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At least 1,441 records · Page 80Linked to original sources
PubMed2006

Seed-specific expression of sesame microsomal oleic acid desaturase is controlled by combinatorial properties between negative cis-regulatory elements in the SeFAD2 promoter and enhancers in the 5'-UTR intron.

The regulation of genes involved in primary lipid metabolism in plants is much less well understood than that in many other pathways in plant biology. In the investigation reported here, we have characterized transcriptional regulatory mechanisms controlling seed-specific FAD2 expression in sesame (Sesamum indicum). FAD2 codes for extra-plastidial FAD2 desaturase, which catalyzes the conversion of oleic acid to linoleic acid. Promoter analysis of the sesame FAD2 gene (SeFAD2) using the beta-glucuronidase (GUS) reporter system demonstrated that the - 660 to - 180 promoter region functions as a negative cis-element in the seed-specific expression of the SeFAD2 gene. Sesame and Arabidopsis FAD2 genes harbor one large intron within their 5'-untranslated region. These introns conferred up to 100-fold enhancement of GUS expression in transgenic Arabidopsis tissues as compared with intron-less controls. Prerequisite cis-elements for the SeFAD2 intron-mediated enhancement of gene expression and the promoter-like activity of SeFAD2 intron were identified. SeFAD2 transcripts were induced by abscisic acid (ABA) in developing sesame seeds, and the - 660 to - 548 and - 179 to - 53 regions in the SeFAD2 promoter were implicated in ABA-responsive signaling. Theses observations indicate that an intron-mediated regulatory mechanism is involved in controlling not only the seed-specific expression of the SeFAD2 gene but also the expression of plant FAD2 genes, which are essential for the synthesis of polyunsaturated fatty acids.

5' Untranslated Regions↗
PubMedDate not supplied

Clinical proteomics: from biomarker discovery and cell signaling profiles to individualized personal therapy.

The discovery of new highly sensitive and specific biomarkers for early disease detection and risk stratification coupled with the development of personalized "designer" therapies holds the key to future treatment of complex diseases such as cancer. Mounting evidence confirms that the low molecular weight (LMW) range of the circulatory proteome contains a rich source of information that may be able to detect early stage disease and stratify risk. Current mass spectrometry (MS) platforms can generate a rapid and high resolution portrait of the LMW proteome. Emerging novel nanotechnology strategies to amplify and harvest these LMW biomarkers in vivo or ex vivo will greatly enhance our ability to discover and characterize molecules for early disease detection, subclassification and prognostic capability of current proteomics modalities. Ultimately genetic mutations giving rise to disease are played out and manifested on a protein level, involving derangements in protein function and information flow within diseased cells and the interconnected tissue microenvironment. Newly developed highly sensitive, specific and linearly dynamic reverse phase protein microarray systems are now able to generate circuit maps of information flow through phosphoprotein networks of pure populations of microdissected tumor cells obtained from patient biopsies. We postulate that this type of enabling technology will provide the foundation for the development of individualized combinatorial therapies of molecular inhibitors to target tumor-specific deranged pathways regulating key biologic processes including proliferation, differentiation, apoptosis, immunity and metastasis. Hence future therapies will be tailored to the specific deranged molecular circuitry of an individual patient's disease. The successful transition of these groundbreaking proteomic technologies from research tools to integrated clinical diagnostic platforms will require ongoing continued development, and optimization with rigorous standardization development and quality control procedures.

Biomarkers↗
PubMed2026

PTBP1 at the host-virus interface: mechanistic roles in viral RNA translation, replication, and immune modulation.

