bluuebunny/crossref_metadata_2025_split huggingface dataset:
New role of the antidepressant imipramine as a Fascin1 inhibitor in colorectal cancer cells
Authors: Alburquerque-González Begoña , Bernabé-García Manuel , Montoro-García Silvia , Bernabé-García Ángel , Rodrigues Priscila Campioni , Ruiz Sanz Javier , López-Calderón Fernando F. , Luque Irene , Nicolas Francisco José , Cayuela María Luisa , Salo Tuula , Pérez-Sánchez Horacio , Conesa-Zamora Pablo 
Published: February 2020

AbstractSerrated adenocarcinoma (SAC) is more invasive, has worse outcomes than conventional colorectal carcinoma (CRC), and is characterized by frequent resistance to anti-epidermal growth factor receptor (EGFR) and overexpression of fascin1, a key protein in actin bundling that plays a causative role in tumor invasion and is overexpressed in different cancer types with poor prognosis. In silico screening of 9591 compounds, including 2037 approved by the Food and Drug Administration (FDA), was performed, and selected compounds were analyzed for their fascin1 binding affinity by differential scanning fluorescence. The results were compared with migrastatin as a typical fascin1 inhibitor. In silico screening and differential scanning fluorescence yielded the FDA-approved antidepressant imipramine as the most evident potential fascin1 blocker. Biophysical and different in vitro actin-bundling assays confirm this activity. Subsequent assays investigating lamellipodia formation and migration and invasion of colorectal cancer cells in vitro using 3D human tissue demonstrated anti-fascin1 and anti-invasive activities of imipramine. Furthermore, expression profiling suggests the activity of imipramine on the actin cytoskeleton. Moreover, in vivo studies using a zebrafish invasion model showed that imipramine is tolerated, its anti-invasive and antimetastatic activities are dose-dependent, and it is associated with both constitutive and induced fascin1 expression. This is the first study that demonstrates an antitumoral role of imipramine as a fascin1 inhibitor and constitutes a foundation for a molecular targeted therapy for SAC and other fascin1-overexpressing tumors.
Investigating the role of the innate immune response in relapse or blast crisis in chronic myeloid leukemia
Authors: Huang Weiqi , Liu Bin , Eklund Elizabeth A. 
Published: February 2020

AbstractChronic myeloid leukemia (CML) is characterized by expression of the tyrosine kinase oncogene, Bcr–abl. Tyrosine kinase inhibitors (TKI) induce prolonged remission in CML, and therapy discontinuation is an accepted approach to patients with reduction in Bcr–abl transcripts of four logs or greater. Half such individuals sustain a therapy free remission, but molecular mechanisms predicting relapse are undefined. We found relative calpain inhibition in CML cells with stabilization of calpain substrates, including βcatenin and Xiap1. Since the Survivin gene is activated by βcatenin, this identified two apoptosis-resistance mechanisms. We found that Survivin impaired apoptosis in leukemia stem cells (LSCs) and Xiap1 in CML granulocytes. Consistent with this, we determined treatment with an inhibitor of Survivin, but not Xiap1, prevented relapse during TKI treatment and after therapy discontinuation in a murine CML model. By transcriptome profiling, we identified activation of innate immune response pathways in murine CML bone marrow progenitors. This was increased by TKI treatment alone, but normalized with addition of a Survivin inhibitor. We found that activation of the innate immune response induced rapid blast crisis in untreated CML mice, and chronic phase relapse during a TKI discontinuation attempt. These results suggest that extrinsic stress exerts adverse effects on CML-LSCs.
Competition experiments in a soil microcosm reveal the impact of genetic and biotic factors on natural yeast populations
Authors: Bleuven Clara , Nguyen Guillaume Q , Després Philippe C , Filteau Marie , Landry Christian R 
Published: February 2020

Abstract
The ability to measure microbial fitness directly in natural conditions and in interaction with other microbes is a challenge that needs to be overcome if we want to gain a better understanding of microbial fitness determinants in nature. Here we investigate the influence of the natural microbial community on the relative fitness of the North American populations SpB, SpC and SpC* of the wild yeast Saccharomyces paradoxus using DNA barcodes and a soil microcosm derived from soil associated with oak trees. We find that variation in fitness among these genetically distinct groups is influenced by the microbial community. Altering the microbial community load and diversity with an irradiation treatment significantly diminishes the magnitude of fitness differences among populations. Our findings suggest that microbial interactions could affect the evolution of yeast lineages in nature by modulating variation in fitness.
Myotubularin-related protein 14 suppresses cardiac hypertrophy by inhibiting Akt
Authors: Zhang Jie-Lei , Zhang Dian-Hong , Li Ya-Peng , Wu Lei-Ming , Liang Cui , Yao Rui , Wang Zheng , Feng Sheng-dong , Wang Zhong-Min , Zhang Yan-Zhou 
Published: February 2020

