bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of Genetic Variation of
NAT2
on Isoniazid and
SLCO1B1
and
CES2
on Rifampin Pharmacokinetics in Ghanaian Children with Tuberculosis
Authors: Dompreh Albert , Tang Xiaoli , Zhou Jianlin , Yang Hongmei , Topletz Ariel , Adu Ahwireng Eugene , Antwi Sampson , Enimil Antony , Langaee Taimour , Peloquin Charles A. , Court Michael H. , Kwara Awewura 
Published: December 2017

ABSTRACT

Isoniazid and rifampin are essential components of first-line antituberculosis (anti-TB) therapy. Understanding the relationship between genetic factors and the pharmacokinetics of these drugs could be useful in optimizing treatment outcomes, but this is understudied in children. We investigated the relationship between N-acetyltransferase type 2 (
NAT2
) genotypes and isoniazid pharmacokinetics, as well as that between the solute carrier organic anion transporter family member 1B1 (encoded by
SLCO1B1
) and carboxylesterase 2 (
CES2
) single nucleotide polymorphisms (SNPs) and rifampin pharmacokinetics in Ghanaian children. Blood samples were collected at times 0, 1, 2, 4, and 8 h postdose in children with tuberculosis on standard first-line therapy for at least 4 weeks. Isoniazid and rifampin concentrations were determined by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, and pharmacokinetic parameters were calculated using noncompartmental analysis. Genotyping of
NAT2
,
SLCO1B1
, and
CES2
SNPs were performed using validated TaqMan genotyping assays. The Kruskal-Wallis test was used to compare pharmacokinetic parameters among the three genotypic groups and was followed by the Wilcoxon rank sum test for pairwise group comparisons. Genotype status inferred by the
NAT2
4-SNP and 7-SNP genotyping panels identified children with a slow acetylator phenotype but not the rapid genotype. For rifampin, only the rare
SLCO1B1*1b
homozygous variant was associated with rifampin pharmacokinetics. Our findings suggest that
NAT2
and
SCLCO1B1*1b
genotyping may have minimal clinical utility in dosing decisions at the population level in Ghanaian children, but it could be useful at the individual level or in populations that have a high frequency of implicated genotypes. Further studies in other populations are warranted.
Enzyme Activities at Different Stages of Plant Biomass Decomposition in Three Species of Fungus-Growing Termites
Authors: da Costa Rafael R. , Hu Haofu , Pilgaard Bo , Vreeburg Sabine M. E. , Schückel Julia , Pedersen Kristine S. K. , Kračun Stjepan K. , Busk Peter K. , Harholt Jesper , Sapountzis Panagiotis , Lange Lene , Aanen Duur K. , Poulsen Michael 
Published: December 2017

ABSTRACTFungus-growing termites rely on mutualistic fungi of the genusTermitomycesand gut microbes for plant biomass degradation. Due to a certain degree of symbiont complementarity, this tripartite symbiosis has evolved as a complex bioreactor, enabling decomposition of nearly any plant polymer, likely contributing to the success of the termites as one of the main plant decomposers in the Old World. In this study, we evaluated which plant polymers are decomposed and which enzymes are active during the decomposition process in two major genera of fungus-growing termites. We found a diversity of active enzymes at different stages of decomposition and a consistent decrease in plant components during the decomposition process. Furthermore, our findings are consistent with the hypothesis that termites transport enzymes from the older mature parts of the fungus comb through young worker guts to freshly inoculated plant substrate. However, preliminary fungal RNA sequencing (RNA-seq) analyses suggest that this likely transport is supplemented with enzymes producedin situ. Our findings support that the maintenance of an external fungus comb, inoculated with an optimal mixture of plant material, fungal spores, and enzymes, is likely the key to the extraordinarily efficient plant decomposition in fungus-growing termites.IMPORTANCEFungus-growing termites have a substantial ecological footprint in the Old World (sub)tropics due to their ability to decompose dead plant material. Through the establishment of an elaborate plant biomass inoculation strategy and through fungal and bacterial enzyme contributions, this farming symbiosis has become an efficient and versatile aerobic bioreactor for plant substrate conversion. Since little is known about what enzymes are expressed and where they are active at different stages of the decomposition process, we used enzyme assays, transcriptomics, and plant content measurements to shed light on how this decomposition of plant substrate is so effectively accomplished.
Replication Rapidly Recovers and Continues in the Presence of Hydroxyurea in Escherichia coli
Authors: Nazaretyan Samvel A. , Savic Neda , Sadek Michael , Hackert Brandy J. , Courcelle Justin , Courcelle Charmain T. 
Published: December 2017

