bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tomorou attenuates progression of rheumatoid arthritis through alteration in ULK-1 independent autophagy pathway in collagen induced arthritis mice model
Authors: Jannat Arooma , John Peter , Bhatti Attya , Hayat Muhammad Qasim 
Published: November 2019

AbstractRheumatoid arthritis (RA) is a multifactorial disease which is complicated by apoptosis resistance. Autophagy is one of the key mechanisms which are involved in the development of resistance to apoptosis as well as to the standard therapies against RA. Aberration in autophagy and apoptosis homeostasis results in the development of oxidative stress thus complicates the pathogenesis of RA. In the given study, tomorou, an indigenous herb of Hunza-Nagar Valley, has been evaluated for its pro-apoptotic, anti-inflammatory, and anti-rheumatic activity. Several major classes of bioactive phytochemicals including steroids, terpenoids, phenols, flavonoids, and essential oils have been detected in the aqueous and ethyl acetate extracts of tomorou through phytochemical analysis. Plant extracts depicted enhanced free radical scavenging activity through di-phenyl-2-picryl hydrazyl hydrate (DPPH) assay and ameliorated the symptoms of arthritis in collagen induced arthritic (CIA) mice model. Moreover, the 6 week extract treatment resulted in the reduction of IL-6 serum levels thus making it an effective anti-inflammatory agent. Upregulation of microtubule-associated proteins light chain 3b (LC3b) and downregulation of UNC51-like kinase 1 (ULK-1) in arthritic mice proposed a ULK-1 independent non-canonical autophagy pathway. Treatment with extracts upregulated the expression of caspase 3 which in turn inhibited the activity of LC3b thus altering the autophagy pathway. However, ULK-1 expression was restored to normal in aqueous extract treated group whereas it was upregulated in ethyl acetate extract treated group. On the other hand, a novel LC3b-independent autophagy pathway was observed in mice treated with ethyl acetate extract due to ULK-1 upregulation. Despite of significantly high IL-6 levels, the arthritic symptoms waned off which suggested the participation of IL-6 in LC3b-independent autophagy pathway in the extract prepared in ethyl acetate. Conclusively, the study established pro-apoptotic, antioxidant, anti-inflammatory and anti-rheumatic activity of tomorou and suggested an intricate autophagy pathway shift.
Identification of predictors of drug sensitivity using patient-derived models of esophageal squamous cell carcinoma
Authors: Su Dan , Zhang Dadong , Jin Jiaoyue , Ying Lisha , Han Miao , Chen Kaiyan , Li Bin , Wu Junzhou , Xie Zhenghua , Zhang Fanrong , Lin Yihui , Cheng Guoping , Li Jing-Yu , Huang Minran , Wang Jinchao , Wang Kailai , Zhang Jianjun , Li Fugen , Xiong Lei , Futreal Andrew , Mao Weimin 
Published: November 2019

AbstractPrevious studies from the Cancer Cell Line Encyclopedia (CCLE) project have adopted commercial pan-cancer cell line models to identify drug sensitivity biomarkers. However, drug sensitivity biomarkers in esophageal squamous cell carcinoma (ESCC) have not been widely explored. Here, eight patient-derived cell lines (PDCs) are successfully established from 123 patients with ESCC. The mutation profiling of PDCs can partially recapture the tumor tissue actionable mutations from 161 patients with ESCC. Based on these mutations and relative pathways in eight PDCs, 46 targeted drugs are selected for screening. Interestingly, some drug and biomarker relationships are established that were not discovered in the CCLE project. For example, CDKN2A or CDKN2B loss is significantly associated with the sensitivity of CDK4/6 inhibitors. Furthermore, both PDC xenografts and patient-derived xenografts confirm CDKN2A/2B loss as a biomarker predictive of CDK4/6 inhibitor sensitivity. Collectively, patient-derived models could predict targeted drug sensitivity associated with actionable mutations in ESCC.
Foxp1 controls brown/beige adipocyte differentiation and thermogenesis through regulating β3-AR desensitization
Authors: Liu Pei , Huang Sixia , Ling Shifeng , Xu Shuqin , Wang Fuhua , Zhang Wei , Zhou Rujiang , He Lin , Xia Xuechun , Yao Zhengju , Fan Ying , Wang Niansong , Hu Congxia , Zhao Xiaodong , Tucker Haley O. , Wang Jiqiu , Guo Xizhi 
Published: November 2019

