bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structural and functional characterization of a ubiquitin variant engineered for tight and specific binding to an alpha‐helical ubiquitin interacting motif
Authors: Manczyk Noah , Yates Bradley P. , Veggiani Gianluca , Ernst Andreas , Sicheri Frank , Sidhu Sachdev S. 
Published: March 2017

AbstractUbiquitin interacting motifs (UIMs) are short α‐helices found in a number of eukaryotic proteins. UIMs interact weakly but specifically with ubiquitin conjugated to other proteins, and in so doing, mediate specific cellular signals. Here we used phage display to generate ubiquitin variants (UbVs) targeting the N‐terminal UIM of the yeast Vps27 protein. Selections yielded UbV.v27.1, which recognized the cognate UIM with high specificity relative to other yeast UIMs and bound with an affinity more than two orders of magnitude higher than that of ubiquitin. Structural and mutational studies of the UbV.v27.1‐UIM complex revealed the molecular details for the enhanced affinity and specificity of UbV.v27.1, and underscored the importance of changes at the binding interface as well as at positions that do not contact the UIM. Our study highlights the power of the phage display approach for selecting UbVs with unprecedented affinity and high selectivity for particular α‐helical UIM domains within proteomes, and it establishes a general approach for the development of inhibitors targeting interactions of this type.
Multifactorial Experimental Design to Optimize the Anti-Inflammatory and Proangiogenic Potential of Mesenchymal Stem Cell Spheroids
Authors: Murphy Kaitlin C. , Whitehead Jacklyn , Falahee Patrick C. , Zhou Dejie , Simon Scott I. , Leach J. Kent 
Published: March 2017

Abstract
Mesenchymal stem cell therapies promote wound healing by manipulating the local environment to enhance the function of host cells. Aggregation of mesenchymal stem cells (MSCs) into three-dimensional spheroids increases cell survival and augments their anti-inflammatory and proangiogenic potential, yet there is no consensus on the preferred conditions for maximizing spheroid function in this application. The objective of this study was to optimize conditions for forming MSC spheroids that simultaneously enhance their anti-inflammatory and proangiogenic nature. We applied a design of experiments (DOE) approach to determine the interaction between three input variables (number of cells per spheroid, oxygen tension, and inflammatory stimulus) on MSC spheroids by quantifying secretion of prostaglandin E2 (PGE2) and vascular endothelial growth factor (VEGF), two potent molecules in the MSC secretome. DOE results revealed that MSC spheroids formed with 40,000 cells per spheroid in 1% oxygen with an inflammatory stimulus (Spheroid 1) would exhibit enhanced PGE2 and VEGF production versus those formed with 10,000 cells per spheroid in 21% oxygen with no inflammatory stimulus (Spheroid 2). Compared to Spheroid 2, Spheroid 1 produced fivefold more PGE2 and fourfold more VEGF, providing the opportunity to simultaneously upregulate the secretion of these factors from the same spheroid. The spheroids induced macrophage polarization, sprout formation with endothelial cells, and keratinocyte migration in a human skin equivalent model—demonstrating efficacy on three key cell types that are dysfunctional in chronic non-healing wounds. We conclude that DOE-based analysis effectively identifies optimal culture conditions to enhance the anti-inflammatory and proangiogenic potential of MSC spheroids.
Pattern recognition for predictive, preventive, and personalized medicine in cancer
Authors: Cheng Tingting , Zhan Xianquan 
Published: March 2017

Abstract
Predictive, preventive, and personalized medicine (PPPM) is the hot spot and future direction in the field of cancer. Cancer is a complex, whole-body disease that involved multi-factors, multi-processes, and multi-consequences. A series of molecular alterations at different levels of genes (genome), RNAs (transcriptome), proteins (proteome), peptides (peptidome), metabolites (metabolome), and imaging characteristics (radiome) that resulted from exogenous and endogenous carcinogens are involved in tumorigenesis and mutually associate and function in a network system, thus determines the difficulty in the use of a single molecule as biomarker for personalized prediction, prevention, diagnosis, and treatment for cancer. A key molecule-panel is necessary for accurate PPPM practice. Pattern recognition is an effective methodology to discover key molecule-panel for cancer. The modern omics, computation biology, and systems biology technologies lead to the possibility in recognizing really reliable molecular pattern for PPPM practice in cancer. The present article reviewed the pathophysiological basis, methodology, and perspective usages of pattern recognition for PPPM in cancer so that our previous opinion on multi-parameter strategies for PPPM in cancer is translated into real research and development of PPPM or precision medicine (PM) in cancer.
Malthus in the Bedroom: Birth Spacing as Birth Control in Pre-Transition England
Authors: Cinnirella Francesco , Klemp Marc , Weisdorf Jacob 
Published: March 2017

