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81.
The influence of antenatal and maternal factors on stillbirths and neonatal deaths in New South Wales, Australia 总被引:1,自引:0,他引:1
This study identified the influences of maternal socio-demographic and antenatal factors on stillbirths and neonatal deaths in New South Wales, Australia. Bivariate and multivariate analyses were used to explore the association of selected antenatal and maternal characteristics with stillbirths and neonatal deaths. The findings of this study showed that stillbirths and neonatal deaths significantly varied by infant sex, maternal age, Aboriginality, maternal country of birth, socioeconomic status, parity, maternal smoking behaviour during pregnancy, maternal diabetes mellitus, maternal hypertension, antenatal care, plurality of birth, low birth weight, place of birth, delivery type, maternal deaths and small gestational age. First-born infants, twins and infants born to teenage mothers, Aboriginal mothers, those who smoked during the pregnancy and those of lower socioeconomic status were at increased risk of stillbirths and neonatal deaths. The most common causes of stillbirths were conditions originating in the perinatal period: intrauterine hypoxia and asphyxia. Congenital malformations, including deformities and chromosomal abnormalities, and disorders related to slow fetal growth, short gestation and low birth weight were the most common causes of neonatal deaths. The findings indicate that very low birth weight (less than 2,000 g) contributed 75.6% of the population-attributable risks to stillbirths and 59.4% to neonatal deaths. Low gestational age (less than 32 weeks) accounted for 77.7% of stillbirths and 87.9% of neonatal deaths. The findings of this study suggest that in order to reduce stillbirths and neonatal deaths, it is essential to include strategies to predict and prevent prematurity and low birth weight, and that there is a need to focus on anti-smoking campaigns during pregnancy, optimizing antenatal care and other healthcare programmes targeted at the socially disadvantaged populations identified in this study. 相似文献
82.
Sibes Bera Krishan K. Pandey Ajaykumar C. Vora Duane P. Grandgenett 《Journal of molecular biology》2009,389(1):183-9796
A macromolecular nucleoprotein complex in retrovirus-infected cells, termed the preintegration complex, is responsible for the concerted integration of linear viral DNA genome into host chromosomes. Isolation of sufficient quantities of the cytoplasmic preintegration complexes for biochemical and biophysical analysis is difficult. We investigated the architecture of HIV-1 nucleoprotein complexes involved in the concerted integration pathway in vitro. HIV-1 integrase (IN) non-covalently juxtaposes two viral DNA termini forming the synaptic complex, a transient intermediate in the integration pathway, and shares properties associated with the preintegration complex. IN slowly processes two nucleotides from the 3′ OH ends and performs the concerted insertion of two viral DNA ends into target DNA. IN remains associated with the concerted integration product, termed the strand transfer complex. The synaptic complex and strand transfer complex can be isolated by native agarose gel electrophoresis. In-gel fluorescence resonance energy transfer measurements demonstrated that the energy transfer efficiencies between the juxtaposed Cy3 and Cy5 5′-end labeled viral DNA ends in the synaptic complex (0.68 ± 0.09) was significantly different from that observed in the strand transfer complex (0.07 ± 0.02). The calculated distances were 46 ± 3 Å and 83 ± 5 Å, respectively. DNaseI footprint analysis of the complexes revealed that IN protects U5 and U3 DNA sequences up to ∼ 32 bp from the end, suggesting two IN dimers were bound per terminus. Enhanced DNaseI cleavages were observed at nucleotide positions 6 and 9 from the terminus on U3 but not on U5, suggesting independent assembly events. Protein-protein cross-linking of IN within these complexes revealed the presence of dimers, tetramers, and a larger multimer (> 120 kDa). Our results suggest a new model where two IN dimers individually assemble on U3 and U5 ends before the non-covalent juxtaposition of two viral DNA ends, producing the synaptic complex. 相似文献
83.
Yingshe Zhao Chengyin Min Siddharth R. Vora Philip C. Trackman Gail E. Sonenshein Kathrin H. Kirsch 《The Journal of biological chemistry》2009,284(3):1385-1393
The lysyl oxidase (LOX) gene encodes an enzyme (LOX)
critical for extracellular matrix maturation. The LOX gene has also
been shown to inhibit the transforming activity of Ras oncogene
signaling. In particular, the pro-peptide domain (LOX-PP) released from the
secreted precursor protein (Pro-LOX) was found to inhibit the transformed
phenotype of breast, lung, and pancreatic cancer cells. However, the
mechanisms of action of LOX-PP remained to be determined. Here, the ability of
LOX-PP to attenuate the integrin signaling pathway, which leads to
phosphorylation of focal adhesion kinase (FAK), and the activation of its
downstream target p130Cas, was determined. In NF639 breast cancer
cells driven by Her-2/neu, which signals via Ras, ectopic Pro-LOX and LOX-PP
expression inhibited fibronectin-stimulated protein tyrosine phosphorylation.
