Showing papers by "University of Lausanne published in 2004"

Postoperative Irradiation With or Without Concomitant Chemotherapy for Locally Advanced Head and Neck Cancer

Abstract: background We compared concomitant cisplatin and irradiation with radiotherapy alone as adjuvant treatment for stage III or IV head and neck cancer. methods After undergoing surgery with curative intent, 167 patients were randomly assigned to receive radiotherapy alone (66 Gy over a period of 6 1 ⁄ 2 weeks) and 167 to receive the same radiotherapy regimen combined with 100 mg of cisplatin per square meter of body-surface area on days 1, 22, and 43 of the radiotherapy regimen. results After a median follow-up of 60 months, the rate of progression-free survival was significantly higher in the combined-therapy group than in the group given radiotherapy alone (P=0.04 by the log-rank test; hazard ratio for disease progression, 0.75; 95 percent confidence interval, 0.56 to 0.99), with 5-year Kaplan–Meier estimates of progression-free survival of 47 percent and 36 percent, respectively. The overall survival rate was also significantly higher in the combined-therapy group than in the radiotherapy group (P=0.02 by the log-rank test; hazard ratio for death, 0.70; 95 percent confidence interval, 0.52 to 0.95), with five-year Kaplan–Meier estimates of overall survival of 53 percent and 40 percent, respectively. The cumulative incidence of local or regional relapses was significantly lower in the combined-therapy group (P=0.007). The estimated five-year cumulative incidence of local or regional relapses (considering death from other causes as a competing risk) was 31 percent after radiotherapy and 18 percent after combined therapy. Severe (grade 3 or higher) adverse effects were more frequent after combined therapy (41 percent) than after radiotherapy (21 percent, P=0.001); the types of severe mucosal adverse effects were similar in the two groups, as was the incidence of late adverse effects. conclusions Postoperative concurrent administration of high-dose cisplatin with radiotherapy is more efficacious than radiotherapy alone in patients with locally advanced head and neck cancer and does not cause an undue number of late complications.

Sequence and comparative analysis of the chicken genome provide unique perspectives on vertebrate evolution

Abstract: We present here a draft genome sequence of the red jungle fowl, Gallus gallus. Because the chicken is a modern descendant of the dinosaurs and the first non-mammalian amniote to have its genome sequenced, the draft sequence of its genome--composed of approximately one billion base pairs of sequence and an estimated 20,000-23,000 genes--provides a new perspective on vertebrate genome evolution, while also improving the annotation of mammalian genomes. For example, the evolutionary distance between chicken and human provides high specificity in detecting functional elements, both non-coding and coding. Notably, many conserved non-coding sequences are far from genes and cannot be assigned to defined functional classes. In coding regions the evolutionary dynamics of protein domains and orthologous groups illustrate processes that distinguish the lineages leading to birds and mammals. The distinctive properties of avian microchromosomes, together with the inferred patterns of conserved synteny, provide additional insights into vertebrate chromosome architecture.

Further characterisation of the 91500 zircon crystal

Abstract: This paper reports the results from a second characterisation of the 91500 zircon, including data from electron probe microanalysis, laser ablation inductively coupled plasma-mass spectrometry (LA-ICP-MS), secondary ion mass spectrometry (SIMS) and laser fluorination analyses. The focus of this initiative was to establish the suitability of this large single zircon crystal for calibrating in situ analyses of the rare earth elements and oxygen isotopes, as well as to provide working values for key geochemical systems. In addition to extensive testing of the chemical and structural homogeneity of this sample, the occurrence of banding in 91500 in both backscattered electron and cathodoluminescence images is described in detail. Blind intercomparison data reported by both LA-ICP-MS and SIMS laboratories indicate that only small systematic differences exist between the data sets provided by these two techniques. Furthermore, the use of NIST SRM 610 glass as the calibrant for SIMS analyses was found to introduce little or no systematic error into the results for zircon. Based on both laser fluorination and SIMS data, zircon 91500 seems to be very well suited for calibrating in situ oxygen isotopic analyses.

