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Biomedical subjects

Eran Segal

Publications and source records attributed to Eran Segal.

At least 19 recordsLinked to original sources
PubMed2024

Pangenomes of human gut microbiota uncover links between genetic diversity and stress response.

The genetic diversity of the gut microbiota has a central role in host health. Here, we created pangenomes for 728 human gut prokaryotic species, quadrupling the genes of strain-specific genomes. Each of these species has a core set of a thousand genes, differing even between closely related species, and an accessory set of genes unique to the different strains. Functional analysis shows high strain variability associates with sporulation, whereas low variability is linked with antibiotic resistance. We further map the antibiotic resistome across the human gut population and find 237 cases of extreme resistance even to last-resort antibiotics, with a predominance among Enterobacteriaceae. Lastly, the presence of specific genes in the microbiota relates to host age and sex. Our study underscores the genetic complexity of the human gut microbiota, emphasizing its significant implications for host health. The pangenomes and antibiotic resistance map constitute a valuable resource for further research.

Humans↗
PubMed2006

A genomic code for nucleosome positioning.

Eukaryotic genomes are packaged into nucleosome particles that occlude the DNA from interacting with most DNA binding proteins. Nucleosomes have higher affinity for particular DNA sequences, reflecting the ability of the sequence to bend sharply, as required by the nucleosome structure. However, it is not known whether these sequence preferences have a significant influence on nucleosome position in vivo, and thus regulate the access of other proteins to DNA. Here we isolated nucleosome-bound sequences at high resolution from yeast and used these sequences in a new computational approach to construct and validate experimentally a nucleosome-DNA interaction model, and to predict the genome-wide organization of nucleosomes. Our results demonstrate that genomes encode an intrinsic nucleosome organization and that this intrinsic organization can explain approximately 50% of the in vivo nucleosome positions. This nucleosome positioning code may facilitate specific chromosome functions including transcription factor binding, transcription initiation, and even remodelling of the nucleosomes themselves.

Base Sequence↗
PubMed2006

Evidence for an instructive mechanism of de novo methylation in cancer cells.

DNA methylation has a role in the regulation of gene expression during normal mammalian development but can also mediate epigenetic silencing of CpG island genes in cancer and other diseases. Many individual genes (including tumor suppressors) have been shown to undergo de novo methylation in specific tumor types, but the biological logic inherent in this process is not understood. To decipher this mechanism, we have adopted a new approach for detecting CpG island DNA methylation that can be used together with microarray technology. Genome-wide analysis by this technique demonstrated that tumor-specific methylated genes belong to distinct functional categories, have common sequence motifs in their promoters and are found in clusters on chromosomes. In addition, many are already repressed in normal cells. These results are consistent with the hypothesis that cancer-related de novo methylation may come about through an instructive mechanism.

Animals↗
PubMed2005

From signatures to models: understanding cancer using microarrays.

Genomics has the potential to revolutionize the diagnosis and management of cancer by offering an unprecedented comprehensive view of the molecular underpinnings of pathology. Computational analysis is essential to transform the masses of generated data into a mechanistic understanding of disease. Here we review current research aimed at uncovering the modular organization and function of transcriptional networks and responses in cancer. We first describe how methods that analyze biological processes in terms of higher-level modules can identify robust signatures of disease mechanisms. We then discuss methods that aim to identify the regulatory mechanisms underlying these modules and processes. Finally, we show how comparative analysis, combining human data with model organisms, can lead to more robust findings. We conclude by discussing the challenges of generalizing these methods from cells to tissues and the opportunities they offer to improve cancer diagnosis and management.

Algorithms↗
PubMed2005

Probabilistic discovery of overlapping cellular processes and their regulation.