AbstractWe use duration models on a well-known historical data set of more than 15,000 families and 60,000 births in England for the period 1540–1850 to show that the sampled families adjusted the timing of their births in accordance with the economic conditions as well as their stock of dependent children. The effects were larger among the lower socioeconomic ranks. Our findings on the existence of parity-dependent as well as parity-independent birth spacing in England are consistent with the growing evidence that marital birth control was present in pre-transitional populations.
Reconfigurable dynamic control allocation for aircraft with actuator failures
Authors: Almutairi S. H. , Aouf N. 
Published: March 2017

ABSTRACTIn this paper, the development of a fault-tolerant control system for an aircraft that exploits both the hardware and analytical redundancy in the system is considered. A control allocation approach is developed where the total control command is computed and distributed among the available control surfaces. The actuator’s position and rate limits are taken into account in the optimisation problem. Existing fault-tolerant control allocation techniques produce look-up tables of control gains based on certain faults in the model. In contrast, the developed reconfigurable approach presented here incorporates a new process that redistributes control efforts which is updated whenever a fault occurs. In order to correlate between control effort redistribution and the fault magnitude, a fuzzy logic scheme is implemented, which handles a wide range of fault magnitudes on-line. The approach is applied for the most severe type of fault, which is the “lock-in-place” (jam) fault. Results show that the developed approach successfully handles the faulty situations and enhances aircraft flying responses by utilising the available healthy controls.
GROWTH AND MINERAL COMPOSITION OF TWO LINEAGES OF THE SEA ASPARAGUS SARCOCORNIA AMBIGUA IRRIGATED WITH SHRIMP FARM SALINE EFFLUENT
Authors: DONCATO KENNIA BRUM , COSTA CÉSAR SERRA BONIFÁCIO 
Published: March 2017

SUMMARYThe sea asparagus Sarcocornia ambigua is a widespread coastal halophyte of South America that has a recent history of successful cultivation with saline shrimp farm effluent and nutritional quality for human and animal diets, as well as chemical characteristics for biofuel production. Two morphologically distinct lineages (BTH1 and BTH2) of S. ambigua were obtained by crossing pure lineages of natural biotypes. The growth and biomass production of f3 and f4 progenies of S. ambigua lineages were evaluated, as well as their macro- and micro-mineral components were investigated by spectrophotometry. The BTH2 lineage showed a 43% higher shoot growth rate, a two times faster branch production and a higher biomass allocation to shoots than in BTH1. BTH1 shoots showed higher concentrations of N, K and Cu than did the BTH2 progenies. The average levels of N, K, P and Ca in BTH1-f4 shoots were higher than those in wild plants of S. ambigua and ranked in the mid-upper range of these mineral contents in other species of the subfamily Salicorniodeae and gourmet vegetables. The mineral profile of the two selected lineages of S. ambigua confirms high nutritional quality of these plants for humans and animals. They can be presented as alternatives to food production with saline effluent from aquaculture on the temperate and tropical coast and/or inland salt-affected soils of South America.
The philometrid nematodePhilometroides acreanensis n. sp. from the stomach wall of the catfishPimelodus blochiiin north-western Brazil
Authors: Cavalcante P.H.O. , Moravec F. , Santos C.P. 
Published: March 2017

AbstractA new nematode species,Philometroides acreanensisn. sp. (Philometridae), is described from female specimens recovered from the stomach wall of the freshwater catfishPimelodus blochiiValenciennes (Pimelodidae) collected in the Acre River (Amazon River basin), Acre State, Brazil. Based on examination by light and scanning electron microscopy, the new species differs from the two other South American congeneric species mainly in the body length of the gravid female (240–280 mm), the length of the oesophagus (1.25 mm in holotype) representing 0.5% of the entire body length, the range of cuticular embossment, as well as the location in the host (stomach), order of the fish host (Siluriformes) and the geographical distribution (Amazon River drainage system). This is the third known species ofPhilometroidesYamaguti, 1935 reported from South America. A key to species ofPhilometroidesoccurring in the fish of America is provided.
Treatment decision-making capacity in non-consensual psychiatric treatment: a multicentre study
Authors: Mandarelli G. , Carabellese F. , Parmigiani G. , Bernardini F. , Pauselli L. , Quartesan R. , Catanesi R. , Ferracuti S. 
Published: March 2017

