inAXL-deficientmice displayed a more differentiated histology, higher nucleoside transporter expression and a more active immune microenvironment compared to PDA inwild-typemice. Finally, we demonstrate that AXL-positive mesenchymal tumor cells are critical for PDA progression and metastasis, emphasizing the potential of AXL as a therapeutic target for PDA patients.
KDS2010, a newly developed reversible MAO-B inhibitor, as an effective therapeutic candidate for Parkinson’s disease
Authors: Nam Min-Ho , Park Jong-Hyun , Song Hyo Jung , Choi Ji Won , Kim Siwon , Jang Bo Ko , Yoon Hyung Ho , Heo Jun Young , Cho Doo-Wan , Yang Young-Su , Han Su-Cheol , Kim Sangwook , Oh Soo-Jin , Jeon Sang Ryong , Park Ki Duk , Lee C. Justin 
Published: July 2020

AbstractBackground and PurposeMonoamine oxidase-B (MAO-B) is a long-standing therapeutic target for Parkinson’s disease (PD), however, previous clinical studies demonstrated discouraging effects of currently available irreversible MAO-B inhibitors. Since KDS2010, a novel, potent, selective, and reversible MAO-B inhibitor, has been developed, here we tested its therapeutic potential in animal models of PD.Experimental ApproachWe designed and synthesized α-aminoamide derivatives and compared the specificity to MAO-B and reversibility of each compound with KDS2010. To investigate the in vivo therapeutic effect, we used MPTP mouse model with two different regimes of 3-day administration (pre-treatment or post-treatment) and 30-day administration. We assessed the therapeutic potential using behavioral and immunohistochemical analyses. Additionally, the functional recovery by KDS2010 was tested in 6-hydroxydopamine-induced and A53T-alpha-synuclein overexpression models. Lastly, to validate the potential as a clinical drug candidate, we investigated the pharmacokinetics and toxicity of KDS2010 in non-human primates.Key ResultsKDS2010 showed the highest potency, specificity, and reversibility among the α-aminoamide derivatives, with high bioavailability (>100%) and BBB permeability. KDS2010 also showed significant neuroprotective and anti-neuroinflammatory effects in the nigrostriatal pathway, leading to an alleviation of MPTP-induced parkinsonism in all administration regimes. In particular, the therapeutic effect of KDS2010 was superior to selegiline, an irreversible MAO-B inhibitor. KDS2010 also showed a potent therapeutic effect in 6-hydroxydopamine and A53T models. Moreover, KDS2010 showed virtually no toxicity or side-effect in non-human primates.Conclusion and ImplicationsKDS2010 shows excellent therapeutic potential and safety in various PD animal models. KDS2010, therefore, could be a next-generation therapeutic candidate for PD.Representative SchematicWhat is already knownKDS2010 is a recently developed potent, selective, and reversible MAO-B inhibitor.MAO-B is critical for PD pathology through astrocytic GABA and H2O2synthesis.What this study addsKDS2010 treatment dramatically recovers from PD-related pathology and motor deficit after pre- and post-treatment regimes in several animal models of PD.KDS2010 exhibits low toxicity and excellent pharmacokinetic profile in non-human primates.What is the clinical significance?KDS2010 is a safe and promising therapeutic candidate for Parkinson’s disease.Reversible MAO-B inhibitors could be more effective for treatment of Parkinson’s disease, overcoming the short-lived actions of irreversible MAO-B inhibitors.
RNF219 interacts with CCR4-NOT in regulating stem cell differentiation
Authors: Du Hao , Chen Chen , Wang Yan , Yang Yang , Che Zhuanzhuan , Liu Xiaoxu , Meng Siyan , Guo Chenghao , Xu Manman , Fang Haitong , Lin Chengqi , Luo Zhuojuan 
Published: July 2020

ABSTRACTRegulation of RNA stability plays a crucial role in gene expression control. Deadenylation is the initial rate-limiting step for the majority of RNA decay events. Here, we show that RING Finger Protein 219 (RNF219) interacts with the CCR4-NOT deadenylase complex. RNF219-CCR4-NOT exhibits deadenylation activityin vitro. RNA-seq analyses identify some of the 2-cell specific genes and the neuronal genes significantly down-regulated upon RNF219 knockdown, while up-regulated after depletion of the CCR4-NOT subunit CNOT10 in mouse embryonic stem (ES) cells. RNF219 depletion leads to impaired neuronal lineage commitment during ES cell differentiation. Our study suggests that RNF219 is a novel interacting partner of CCR4-NOT, and required for maintenance of ES cell pluripotency.
A High-efficacy CRISPRi System for Gene Function Discovery inZymomonas mobilis
Authors: Banta Amy B. , Enright Amy L. , Siletti Cheta , Peters Jason M. 
Published: July 2020

