Browse Health
Radiologist
6 years of experience

Education ?

Medical School Score Rankings
Harvard University (2004)
  • Currently 4 of 4 apples
Top 25%

Awards & Distinctions ?

Associations
American Board of Radiology

Affiliations ?

Dr. Kamath is affiliated with 3 hospitals.

Hospital Affilations

Score

Rankings

  • Brigham and Women's Hospital
    75 Francis St, Boston, MA 02115
    • Currently 4 of 4 crosses
    Top 25%
  • Massachusetts General Hospital
    55 Fruit St, Boston, MA 02114
    • Currently 4 of 4 crosses
    Top 25%
  • Massachusetts Eye And Ear Infirmary
    243 Charles St, Boston, MA 02114
  • Publications & Research

    Dr. Kamath has contributed to 26 publications.
    Title Case Records of the Massachusetts General Hospital. Case 33-2011. A 56-year-old Man with Hypophosphatemia.
    Date November 2011
    Journal The New England Journal of Medicine
    Title Improvement in Hematological, Visceral, and Skeletal Manifestations of Gaucher Disease Type 1 with Oral Eliglustat Tartrate (genz-112638) Treatment: 2-year Results of a Phase 2 Study.
    Date December 2010
    Journal Blood
    Excerpt

    Eliglustat tartrate is an investigational oral substrate reduction therapy for Gaucher disease type 1 that is pharmacologically distinct from intravenous enzyme replacement therapy. Eliglustat tartrate improved clinical manifestations in patients who received 50 or 100 mg twice daily for 1 year during an open-label phase 2 study (Blood. 2010;116(6):893-899). We report further improvements after 2 years of treatment in 20 patients (11 females, 9 males; mean age, 33 years) with baseline splenomegaly and thrombocytopenia and/or anemia. Statistically significant (P < .001) percentage improvements from baseline occurred in platelet count (mean ± SD, 81% ± 56%), hemoglobin level (20% ± 15%), spleen volume (-52% ± 11%), and liver volume (-24% ± 13%). Mean platelet count increased ∼ 50 000/mm(3). Mean hemoglobin level increased 2.1 g/dL overall and 3.1 g/dL in 10 patients with baseline anemia. Organ volume reductions were greatest in patients with severe baseline organomegaly. Seventeen (85%) patients met established therapeutic goals for ≥ 3 of the 4 parameters. Lumbar spine bone mineral density increased 7.8% ± 10.6% (P = .01) and T-score 0.6 ± 0.8 (P = .012), with major gains in osteoporotic and osteopenic patients. Magnetic resonance imaging assessment showed that bone marrow infiltration by Gaucher cells was decreased (8/18 patients) or stable (10/18 patients). No safety-related trends emerged during 2 years of treatment. This multisite, open-label, single-arm phase 2 study is registered at www.clinicaltrials.gov as NCT00358150.

    Title The Year in Review: Recent Advances in Musculoskeletal Radiology and Biology.
    Date April 2010
    Journal Skeletal Radiology
    Title Genome-wide Rnai of C. Elegans Using the Hypersensitive Rrf-3 Strain Reveals Novel Gene Functions.
    Date January 2006
    Journal Plos Biology
    Excerpt

    RNA-mediated interference (RNAi) is a method to inhibit gene function by introduction of double-stranded RNA (dsRNA). Recently, an RNAi library was constructed that consists of bacterial clones expressing dsRNA, corresponding to nearly 90% of the 19,427 predicted genes of C. elegans. Feeding of this RNAi library to the standard wild-type laboratory strain Bristol N2 detected phenotypes for approximately 10% of the corresponding genes. To increase the number of genes for which a loss-of-function phenotype can be detected, we undertook a genome-wide RNAi screen using the rrf-3 mutant strain, which we found to be hypersensitive to RNAi. Feeding of the RNAi library to rrf-3 mutants resulted in additional loss-of-function phenotypes for 393 genes, increasing the number of genes with a phenotype by 23%. These additional phenotypes are distributed over different phenotypic classes. We also studied interexperimental variability in RNAi results and found persistent levels of false negatives. In addition, we used the RNAi phenotypes obtained with the genome-wide screens to systematically clone seven existing genetic mutants with visible phenotypes. The genome-wide RNAi screen using rrf-3 significantly increased the functional data on the C. elegans genome. The resulting dataset will be valuable in conjunction with other functional genomics approaches, as well as in other model organisms.

