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PubMed1997

Predictors of the progression of renal disease in the Modification of Diet in Renal Disease Study.

The Modification of Diet in Renal Disease (MDRD) Study examined the effects of dietary protein restriction and strict blood pressure control on the decline in glomerular filtration rate (GFR) in 840 patients with diverse renal diseases. We describe a systematic analysis to determine baseline factors that predict the decline in GFR, or which alter the efficacy of the diet or blood pressure interventions. Univariate analysis identified 18 of 41 investigated baseline factors as significant (P < 0.05) predictors of GFR decline. In multivariate analysis, six factors--greater urine protein excretion, diagnosis of polycystic kidney disease (PKD), lower serum transferrin, higher mean arterial pressure, black race, and lower serum HDL cholesterol--independently predicted a faster decline in GFR. Together with the study interventions, these six factors accounted for 34.5% and 33.9% of the variance between patients in GFR slopes in Studies A and B, respectively, with proteinuria and PKD playing the predominant role. The mean rate of GFR decline was not significantly related to baseline GFR, suggesting an approximately linear mean GFR decline as renal disease progresses. The 41 baseline predictors were also assessed for their interactions with the diet and blood pressure interventions. A greater benefit of the low blood pressure intervention was found in patients with higher baseline urine protein. None of the 41 baseline factors were shown to predict a greater or lesser effect of dietary protein restriction.

Blood Pressure↗

PubMed2006

A novel computational model of the circadian clock in Arabidopsis that incorporates PRR7 and PRR9.

In plants, as in animals, the core mechanism to retain rhythmic gene expression relies on the interaction of multiple feedback loops. In recent years, molecular genetic techniques have revealed a complex network of clock components in Arabidopsis. To gain insight into the dynamics of these interactions, new components need to be integrated into the mathematical model of the plant clock. Our approach accelerates the iterative process of model identification, to incorporate new components, and to systematically test different proposed structural hypotheses. Recent studies indicate that the pseudo-response regulators PRR7 and PRR9 play a key role in the core clock of Arabidopsis. We incorporate PRR7 and PRR9 into an existing model involving the transcription factors TIMING OF CAB (TOC1), LATE ELONGATED HYPOCOTYL (LHY) and CIRCADIAN CLOCK ASSOCIATED (CCA1). We propose candidate models based on experimental hypotheses and identify the computational models with the application of an optimization routine. Validation is accomplished through systematic analysis of various mutant phenotypes. We introduce and apply sensitivity analysis as a novel tool for analyzing and distinguishing the characteristics of proposed architectures, which also allows for further validation of the hypothesized structures.

Arabidopsis↗

PubMed2007

Tissue-specific regulatory elements in mammalian promoters.

Transcription factor-binding sites and the cis-regulatory modules they compose are central determinants of gene expression. We previously showed that binding site motifs and modules in proximal promoters can be used to predict a significant portion of mammalian tissue-specific transcription. Here, we report on a systematic analysis of promoters controlling tissue-specific expression in heart, kidney, liver, pancreas, skeletal muscle, testis and CD4 T cells, for both human and mouse. We integrated multiple sources of expression data to compile sets of transcripts with strong evidence for tissue-specific regulation. The analysis of the promoters corresponding to these sets produced a catalog of predicted tissue-specific motifs and modules, and cis-regulatory elements. Predicted regulatory interactions are supported by statistical evidence, and provide a foundation for targeted experiments that will improve our understanding of tissue-specific regulatory networks. In a broader context, methods used to construct the catalog provide a model for the analysis of genomic regions that regulate differentially expressed genes.

Algorithms↗

PubMed2004

Pack-MULE transposable elements mediate gene evolution in plants.