ABSTRACTZymomonas mobilisis a promising biofuel producer due to its high alcohol tolerance and streamlined metabolism that efficiently converts sugar to ethanol.Z. mobilisgenes are poorly characterized relative to model bacteria, hampering our ability to rationally engineer the genome with pathways capable of converting sugars from plant hydrolysates into valuable biofuels and bioproducts. Many of the unique properties that makeZ. mobilisan attractive biofuel producer are controlled by essential genes; however, these genes cannot be manipulated using traditional genetic approaches (e.g., deletion or transposon insertion) because they are required for viability. CRISPR interference (CRISPRi) is a programmable gene knockdown system that can precisely control the timing and extent of gene repression, thus enabling targeting of essential genes. Here, we establish a stable, high-efficacy CRISPRi system inZ. mobilisthat is capable of perturbing all genes—including essentials. We show thatZ. mobilisCRISPRi causes either strong knockdowns (>100-fold) using single guide RNA (sgRNA) spacers that perfectly match target genes, or partial knockdowns using spacers with mismatches. We demonstrate the efficacy ofZ. mobilisCRISPRi by targeting essential genes that are universally conserved in bacteria, key to the efficient metabolism ofZ. mobilis, or underlie alcohol tolerance. OurZ. mobilisCRISPRi system will enable comprehensive gene function discovery, opening a path to rational design of biofuel production strains with improved yields.IMPORTANCEBiofuels produced by microbial fermentation of plant feedstocks provide renewable and sustainable energy sources that have the potential to mitigate climate change and improve energy security. Engineered strains of the bacteriumZ. mobiliscan convert sugars extracted from plant feedstocks into next generation biofuels such as isobutanol; however, conversion by these strains remains inefficient due to key gaps in our knowledge about genes involved in metabolism and stress responses such as alcohol tolerance. Here, we develop CRISPRi as a tool to characterize gene function inZ. mobilis. We identify genes that are essential for growth, required to ferment sugar to ethanol, and involved in resistance to alcohol. OurZ. mobilisCRISPRi system makes it straightforward to define gene function and can be applied to improve strain engineering and increase biofuel yields.
Simple phenotypic tests to improve accuracy in screening chromosomal and plasmid-mediated colistin resistance in gram-negative bacilli
Authors: Pasteran Fernando , Danze Diego , Menocal Alejandra , Cabrera Carla , Castillo Ignacio , Albornoz Ezequiel , Lucero Celeste , Rapoport Melina , Ceriana Paola , Corso Alejandra 
Published: July 2020

ABSTRACTCLSI and EUCAST recommends that only broth microdilution (BMD) should be used for routine colistin susceptibility testing, however, it could be difficult to perform in resource-poor settings. The purpose of this study was to evaluate the accuracy of an agar spot test (COL-AS) and a colistin drop test (COL-DT) as compared to BMD. COL-AS and COL-DT were challenged with a collection of 271 Gram-negative bacilli clinical isolates: 195 Enterobacterales (including 63 mcr-1 positive strains), 37 Acinetobacter spp. and 39 P. aeruginosa. For COL-AS, 3.0µg/ml (final concentration) of colistin was added to a Mueller-Hinton agar plate and subsequently swabbed with a 0.5 McFarland suspension of tested strain within 1cm2 spot. For COL-DT, 10µl of a 16µg/ml colistin solution was dripped on the surface of a Mueller-Hinton agar plate, previously inoculated with a lawn of tested strain (0.5 McFarland). Colistin solution was made either, by dissolving powder or by disk elution in CA-MHB. Overall, 141/271 (52%) isolates were categorized as colistin resistant by reference BMD. COL-AS yielded a categorical agreement (CA) of 95.5% compared to BMD, with 0.7% very major errors and 3.8% major errors. COL-DR yielded a CA of 96.2% compared to BMD, with 0.7% and 0% very major errors and 3.1% and 3.8% major errors, for colistin powder and disk elution solutions, respectively. Most major errors occurred for mcr-1 producing strains with MICs that fluctuated from 2 to 4 μg/ml. In conclusion, we developed and validated methods suited to the systematic screening of resistance to colistin in gram negative bacilli.Clinical relevancecolistin continues to be one of the last-line therapeutic options to treat carbapenemase-producing gram negative bacilli. The BMD reference methodology, the only one accepted by current standards for evaluating colistin sensitivity, is difficult to implement in laboratories from low-resource countries. In this work, we propose two simple methodologies to screen for colistin resistance, with a performance equivalent to the reference method in detecting resistance to colistin, both of plasmid (mcr) and chromosomal nature. Furthermore, the methods validated here allowed a better identification of those producers of mcr producer with borderline MICs. These screening tests can be routinely performed in addition to the tests currently in use. showed long stability during storage and some of them do not require colistin powder as the source of antibiotic, an important limitation in low-resource countries.
Prolonged inhibitory effect of repeated period tibial nerve stimulation on the micturition reflex in the rat
Authors: Zeng Jiawen , Zeng Shaohua , Jiang Chonghe , Lindström Sivert 
Published: July 2020