An improved approach for predicting the distribution of rare and endangered species from occurrence and pseudo-absence data

Abstract: Summary 1. Few examples of habitat-modelling studies of rare and endangered species exist in the literature, although from a conservation perspective predicting their distribution would prove particularly useful. Paucity of data and lack of valid absences are the probable reasons for this shortcoming. Analytic solutions to accommodate the lack of absence include the ecological niche factor analysis (ENFA) and the use of generalized linear models (GLM) with simulated pseudo-absences. 2. In this study we tested a new approach to generating pseudo-absences, based on a preliminary ENFA habitat suitability (HS) map, for the endangered species Eryngium alpinum . This method of generating pseudo-absences was compared with two others: (i) use of a GLM with pseudo-absences generated totally at random, and (ii) use of an ENFA only. 3. The influence of two different spatial resolutions (i.e. grain) was also assessed for tackling the dilemma of quality (grain) vs. quantity (number of occurrences). Each combination of the three above-mentioned methods with the two grains generated a distinct HS map. 4. Four evaluation measures were used for comparing these HS maps: total deviance explained, best kappa, Gini coefficient and minimal predicted area (MPA). The last is a new evaluation criterion proposed in this study. 5. Results showed that (i) GLM models using ENFA-weighted pseudo-absence provide better results, except for the MPA value, and that (ii) quality (spatial resolution and locational accuracy) of the data appears to be more important than quantity (number of occurrences). Furthermore, the proposed MPA value is suggested as a useful measure of model evaluation when used to complement classical statistical measures. 6. Synthesis and applications. We suggest that the use of ENFA-weighted pseudoabsence is a possible way to enhance the quality of GLM-based potential distribution maps and that data quality (i.e. spatial resolution) prevails over quantity (i.e. number of data). Increased accuracy of potential distribution maps could help to define better suitable areas for species protection and reintroduction.

c-Myc controls the balance between hematopoietic stem cell self-renewal and differentiation

Abstract: The activity of adult stem cells is essential to replenish mature cells constantly lost due to normal tissue turnover. By a poorly understood mechanism, stem cells are maintained through self-renewal while concomitantly producing differentiated progeny. Here, we provide genetic evidence for an unexpected function of the c-Myc protein in the homeostasis of hematopoietic stem cells (HSCs). Conditional elimination of c-Myc activity in the bone marrow (BM) results in severe cytopenia and accumulation of HSCs in situ. Mutant HSCs self-renew and accumulate due to their failure to initiate normal stem cell differentiation. Impaired differentiation of c-Myc-deficient HSCs is linked to their localization in the differentiation preventative BM niche environment, and correlates with up-regulation of N-cadherin and a number of adhesion receptors, suggesting that release of HSCs from the stem cell niche requires c-Myc activity. Accordingly, enforced c-Myc expression in HSCs represses N-cadherin and integrins leading to loss of self-renewal activity at the expense of differentiation. Endogenous c-Myc is differentially expressed and induced upon differentiation of long-term HSCs. Collectively, our data indicate that c-Myc controls the balance between stem cell self-renewal and differentiation, presumably by regulating the interaction between HSCs and their niche.

RIP1 is an essential mediator of Toll-like receptor 3-induced NF-kappa B activation.

Abstract: Stimulation of Toll-like receptors (TLRs) initiates potent innate immune responses through Toll-interleukin 1 receptor (TIR) domain-containing adaptors such as MyD88 and Trif. Analysis of Trif-deficient mice has shown that TLR3-dependent activation of the transcription factor NF-kappa B by the TLR3 ligand double-stranded RNA is Trif dependent. Here we investigated the 'downstream' signaling events that regulate TLR3-dependent Trif-induced NF-kappa B activation. Trif recruited the kinases receptor interacting protein (RIP)-1 and RIP3 through its RIP homotypic interaction motif. In the absence of RIP1, TLR3-mediated signals activating NF-kappa B, but not the kinase JNK or interferon-beta, were abolished, suggesting that RIP1 mediates Trif-induced NF-kappa B activation. In contrast, the presence of RIP3 negatively regulated the Trif-RIP1-induced NF-kappa B pathway. Therefore, in contrast to other TLRs, which use interleukin 1 receptor-associated kinase (IRAK) proteins to activate NF-kappa B, TLR 3-induced NF-kappa B activation is dependent on RIP kinases.