Viruses require the involvement of host RNA binding proteins for completion of important steps of their life cycle. Polypyrimidine tract binding protein 1 (PTBP1) is an RNA-binding protein found ubiquitously which performs important regulatory functions like alternative splicing, RNA stability, RNA localization, and translation by virtue of its four RRMs and shuttling between nucleus and cytoplasm. There is increasing evidence showing that many viruses make use of such regulatory roles of PTBP1 to facilitate their gene expression and replication. This review describes the existing mechanistic knowledge about the PTBP1 functions during viral infection, paying attention to the role of PTBP1 in viral RNA translation, viral RNA genome replication, and regulation of host antiviral response. Special attention is paid to the regulation by PTBP1 of IRES-dependent translation of enteroviruses and hepatitis C virus, as well as to the PTBP1 contribution to RNA stabilization, long-distance RNA interactions, and genome cyclization of flaviviruses such as dengue virus and Japanese encephalitis virus. Recent data on the PTBP1 function in coronavirus RNA metabolism are discussed as well. Furthermore, the role of PTBP1 in being both proviral and antiviral is reviewed in terms of innate immunity signalling pathways, stress granule biology, and virus-host interaction. Finally, we will explore the possibility of PTBP1 being used as a host-directed antiviral drug target despite the hurdles in doing so considering its multifunctionality as an essential cellular RNA-binding protein.

Polypyrimidine Tract-Binding Protein↗
PubMed2006

Characterizations of a hypomorphic argonaute1 mutant reveal novel AGO1 functions in Arabidopsis lateral organ development.

Genes that encode the ARGONAUTE (AGO) proteins make up a highly conserved family, and several members in the family have been defined to function in posttranscriptional gene silencing (PTGS) in plants, quelling in fungi and RNAi in animals. The Arabidopsis AGO1 gene has been demonstrated to be crucial in multiple RNA silencing pathways (PTGS, microRNA and trans-acting siRNA pathways); however, its biological functions do not seem to be fully addressed. Here we report characterizations of a new hypomorphic ago1 allele, ago1-37, and show novel AGO1 functions important in lateral organ development. We found that double mutants combining ago1-37 with asymmetric leaves1 (as1) or asymmetric leaves2 (as2) produced more severe phenotypes than the single mutants, indicating that AGO1 genetically interacts with AS1 and AS2 for plant development. Similar to the previously characterized mutants rdr6, sgs3 and zippy, which are deficient in the trans-acting siRNA activity, ago1-37 also showed an earlier phase transition from juvenile to adult leaves. Moreover, based on the detailed phenotypic analyses of single and double mutant plants, we found that the AGO1 functions are required for repressing several class I KNOTTED1-like homeobox (KNOX) genes in leaves, and for specifying both adaxial and abaxial identities of the leaf and petal. Our results demonstrate several important AGO1 functions in plant lateral organ development.

Alleles↗
PubMed2000

Deactivation of the sympathetic nervous system in patients with chronic congestive heart failure.

In this article, we review the basic biology, signal transduction pathways, and clinical pharmacology associated with cardiac beta-adrenergic receptors (beta-ARs) in the context of the use of beta-blocking agents in patients with chronic congestive heart failure. Adrenergic receptors, particularly the beta-AR subtypes (beta(1)-AR and beta(2)-AR), are known to play a critical role in the modulation of cardiac function, providing for both "adaptive" and "maladaptive" compensatory changes. In the context of exercise or self-preservation, the adrenergic nervous system, acting via beta-ARs permits an appropriately rapid, highly-dynamic increase in cardiac function. Conversely, in individuals with chronic congestive heart failure, the sustained, heightened activation of adrenergic nervous system, as manifested by increases in circulating catecholamines, results in down- regulation and desensitization of myocardial beta-ARs, and potentially, significant myocardial damage. A number of recent clinical trials have demonstrated a marked mortality benefit from using beta-blocking agents such as metoprolol and carvedilol in patients with heart failure. The pharmacologic properties of several of these drugs and some of the specifics of their usefulness and limitations are discussed herein.

Adrenergic beta-Antagonists↗
PubMed1989

Role of cholesterol in the stability of pH-sensitive, large unilamellar liposomes prepared by the detergent-dialysis method.

