bluuebunny/crossref_metadata_2025_split huggingface dataset:
Centromere and telomere sequence alterations reflect the rapid genome evolution within the carnivorous plant genus Genlisea
Authors: Tran Trung D. , Cao Hieu X. , Jovtchev Gabriele , Neumann Pavel , Novák Petr , Fojtová Miloslava , Vu Giang T.H. , Macas Jiří , Fajkus Jiří , Schubert Ingo , Fuchs Joerg 
Published: October 2015

SummaryLinear chromosomes of eukaryotic organisms invariably possess centromeres and telomeres to ensure proper chromosome segregation during nuclear divisions and to protect the chromosome ends from deterioration and fusion, respectively. While centromeric sequences may differ between species, with arrays of tandemly repeated sequences and retrotransposons being the most abundant sequence types in plant centromeres, telomeric sequences are usually highly conserved among plants and other organisms. The genome size of the carnivorous genus Genlisea (Lentibulariaceae) is highly variable. Here we study evolutionary sequence plasticity of these chromosomal domains at an intrageneric level. We show that Genlisea nigrocaulis (1C = 86 Mbp; 2n = 40) and G. hispidula (1C = 1550 Mbp; 2n = 40) differ as to their DNA composition at centromeres and telomeres. G. nigrocaulis and its close relative G. pygmaea revealed mainly 161 bp tandem repeats, while G. hispidula and its close relative G. subglabra displayed a combination of four retroelements at centromeric positions. G. nigrocaulis and G. pygmaea chromosome ends are characterized by the Arabidopsis‐type telomeric repeats (TTTAGGG); G. hispidula and G. subglabra instead revealed two intermingled sequence variants (TTCAGG and TTTCAGG). These differences in centromeric and, surprisingly, also in telomeric DNA sequences, uncovered between groups with on average a > 9‐fold genome size difference, emphasize the fast genome evolution within this genus. Such intrageneric evolutionary alteration of telomeric repeats with cytosine in the guanine‐rich strand, not yet known for plants, might impact the epigenetic telomere chromatin modification.
Fuzzy Generalized Predictive Control for Nonlinear Brushless Direct
Current Motor
Authors: Wang Bin , Shi Ke , Zhang Cheng , Zhu Delan 
Published: October 2015

Abstract
In the study, a novel fuzzy generalized predictive control (GPC) scheme is proposed for the stability control of nonlinear brushless DC motor (BLDCM). First, the fuzzy predictive model of BLDCM is presented via Takagi–Sugeno fuzzy model. Then, based on the controlled autoregressive moving average (CARMA) model transformed by Takagi–Sugeno fuzzy model of BLDCM, a new fuzzy GPC scheme for the nonlinear BLDCM is designed by combining fuzzy techniques and GPC theory, and the rigorous mathematical derivation is given. Finally, numerical simulations are implemented to verify the effectiveness and superiority of the proposed scheme. It also provides reference for other nonlinear even chaos control in actual project.
Structural Basis of Metallo-β-Lactamase Inhibition by Captopril Stereoisomers
Authors: Brem Jürgen , van Berkel Sander S. , Zollman David , Lee Sook Y. , Gileadi Opher , McHugh Peter J. , Walsh Timothy R. , McDonough Michael A. , Schofield Christopher J. 
Published: October 2015

ABSTRACT

β-Lactams are the most successful antibacterials, but their effectiveness is threatened by resistance, most importantly by production of serine- and metallo-β-lactamases (MBLs). MBLs are of increasing concern because they catalyze the hydrolysis of almost all β-lactam antibiotics, including recent-generation carbapenems. Clinically useful serine-β-lactamase inhibitors have been developed, but such inhibitors are not available for MBLs.
l
-Captopril, which is used to treat hypertension via angiotensin-converting enzyme inhibition, has been reported to inhibit MBLs by chelating the active site zinc ions via its thiol(ate). We report systematic studies on B1 MBL inhibition by all four captopril stereoisomers. High-resolution crystal structures of three MBLs (IMP-1, BcII, and VIM-2) in complex with either the
l
- or
d
-captopril stereoisomer reveal correlations between the binding mode and inhibition potency. The results will be useful in the design of MBL inhibitors with the breadth of selectivity required for clinical application against carbapenem-resistant
Enterobacteriaceae
and other organisms causing MBL-mediated resistant infections.
Pharmacokinetic-Pharmacodynamic Model for the Effect of
l
-Arginine on Endothelial Function in Patients with Moderately Severe Falciparum Malaria
Authors: Brussee Janneke M. , Yeo Tsin W. , Lampah Daniel A. , Anstey Nicholas M. , Duffull Stephen B. 
Published: October 2015

