Showing papers by "University of Cologne published in 2001"

Classification and diagnostic prediction of cancers using gene expression profiling and artificial neural networks

Abstract: The purpose of this study was to develop a method of classifying cancers to specific diagnostic categories based on their gene expression signatures using artificial neural networks (ANNs). We trained the ANNs using the small, round blue-cell tumors (SRBCTs) as a model. These cancers belong to four distinct diagnostic categories and often present diagnostic dilemmas in clinical practice. The ANNs correctly classified all samples and identified the genes most relevant to the classification. Expression of several of these genes has been reported in SRBCTs, but most have not been associated with these cancers. To test the ability of the trained ANN models to recognize SRBCTs, we analyzed additional blinded samples that were not previously used for the training procedure, and correctly classified them in all cases. This study demonstrates the potential applications of these methods for tumor diagnosis and the identification of candidate targets for therapy.

Simulation of pedestrian dynamics using a two dimensional cellular automaton

Abstract: We propose a two-dimensional cellular automaton model to simulate pedestrian tra.c. It is a vmax = 1 model with exclusion statistics and parallel dynamics. Long-range interactions between the pedestrians are mediated by a so-called "oor #eld which modi4es the transition rates to neighbouring cells. This 4eld, which can be discrete or continuous, is subject to di7usion and decay. Furthermore it can be modi4ed by the motion ofthe pedestrians. Theref ore, the model uses an idea similar to chemotaxis, but with pedestrians following a virtual rather than a chemical trace. Our main goal is to show that the introduction ofsuch a :oor 4eld is su.cient to model collective e7ects and self-organization encountered in pedestrian dynamics, e.g. lane formation in counter:ow through a large corridor. As an application we also present simulations ofthe evacuation ofa large room with reduced visibility, e.g. due to f ailure oflights or smoke. c 2001 Elsevier Science B.V. All rights reserved.

Reactive oxygen species as intracellular messengers during cell growth and differentiation.

Abstract: Reactive oxygen species (ROS) are generated following ligand-receptor interactions and function as specific second messengers in signaling cascades involved in cell proliferation and differentiation.

Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas

Abstract: Genomic instability promotes tumorigenesis and can occur through various mechanisms, including defective segregation of chromosomes or inactivation of DNA mismatch repair. Although B-cell lymphomas are associated with chromosomal translocations that deregulate oncogene expression, a mechanism for genome-wide instability during lymphomagenesis has not been described. During B-cell development, the immunoglobulin variable (V) region genes are subject to somatic hypermutation in germinal-centre B cells. Here we report that an aberrant hypermutation activity targets multiple loci, including the proto-oncogenes PIM1, MYC, RhoH/TTF (ARHH) and PAX5, in more than 50% of diffuse large-cell lymphomas (DLCLs), which are tumours derived from germinal centres. Mutations are distributed in the 5' untranslated or coding sequences, are independent of chromosomal translocations, and share features typical of V-region-associated somatic hypermutation. In contrast to mutations in V regions, however, these mutations are not detectable in normal germinal-centre B cells or in other germinal-centre-derived lymphomas, suggesting a DLCL-associated malfunction of somatic hypermutation. Intriguingly, the four hypermutable genes are susceptible to chromosomal translocations in the same region, consistent with a role for hypermutation in generating translocations by DNA double-strand breaks. By mutating multiple genes, and possibly by favouring chromosomal translocations, aberrant hypermutation may represent the major contributor to lymphomagenesis.

Filamins as integrators of cell mechanics and signalling.

Abstract: Filamins are large actin-binding proteins that stabilize delicate three-dimensional actin webs and link them to cellular membranes. They integrate cellular architectural and signalling functions and are essential for fetal development and cell locomotion. Here, we describe the history, structure and function of this group of proteins.

