bluuebunny/crossref_metadata_2025_split huggingface dataset:
Infection with mosquito-borne alphavirus induces selective loss of dopaminergic neurons, neuroinflammation and widespread protein aggregation
Authors: Bantle Collin M. , Phillips Aaron T. , Smeyne Richard J. , Rocha Savannah M. , Olson Ken E. , Tjalkens Ronald B. 
Published: September 2019

AbstractNeuroinvasive infections with mosquito-borne alphaviruses such as Western equine encephalitis virus (WEEV) can cause post-encephalitic parkinsonism. To understand the mechanisms underlying these neurological effects, we examined the capacity of WEEV to induce progressive neurodegeneration in outbred CD-1 mice following non-lethal encephalitic infection. Animals were experientally infected with recombinant WEEV expressing firefly luciferase or dsRed (RFP) reporters and the extent of viral replication was controlled using passive immunotherapy. WEEV spread along the neuronal axis from the olfactory bulb to the entorhinal cortex, hippocampus and basal midbrain by 4 days post infection (DPI). Infection caused activation of microglia and astrocytes, selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and neurobehavioral abnormalities. After 8 weeks, surviving mice displayed continued loss of dopamine neurons in the SNpc, lingering glial cell activation and gene expression profiles consistent with a neurodegenerative phenotype. Strikingly, prominent proteinase K-resistant protein aggregates were present in the the entorhinal cortex, hippocampus and basal midbrain that stained positively for phospho-serine129 α-synuclein (SNCA). These results indicate that WEEV may cause lasting neurological deficits through a severe neuroinflammatory response promoting both neuronal injury and protein aggregation in surviving individuals.
Use of a Lymphatic Drug Delivery System and Sonoporation to Target Malignant Metastatic Breast Cancer Cells Proliferating in the Marginal Sinuses
Authors: Kato Shigeki , Shirai Yuko , Sakamoto Maya , Mori Shiro , Kodama Tetsuya 
Published: September 2019

AbstractLymph node (LN) metastasis through the lymphatic network is a major route for cancer dissemination. Tumor cells reach the marginal sinuses of LNs via afferent lymphatic vessels (LVs) and form metastatic lesions that lead to distant metastasis. Thus, targeting of metastatic cells in the marginal sinuses could improve cancer treatment outcomes. Here, we investigated whether lymphatic administration of a drug combined with sonoporation could be used to treat a LN containing proliferating murine FM3A breast cancer cells, which are highly invasive, in its marginal sinus. First, we used contrast-enhanced high-frequency ultrasound and histopathology to analyze the structure of LVs in MXH10/Mo-lpr/lpr mice, which exhibit systemic lymphadenopathy. We found that contrast agent injected into the subiliac LN flowed into the marginal sinus of the proper axillary LN (PALN) and reached the cortex. Next, we examined the anti-tumor effects of our proposed technique. We found that a strong anti-tumor effect was achieved by lymphatic administration of doxorubicin and sonoporation. Furthermore, our proposed method prevented tumor cells in the marginal sinus from invading the parenchyma of the PALN and resulted in tumor necrosis. We conclude that lymphatic administration of a drug combined with sonoporation could exert a curative effect in LNs containing metastatic cells in their marginal sinuses.
pLG72 levels increase in early phase of Alzheimer’s disease but decrease in late phase
Authors: Lin Chieh-Hsin , Chiu Chih-Chiang , Huang Chiung-Hsien , Yang Hui-Ting , Lane Hsien-Yuan 
Published: September 2019

