bluuebunny/crossref_metadata_2025_split huggingface dataset:
Calcium/calmodulin-dependent kinase kinase 2 regulates hematopoietic stem and progenitor cell regeneration
Authors: Racioppi Luigi , Lento William , Huang Wei , Arvai Stephanie , Doan Phuong L , Harris Jeffrey R , Marcon Fernando , Nakaya Helder I , Liu Yaping , Chao Nelson 
Published: October 2017

AbstractHematopoietic stem and progenitor cells (HSPCs) are predominantly quiescent in adults, but proliferate in response to bone marrow (BM) injury. Here, we show that deletion of Ca2+/calmodulin (CaM)-dependent protein kinase kinase 2 (CaMKK2) promotes HSPC regeneration and hematopoietic recovery following radiation injury. Using Camkk2-enhanced green fluorescent protein (EGFP) reporter mice, we found that Camkk2 expression is developmentally regulated in HSPC. Deletion of Camkk2 in HSPC results in a significant downregulation of genes affiliated with the quiescent signature. Accordingly, HSPC from Camkk2 null mice have a high proliferative capability when stimulated in vitro in the presence of BM-derived endothelial cells. In addition, Camkk2 null mice are more resistant to radiation injury and show accelerated hematopoietic recovery, enhanced HSPC regeneration and ultimately a prolonged survival following sublethal or lethal total body irradiation. Mechanistically, we propose that CaMKK2 regulates the HSPC response to hematopoietic damage by coupling radiation signaling to activation of the anti-proliferative AMP-activated protein kinase. Finally, we demonstrated that systemic administration of the small molecule CaMKK2 inhibitor, STO-609, to irradiated mice enhanced HSPC recovery and improved survival. These findings identify CaMKK2 as an important regulator of HSPC regeneration and demonstrate CaMKK2 inhibition is a novel approach to promoting hematopoietic recovery after BM injury.
Engineered fibroblast growth factor 19 protects from acetaminophen-induced liver injury and stimulates aged liver regeneration in mice
Authors: Alvarez-Sola Gloria , Uriarte Iker , Latasa Maria U , Jimenez Maddalen , Barcena-Varela Marina , Santamaría Eva , Urtasun Raquel , Rodriguez-Ortigosa Carlos , Prieto Jesús , Corrales Fernando J , Baulies Anna , García-Ruiz Carmen , Fernandez-Checa Jose C , Berraondo Pedro , Fernandez-Barrena Maite G , Berasain Carmen , Avila Matías A 
Published: October 2017

AbstractThe liver displays a remarkable regenerative capacity triggered upon tissue injury or resection. However, liver regeneration can be overwhelmed by excessive parenchymal destruction or diminished by pre-existing conditions hampering repair. Fibroblast growth factor 19 (FGF19, rodent FGF15) is an enterokine that regulates liver bile acid and lipid metabolism, and stimulates hepatocellular protein synthesis and proliferation. FGF19/15 is also important for liver regeneration after partial hepatectomy (PH). Therefore recombinant FGF19 would be an ideal molecule to stimulate liver regeneration, but its applicability may be curtailed by its short half-life. We developed a chimaeric molecule termed Fibapo in which FGF19 is covalently coupled to apolipoprotein A-I. Fibapo retains FGF19 biological activities but has significantly increased half-life and hepatotropism. Here we evaluated the pro-regenerative activity of Fibapo in two clinically relevant models where liver regeneration may be impaired: acetaminophen (APAP) poisoning, and PH in aged mice. The only approved therapy for APAP intoxication is N-acetylcysteine (NAC) and no drugs are available to stimulate liver regeneration. We demonstrate that Fibapo reduced liver injury and boosted regeneration in APAP-intoxicated mice. Fibapo improved survival of APAP-poisoned mice when given at later time points, when NAC is ineffective. Mechanistically, Fibapo accelerated recovery of hepatic glutathione levels, potentiated cell growth-related pathways and increased functional liver mass. When Fibapo was administered to old mice prior to PH, liver regeneration was markedly increased. The exacerbated injury developing in these mice upon PH was attenuated, and the hepatic biosynthetic capacity was enhanced. Fibapo reversed metabolic and molecular alterations that impede regeneration in aged livers. It reduced liver steatosis and downregulated p21 and hepatocyte nuclear factor 4 α (Hnf4α) levels, whereas it stimulated Foxm1b gene expression. Together our findings indicate that FGF19 variants retaining the metabolic and growth-promoting effects of this enterokine may be valuable for the stimulation of liver regeneration.
Regulation of RIP3 by the transcription factor Sp1 and the epigenetic regulator UHRF1 modulates cancer cell necroptosis
Authors: Yang Chengkui , Li Jun , Yu Lu , Zhang Zili , Xu Feng , Jiang Lang , Zhou Xiuxia , He Sudan 
Published: October 2017