Mutator-like transposable elements (MULEs) are found in many eukaryotic genomes and are especially prevalent in higher plants. In maize, rice and Arabidopsis a few MULEs were shown to carry fragments of cellular genes. These chimaeric elements are called Pack-MULEs in this study. The abundance of MULEs in rice and the availability of most of the genome sequence permitted a systematic analysis of the prevalence and nature of Pack-MULEs in an entire genome. Here we report that there are over 3,000 Pack-MULEs in rice containing fragments derived from more than 1,000 cellular genes. Pack-MULEs frequently contain fragments from multiple chromosomal loci that are fused to form new open reading frames, some of which are expressed as chimaeric transcripts. About 5% of the Pack-MULEs are represented in collections of complementary DNA. Functional analysis of amino acid sequences and proteomic data indicate that some captured gene fragments might be functional. Comparison of the cellular genes and Pack-MULE counterparts indicates that fragments of genomic DNA have been captured, rearranged and amplified over millions of years. Given the abundance of Pack-MULEs in rice and the widespread occurrence of MULEs in all characterized plant genomes, gene fragment acquisition by Pack-MULEs might represent an important new mechanism for the evolution of genes in higher plants.

Base Sequence↗

PubMed2004

Rational siRNA design for RNA interference.

Short-interfering RNAs suppress gene expression through a highly regulated enzyme-mediated process called RNA interference (RNAi). RNAi involves multiple RNA-protein interactions characterized by four major steps: assembly of siRNA with the RNA-induced silencing complex (RISC), activation of the RISC, target recognition and target cleavage. These interactions may bias strand selection during siRNA-RISC assembly and activation, and contribute to the overall efficiency of RNAi. To identify siRNA-specific features likely to contribute to efficient processing at each step, we performed a systematic analysis of 180 siRNAs targeting the mRNA of two genes. Eight characteristics associated with siRNA functionality were identified: low G/C content, a bias towards low internal stability at the sense strand 3'-terminus, lack of inverted repeats, and sense strand base preferences (positions 3, 10, 13 and 19). Further analyses revealed that application of an algorithm incorporating all eight criteria significantly improves potent siRNA selection. This highlights the utility of rational design for selecting potent siRNAs and facilitating functional gene knockdown studies.

Animals↗

PubMed2005

Second-generation shRNA libraries covering the mouse and human genomes.

Loss-of-function phenotypes often hold the key to understanding the connections and biological functions of biochemical pathways. We and others previously constructed libraries of short hairpin RNAs that allow systematic analysis of RNA interference-induced phenotypes in mammalian cells. Here we report the construction and validation of second-generation short hairpin RNA expression libraries designed using an increased knowledge of RNA interference biochemistry. These constructs include silencing triggers designed to mimic a natural microRNA primary transcript, and each target sequence was selected on the basis of thermodynamic criteria for optimal small RNA performance. Biochemical and phenotypic assays indicate that the new libraries are substantially improved over first-generation reagents. We generated large-scale-arrayed, sequence-verified libraries comprising more than 140,000 second-generation short hairpin RNA expression plasmids, covering a substantial fraction of all predicted genes in the human and mouse genomes. These libraries are available to the scientific community.

Animals↗

PubMed2004

Atomic dynamics and Marangoni films during liquid-metal spreading.

Despite its apparent simplicity, spreading of liquid metals at high temperatures has defied description and generalization. Wetting at high temperature is usually accompanied by interdiffusion and chemical reaction, but the forces that drive reactive spreading and the mechanisms that control its kinetics have been very poorly understood. The unsolved challenge has been to link macroscopic measurements such as the dynamic contact angle or the speed of a moving liquid front to phenomena occurring at the microscopic and even atomic level in the vicinity of the triple solid-liquid-vapour junction. We have taken a big step towards meeting this challenge. Our systematic analysis of the spreading of metal-metal systems with varying degrees of mutual solubility allows us to report on the fundamental differences between the mechanisms controlling spreading of organic liquids and liquid metals and on formation of Marangoni films driven by surface-tension gradients in high-temperature systems.

Computer Simulation↗

PubMed2003

Killing the messenger: short RNAs that silence gene expression.

Short interfering RNAs can be used to silence gene expression in a sequence-specific manner in a process that is known as RNA interference. The application of RNA interference in mammals has the potential to allow the systematic analysis of gene expression and holds the possibility of therapeutic gene silencing. Much of the promise of RNA interference will depend on the recent advances in short-RNA-based silencing technologies.

Animals↗

PubMed2025

Systematic decoding of functional enhancer connectomes and risk variants in human glioma.