ABSTRACT

In both prokaryotes and eukaryotes, hydroxyurea is suggested to inhibit DNA replication by inactivating ribonucleotide reductase and depleting deoxyribonucleoside triphosphate pools. In this study, we show that the inhibition of replication in
Escherichia coli
is transient even at concentrations of 0.1 M hydroxyurea and that replication rapidly recovers and continues in its presence. The recovery of replication does not require the alternative ribonucleotide reductases NrdEF and NrdDG or the translesion DNA polymerases II (Pol II), Pol IV, and Pol V. Ribonucleotides are incorporated at higher frequencies during replication in the presence of hydroxyurea. However, they do not contribute significantly to the observed synthesis or toxicity. Hydroxyurea toxicity was observed only under conditions where the stability of hydroxyurea was compromised and by-products known to damage DNA directly were allowed to accumulate. The results demonstrate that hydroxyurea is not a direct or specific inhibitor of DNA synthesis
in vivo
and that the transient inhibition observed is most likely due to a general depletion of iron cofactors from enzymes when 0.1 M hydroxyurea is initially applied. Finally, the results support previous studies suggesting that hydroxyurea toxicity is mediated primarily through direct DNA damage induced by the breakdown products of hydroxyurea, rather than by inhibition of replication or depletion of deoxyribonucleotide levels in the cell.

IMPORTANCE
Hydroxyurea is commonly suggested to function by inhibiting DNA replication through the inactivation of ribonucleotide reductase and depleting deoxyribonucleoside triphosphate pools. Here, we show that hydroxyurea only transiently inhibits replication in
Escherichia coli
before replication rapidly recovers and continues in the presence of the drug. The recovery of replication does not depend on alternative ribonucleotide reductases, translesion synthesis, or RecA. Further, we show that hydroxyurea toxicity is observed only in the presence of toxic intermediates that accumulate when hydroxyurea breaks down, damage DNA, and induce lethality. The results demonstrate that hydroxyurea toxicity is mediated indirectly by the formation of DNA damage, rather than by inhibition of replication or depletion of deoxyribonucleotide levels in the cell.
GalNAc-Specific Soybean Lectin Inhibits HIV Infection of Macrophages through Induction of Antiviral Factors
Authors: Zhou Runhong , Wang Xu , Liu Hang , Guo Le , Su Qijian , Wang He , Vasiliadis Theodore , Ho Wenzhe , Li Jieliang 
Published: December 2017

ABSTRACTAlthough it has been shown that some mannose-binding lectins (MBLs) exhibit significant activity against HIV infection, little is known about whetherN-acetylgalactosamine (GalNAc)-binding lectins have the ability to inhibit HIV infection. Here, we demonstrate that a soybean-derived lectin (SBL) with GalNAc-binding affinity could potently suppress HIV infection of macrophages in a dose-dependent fashion. Unlike the MBLs, which block HIV only through binding to the glycosylated envelope proteins (gp120 and gp41) of the virus, SBL inhibited HIV at multiple steps of the virus infection/replication cycle. SBL could activate the beta interferon (IFN-β)–STAT signaling pathway, resulting in the upregulation of a number of antiviral interferon-stimulated genes (ISGs) in macrophages. In addition, SBL treatment of macrophages induced the production of C-C chemokines, which bind to HIV entry coreceptor CCR5. Deglycosylation of cell surface galactosyl moieties or presaturation of GalNAc-binding capacity could compromise SBL-mediated induction of the antiviral factors. Furthermore, SBL exerted its anti-HIV activity in the low nanomolar range with no mitogenic effect on CD4+T cells, a major advantage in the development of SBL as a potential anti-HIV agent compared with MBLs. These data indicate a necessity to further investigate SBL as an alternative and cost-effective anti-HIV natural product.IMPORTANCEMannose-binding lectins (MBLs) can block the attachment of HIV to target cells and have been suggested as anti-HIV microbicides. However, the mitogenic effect of MBLs on CD4+T cells limits this potential in clinical settings. Lectins with galactose (Gal)- orN-acetylgalactosamine (GalNAc)-binding specificity are another important category of carbohydrate-binding proteins (CBP). Compared to high-mannose N-linked glycans, GalNAc-type glycans present much less in HIV gp120 or gp41 glycosylation. Here, we demonstrate that GalNAc-specific soybean lectin (SBL) triggers antiviral signaling via recognition of the cell surface galactosyl group of macrophages, which results in the suppression of HIV at multiple steps. More importantly, SBL has no mitogenic effect on the activation of CD4+T cells, a major advantage in the development of Gal/GalNAc-specific lectins as naturopathic anti-HIV agents.
Genetic risk factors for late age-related macular degeneration in India
Authors: Rajendran Anand , Dhoble Pankaja , Sundaresan Periasamy , Saravanan Vijayan , Vashist Praveen , Nitsch Dorothea , Smeeth Liam , Chakravarthy Usha , Ravindran Ravilla D , Fletcher Astrid E 
Published: December 2017