Abstractβ-Adrenergic receptor (β-AR) signaling is a pathway controlling adaptive thermogenesis in brown or beige adipocytes. Here we investigate the biological roles of the transcription factor Foxp1 in brown/beige adipocyte differentiation and thermogenesis. Adipose-specific deletion of Foxp1 leads to an increase of brown adipose activity and browning program of white adipose tissues. The Foxp1-deficient mice show an augmented energy expenditure and are protected from diet-induced obesity and insulin resistance. Consistently, overexpression of Foxp1 in adipocytes impairs adaptive thermogenesis and promotes diet-induced obesity. A robust change in abundance of the β3-adrenergic receptor (β3-AR) is observed in brown/beige adipocytes from both lines of mice. Molecularly, Foxp1 directly represses β3-AR transcription and regulates its desensitization behavior. Taken together, our findings reveal Foxp1 as a master transcriptional repressor of brown/beige adipocyte differentiation and thermogenesis, and provide an important clue for its targeting and treatment of obesity.
Homogentisic acid-derived pigment as a biocompatible label for optoacoustic imaging of macrophages
Authors: Weidenfeld Ina , Zakian Christian , Duewell Peter , Chmyrov Andriy , Klemm Uwe , Aguirre Juan , Ntziachristos Vasilis , Stiel Andre C. 
Published: November 2019

AbstractMacrophages are one of the most functionally-diverse cell types with roles in innate immunity, homeostasis and disease making them attractive targets for diagnostics and therapy. Photo- or optoacoustics could provide non-invasive, deep tissue imaging with high resolution and allow to visualize the spatiotemporal distribution of macrophages in vivo. However, present macrophage labels focus on synthetic nanomaterials, frequently limiting their ability to combine both host cell viability and functionality with strong signal generation. Here, we present a homogentisic acid-derived pigment (HDP) for biocompatible intracellular labeling of macrophages with strong optoacoustic contrast efficient enough to resolve single cells against a strong blood background. We study pigment formation during macrophage differentiation and activation, and utilize this labeling method to track migration of pro-inflammatory macrophages in vivo with whole-body imaging. We expand the sparse palette of macrophage labels for in vivo optoacoustic imaging and facilitate research on macrophage functionality and behavior.
Independent control of the thermodynamic and kinetic properties of aptamer switches
Authors: Wilson Brandon D. , Hariri Amani A. , Thompson Ian A. P. , Eisenstein Michael , Soh H. Tom 
Published: November 2019

AbstractMolecular switches that change their conformation upon target binding offer powerful capabilities for biotechnology and synthetic biology. Aptamers are useful as molecular switches because they offer excellent binding properties, undergo reversible folding, and can be engineered into many nanostructures. Unfortunately, the thermodynamic and kinetic properties of the aptamer switches developed to date are intrinsically coupled, such that high temporal resolution can only be achieved at the cost of lower sensitivity or high background. Here, we describe a design strategy that decouples and enables independent control over the thermodynamics and kinetics of aptamer switches. Starting from a single aptamer, we create an array of aptamer switches with effective dissociation constants ranging from 10 μM to 40 mM and binding kinetics ranging from 170 ms to 3 s. Our strategy is broadly applicable to other aptamers, enabling the development of switches suitable for a diverse range of biotechnology applications.
Evidence for a causal role by mouse mammary tumour-like virus in human breast cancer
Authors: Lawson James S. , Glenn Wendy K. 
Published: November 2019

AbstractWe have reviewed the evidence relevant to mouse mammary tumour viruses (MMTV) and human breast cancer. The prevalence of MMTV- like gene sequences is 15-fold higher in human breast cancer than in normal human breast tissue controls and is present in up to 40% of human breast cancers. MMTV-like gene sequences can be identified in benign breast tissues 1–11 years before the development of positive MMTV-like breast cancer in the same women. The prevalence of MMTV antibodies in sera from women with breast cancer is 5-fold higher than in normal women. MMTV can infect human breast epithelial cells and integrate at random into the human genome located in those cells. MMTV-like gene sequences are present in human milk from normal lactating women and with increased prevalence in milk from women at risk of breast cancer. MMTV-like virus associated human breast cancer has strikingly similar features to MMTV-associated mouse mammary tumours. These features include almost identical nucleotide sequences and structure of the MMTV genome, histology, superantigen expression, MMTV infection of B and T lymphocytes and hormone dependence. MMTV-like gene sequences have also been identified in dogs, cats, monkeys, mice and rats. Saliva has been identified as the most plausible means of transmission from human to human and possibly from dogs to humans. The evidence meets the classic causal criteria. A causal role for MMTV-like viruses in human breast cancer is highly likely.
Viral emergence in marine mammals in the North Pacific may be linked to Arctic sea ice reduction
Authors: VanWormer E. , Mazet J. A. K. , Hall A. , Gill V. A. , Boveng P. L. , London J. M. , Gelatt T. , Fadely B. S. , Lander M. E. , Sterling J. , Burkanov V. N. , Ream R. R. , Brock P. M. , Rea L. D. , Smith B. R. , Jeffers A. , Henstock M. , Rehberg M. J. , Burek-Huntington K. A. , Cosby S. L. , Hammond J. A. , Goldstein T. 
Published: November 2019