Diagnosing Schizophrenia in the Initial Prodromal Phase

Abstract: Background In schizophrenia research, early detection in the initial prodrome before first psychotic episodes is a major topic Therefore, the prognostic accuracy of initial prodromal symptoms was examined prospectively Methods The study sample was composed of patients referred to outpatient departments of German psychiatric university departments, because of diagnostic problems, between 1987 and 1991 They were examined with the Bonn Scale for the Assessment of Basic Symptoms and the Ninth Version of the Present State Examination to detect an incipient schizophrenic disorder Of 385 patients showing no schizophrenia-characteristic symptoms, between 1995 and 1998, 110 with and 50 without initial prodromal symptoms were followed up and reexamined with the same instruments for a transition to schizophrenia Results During a mean follow-up period of 96 years, 79 (494%) of the 160 patients had transited to schizophrenia The absence of prodromal symptoms excluded a subsequent schizophrenia with a probability of 96% (sensitivity: 098; false-negative predictions: 13%), whereas their presence predicted schizophrenia with a probability of 70% (specificity: 059; false-positive predictions: 20%) Certain disturbances, such as thought interference, disturbances of receptive language, or visual distortions, predicted schizophrenia, even with a probability up to 91% (specificity: 085-091; false-positive predictions: 19%-75%) Conclusions The Bonn Scale for the Assessment of Basic Symptoms operationalization of prodromal symptoms performed well in the early detection of schizophrenia It therefore might be useful for the prediction of the disorder, especially if it is further refined to select those items with particularly high prognostic accuracy

Notch signaling is required for arterial-venous differentiation during embryonic vascular development.

Abstract: Recent evidence indicates that acquisition of artery or vein identity during vascular development is governed, in part, by genetic mechanisms. The artery-specific expression of a number of Notch signaling genes in mouse and zebrafish suggests that this pathway may play a role in arterial-venous cell fate determination during vascular development. We show that loss of Notch signaling in zebrafish embryos leads to molecular defects in arterial-venous differentiation, including loss of artery-specific markers and ectopic expression of venous markers within the dorsal aorta. Conversely, we find that ectopic activation of Notch signaling leads to repression of venous cell fate. Finally, embryos lacking Notch function exhibit defects in blood vessel formation similar to those associated with improper arterial-venous specification. Our results suggest that Notch signaling is required for the proper development of arterial and venous blood vessels, and that a major role of Notch signaling in blood vessels is to repress venous differentiation within developing arteries. Movies available on-line

Coronary Magnetic Resonance Angiography for the Detection of Coronary Stenoses

Abstract: Background An accurate, noninvasive technique for the diagnosis of coronary disease would be an important advance. We investigated the accuracy of coronary magnetic resonance angiography among patients with suspected coronary disease in a prospective, multicenter study. Methods Coronary magnetic resonance angiography was performed during free breathing in 109 patients before elective x-ray coronary angiography, and the results of the two diagnostic procedures were compared. Results A total of 636 of 759 proximal and middle segments of coronary arteries (84 percent) were interpretable on magnetic resonance angiography. In these segments, 78 (83 percent) of 94 clinically significant lesions (those with a ≥50 percent reduction in diameter on x-ray angiography) were also detected by magnetic resonance angiography. Overall, coronary magnetic resonance angiography had an accuracy of 72 percent (95 percent confidence interval, 63 to 81 percent) in diagnosing coronary artery disease. The sensitivity, specificity,...

Modeling the formation of secondary organic aerosol within a comprehensive air quality model system

Abstract: The Secondary Organic Aerosol Model (SORGAM) has been developed for use in comprehensive air quality model systems. Coupled to a chemistry-transport model, SORGAM is capable of simulating secondary organic aerosol (SOA) formation including the production of low-volatility products and their subsequent gas/particle partitioning. The current model formulation assumes that all SOA compounds interact and form a quasi-ideal solution. This has significant impact on the gas/particle partitioning, since in this case the saturation concentrations of the SOA compounds depend on the composition of the SOA and the amount of absorbing material present. Box model simulations have been performed to investigate the sensitivity of the model against several parameters. Results clearly show the importance of the temperature dependence of saturation concentrations on the partitioning process. Furthermore, SORGAM has been coupled to the comprehensive European Air Pollution and Dispersion/Modal Aerosol Dynamics Model for Europe air quality model system, and results of a three-dimensional model application are presented. The model results indicate that assuming interacting SOA compounds, biogenic and anthropogenic contributions significantly influence each other and cannot be treated independently.