Genetic and epigenetic variations contribute to the progression of glioma, but the mechanisms underlying these effects, particularly for enhancer-associated genetic variations in non-coding regions, still remain unclear. Here we performed high-throughput CRISPR interference screening to identify pro-tumour enhancers in glioma cells. By integrating genome-wide H3K27ac HiChIP data, we identified the target genes of these pro-tumour enhancers and revealed the essential role of enhancer connectomes in promoting glioma progression. Through systematic analysis of enhancers carrying glioma risk-associated single-nucleotide polymorphisms (SNPs), we found that these SNPs can promote glioma progression through the enhancer connectome. Using CRISPR-Cas9-mediated enhancer interference and SNP editing, we demonstrated that glioma-specific enhancer carrying the risk SNP rs2297440 regulates SOX18 expression by specifically recruiting transcription factor MEIS1 binding, thereby contributing to glioma progression. Our study sheds light on the molecular mechanisms underlying glioma susceptibility and provides potential therapeutic targets to treat glioma.

Humans↗

PubMed2006

S-nitrosylation of cysteine 289 of the AT1 receptor decreases its binding affinity for angiotensin II.

1. Nitric oxide (NO) is known to affect the properties of various proteins via the S-nitrosylation of cysteine residues. This study evaluated the direct effects of the NO donor sodium nitroprusside (SNP) on the pharmacological properties of the AT1 receptor for angiotensin II expressed in HEK-293 cells. 2. SNP dose-dependently decreased the binding affinity of the AT1 receptor without affecting its total binding capacity. This modulatory effect was reversed within 5 min of removing SNP. 3. The effect of SNP was not modified in the presence of the G protein uncoupling agent GTPgammaS or the soluble guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one. 4. The binding properties of a mutant AT1 receptor in which all five cysteine residues within the transmembrane domains had been replaced by serine was not affected by SNP. Systematic analysis of mutant AT1 receptors revealed that cysteine 289 conferred the sensitivity to SNP. 5. These results suggest that NO decreased the binding affinity of the AT1 receptor by S-nitrosylation of cysteine 289. This modulatory mechanism may be particularly relevant in pathophysiological situations where the beneficial effects of NO oppose the deleterious effects of angiotensin II.

Amino Acid Substitution↗

PubMed2004

Failure of trilineage blood cell reconstitution after initial neutrophil engraftment in patients undergoing allogeneic hematopoietic cell transplantation - frequency and outcomes.

The outcomes of patients who experience the failure to reconstitute a trilineage of blood cells after initial neutrophil engraftment were evaluated in 178 patients with hematologic disorders, who underwent allogeneic HCT. Of 165 qualified patients (five with primary engraftment failure; eight deaths before day 60 of HCT), 43 (26%) satisfied the criteria for the initial (n=22; failure of platelet >20 000/microl or red blood cell transfusion independence/reticulocyte count >/=1.0% by day 60) or subsequent (n=21, ANC <500/microl for >/=3 days, platelet <20 000/microl for >/=7 days, or red blood cells transfusion/reticulocyte <1.0% after initial trilineage reconstitution) failure. GVHD was the most common clinical condition associated with cytopenia (n=24). In all, 20 patients (47%) recovered at least partially with a median of 52 days (range 8-323) later, with 12 of those 20 patients recovering completely. The eventual reconstitution failure rate was 14% (23/163 patients). The number of cell lineages involved in the cytopenia was the only independent variable that predicted partial recovery (1 lineage vs 2-3 lineages with odds ratio of 8.69 (95% CI 1.96-38.60), P=0.004). Five/20 patients with vs 20/23 patients without partial recovery died. Trilineage reconstitution failures after allogeneic HCT need systematic analysis in the future studies.

Adolescent↗

PubMed2002

Microarray, SAGE and their applications to cardiovascular diseases.

The wealth of DNA data generated by the human genome project coupling with recently invented high-throughput gene expression profiling techniques has dramatically sped up the process for biomedical researchers on elucidating the role of genes in human diseases. One powerful method to reveal insight into gene functions is the systematic analysis of gene expression. Two popular high-throughput gene expression technologies, microarray and Serial Analysis of Gene Expression (SAGE) are capable of producing large amounts of gene expression data with the potential of providing novel insights into fundamental disease processes, especially complex syndromes such as cardiovascular disease, whose etiologies are due to multiple genetic factors and their interplay with the environment. Microarray and SAGE have already been used to examine gene expression patterns of cell-culture, animal and human tissues models of cardiovascular diseases. In this review, we will first give a brief introduction of microarray and SAGE technologies and point out their limitations. We will then discuss the major discoveries and the new biological insights that have emerged from their applications to cardiovascular diseases. Finally we will touch upon potential challenges and future developments in this area.

