bluuebunny/crossref_metadata_2025_split huggingface dataset:
Extrasynaptic NMDA receptor-induced tau overexpression mediates neuronal death through suppressing survival signaling ERK phosphorylation
Authors: Sun Xu-Ying , Tuo Qing-Zhang , Liuyang Zhen-Yu , Xie Ao-Ji , Feng Xiao-Long , Yan Xiong , Qiu Mei , Li Shen , Wang Xiu-Lian , Cao Fu-Yuan , Wang Xiao-Chuan , Wang Jian-Zhi , Liu Rong 
Published: November 2016

AbstractIntracellular accumulation of the hyperphosphorylated tau is a pathological hallmark in the brain of Alzheimer disease. Activation of extrasynaptic NMDA receptors (E-NMDARs) induces excitatory toxicity that is involved in Alzheimer’s neurodegeneration. However, the intrinsic link between E-NMDARs and the tau-induced neuronal damage remains elusive. In the present study, we showed in cultured primary cortical neurons that activation of E-NMDA receptors but not synaptic NMDA receptors dramatically increased tau mRNA and protein levels, with a simultaneous neuronal degeneration and decreased neuronal survival. Memantine, a selective antagonist of E-NMDARs, reversed E-NMDARs-induced tau overexpression. Activation of E-NMDARs in wild-type mouse brains resulted in neuron loss in hippocampus, whereas tau deletion in neuronal cultures and in the mouse brains rescued the E-NMDARs-induced neuronal death and degeneration. The E-NMDARs-induced tau overexpression was correlated with a reduced ERK phosphorylation, whereas the increased MEK activity, decreased binding and activity of ERK phosphatase to ERK, and increased ERK phosphorylation were observed in tau knockout mice. On the contrary, addition of tau proteins promoted ERK dephosphorylation in vitro. Taking together, these results indicate that tau overexpression mediates the excitatory toxicity induced by E-NMDAR activation through inhibiting ERK phosphorylation.
Doxorubicin attenuates CHIP-guarded HSF1 nuclear translocation and protein stability to trigger IGF-IIR-dependent cardiomyocyte death
Authors: Huang Chih-Yang , Kuo Wei-Wen , Lo Jeng-Fan , Ho Tsung-Jung , Pai Pei-ying , Chiang Shu-Fen , Chen Pei-Yu , Tsai Fu-Jen , Tsai Chang-Hai , Huang Chih-Yang 
Published: November 2016

AbstractDoxorubicin (DOX) is one of the most effective antitumor drugs, but its cardiotoxicity has been a major concern for its use in cancer therapy for decades. Although DOX-induced cardiotoxicity has been investigated, the underlying mechanisms responsible for this cardiotoxicity have not been completely elucidated. Here, we found that the insulin-like growth factor receptor II (IGF-IIR) apoptotic signaling pathway was responsible for DOX-induced cardiotoxicity via proteasome-mediated heat shock transcription factor 1 (HSF1) degradation. The carboxyl-terminus of Hsp70 interacting protein (CHIP) mediated HSF1 stability and nuclear translocation through direct interactions via its tetratricopeptide repeat domain to suppress IGF-IIR expression and membrane translocation under physiological conditions. However, DOX attenuated the HSF1 inhibition of IGF-IIR expression by diminishing the CHIP–HSF1 interaction, removing active nuclear HSF1 and triggering HSF1 proteasomal degradation. Overexpression of CHIP redistributed HSF1 into the nucleus, inhibiting IGF-IIR expression and preventing DOX-induced cardiomyocyte apoptosis. Moreover, HSF1A, a small molecular drug that enhances HSF1 activity, stabilized HSF1 expression and minimized DOX-induced cardiac damage in vitro and in vivo. Our results suggest that the cardiotoxic effects of DOX result from the prevention of CHIP-mediated HSF1 nuclear translocation and activation, which leads to an upregulation of the IGF-IIR apoptotic signaling pathway. We believe that the administration of an HSF1 activator or agonist may further protect against the DOX-induced cell death of cardiomyocytes.
A novel crosstalk between CCAR2 and AKT pathway in the regulation of cancer cell proliferation
Authors: Restelli Michela , Magni Martina , Ruscica Vincenzo , Pinciroli Patrizia , De Cecco Loris , Buscemi Giacomo , Delia Domenico , Zannini Laura 
Published: November 2016