In this paper, we explore modeling overlapping biological processes. We discuss a probabilistic model of overlapping biological processes, gene membership in those processes, and an addition to that model that identifies regulatory mechanisms controlling process activation. A key feature of our approach is that we allow genes to participate in multiple processes, thus providing a more biologically plausible model for the process of gene regulation. We present algorithms to learn each model automatically from data, using only genomewide measurements of gene expression as input. We compare our results to those obtained by other approaches and show that significant benefits can be gained by modeling both the organization of genes into overlapping cellular processes and the regulatory programs of these processes. Moreover, our method successfully grouped genes known to function together, recovered many regulatory relationships that are known in the literature, and suggested novel hypotheses regarding the regulatory role of previously uncharacterized proteins.

Computational Biology↗
PubMed2005

Assessing fluid-responsiveness by a standardized ventilatory maneuver: the respiratory systolic variation test.

Respiratory-induced changes in arterial blood pressure predict fluid responsiveness. However, the accuracy of these variables is affected by the preset tidal volume and by the early inspiratory increase in arterial blood pressure. We have therefore calculated the slope produced by the minimal systolic blood pressures (plotted against the respective airway pressures) during a ventilatory maneuver consisting of four incremental, successive, pressure-controlled breaths, termed the Respiratory Systolic Variation Test (RSVT). In 14 ventilated patients, after major vascular surgery, the slope of the RSVT decreased significantly after intravascular fluid administration and correlated with the end-diastolic area and with changes in cardiac output better than filling pressures. This preliminary study suggests that a standardized ventilatory maneuver may be useful in guiding fluid therapy in ventilated patients.

Body Fluids↗
PubMed2005

[Prevention of procedural pain in pediatric hematology-oncology].

Procedural pain includes any pain or discomfort inflicted by medical care or treatment. Procedural pain is the leading cause of pain and discomfort in children with malignancies. During the last five years the authors employed a multidisciplinary team including oncologists, anesthesiologists, nurses and ancillary and support staff, aiming to treat and minimize procedural pain. The research retrospectively studied the effectiveness of this approach in reducing pain. The authors also compared the advantages and disadvantages of their approach to different options described in the literature and available in other institutions.

Child↗
PubMed2004

A transcriptional profile of aging in the human kidney.

In this study, we found 985 genes that change expression in the cortex and the medulla of the kidney with age. Some of the genes whose transcripts increase in abundance with age are known to be specifically expressed in immune cells, suggesting that immune surveillance or inflammation increases with age. The age-regulated genes show a similar aging profile in the cortex and the medulla, suggesting a common underlying mechanism for aging. Expression profiles of these age-regulated genes mark not only age, but also the relative health and physiology of the kidney in older individuals. Finally, the set of aging-regulated kidney genes suggests specific mechanisms and pathways that may play a role in kidney degeneration with age.

Adult↗
PubMed2004

A module map showing conditional activity of expression modules in cancer.

DNA microarrays are widely used to study changes in gene expression in tumors, but such studies are typically system-specific and do not address the commonalities and variations between different types of tumor. Here we present an integrated analysis of 1,975 published microarrays spanning 22 tumor types. We describe expression profiles in different tumors in terms of the behavior of modules, sets of genes that act in concert to carry out a specific function. Using a simple unified analysis, we extract modules and characterize gene-expression profiles in tumors as a combination of activated and deactivated modules. Activation of some modules is specific to particular types of tumor; for example, a growth-inhibitory module is specifically repressed in acute lymphoblastic leukemias and may underlie the deregulated proliferation in these cancers. Other modules are shared across a diverse set of clinical conditions, suggestive of common tumor progression mechanisms. For example, the bone osteoblastic module spans a variety of tumor types and includes both secreted growth factors and their receptors. Our findings suggest that there is a single mechanism for both primary tumor proliferation and metastasis to bone. Our analysis presents multiple research directions for diagnostic, prognostic and therapeutic studies.

Databases, Genetic↗
PubMed2004

Disruption of yeast forkhead-associated cell cycle transcription by oxidative stress.