AbstractpLG72, named as D-amino acid oxidase activator (although it is not an activator of D-amino acid oxidase demonstrated by later studies), in mitochondria has been regarded as an important modulator of D-amino acid oxidase that can regulate the N-methyl-D-aspartate receptor (NMDAR). Both oxidative stress in mitochondria and NMDAR neurotransmission play essential roles in the process of neurodegenerative dementia. The aim of the study was to investigate whether pLG72 levels changed with the severity of neurodegenerative dementia. We enrolled 376 individuals as the overall cohort, consisting of five groups: healthy elderly, amnestic mild cognitive impairment [MCI], mild Alzheimer’s disease [AD], moderate AD, and severe AD. pLG72 levels in plasma were measured using Western blotting. The severity of cognitive deficit was principally evaluated by Clinical Dementia Rating Scale. A gender- and age- matched cohort was selected to elucidate the effects of gender and age. pLG72 levels increased in the MCI and mild AD groups when compared to the healthy group. However, pLG72 levels in the moderate and severe AD groups were lower than those in the mild AD group. D-serine level and D- to total serine ratio were significantly different among the five groups. L-serine levels were correlated with the pLG72 levels. The results in the gender- and age- matched cohort were similar to those of the overall cohort. The finding supports the hypothesis of NMDAR hypofunction in early-phase dementia and NMDAR hyperfunction in late-phase dementia. Further studies are warranted to test whether pLG72 could reflect the function of NMDAR.
Lithium-ion Battery Thermal Safety by Early Internal Detection, Prediction and Prevention
Authors: Li Bing , Parekh Mihit H. , Adams Ryan A. , Adams Thomas E. , Love Corey T. , Pol Vilas G. , Tomar Vikas 
Published: September 2019

AbstractTemperature rise in Lithium-ion batteries (LIBs) due to solid electrolyte interfaces breakdown, uncontrollable exothermic reactions in electrodes and Joule heating can result in the catastrophic failures such as thermal runaway, which is calling for reliable real-time electrode temperature monitoring. Here, we present a customized LIB setup developed for early detection of electrode temperature rise during simulated thermal runaway tests incorporating a modern additive manufacturing-supported resistance temperature detector (RTD). An advanced RTD is embedded in a 3D printed polymeric substrate and placed behind the electrode current collector of CR2032 coin cells that can sustain harsh electrochemical operational environments (acidic electrolyte without Redox, short-circuiting, leakage etc.) without participating in electrochemical reactions. The internal RTD measured an average 5.8 °C higher temperature inside the cells than the external RTD with almost 10 times faster detection ability, prohibiting thermal runaway events without interfering in the LIBs’ operation. A temperature prediction model is developed to forecast battery surface temperature rise stemming from measured internal and external RTD temperature signatures.
Fluxomic Analysis Reveals Central Carbon Metabolism Adaptation for Diazotroph Azotobacter vinelandii Ammonium Excretion
Authors: Wu Chao , Herold Ryan A. , Knoshaug Eric P. , Wang Bo , Xiong Wei , Laurens Lieve M. L. 
Published: September 2019

AbstractDiazotrophic bacteria are an attractive biological alternative to synthetic nitrogen fertilizers due to their remarkable capacity to fix atmospheric nitrogen gas to ammonium via nitrogenase enzymes. However, how diazotrophic bacteria tailor central carbon catabolism to accommodate the energy requirement for nitrogenase activity is largely unknown. In this study, we used Azotobacter vinelandii DJ and an ammonium excreting mutant, AV3 (ΔNifL), to investigate central carbon metabolism fluxes and central cell bioenergetics in response to ammonium availability and nitrogenase activity. Enabled by the powerful and reliable methodology of 13C-metabolic flux analysis, we show that the respiratory TCA cycle is upregulated in association with increased nitrogenase activity and causes a monotonic decrease in specific growth rate. Whereas the activity of the glycolytic Entner–Doudoroff pathway is positively correlated with the cell growth rate. These new observations are formulated into a 13C-metabolic flux model which further improves the understanding and interpretation of intracellular bioenergetics. This analysis leads to the conclusion that, under aerobic conditions, respiratory TCA metabolism is responsible for the supply of additional ATP and reducing equivalents required for elevated nitrogenase activity. This study provides a quantitative relationship between central carbon and nitrogen metabolism in an aerobic diazotroph for the first time.
Phylogenetic and functional characterisation of the Haemophilus influenzae multidrug efflux pump AcrB
Authors: Zwama Martijn , Yamaguchi Akihito , Nishino Kunihiko 
Published: September 2019