AbstractCardiac hypertrophy (CH) is an independent risk factor for many cardiovascular diseases, and is one of the primary causes of morbidity and mortality in elderly people. Pathological CH involves excessive protein synthesis, increased cardiomyocyte size, and ultimately the development of heart failure. Myotubularin-related protein 14 (MTMR14) is a member of the myotubularin (MTM)-related protein family, which is involved in apoptosis, aging, inflammation, and autophagy. However, its exact function in CH is still unclear. Herein, we investigated the roles of MTMR14 in CH. We show that MTMR14 expression was increased in hypertrophic mouse hearts. Mice deficient in heart MTMR14 exhibited an aggravated aortic-banding (AB)-induced CH phenotype. In contrast, MTMR14 overexpression prevented pressure overload-induced hypertrophy. At the molecular level, prevention of CH in the absence of MTMR14 involved elevations in Akt pathway components, which are key elements that regulate apoptosis and cell proliferation. These results demonstrate that MTMR14 is a new molecular target for the treatment of CH.
Collaborative interactions of heterogenous ribonucleoproteins contribute to transcriptional regulation of sterol metabolism in mice
Authors: Zhang Zhengyi , Feng An-Chieh , Salisbury David , Liu Xin , Wu Xiaohui , Kim Jason , Lapina Irina , Wang Dan , Lee Brennan , Fraga Josue , Pan Calvin , Williams Kevin J. , Lusis Aldons J. , Scumpia Phil , Sallam Tamer 
Published: February 2020

AbstractHeterogeneous nuclear ribonucleoproteins (hnRNPs) are a group of functionally versatile proteins that play critical roles in the biogenesis, cellular localization and transport of RNA. Here, we outline a role for hnRNPs in gene regulatory circuits controlling sterol homeostasis. Specifically, we find that tissue-selective loss of the conserved hnRNP RALY enriches for metabolic pathways. Liver-specific deletion of RALY alters hepatic lipid content and serum cholesterol level. In vivo interrogation of chromatin architecture and genome-wide RALY-binding pattern reveal insights into its cooperative interactions and mode of action in regulating cholesterogenesis. Interestingly, we find that RALY binds the promoter region of the master metabolic regulator Srebp2 and show that it directly interacts with coactivator Nuclear Transcription Factor Y (NFY) to influence cholesterogenic gene expression. Our work offers insights into mechanisms orchestrating selective promoter activation in metabolic control and a model by which hnRNPs can impact health and disease states.
Pan-cancer analysis reveals cooperativity of both strands of microRNA that regulate tumorigenesis and patient survival
Authors: Mitra Ramkrishna , Adams Clare M. , Jiang Wei , Greenawalt Evan , Eischen Christine M. 
Published: February 2020

AbstractRecently, both 5p and 3p miRNA strands are being recognized as functional instead of only one, leaving many miRNA strands uninvestigated. To determine whether both miRNA strands, which have different mRNA-targeting sequences, cooperate to regulate pathways/functions across cancer types, we evaluate genomic, epigenetic, and molecular profiles of >5200 patient samples from 14 different cancers, and RNA interference and CRISPR screens in 290 cancer cell lines. We identify concordantly dysregulated miRNA 5p/3p pairs that coordinately modulate oncogenic pathways and/or cell survival/growth across cancers. Down-regulation of both strands of miR-30a and miR-145 recurrently increased cell cycle pathway genes and significantly reduced patient survival in multiple cancers. Forced expression of all four strands show cooperativity, reducing cell cycle pathways and inhibiting lung cancer cell proliferation and migration. Therefore, we identify miRNA whose 5p/3p strands function together to regulate core tumorigenic processes/pathways and reveal a previously unknown pan-cancer miRNA signature with patient prognostic power.
Relaxed sequence constraints favor mutational freedom in idiosyncratic metazoan mitochondrial tRNAs
Authors: Kuhle Bernhard , Chihade Joseph , Schimmel Paul 
Published: February 2020