Importantly, phosphorylation of FAK on Tyr-397 and Tyr-576, and
p130Cas were substantially reduced. The amount of endogenous
p130Cas in the Triton X-100-insoluble protein fraction, and
fibronectin-activated haptotaxis were decreased. Interestingly, expression of
mature LOX enzyme enhanced fibronectin-stimulated integrin signaling. Of note,
treatment with recombinant LOX-PP selectively reduced fibronectin-mediated
haptotaxis of NF639, MDA-MB-231, and Hs578T breast cancer cells. Thus,
evidence is provided that one mechanism of action of LOX-PP tumor suppression
is to block fibronectin-stimulated signaling and cell migration.The lysyl oxidase
(LOX)2 gene
family is comprised of five members LOX, LOXL1, LOXL2, LOXL3, and
LOXL4, which encode enzymes that modify extracellular matrix (ECM)
proteins to promote their cross-linking and deposition
(1). The LOX gene is
the best characterized and codes for the synthesis of a secreted 50-kDa
glycosylated pro-enzyme (Pro-LOX). Pro-LOX is extracellularly processed by
proteolytic cleavage to a mature active 32-kDa enzyme (LOX) and an 18-kDa
pro-peptide (LOX-PP) by the procollagen C proteinases bone morphogenic
protein-1 (BMP-1), and the related tolloid-like proteins TLL1 and TLL2
(2–4).
In murine Pro-LOX, proteolytic processing occurs between amino acids Gly-162
and Asp-163, generating LOX-PP containing 141 amino acids
(5). LOX-PP contains two
consensus N-glycosylation sites, Asn-91 and Asn-138 (murine sequence)
(2) and several
O-glycosylation
sites.3 LOX-PP does
not contain any known protein domains, and structural prediction analysis
indicates that LOX-PP assembles as an intrinsically disordered protein
(6). Among the LOX family
members, the C-terminal ends encode the enzyme domain and are highly
conserved, whereas the N-terminal ends that encode the pro-peptide region have
variable sequences. Based on structural and sequence similarities of the
pro-peptide regions, the LOX family members can be divided into two subgroups:
LOXL2, LOXL3, and LOXL4 as one group whose propeptide
regions contain four scavenger receptor cysteine-rich domains, and
LOX and LOXL1 as a separate group with much simpler and
smaller pro-peptide region containing no cysteine residues (reviewed in Ref.
1). In contrast to Pro-LOX, the
exact maturation site of Pro-LOXL1 is still unidentified.LOX is essential in the formation of blood vessels and in maintaining their
normal characteristics
(7–9).
Up-regulation of LOX expression has been described in stromal cells
that surround ductal breast and broncho-pulmonary carcinomas
(10).Expression of the LOX gene was found to inhibit the transforming
activity of the Ras oncogene in NIH 3T3 fibroblasts and hence was
named the “ras recision” gene (rrg)
(11,
12). The LOX gene was
shown to inhibit growth in soft agar of NIH 3T3 fibroblasts and to attenuate
Ras-mediated activation of phosphatidylinositol 3-kinase (PI3K), Akt, and
Erk1/2 kinases and NF-κB activation
(13). More recently, the
rrg activity was mapped to the 18-kDa LOX-PP. Specifically, LOX-PP
was shown to inhibit Ras-mediated transformation of fibroblasts as determined
by reduced growth in soft agar, localization of PDK1 to the membrane, and
activation of NF-κB
(14). Furthermore, the
inhibitory effects of LOX-PP on Ras signaling were extended to breast,
pancreatic, and lung cancer cells
(6,
14,
15). LOX-PP expression in
these carcinoma cells reverted Her-2/neu- and Ras-mediated epithelial to
mesenchymal transition (EMT), leading to increased expression of E-cadherin
and γ-catenin, and reduced levels of Snail, vimentin, and/or BCL-2
(7,
15). Furthermore, LOX-PP
expression reduced tumor formation in a xenograft model by
Her-2/neu-overexpressing NF639 cells
(6).Acquisition of the ability to invade the ECM is essential to EMT. The ECM
has multiple mechanical and signaling functions. The ECM defines interfaces
between tissues, provides a scaffold for cell traction, and a substrate for
cell migration and adhesion. It is composed of a complex of proteins such as
collagens, fibronectin, and laminin, which can interact and bind various
growth factors (16).