Large unilamellar liposomes prepared by an octyl glucoside-dialysis method were examined for stability at 37 degrees C in the presence or absence of human plasma, using the release of the entrapped calcein as a fluorescence marker. The liposomes were acid-sensitive as they were composed of dioleoylphosphatidylethanolamine, oleic acid and cholesterol. The stability of the liposomes in the absence of plasma was significantly enhanced with increasing cholesterol content. However, the maximal calcein release at pH 5 decreased linearly with increasing cholesterol content of the liposome, indicating that cholesterol had reduced the acid-sensitivity of the liposomes. In the presence of human plasma, calcein release exhibited a biphasic behavior with a fast (plasma-sensitive) and a slow (plasma-resistant) component. Inclusion of cholesterol in the liposomes resulted in an increased proportion of the plasma-resistant component. Liposomes pretreated with human plasma, after removal of excess plasma and the released calcein by gel-filtration, showed a remarkable stability both in the presence and absence of human plasma. The acid-sensitivity of the plasma-treated liposomes with 40% cholesterol was the same as that of the untreated liposomes. These results are discussed in terms of the mechanism by which these liposomes deliver their contents to the cytoplasm of the cells via the endocytic pathway, a known biological activity of the type of liposome described here.

Blood↗
PubMed1983

Skin conductance: a potentially sensitive test for depression.

The mean resting skin conductance level (SCL) in 31 inpatients with major unipolar depression was 2.63 mumho/cm2 +/- SD 1.41 compared to 7.81 mumho/cm2 +/- SD 3.0 in the control group. The best criterion below which an SCL could be considered abnormal was 4.3 mumho/cm2 with a resulting sensitivity of 87% and specificity of 89%. There was a significant difference in SCL between males and females but none between drug-free and medicated patients. SCL was abnormal in all depression subtypes. The SCL may represent a biological final common pathway in depression and may prove to be a very effective diagnostic test for depression.

Adult↗
PubMed1988

Effects of HIV infection, perceived health and clinical status on a cohort at risk for AIDS.

Data from a general population sample of 621 healthy homosexual men are used to evaluate the social and emotional effects of HIV antibody status, clinical signs detected by medical examination, and subjectively perceived symptoms. Participants are unaware of their serologic status at the time of data collection, thus allowing the effects of the virus to be separated from reactions to the knowledge of serologic status. The data show that seropositivity for HIV is not associated with elevated levels of social or emotional impairment. Clinical signs lead to impairment in baseline data, but these effects do not persist at a second wave. This weakening suggests that the effects are mediated by psychological pathways rather than biologic ones. This suspicion is confirmed in further analyses, which show that the effects of clinical signs are mediated by subjectively perceived symptoms. These results show that neither social nor emotional impairment is likely to be a prodromal sign of HIV infection in otherwise healthy homosexual men. The substantial levels of distress found among these men is more directly influenced by psychological determinants than biologic ones. This suggests that physicians should be aware of the psychological toll imposed on gay men who develop health problems in the current atmosphere of uncertainty regarding risk of AIDS.

AIDS Serodiagnosis↗
PubMed1987

The combined use of size-exclusion and reversed-phase high-performance liquid chromatography for characterization of beta-endorphin processing pathways.

A method is described for the separation and analysis of multiple molecular forms of immunoreactive beta-endorphin and its alpha-N-acetylated congeners by a combination of reversed-phase and size-exclusion high-performance liquid chromatography coupled with two specific radioimmunoassays. Both chromatographic procedures are fast (less than 50 min per analysis) providing good resolution and high recovery (greater than 90%). The solvents used in both systems are ultraviolet transparent (less than 214 nm), non-corrosive, low salt (less than 0.05 M) and after evaporation fully compatible with subsequent radioimmunoassay. We have evaluated these techniques using both synthetic and purified peptide standards and have applied these procedures to characterize immunoreactive beta-endorphin and alpha-N-acetylendorphin in rat and sheep pituitary extracts, and the low levels found in sheep hypothalamus and rat ovary. These chromatographic procedures are not only applicable to the study of pro-opiomelanocortin-derived peptides, but also could be employed to examine the processing pathways of other biologically active polypeptides, in both central and peripheral tissue extracts.

Animals↗
PubMed1989

Endogenous inhibition of arachidonic acid metabolism in the endometrium of the sheep.