Background/AimsThere are limited data from India on genetic variants influencing late age-related macular degeneration (AMD). We have previously reported associations from a population-based study in India (the India age-related eye disease study (INDEYE)) of early AMD and single nucleotide polymorphisms (SNPs) in ARMS2/HTRA1 and no association with CFH, C2 or CFB. Late AMD cases were too few for meaningful analyses. We aimed to investigate SNPs for late AMD through case enrichment and extend the loci for early AMD.MethodsFundus images of late AMD hospital cases were independently graded by the modified Wisconsin AMD grading scheme. In total 510 cases with late AMD (14 geographic atrophy and 496 neovascular AMD (nvAMD)), 1876 with early AMD and 1176 with no signs of AMD underwent genotyping for selected SNPs. We investigated genotype and per-allele additive associations (OR and 95% CIs) with nvAMD or early AMD. Bonferroni adjusted P values are presented.ResultsWe found associations with nvAMD for CFHY402H variant (rs1061170) (OR=1.99, 95% CI 1.67 to 2.37, P=10−6), ARMS2 (rs10490924) (OR=2.94, 95% CI 2.45 to 3.52, P=10−9), C2 (rs547154) (OR=0.67, 95% CI 0.53 to 0.85, P=0.01), ABCA1 (rs1883025) (OR=0.77, 95% CI 0.65 to 0.92, P=0.04) and an SNP near VEGFA (rs4711751) (OR=0.64, 95% CI 0.54 to 0.77, P=10−3). We found no associations of TLR3 (rs3775291), CFD (rs3826945), FRK (rs1999930) or LIPC (rs10468017) or APOE ε4 alleles with nvAMD or early AMD, nor between early AMD and rs1883025 or rs4711751.ConclusionsThe major genetic determinants of nvAMD risk in India are similar to those in other ancestries, while findings for early AMD suggest potential differences in the pathophysiology of AMD development.
Does greater individual social capital improve the management of hypertension? Cross-national analysis of 61 229 individuals in 21 countries
Authors: Palafox Benjamin , Goryakin Yevgeniy , Stuckler David , Suhrcke Marc , Balabanova Dina , Alhabib Khalid F , Avezum Alvaro , Bahonar Ahmad , Bai Xiulin , Chifamba Jephat , Dans Antonio L , Diaz Rafael , Gupta Rajeev , Iqbal Romaina , Ismail Noorhassim , Kaur Manmeet , Keskinler Mirac V , Khatib Rasha , Kruger Annamarie , Kruger Iolanthe M , Lanas Fernando , Lear Scott A , Li Wei , Liu Jia , Lopez-Jaramillo Patricio , Peer Nasheeta , Poirier Paul , Rahman Omar , Pillai Rajamohanan K , Rangarajan Sumathy , Rosengren Annika , Swaminathan Sumathi , Szuba Andrzej , Teo Koon , Wang Yang , Wielgosz Andreas , Yeates Karen E , Yusufali Afzalhussein , Yusuf Salim , McKee Martin 
Published: December 2017