Fibronectin is of particular interest because it was recently shown to
interact with the C terminus of Pro-LOX
(17). Binding of fibronectin
to its receptors (e.g. integrins
α5β1 or
αvβ1) stimulates the tyrosine phosphorylation
of cellular proteins, in particular that of focal adhesion kinase (FAK)
(18). Little is known about
the mechanism of action of LOX-PP. Here, we have asked whether the tumor
suppressor activity of LOX-PP attenuates the activation of the integrin
signaling pathway in breast cancer cells. We report that LOX-PP attenuates FAK
signaling and activation of its downstream target p130Cas and is a
robust inhibitor of fibronectin-stimulated cell migration. 相似文献
84.
Mohsin Abbas Zaidi Gongyin Ye Hongwei Yao Taek H. You Evelin Loit Donald H. Dean Sheikh Riazuddin Illimar Altosaar 《Molecular biotechnology》2009,43(3):232-242
Nucleotide sequence encoding the truncated insecticidal Cry1Ca1 protein from Bacillus thuringiensis was extensively modified based on the codon usage of rice genes. The overall G + C contents of the synthetic cry1Ca1 coding sequence were raised to 65% with an additional bias of enriching for G and C ending codons as preferred by monocots.
The synthetic gene was introduced into the Chinese japonica variety, Xiushui 11, by Agrobacterium-mediated transformation. Transgenic rice plants harboring this gene were highly resistant to Chilo
suppressalis and Spodoptera litura larvae as revealed by insect bioassays. High levels of Cry1Ca1 protein were obtained in the leaves of transgenic rice, which
were effective in achieving 100% mortality of S. litura and C. suppressalis larvae. The levels of Cry1Ca1 expression in the leaves of these transgenic plants were up to 0.34% of the total soluble proteins.
The larvae of C. suppressalis and S.
litura could consume a maximum of 1.89 and 4.89 mm2 of transgenic leaf area whereas the consumption of non-transgenic leaves by these larvae was significantly higher; 58.33 and
61.22 mm2, respectively. Analysis of R1 transgenic plants indicated that the cry1Ca1 was inherited by the progeny plants and provided complete protection against C. suppressalis and S.
litura larvae. 相似文献
85.
Sonali Vora Asad Abbas Chong J Kim Taryn LS Summerfield Juan P Kusanovic Jay D Iams Roberto Romero Douglas A Kniss William E AckermanIV 《Reproductive biology and endocrinology : RB&E》2010,8(1):8
Background
The objective of this study was to quantify the nuclear localization and DNA binding activity of p65, the major transactivating nuclear factor-kappa B (NF-kappaB) subunit, in full-thickness fetal membranes (FM) and myometrium in the absence or presence of term or preterm labor. 相似文献86.
Fatty acids are central hydrocarbon intermediates in the biosynthesis of diesel from renewable sources. We have engineered an Escherichia coli cell line that produces 4.5 g/L/day total fatty acid in a fed-batch fermentation. However, further enhancement of fatty acid biosynthesis in this cell line proved unpredictable. To develop a more reliable engineering strategy, a cell-free system was developed that enabled direct, quantitative investigation of fatty acid biosynthesis and its regulation in E. coli. Using this system, the strong dependence of fatty acid synthesis on malonyl-CoA availability and several important phenomena in fatty acid synthesis were verified. Results from this cell-free system were confirmed via the generation and analysis of metabolically engineered strains of E. coli. Our quantitative findings highlight the enormous catalytic potential of the E. coli fatty acid biosynthetic pathway, and target specific steps for protein and metabolic engineering to enhance the catalytic conversion of glucose into biodiesel. 相似文献
87.
Yi-Hung Carol Tan Soundararajan Krishnaswamy Suvobroto Nandi Rajani Kanteti Sapana Vora Kenan Onel Rifat Hasina Fang-Yi Lo Essam El-Hashani Gustavo Cervantes Matthew Robinson Stephen C. Kales Stanley Lipkowitz Theodore Karrison Martin Sattler Everett E. Vokes Yi-Ching Wang Ravi Salgia 《PloS one》2010,5(1)
Background
Non-small cell lung cancer (NSCLC) is a heterogeneous group of disorders with a number of genetic and proteomic alterations. c-CBL is an E3 ubiquitin ligase and adaptor molecule important in normal homeostasis and cancer. We determined the genetic variations of c-CBL, relationship to receptor tyrosine kinases (EGFR and MET), and functionality in NSCLC.Methods and Findings
Using archival formalin-fixed paraffin embedded (FFPE) extracted genomic DNA, we show that c-CBL mutations occur in somatic fashion for lung cancers. c-CBL mutations were not mutually exclusive of MET or EGFR mutations; however they were independent of p53 and KRAS mutations. In normal/tumor pairwise analysis, there was significant loss of heterozygosity (LOH) for the c-CBL locus (22%, n = 8/37) and none of these samples revealed any mutation in the remaining copy of c-CBL. The c-CBL LOH also positively correlated with EGFR and MET mutations observed in the same samples. Using select c-CBL somatic mutations such as S80N/H94Y, Q249E and W802* (obtained from Caucasian, Taiwanese and African-American samples, respectively) transfected in NSCLC cell lines, there was increased cell viability and cell motility.Conclusions
Taking the overall mutation rate of c-CBL to be a combination as somatic missense mutation and LOH, it is clear that c-CBL is highly mutated in lung cancers and may play an essential role in lung tumorigenesis and metastasis. 相似文献88.