    Title Somatic Misexpression of Germline P Granules and Enhanced Rna Interference in Retinoblastoma Pathway Mutants.
    Date August 2005
    Journal Nature
    Excerpt

    Caenorhabditis elegans homologues of the retinoblastoma (Rb) tumour suppressor complex specify cell lineage during development. Here we show that mutations in Rb pathway components enhance RNA interference (RNAi) and cause somatic cells to express genes and elaborate perinuclear structures normally limited to germline-specific P granules. Furthermore, particular gene inactivations that disrupt RNAi reverse the cell lineage transformations of Rb pathway mutants. These findings suggest that mutations in Rb pathway components cause cells to revert to patterns of gene expression normally restricted to germ cells. Rb may act by a similar mechanism to transform mammalian cells.

    Title Functional Genomic Analysis of Rna Interference in C. Elegans.
    Date May 2005
    Journal Science (new York, N.y.)
    Excerpt

    RNA interference (RNAi) of target genes is triggered by double-stranded RNAs (dsRNAs) processed by conserved nucleases and accessory factors. To identify the genetic components required for RNAi, we performed a genome-wide screen using an engineered RNAi sensor strain of Caenorhabditis elegans. The RNAi screen identified 90 genes. These included Piwi/PAZ proteins, DEAH helicases, RNA binding/processing factors, chromatin-associated factors, DNA recombination proteins, nuclear import/export factors, and 11 known components of the RNAi machinery. We demonstrate that some of these genes are also required for germline and somatic transgene silencing. Moreover, the physical interactions among these potential RNAi factors suggest links to other RNA-dependent gene regulatory pathways.

    Title Thromboembolic Events in Patients Treated with Definitive Chemotherapy and Radiation Therapy for Invasive Cervical Cancer.
    Date March 2005
    Journal Gynecologic Oncology
    Excerpt

    OBJECTIVES: Determine the incidence of and risk factors for thromboembolic events (TE) in patients treated with definitive chemoradiation for cervical cancer at our institution. METHODS: A retrospective chart review was performed of all patients with a diagnosis of invasive carcinoma of the cervix (FIGO Stage IB-IVA) treated with definitive chemoradiation at University of Iowa Hospitals and Clinics (UIHC) from July 2002 to December 2003. Forty-eight patients met these criteria. All but one patient received 45 Gy to the pelvis followed by brachytherapy, IMRT, or conformal boost. One patient received 39.6 Gy to the pelvis. Cisplatin chemotherapy, 40 mg/m squared, was given weekly for 6 weeks. Data were collected for FIGO stage, age, body mass index (BMI), and smoking history. TE were confirmed by Doppler ultrasound or pulmonary imaging. Log-rank tests were used to examine the association between time to TE and the variables FIGO stage and smoking status. The association between time to TE and the continuous variables age and BMI was examined with Cox proportional hazards regression. All tests were two-sided and carried out to the 5% level of significance using the SAS statistical software package. RESULTS: Minimum follow-up was 8 months. Eight patients (16.7%) developed a TE. The associations were not statistically significant for stage (P = 0.72), smoking status (P = 0.72), age (P = 0.63) or BMI (P = 0.86). Risk factors were similar in both groups. Data review suggests that the entire group had risk factors for TE. CONCLUSIONS: We noted a high incidence of TE (16.7%) in patients treated at UIHC with chemoradiation for invasive cervical cancer. We did not find a statistical association between age, stage, smoking history, or BMI and risk of TE in this group. Patients with and without TE had multiple risk factors for TE.

    Title Genome-wide Rnai Identifies P53-dependent and -independent Regulators of Germ Cell Apoptosis in C. Elegans.
    Date March 2005
    Journal Cell Death and Differentiation
    Excerpt

    We used genome-wide RNA interference (RNAi) to identify genes that affect apoptosis in the C. elegans germ line. RNAi-mediated knockdown of 21 genes caused a moderate to strong increase in germ cell death. Genetic epistasis studies with these RNAi candidates showed that a large subset (16/21) requires p53 to activate germ cell apoptosis. Apoptosis following knockdown of the genes in the p53-dependent class also depended on a functional DNA damage response pathway, suggesting that these genes might function in DNA repair or to maintain genome integrity. As apoptotic pathways are conserved, orthologues of the worm germline apoptosis genes presented here could be involved in the maintenance of genomic stability, p53 activation, and fertility in mammals.