AbstractReceptor-interacting kinase-3 (RIP3) is a key regulator of necroptosis. It has been shown that the expression of RIP3 is silenced in most cancer cells and tissues due to genomic methylation. However, the regulatory mechanisms controlling RIP3 expression in cancer cells have not been fully elucidated. Here, we report that Sp1, a well-characterized zinc-finger transcription factor, directly regulates RIP3 expression in cancer cells. Knockdown of endogenous Sp1 significantly decreases the transcription of Rip3, thereby further inhibiting necroptosis. The re-expression of Sp1 restores the necroptotic response. In addition, knockdown of epigenetic regulator UHRF1 (ubiquitin-like, containing PHD and RING finger domains 1) in RIP3-null cancer cells reduces the methylation level of the Rip3 promoter. This effect is sufficient to trigger the expression of RIP3 in RIP3-null cancer cells. The induced expression of RIP3 by UHRF1 RNAi depends on the presence of Sp1. Remarkably, the ectopic expression of RIP3 in RIP3-null cancer cells results in a decrease in tumor growth in mice. Therefore, our findings offer insights into RIP3 expression control in cancer cells and suggest an inhibitory effect of RIP3 on tumorigenesis.
Long non-coding RNA SNHG20 promotes non-small cell lung cancer cell proliferation and migration by epigenetically silencing of P21 expression
Authors: Chen Zhenyao , Chen Xin , Chen Ping , Yu Shanxun , Nie Fengqi , Lu Binbin , Zhang Te , Zhou Yue , Chen Qinnan , Wei Chenchen , Wang Wei , Wang Zhaoxia 
Published: October 2017

AbstractMounting evidence demonstrates that long non-coding RNAs (lncRNAs) are novel transcripts governing multiple biological processes, and their dysregulation is involved in the development and progression of multiple types of cancers. Small Nucleolar RNA Host Gene 20 (SNHG20) is a 2183 bp lncRNA, and its overexpression predicts poor prognosis in colorectal cancer and hepatocellular carcinoma. However, the clinical relevance of SNHG20 and its molecular mechanisms affecting cancer cell phenotype have not been documented. Here, we found that SNHG20 was upregulated in non-small cell lung cancer (NSCLC) tissues compared with normal samples. Higher SNHG20 expression was significantly associated with advanced tumor, lymph node and metastases (TNM) stage and tumor size, as well as poorer overall survival. Moreover, knockdown of SNHG20 repressed NSCLC cell proliferation, migration and induced cell apoptosis. Mechanistic investigations revealed that SNHG20 could interact with EZH2 (enhancer of zeste homolog 2), thereby repressing P21 expression. Furthermore, rescue experiments indicated that SNHG20 functioned as an oncogene partly via repressing p21 in NSCLC cells. Taken together, our findings demonstrate that SNHG20 is a new candidate for use in NSCLC diagnosis, prognosis and therapy.
Relationships between structure, in vivo function and long-range axonal target of cortical pyramidal tract neurons
Authors: Rojas-Piloni Gerardo , Guest Jason M. , Egger Robert , Johnson Andrew S. , Sakmann Bert , Oberlaender Marcel 
Published: October 2017

AbstractPyramidal tract neurons (PTs) represent the major output cell type of the neocortex. To investigate principles of how the results of cortical processing are broadcasted to different downstream targets thus requires experimental approaches, which provide access to the in vivo electrophysiology of PTs, whose subcortical target regions are identified. On the example of rat barrel cortex (vS1), we illustrate that retrograde tracer injections into multiple subcortical structures allow identifying the long-range axonal targets of individual in vivo recorded PTs. Here we report that soma depth and dendritic path lengths within each cortical layer of vS1, as well as spiking patterns during both periods of ongoing activity and during sensory stimulation, reflect the respective subcortical target regions of PTs. We show that these cellular properties result in a structure–function parameter space that allows predicting a PT’s subcortical target region, without the need to inject multiple retrograde tracers.
MRE11 and EXO1 nucleases degrade reversed forks and elicit MUS81-dependent fork rescue in BRCA2-deficient cells
Authors: Lemaçon Delphine , Jackson Jessica , Quinet Annabel , Brickner Joshua R. , Li Shan , Yazinski Stephanie , You Zhongsheng , Ira Grzegorz , Zou Lee , Mosammaparast Nima , Vindigni Alessandro 
Published: October 2017