ABSTRACT

Impaired organ perfusion in severe falciparum malaria arises from microvascular sequestration of parasitized cells and endothelial dysfunction. Endothelial dysfunction in malaria is secondary to impaired nitric oxide (NO) bioavailability, in part due to decreased plasma concentrations of
l
-arginine, the substrate for endothelial cell NO synthase. We quantified the time course of the effects of adjunctive
l
-arginine treatment on endothelial function in 73 patients with moderately severe falciparum malaria derived from previous studies. Three groups of 10 different patients received 3 g, 6 g, or 12 g of
l
-arginine as a half-hour infusion. The remaining 43 received saline placebo. A pharmacokinetic-pharmacodynamic (PKPD) model was developed to describe the time course of changes in exhaled NO concentrations and reactive hyperemia-peripheral arterial tonometry (RH-PAT) index values describing endothelial function and then used to explore optimal dosing regimens for
l
-arginine. A PK model describing arginine concentrations in patients with moderately severe malaria was extended with two pharmacodynamic biomeasures, the intermediary biochemical step (NO production) and endothelial function (RH-PAT index). A linear model described the relationship between arginine concentrations and exhaled NO. NO concentrations were linearly related to RH-PAT index. Simulations of dosing schedules using this PKPD model predicted that the time within therapeutic range would increase with increasing arginine dose. However, simulations demonstrated that regimens of continuous infusion over longer periods would prolong the time within the therapeutic range even more. The optimal dosing regimen for
l
-arginine is likely to be administration schedule dependent. Further studies are necessary to characterize the effects of such continuous infusions of
l
-arginine on NO and microvascular reactivity in severe malaria.
Alkyl Amine Bevirimat Derivatives Are Potent and Broadly Active HIV-1 Maturation Inhibitors
Authors: Urano Emiko , Ablan Sherimay D. , Mandt Rebecca , Pauly Gary T. , Sigano Dina M. , Schneider Joel P. , Martin David E. , Nitz Theodore J. , Wild Carl T. , Freed Eric O. 
Published: October 2015

ABSTRACT
Concomitant with the release of human immunodeficiency virus type 1 (HIV-1) particles from the infected cell, the viral protease cleaves the Gag polyprotein precursor at a number of sites to trigger virus maturation. We previously reported that a betulinic acid-derived compound, bevirimat (BVM), blocks HIV-1 maturation by disrupting a late step in protease-mediated Gag processing: the cleavage of the capsid-spacer peptide 1 (CA-SP1) intermediate to mature CA. BVM was shown in multiple clinical trials to be safe and effective in reducing viral loads in HIV-1-infected patients. However, naturally occurring polymorphisms in the SP1 region of Gag (e.g., SP1-V7A) led to a variable response in some BVM-treated patients. The reduced susceptibility of SP1-polymorphic HIV-1 to BVM resulted in the discontinuation of its clinical development. To overcome the loss of BVM activity induced by polymorphisms in SP1, we carried out an extensive medicinal chemistry campaign to develop novel maturation inhibitors. In this study, we focused on alkyl amine derivatives modified at the C-28 position of the BVM scaffold. We identified a set of derivatives that are markedly more potent than BVM against an HIV-1 clade B clone (NL4-3) and show robust antiviral activity against a variant of NL4-3 containing the V7A polymorphism in SP1. One of the most potent of these compounds also strongly inhibited a multiclade panel of primary HIV-1 isolates. These data demonstrate that C-28 alkyl amine derivatives of BVM can, to a large extent, overcome the loss of susceptibility imposed by polymorphisms in SP1.
Activation of the Classical Mitogen-Activated Protein Kinases Is Part of the Shiga Toxin-Induced Ribotoxic Stress Response and May Contribute to Shiga Toxin-Induced Inflammation
Authors: Jandhyala Dakshina M. , Ahluwalia Amrita , Schimmel Jennifer J. , Rogers Arlin B. , Leong John M. , Thorpe Cheleste M. 
Published: October 2015