Aims.To evaluate treatment decision-making capacity (DMC) to consent to psychiatric treatment in involuntarily committed patients and to further investigate possible associations with clinical and socio-demographic characteristics of patients.Methods.131 involuntarily hospitalised patients were recruited in three university hospitals. Mental capacity to consent to treatment was measured with the MacArthur Competence Assessment Tool for Treatment (MacCAT-T); psychiatric symptoms severity (Brief Psychiatric Rating Scale, BPRS-E) and cognitive functioning (Mini Mental State Examination, MMSE) were also assessed.Results.Mental capacity ratings for the 131 involuntarily hospitalised patients showed that patients affected by bipolar disorders (BD) scored generally better than those affected by schizophrenia spectrum disorders (SSD) in MacCAT-T appreciation (p< 0.05) and reasoning (p< 0.01). Positive symptoms were associated with poorer capacity to appreciate (r= −0.24;p< 0.01) and reason (r= −0.27;p< 0.01) about one's own treatment. Negative symptoms were associated with poorer understanding of treatment (r= −0.23;p< 0.01). Poorer cognitive functioning, as measured by MMSE, negatively affected MacCAT-T understanding in patients affected by SSD, but not in those affected by BD (SSDr= 0.37;p< 0.01; BDr= −0.01;p= 0.9). Poorer MacCAT-T reasoning was associated with more manic symptoms in the BD group of patients but not in the SSD group (BDr= −0.32;p< 0.05; SSDr= 0.03;p= 0.8). Twenty-two per cent (n= 29) of the 131 recruited patients showed high treatment DMC as defined by having scored higher than 75% ofunderstanding, appreciating and reasoningMacCAT-T subscales maximum sores and 2 atexpressing a choice. The remaining involuntarily hospitalised patients where considered to have low treatment DMC. Chi-squared disclosed that 32% of BD patients had high treatment DMC compared with 9% of SSD patients (p< 0.001).Conclusions.Treatment DMC can be routinely assessed in non-consensual psychiatric settings by the MacCAT-T, as is the case of other clinical variables. Such approach can lead to the identification of patients with high treatment DMC, thus drawing attention to possible dichotomy between legal and clinical status.
The FOXM1–ABCC5 axis contributes to paclitaxel resistance in nasopharyngeal carcinoma cells
Authors: Hou Youxiang , Zhu Qianling , Li Zheng , Peng Yongbo , Yu Xiaohui , Yuan Bowen , Liu Yijun , Liu Youhong , Yin Linglong , Peng Yuchong , Jiang Zhenghua , Li Jinping , Xie Bowen , Duan Yumei , Tan Guolin , Gulina Kurban , Gong Zhicheng , Sun Lunquan , Fan Xuegong , Li Xiong 
Published: March 2017

AbstractPaclitaxel is clinically used as a first-line chemotherapeutic regimen for several cancer types, including head and neck cancers. However, acquired drug resistance results in the failure of therapy, metastasis and relapse. The drug efflux mediated by ATP-binding cassette (ABC) transporters and the survival signals activated by forkhead box (FOX) molecules are critical in the development of paclitaxel drug resistance. Whether FOX molecules promote paclitaxel resistance through drug efflux remains unknown. In this study, we developed several types of paclitaxel-resistant (TR) nasopharyngeal carcinoma (NPC) cells. These TR NPC cells acquired cancer stem cell (CSC) phenotypes and underwent epithelial to mesenchymal transition (EMT), and developed multidrug resistance. TR cells exhibited stronger drug efflux than parental NPC cells, leading to the reduction of intracellular drug concentrations and drug insensitivity. After screening the gene expression of ABC transporters and FOX molecules, we found that FOXM1 and ABCC5 were consistently overexpressed in the TR NPC cells and in patient tumor tissues. Further studies demonstrated that FOXM1 regulated abcc5 gene transcription by binding to the FHK consensus motifs at the promoter. The depletion of FOXM1 or ABCC5 with siRNA significantly blocked drug efflux and increased the intracellular concentrations of paclitaxel, thereby promoting paclitaxel-induced cell death. Siomycin A, a FOXM1 inhibitor, significantly enhanced in vitro cell killing by paclitaxel in drug-resistant NPC cells. This study is the first to identify the roles of FOXM1 in drug efflux and paclitaxel resistance by regulating the gene transcription of abcc5, one of the ABC transporters. Small molecular inhibitors of FOXM1 or ABCC5 have the potential to overcome paclitaxel chemoresistance in NPC patients.
Deconvolution of Buparlisib’s mechanism of action defines specific PI3K and tubulin inhibitors for therapeutic intervention
Authors: Bohnacker Thomas , Prota Andrea E. , Beaufils Florent , Burke John E. , Melone Anna , Inglis Alison J. , Rageot Denise , Sele Alexander M. , Cmiljanovic Vladimir , Cmiljanovic Natasa , Bargsten Katja , Aher Amol , Akhmanova Anna , Díaz J. Fernando , Fabbro Doriano , Zvelebil Marketa , Williams Roger L. , Steinmetz Michel O. , Wymann Matthias P. 
Published: March 2017