IntroductionSocial capital, characterised by trust, reciprocity and cooperation, is positively associated with a number of health outcomes. We test the hypothesis that among hypertensive individuals, those with greater social capital are more likely to have their hypertension detected, treated and controlled.MethodsCross-sectional data from 21 countries in the Prospective Urban and Rural Epidemiology study were collected covering 61 229 hypertensive individuals aged 35–70 years, their households and the 656 communities in which they live. Outcomes include whether hypertensive participants have their condition detected, treated and/or controlled. Multivariate statistical models adjusting for community fixed effects were used to assess the associations of three social capital measures: (1) membership of any social organisation, (2) trust in other people and (3) trust in organisations, stratified into high-income and low-income country samples.ResultsIn low-income countries, membership of any social organisation was associated with a 3% greater likelihood of having one’s hypertension detected and controlled, while greater trust in organisations significantly increased the likelihood of detection by 4%. These associations were not observed among participants in high-income countries.ConclusionAlthough the observed associations are modest, some aspects of social capital are associated with better management of hypertension in low-income countries where health systems are often weak. Given that hypertension affects millions in these countries, even modest gains at all points along the treatment pathway could improve management for many, and translate into the prevention of thousands of cardiovascular events each year.
Protocol for the BRECAR study: a prospective cohort follow-up on the impact of breast reconstruction timing on health-related quality of life in women with breast cancer
Authors: Herrera de la Muela Maria , García López Enrique , Frías Aldeguer Laura , Gómez-Campelo Paloma 
Published: December 2017

IntroductionThe completion of postmastectomy breast reconstruction (BR) in women with breast cancer can last from months to years, and to our knowledge, there is a lack of studies that analyse how the different types and times of reconstruction impact on the patient’s quality of life and psychosocial adjustment.The primary aim of the BREast Cancer Reconstruction (BRECAR Study) is twofold. First, to describe health-related quality of life (HRQoL), overall satisfaction with surgery and psychological impact (body image, self-esteem, depression and anxiety) on women who will have undergone a mastectomy with planned BR, considering the varied timing of BR procedures (immediate BR (iBR), delayed BR (dBR) and two-stage BR (2sBR)). To measure the impact on surgical outcomes, we will obtain data prior to and after surgery (6–9 and at 18 months of follow-up). Second, to analyse sociodemographic, clinical and psychosocial factors associated with HRQoL, satisfaction with surgery and psychological impact.Methods and analysisA prospective, observational, clinical cohort study of women diagnosed with breast cancer who have an indication for mastectomy treated at La Paz University Hospital (Madrid, Spain).Patients will be classified into one of three groups under conditions of routine clinical practice, based on the type of BR planned: the iBR group, the dBR group and the 2sBR group.Under typical clinical practice conditions, we will perform three visits: baseline visit (presurgery), V1 (6–9 months after diagnosis) and V2 (18 months after diagnosis). A sample size of 210 patients is estimated.Ethics and disseminationThe study protocol and informed consent form have been reviewed and approved by the Institutional Review Board of La Paz Hospital (no. PI-2036). Dissemination of results will be via journal articles and conference presentations.
Theoretical study of phonon dispersion, elastic, mechanical and thermodynamic properties of barium chalcogenides
Authors: Musari A. A. , Orukombo S. A. 
Published: December 2017

Barium chalcogenides are known for their high-technological importance and great scientific interest. Detailed studies of their elastic, mechanical, dynamical and thermodynamic properties were carried out using density functional theory and plane-wave pseudo potential method within the generalized gradient approximation. The optimized lattice constants were in good agreement when compared with experimental data. The independent elastic constants, calculated from a linear fit of the computed stress–strain function, were used to determine the Young’s modulus (E), bulk modulus (B), shear modulus (G), Poisson’s ratio ([Formula: see text]) and Zener’s anisotropy factor (A). Also, the Debye temperature and sound velocities for barium chalcogenides were estimated from the three independent elastic constants. The calculations of phonon dispersion showed that there are no negative frequencies throughout the Brillouin zone. Hence barium chalcogenides have dynamically stable NaCl-type crystal structure. Finally, their thermodynamic properties were calculated in the temperature range of 0–1000 K and their constant-volume specific heat capacities at room-temperature were reported.
Cosmology with an interacting van der Waals fluid
Authors: Elizalde E. , Khurshudyan M. 
Published: December 2017