The effects of oxidative stress on yeast cell cycle depend on the stress-exerting agent. We studied the effects of two oxidative stress agents, hydrogen peroxide (HP) and the superoxide-generating agent menadione (MD). We found that two small coexpressed groups of genes regulated by the Mcm1-Fkh2-Ndd1 transcription regulatory complex are sufficient to account for the difference in the effects of HP and MD on the progress of the cell cycle, namely, G1 arrest with MD and an S phase delay followed by a G2/M arrest with HP. Support for this hypothesis is provided by fkh1fkh2 double mutants, which are affected by MD as we find HP affects wild-type cells. The apparent involvement of a forkhead protein in HP-induced cell cycle arrest, similar to that reported for Caenorhabditis elegans and human, describes a potentially novel stress response pathway in yeast.

Cell Cycle↗
PubMed2004

Sfp1 is a stress- and nutrient-sensitive regulator of ribosomal protein gene expression.

Yeast cells modulate their protein synthesis capacity in response to physiological needs through the transcriptional control of ribosomal protein (RP) genes. Here we demonstrate that the transcription factor Sfp1, previously shown to play a role in the control of cell size, regulates RP gene expression in response to nutrients and stress. Under optimal growth conditions, Sfp1 is localized to the nucleus, bound to the promoters of RP genes, and helps promote RP gene expression. In response to inhibition of target of rapamycin (TOR) signaling, stress, or changes in nutrient availability, Sfp1 is released from RP gene promoters and leaves the nucleus, and RP gene transcription is down-regulated. Additionally, cells lacking Sfp1 fail to appropriately modulate RP gene expression in response to environmental cues. We conclude that Sfp1 integrates information from nutrient- and stress-responsive signaling pathways to help control RP gene expression.

Cyclic AMP-Dependent Protein Kinases↗
PubMed2004

Perianesthetic dental injuries: analysis of incident reports.

STUDY OBJECTIVE: To conduct a retrospective analysis of incident reports concerning dental injury, the most common cause for litigation against anesthesiologists, to determine specific risk factors that will help in formulating a risk reduction strategy for this clinical problem. DESIGN: Retrospective chart review of a large professional liability insurer. INTERVENTIONS: Of 40 hospitals that report to the MRM Co. as part of the professional liability insurance, during the years 1992-1999, 18 hospitals reported dental injury. A Maxillofacial surgeon (GN) and an anesthesiologist (ES), using a structured form, reviewed the reports. Evaluation of the cost of injury was determined from the patient's claims or from an evaluation of rehabilitation plan constructed by the maxillofacial surgery consultants to the company. MEASUREMENTS AND MAIN RESULTS: There were 203 incidents due to dental injury. The patients were most commonly in their 5(th) to 7(th) decade. Eighty six percent of the injured teeth were the upper incisors. Lower incisors were more likely to be injured during an urgent intubation, or due to airway manipulation other than intubation. (i.e., oral airway insertion) In only 38 (18.6%) cases was there a previous assessment of an expected difficult intubation. Dentition was judged to be pathological in 32% of the patients. CONCLUSIONS: In elective intubation, the teeth most likely to be injured are the upper incisors, in patients aged 50-70 years. In most cases dental injury is not associated with a pre-event prediction of difficult intubation.

Adolescent↗
PubMed2004

Monitoring intravascular volumes to direct hypertensive, hypervolemic therapy in a patient with vasospasm.

The common therapeutic approach to patients, who develop vasospasm following subarachnoid hemorrhage, is usually composed of hypertension, hypervolemia, and hemodilution (HHH). This therapy often leads to cardiopulmonary complications, including significant heart failure and pulmonary edema. We describe a 40-year-old woman who developed vasospasm 8 days after surgery for clipping an aneurysm, following a large subarachnoid hemorrhage. The patient required HHH therapy with a very high blood pressure to optimize her clinical neurologic status, but she started to develop pulmonary edema resulting from this therapy. This manifested as a need for increasing oxygen to maintain a normal arterial saturation. To avoid further hemodynamic compromise, we used a new monitor of cardiac function to measure intravascular volumes and quantify pulmonary edema to help titrate the fluid management of a patient in severe vasospasm. We conclude that monitoring volumes with the PiCCO cardiac monitor can help make clinical decisions in patients requiring HHH. This enables maintaining a hypertensive and hypervolemic state while avoiding cardiopulmonary complications such as heart failure and pulmonary edema. It may also help prevent the need for mechanical ventilation in these situations.