AbstractMultidrug resistance in Gram-negative bacteria can arise by the over-expression of multidrug efflux pumps, which can extrude a wide range of antibiotics. Here we describe the ancestral Haemophilus influenzae efflux pump AcrB (AcrB-Hi). We performed a phylogenetic analysis of hundreds of RND-type transporters. We found that AcrB-Hi is a relatively ancient efflux pump, which nonetheless can export the same range of antibiotics as its evolved colleague from Escherichia coli. AcrB-Hi was not inhibited by the efflux pump inhibitor ABI-PP, and could export bile salts weakly. This points to an environmental adaptation of RND transporters. We also explain the sensitivity of H. influenzae cells to β-lactams and novobiocin by the outer membrane porin OmpP2. This porin counterbalances the AcrB-Hi efflux by leaking the drugs back into the cells. We hypothesise that multidrug recognition by RND-type pumps is not an evolutionarily acquired ability, and has been present since ancient promiscuous transporters.
Hibernation induces widespread transcriptional remodeling in metabolic tissues of the grizzly bear
Authors: Jansen Heiko T. , Trojahn Shawn , Saxton Michael W. , Quackenbush Corey R. , Evans Hutzenbiler Brandon D. , Nelson O. Lynne , Cornejo Omar E. , Robbins Charles T. , Kelley Joanna L. 
Published: September 2019

AbstractRevealing the mechanisms underlying the reversible physiology of hibernation could have applications to both human and animal health as hibernation is often associated with disease-like states. The present study uses RNA-sequencing to reveal the tissue and seasonal transcriptional changes occurring in grizzly bears (Ursus arctos horribilis). Comparing hibernation to other seasons, bear adipose has a greater number of differentially expressed genes than liver and skeletal muscle. During hyperphagia, adipose has more than 900 differentially expressed genes compared to active season. Hibernation is characterized by reduced expression of genes associated with insulin signaling, muscle protein degradation, and urea production, and increased expression within muscle protein anabolic pathways. Across all three tissues we find a subset of shared differentially expressed genes, some of which are uncharacterized, that together may reflect a common regulatory mechanism. The identified gene families could be useful for developing novel therapeutics to treat human and animal diseases.
Development of R7BP inhibitors through cross-linking coupled mass spectrometry and integrated modeling
Authors: Adikaram Poorni R. , Zhang Jian-Hua , Kittock Claire M. , Pandey Mritunjay , Hassan Sergio A. , Lue Nicole G. , Wang Guanghui , Gucek Marjan , Simonds William F. 
Published: September 2019

AbstractProtein-protein interaction (PPI) networks are known to be valuable targets for therapeutic intervention; yet the development of PPI modulators as next-generation drugs to target specific vertices, edges, and hubs has been impeded by the lack of structural information of many of the proteins and complexes involved. Building on recent advancements in cross-linking mass spectrometry (XL-MS), we describe an effective approach to obtain relevant structural data on R7BP, a master regulator of itch sensation, and its interfaces with other proteins in its network. This approach integrates XL-MS with a variety of modeling techniques to successfully develop antibody inhibitors of the R7BP and RGS7/Gβ5 duplex interaction. Binding and inhibitory efficiency are studied by surface plasmon resonance spectroscopy and through an R7BP-derived dominant negative construct. This approach may have broader applications as a tool to facilitate the development of PPI modulators in the absence of crystal structures or when structural information is limited.
TRPM8 facilitates proliferation and immune evasion of esophageal cancer cells
Authors: Lan Xinyan , Zhao Jun , Song Chunjing , Yuan Qiuxiang , Liu Xiaojun 
Published: September 2019