Morphine and alternative opioids in cancer pain : the EAPC recommendations

Abstract: An expert working group of the European Association for Palliative Care has revised and updated its guidelines on the use of morphine in the management of cancer pain. The revised recommendations presented here give guidance on the use of morphine and the alternative strong opioid analgesics which have been introduced in many parts of the world in recent years. Practical strategies for dealing with difficult situations are described presenting a consensus view where supporting evidence is lacking. The strength of the evidence on which each recommendation is based is indicated.

Mechanisms of chromosomal translocations in B cell lymphomas.

Abstract: Reciprocal chromosomal translocations involving the immunoglobulin (Ig) loci are a hallmark of most mature B cell lymphomas and usually result in dysregulated expression of oncogenes brought under the control of the Ig enhancers. Although the precise mechanisms involved in the development of these translocations remains essentially unknown, a clear relationship has been established with the mechanisms that lead to Ig gene remodeling, including V(D)J recombination, isotype switching and somatic hypermutation. The common denominator of these three processes in the formation of Ig-associated translocations is probably represented by the fact that each of these processes intrinsically generates double-strand DNA breaks. Since isotype switching and somatic hypermutation occur in germinal center (GC) B cells, the origin of a large number of B cell lymphomas from GC B cells is likely closely related to aberrant hypermutation and isotype switching activity in these B cells.

Wallerian degeneration of injured axons and synapses is delayed by a Ube4b/Nmnat chimeric gene.

Abstract: Axons and their synapses distal to an injury undergo rapid Wallerian degeneration, but axons in the C57BL/WldS mouse are protected. The degenerative and protective mechanisms are unknown. We identified the protective gene, which encodes an N-terminal fragment of ubiquitination factor E4B (Ube4b) fused to nicotinamide mononucleotide adenylyltransferase (Nmnat), and showed that it confers a dose-dependent block of Wallerian degeneration. Transected distal axons survived for two weeks, and neuromuscular junctions were also protected. Surprisingly, the Wld protein was located predominantly in the nucleus, indicating an indirect protective mechanism. Nmnat enzyme activity, but not NAD+ content, was increased fourfold in WldS tissues. Thus, axon protection is likely to be mediated by altered ubiquitination or pyridine nucleotide metabolism.

Poly‐Lactic‐Acid for coating of endovascular stents: preliminary results in canine experimental av‐fistulae

Abstract: Poly-Lactic-Acid (PLA) was evaluated for coating of vascular endoprostheses in the treatment of experimental arterio-venous-fistulae (AVF). Bilateral carotid – external jugular AVF were created in 5 adult dogs. 7 PLA coated nitinol stents were placed via a transfemoral approach covering 5 AVF. The contralateral AVF remained untreated. Angiography was performed immediately after stent placement, at weeks 1 and 3 and at months 3, 6 and 9. All grafts were removed and underwent histologic examination. In 2 cases the occlusion of the AVF was successful, while misplacement occurred in 3 cases. Occlusion of the parent vessel was disclosed in 3 cases. Histologic examination revealed a mild inflammatory reaction with the presence of macrophages. There was no foreign-body reaction or fragmentation of the arterial vessel wall. PLA, which is a well-known biodegradable material, showed a good mid-term biocompatibility. Elastic mismatch of the non-elastic coating and the self-expandable nitinol stent caused misplacement. Frequent vessel-occlusions were probably due to PLA-filaments fraying into the vessel lumen. Using a different textile structure PLA might be a material suitable for coating endovascular stents. Poly-Laktid zur Ummantelung von Gefasprothesen: erste tierexperimentelle Ergebnisse in der Behandlung arterio-venoser Gefaskurzschlusse In der vorliegenden Arbeit wurden mit Poly-Laktid ummantelte Gefasprothesen in der Behandlung von experimentell angelegten arterio-venosen Gefaskurzschlussen getestet. Gefaskurzschlussverbindungen der Halsarterien mit der parallel dazu verlaufenden, tiefen Halsvene wurden in 5 Hunden operativ angelegt. 7 mit Poly-Laktid ummantelte Gefasprothesen aus Nitinol wurden in jeweils eine Halsarterie implantiert, so dass die Gefaskurzschlussverbindung vollstandig uberdeckt war. Die gegenuberliegende Seite verblieb als Kontrolle unbehandelt. Radiologische Gefasdarstellungen erfolgten unmittelbar nach Implantation der Gefasprothese, nach 1 und 3 Wochen sowie nach 3, 6 und 9 Monaten. Alle Prothesen wurden operativ entfernt und feingeweblich untersucht. Ein erfolgreicher Verschluss der Kurzschlussverbindung gelang lediglich in 2 Fallen. In den 3 ubrigen Fallen kam es zu einer Fehlplatzierung der Gefasprothese. Gefasverschlusse der geschienten Arterien wurden in 3 Fallen beobachtet. Die feingewebliche Untersuchung zeigte geringe, entzundliche Zellreaktionen. Fremdkorperreaktionen bzw. Destruktionen der Gefaswand wurden nicht beobachtet. Mittelfristig zeigte Poly-Laktid, ein biologisch abbaubares Material, eine gute Biokompatibilitat. Das Missverhaltnis zwischen der nichtelastischen Poly-Laktid Ummantelung und der elastischen Gefasprothese erschwerte die zielgenaue, endovaskulare Platzierung. Wahrscheinlich verursachten die endstandigen Auffaserungen der Poly-Laktid-Ummantelung die haufigen Gefasverschlusse. Unter Verwendung anderer Webstrukturen konnte Poly-Laktid ein interessantes Material zur Ummantelung von Gefasprothesen sein.