    Title Sixteen-detector Row Ct of Abdomen and Pelvis: Study for Optimization of Z-axis Modulation Technique Performed in 153 Patients.
    Date November 2004
    Journal Radiology
    Excerpt

    PURPOSE: To retrospectively determine the optimal noise indexes required to obtain diagnostically acceptable computed tomographic (CT) images of the abdomen and pelvis with z-axis modulation. MATERIALS AND METHODS: Ninety-five patients underwent 16-section multi-detector row CT of the abdomen and pelvis with z-axis modulation at noise indexes of 10.5, 11.0, 11.5, and 12.0 HU with 10-380 mA. Subsequently, 58 patients were scanned at noise indexes of 12.5 and 15.0 HU with 75-380 mA. The weights of all subjects were recorded, and transverse and anteroposterior diameters were measured. The CT images were evaluated for abnormalities and graded for image quality in terms of noise and diagnostic acceptability by using a five-point scale. Objective noise in the liver parenchyma was measured, and the tube current was recorded at each section in all 153 patients. Statistical analyses were performed to determine the appropriate noise index and to assess the effect of patient weight and abdominal diameters on image noise and diagnostic acceptability at different noise indexes. Tube current-time products (in milliampere seconds) at various noise indexes were compared with those at CT previously performed without z-axis modulation. RESULTS: No significant difference in subjective image noise or diagnostic acceptability was found at noise indexes of 10.5-15.0 HU (P =.14), and objective noise was significantly inferior only at a noise index of 15.0 HU (P =.009). Compared with CT scanning at a 10.5-HU noise index, CT scanning at 12.5- and 15.0-HU noise indexes yielded, respectively, 10.0% and 41.3% reductions in radiation exposure. Patient weight and abdominal diameters affected subjective image quality. CONCLUSION: Use of a 15.0-HU noise index at 75-380 mA results in acceptable subjective image noise and diagnostic acceptability but significantly greater objective image noise at routine abdominal-pelvic CT. For greater image quality demands, a noise index of 12.5 HU results in acceptable image quality and a 19.6% reduction in radiation exposure.

    Title Comparison of Z-axis Automatic Tube Current Modulation Technique with Fixed Tube Current Ct Scanning of Abdomen and Pelvis.
    Date September 2004
    Journal Radiology
    Excerpt

    PURPOSE: To compare image quality, diagnostic acceptability, and radiation exposure associated with 16-section multi-detector row computed tomographic (CT) examinations of abdomen and pelvis performed with z-axis modulation technique of automatic tube current modulation and with manual selection of fixed tube current. MATERIALS AND METHODS: Sixty-two consecutive subjects (mean age, 60 years; age range, 19-84 years; male-to-female ratio, 35:27) underwent follow-up CT of abdomen and pelvis with use of a 16-section multi-detector row scanner and z-axis modulation technique (10.5-12.0-HU noise index, 10-380 mA). Scanning parameters included 140 kVp, 0.5-1.0-second gantry rotation time, 0.938:1 beam pitch, and 5-mm reconstructed section thickness. For each subject, images obtained with z-axis modulation were compared with previous images obtained with fixed tube current (200-300 mA) and with other parameters identical. Images were compared for noise and diagnostic acceptability by two subspecialty radiologists using a five-point scale (1, unacceptable; 3, acceptable; 5, excellent) at five levels: upper liver at diaphragm, porta hepatis, right kidney hilum, iliac crest, and upper margin of acetabulum. Tube current and gantry rotation time used for acquisitions at these levels were recorded. Data were analyzed with parametric and nonparametric statistical tests. RESULTS: Although no significant differences were found (P =.34), images acquired with z-axis modulation at the levels of the upper liver (diaphragm) and acetabulum had a higher noise and lower diagnostic quality, compared with images acquired with fixed tube current. Compared with fixed tube current, z-axis modulation resulted in tube current-time product reduction in 54 (87%) of 62 examinations (mean reduction, 71.2 mAs) and increase in eight (13%) (mean increase, 17.0 mAs). CONCLUSION: Compared with manually selected fixed tube current, z-axis automatic tube current modulation resulted in reduced tube current-time product and similar image noise and diagnostic acceptability at CT of abdomen and pelvis.