AbstractEsophageal cancer is seen with increasing incidence, but the underlying mechanism of esophageal cancer is still unknown. Transient receptor potential melastatin (TRPM) is non-selective cation channels. It has been verified that TRPM channels play crucial roles in development and progression of multiple tumors. Increasing studies have shown that TRPM8, a member of TRPM channels, promotes growth of tumors. However, it is still unclear whether TRPM8 has biological effect on esophageal cancer. In the current work, we found that TRPM8 was overexpressed in esophageal cancer samples and cell lines. Further investigation revealed that TRPM8 promoted proliferation of esophageal cancer cells. Next, the co-incubation assay including EC109 cells and CD8+ T cells revealed that TRPM8 overexpression and TRPM8 agonist reduced the cytotoxic effect of CD8+ T cell on esophageal cancer cells. Finally, we explored the mechanism and found that calcineurin-nuclear factor of activated T cells 3 (NFATc3) pathway contributed to the expression of programmed death ligand 1 (PD-L1) induced by TRPM8 overexpression and TRPM8 agonist, which might lead to immune evasion of esophageal cancer cells. These findings uncovered the crucial role of TRPM8 in the pathogenesis of esophageal cancer.
Oxytocin system alleviates intestinal inflammation by regulating macrophages polarization in experimental colitis
Authors: Tang Yan , Shi Yao , Gao Yifei , Xu Xiaomeng , Han Ting , Li Jingxin , Liu Chuanyong 
Published: September 2019

Abstract
Inflammatory bowel disease (IBD) is a chronic intestinal inflammation, but the accurate etiology remains to be elucidated. Increasing evidence has shown that macrophages polarize to different phenotypes depending on the intestinal microenvironment and are associated with the progression of IBD. In the present study, we investigated the effect of oxytocin, a neuroendocrinal, and pro-health peptide, on the modulation of macrophages polarization and the progression of experimental colitis. Our data demonstrated that oxytocin decreased the sensitivity of macrophages to lipopolysaccharide stimulation with lower expression of inflammatory cytokines, like IL-1β, IL-6, and TNF-α, but increased the sensitivity to IL-4 stimulation with enhanced expression of M2-type genes, arginase I (Arg1), CD206, and chitinase-like 3 (Chil3). This bidirectional modulation was partly due to the up-regulation of β-arrestin2 and resulted in the inhibition of NF-κB signaling and reinforcement of Signal transducer and activator of transcription (STAT) 6 phosphorylation. Moreover, oxytocin receptor (OXTR) myeloid deficiency mice were more susceptible to dextran sulfate sodium (DSS) intervention compared with the wild mice. For the first time, we reveal that oxytocin–oxytocin receptor system participates in modulating the polarization of macrophages to an anti-inflammatory phenotype and alleviates experimental colitis. These findings provide new potential insights into the pathogenesis and therapy of IBD.
Intensity Resolution in Individuals With Parkinson's Disease: Sensory and Auditory Memory Limitations
Authors: Richardson Kelly C. , Sussman Joan E. 
Published: September 2019

Purpose
The purpose of the current study was to examine sensory and auditory memory limitations on intensity resolution in individuals with Parkinson's disease as compared to healthy older and younger adults.

Method

Nineteen individuals with Parkinson's disease, 10 healthy age- and hearing-matched adults, and 10 healthy young adults were studied. The listeners participated in 2 intensity discrimination tasks: a lower memory load 4IAX task (sensory limitations) and a higher memory load ABX task (auditory memory limitations). Intensity resolution was examined across groups and tasks using a bias-free measurement of signal detectability known as
d
′ (
d
-prime). Listeners also participated in a loudness scaling task where they were instructed to rate the loudness level of each signal intensity along the experimental continuum using a computerized 150-mm visual analog scale.

Results

Intensity discrimination sensitivity (
d
′) was significantly poorer in the 4IAX and ABX conditions for the individuals with Parkinson's disease, as compared to the older and younger controls. Furthermore, a significant age-related difference was identified for the loudness scaling condition. The younger controls rated most stimuli along the experimental continuum significantly louder as compared to the older controls and the individuals with Parkinson's disease.