ABSTRACTInfection with enterohemorrhagicEscherichia coli(EHEC) can result in severe disease, including hemorrhagic colitis and the hemolytic uremic syndrome. Shiga toxins (Stx) are the key EHEC virulence determinant contributing to severe disease. Despite inhibiting protein synthesis, Shiga toxins paradoxically induce the expression of proinflammatory cytokines from various cell typesin vitro, including intestinal epithelial cells (IECs). This effect is mediated in large part by the ribotoxic stress response (RSR). The Shiga toxin-induced RSR is known to involve the activation of the stress-activated protein kinases (SAPKs) p38 and JNK. In some cell types, Stx also can induce the classical mitogen-activated protein kinases (MAPKs) or ERK1/2, but the mechanism(s) by which this activation occurs is unknown. In this study, we investigated the mechanism by which Stx activates ERK1/2s in IECs and the contribution of ERK1/2 activation to interleukin-8 (IL-8) expression. We demonstrate that Stx1 activates ERK1/2 in a biphasic manner: the first phase occurs in response to StxB1 subunit, while the second phase requires StxA1 subunit activity. We show that the A subunit-dependent ERK1/2 activation is mediated through ZAK-dependent signaling, and inhibition of ERK1/2 activation via the MEK1/2 inhibitors U0126 and PD98059 results in decreased Stx1-mediated IL-8 mRNA. Finally, we demonstrate that ERK1/2 are activatedin vivoin the colon of Stx2-intoxicated infant rabbits, a model in which Stx2 induces a primarily neutrophilic inflammatory response. Together, our data support a role for ERK1/2 activation in the development of Stx-mediated intestinal inflammation.
Protein Analysis of Sapienic Acid-Treated Porphyromonas gingivalis Suggests Differential Regulation of Multiple Metabolic Pathways
Authors: Fischer Carol L. , Dawson Deborah V. , Blanchette Derek R. , Drake David R. , Wertz Philip W. , Brogden Kim A. 
Published: October 2015

ABSTRACTLipids endogenous to skin and mucosal surfaces exhibit potent antimicrobial activity againstPorphyromonas gingivalis, an important colonizer of the oral cavity implicated in periodontitis. Our previous work demonstrated the antimicrobial activity of the fatty acid sapienic acid (C16:1Δ6) againstP. gingivalisand found that sapienic acid treatment alters both protein and lipid composition from those in controls. In this study, we further examined whole-cell protein differences between sapienic acid-treated bacteria and untreated controls, and we utilized open-source functional association and annotation programs to explore potential mechanisms for the antimicrobial activity of sapienic acid. Our analyses indicated that sapienic acid treatment induces a unique stress response inP. gingivalisresulting in differential expression of proteins involved in a variety of metabolic pathways. This network of differentially regulated proteins was enriched in protein-protein interactions (P= 2.98 × 10−8), including six KEGG pathways (Pvalue ranges, 2.30 × 10−5to 0.05) and four Gene Ontology (GO) molecular functions (Pvalue ranges, 0.02 to 0.04), with multiple suggestive enriched relationships in KEGG pathways and GO molecular functions. Upregulated metabolic pathways suggest increases in energy production, lipid metabolism, iron acquisition and processing, and respiration. Combined with a suggested preferential metabolism of serine, which is necessary for fatty acid biosynthesis, these data support our previous findings that the site of sapienic acid antimicrobial activity is likely at the bacterial membrane.IMPORTANCEP. gingivalisis an important opportunistic pathogen implicated in periodontitis. Affecting nearly 50% of the population, periodontitis is treatable, but the resulting damage is irreversible and eventually progresses to tooth loss. There is a great need for natural products that can be used to treat and/or prevent the overgrowth of periodontal pathogens and increase oral health. Sapienic acid is endogenous to the oral cavity and is a potent antimicrobial agent, suggesting a potential therapeutic or prophylactic use for this fatty acid. This study examines the effects of sapienic acid treatment onP. gingivalisand highlights the membrane as the likely site of antimicrobial activity.
Tobramycin-Treated Pseudomonas aeruginosa PA14 Enhances Streptococcus constellatus 7155 Biofilm Formation in a Cystic Fibrosis Model System
Authors: Price Katherine E. , Naimie Amanda A. , Griffin Edward F. , Bay Charles , O'Toole George A. 
Published: October 2015