Cardiovascular Diseases↗

PubMed2001

Five decades of trends in anemia in Israeli infants: implications for food fortification policy.

OBJECTIVE: To describe the secular trends in the prevalence rates of iron-deficiency anemia (IDA) in infants in Israel, identify population group differences and assess the effectiveness of the 1985 Public Health directives on iron supplementation and avoidance of cow's milk in the first year of life. DESIGN: A systematic analysis of published and unpublished cross-sectional studies. METHODS: IDA rates in 1-y-old infants between 1946 and 1997 were assessed from published papers and reports. Rates for Arab infants were available from 1984. Data on routine hemoglobin tests on 1-y-old infants for Arabs and Jews separately were obtained from four health districts for the period 1987 to 1997. Analyses were done for the periods prior to and following the Public Health directives. RESULTS: The prevalence of IDA in Jewish infants declined from 68% in 1946 to 50% in 1985 at an average annual rate of -1.43%. Following the iron supplementation directives, the average annual rate of decline increased to -4.0% and reached a prevalence of about 11% in 1996. IDA rates in Arab infants declined by an annual average of -3.7%, and were consistently almost twice as high as for Jewish infants. CONCLUSIONS: Despite the contribution of the iron supplementation program to the reduction in TDA, the persistently high rates indicate inadequate iron content in the diet. This emphasizes the important role of a national food fortification program, using staple foods commonly consumed.

Anemia, Iron-Deficiency↗

PubMed2004

The unfolded protein response represses differentiation through the RPD3-SIN3 histone deacetylase.

In Saccharomyces cerevisiae, splicing of HAC1 mRNA is initiated in response to the accumulation of unfolded proteins in the endoplasmic reticulum by the transmembrane kinase-endoribonuclease Ire1p. Spliced Hac1p (Hac1ip) is a negative regulator of differentiation responses to nitrogen starvation, pseudohyphal growth, and meiosis. Here we show that the RPD3-SIN3 histone deacetylase complex (HDAC), its catalytic activity, recruitment of the HDAC to the promoters of early meiotic genes (EMGs) by Ume6p, and the Ume6p DNA-binding site URS1 in the promoters of EMGs are required for nitrogen-mediated negative regulation of EMGs and meiosis by Hac1ip. Co-immunoprecipitation experiments demonstrated that Hac1ip can interact with the HDAC in vivo. Systematic analysis of double deletion strains revealed that HAC1 is a peripheral component of the HDAC. In summary, nitrogen-induced synthesis of Hac1ip and association of Hac1ip with the HDAC are physiological events in the regulation of EMGs by nutrients. These data also define for the first time a gene class that is under negative control by the UPR, and provide the framework for a novel mechanism through which bZIP proteins repress transcription.

Binding Sites↗

PubMed2005

mPER1-mediated nuclear export of mCRY1/2 is an important element in establishing circadian rhythm.

Receptor-mediated nucleocytoplasmic transport of clock proteins is an important, conserved element of the core mechanism for circadian rhythmicity. A systematic analysis of the nuclear export characteristics for the different murine period (mPER) and cryptochrome (mCRY) proteins using Xenopus oocytes as an experimental system demonstrates that all three mPER proteins, but neither mCRY1 nor mCRY2, are exported if injected individually. However, nuclear injection of heterodimeric complexes that contain combinations of mPER and mCRY proteins shows that mPER1 serves as an export adaptor for mCRY1 and mCRY2. Functional analysis of dominant-negative mPER1 variants designed either to sequester mPER3 to the cytoplasm or to inhibit nuclear export of mCRY1/2 in synchronized, stably transfected fibroblasts suggests that mPER1-mediated export of mCRY1/2 defines an important new element of the core clock machinery in vertebrates.

Active Transport, Cell Nucleus↗

PubMed2004

Vardenafil (Levitra) for erectile dysfunction: a systematic review and meta-analysis of clinical trial reports.