Clinical Trial Substantiates the Predictive Value of O-6-Methylguanine-DNA Methyltransferase Promoter Methylation in Glioblastoma Patients Treated with Temozolomide

Abstract: Purpose: In the setting of a prospective clinical trial, we determined the predictive value of the methylation status of the O-6-methylguanine-DNA methyltransferase ( MGMT ) promoter for outcome in glioblastoma patients treated with the alkylating agent temozolomide. Expression of this excision repair enzyme has been associated with resistance to alkylating chemotherapy. Experimental Design: The methylation status of MGMT in the tumor biopsies was evaluated in 38 patients undergoing resection for newly diagnosed glioblastoma and enrolled in a Phase II trial testing concomitant and adjuvant temozolomide and radiation. The epigenetic silencing of the MGMT gene was determined using methylation-specific PCR. Results: Inactivation of the MGMT gene by promoter methylation was associated with longer survival ( P = 0.0051; Log-rank test). At 18 months, survival was 62% (16 of 26) for patients testing positive for a methylated MGMT promoter but reached only 8% (1 of 12) in absence of methylation ( P = 0.002; Fisher’s exact test). In the presence of other clinically relevant factors, methylation of the MGMT promoter remains the only significant predictor ( P = 0.017; Cox regression). Conclusions: This prospective clinical trial identifies MGMT -methylation status as an independent predictor for glioblastoma patients treated with a methylating agent. The association of the epigenetic inactivation of the DNA repair gene MGMT with better outcome in this homogenous cohort may have important implications for the design of future trials and supports efforts to deplete MGMT by O -6-benzylguanine, a noncytotoxic substrate of this enzyme.

Astrocytes contain a vesicular compartment that is competent for regulated exocytosis of glutamate

Abstract: Astrocytes establish rapid cell-to-cell communication through the release of chemical transmitters. The underlying mechanisms and functional significance of this release are, however, not well understood. Here we identify an astrocytic vesicular compartment that is competent for glutamate exocytosis. Using postembedding immunogold labeling of the rat hippocampus, we show that vesicular glutamate transporters (VGLUT1/2) and the vesicular SNARE protein, cellubrevin, are both expressed in small vesicular organelles that resemble synaptic vesicles of glutamatergic terminals. Astrocytic vesicles, which are not as densely packed as their neuronal counterparts, can be observed in small groups at sites adjacent to neuronal structures bearing glutamate receptors. Fluorescently tagged VGLUT-containing vesicles were studied dynamically in living astrocytes by total internal reflection fluorescence (TIRF) microscopy. After activation of metabotropic glutamate receptors, astrocytic vesicles underwent rapid (milliseconds) Ca2+- and SNARE-dependent exocytic fusion that was accompanied by glutamate release. These data document the existence of a Ca2+-dependent quantal glutamate release activity in glia that was previously considered to be specific to synapses.

The PIDDosome, a Protein Complex Implicated in Activation of Caspase-2 in Response to Genotoxic Stress

Abstract: Apoptosis is triggered by activation of initiator caspases upon complex-mediated clustering of the inactive zymogen, as occurs in the caspase-9-activating apoptosome complex. Likewise, caspase-2, which is involved in stress-induced apoptosis, is recruited into a large protein complex, the molecular composition of which remains elusive. We show that activation of caspase-2 occurs in a complex that contains the death domain-containing protein PIDD, whose expression is induced by p53, and the adaptor protein RAIDD. Increased PIDD expression resulted in spontaneous activation of caspase-2 and sensitization to apoptosis by genotoxic stimuli. Because PIDD functions in p53-mediated apoptosis, the complex assembled by PIDD and caspase-2 is likely to regulate apoptosis induced by genotoxins.

Extreme Value Dependence in Financial Markets: Diagnostics, Models, and Financial Implications

Abstract: This article presents a general framework for identifying and modeling the joint-tail distribution based on multivariate extreme value theories. We argue that the multivariate approach is the most efficient and effective way to study extreme events such as systemic risk and crisis. We show, using returns on five major stock indices, that the use of traditional dependence measures could lead to inaccurate portfolio risk assessment. We explain how the framework proposed here could be exploited in a number of finance applications such as portfolio selection, risk management, Sharpe ratio targeting, hedging, option valuation, and credit risk analysis.

Peroxisome-proliferator-activated receptors and cancers: complex stories.