ABSTRACT

Cystic fibrosis (CF) is a human genetic disorder which results in a lung environment that is highly conducive to chronic microbial infection. Over the past decade, deep-sequencing studies have demonstrated that the CF lung can harbor a highly diverse polymicrobial community. We expanded our existing
in vitro
model of
Pseudomonas aeruginosa
biofilm formation on CF-derived airway cells to include this broader set of CF airway colonizers to investigate their contributions to CF lung disease, particularly as they relate to the antibiotic response of the population. Using this system, we identified an interspecies interaction between
P. aeruginosa
, a bacterium associated with declining lung function and worsening disease, and
Streptococcus constellatus
, a bacterium correlated with the onset of pulmonary exacerbations in CF patients. The growth rate and cytotoxicity of
S. constellatus
7155 and
P. aeruginosa
PA14 were unchanged when grown together as mixed biofilms in the absence of antibiotics. However, the addition of tobramycin, the frontline maintenance therapy antibiotic for individuals with CF, to a mixed biofilm of
S. constellatus
7155 and
P. aeruginosa
PA14 resulted in enhanced
S. constellatus
biofilm formation. Through a candidate genetic approach, we showed that
P. aeruginosa
rhamnolipids were reduced upon tobramycin exposure, allowing for
S. constellatus
7155 biofilm enhancement, and monorhamnolipids were sufficient to reduce
S. constellatus
7155 biofilm viability in the absence of tobramycin. While the findings presented here are specific to a biofilm of
S. constellatus
7155 and
P. aeruginosa
PA14, they highlight the potential of polymicrobial interactions to impact antibiotic tolerance in unanticipated ways.

IMPORTANCE
Deep-sequencing studies have demonstrated that the CF lung can harbor a diverse polymicrobial community. By recapitulating the polymicrobial communities observed in the CF lung and identifying mechanisms of interspecies interactions, we have the potential to select the best therapy for a given bacterial community and reveal potential opportunities for novel therapeutic interventions. Using an
in vitro
model of bacterial infection on CF airway cells, we tested how a particular polymicrobial community grows, damages human cells, and responds to antibiotics in single and mixed infections. We describe here the mechanism of an interspecies interaction between two pathogens in the CF lung,
P. aeruginosa
and
S. constellatus
, which is potentiated by a commonly prescribed antibiotic, tobramycin.
Robotic, laparoscopic and open surgery for gastric cancer compared on surgical, clinical and oncological outcomes: a multi-institutional chart review. A study protocol of the International study group on Minimally Invasive surgery for GASTRIc Cancer—IMIGASTRIC
Authors: Desiderio Jacopo , Jiang Zhi-Wei , Nguyen Ninh T , Zhang Shu , Reim Daniel , Alimoglu Orhan , Azagra Juan-Santiago , Yu Pei-Wu , Coburn Natalie G , Qi Feng , Jackson Patrick G , Zang Lu , Brower Steven T , Kurokawa Yukinori , Facy Olivier , Tsujimoto Hironori , Coratti Andrea , Annecchiarico Mario , Bazzocchi Francesca , Avanzolini Andrea , Gagniere Johan , Pezet Denis , Cianchi Fabio , Badii Benedetta , Novotny Alexander , Eren Tunc , Leblebici Metin , Goergen Martine , Zhang Ben , Zhao Yong-Liang , Liu Tong , Al-Refaie Waddah , Ma Junjun , Takiguchi Shuji , Lequeu Jean-Baptiste , Trastulli Stefano , Parisi Amilcare 
Published: October 2015

IntroductionGastric cancer represents a great challenge for healthcare providers and requires a multidisciplinary treatment approach in which surgery plays a major role. Minimally invasive surgery has been progressively developed, first with the advent of laparoscopy and recently with the spread of robotic surgery, but a number of issues are currently being debated, including the limitations in performing an effective extended lymph node dissection, the real advantages of robotic systems, the role of laparoscopy for Advanced Gastric Cancer, the reproducibility of a total intracorporeal technique and the oncological results achievable during long-term follow-up.Methods and analysisA multi-institutional international database will be established to evaluate the role of robotic, laparoscopic and open approaches in gastric cancer, comprising of information regarding surgical, clinical and oncological features. A chart review will be conducted to enter data of participants with gastric cancer, previously treated at the participating institutions. The database is the first of its kind, through an international electronic submission system and a HIPPA protected real time data repository from high volume gastric cancer centres.Ethics and disseminationThis study is conducted in compliance with ethical principles originating from the Helsinki Declaration, within the guidelines of Good Clinical Practice and relevant laws/regulations. A multicentre study with a large number of patients will permit further investigation of the safety and efficacy as well as the long-term outcomes of robotic, laparoscopic and open approaches for the management of gastric cancer.Trial registration numberNCT02325453; Pre-results.
Implications of the first AMS-02 antiproton data for dark matter
Authors: Jin Hong-Bo , Wu Yue-Liang , Zhou Yu-Feng 
Published: October 2015