AbstractMetazoan complexity and life-style depend on the bioenergetic potential of mitochondria. However, higher aerobic activity and genetic drift impose strong mutation pressure and risk of irreversible fitness decline in mitochondrial (mt)DNA-encoded genes. Bilaterian mitochondria-encoded tRNA genes, key players in mitochondrial activity, have accumulated mutations at significantly higher rates than their cytoplasmic counterparts, resulting in foreshortened and fragile structures. Here we show that fragility of mt tRNAs coincided with the evolution of bilaterian animals. We demonstrate that bilaterians compensated for this reduced structural complexity in mt tRNAs by sequence-independent induced-fit adaption to the cognate mitochondrial aminoacyl-tRNA synthetase (aaRS). Structural readout by nuclear-encoded aaRS partners relaxed the sequence constraints on mt tRNAs and facilitated accommodation of functionally disruptive mutational insults by cis-acting epistatic compensations. Our results thus suggest that mutational freedom in mt tRNA genes is an adaptation to increased mutation pressure that was associated with the evolution of animal complexity.
A serine/threonine protein kinase encoding gene KERNEL NUMBER PER ROW6 regulates maize grain yield
Authors: Jia Haitao , Li Manfei , Li Weiya , Liu Lei , Jian Yinan , Yang Zhixing , Shen Xiaomeng , Ning Qiang , Du Yanfang , Zhao Ran , Jackson David , Yang Xiaohong , Zhang Zuxin 
Published: February 2020

AbstractIncreasing grain yield of maize (Zea maysL.) is required to meet the rapidly expanding demands for maize-derived food, feed, and fuel. Breeders have enhanced grain productivity of maize hybrids by pyramiding desirable characteristics for larger ears. However, loci selected for improving grain productivity remain largely unclear. Here, we show that a serine/threonine protein kinase encoding geneKERNEL NUMBER PER ROW6 (KNR6)determines pistillate floret number and ear length. Overexpression ofKNR6or introgression of alleles lacking the insertions of two transposable elements in the regulatory region ofKNR6can significantly enhance grain yield. Further in vitro evidences indicate that KNR6 can interact with an Arf GTPase-activating protein (AGAP) and its phosphorylation by KNR6 may affect ear length and kernel number. This finding provides knowledge basis to enhance maize hybrids grain yield.
Prevention of aspartimide formation during peptide synthesis using cyanosulfurylides as carboxylic acid-protecting groups
Authors: Neumann Kevin , Farnung Jakob , Baldauf Simon , Bode Jeffrey W. 
Published: February 2020

AbstractAlthough peptide chemistry has made great progress, the frequent occurrence of aspartimide formation during peptide synthesis remains a formidable challenge. Aspartimide formation leads to low yields in addition to costly purification or even inaccessible peptide sequences. Here, we report an alternative approach to address this longstanding challenge of peptide synthesis by utilizing cyanosulfurylides to mask carboxylic acids by a stable C–C bond. These functional groups—formally zwitterionic species—are exceptionally stable to all common manipulations and impart improved solubility during synthesis. Deprotection is readily and rapidly achieved under aqueous conditions with electrophilic halogenating agents via a highly selective C–C bond cleavage reaction. This protecting group is employed for the synthesis of a range of peptides and proteins including teduglutide, ubiquitin, and the low-density lipoprotein class A. This protecting group strategy has the potential to overcome one of the most difficult aspects of modern peptide chemistry.
Microglia control vascular architecture via a TGFβ1 dependent paracrine mechanism linked to tissue mechanics
Authors: Dudiki Tejasvi , Meller Julia , Mahajan Gautam , Liu Huan , Zhevlakova Irina , Stefl Samantha , Witherow Conner , Podrez Eugene , Kothapalli Chandrasekhar R. , Byzova Tatiana V. 
Published: February 2020

AbstractTissue microarchitecture and mechanics are important in development and pathologies of the Central Nervous System (CNS); however, their coordinating mechanisms are unclear. Here, we report that during colonization of the retina, microglia contacts the deep layer of high stiffness, which coincides with microglial bipolarization, reduction in TGFβ1 signaling and termination of vascular growth. Likewise, stiff substrates induce microglial bipolarization and diminish TGFβ1 expression in hydrogels. Both microglial bipolarization in vivo and the responses to stiff substrates in vitro require intracellular adaptor Kindlin3 but not microglial integrins. Lack of Kindlin3 causes high microglial contractility, dysregulation of ERK signaling, excessive TGFβ1 expression and abnormally-patterned vasculature with severe malformations in the area of photoreceptors. Both excessive TGFβ1 signaling and vascular defects caused by Kindlin3-deficient microglia are rescued by either microglial depletion or microglial knockout of TGFβ1 in vivo. This mechanism underlies an interplay between microglia, vascular patterning and tissue mechanics within the CNS.
Structural basis for substrate specificity and catalysis of α1,6-fucosyltransferase
Authors: García-García Ana , Ceballos-Laita Laura , Serna Sonia , Artschwager Raik , Reichardt Niels C. , Corzana Francisco , Hurtado-Guerrero Ramon 
Published: February 2020