Arachidonic acid is metabolised via the cyclo-oxygenase pathway to several biologically active metabolites. These metabolites control important reproductive functions like luteolysis of the corpus luteum. The metabolism of arachidonic acid was studied by the enzymatic conversion of [1-14C]-labelled arachidonic acid in sheep endometrial tissue. The inhibitory capacity of sheep endometrial tissue was measured by the enzymatic conversion of [1-14C]-arachidonic acid by sheep seminal vesicular gland microsomes. Endometrial microsomes converted arachidonic acid into different prostaglandins and monohydroxy acids but at a low rate. A factor(s) inhibiting both prostaglandin and monohydroxy acid synthesis was found in both the microsomal and cytosolic fractions of endometrial tissue. A very high inhibitory potency of prostaglandin and monohydroxy acid synthesis, calculated as IC50 values, was found in cytosolic fractions. For comparison IC50 values of indomethacin, mefenamic acid, carprofen and acetylsalicylic acid were also calculated in this in vitro system. These data indicate that both prostaglandin and monohydroxy acid synthesizing capacities and an inhibitory factor(s) are present in sheep endometrium and possibly regulate arachidonic acid metabolism in this tissue.

Animals↗
PubMed2006

Evaluation of mitochondrial membrane potential using a computerized device with a tetraphenylphosphonium-selective electrode.

Mitochondrial membrane potential (Deltapsi(m)) plays important roles in the normal function of cells and in pathobiochemical situations. The application of ion-selective electrodes for the measurement of Deltapsi(m) is important for studying normal biological reactions and pathways and mitochondrial diseases. We constructed and optimized a computerized device for real-time monitoring of the Deltapsi(m), which included modification of tetraphenylphosphonium (TPP(+))-selective membrane that improved reproducibility of the TPP(+)-selective electrode. Application of MATLAB software increased the sensitivity of the system. We tested our improved device for membrane potential measurements of isolated mitochondria (in absolute scale of millivolts). In addition, we assessed relative changes of Deltapsi(m) (as changes in TPP(+) concentration) of digitonin-permeabilized cells (hepatocytes, control transmitochondrial cybrids, HeLa G and BSC-40) after addition of substrates, inhibitors, and uncoupler of respiratory chain. Our system can be successfully used for studies of many aspects of the regulation of mitochondrial bioenergetics and as a diagnostic tool for mitochondrial oxidative phosphorylation disorders.

Animals↗
PubMed2006

A chemiluminescence-based reporter system to monitor nonsense-mediated mRNA decay.

Nonsense-mediated mRNA decay (NMD) is a surveillance pathway that mediates rapid degradation of transcripts bearing premature translation termination codons (PTCs) and thereby limits the expression of unproductively processed mRNAs and the synthesis of C-terminally truncated peptides. Both its importance as a means to control gene expression and in the context of genetic and acquired human diseases call for an exploration of the mammalian NMD pathway using chemical biology approaches. Here, we describe a novel cell-based chemiluminescence reporter system that recapitulates the hallmark features of mammalian NMD. The assay is characterized by its high sensitivity, robustness, and its potential for automated handling. Limiting NMD efficiency by RNAi-mediated depletion of the essential NMD factor UPF1 markedly and specifically increased the NMD reporter mRNA level and resulted in a proportional increase in protein expression reflected by Renilla luminescence. The PI 3-kinase inhibitor wortmannin has previously been found to up-modulate PTC-containing transcripts by inhibiting the UPF1 kinase SMG1. Wortmannin treatment enhanced NMD reporter expression in our system in a dose-dependent way, illustrating its utility for small molecule screening.

Androstadienes↗
PubMed2006

Mitochondrial depolarization and the role of uncoupling proteins in ischemia tolerance.