Adult↗
PubMed2004

Accuracy of transpulmonary thermodilution versus gravimetric measurement of extravascular lung water.

OBJECTIVE: Pulmonary edema is a severe and often life-threatening condition. The diagnosis of pulmonary edema and its quantification have great clinical significance and yet can be difficult. A new technique based on thermodilution measurement using a single indicator has recently been developed (PiCCO, Pulsion Medical Systems, AG Germany). This method allows the measurement of extravascular lung water and thus can quantify degree of pulmonary edema. The technique has not been compared with a gold standard, gravimetric measurement of extravascular lung water. Therefore, the objective of this study was to determine the ability of extravascular lung water measurement with the PiCCO to reflect the extravascular lung water as measured with a gravimetric technique in a dog model of pulmonary edema. DESIGN: Prospective, randomized animal study. SETTING: A university animal research laboratory. SUBJECTS: Fifteen mongrel dogs (n = 5/group) weighing 20-30 kg. INTERVENTIONS: The dogs were anesthetized and mechanically ventilated. Five dogs served as controls; in five dogs hydrostatic pulmonary edema was induced using inflation of a left atrial balloon combined with fluid administration to maintain a high pulmonary artery occlusion pressure; and in five dogs pulmonary edema was induced by intravenous injection of oleic acid. After a period of stabilization in a state of pulmonary edema, extravascular lung water was measured with the PiCCO monitor. The animals were then killed, and extravascular lung water was measured using a gravimetric technique. MEASUREMENTS AND MAIN RESULTS: There was a very close (r =.967, p <.001) relationship between transpulmonary thermodilution and gravimetric measurements. The measurement with the PiCCO was consistently higher, by 3.01 +/- 1.34 mL/kg, than the gravimetric measurement. CONCLUSIONS: Measurement of extravascular lung water using transpulmonary thermodilution with a single indicator is very closely correlated with gravimetric measurement of lung water in both increased permeability and hydrostatic pulmonary edema.

Animals↗
PubMed2003

A gene-coexpression network for global discovery of conserved genetic modules.

To elucidate gene function on a global scale, we identified pairs of genes that are coexpressed over 3182 DNA microarrays from humans, flies, worms, and yeast. We found 22,163 such coexpression relationships, each of which has been conserved across evolution. This conservation implies that the coexpression of these gene pairs confers a selective advantage and therefore that these genes are functionally related. Many of these relationships provide strong evidence for the involvement of new genes in core biological functions such as the cell cycle, secretion, and protein expression. We experimentally confirmed the predictions implied by some of these links and identified cell proliferation functions for several genes. By assembling these links into a gene-coexpression network, we found several components that were animal-specific as well as interrelationships between newly evolved and ancient modules.

Animals↗
PubMed2003

The modular era of functional genomics.

A report on the Keystone Symposium 'Functional Genomics: Global Analysis of Complex Biological Systems', Santa Fe, USA, 20-24 February 2003.

Gene Expression Regulation↗
PubMed2003

Module networks: identifying regulatory modules and their condition-specific regulators from gene expression data.

Much of a cell's activity is organized as a network of interacting modules: sets of genes coregulated to respond to different conditions. We present a probabilistic method for identifying regulatory modules from gene expression data. Our procedure identifies modules of coregulated genes, their regulators and the conditions under which regulation occurs, generating testable hypotheses in the form 'regulator X regulates module Y under conditions W'. We applied the method to a Saccharomyces cerevisiae expression data set, showing its ability to identify functionally coherent modules and their correct regulators. We present microarray experiments supporting three novel predictions, suggesting regulatory roles for previously uncharacterized proteins.

Algorithms↗