AbstractBackgroundThe aims of this study was determine if stimulation of tibial nerve afferents could induce a prolonged modulation of the micturition reflex in the rats.MethodsFifteen female Sprague Dawley rats (250-350 g) were fully decorticated and paralysed for the study. Tibial nerve stimulation (TNS) was delivered by inserting two pairs of needle electrodes close to the nerves at the level of the medial malleolus. Constant flow cystometries (0.07 ml/min) at about 10 min interval were performed and the micturition threshold volume (MTV) was recorded and used as the dependent variable. After 4 – 5 stable control recordings, the tibial nerves of both sides were stimulated continuously for 5 min at 10 Hz, 3 times threshold for α-motor axons. Six times of same stimulation were applied repeatedly with an interval of 5 min between the stimulations. The mean MTV was compiled from several cystometries in each half hour before the TNS and during, after 6 periods TNS.ResultsDuring the experiment, all the animals survived in a good condition with reasonably stable micturition reflexes, a significant increase in MTV was revealed after TNS. The best effect (mean 178%) occurred during the first 30 min after 6 periods of stimulation. This clear threshold increase remained for at least 5 h.ConclusionsA prolonged increase in MTV was demonstrated by a short periods of TNS repeatedly. This post stimulation modulatory effects of micturition reflex would provide a theoretical explanation for the clinical beneficial effect of TNS in patients with overactive bladder (OAB).
Curcumin combined with Glu-GNPs enhancing radiosensitivity of transplanted tumor of MDA-MB-231-luc cells in nude mice
Authors: Li Mengjie , Guo Tingting , Wu Yujian , Lin Jiayi , Yang Ke , Hu Chenxia 
Published: July 2020

AbstractBreast cancer is the first cause of cancer death in women all over the world. And the morbidity of breast cancer has been increasing in recent years. Nowadays, the treatment of breast cancer is still a problem. Radiotherapy resistance is one of the important factors leading to poor prognosis of clinical treatment. Curcumin, a plant polyphenol from Curcuma longa, has antitumor activity and inhibition of tumor recurrence and metastasis. However, the influence of curcumin on radiosensitivity of breast carcinoma xenografts, the synergistic effect and possible mechanism of curcumin and Glucose-Gold nanoparticles (Glu-GNPs) in nude mice in vivo need to be further explored. The model of transplanted tumor in nude mice was established and sensitized by intravenous injection of curcumin and Glu-GNPs. The results showed that curcumin can significantly inhibit the growth of tumor, and has no obvious effect on the body weight of nude mice, and Curcumin, Glu-GNPs and X-ray irradiation treatment alone or in combination could reduce the expression ofVEGFandHSP90mRNA and protein compared with model group in tumor tissue. The inhibition of irradiation resistance may be related to inhibiting the synthesis ofVEGFandHSP90. This study suggested that curcumin and Glu-GNPs have the radiosensitization effect in vivo, which provides an experimental basis for the clinical development of green radiosensitizers.
Analysis of the transcriptome and DNA methylome in response to acute and recurrent low glucose in human primary astrocytes
Authors: Potter Paul G Weightman , Washer Sam , Jeffries Aaron R , Holley Janet E , Gutowski Nick J , Dempster Emma , Beall Craig 
Published: July 2020

ABSTRACTAims/hypothesisRecurrent hypoglycaemia (RH) is a major side-effect of intensive insulin therapy for people with diabetes. Changes in hypoglycaemia sensing by the brain contribute to the development of impaired counterregulatory responses to and awareness of hypoglycaemia. Little is known about the intrinsic changes in human astrocytes in response to acute and recurrent low glucose (RLG) exposure.MethodsHuman primary astrocytes (HPA) were exposed to zero, one, three or four bouts of low glucose (0.1 mmol/l) for three hours per day for four days to mimic RH. On the fourth day, DNA and RNA were collected. Differential gene expression and ontology analyses were performed using DESeq2 and GOseq respectively. DNA methylation was assessed using the Infinium MethylationEPIC BeadChip platform.Results24 differentially expressed genes (DEGs) were detected (after correction for multiple comparisons). One bout of low glucose exposure had the largest effect on gene expression. Pathway analyses revealed that endoplasmic-reticulum (ER) stress-related genes such asHSPA5,XBP1, andMANF, involved in the unfolded protein response (UPR), were all significantly increased following LG exposure, which was diminished following RLG. There was little correlation between differentially methylated positions and changes in gene expression yet the number of bouts of LG exposure produced distinct methylation signatures.Conclusions/interpretationThese data suggest that exposure of human astrocytes to transient LG triggers activation of genes involved in the UPR linked to endoplasmic reticulum (ER) stress. Following RLG, the activation of UPR related genes was diminished, suggesting attenuated ER stress. This may be mediated by metabolic adaptations to better preserve intracellular and/or ER ATP levels, but this requires further investigation.
Single species RNA purification with DNA nanoswitches
Authors: Zhou Lifeng , Cavaliere Cassandra , Hayden Andrew , Dey Paromita , Mao Song , Chandrasekaran Arun Richard , Sheng Jia , Dey Bijan K. , Halvorsen Ken 
Published: July 2020

AbstractWe report a novel method to purify individual RNA species using programmable DNA nanoswitches to facilitate RNA capture, release, and isolation. We validate sequence-based purification of microRNA, rRNA, and an mRNA fragment from total RNA, demonstrate multiplexing with two different RNA species, and show an application with downstream LC/MS analysis to identify RNA modifications. The simplicity, low cost, and low sample requirements of our method make it suitable for easy adoption.