AbstractCore-fucosylation is an essential biological modification by which a fucose is transferred from GDP-β-L-fucose to the innermost N-acetylglucosamine residue of N-linked glycans. A single human enzyme α1,6-fucosyltransferase (FUT8) is the only enzyme responsible for this modification via the addition of an α-1,6-linked fucose to N-glycans. To date, the details of substrate recognition and catalysis by FUT8 remain unknown. Here, we report the crystal structure of FUT8 complexed with GDP and a biantennary complex N-glycan (G0), which provides insight into both substrate recognition and catalysis. FUT8 follows an SN2 mechanism and deploys a series of loops and an α-helix which all contribute in forming the binding site. An exosite, formed by one of these loops and an SH3 domain, is responsible for the recognition of branched sugars, making contacts specifically to the α1,3 arm GlcNAc, a feature required for catalysis. This information serves as a framework for inhibitor design, and helps to assess its potential as a therapeutic target.
Gaze, behavioral, and clinical data for phantom limbs after hand amputation from 15 amputees and 29 controls
Authors: Saetta Gianluca , Cognolato Matteo , Atzori Manfredo , Faccio Diego , Giacomino Katia , Mittaz Hager Anne-Gabrielle , Tiengo Cesare , Bassetto Franco , Müller Henning , Brugger Peter 
Published: February 2020

AbstractDespite recent advances in prosthetics, many upper limb amputees still use prostheses with some reluctance. They often do not feel able to incorporate the artificial hand into their bodily self. Furthermore, prosthesis fitting is not usually tailored to accommodate the characteristics of an individual’s phantom limb sensations. These are experienced by almost all persons with an acquired amputation and comprise the motor and postural properties of the lost limb. This article presents and validates a multimodal dataset including an extensive qualitative and quantitative assessment of phantom limb sensations in 15 transradial amputees, surface electromyography and accelerometry data of the forearm, and measurements of gaze behavior during exercises requiring pointing or repositioning of the forearm and the phantom hand. The data also include acquisitions from 29 able-bodied participants, matched for gender and age. Special emphasis was given to tracking the visuo-motor coupling between eye-hand/eye-phantom during these exercises.
Pollen defenses negatively impact foraging and fitness in a generalist bee (Bombus impatiens: Apidae)
Authors: Brochu Kristen K. , van Dyke Maria T. , Milano Nelson J. , Petersen Jessica D. , McArt Scott H. , Nault Brian A. , Kessler André , Danforth Bryan N. 
Published: February 2020

AbstractPlants may benefit from limiting the community of generalist floral visitors if the species that remain are more effective pollinators and less effective pollenivores. Plants can reduce access to pollen through altered floral cues or morphological structures, but can also reduce consumption through direct pollen defenses. We observed thatEucera (Peponapis) pruinosa, a specialist bee onCucurbitaplants, collected pure loads of pollen while generalist honey bees and bumble bees collected negligible amounts of cucurbit pollen, even though all groups of bees visited these flowers. Cucurbit flowers have no morphological adaptations to limit pollen collection by bees, thus we assessed their potential for physical, nutritional, and chemical pollen traits that might act as defenses to limit pollen loss to generalist pollinators. Bumble bee (Bombus impatiens) microcolonies experienced reduced pollen consumption, mortality, and reproduction as well as increased stress responses when exposed to nutritional and mechanical pollen defenses. These bees also experienced physiological effects of these defenses in the form of hindgut expansion and gut melanization. Chemical defenses alone increased the area of gut melanization in larger bees and induced possible compensatory feeding. Together, these results suggest that generalist bumble bees avoid collecting cucurbit pollen due to the physiological costs of physical and chemical pollen defenses.
Phase I studies of vorinostat with ixazomib or pazopanib imply a role of antiangiogenesis-based therapy for TP53 mutant malignancies
Authors: Wang Yudong , Janku Filip , Piha-Paul Sarina , Hess Kenneth , Broaddus Russell , Liu Lidong , Shi Naiyi , Overman Michael , Kopetz Scott , Subbiah Vivek , Naing Aung , Hong David , Tsimberidou Apostolia M. , Karp Daniel , Yao James , Fu Siqing 
Published: February 2020