AbstractHuman CCAR2 has recently emerged as having a pivotal role in the DNA damage response, promoting apoptosis and repair of heterochromatic DNA breaks. However, less is known about the function of CCAR2 in tumor formation and cancer progression. Here, we demonstrate, for the first time, that CCAR2 loss inhibits the proliferation of cancer cells, but preserves the growth of normal cells. Investigating the mechanisms responsible for this differential effect, we found that CCAR2 depletion specifically impairs the activation of AKT pathway in cancer cells, but not in normal cells, by reducing AKT phosphorylation on Ser473. This effect is achieved through the transcriptional upregulation ofTRB3gene and accumulation of TRB3 protein, which then binds to and inhibits the phosphorylation and activation of AKT. The defective activation of AKT finally results in reduced GSK3βphosphorylation, prevention of G1/S transition and inhibition of cancer cell growth. These results establish an important role for CCAR2 in cancer cells proliferation and could shed new light on novel therapeutic strategies against cancer, devoid of detrimental side effects.
What causes mating system shifts in plants? Arabidopsis lyrata as a case study
Authors: Mable B K , Hagmann J , Kim S-T , Adam A , Kilbride E , Weigel D , Stift M 
Published: November 2016

AbstractThe genetic breakdown of self-incompatibility (SI) and subsequent mating system shifts to inbreeding has intrigued evolutionary geneticists for decades. Most of our knowledge is derived from interspecific comparisons between inbreeding species and their outcrossing relatives, where inferences may be confounded by secondary mutations that arose after the initial loss of SI. Here, we study an intraspecific breakdown of SI and its consequences in North American Arabidopsis lyrata to test whether: (1) particular S-locus haplotypes are associated with the loss of SI and/or the shift to inbreeding; (2) a population bottleneck may have played a role in driving the transition to inbreeding; and (3) the mutation(s) underlying the loss of SI are likely to have occurred at the S-locus. Combining multiple approaches for genotyping, we found that outcrossing populations on average harbour 5 to 9 S-locus receptor kinase (SRK) alleles, but only two, S1 and S19, are shared by most inbreeding populations. Self-compatibility (SC) behaved genetically as a recessive trait, as expected from a loss-of-function mutation. Bulked segregant analysis in SC × SI F2 individuals using deep sequencing confirmed that all SC plants were S1 homozygotes but not all S1 homozygotes were SC. This was also revealed in population surveys, where only a few S1 homozygotes were SC. Together with crossing data, this suggests that there is a recessive factor that causes SC that is physically unlinked to the S-locus. Overall, our results emphasise the value of combining classical genetics with advanced sequencing approaches to resolve long outstanding questions in evolutionary biology.
Splenic differentiation and emergence of CCR5+CXCL9+CXCL10+ monocyte-derived dendritic cells in the brain during cerebral malaria
Authors: Hirako Isabella C. , Ataide Marco A. , Faustino Lucas , Assis Patricia A. , Sorensen Elizabeth W. , Ueta Hisashi , Araújo Natalia M. , Menezes Gustavo B. , Luster Andrew D. , Gazzinelli Ricardo T. 
Published: November 2016

AbstractDendritic cells have an important role in immune surveillance. After being exposed to microbial components, they migrate to secondary lymphoid organs and activate T lymphocytes. Here we show that during mouse malaria, splenic inflammatory monocytes differentiate into monocyte-derived dendritic cells (MO-DCs), which are CD11b+F4/80+CD11c+MHCIIhighDC-SIGNhighLy6c+ and express high levels of CCR5, CXCL9 and CXCL10 (CCR5+CXCL9/10+ MO-DCs). We propose that malaria-induced splenic MO-DCs take a reverse migratory route. After differentiation in the spleen, CCR5+CXCL9/10+ MO-DCs traffic to the brain in a CCR2-independent, CCR5-dependent manner, where they amplify the influx of CD8+ T lymphocytes, leading to a lethal neuropathological syndrome.
An anti-infective synthetic peptide with dual antimicrobial and immunomodulatory activities
Authors: Silva O. N. , de la Fuente-Núñez C. , Haney E. F. , Fensterseifer I. C. M. , Ribeiro S. M. , Porto W. F. , Brown P. , Faria-Junior C. , Rezende T. M. B. , Moreno S. E. , Lu T. K. , Hancock R. E. W. , Franco O. L. 
Published: November 2016