    Title Radiation from "extra" Images Acquired with Abdominal And/or Pelvic Ct: Effect of Automatic Tube Current Modulation.
    Date September 2004
    Journal Radiology
    Excerpt

    PURPOSE: To retrospectively determine the number and usefulness of images acquired beyond the intended anatomic area of interest with abdominal and/or pelvic computed tomography (CT) and to assess the effect of automatic tube current modulation (ATCM) on associated radiation. MATERIALS AND METHODS: Superior and inferior levels at routine abdominal and/or pelvic CT were defined as the dome of the diaphragm and the inferior margin of the pubic symphysis, respectively. Records of 106 consecutive examinations (male-to-female ratio, 45:61; age range, 21-86 years) performed from June 1 to June 30, 2003, were reviewed to determine the number of "extra" images. Sixty-two abdominal and/or pelvic CT examinations performed concurrently with chest or thigh CT or for trauma were not included in the 106. Abdominal and/or pelvic CT was performed with either ATCM (n = 44) or manual selection of tube current (n = 62). CT parameters recorded for each extra image included tube current, peak kilovoltage, and gantry rotation time. Mean and median tube current-time products were calculated for extra images. Extra images were analyzed for pathologic findings. Statistical analysis was performed with the Student t test. RESULTS: Extra images were acquired above the dome of the diaphragm in 103 (97%) of 106 examinations and below the pubic symphysis in 100 (94%) of 106. A total of 1,280 extra images were acquired in 106 examinations (mean, 12 images per examination). Nineteen additional findings were observed on extra images. With ATCM, mean tube current-time product was 74.5 and 120.6 mAs for extra images acquired above the diaphragm and below the pubic symphysis, respectively; with manual selection, mean tube current-time products were 167.5 and 168.3 mAs (P <.05). CONCLUSION: Most extra images acquired at abdominal and/or pelvic CT contributed no additional information. With ATCM, the radiation dose was reduced by a mean of 56% (median, 72%) for extra images above the diaphragm and 29% (median, 36%) for images below the pubic symphysis, compared with dose levels with manual selection.

    Title Genome-wide Rnai Screening in Caenorhabditis Elegans.
    Date February 2004
    Journal Methods (san Diego, Calif.)
    Excerpt

    In Caenorhabditis elegans, introduction of double-stranded RNA (dsRNA) results in the specific inactivation of an endogenous gene with corresponding sequence; this technique is known as RNA interference (RNAi). It has previously been shown that RNAi can be performed by direct microinjection of dsRNA into adult hermaphrodite worms, by soaking worms in a solution of dsRNA, or by feeding worms Escherichia coli expressing target-gene dsRNA. We have developed a simple optimized protocol exploiting this third mode of dsRNA introduction, RNAi by feeding, which allows rapid and effective analysis of gene function in C. elegans. Furthermore, we have constructed a library of bacterial strains corresponding to roughly 86% of the estimated 19,000 predicted genes in C. elegans, and we have used it to perform genome-wide analyses of gene function. This library is publicly available, reusable resource allowing for rapid large-scale RNAi experiments. We have used this library to perform genome-wide analyses of gene function in C. elegans. Here, we describe the protocols used for bacterial library construction and for high-throughput screening in C. elegans using RNAi by feeding.

    Title A Genome-wide Screen Identifies 27 Genes Involved in Transposon Silencing in C. Elegans.
    Date January 2004
    Journal Current Biology : Cb
    Excerpt

    Transposon jumps are a major cause of genome instability. In the C. elegans strain Bristol N2, transposons are active in somatic cells, but they are silenced in the germline, presumably to protect the germline from mutations. Interestingly, the transposon-silencing mechanism shares factors with the RNAi machinery. To better understand the mechanism of transposon silencing, we performed a genome-wide RNAi screen for genes that, when silenced, cause transposition of Tc1 in the C. elegans germline. We identified 27 such genes, among which are mut-16, a mutator that was previously found but not identified at the molecular level, ppw-2, a member of the argonaute family, and several factors that indicate a role for chromatin structure in the regulation of transposition. Some of the newly identified genes are also required for cosuppression and therefore represent the shared components of the two pathways. Since most of the newly identified genes have clear homologs in other species, and since transposons are found from protozoa to human, it seems likely that they also protect other genomes against transposon activity in the germline.