Modest depolarization of the mitochondrial inner membrane potential is known to attenuate mitochondrial reactive oxygen species generation. Transient pharmacologic uncoupling of mitochondrial oxidative phosphorylation results in modest depolarization of the mitochondrial membrane potential and confers protection against subsequent cardiac ischemia-reperfusion injury. Whether cardiac mitochondria have an innate capacity to temporally self-modulate their membrane potential as a possible adaptive mechanism in the context of cardiac ischemia and early reperfusion is supported by emerging data and is an intriguing concept that warrants further investigation. The objective of this review is to explore the various mechanisms whereby mitochondrial depolarization can be evoked in the context of both cardiac ischemia and reperfusion and in response to the cardioprotective program of ischemic preconditioning. The potential regulatory pathways orchestrating this biological perturbation of mitochondrial function are explored from the level of signal transduction to potential transcription-mediated modulations of nuclear-encoded mitochondrial inner membrane proteins, emphasizing the potential function of the mitochondrial uncoupling proteins.

Humans↗
PubMed2004

Einstein's Institute for Aging Research: collaborative and programmatic approaches in the search for successful aging.

While aging research has been progressing rapidly recently, the involvement of multiple organs and systems in the aging process has hampered a comprehensive assessment of some of aging's basic features. In response to this problem, the Institute for Aging Research at Einstein did not emerge out of the traditional geriatric programs, but through enhanced collaborations between basic and clinical scientists who had successful careers in the research of a specific organ or system. The strength of the Center derives from three specific programs focused on a specific area of aging research. The programs focus on the Biology of Aging, Genetics of Aging and the Aging Brain. Each programmatic area is characterized by collaboration between basic and clinical scientists. In addition to addressing the traditional questions about the mechanisms of involution, the programs also examine the mechanisms for exceptional and healthy longevity. The mechanisms favoring longevity are being examined in models of caloric restriction (biological nutrient sensing pathways), in human centenarians (longevity genes), and in longitudinal studies identifying humans who maintain excellent cognitive function (protection from Alzheimer's). Each programmatic area is enhanced by common research core laboratory and by the creation of a scientific training program for new investigators. In addition to the investigators involved in the program project, the Institute for Aging Research includes other investigators with funded aging research who participate in journal clubs, seminars, and in specific collaborations. We suggest that this Institute serve as a model that gerontologists at other institutions should consider as they evaluate opportunities for collaborative, multi-disciplinary approaches to enhance aging research.

Academies and Institutes↗
PubMed2004

Vascular genetic factors and human longevity.

Complex inter-relationships between age-associated illnesses, such as vascular disease and Alzheimer's disease (AD), suggest that biological and genetic pathways may be worthy of examination in centenarian populations to provide insights into human longevity. This is also borne out by the involvement of lipoprotein metabolism and a number of vascular genetic risk factors. Repeated findings of a higher frequency of the apolipoprotein E (APOE) epsilon4 allele in middle-aged subjects compared with centenarians were reported. Furthermore, we have also shown how in different populations there is a significant trend in reduction of serum APOE levels from APOE epsilon2- to epsilon4-carrier as well as significant differences in serum APOE levels respect to age in epsilon4-carriers but only after adjustment for HDL cholesterol. In contrast, findings of increased prevalence of the angiotensin I converting enzyme 1 (ACE1) D allele in French centenarians have not been replicated, suggesting the possibility that regional differences may occur in ACE1(*)D frequency within Europe in centenarians, as has been recently reported for APOE epsilon2 and epsilon4 alleles. A number of studies have examined the potential role in longevity of other genes involved in vascular risk, haemostasis, and blood pressure regulation [methyltetrahydrofolatereductase (MTHFR), apolipoprotein A1 (APOA-I), apolipoprotein C3 (APOC-III), apolipoprotein A4 (APOA-IV), paraoxonase 1 (PON1), plasminogen activator inhibitor type I (PAI-1)], with contrasting results. While further studies are needed to confirm the possible role of APOE concentration as putative longevity factor, this paper provides an overview of genetic vascular factors potentially involved in human longevity.

Aging↗
PubMedDate not supplied

Unraveling a complex genetic disease: age-related macular degeneration.