AbstractWe performed two phase I trials of the histone deacetylase inhibitor vorinostat combined with either the vascular endothelial growth factor inhibitor pazopanib (NCT01339871) or the proteasome inhibitor ixazomib (NCT02042989) in patients with metastatic TP53 mutant solid tumors. Both trials followed a 3 + 3 dose-escalation design allowing for a dose expansion cohort of up to 14 additional patients with a specific tumor type. Patients had to have a confirmed TP53 mutation to be enrolled in NCT02042989. Among patients enrolled in NCT01339871, TP53 mutation status was determined for those for whom tumor specimens were available. The results of NCT01339871 were reported previously. Common treatment-related adverse events in NCT02042989 included anemia, thrombocytopenia, fatigue, nausea, vomiting, and diarrhea. Compared with patients with metastatic TP53 hotspot mutant solid tumors who were treated with ixazomib and vorinostat (n = 59), those who were treated with pazopanib and vorinostat (n = 11) had a significantly higher rate of clinical benefit, defined as stable disease lasting ≥6 months or an objective response (3.4% vs. 45%; p < 0.001), a significantly longer median progression-free survival duration (1.7 months [95% confidence interval (CI), 1.1–2.3] vs. 3.5 months [95% CI, 1.7–5.2]; p = 0.002), and a longer median overall survival duration (7.3 months [95% CI, 4.8–9.8] vs. 12.7 months [95% CI, 7.1–18.3]; p = 0.24). Our two phase I trials provide preliminary evidence supporting the use of antiangiogenisis-based therapy in patients with metastatic TP53 mutant solid tumors, especially in those with metastatic sarcoma or metastatic colorectal cancer.
A tiny new Middle Triassic stem-lepidosauromorph from Germany: implications for the early evolution of lepidosauromorphs and the Vellberg fauna
Authors: Sobral Gabriela , Simões Tiago R. , Schoch Rainer R. 
Published: February 2020

AbstractThe Middle Triassic was a time of major changes in tetrapod faunas worldwide, but the fossil record for this interval is largely obscure for terrestrial faunas. This poses a severe limitation to our understanding on the earliest stages of diversification of lineages representing some of the most diverse faunas in the world today, such as lepidosauromorphs (e.g., lizards and tuataras). Here, we report a tiny new lepidosauromorph from the Middle Triassic from Vellberg (Germany), which combines a mosaic of features from both early evolving squamates and rhynchocephalians, such as the simultaneous occurrence of a splenial bone and partial development of acrodonty. Phylogenetic analyses applying different optimality criteria, and combined morphological and molecular data, consistently recover the new taxon as a stem-lepidosauromorph, implying stem-lepidosauromorph species coinhabited areas comprising today’s central Europe at the same time as the earliest known rhynchocephalians and squamates. It further demonstrates a more complex evolutionary scenario for dental evolution in early lepidosauromorphs, with independent acquisitions of acrodonty early in their evolutionary history. The small size of most terrestrial vertebrates from Vellberg is conspicuous, contrasting to younger Triassic deposits worldwide, but comparable to Early Triassic faunas, suggesting a potential long-lasting Lilliput effect in this fauna.
Neural correlates of subjective timing precision and confidence
Authors: Arnold Derek H. , Hohaia Wiremu , Yarrow Kielan 
Published: February 2020

AbstractHumans perceptual judgments are imprecise, as repeated exposures to the same physical stimulation (e.g. audio-visual inputs separated by a constant temporal offset) can result in different decisions. Moreover, there can be marked individual differences – precise judges will repeatedly make the same decision about a given input, whereas imprecise judges will make different decisions. The causes are unclear. We examined this using audio-visual (AV) timing and confidence judgments, in conjunction with electroencephalography (EEG) and multivariate pattern classification analyses. One plausible cause of differences in timing precision is that it scales with variance in the dynamics of evoked brain activity. Another possibility is that equally reliable patterns of brain activity are evoked, but there are systematic differences that scale with precision. Trial-by-trial decoding of input timings from brain activity suggested precision differences may not result from variable dynamics. Instead, precision was associated with evoked responses that were exaggerated (more different from baseline) ~300 ms after initial physical stimulations. We suggest excitatory and inhibitory interactions within a winner-take-all neural code for AV timing might exaggerate responses, such that evoked response magnitudes post-stimulation scale with encoding success.