Trials of the efficacy and safety of vardenafil in the treatment of male erectile dysfunction (ED) were meta-analysed. All available databases were searched (January 1, 2001-November 30, 2003). Trials were eligible if they included men with ED, compared vardenafil with placebo, were randomized, were at least of 12 weeks duration, and assessed clinically relevant outcomes. Two reviewers independently evaluated study quality and extracted data in a standardized fashion. Nine trials (6809 men) met the inclusion criteria. In results pooled from seven fixed-dose trials, vardenafil increases the Erectile Function domain of the International Index of Erectile Function questionnaire by 6.18 units (weighted mean difference (WMD)). Vardenafil also increases the percentage of erections firm enough to allow vaginal penetration (WMD: 26) and the percentage of sexual attempts that were successful per participant (WMD: 29.8). The percentage of men agreeing with the statement that 'the treatment they have been taking over the past 4 weeks improved their erections', is also in favour of vardenafil (relative risk (RR): 3). These efficacy variables appeared greater at higher doses, although there are no significant differences between 10 and 20 mg dose. The same results were extracted for the two flexible 'as needed' dosing trials. Discontinuations are greater at the vardenafil groups compared to placebo (RR: 2.25). Specific adverse events with vardenafil included flushing, dyspepsia, headache, and rhinitis. Vardenafil was not significantly associated with serious cardiovascular events or death. Vardenafil, in all treatment regimens, shows to possess superior efficacy to placebo in the treatment of patients with erectile dysfunction. More data is needed on patients' subgroups.

3',5'-Cyclic-GMP Phosphodiesterases↗

PubMed2006

Detection limit of methods to assess fluid status changes in dialysis patients.

Technical systems for an accurate and practicable fluid management of dialysis patients are urgently needed, since current clinical methods are partially subjective, imprecise, and time consuming. Such new systems should not only allow the determination of the target normohydration weight, but also must be able to detect clinically relevant changes in fluid volume ( approximately 1 l). This study focuses on the systematic analysis of the detection limit of several candidate methods for fluid management. In a cohort of 16 new dialysis patients, several candidate methods were applied in parallel during each treatment of the initial weight reduction phase: the measurement of vena cava diameter (VCD), vena cava collapsibility index (CI), the blood volume drop during an ultrafiltration (UF) bolus (Deltarelative blood volume (RBV)-), the rebound after the UF bolus (DeltaRBV+), and the extracellular fluid volume determined with whole body bioimpedance spectroscopy (BIS). A clinical reference method was used to manage the fluid status of patients. All methods showed significant correlations with predialysis weight. The detection limits W(lim) of candidate methods for changes in fluid status were assessed as W(lim)=0.87 kg+/-0.64 kg (BIS), 1.74 kg+/-1.56 kg (VCD), 2.3 kg+/-1.0 kg (DeltaRBV-), 7.4 kg+/-8.5 kg (CI), 40 kg+/-108 kg (DeltaRBV+). Only BIS shows a satisfactorily low detection limit W(lim), whereas W(lim) was rated as critical for the VCD and DeltaRBV- methods, and as unacceptable for the CI and DeltaRBV+ methods. Bioimpedance spectroscopy appears to be the most promising method for a practical fluid management system in dialysis.

Adult↗

PubMed1997

Chronic lymphocytic leukemia: a changing natural history?

There are some data suggesting that the natural history of chronic lymphocytic leukemia (CLL) may be changing, but a systematic analysis of this topic is lacking. To address this issue, we examined two cohorts of CLL patients in whom the diagnosis was established in 1960-1979 (group I) and in 1980-1989 (group II), respectively. Striking differences were observed between both cohorts. The diagnosis in the second group was established at higher age (65.8 vs 61.3 years; P = 0.0001), both in males (63.8 vs 59.1 years; P = 0.004) and females (68.3 vs 64.2 years; P = 0.01); the proportion of patients in whom the diagnosis was established in low-risk clinical stage (Binet's A) was significantly higher in group II (65.7% vs 42.6%; P < 0.001), and the survival was more than double in group II (median of 11.1 vs 5.3 years; P < 0.0001). Moreover, the impact of the disease on life expectancy was much lower in the more recent cohort. These differences may be due, at least in part, to changes in the natural history of the disease.

Age Factors↗