bluuebunny/crossref_metadata_2025_split huggingface dataset:
A sexually dimorphic pre-stressed translational signature in CA3 pyramidal neurons of BDNF Val66Met mice
Authors: Marrocco Jordan , Petty Gordon H. , Ríos Mariel B. , Gray Jason D. , Kogan Joshua F. , Waters Elizabeth M. , Schmidt Eric F. , Lee Francis S. , McEwen Bruce S. 
Published: October 2017

AbstractMales and females use distinct brain circuits to cope with similar challenges. Using RNA sequencing of ribosome-bound mRNA from hippocampal CA3 neurons, we found remarkable sex differences and discovered that female mice displayed greater gene expression activation after acute stress than males. Stress-sensitive BDNF Val66Met mice of both sexes show a pre-stressed translational phenotype in which the same genes that are activated without applied stress are also induced in wild-type mice by an acute stressor. Behaviourally, only heterozygous BDNF Val66Met females exhibit spatial memory impairment, regardless of acute stress. Interestingly, this effect is not observed in ovariectomized heterozygous BDNF Val66Met females, suggesting that circulating ovarian hormones induce cognitive impairment in Met carriers. Cognitive deficits are not observed in males of either genotype. Thus, in a brain region not normally associated with sex differences, this work sheds light on ways that genes, environment and sex interact to affect the transcriptome’s response to a stressor.
Humoral protection against mosquito bite-transmitted Plasmodium falciparum infection in humanized mice
Authors: Sack Brandon K. , Mikolajczak Sebastian A. , Fishbaugher Matthew , Vaughan Ashley M. , Flannery Erika L. , Nguyen Thao , Betz Will , Jane Navarro Mary , Foquet Lander , Steel Ryan W. J. , Billman Zachary P. , Murphy Sean C. , Hoffman Stephen L. , Chakravarty Sumana , Sim B. Kim Lee , Behet Marije , Reuling Isaie J. , Walk Jona , Scholzen Anja , Sauerwein Robert W. , Ishizuka Andrew S. , Flynn Barbara , Seder Robert A. , Kappe Stefan H. I. 
Published: October 2017

AbstractA malaria vaccine that prevents infection will be an important new tool in continued efforts of malaria elimination, and such vaccines are under intense development for the major human malaria parasitePlasmodium falciparum(Pf). Antibodies elicited by vaccines can block the initial phases of parasite infection when sporozoites are deposited into the skin by mosquito bite and then target the liver for further development. However, there are currently no standardized in vivo preclinical models that can measure the inhibitory activity of antibody specificities againstPfsporozoite infection via mosquito bite. Here, we use human liver-chimeric mice as a challenge model to assess prevention of naturalPfsporozoite infection by antibodies. We demonstrate that these mice are consistently infected withPfby mosquito bite and that this challenge can be combined with passive transfer of either monoclonal antibodies or polyclonal human IgG from immune serum to measure antibody-mediated blocking of parasite infection using bioluminescent imaging. This methodology is useful to down-select functional antibodies and to investigate mechanisms or immune correlates of protection in clinical trials, thereby informing rational vaccine optimization.
Enhanced Therapeutic Treatment of Colorectal Cancer Using Surface-Modified Nanoporous Acupuncture Needles
Authors: Lee Bo Ram , Kim Hye-Rim , Choi Eun-Sook , Cho Jung-Hoon , Kim Nam-Jun , Kim Jung-Hee , Lee Kyeong-Min , Razzaq Abdul , Choi Hansaem , Hwang Yunju , Grimes Craig A. , Lee Bong-Hyo , Kim Eunjoo , In Su-Il 
Published: October 2017