AbstractAntibiotic-resistant infections are predicted to kill 10 million people per year by 2050, costing the global economy $100 trillion. Therefore, there is an urgent need to develop alternative technologies. We have engineered a synthetic peptide called clavanin-MO, derived from a marine tunicate antimicrobial peptide, which exhibits potent antimicrobial and immunomodulatory properties both in vitro and in vivo. The peptide effectively killed a panel of representative bacterial strains, including multidrug-resistant hospital isolates. Antimicrobial activity of the peptide was demonstrated in animal models, reducing bacterial counts by six orders of magnitude, and contributing to infection clearance. In addition, clavanin-MO was capable of modulating innate immunity by stimulating leukocyte recruitment to the site of infection, and production of immune mediators GM-CSF, IFN-γ and MCP-1, while suppressing an excessive and potentially harmful inflammatory response by increasing synthesis of anti-inflammatory cytokines such as IL-10 and repressing the levels of pro-inflammatory cytokines IL-12 and TNF-α. Finally, treatment with the peptide protected mice against otherwise lethal infections caused by both Gram-negative and -positive drug-resistant strains. The peptide presented here directly kills bacteria and further helps resolve infections through its immune modulatory properties. Peptide anti-infective therapeutics with combined antimicrobial and immunomodulatory properties represent a new approach to treat antibiotic-resistant infections.
Fluselenamyl: A Novel Benzoselenazole Derivative for PET Detection of Amyloid Plaques (Aβ) in Alzheimer’s Disease
Authors: Sundaram G. S. M. , Dhavale Dhruva D. , Prior Julie L. , Yan Ping , Cirrito John , Rath Nigam P. , Laforest Richard , Cairns Nigel J. , Lee Jin-Moo , Kotzbauer Paul T. , Sharma Vijay 
Published: November 2016

AbstractFluselenamyl (5), a novel planar benzoselenazole shows traits desirable of enabling noninvasive imaging of Aβ pathophysiology in vivo; labeling of both diffuse (an earlier manifestation of neuritic plaques) and fibrillar plaques in Alzheimer’s disease (AD) brain sections, and remarkable specificity for mapping Aβ compared with biomarker proteins of other neurodegenerative diseases. Employing AD homogenates, [18F]-9, a PET tracer demonstrates superior (2–10 fold higher) binding affinity than approved FDA tracers, while also indicating binding to high affinity site on Aβ plaques. Pharmacokinetic studies indicate high initial influx of [18F]-9 in normal mice brains accompanied by rapid clearance in the absence of targeted plaques. Following incubation in human serum, [18F]-9 indicates presence of parental compound up to 3h thus indicating its stability. Furthermore, in vitro autoradiography studies of [18F]-9 with AD brain tissue sections and ex vivo autoradiography studies in transgenic mouse brain sections show cortical Aβ binding, and a fair correlation with Aβ immunostaining. Finally, multiphoton- and microPET/CT imaging indicate its ability to penetrate brain and label parenchymal plaques in transgenic mice. Following further validation of its performance in other AD rodent models and nonhuman primates, Fluselenamyl could offer a platform technology for monitoring earliest stages of Aβ pathophysiology in vivo.
LPA receptor activity is basal specific and coincident with early pregnancy and involution during mammary gland postnatal development
Authors: Acosta Deanna , Bagchi Susmita , Broin Pilib Ó , Hollern Daniel , Racedo Silvia E. , Morrow Bernice , Sellers Rani S. , Greally John M. , Golden Aaron , Andrechek Eran , Wood Teresa , Montagna Cristina 
Published: November 2016

AbstractDuring pregnancy, luminal and basal epithelial cells of the adult mammary gland proliferate and differentiate resulting in remodeling of the adult gland. While pathways that control this process have been characterized in the gland as a whole, the contribution of specific cell subtypes, in particular the basal compartment, remains largely unknown. Basal cells provide structural and contractile support, however they also orchestrate the communication between the stroma and the luminal compartment at all developmental stages. Using RNA-seq, we show that basal cells are extraordinarily transcriptionally dynamic throughout pregnancy when compared to luminal cells. We identified gene expression changes that define specific basal functions acquired during development that led to the identification of novel markers. Enrichment analysis of gene sets from 24 mouse models for breast cancer pinpoint to a potential new function for insulin-like growth factor 1 (Igf1r) in the basal epithelium during lactogenesis. We establish that β-catenin signaling is activated in basal cells during early pregnancy, and demonstrate that this activity is mediated by lysophosphatidic acid receptor 3 (Lpar3). These findings identify novel pathways active during functional maturation of the adult mammary gland.
Non-invasive, transient determination of the core temperature of a heat-generating solid body
Authors: Anthony Dean , Sarkar Daipayan , Jain Ankur 
Published: November 2016