Conclusions
The present discrimination data suggest sensory and auditory memory limitations may contribute to the intensity resolution issues associated with Parkinson's disease. Age-related differences in loudness scaling will be reviewed.
Diagnosing Conductive Dysfunction in Infants Using Wideband Acoustic Immittance: Validation and Development of Predictive Models
Authors: Myers Joshua , Kei Joseph , Aithal Sreedevi , Aithal Venkatesh , Driscoll Carlie , Khan Asaduzzaman , Manuel Alehandrea , Joseph Anjali , Malicka Alicja N. 
Published: September 2019

Purpose

The aims of this study were (a) to validate the wideband acoustic immittance (WAI) model developed by
Myers et al. (2018a)
in a new sample of neonates and (b) to develop a prediction model for diagnosing middle ear dysfunction in infants aged 6–18 months using wideband absorbance, controlling for the effect of age.

Method

Tympanometry, distortion product otoacoustic emissions, and WAI were measured in 124 neonates and longitudinally in 357 infants at 6, 12, and 18 months of age. Results of tympanometry and distortion product otoacoustic emissions were used to assess middle ear function of each infant. For the first study, results from the neonates were applied to the diagnostic WAI model developed by
Myers et al. (2018a)
. For the second study, a prediction model was developed using results from the 6- to 18-month-old infants. Results from 1 ear of infants in each age group (6, 12, and 18 months) were used to develop the model. The amount of bias (overfitting) was estimated with bootstrap resampling and by applying the model to the opposite ears (the test sample). Performance was assessed using measures of discrimination (
c
-index) and calibration (calibration curves).

Results

For the validation study, the
Myers et al. (2018a)
model was well calibrated and had a
c
-index of 0.837 when applied to a new sample of neonates. Although this was lower than the apparent performance
c
-index of 0.876 reported by Myers et al., it was close to the bias-corrected estimate of 0.845. The model developed for 6- to 18-month-old infants had satisfactory calibration and apparent, bias-corrected, and test sample
c
-index of 0.884, 0.867, and 0.887, respectively.

Conclusions
The validated and developed models may be clinically useful, and further research validating, updating, and assessing the clinical impact of the models is warranted.
Impact of Nonmodal Phonation on Estimates of Subglottal Pressure From Neck-Surface Acceleration in Healthy Speakers
Authors: Marks Katherine L. , Lin Jonathan Z. , Fox Annie B. , Toles Laura E. , Mehta Daryush D. 
Published: September 2019

Purpose
The purpose of this study was to evaluate the effects of nonmodal phonation on estimates of subglottal pressure (Ps) derived from the magnitude of a neck-surface accelerometer (ACC) signal and to confirm previous findings regarding the impact of vowel contexts and pitch levels in a larger cohort of participants.

Method
Twenty-six vocally healthy participants (18 women, 8 men) were asked to produce a series of p-vowel syllables with descending loudness in 3 vowel contexts (/a/, /i/, and /u/), 3 pitch levels (comfortable, high, and low), and 4 elicited phonatory conditions (modal, breathy, strained, and rough). Estimates of Ps for each vowel segment were obtained by averaging the intraoral air pressure plateau before and after each segment. The root-mean-square magnitude of the neck-surface ACC signal was computed for each vowel segment. Three linear mixed-effects models were used to statistically assess the effects of vowel, pitch, and phonatory condition on the linear relationship (slope and intercept) between Ps and ACC signal magnitude.

Results
Results demonstrated statistically significant linear relationships between ACC signal magnitude and Ps within participants but with increased intercepts for the nonmodal phonatory conditions; slopes were affected to a lesser extent. Vowel and pitch contexts did not significantly affect the linear relationship between ACC signal magnitude and Ps.

Conclusion
The classic linear relationship between ACC signal magnitude and Ps is significantly affected when nonmodal phonation is produced by a speaker. Future work is warranted to further characterize nonmodal phonatory characteristics to improve the ACC-based prediction of Ps during naturalistic speech production.