    Title Genes That Act Downstream of Daf-16 to Influence the Lifespan of Caenorhabditis Elegans.
    Date July 2003
    Journal Nature
    Excerpt

    Ageing is a fundamental, unsolved mystery in biology. DAF-16, a FOXO-family transcription factor, influences the rate of ageing of Caenorhabditis elegans in response to insulin/insulin-like growth factor 1 (IGF-I) signalling. Using DNA microarray analysis, we have found that DAF-16 affects expression of a set of genes during early adulthood, the time at which this pathway is known to control ageing. Here we find that many of these genes influence the ageing process. The insulin/IGF-I pathway functions cell non-autonomously to regulate lifespan, and our findings suggest that it signals other cells, at least in part, by feedback regulation of an insulin/IGF-I homologue. Furthermore, our findings suggest that the insulin/IGF-I pathway ultimately exerts its effect on lifespan by upregulating a wide variety of genes, including cellular stress-response, antimicrobial and metabolic genes, and by downregulating specific life-shortening genes.

    Title Identification of Genes That Protect the C. Elegans Genome Against Mutations by Genome-wide Rnai.
    Date March 2003
    Journal Genes & Development
    Excerpt

    An RNA interference (RNAi)-based genome-wide screen was performed to detect genes that contribute to genome stability in somatic cells of Caenorhabditis elegans. We identified 61 such genes; these also affect spontaneous mutagenesis in the germ line. Their sequence suggests a role in DNA repair and/or replication, in chromatin remodeling, or in cell cycle control; there are also many novel genes that are highly conserved from yeast to human. Because known mutator genes are causally involved in many hereditary and sporadic human cancers, it is likely that some of these new mutators are equally relevant in cancer etiology.

    Title Genetic Analysis of Tissue Aging in Caenorhabditis Elegans: a Role for Heat-shock Factor and Bacterial Proliferation.
    Date March 2003
    Journal Genetics
    Excerpt

    The genetic analysis of life span has revealed many interesting genes and pathways; however, our understanding of aging has been limited by the lack of a way to assay the aging process itself. Here we show that the tissues of aging worms have a characteristic appearance that is easy to recognize and quantify using Nomarski optics. We have used this assay to determine whether life-span mutations affect the rate of aging, to identify animals that age more rapidly than normal, and to infer the cause of death in C. elegans. Mutations that reduce insulin/IGF-1 signaling double the life span of C. elegans, and we find that tissue decline is slowed in these mutants. Thus this endocrine system appears to influence the rate at which tissues age. This effect extends even to the germline, which is the only mitotically active tissue in the adult. We find that Nomarski microscopy also allows a ready distinction between short-lived mutants that age more rapidly than normal and those that are simply sick, and we have identified an RNAi clone that confers a dramatic rapid-aging phenotype. This clone encodes the C. elegans heat-shock factor (HSF), a transcription factor that regulates the response to heat and oxidative stress. This suggests that heat-shock proteins, many of which act as chaperones, may function in normal animals to slow the rate of aging. Finally, we have identified a cause of death of C. elegans: namely, proliferating bacteria. This suggests that increased susceptibility to bacterial infections contributes to mortality in these animals, just as it does in humans.

    Title Systematic Functional Analysis of the Caenorhabditis Elegans Genome Using Rnai.
    Date February 2003
    Journal Nature
    Excerpt

    A principal challenge currently facing biologists is how to connect the complete DNA sequence of an organism to its development and behaviour. Large-scale targeted-deletions have been successful in defining gene functions in the single-celled yeast Saccharomyces cerevisiae, but comparable analyses have yet to be performed in an animal. Here we describe the use of RNA interference to inhibit the function of approximately 86% of the 19,427 predicted genes of C. elegans. We identified mutant phenotypes for 1,722 genes, about two-thirds of which were not previously associated with a phenotype. We find that genes of similar functions are clustered in distinct, multi-megabase regions of individual chromosomes; genes in these regions tend to share transcriptional profiles. Our resulting data set and reusable RNAi library of 16,757 bacterial clones will facilitate systematic analyses of the connections among gene sequence, chromosomal location and gene function in C. elegans.