AbstractThe breast cancer susceptibility proteins BRCA1 and BRCA2 have emerged as key stabilizing factors for the maintenance of replication fork integrity following replication stress. In their absence, stalled replication forks are extensively degraded by the MRE11 nuclease, leading to chemotherapeutic sensitivity. Here we report that BRCA proteins prevent nucleolytic degradation by protecting replication forks that have undergone fork reversal upon drug treatment. The unprotected regressed arms of reversed forks are the entry point for MRE11 in BRCA-deficient cells. The CtIP protein initiates MRE11-dependent degradation, which is extended by the EXO1 nuclease. Next, we show that the initial limited resection of the regressed arms establishes the substrate for MUS81 in BRCA2-deficient cells. In turn, MUS81 cleavage of regressed forks with a ssDNA tail promotes POLD3-dependent fork rescue. We propose that targeting this pathway may represent a new strategy to modulate BRCA2-deficient cancer cell response to chemotherapeutics that cause fork degradation.
Enrichment of milk with magnesium provides healthier and safer dairy products
Authors: Ben-Ishay Noa , Oknin Hilla , Steinberg Doron , Berkovich Zipi , Reifen Ram , Shemesh Moshe 
Published: October 2017

AbstractBiofilms on the surfaces of milk-processing equipment are often a major source of contamination of dairy products. Members of the genus Bacillus appear to be among the most commonly found bacteria in dairy farms and processing plants. Bacillus species may thrive in dairy farm equipment and in dairy products since they can form robust biofilms during growth within milk. We found that fortification of milk with magnesium mitigated biofilm formation by Bacillus species, and thus could notably reduce dairy product spoilage. We also show that the mode of action of Mg2+ ions is specific to inhibition of transcription of genes involved in biofilm formation. Our further findings indicate that in the presence of Mg2+ bacterial cells are hypersensitive to the heat pasteurization applied during milk processing. Additionally, we demonstrated that enrichment of milk with magnesium improved technological properties of milk products such as soft cheeses. Finally, we report that there is a notable increase in the intestinal bioavailability potential of magnesium from supplemented milk compared with that from non-supplemented milk.
CETSA quantitatively verifies in vivo target engagement of novel RIPK1 inhibitors in various biospecimens
Authors: Ishii Tsuyoshi , Okai Takuro , Iwatani-Yoshihara Misa , Mochizuki Manabu , Unno Satoko , Kuno Masako , Yoshikawa Masato , Shibata Sachio , Nakakariya Masanori , Yogo Takatoshi , Kawamoto Tomohiro 
Published: October 2017

AbstractThe proof of target engagement (TE) is a key element for evaluating potential investment in drug development. The cellular thermal shift assay (CETSA) is expected to facilitate direct measurement of intracellular TE at all stages of drug development. However, there have been no reports of applying this technology to comprehensive animal and clinical studies. This report demonstrates that CETSA can not only quantitatively evaluate the drug-TE in mouse peripheral blood, but also confirm TE in animal tissues exemplified by using the receptor interacting protein 1 kinase (RIPK1) lead compound we have developed. Our established semi-automated system allows evaluation of the structure-activity relationship using native RIPK1 in culture cell lines, and also enables estimation of drug occupancy ratio in mouse peripheral blood mononuclear cells. Moreover, optimized tissue homogenisation enables monitoring of the in vivo drug-TE in spleen and brain. Our results indicate that CETSA methodology will provide an efficient tool for preclinical and clinical drug development.
Endogenously generated 2-aminoacrylate inhibits motility in Salmonella enterica
Authors: Borchert Andrew J. , Downs Diana M. 
Published: October 2017