AbstractAcupuncture originated within the auspices of Oriental medicine, and today is used as an alternative method for treating various diseases and symptoms. The physiological mechanisms of acupuncture appear to involve the release of endogenous opiates and neurotransmitters, with the signals mediating through electrical stimulation of the central nervous system (CNS). Earlier we reported a nanoporous stainless steel acupuncture needle with enhanced therapeutic properties, evaluated by electrophysiological and behavioral responses in Sprague-Dawley (SD) rats. Herein, we investigate molecular changes in colorectal cancer (CRC) rats by acupuncture treatment using the nanoporous needles. Treatment at acupoint HT7 is found most effective at reducing average tumor size, β-catenin expression levels, and the number of aberrant crypt foci in the colon endothelium. Surface modification of acupuncture needles further enhances the therapeutic effects of acupuncture treatment in CRC rats.
A new stress sensor and risk factor for suicide: the T allele of the functional genetic variant in the GABRA6 gene
Authors: Gonda Xenia , Sarginson Jane , Eszlari Nora , Petschner Peter , Toth Zoltan G. , Baksa Daniel , Hullam Gabor , Anderson Ian M. , Deakin J. F. William , Juhasz Gabriella , Bagdy Gyorgy 
Published: October 2017

AbstractLow GABA transmission has been reported in suicide, and GABRA6 rs3219151 T allele has been associated with greater physiological and endocrine stress response in previous studies. Although environmental stress also plays a role in suicide, the possible role of this allele has not been investigated in this respect. In our present study effect of rs3219151 of GABRA6 gene in interaction with recent negative life events on lifetime and current depression, current anxiety, as well as lifetime suicide were investigated using regression models in a white European general sample of 2283 subjects. Post hoc measures for phenotypes related to suicide risk were also tested for association with rs3219151 in interaction with environmental stress. No main effect of the GABRA6 rs3219151 was detected, but in those exposed to recent negative life events GABRA6 T allele increased current anxiety and depression as well as specific elements of suicide risk including suicidal and death-related thoughts, hopelessness, restlessness and agitation, insomnia and impulsiveness as measured by the STOP task. Our data indicate that stress-associated suicide risk is elevated in carriers of the GABRA6 rs3219151 T allele with several independent markers and predictors of suicidal behaviours converging to this increased risk.
Establishment of a repeated social defeat stress model in female mice
Authors: Takahashi Aki , Chung Jia-Ru , Zhang Song , Zhang Hongxing , Grossman Yael , Aleyasin Hossein , Flanigan Meghan E. , Pfau Madeline L. , Menard Caroline , Dumitriu Dani , Hodes Georgia E. , McEwen Bruce S. , Nestler Eric J. , Han Ming-Hu , Russo Scott J. 
Published: October 2017

AbstractNumerous studies have employed repeated social defeat stress (RSDS) to study the neurobiological mechanisms of depression in rodents. An important limitation of RSDS studies to date is that they have been conducted exclusively in male mice due to the difficulty of initiating attack behavior directed toward female mice. Here, we establish a female mouse model of RSDS by inducing male aggression toward females through chemogenetic activation of the ventrolateral subdivision of the ventromedial hypothalamus (VMHvl). We demonstrate that females susceptible to RSDS display social avoidance, anxiety-like behavior, reduction of body weight, and elevated levels of circulating interleukin 6. In contrast, a subset of mice we term resilient only display anxiety-like behaviors after RSDS. This model allows for investigation of sex differences in the neurobiological mechanisms of defeat‒induced depression‒like behaviors. A robust female social defeat model is a critical first step in the identification and development of novel therapeutic compounds to treat depression and anxiety disorders in women.
The prognostic correlation of AFP level at diagnosis with pathological grade, progression, and survival of patients with hepatocellular carcinoma
Authors: Bai Dou-Sheng , Zhang Chi , Chen Ping , Jin Sheng-Jie , Jiang Guo-Qing 
Published: October 2017