A model for the late-time accelerated expansion of the Universe is considered where a van der Waals fluid interacting with matter plays the role of dark energy. The transition towards this phase in the cosmic evolution history is discussed in detail and, moreover, a complete classification of the future finite-time singularities is obtained for six different possible forms of the nongravitational interaction between dark energy (the van der Waals fluid) and dark matter. This study shows, in particular, that a Universe with a noninteracting three-parameter van der Waals fluid can evolve into a Universe characterized by a type IV (generalized sudden) singularity. On the other hand, for certain values of the parameters, exit from the accelerated expanding phase is possible in the near future, what means that the expansion of the Universe in the future could become decelerated – to our knowledge, this interesting situation is not commonplace in the literature. On the other hand, our study shows that space can be divided into different regions. For some of them, in particular, the nongravitational interactions [Formula: see text], [Formula: see text] and [Formula: see text] may completely suppress future finite-time singularity formation, for sufficiently high values of [Formula: see text]. On the other hand, for some other regions of the parameter space, the mentioned interactions would not affect the singularity type, namely the type IV singularity generated in the case of the noninteracting model would be preserved. A similar conclusion has been archived for the cases of [Formula: see text], [Formula: see text] and [Formula: see text] nongravitational interactions, with only one difference: the [Formula: see text] interaction will change the type IV singularity of the noninteracting model into a type II (the sudden) singularity.
THE SIMULATION STUDY ON THE DEFORMATION OF RABBIT CORNEA AFTER REFRACTIVE SURGERY WITH DIFFERENT CUTTING THICKNESS
Authors: ZHANG DI , SUN TAIFENG , ZHANG HAIXIA , LI LIN 
Published: December 2017

Based on the inflation tests data of rabbit cornea, finite element analysis has been applied to determine the material parameters, simulate corneal refractive surgery and study postoperative corneal deformations. The corneal profile and apical displacement data were recorded during the inflation experiment of five rabbit corneas. Inverse finite element method was applied to determine the material parameters from the corneal apical displacements. Based on the determined material parameters and the corneal profile information, we established five corneal geometry models that simulate refractive surgery with different cutting amounts. We analyzed displacements at corneal apex and cutting edge, corneal surface curvatures under different pressures. Both Ogden model ([Formula: see text]) and Yeoh model ([Formula: see text]) gave good fits to the experiment data. The maximum of error square sum between the calculated value and the experimental value of the displacements per point at the corneal profile was less than 0.06[Formula: see text]mm. For each model with the increase of pressure, the displacement at cutting edge was larger than that at corneal apex, both of them increased, and curvature radius of anterior and posterior corneal surface increased slowly, but the refractive power decreased slowly and tended to be a stable value. Under the same pressure, the larger the cutting amount, the larger the displacements at corneal apex and cutting edge with a cutting edge displacement of about 1.10 (less ablation model) and 1.02 (larger ablation model) times the corneal vertex displacement. Both Ogden model and Yeoh model can be used to describe corneal mechanical responses of inflation experiment. After refractive surgery, the displacement at cutting edge is larger than that at corneal apex, the curvature radius of anterior (posterior) corneal surface increases (decreases), and the refractive power decreases.
CXCR4 Promotes Neuroblastoma Growth and Therapeutic Resistance through miR-15a/16-1–Mediated ERK and BCL2/Cyclin D1 Pathways
Authors: Klein Shiri , Abraham Michal , Bulvik Baruch , Dery Elia , Weiss Ido D. , Barashi Neta , Abramovitch Rinat , Wald Hanna , Harel Yaniv , Olam Devorah , Weiss Lola , Beider Katia , Eizenberg Orly , Wald Ori , Galun Eithan , Pereg Yaron , Peled Amnon 
Published: December 2017

AbstractCXCR4 expression in neuroblastoma tumors correlates with disease severity. In this study, we describe mechanisms by which CXCR4 signaling controls neuroblastoma tumor growth and response to therapy. We found that overexpression of CXCR4 or stimulation with CXCL12 supports neuroblastoma tumorigenesis. Moreover, CXCR4 inhibition with the high-affinity CXCR4 antagonist BL-8040 prevented tumor growth and reduced survival of tumor cells. These effects were mediated by the upregulation of miR-15a/16-1, which resulted in downregulation of their target genes BCL-2 and cyclin D1, as well as inhibition of ERK. Overexpression of miR-15a/16-1 in cells increased cell death, whereas antagomirs to miR-15a/16-1 abolished the proapoptotic effects of BL-8040. CXCR4 overexpression also increased miR-15a/16-1, shifting their oncogenic dependency from the BCL-2 to the ERK signaling pathway. Overall, our results demonstrate the therapeutic potential of CXCR4 inhibition in neuroblastoma treatment and provide a rationale to test combination therapies employing CXCR4 and BCL-2 inhibitors to increase the efficacy of these agents.Significance: These results provide a mechanistic rationale for combination therapy of CXCR4 and BCL-2 inhibitors to treat a common and commonly aggressive pediatric cancer.Cancer Res; 78(6); 1471–83. ©2017 AACR.