Abstract: Peroxisome-proliferator-activated receptors (PPARs) are nuclear hormone receptors that mediate the effects of fatty acids and their derivatives at the transcriptional level Through these pathways, PPARs can regulate cell proliferation, differentiation and survival, so controlling carcinogenesis in various tissues But what are the links between each PPAR isotype and carcinogenesis and what is the relevance of these findings to human pathology and therapy?

A conserved transcript pattern in response to a specialist and a generalist herbivore

Abstract: Transcript patterns elicited in response to attack reveal, at the molecular level, how plants respond to aggressors. These patterns are fashioned both by inflicted physical damage as well as by biological components displayed or released by the attacker. Different types of attacking organisms might therefore be expected to elicit different transcription programs in the host. Using a large-scale DNA microarray, we characterized gene expression in damaged as well as in distal Arabidopsis thaliana leaves in response to the specialist insect, Pieris rapae. More than 100 insect-responsive genes potentially involved in defense were identified, including genes involved in pathogenesis, indole glucosinolate metabolism, detoxification and cell survival, and signal transduction. Of these 114 genes, 111 were induced in Pieris feeding, and only three were repressed. Expression patterns in distal leaves were markedly similar to those of local leaves. Analysis of wild-type and jasmonate mutant plants, coupled with jasmonate treatment, showed that between 67 and 84% of Pieris-regulated gene expression was controlled, totally or in part, by the jasmonate pathway. This was correlated with increased larval performance on the coronatine insensitive1 glabrous1 (coi1-1 gl1) mutant. Independent mutations in COI1 and GL1 led to a faster larval weight gain, but the gl1 mutation had relatively little effect on the expression of the insect-responsive genes examined. Finally, we compared transcript patterns in Arabidopis in response to larvae of the specialist P. rapae and to a generalist insect, Spodoptera littoralis. Surprisingly, given the complex nature of insect salivary components and reported differences between species, almost identical transcript profiles were observed. This study also provides a robustly characterized gene set for the further investigation of plant–insect interaction.

The use of uniaxial accelerometry for the assessment of physical-activity-related energy expenditure: a validation study against whole-body indirect calorimetry.

Abstract: Assessing the total energy expenditure (TEE) and the levels of physical activity in free-living conditions with non-invasive techniques remains a challenge. The purpose of the present study was to investigate the accuracy of a new uniaxial accelerometer for assessing TEE and physical-activity-related energy expenditure (PAEE) over a 24 h period in a respiratory chamber, and to establish activity levels based on the accelerometry ranges corresponding to the operationally defined metabolic equivalent (MET) categories. In study 1, measurement of the 24 h energy expenditure of seventy-nine Japanese subjects (40 (SD 12) years old) was performed in a large respiratory chamber. During the measurements, the subjects wore a uniaxial accelerometer (Lifecorder; Suzuken Co. Ltd, Nagoya, Japan) on their belt. Two moderate walking exercises of 30 min each were performed on a horizontal treadmill. In study 2, ten male subjects walked at six different speeds and ran at three different speeds on a treadmill for 4 min, with the same accelerometer. O2 consumption was measured during the last minute of each stage and was expressed in MET. The measured TEE was 8447 (SD 1337) kJ/d. The accelerometer significantly underestimated TEE and PAEE (91·9 (SD 5·4) and 92·7 (SD 17·8) % chamber value respectively); however, there was a significant correlation between the two values (r 0·928 and 0·564 respectively; P, 0·001). There was a strong correlation between the activity levels and the measured MET while walking (r 2 0·93; P, 0·001). Although TEE and PAEE were systematically underestimated during the 24 h period, the accelerometer assessed energy expenditure well during both the exercise period and the non-structured activities. Individual calibration factors may help to improve the accuracy of TEE estimation, but the average calibration factor for the group is probably sufficient for epidemiological research. This method is also important for assessing the diurnal profile of physical activity.