AbstractThe purpose of this study was to conduct a comprehensive study of the clinical correlation between the alpha-fetoprotein (AFP) level at diagnosis and pathological grades, progression, and survival of patients with hepatocellular carcinoma (HCC). A total of 78,743 patients in Surveillance, Epidemiology, and End Results Program (SEER)-registered HCC was analyzed. The AFP test results for patients with HCC were mainly recorded as AFP-negative and AFP-positive. Logistic regression analysis revealed that the AFP level at diagnosis was an independent risk factor of pathological grade (odds ratio [OR], 2.559; 95% confidence interval [CI], 2.075–3.157; P < 0.001), TNM-7 stage (OR, 2.794; CI, 2.407–3.242; P < 0.001), and tumor size (OR, 1.748; 95% CI, 1.574–1.941; P < 0.001). Multivariable Cox regression analyses identified AFP level as an independent predictor of survival risk of patients with HCC who did not undergo surgery (hazard ratio [HR], 1.660; 95% CI, 1.534–1.797; P < 0.001), and those who underwent surgery (HR, 1.534; 95% CI, 1.348–1.745; P < 0.001). The AFP level at diagnosis was an independent risk predictor associated with pathological grade, progression, and survival. Further, surgery may not significantly reverse the adverse effects of AFP-positive compared with AFP-negative.
DUSP5 functions as a feedback regulator of TNFα-induced ERK1/2 dephosphorylation and inflammatory gene expression in adipocytes
Authors: Habibian Justine S. , Jefic Mitra , Bagchi Rushita A. , Lane Robert H. , McKnight Robert A. , McKinsey Timothy A. , Morrison Ron F. , Ferguson Bradley S. 
Published: October 2017

AbstractAdipose tissue inflammation is a central pathological element that regulates obesity-mediated insulin resistance and type II diabetes. Evidence demonstrates that extracellular signal-regulated kinase (ERK 1/2) activation (i.e. phosphorylation) links tumor necrosis factor α (TNFα) to pro-inflammatory gene expression in the nucleus. Dual specificity phosphatases (DUSPs) inactivate ERK 1/2 through dephosphorylation and can thus inhibit inflammatory gene expression. We report that DUSP5, an ERK1/2 phosphatase, was induced in epididymal white adipose tissue (WAT) in response to diet-induced obesity. Moreover, DUSP5 mRNA expression increased during obesity development concomitant to increases in TNFα expression. Consistent with in vivo findings, DUSP5 mRNA expression increased in adipocytes in response to TNFα, parallel with ERK1/2 dephosphorylation. Genetic loss of DUSP5 exacerbated TNFα-mediated ERK 1/2 signaling in 3T3-L1 adipocytes and in adipose tissue of mice. Furthermore, inhibition of ERK 1/2 and c-Jun N terminal kinase (JNK) signaling attenuated TNFα-induced DUSP5 expression. These data suggest that DUSP5 functions in the feedback inhibition of ERK1/2 signaling in response to TNFα, which resulted in increased inflammatory gene expression. Thus, DUSP5 potentially acts as an endogenous regulator of adipose tissue inflammation; although its role in obesity-mediated inflammation and insulin signaling remains unclear.
Nuclear factor (erythroid derived 2)-like 2 activation increases exercise endurance capacity via redox modulation in skeletal muscles
Authors: Oh Sechang , Komine Shoichi , Warabi Eiji , Akiyama Kentaro , Ishii Akiko , Ishige Kazunori , Mizokami Yuji , Kuga Keisuke , Horie Masaki , Miwa Yoshihiro , Iwawaki Takao , Yamamoto Masayuki , Shoda Junichi 
Published: October 2017