    Title Genome-wide Rnai Analysis of Caenorhabditis Elegans Fat Regulatory Genes.
    Date February 2003
    Journal Nature
    Excerpt

    Regulation of body fat storage involves signalling between centres that regulate feeding in the brain and sites of fat storage and use in the body. Here we describe an assay for analysing fat storage and mobilization in living Caenorhabditis elegans. By using RNA-mediated interference (RNAi) to disrupt the expression of each of the 16,757 worm genes, we have systematically screened the C. elegans genome for genes necessary for normal fat storage. We identify 305 gene inactivations that cause reduced body fat and 112 gene inactivations that cause increased fat storage. Analysis of the fat-reducing gene inactivations in insulin, serotonin and tubby signalling mutants of C. elegans, which have increased body fat, identifies a core set of fat regulatory genes as well as pathway-specific fat regulators. Many of the newly identified worm fat regulatory genes have mammalian homologues, some of which are known to function in fat regulation. Other C. elegans fat regulatory genes that are conserved across animal phylogeny, but have not previously been implicated in fat storage, may point to ancient and universal features of fat storage regulation, and identify targets for treating obesity and its associated diseases.

    Title A Systematic Rnai Screen Identifies a Critical Role for Mitochondria in C. Elegans Longevity.
    Date January 2003
    Journal Nature Genetics
    Excerpt

    We report a systematic RNA interference (RNAi) screen of 5,690 Caenorhabditis elegans genes for gene inactivations that increase lifespan. We found that genes important for mitochondrial function stand out as a principal group of genes affecting C. elegans lifespan. A classical genetic screen identified a mutation in the mitochondrial leucyl-tRNA synthetase gene (lrs-2) that impaired mitochondrial function and was associated with longer-lifespan. The long-lived worms with impaired mitochondria had lower ATP content and oxygen consumption, but differential responses to free-radical and other stresses. These data suggest that the longer lifespan of C. elegans with compromised mitochrondria cannot simply be assigned to lower free radical production and suggest a more complex coupling of metabolism and longevity.

    Title Rates of Behavior and Aging Specified by Mitochondrial Function During Development.
    Date January 2003
    Journal Science (new York, N.y.)
    Excerpt

    To explore the role of mitochondrial activity in the aging process, we have lowered the activity of the electron transport chain and adenosine 5'-triphosphate (ATP) synthase with RNA interference (RNAi) in Caenorhabditis elegans. These perturbations reduced body size and behavioral rates and extended adult life-span. Restoring messenger RNA to near-normal levels during adulthood did not elevate ATP levels and did not correct any of these phenotypes. Conversely, inhibiting respiratory-chain components during adulthood only did not reset behavioral rates and did not affect life-span. Thus, the developing animal appears to contain a regulatory system that monitors mitochondrial activity early in life and, in response, establishes rates of respiration, behavior, and aging that persist during adulthood.

    Title Effectiveness of Specific Rna-mediated Interference Through Ingested Double-stranded Rna in Caenorhabditis Elegans.
    Date October 2001
    Journal Genome Biology
    Excerpt

    BACKGROUND: In Caenorhabditis elegans, injection of double-stranded RNA (dsRNA) results in the specific inactivation of genes containing homologous sequences, a technique termed RNA-mediated interference (RNAi). It has previously been shown that RNAi can also be achieved by feeding worms Escherichia coli expressing dsRNA corresponding to a specific gene; this mode of dsRNA introduction is conventionally considered to be less efficient than direct injection, however, and has therefore seen limited use, even though it is considerably less labor-intensive. RESULTS: Here we present an optimized feeding method that results in phenotypes at least as strong as those produced by direct injection of dsRNA for embryonic lethal genes, and stronger for genes with post-embryonic phenotypes. In addition, the interference effect generated by feeding can be titrated to uncover a series of hypomorphic phenotypes informative about the functions of a given gene. Using this method, we screened 86 random genes on consecutive cosmids and identified functions for 13 new genes. These included two genes producing an uncoordinated phenotype (a previously uncharacterized POU homeodomain gene, ceh-6, and a gene encoding a MADS-box protein) and one gene encoding a novel protein that results in a high-incidence-of-males phenotype. CONCLUSIONS: RNAi by feeding can provide significant information about the functions of an individual gene beyond that provided by injection. Moreover, it can be used for special applications for which injection or the use of mutants is sometimes impracticable (for example, titration, biochemistry and large-scale screening). Thus, RNAi by feeding should make possible new experimental approaches for the use of genomic sequence information.