The SLC2 family of facilitated hexose and polyol transporters

Abstract: The SLC2 family of glucose and polyol transporters comprises 13 members, the glucose transporters (GLUT) 1–12 and the H+-myo-inositol cotransporter (HMIT) These proteins all contain 12 transmembrane domains with both the amino and carboxy-terminal ends located on the cytoplasmic side of the plasma membrane and a N-linked oligosaccharide side-chain located either on the first or fifth extracellular loop Based on sequence comparison, the GLUT isoforms can be grouped into three classes: class I comprises GLUT1–4; class II, GLUT6, 8, 10, and 12 and class III, GLUT5, 7, 9, 11 and HMIT Despite their sequence similarity and the presence of class-specific signature sequences, these transporters carry various hexoses and HMIT is a H+/myo-inositol co-transporter Furthermore, the substrate transported by some isoforms has not yet been identified Tissue- and cell-specific expression of the well-characterized GLUT isoforms underlies their specific role in the control of whole-body glucose homeostasis Numerous studies with transgenic or knockout mice indeed support an important role for these transporters in the control of glucose utilization, glucose storage and glucose sensing Much remains to be learned about the transport functions of the recently discovered isoforms (GLUT6–13 and HMIT) and their physiological role in the metabolism of glucose, myo-inositol and perhaps other substrates

Fingerprints and Other Ridge Skin Impressions

Abstract: Since its publication, the first edition of Fingerprints and Other Ridge Skin Impressions has become a classic in the field. This second edition is completely updated, focusing on the latest technology and techniques—including current detection procedures, applicable processing and analysis methods—all while incorporating the expansive growth of literature on the topic since the publication of the original edition. Forensic science has been challenged in recent years as a result of errors, courts and other scientists contesting verdicts, and changes of a fundamental nature related to previous claims of infallibility and absolute individualization. As such, these factors represent a fundamental change in the way training, identifying, and reporting should be conducted. This book addresses these questions with a clear viewpoint as to where the profession—and ridge skin identification in particular—must go and what efforts and research will help develop the field over the next several years. The second edition introduces several new topics, including Discussion of ACE-V and research results from ACE-V studies Computerized marking systems to help examiners produce reports New probabilistic models and decision theories about ridge skin evidence interpretation, introducing Bayesnet tools Fundamental understanding of ridge mark detection techniques, with the introduction of new aspects such as nanotechnology, immunology and hyperspectral imaging Overview of reagent preparation and application Chapters cover all aspects of the subject, including the formation of friction ridges on the skin, the deposition of latent marks, ridge skin mark identification, the detection and enhancement of such marks, as well the recording of fingerprint evidence. The book serves as an essential reference for practitioners working in the field of fingermark detection and identification, as well as legal and police professionals and anyone studying forensic science with a view to understanding current thoughts and challenges in dactyloscopy.

The AGNP-TDM expert group consensus guidelines: therapeutic drug monitoring in psychiatry.

Abstract: Therapeutic Drug Monitoring (TDM) is a valid tool to optimise pharmacotherapy. It enables the clinician to adjust the dosage of drugs according to the characteristics of the individual patient. In psychiatry, TDM is an established procedure for lithium, some antidepressants and antipsychotics. In spite of its obvious advantages, however, the use of TDM in everyday clinical practice is far from optimal. The interdisciplinary TDM group of the Arbeitsgemeinschaft fur Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) has therefore worked out consensus guidelines to assist psychiatrists and laboratories involved in psychotropic drug analysis to optimise the use of TDM of psychotropic drugs. Five research-based levels of recommendation were defined with regard to routine monitoring of plasma concentrations for dose titration of 65 psychoactive drugs: (1) strongly recommended, (2) recommended, (3) useful, (4) probably useful and (5) not recommended. A second approach defined indications to use TDM, e. g. control of compliance, lack of clinical response or adverse effects at recommended doses, drug interactions, pharmacovigilance programs, presence of a genetic particularity concerning the drug metabolism, children, adolescents and elderly patients. Indications for TDM are relevant for all drugs either with or without validated therapeutic ranges. When studies on therapeutic ranges are lacking, target ranges should be plasma concentrations that are normally observed at therapeutic doses of the drug. Therapeutic ranges of plasma concentrations that are considered to be optimal for treatment are proposed for those drugs, for which the evaluation of the literature demonstrated strong evidence. Moreover, situations are defined when pharmacogenetic (phenotyping or genotyping) tests are informative in addition to TDM. Finally, practical instructions are given how to use TDM. They consider preparation of TDM, analytical procedures, reporting and interpretation of results and the use of information for patient treatment. Using the consensus guideline will help to ensure optimal clinical benefit of TDM in psychiatry.