AbstractWhile temperature on the surface of a heat-generating solid body can be easily measured using a variety of methods, very few techniques exist for non-invasively measuring the temperature inside the solid body as a function of time. Measurement of internal temperature is very desirable since measurement of just the surface temperature gives no indication of temperature inside the body, and system performance and safety is governed primarily by the highest temperature, encountered usually at the core of the body. This paper presents a technique to non-invasively determine the internal temperature based on the theoretical relationship between the core temperature and surface temperature distribution on the outside of a heat-generating solid body as functions of time. Experiments using infrared thermography of the outside surface of a thermal test cell in a variety of heating and cooling conditions demonstrate good agreement of the predicted core temperature as a function of time with actual core temperature measurement using an embedded thermocouple. This paper demonstrates a capability to thermally probe inside solid bodies in a non-invasive fashion. This directly benefits the accurate performance prediction and control of a variety of engineering systems where the time-varying core temperature plays a key role.
Improving virus production through quasispecies genomic selection and molecular breeding
Authors: Pérez-Rodríguez Francisco J. , D’Andrea Lucía , de Castellarnau Montserrat , Costafreda Maria Isabel , Guix Susana , Ribes Enric , Quer Josep , Gregori Josep , Bosch Albert , Pintó Rosa M. 
Published: November 2016

AbstractVirus production still is a challenging issue in antigen manufacture, particularly with slow-growing viruses. Deep-sequencing of genomic regions indicative of efficient replication may be used to identify high-fitness minority individuals suppressed by the ensemble of mutants in a virus quasispecies. Molecular breeding of quasispecies containing colonizer individuals, under regimes allowing more than one replicative cycle, is a strategy to select the fittest competitors among the colonizers. A slow-growing cell culture-adapted hepatitis A virus strain was employed as a model for this strategy. Using genomic selection in two regions predictive of efficient translation, the internal ribosome entry site and the VP1-coding region, high-fitness minority colonizer individuals were identified in a population adapted to conditions of artificially-induced cellular transcription shut-off. Molecular breeding of this population with a second one, also adapted to transcription shut-off and showing an overall colonizer phenotype, allowed the selection of a fast-growing population of great biotechnological potential.
Structural characterisation of high affinity Siglec-2 (CD22) ligands in complex with whole Burkitt’s lymphoma (BL) Daudi cells by NMR spectroscopy
Authors: Madge Paul D. , Maggioni Andrea , Pascolutti Mauro , Amin Moein , Waespy Mario , Bellette Bernadette , Thomson Robin J. , Kelm Sørge , von Itzstein Mark , Haselhorst Thomas 
Published: November 2016

AbstractSiglec-2 undergoes constitutive endocytosis and is a drug target for autoimmune diseases and B cell-derived malignancies, including hairy cell leukaemia, marginal zone lymphoma, chronic lymphocytic leukaemia and non-Hodgkin’s lymphoma (NHL). An alternative to current antibody-based therapies is the use of liposomal nanoparticles loaded with cytotoxic drugs and decorated with Siglec-2 ligands. We have recently designed the first Siglec-2 ligands (9-biphenylcarboxamido-4-meta-nitrophenyl-carboxamido-Neu5Acα2Me, 9-BPC-4-mNPC-Neu5Acα2Me) with simultaneous modifications at C-4 and C-9 position. In the current study we have used Saturation Transfer Difference (STD) NMR spectroscopy to monitor the binding of 9-BPC-4-mNPC-Neu5Acα2Me to Siglec-2 present on intact Burkitt’s lymphoma Daudi cells. Pre-treatment of cells with periodate resulted in significantly higher STD NMR signal intensities for 9-BPC-4-mNPC-Neu5Acα2Me as the cells were more susceptible to ligand binding because cis-binding on the cell surface was removed. Quantification of STD NMR effects led to a cell-derived binding epitope of 9-BPC-4-mNPC-Neu5Acα2Me that facilitated the design and synthesis of C-2, C-3, C-4 and C-9 tetra-substituted Siglec-2 ligands showing an 88-fold higher affinity compared to 9-BPC-Neu5Acα2Me. This is the first time a NMR-based binding study of high affinity Siglec-2 (CD22) ligands in complex with whole Burkitt’s lymphoma Daudi cells has been described that might open new avenues in developing tailored therapeutics and personalised medicine.
Cassava brown streak virus has a rapidly evolving genome: implications for virus speciation, variability, diagnosis and host resistance
Authors: Alicai Titus , Ndunguru Joseph , Sseruwagi Peter , Tairo Fred , Okao-Okuja Geoffrey , Nanvubya Resty , Kiiza Lilliane , Kubatko Laura , Kehoe Monica A. , Boykin Laura M. 
Published: November 2016