AbstractBKM120 (Buparlisib) is one of the most advanced phosphoinositide 3-kinase (PI3K) inhibitors for the treatment of cancer, but it interferes as an off-target effect with microtubule polymerization. Here, we developed two chemical derivatives that differ from BKM120 by only one atom. We show that these minute changes separate the dual activity of BKM120 into discrete PI3K and tubulin inhibitors. Analysis of the compounds cellular growth arrest phenotypes and microtubule dynamics suggest that the antiproliferative activity of BKM120 is mainly due to microtubule-dependent cytotoxicity rather than through inhibition of PI3K. Crystal structures of BKM120 and derivatives in complex with tubulin and PI3K provide insights into the selective mode of action of this class of drugs. Our results raise concerns over BKM120’s generally accepted mode of action, and provide a unique mechanistic basis for next-generation PI3K inhibitors with improved safety profiles and flexibility for use in combination therapies.
RETRACTED ARTICLE: TRIB2 confers resistance to anti-cancer therapy by activating the serine/threonine protein kinase AKT
Authors: Hill Richard , Madureira Patricia A. , Ferreira Bibiana , Baptista Inês , Machado Susana , Colaço Laura , dos Santos Marta , Liu Ningshu , Dopazo Ana , Ugurel Selma , Adrienn Angyal , Kiss-Toth Endre , Isbilen Murat , Gure Ali O. , Link Wolfgang 
Published: March 2017

AbstractIntrinsic and acquired resistance to chemotherapy is the fundamental reason for treatment failure for many cancer patients. The identification of molecular mechanisms involved in drug resistance or sensitization is imperative. Here we report that tribbles homologue 2 (TRIB2) ablates forkhead box O activation and disrupts the p53/MDM2 regulatory axis, conferring resistance to various chemotherapeutics. TRIB2 suppression is exerted via direct interaction with AKT a key signalling protein in cell proliferation, survival and metabolism pathways. Ectopic or intrinsic high expression of TRIB2 induces drug resistance by promoting phospho-AKT (at Ser473) via its COP1 domain. TRIB2 expression is significantly increased in tumour tissues from patients correlating with an increased phosphorylation of AKT, FOXO3a, MDM2 and an impaired therapeutic response. This culminates in an extremely poor clinical outcome. Our study reveals a novel regulatory mechanism underlying drug resistance and suggests that TRIB2 functions as a regulatory component of the PI3K network, activating AKT in cancer cells.
Structure-guided mutagenesis reveals a hierarchical mechanism of Parkin activation
Authors: Tang Matthew Y. , Vranas Marta , Krahn Andrea I. , Pundlik Shayal , Trempe Jean- François , Fon Edward A. 
Published: March 2017

AbstractParkin and PINK1 function in a common pathway to clear damaged mitochondria. Parkin exists in an auto-inhibited conformation stabilized by multiple interdomain interactions. The binding of PINK1-generated phospho-ubiquitin and the phosphorylation of the ubiquitin-like (Ubl) domain of Parkin at Ser65 release its auto-inhibition, but how and when these events take place in cells remain to be defined. Here we show that mutations that we designed to activate Parkin by releasing the Repressor Element of Parkin (REP) domain, or by disrupting the interface between the RING0:RING2 domains, can completely rescue mutations in the Parkin Ubl that are defective in mitochondrial autophagy. Using a FRET reporter assay we show that Parkin undergoes a conformational change upon phosphorylation that can be mimicked by mutating Trp403 in the REP. We propose a hierarchical model whereby pUb binding on mitochondria enables Parkin phosphorylation, which, in turn, leads to REP removal, E3 ligase activation and mitophagy.
The purinergic receptor P2X5 regulates inflammasome activity and hyper-multinucleation of murine osteoclasts
Authors: Kim Hyunsoo , Walsh Matthew C. , Takegahara Noriko , Middleton Sarah A. , Shin Hong-In , Kim Junhyong , Choi Yongwon 
Published: March 2017