AbstractClimate change-driven alterations in Arctic environments can influence habitat availability, species distributions and interactions, and the breeding, foraging, and health of marine mammals. Phocine distemper virus (PDV), which has caused extensive mortality in Atlantic seals, was confirmed in sea otters in the North Pacific Ocean in 2004, raising the question of whether reductions in sea ice could increase contact between Arctic and sub-Arctic marine mammals and lead to viral transmission across the Arctic Ocean. Using data on PDV exposure and infection and animal movement in sympatric seal, sea lion, and sea otter species sampled in the North Pacific Ocean from 2001–2016, we investigated the timing of PDV introduction, risk factors associated with PDV emergence, and patterns of transmission following introduction. We identified widespread exposure to and infection with PDV across the North Pacific Ocean beginning in 2003 with a second peak of PDV exposure and infection in 2009; viral transmission across sympatric marine mammal species; and association of PDV exposure and infection with reductions in Arctic sea ice extent. Peaks of PDV exposure and infection following 2003 may reflect additional viral introductions among the diverse marine mammals in the North Pacific Ocean linked to change in Arctic sea ice extent.
Cellular elements in the developing caecum of Japanese quail (Coturnix coturnix japonica): morphological, morphometrical, immunohistochemical and electron-microscopic studies
Authors: AbuAli Aalaa M. , Mokhtar Doaa M. , Ali Reda A. , Wassif Ekbal T. , Abdalla K. E. H 
Published: November 2019

AbstractThe present study aims to investigate the histological, histochemical and electron microscopic changes of the caecal proximal part of Japanese quail during both pre- and post-hatching periods starting from the 2ndembryonic day (ED) until four weeks post-hatching. On the 2ndand 3rdED, the primordia of caeca appeared as bilateral swelling on the wall of the hindgut. On the 7thED, the lamina propria/submucosa contained the primordia of glands. On the 8thED, rodlet cells could be observed amongst the epithelial cells. On the 9thED, the caeca began to divide into three parts with more developed layers. With age, the height and number of villi increased. On the 13thED, immature microfold cells (M-cells) could be identified between the surface epithelium of the villi. The caecal tonsils (CTs) appeared in the form of aggregations of lymphocytes, macrophages, dendritic cells and different types of leukocytes. Telocytes and crypts of Lieberkuhn were observed at this age. On hatching day, the crypts of Lieberkuhn were well-defined and formed of low columnar epithelium, goblet cells, and enteroendocrine cells. Post-hatching, the lumen was filled with villi that exhibited two forms: (1) tongue-shaped villi with tonsils and (2) finger-shaped ones without tonsils. The villi lining epithelium contained simple columnar cells with microvilli that were dispersed with many goblet cells, in addition to the presence of a high number of intra-epithelial lymphocytes and basophils. Moreover, the submucosa was infiltrated by numerous immune cells. CD3 immunomarker was expressed in intraepithelial lymphocytes, while CD20 immunomarker showed focal positivity in CTs. In conclusion, the caecal immune structures of quails at post-hatching were more developed than those in pre-hatching life. The high frequency of immune cells suggests that this proximal part may be a site for immunological surveillance in the quail caecum. The cellular organisation of the caecum and its relation to the immunity was discussed.
Novel QUEST MRI In Vivo Measurement of Noise-induced Oxidative Stress in the Cochlea
Authors: Kühl André , Dixon Angela , Hali Mirabela , Apawu Aaron K. , Muca Antonela , Sinan Moaz , Warila James , Braun Rod D. , Berkowitz Bruce A. , Holt Avril Genene 
Published: November 2019