Plasma and Cerebrospinal Fluid Population Pharmacokinetics of Temozolomide in Malignant Glioma Patients

Abstract: Purpose: Scarce information is available on the brain penetration of temozolomide (TMZ), although this novel methylating agent is mainly used for the treatment of malignant brain tumors. The purpose was to assess TMZ pharmacokinetics in plasma and cerebrospinal fluid (CSF) along with its inter-individual variability, to characterize covariates and to explore relationships between systemic or cerebral drug exposure and clinical outcomes. Experimental Design: TMZ levels were measured by high-performance liquid chromatography in plasma and CSF samples from 35 patients with newly diagnosed or recurrent malignant gliomas. The population pharmacokinetic analysis was performed with nonlinear mixed-effect modeling software. Drug exposure, defined by the area under the concentration-time curve (AUC) in plasma and CSF, was estimated for each patient and correlated with toxicity, survival, and progression-free survival. Results: A three-compartment model with first-order absorption and transfer rates between plasma and CSF described the data appropriately. Oral clearance was 10 liter/h; volume of distribution ( V D ), 30.3 liters; absorption constant rate, 5.8 h −1 ; elimination half-time, 2.1 h; transfer rate from plasma to CSF ( K plasma→CSF ), 7.2 × 10 −4 h −1 and the backwards rate, 0.76 h −1 . Body surface area significantly influenced both clearance and V D , and clearance was sex dependent. The AUC CSF corresponded to 20% of the AUC plasma . A trend toward an increased K plasma→CSF of 15% was observed in case of concomitant radiochemotherapy. No significant correlations between AUC in plasma or CSF and toxicity, survival, or progression-free survival were apparent after deduction of dose-effect. Conclusions: This is the first human pharmacokinetic study on TMZ to quantify CSF penetration. The AUC CSF /AUC plasma ratio was 20%. Systemic or cerebral exposures are not better predictors than the cumulative dose alone for both efficacy and safety.

The TRANSMED Transects in Space and Time: Constraints on the Paleotectonic Evolution of the Mediterranean Domain

Abstract: The Phanerozoic evolution of the western Tethyan region was dominated by terrane collisions and accretions, during the Variscan, Cimmerian and Alpine cycles. Most terranes were derived from Gondwana and present a similar early Palaeozoic evolution. Subsequently, they were detached from Gondwana and affected by different deformation and metamorphic events, which permit to decipher their geodynamic history. Lithospheric scale peri-Mediterranean transects show the present-day juxtaposition of these terranes, but do not allow to unravel their exotic nature or their duplication. To create a reliable palinspastic model around these transects, plate tectonics constraints must be taken into consideration in order to assess the magnitude of lateral displacements. For most of the transects and their different segments, thousand km scale differential transport can be demonstrated.

Cryo-electron microscopy of vitreous sections

Abstract: Since the beginning of the 1980s, cryo-electron microscopy of a thin film of vitrified aqueous suspension has made it possible to observe biological particles in their native state, in the absence of the usual artefacts of dehydration and staining. Combined with 3-d reconstruction, it has become an important tool for structural molecular biology. Larger objects such as cells and tissues cannot generally be squeezed in a thin enough film. Cryo-electron microscopy of vitreous sections (CEMOVIS) provides then a solution. It requires vitrification of a sizable piece of biological material and cutting it into ultrathin sections, which are observed in the vitrified state. Each of these operations raises serious difficulties that have now been overcome. In general, the native state seen with CEMOVIS is very different from what has been seen before and it is seen in more detail. CEMOVIS will give its full potential when combined with computerized electron tomography for 3-d reconstruction.

Gelsolin superfamily proteins: key regulators of cellular functions

Abstract: Cytoskeletal rearrangement occurs in a variety of cellular processes and involves a wide spectrum of proteins. Among these, the gelsolin superfamily proteins control actin organization by severing filaments, capping filament ends and nucleating actin assembly [1]. Gelsolin is the founding member of this family, which now contains at least another six members: villin, adseverin, capG, advillin, supervillin and flightless I. In addition to their respective role in actin filament remodeling, these proteins have some specific and apparently non-overlapping particular roles in several cellular processes, including cell motility, control of apoptosis and regulation of phagocytosis (summarized in table 1). Evidence suggests that proteins belonging to the gelsolin superfamily may be involved in other processes, including gene expression regulation. This review will focus on some of the known functions of the gelsolin superfamily proteins, thus providing a basis for reflection on other possible and as yet incompletely understood roles for these proteins.