AbstractSulforaphane (SFN) plays an important role in preventing oxidative stress by activating the nuclear factor (erythroid derived 2)-like 2 (Nrf2) signalling pathway. SFN may improve exercise endurance capacity by counteracting oxidative stress-induced damage during exercise. We assessed running ability based on an exhaustive treadmill test (progressive-continuous all-out) and examined the expression of markers for oxidative stress and muscle damage. Twelve- to 13-week-old Male wild-type mice (Nrf2+/+) and Nrf2-null mice (Nrf2−/−) on C57BL/6J background were intraperitoneally injected with SFN or vehicle prior to the test. The running distance of SFN-injected Nrf2+/+ mice was significantly greater compared with that of uninjected mice. Enhanced running capacity was accompanied by upregulation of Nrf2 signalling and downstream genes. Marker of oxidative stress in SFN-injected Nrf2+/+ mice were lower than those in uninjected mice following the test. SFN produced greater protection against muscle damage during exhaustive exercise conditions in Nrf2+/+ mice than in Nrf2−/− mice. SFN-induced Nrf2 upregulation, and its antioxidative effects, might play critical roles in attenuating muscle fatigue via reduction of oxidative stress caused by exhaustive exercise. This in turn leads to enhanced exercise endurance capacity. These results provide new insights into SFN-induced upregulation of Nrf2 and its role in improving exercise performance.
A novel immunohistochemical score to predict early mortality in acute myeloid leukemia patients based on indoleamine 2,3 dioxygenase expression
Authors: Mangaonkar Abhishek , Mondal Ashis Kumar , Fulzule Sadanand , Pundkar Chetan , Park Eun Jeong , Jillella Anand , Kota Vamsi , Xu Hongyan , Savage Natasha M. , Shi Huidong , Munn David , Kolhe Ravindra 
Published: October 2017

AbstractIndoleamine 2,3 dioxygenase-1 (IDO-1) is an enzyme in the kynurenine pathway which augments tumor-induced immune tolerance. Previous studies in childhood acute myeloid leukemia (AML) have shown a negative correlation of IDO-1 mRNA expression with outcomes. The aim of our study was to develop a practical and objective immunohistochemical technique to quantify IDO-1 expression on diagnostic bone marrow biopsies of AML patients in order to facilitate its use in routine clinical practice. IDO-1 mRNA was extracted from diagnostic bone marrow specimens from 29 AML patients. IDO-1 protein expression was assessed in 40 cases via immunohistochemistry and quantified by a novel ‘composite IDO-1 score’. In a univariate analysis, higher age (p = 0.0018), male gender (p = 0.019), high risk cytogenetics (p = 0.002), higher IDO-1 mRNA (p = 0.005), higher composite IDO-1 score (p < 0.0001) and not undergoing allogeneic stem cell transplant (SCT, p = 0.0005) predicted poor overall survival. In a multivariate model that included the aforementioned variables, higher composite IDO-1 score (p = 0.007) and not undergoing allogeneic SCT (p = 0.007) was found to significantly predict poor outcomes. Further, patients who failed induction had higher composite IDO-1 score (p = 0.01). In conclusion, ‘composite IDO-1 score’ is a prognostic tool that can help identify a certain subset of AML patients with ‘early mortality’. This unique subset of patients can potentially benefit from specific IDO-1 inhibitor therapy, currently in clinical trials.
Development of A Machine Learning Algorithm to Classify Drugs Of Unknown Fetal Effect
Authors: Boland Mary Regina , Polubriaginof Fernanda , Tatonetti Nicholas P. 
Published: October 2017

AbstractMany drugs commonly prescribed during pregnancy lack a fetal safety recommendation – called FDA ‘category C’ drugs. This study aims to classify these drugs into harmful and safe categories using knowledge gained from chemoinformatics (i.e., pharmacological similarity with drugs of known fetal effect) and empirical data (i.e., derived from Electronic Health Records). Our fetal loss cohort contains 14,922 affected and 33,043 unaffected pregnancies and our congenital anomalies cohort contains 5,658 affected and 31,240 unaffected infants. We trained a random forest to classify drugs of unknown pregnancy class into harmful or safe categories, focusing on two distinct outcomes: fetal loss and congenital anomalies. Our models achieved an out-of-bag accuracy of 91% for fetal loss and 87% for congenital anomalies outperforming null models. Fifty-seven ‘category C’ medications were classified as harmful for fetal loss and eleven for congenital anomalies. This includes medications with documented harmful effects, including naproxen, ibuprofen and rubella live vaccine. We also identified several novel drugs, e.g., haloperidol, that increased the risk of fetal loss. Our approach provides important information on the harmfulness of ‘category C’ drugs. This is needed, as no FDA recommendation exists for these drugs’ fetal safety.
Quantifying the relative immune cell activation from whole tissue/organ-derived differentially expressed gene data
Authors: Wijaya Edward , Igarashi Yoshinobu , Nakatsu Noriyuki , Haseda Yasunari , Billaud Joel , Chen Yi-An , Mizuguchi Kenji , Yamada Hiroshi , Ishii Ken , Aoshi Taiki 
Published: October 2017