    Title Roles for 147 Embryonic Lethal Genes on C.elegans Chromosome I Identified by Rna Interference and Video Microscopy.
    Date September 2001
    Journal The Embo Journal
    Excerpt

    Early embryonic development involves complex events such as the regulation of cell division and the establishment of embryonic polarity. To identify genes involved in these events, we collected four-dimensional time-lapse video recordings of the first three cell divisions and analysed terminal phenotypes after RNA interference of 147 embryonic lethal genes previously identified in a systematic screen of Caenorhabditis elegans chromosome I. Over half gave defects in early processes such as meiosis, the assembly or position of the first mitotic spindle, cytokinesis, and proper nuclear positioning. For some phenotypic classes, the majority of genes are involved in a shared biochemical process. In addition, we identified loss-of-function phenotypes for genes of unknown function, but for which homologues exist in other organisms, shedding light on the function of these uncharacterized genes. When applied to the whole genome, this approach should identify the vast majority of genes required for early cell processes, paving the way for a greatly improved understanding of these processes and their regulation at the molecular level.

    Title Functional Genomic Analysis of C. Elegans Chromosome I by Systematic Rna Interference.
    Date December 2000
    Journal Nature
    Excerpt

    Complete genomic sequence is known for two multicellular eukaryotes, the nematode Caenorhabditis elegans and the fruit fly Drosophila melanogaster, and it will soon be known for humans. However, biological function has been assigned to only a small proportion of the predicted genes in any animal. Here we have used RNA-mediated interference (RNAi) to target nearly 90% of predicted genes on C. elegans chromosome I by feeding worms with bacteria that express double-stranded RNA. We have assigned function to 13.9% of the genes analysed, increasing the number of sequenced genes with known phenotypes on chromosome I from 70 to 378. Although most genes with sterile or embryonic lethal RNAi phenotypes are involved in basal cell metabolism, many genes giving post-embryonic phenotypes have conserved sequences but unknown function. In addition, conserved genes are significantly more likely to have an RNAi phenotype than are genes with no conservation. We have constructed a reusable library of bacterial clones that will permit unlimited RNAi screens in the future; this should help develop a more complete view of the relationships between the genome, gene function and the environment.

    Title Mutational and Structural Analysis of the Lectin Activity in Binding Domain 2 of Ricin B Chain.
    Date March 1995
    Journal Protein Engineering
    Excerpt

    The study of the lectin binding sites of ricin B chain and of other homologous members of the small gene family that make up ricin-like molecules has revealed a number of key contact residues involved in sugar binding. In particular, on the basis of data generated by the X-ray crystallographic structure of ricin, comparisons of sequence homologies to other ricin-like molecules and substrate binding studies with these molecules, it has been proposed that His248 of Ricinus communis agglutinin (RCA) B chain may interfere with galactose binding in the second binding domain of that lectin. To test that hypothesis, single binding domain 2 (SBD2) of ricin B chain was expressed as a gene 3 fusion protein on the surface of fd phage to measure directly the effect of mutational changes on this binding site. Replacement of tyrosine with histidine at amino acid position 248 of SBD2 of ricin B chain was shown to reduce lectin activity. The sequences of RCA and ricin B chains were aligned and compared with the tertiary structure of ricin B chain to select various mutations that were introduced as controls in the study. One of these controls, Leu247 to Val247, displayed increased affinity for galactosides. The role of sequence changes is discussed in relation to the structural and functional divergence in these molecules.

    Title Growth of Yeast Colonies on Solid Media.
    Date September 1989
    Journal Journal of General Microbiology
    Excerpt

    Colonies on nutrient agar of the aerobic yeast Candida utilis show linear increases in diameter and height with time throughout most of the growth cycle. The concentration of glucose in the agar has a negligible effect on radial growth rate although an increase in the glucose concentration prolongs the linear radial growth phase. The rate of increase in height of the colony is proportional to the square root of the initial glucose concentration. A new model that considers both glucose diffusion and oxygen diffusion in the colony is consistent with the observed colony profiles.

    Title The Year in Review: Recent Advances in Musculoskeletal Radiology and Biology.
    Date
    Journal Skeletal Radiology

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