AbstractMembers of the broadly distributed Rid/YER057c/UK114 protein family have imine/enamine deaminase activity, notably on 2-aminoacrylate (2AA). Strains of Salmonella enterica, and other organisms lacking RidA, have diverse growth phenotypes, attributed to the accumulation of 2AA. In S. enterica, 2AA inactivates a number of pyridoxal 5’-phosephate(PLP)-dependent enzymes, some of which have been linked to the growth phenotypes of a ridA mutant. This study used transcriptional differences between S. enterica wild-type and ridA strains to explore the breadth of the cellular consequences that resulted from accumulation of 2AA. Accumulation of endogenously generated 2AA in a ridA mutant resulted in lower expression of genes encoding many flagellar assembly components, which led to a motility defect. qRT-PCR results were consistent with the motility phenotype of a ridA mutant resulting from a defect in FlhD4C2 activity. In total, the results of comparative transcriptomics correctly predicted a 2AA-dependent motility defect and identified additional areas of metabolism impacted by the metabolic stress of 2AA in Salmonella enterica. Further, the data emphasized the value of integrating global approaches with biochemical genetic approaches to understand the complex system of microbial metabolism.
Cognition in the field: comparison of reversal learning performance in captive and wild passerines
Authors: Cauchoix M. , Hermer E. , Chaine A. S. , Morand-Ferron J. 
Published: October 2017

AbstractAnimal cognitive abilities have traditionally been studied in the lab, but studying cognition in nature could provide several benefits including reduced stress and reduced impact on life-history traits. However, it is not yet clear to what extent cognitive abilities can be properly measured in the wild. Here we present the first comparison of the cognitive performance of individuals from the same population, assessed using an identical test, but in contrasting contexts: in the wild vs. in controlled captive conditions. We show that free-ranging great tits (Parus major) perform similarly to deprived, captive birds in a successive spatial reversal-learning task using automated operant devices. In both captive and natural conditions, more than half of birds that contacted the device were able to perform at least one spatial reversal. Moreover, both captive and wild birds showed an improvement of performance over successive reversals, with very similar learning curves observed in both contexts for each reversal. Our results suggest that it is possible to study cognitive abilities of wild animals directly in their natural environment in much the same way that we study captive animals. Such methods open numerous possibilities to study and understand the evolution and ecology of cognition in natural populations.
Amyloidogenic motifs revealed by n-gram analysis
Authors: Burdukiewicz Michał , Sobczyk Piotr , Rödiger Stefan , Duda-Madej Anna , Mackiewicz Paweł , Kotulska Małgorzata 
Published: October 2017

AbstractAmyloids are proteins associated with several clinical disorders, including Alzheimer’s, and Creutzfeldt-Jakob’s. Despite their diversity, all amyloid proteins can undergo aggregation initiated by short segments called hot spots. To find the patterns defining the hot spots, we trained predictors of amyloidogenicity, using n-grams and random forest classifiers. Since the amyloidogenicity may not depend on the exact sequence of amino acids but on their more general properties, we tested 524,284 reduced amino acid alphabets of different lengths (three to six letters) to find the alphabet providing the best performance in cross-validation. The predictor based on this alphabet, called AmyloGram, was benchmarked against the most popular tools for the detection of amyloid peptides using an external data set and obtained the highest values of performance measures (AUC: 0.90, MCC: 0.63). Our results showed sequential patterns in the amyloids which are strongly correlated with hydrophobicity, a tendency to form β-sheets, and lower flexibility of amino acid residues. Among the most informative n-grams of AmyloGram we identified 15 that were previously confirmed experimentally. AmyloGram is available as the web-server: http://smorfland.uni.wroc.pl/shiny/AmyloGram/ and as the R package AmyloGram. R scripts and data used to produce the results of this manuscript are available at http://github.com/michbur/AmyloGramAnalysis.
Influence of adaptive capacity on the outcome of climate change vulnerability assessment
Authors: Ofori Benjamin Y. , Stow Adam J. , Baumgartner John B. , Beaumont Linda J. 
Published: October 2017