In most of the Western world, age-related macular degeneration (AMD) remains the largest single cause of severe visual impairment, and its prevalence continues to increase. It is considered to be a complex disease, in which multiple genes and environment play a role in pathogenesis. Several environmental insults are implicated with smoking, serum cholesterol, hypertension, sunlight exposure, and many other factors being variously associated with disease pathogenesis. Until recently, there have been relatively few breakthroughs to further our understanding of the genetics of AMD, despite remarkable progress in molecular genetic techniques over the last 20 years, and the fact that many rare inherited macular diseases have had their causative genes mapped. Development of new tools such as high-density single-nucleotide polymorphism chips and microarrays have changed the face of genetic research, but have yet to directly translate into improved clinical outcomes in ophthalmology. However with the recent finding of the Tyr402His polymorphism in the complement factor H gene being implicated in AMD, we are about to witness a new wave of research in this disease. Not only does the identification of a biologically plausible gene identify a new pathway, but it also identifies new biological mechanisms for disease, avenues to pursue treatment, and a better understanding of how the environment interacts with the genetic background to create disease. This article aims to review the process of gene discovery in complex disease, why the search for genes remains difficult, how to translate laboratory findings to a clinical setting, and how these findings will impact on disease treatment and public health issues.

Genetic Variation↗
PubMed2002

Sporadic fundic gland polyps with epithelial dysplasia : evidence for preferential targeting for mutations in the adenomatous polyposis coli gene.

Gastric fundic gland polyps (FGPs) occur in two distinct clinicopathological scenarios: sporadic and familial adenomatous polyposis (FAP) associated. FAP-associated FGPs arise through somatic second hit alterations of the adenomatous polyposis coli (APC) gene and frequently demonstrate epithelial dysplasia (Am J Pathol 2000, 157:747-754). Sporadic FGPs, in contrast, tend to contain beta-catenin gene mutations and only infrequently show dysplasia (Am J Pathol 2001, 158:1005-1010). However, sporadic FGPs with dysplasia have not been previously investigated. We studied 13 sporadic FGPs with surface/foveolar low-grade dysplasia or changes indefinite for dysplasia for alterations in the APC/beta-catenin pathway, using chromosome 5q allelic loss assays and direct DNA sequencing of the mutation cluster region in exon 15 of APC and the phosphorylation region in exon 3 of beta-catenin. In addition, to evaluate for possible additional genetic alterations in FGPs, all cases were evaluated for microsatellite instability using fluorescent-based amplification of a standard panel of five microsatellite markers. Alterations in APC were present in seven (53.8%) FGPs, including two cases with bi-allelic APC inactivation (truncating intragenic mutation plus 5q allelic loss), two cases with APC mutation only, and three cases with 5q allelic loss only. In contrast, only two (15.4%) FGPs contained stabilizing beta-catenin mutations. All 13 FGPs were microsatellite stable. These results indicate that sporadic FGPs with dysplasia/indefinite for dysplasia are molecularly similar to FAP-associated FGPs, and are dissimilar to the more common sporadic nondysplastic FGPs. Mutations in APC and beta-catenin, despite occurring in the same genetic pathway, show differing biological properties, a phenomenon that has previously been demonstrated in colorectal neoplasms. The lack of microsatellite instability in FGPs in this study and of K-ras mutations in a previous study suggests that secondary genetic alterations are rare in both dysplastic and nondysplastic FGPs.

Adult↗
PubMed2004

[Porphyrin catalysts: a tool for preparation of metabolite models].

The porphyrin complexes of manganese catalysts are biomimetic catalysts whose structural analogy with the active site of cytochrome P-450 enzymes can be used to obtain synthetic models of therapeutic agent metabolites. Mn(TDCOO)Cl, a second generation porphyrin, has proven robust enout to be used for scaled-up production in the presence of hydrogen peroxide and imidazole. For this purpose, an improvement in substrate oxidation was obtained by adjunction of formic acid to the reaction medium which preserved the cocatalyst and the catalyst. It was shown that addition of acid played an active role in the oxidation process. After this optimization, the system was used to oxidate the two enantiomers of methyloctalone, an essential chiral intermediate in the synthesis of terpenoids and steroids. The efficacy of this biomimetic method for the preparation of large amounts of oxidized chiral synthons was better than obtained with biological ex vivo pathways.

Animals↗