AbstractExcessive bone resorption by osteoclasts (OCs) can result in serious clinical outcomes, including bone loss that may weaken skeletal or periodontal strength. Proper bone homeostasis and skeletal strength are maintained by balancing OC function with the bone-forming function of osteoblasts. Unfortunately, current treatments that broadly inhibit OC differentiation or function may also interfere with coupled bone formation. We therefore identified a factor, the purinergic receptor P2X5 that is highly expressed during the OC maturation phase, and which we show here plays no apparent role in early bone development and homeostasis, but which is required for osteoclast-mediated inflammatory bone loss and hyper-multinucleation of OCs. We further demonstrate that P2X5 is required for ATP-mediated inflammasome activation and IL-1β production by OCs, and that P2X5-deficient OC maturation is rescued in vitro by addition of exogenous IL-1β. These findings identify a mechanism by which OCs react to inflammatory stimuli, and may identify purinergic signaling as a therapeutic target for bone loss-related inflammatory conditions.
Weaning age influences the severity of gastrointestinal microbiome shifts in dairy calves
Authors: Meale S. J. , Li S. C. , Azevedo P. , Derakhshani H. , DeVries T. J. , Plaizier J. C. , Steele M. A. , Khafipour E. 
Published: March 2017

AbstractRuminants microbial consortium is responsible for ruminal fermentation, a process which converts fibrous feeds unsuitable for human consumption into desirable dairy and meat products, begins to establish soon after birth. However, it undergoes a significant transition when digestion shifts from the lower intestine to ruminal fermentation. We hypothesised that delaying the transition from a high milk diet to an exclusively solid food diet (weaning) would lessen the severity of changes in the gastrointestinal microbiome during this transition. β-diversity of ruminal and faecal microbiota shifted rapidly in early-weaned calves (6 weeks), whereas, a more gradual shift was observed in late-weaned calves (8 weeks) up to weaning. Bacteroidetes and Firmicutes were the most abundant ruminal phyla in pre- and post-weaned calves, respectively. Yet, the relative abundance of these phyla remained stable in faeces (P ≥ 0.391). Inferred gene families assigned to KEGG pathways revealed an increase in ruminal carbohydrate metabolism (P ≤ 0.009) at 9, compared to 5 weeks. Conversely, carbohydrate metabolism in faeces declined (P ≤ 0.002) following a change in weaning status (i.e., the shift from pre- to post-weaning). Our results indicate weaning later facilitates a more gradual shift in microbiota and could potentially explain the negative effects of early-weaning associated with feeding a high-plane of pre-weaning nutrition.
Benzyl butyl phthalate decreases myogenic differentiation of endometrial mesenchymal stem/stromal cells through miR-137-mediated regulation of PITX2
Authors: Chen Hung-Sheng , Hsu Chia-Yi , Chang Yu-Chia , Chuang Hui-Yu , Long Cheng-Yu , Hsieh Tsung-Hua , Tsai Eing-Mei 
Published: March 2017

AbstractPhthalate, an environmental toxin, has been considered as an endocrine-disrupting chemical. Growing evidence has demonstrated links between endocrine-disrupting chemicals, tissue development, and reproductive physiology, but the mechanisms of gene expression regulation by environmental factors that affect cell differentiation are unclear. Herein, we investigated the effects of butyl benzyl phthalate (BBP) on human endometrial mesenchymal stem/stromal cell (EN-MSC) differentiation and identified a novel signaling pathway. Differentiation of endometrial mesenchymal stem/stromal cells decreased after administration of BBP. We analyzed BBP regulation of gene expression in EN-MSC using cDNA microarrays and Ingenuity Pathway Analysis software to identify affected target genes and their biological functions. PITX2 emerged as a common gene hit from separate screens targeting skeletal and muscular disorders, cell morphology, and tissue development. BBP decreased transcription of PITX2 and elevated expression of the microRNA miR-137, the predicted upstream negative regulator of PITX2. These data indicated that BBP affects PITX2 expression through miR-137 targeting of the 3′ untranslated region of PITX2 mRNA. PITX2 down-regulation also decreased MyoD transcript levels in EN-MSC. Our results demonstrate that BBP decreases EN-MSC myogenic differentiation through up-regulation of miR-137, contribute to our understanding of EN-MSC differentiation, and underline the hazardous potential of environmental hormones.