AbstractClimate change vulnerability assessment (CCVA) has become a mainstay conservation decision support tool. CCVAs are recommended to incorporate three elements of vulnerability – exposure, sensitivity and adaptive capacity – yet, lack of data frequently leads to the latter being excluded. Further, weighted or unweighted scoring schemes, based on expert opinion, may be applied. Comparisons of these approaches are rare. In a CCVA for 17 Australian lizard species, we show that membership within three vulnerability categories (low, medium and high) generally remained similar regardless of the framework or scoring scheme. There was one exception however, where, under the warm/dry scenario for 2070, including adaptive capacity lead to five fewer species being classified as highly vulnerable. Two species, Eulamprus leuraensis and E. kosciuskoi, were consistently ranked the most vulnerable, primarily due to projected losses in climatically suitable habitat, narrow thermal tolerance and specialist habitat requirements. Our findings provide relevant information for prioritizing target species for conservation and choosing appropriate conservation actions. We conclude that for the species included in this study, the framework and scoring scheme used had little impact on the identification of the most vulnerable species. We caution, however, that this outcome may not apply to other taxa or regions.
A large predatory reef fish species moderates feeding and activity patterns in response to seasonal and latitudinal temperature variation
Authors: Scott Molly , Heupel Michelle , Tobin Andrew , Pratchett Morgan 
Published: October 2017

AbstractClimate-driven increases in ocean temperatures are expected to affect the metabolic requirements of marine species substantially. To mitigate the impacts of increasing temperatures in the short-term, it may be necessary for ectothermic organisms to alter their foraging behaviour and activity. Herein, we investigate seasonal variation in foraging behaviour and activity of latitudinally distinct populations of a large coral reef predator, the common coral trout, Plectropomus leopardus, from the Great Barrier Reef, Australia. P. leopardus exhibited increased foraging frequency in summer versus winter time, irrespective of latitude, however, foraging frequency substantially declined at water temperatures >30 °C. Foraging frequency also decreased with body size but there was no interaction with temperature. Activity patterns were directly correlated with water temperature; during summer, the low-latitude population of P. leopardus spent up to 62% of their time inactive, compared with 43% for the high-latitude population. The impact of water temperature on activity patterns was greatest for larger individuals. These results show that P. leopardus moderate their foraging behaviour and activity according to changes in ambient temperatures. It seems likely that increasing ocean temperatures may impose significant constraints on the capacity of large-bodied fishes to obtain sufficient prey resources while simultaneously conserving energy.
EEG Transients in the Sigma Range During non-REM Sleep Predict Learning in Dogs
Authors: Iotchev Ivaylo Borislavov , Kis Anna , Bódizs Róbert , van Luijtelaar Gilles , Kubinyi Enikő 
Published: October 2017

AbstractSleep spindles are phasic bursts of thalamo-cortical activity, visible in the cortex as transient oscillations in the sigma range (usually defined in humans as 12–14 or 9–16 Hz). They have been associated with sleep-dependent memory consolidation and sleep stability in humans and rodents. Occurrence, frequency, amplitude and duration of sleep spindles co-vary with age, sex and psychiatric conditions. Spindle analogue activity in dogs has been qualitatively described, but never quantified and related to function. In the present study we used an adjusted version of a detection method previously validated in children to test whether detections in the dogs show equivalent functional correlates as described in the human literature. We found that the density of EEG transients in the 9–16 Hz range during non-REM sleep relates to memory and is characterized by sexual dimorphism similarly as in humans. The number of transients/minute was larger in the learning condition and for female dogs, and correlated with the increase of performance during recall. It can be concluded that in dogs, automatic detections in the 9–16 Hz range, in particular the slow variant (<13 Hz), are functional analogues of human spindles.
Exotic superfluidity and pairing phenomena in atomic Fermi gases in mixed dimensions
Authors: Zhang Leifeng , Che Yanming , Wang Jibiao , Chen Qijin 
Published: October 2017

AbstractAtomic Fermi gases have been an ideal platform for simulating conventional and engineering exotic physical systems owing to their multiple tunable control parameters. Here we investigate the effects of mixed dimensionality on the superfluid and pairing phenomena of a two-component ultracold atomic Fermi gas with a short-range pairing interaction, while one component is confined on a one-dimensional (1D) optical lattice whereas the other is in a homogeneous 3D continuum. We study the phase diagram and the pseudogap phenomena throughout the entire BCS-BEC crossover, using a pairing fluctuation theory. We find that the effective dimensionality of the non-interacting lattice component can evolve from quasi-3D to quasi-1D, leading to strong Fermi surface mismatch. Upon pairing, the system becomes effectively quasi-two dimensional in the BEC regime. The behavior of T
c
bears similarity to that of a regular 3D population imbalanced Fermi gas, but with a more drastic departure from the regular 3D balanced case, featuring both intermediate temperature superfluidity and possible pair density wave ground state. Unlike a simple 1D optical lattice case, T
c
in the mixed dimensions has a constant BEC asymptote.