Gary J. Vora Carolyn E. Meador David A. Stenger Joanne D. Andreadis 《Applied microbiology》2004,70(5):3047-3054
DNA microarray-based screening and diagnostic technologies have long promised comprehensive testing capabilities. However, the potential of these powerful tools has been limited by front-end target-specific nucleic acid amplification. Despite the sensitivity and specificity associated with PCR amplification, the inherent bias and limited throughput of this approach constrain the principal benefits of downstream microarray-based applications, especially for pathogen detection. To begin addressing alternative approaches, we investigated four front-end amplification strategies: random primed, isothermal Klenow fragment-based, 29 DNA polymerase-based, and multiplex PCR. The utility of each amplification strategy was assessed by hybridizing amplicons to microarrays consisting of 70-mer oligonucleotide probes specific for enterohemorrhagic Escherichia coli O157:H7 and by quantitating their sensitivities for the detection of O157:H7 in laboratory and environmental samples. Although nearly identical levels of hybridization specificity were achieved for each method, multiplex PCR was at least 3 orders of magnitude more sensitive than any individual random amplification approach. However, the use of Klenow-plus-Klenow and 29 polymerase-plus-Klenow tandem random amplification strategies provided better sensitivities than multiplex PCR. In addition, amplification biases among the five genetic loci tested were 2- to 20-fold for the random approaches, in contrast to >4 orders of magnitude for multiplex PCR. The same random amplification strategies were also able to detect all five diagnostic targets in a spiked environmental water sample that contained a 63-fold excess of contaminating DNA. The results presented here underscore the feasibility of using random amplification approaches and begin to systematically address the versatility of these approaches for unbiased pathogen detection from environmental sources. 相似文献
89.
Vora GJ Meador CE Stenger DA Andreadis JD 《Applied and environmental microbiology》2004,70(5):3047-3054
DNA microarray-based screening and diagnostic technologies have long promised comprehensive testing capabilities. However, the potential of these powerful tools has been limited by front-end target-specific nucleic acid amplification. Despite the sensitivity and specificity associated with PCR amplification, the inherent bias and limited throughput of this approach constrain the principal benefits of downstream microarray-based applications, especially for pathogen detection. To begin addressing alternative approaches, we investigated four front-end amplification strategies: random primed, isothermal Klenow fragment-based, phi29 DNA polymerase-based, and multiplex PCR. The utility of each amplification strategy was assessed by hybridizing amplicons to microarrays consisting of 70-mer oligonucleotide probes specific for enterohemorrhagic Escherichia coli O157:H7 and by quantitating their sensitivities for the detection of O157:H7 in laboratory and environmental samples. Although nearly identical levels of hybridization specificity were achieved for each method, multiplex PCR was at least 3 orders of magnitude more sensitive than any individual random amplification approach. However, the use of Klenow-plus-Klenow and phi29 polymerase-plus-Klenow tandem random amplification strategies provided better sensitivities than multiplex PCR. In addition, amplification biases among the five genetic loci tested were 2- to 20-fold for the random approaches, in contrast to >4 orders of magnitude for multiplex PCR. The same random amplification strategies were also able to detect all five diagnostic targets in a spiked environmental water sample that contained a 63-fold excess of contaminating DNA. The results presented here underscore the feasibility of using random amplification approaches and begin to systematically address the versatility of these approaches for unbiased pathogen detection from environmental sources. 相似文献
90.
The anthrax toxin consists of protective antigen (PA), lethal factor (LF) and edema factor (EF). PA mediates the entry of LF and EF to the cytosol where they exert their effects. Although PA is the major component of the vaccines against anthrax, LF has also been found to play an important role in enhancing protective immunity. We have developed an osmolyte-inducible LF expression system. The protein expression system contributed no additional amino acids to the recombinant LF making it suitable for the human vaccine trials. 相似文献