AbstractEffective personalized therapeutic treatment for hearing loss is currently not available. Cochlear oxidative stress is commonly identified in the pathogenesis of hearing loss based upon findings from excised tissue, thus suggesting a promising druggable etiology. However, the timing and site(s) to target for anti-oxidant treatment in vivo are not clear. Here, we address this long-standing problem with QUEnch-assiSTed Magnetic Resonance Imaging (QUEST MRI), which non-invasively measures excessive production of free radicals without an exogenous contrast agent. QUEST MRI is hypothesized to be sensitive to noise-evoked cochlear oxidative stress in vivo. Rats exposed to a loud noise event that resulted in hair cell loss and reduced hearing capability had a supra-normal MRI R1 value in their cochleae that could be corrected with anti-oxidants, thus non-invasively indicating cochlear oxidative stress. A gold-standard oxidative damage biomarker [heme oxidase 1 (HO-1)] supported the QUEST MRI result. The results from this study highlight QUEST MRI as a potentially transformative measurement of cochlear oxidative stress in vivo that can be used as a biomarker for improving individual evaluation of anti-oxidant treatment efficacy in currently incurable oxidative stress-based forms of hearing loss.
Considerations for ultrasound exposure during transcranial MR acoustic radiation force imaging
Authors: Phipps M. Anthony , Jonathan Sumeeth V. , Yang Pai-Feng , Chaplin Vandiver , Chen Li Min , Grissom William A. , Caskey Charles F. 
Published: November 2019

AbstractThe aim of this study was to improve the sensitivity of magnetic resonance-acoustic radiation force imaging (MR-ARFI) to minimize pressures required to localize focused ultrasound (FUS) beams, and to establish safe FUS localization parameters for ongoing ultrasound neuromodulation experiments in living non-human primates. We developed an optical tracking method to ensure that the MR-ARFI motion-encoding gradients (MEGs) were aligned with a single-element FUS transducer and that the imaged slice was prescribed at the optically tracked location of the acoustic focus. This method was validated in phantoms, which showed that MR-ARFI-derived displacement sensitivity is maximized when the MR-ARFI MEGs were maximally aligned with the FUS propagation direction. The method was then applied in vivo to acquire displacement images in two healthy macaque monkeys (M fascicularis) which showed the FUS beam within the brain. Temperature images were acquired using MR thermometry to provide an estimate of in vivo brain temperature changes during MR-ARFI, and pressure and thermal simulations of the acoustic pulses were performed using the k-Wave package which showed no significant heating at the focus of the FUS beam. The methods presented here will benefit the multitude of transcranial FUS applications as well as future human applications.
Predation on endangered species by human-subsidized domestic cats on Tokunoshima Island
Authors: Maeda Tamao , Nakashita Rumiko , Shionosaki Kazumi , Yamada Fumio , Watari Yuya 
Published: November 2019

AbstractIt is important to unravel how invasive species impact native ecosystems in order to control them effectively. The presence of abundant exotic prey promotes population growth of invasive predators, thereby enhancing the predation pressure on native prey (hyper-predation). Not only the exotic prey but also feeding by humans is likely to cause “hyper-predation”. However, the contribution of artificial resources to this was underestimated in previous studies. Here, we combined fecal and stable isotope analyses to reveal short- and long-term food habits of free-ranging cats on Tokunoshima Island. Although 20.1% of the feral cat feces contained evidence of forest-living species, stable isotope analysis suggested that the cats were mostly dependent on artificial resources. In addition, a general linear model analysis showed that their diet was strongly correlated with landscape variables. These results indicate that the invasive free-ranging cats are aided by anthropogenic feeding, and they move from the human habituated area to natural areas with high biodiversity. These findings suggest the possibility of human feeding indirectly accelerates the effect of cat predation, and call for a further study on their demography. Cat management mainly involves trapping, but our findings show that educating local residents to stop feeding free-ranging cats and keeping pet cats indoors are also important.
Ligand-Induced Conformational Dynamics of A Tyramine Receptor from Sitophilus oryzae
Authors: Braza Mac Kevin E. , Gazmen Jerrica Dominique N. , Yu Eizadora T. , Nellas Ricky B. 
Published: November 2019