AbstractEvaluation of immune responses in individual immune cell types is important for the development of new medicines. Here, we propose a computational method designated ICEPOP (Immune CEll POPulation) to estimate individual immune cell type responses from bulk tissue and organ samples. The relative gene responses are scored for each cell type by using the data from differentially expressed genes derived from control- vs drug-treated sample pairs, and the data from public databases including ImmGen and IRIS, which contain gene expression profiles of a variety of immune cells. By ICEPOP, we analysed cell responses induced by vaccine-adjuvants in the mouse spleen, and extended the analyses to human peripheral blood mononuclear cells and gut biopsy samples focusing on human papilloma virus vaccination and inflammatory bowel disease treatment with Infliximab. In both mouse and human datasets, our method reliably quantified the responding immune cell types and provided insightful information, demonstrating that our method is useful to evaluate immune responses from bulk sample-derived gene expression data. ICEPOP is available as an interactive web site (https://vdynamics.shinyapps.io/icepop/) and Python package (https://github.com/ewijaya/icepop).
Genetic status of KRAS modulates the role of Neuropilin-1 in tumorigenesis
Authors: Vivekanandhan Sneha , Yang Lijuan , Cao Ying , Wang Engfeng , Dutta Shamit K. , Sharma Anil K. , Mukhopadhyay Debabrata 
Published: October 2017

AbstractNeuropilin-1 (NRP1), a non–tyrosine kinase receptor, is overexpressed in many cancers including pancreatic and lung cancers. Inhibition of NRP1 expression, however, has differing pro-tumor vs. anti-tumor effects, depending on the cancer types. To understand the differential role of NRP1 in tumorigenesis process, we utilized cells from two different cancer types, pancreatic and lung, each containing either wild type KRAS (KRASwt) or mutant KRAS (KRASmt). Inhibition of NRP1 expression by shRNA in both pancreatic and lung cancer cells containing dominant active KRASmt caused increased cell viability and tumor growth. On the contrary, inhibition of NRP1, in the tumor cells containing KRASwt showed decreased tumor growth. Importantly, concurrent inhibition of KRASmt and NRP1 in the tumor cells reverses the increased viability and leads to tumor inhibition. We found that NRP1 shRNA expressing KRASmt tumor cells caused increased cell viability by decreasing SMAD2 phosphorylation. Our findings demonstrate that the effects of NRP1 knockdown in cancer cells are dependent on the genetic status of KRAS.
Tumor-Penetrating Delivery of siRNA against TNFα to Human Vestibular Schwannomas
Authors: Ren Yin , Sagers Jessica E. , Landegger Lukas D. , Bhatia Sangeeta N. , Stankovic Konstantina M. 
Published: October 2017