AbstractCassava is a major staple food for about 800 million people in the tropics and sub-tropical regions of the world. Production of cassava is significantly hampered by cassava brown streak disease (CBSD), caused by Cassava brown streak virus (CBSV) and Ugandan cassava brown streak virus (UCBSV). The disease is suppressing cassava yields in eastern Africa at an alarming rate. Previous studies have documented that CBSV is more devastating than UCBSV because it more readily infects both susceptible and tolerant cassava cultivars, resulting in greater yield losses. Using whole genome sequences from NGS data, we produced the first coalescent-based species tree estimate for CBSV and UCBSV. This species framework led to the finding that CBSV has a faster rate of evolution when compared with UCBSV. Furthermore, we have discovered that in CBSV, nonsynonymous substitutions are more predominant than synonymous substitution and occur across the entire genome. All comparative analyses between CBSV and UCBSV presented here suggest that CBSV may be outsmarting the cassava immune system, thus making it more devastating and harder to control.
Voluntary control of intracortical oscillations for reconfiguration of network activity
Authors: Corlier Juliana , Valderrama Mario , Navarrete Miguel , Lehongre Katia , Hasboun Dominique , Adam Claude , Belaid Hayat , Clémenceau Stéphane , Baulac Michel , Charpier Stéphane , Navarro Vincent , Le Van Quyen Michel 
Published: November 2016

AbstractVoluntary control of oscillatory activity represents a key target in the self-regulation of brain function. Using a real-time closed-loop paradigm and simultaneous macro- and micro-electrode recordings, we studied the effects of self-induced intracortical oscillatory activity (4–8 Hz) in seven neurosurgical patients. Subjects learned to robustly and specifically induce oscillations in the target frequency, confirmed by increased oscillatory event density. We have found that the session-to-session variability in performance was explained by the functional long-range decoupling of the target area suggesting a training-induced network reorganization. Downstream effects on more local activities included progressive cross-frequency-coupling with gamma oscillations (30–120 Hz), and the dynamic modulation of neuronal firing rates and spike timing, indicating an improved temporal coordination of local circuits. These findings suggest that effects of voluntary control of intracortical oscillations can be exploited to specifically target plasticity processes to reconfigure network activity, with a particular relevance for memory function or skill acquisition.
Clinical Significance of Nontuberculous Mycobacteria Isolated From Respiratory Specimens in a Chinese Tuberculosis Tertiary Care Center
Authors: Duan Hongfei , Han Xiqin , Wang Qingfeng , Wang Jing , Wang Jun , Chu Naihui , Huang Hairong 
Published: November 2016

AbstractThe clinical relevance of non-tuberculous mycobacteria (NTM) has been reported to be different dramatically by species or by regions, however, no such evaluation has been performed in China.A retrospective study was performed in Beijing Chest Hospital. All the NTM strains isolated from respiratory specimens in the past 5 years, and patients’ clinical records (symptoms and radiographic information etc.) were investigated. The clinical relevance was evaluated according to the criteria recommended by the American Thoracic society. Totally 232 NTM strains were recruited, among them, M. intracellulare was the dominant species (40.5%), followed by M. abscessus (28.4%). 109 patients, with 185 total isolates, had full clinical records available for review. 84.4% (38/45), 85.7% (24/28%) and 63.6% (7/11) of patients with isolation of M. intracellulare, M. abscessus and M. kansasii, respectively, were categorized as definite NTM disease. Whereas all the 10 patients with isolation of M. gordonae were defined as unlikely NTM disease. The majority of NTMs isolates yielded from respiratory specimens in Beijing Chest Hospital were clinically significant, and M. intracellulare and M. abscessus was the dominated species of NTM lung disease. NTM lung infections demonstrated some specific chest radiograph characteristics.