AbstractTyramine receptor (TyrR) is a biogenic amine G protein-coupled receptor (GPCR) associated with many important physiological functions in insect locomotion, reproduction, and pheromone response. Binding of specific ligands to the TyrR triggers conformational changes, relays the signal to G proteins, and initiates an appropriate cellular response. Here, we monitor the binding effect of agonist compounds, tyramine and amitraz, to aSitophilus oryzaetyramine receptor (SoTyrR) homology model and their elicited conformational changes. All-atom molecular dynamics (MD) simulations of SoTyrR-ligand complexes have shown varying dynamic behavior, especially at the intracellular loop 3 (IL3) region. Moreover, in contrast to SoTyrR-tyramine, SoTyrR-amitraz and non-liganded SoTyrR shows greater flexibility at IL3 residues and were found to be coupled to the most dominant motion in the receptor. Our results suggest that the conformational changes induced by amitraz are different from the natural ligand tyramine, albeit being both agonists of SoTyrR. This is the first attempt to understand the biophysical implication of amitraz and tyramine binding to the intracellular domains of TyrR. Our data may provide insights into the early effects of ligand binding to the activation process of SoTyrR.
Gemcitabine plus nab-paclitaxel for locally advanced or borderline resectable pancreatic cancer
Authors: Tsujimoto Akiko , Sudo Kentaro , Nakamura Kazuyoshi , Kita Emiri , Hara Ryusuke , Takayama Wataru , Ishii Hiroshi , Yamaguchi Taketo 
Published: November 2019

AbstractOverall survival in a phase III study for metastatic pancreatic cancer has significantly improved with gemcitabine (GEM) plus nab-paclitaxel. However, to date, there is limited data on the efficacy and safety of its use for patients with locally advanced (LA) or borderline resectable pancreatic cancer (BRPC). Here, we investigated the efficacy and safety of first-line GEM plus nab-paclitaxel for LA or BRPC. We retrospectively analysed consecutive patients with pathologically confirmed, untreated LA or BRPC who started receiving first-line GEM plus nab-paclitaxel. A total of 30 patients (LA, n = 22; BRPC, n = 8) were analysed. Twelve patients (40%) without distant metastasis received additional chemoradiotherapy using S-1. Laparotomy was performed on 8 patients and 6 (20%; LA, n = 3; BR, n = 3) achieved R0 resection. Objective response rate was 44.8%. For all patients, median progression-free survival and overall survival were 14.8 and 29.9 months, respectively. Median overall survival for LA was 24.1 months with a 2-year survival rate of 50.8%. The most frequently observed grade 3 or 4 toxicities were neutropenia (73%) and biliary infection (13%). First-line GEM plus nab-paclitaxel was well-tolerated and feasible with an encouraging survival for LA or BRPC.
The Cholesteryl Ester Transfer Protein Inhibitor, des-Fluoro-Anacetrapib, Prevents Vein Bypass-induced Neointimal Hyperplasia in New Zealand White Rabbits
Authors: Wu Ben J. , Li Yue. , Ong Kwok-Leung , Sun Yidan , Johns Douglas , Barter Philip J. , Rye Kerry-Anne 
Published: November 2019

AbstractCoronary artery bypass grafting is among the most commonly performed of all cardiovascular surgical procedures. However, graft failure due to stenosis reduces the long-term benefit of the intervention. This study asks if elevating plasma high density lipoprotein cholesterol (HDL-C) levels by inhibition of cholesteryl ester transfer protein (CETP) activity with des-fluoro-anacetrapib, an analog of the CETP inhibitor anacetrapib, prevents vein bypass-induced neointimal hyperplasia. NZW rabbits were placed on a normal chow diet or chow containing 0.14% (wt/wt) des-fluoro-anacetrapib for 6 weeks. Bypass grafting of the jugular vein to the common carotid artery was performed 2 weeks after starting dietary des-fluoro-anacetrapib supplementation. The animals were euthanised 4 weeks post-bypass grafting. Relative to control, dietary supplementation with des-fluoro-anacetrapib reduced plasma CETP activity by 89 ± 6.9%, increased plasma apolipoprotein A-I levels by 24 ± 5.5%, increased plasma HDL-C levels by 93 ± 26% and reduced intimal hyperplasia in the grafted vein by 38 ± 6.2%. Des-fluoro-anacetrapib treatment was also associated with decreased bypass grafting-induced endothelial expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), endothelial dysfunction, and smooth muscle cell (SMC) proliferation in the grafted vein. In conclusion, increasing HDL-C levels by inhibiting CETP activity is associated with inhibition of intimal hyperplasia in grafted veins, reduced inflammatory responses, improved endothelial function, and decreased SMC proliferation.