The implications of the first AMS-02 [Formula: see text] data for the propagation of cosmic rays and the properties of dark matter (DM) are discussed. Using various diffusive re-acceleration (DR) propagation models, one can derive very conservative upper limits on the DM annihilation cross sections. The limits turned out to be compatible with that from the Fermi-LAT gamma-ray data on the dwarf spheroidal satellite galaxies. The flattening of the [Formula: see text] spectrum above [Formula: see text] 100 GeV in the current data still leaves some room for TeV scale DM particles. More antiproton data at high kinetic energies are needed to constrain the properties of the DM particles.
Merlin/NF2 Suppresses Pancreatic Tumor Growth and Metastasis by Attenuating the FOXM1-Mediated Wnt/β-Catenin Signaling
Authors: Quan Ming , Cui Jiujie , Xia Tian , Jia Zhiliang , Xie Dacheng , Wei Daoyan , Huang Suyun , Huang Qian , Zheng Shaojiang , Xie Keping 
Published: October 2015

Abstract
Merlin, the protein encoded by the NF2 gene, is a member of the band 4.1 family of cytoskeleton-associated proteins and functions as a tumor suppressor for many types of cancer. However, the roles and mechanism of Merlin expression in pancreatic cancer have remained unclear. In this study, we sought to determine the impact of Merlin expression on pancreatic cancer development and progression using human tissue specimens, cell lines, and animal models. Decreased expression of Merlin was pronounced in human pancreatic tumors and cancer cell lines. Functional analysis revealed that restored expression of Merlin inhibited pancreatic tumor growth and metastasis in vitro and in vivo. Furthermore, Merlin suppressed the expression of Wnt/β-catenin signaling downstream genes and the nuclear expression of β-catenin protein, and overexpression of Forkhead box M1 (FOXM1) attenuated the suppressive effect of Merlin on Wnt/β-catenin signaling. Mechanistically, Merlin decreased the stability of FOXM1 protein, which plays critical roles in nuclear translocation of β-catenin. Collectively, these findings demonstrated that Merlin critically regulated pancreatic cancer pathogenesis by suppressing FOXM1/β-catenin signaling, suggesting that targeting novel Merlin/FOXM1/β-catenin signaling is an effective therapeutic strategy for pancreatic cancer. Cancer Res; 75(22); 4778–89. ©2015 AACR.
JX06 Selectively Inhibits Pyruvate Dehydrogenase Kinase PDK1 by a Covalent Cysteine Modification
Authors: Sun Wenyi , Xie Zuoquan , Liu Yifu , Zhao Dan , Wu Zhixiang , Zhang Dadong , Lv Hao , Tang Shuai , Jin Nan , Jiang Hualiang , Tan Minjia , Ding Jian , Luo Cheng , Li Jian , Huang Min , Geng Meiyu 
Published: October 2015

Abstract
Pyruvate dehydrogenase kinase PDK1 is a metabolic enzyme responsible for switching glucose metabolism from mitochondrial oxidation to aerobic glycolysis in cancer cells, a general hallmark of malignancy termed the Warburg effect. Herein we report the identification of JX06 as a selective covalent inhibitor of PDK1 in cells. JX06 forms a disulfide bond with the thiol group of a conserved cysteine residue (C240) based on recognition of a hydrophobic pocket adjacent to the ATP pocket of the PDK1 enzyme. Our investigations of JX06 mechanism suggested that covalent modification at C240 induced conformational changes at Arginine 286 through Van der Waals forces, thereby hindering access of ATP to its binding pocket and in turn impairing PDK1 enzymatic activity. Notably, cells with a higher dependency on glycolysis were more sensitive to PDK1 inhibition, reflecting a metabolic shift that promoted cellular oxidative stress and apoptosis. Our findings offer new mechanistic insights including how to therapeutically target PDK1 by covalently modifying the C240 residue. Cancer Res; 75(22); 4923–36. ©2015 AACR.