AbstractVestibular schwannoma (VS) is the most common tumor of the cerebellopontine angle, and it typically presents with sensorineural hearing loss. The genomic landscape of schwannoma is complex and many of the molecules implicated in VS pathogenesis represent targets not amenable to antibody-based or small molecule therapeutics. Tumor-targeted delivery of small interfering RNA (siRNA) therapeutics provides a direct and effective means to interrogate targets while minimizing off-target effects. To establish a preclinical model for therapeutic inhibition of putative targets in VS, archived tumor specimens, fresh tumor cells derived from patients with sporadic VS, and an established schwannoma cell line were screened. Nanoparticles directed by the tumor-homing peptide iRGD were selectively taken up by primary VS cultures in vitro via interactions with αvβ3/β5 integrins and neuropilin-1 (NRP-1). Cellular uptake was inhibited by a neutralizing antibody against αv integrin in a dose-dependent manner. When applied to primary VS cultures, iRGD-targeted nanoparticles delivered siRNA directed against TNFα in a receptor-specific fashion to potently silence gene expression and protein secretion. Taken together, our results provide a proof of principle for tumor-targeted, nanoparticle-mediated delivery of siRNA to VS and establish a novel platform for the development and pre-clinical screening of molecular therapeutics against VS.
Resveratrol therapeutics combines both antimicrobial and immunomodulatory properties against respiratory infection by nontypeable Haemophilus influenzae
Authors: Euba Begoña , López-López Nahikari , Rodríguez-Arce Irene , Fernández-Calvet Ariadna , Barberán Montserrat , Caturla Nuria , Martí Sara , Díez-Martínez Roberto , Garmendia Junkal 
Published: October 2017

AbstractThe respiratory pathogen nontypeable Haemophilus influenzae (NTHi) is an important cause of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) that requires efficient treatments. A previous screening for host genes differentially expressed upon NTHi infection identified sirtuin-1, which encodes a NAD-dependent deacetylase protective against emphysema and is activated by resveratrol. This polyphenol concomitantly reduces NTHi viability, therefore highlighting its therapeutic potential against NTHi infection at the COPD airway. In this study, resveratrol antimicrobial effect on NTHi was shown to be bacteriostatic and did not induce resistance development in vitro. Analysis of modulatory properties on the NTHi-host airway epithelial interplay showed that resveratrol modulates bacterial invasion but not subcellular location, reduces inflammation without targeting phosphodiesterase 4B gene expression, and dampens β defensin-2 gene expression in infected cells. Moreover, resveratrol therapeutics against NTHi was evaluated in vivo on mouse respiratory and zebrafish septicemia infection model systems, showing to decrease NTHi viability in a dose-dependent manner and reduce airway inflammation upon infection, and to have a significant bacterial clearing effect without signs of host toxicity, respectively. This study presents resveratrol as a therapeutic of particular translational significance due to the attractiveness of targeting both infection and overactive inflammation at the COPD airway.
Spatially restricted loading of BRD2 at DNA double-strand breaks protects H4 acetylation domains and promotes DNA repair
Authors: Gursoy-Yuzugullu Ozge , Carman Chelsea , Price Brendan D. 
Published: October 2017

AbstractThe n-terminal tail of histone H4 recruits repair proteins, including 53BP1, to DNA double-strand breaks (DSB) and undergoes dynamic acetylation during DSB repair. However, how H4 acetylation (H4Ac) recruits repair proteins and reorganizes chromatin during DNA repair is unclear. Here, we show that the bromodomain protein BRD2 is recruited to DSBs. This recruitment requires binding of BRD2’s tandem bromodomains to H4Ac, which is generated at DSBs by the Tip60/KAT5 acetyltransferase. Binding of BRD2 to H4Ac protects the underlying acetylated chromatin from attack by histone deacetylases and allows acetylation to spread along the flanking chromatin. However, BRD2 recruitment is spatially restricted to a chromatin domain extending only 2 kb either side of the DSB, and BRD2 does not spread into the chromatin domains flanking the break. Instead, BRD2 facilitates recruitment of a second bromodomain protein, ZMYND8, which spreads along the flanking chromatin, but is excluded from the DSB region. This creates a spatially restricted H4Ac/BRD2 domain which reorganizes chromatin at DSBs, limits binding of the L3MBTL1 repressor and promotes 53BP1 binding, while limiting end-resection of DSBs. BRD2 therefore creates a restricted chromatin environment surrounding DSBs which facilitates DSB repair and which is framed by extensive ZMYND8 domains on the flanking chromatin.