Symptoms during cancer pain treatment following WHO-guidelines: a longitudinal follow-up study of symptom prevalence, severity and etiology.

Abstract: Most patients with advanced cancer develop diverse symptoms that can limit the efficacy of pain treatment and undermine their quality of life. The present study surveys symptom prevalence, etiology and severity in 593 cancer patients treated by a pain service. Non-opioid analgesics, opioids and adjuvants were administered following the WHO-guidelines for cancer pain relief. Other symptoms were systematically treated by appropriate adjuvant drugs. Pain and symptom severity was measured daily by patient self-assessment; the physicians of the pain service assessed symptom etiology and the severity of confusion, coma and gastrointestinal obstruction at each visit. The patients were treated for an average period of 51 days. Efficacy of pain treatment was good in 70%, satisfactory in 16% and inadequate in 14% of patients. The initial treatment caused a significant reduction in the average number of symptoms from four to three. Prevalence and severity of anorexia, impaired activity, confusion, mood changes, insomnia, constipation, dyspepsia, dyspnoea, coughing, dysphagia and urinary symptoms were significantly reduced, those of sedation, other neuropsychiatric symptoms and dry mouth were significantly increased and those of coma, vertigo, diarrhea, nausea, vomiting, intestinal obstruction, erythema, pruritus and sweating remained unchanged. The most frequent symptoms were impaired activity (74% of days), mood changes (22%), constipation (23%), nausea (23%) and dry mouth (20%). The highest severity scores were associated with impaired activity, sedation, coma, intestinal obstruction, dysphagia and urinary symptoms. Of all 23 symptoms, only constipation, erythema and dry mouth were assessed as being most frequently caused by the analgesic regimen. In conclusion, the high prevalence and severity of many symptoms in far advanced cancer can be reduced, if pain treatment is combined with systematic symptom control. Nevertheless, general, neuropsychiatric and gastrointestinal symptoms are experienced during a major part of treatment time and pain relief was inadequate in 14% of patients. Cancer pain management has to be embedded in a frame of palliative care, taking all the possibilities of symptom management into consideration.

Demographic variations in the rising incidence of esophageal adenocarcinoma in white males.

Abstract: BACKGROUND The rise in adenocarcinoma (AC) of the esophagus has been reported in several papers. However, the results are only comparable to a limited extent, because they are based on differing periods and different computational methods. The purpose of the current investigation was to collect the available data and to analyze them in a unified manner. METHODS The authors requested data on the incidence of AC of the esophagus for each year since 1960 from 43 tumor registries in North America, Europe, and Australia. The data from 22 centers were used. The trend was calculated by fitting the data to an exponential growth model. RESULTS The incidence of AC of the esophagus in white males is rising in most countries. The highest values of the estimated incidence rate in the year 2000 were found in Great Britain (5.0– 8.7 cases per 100,000 population) and in Australia (4.8 cases per 100,000 population) followed by The Netherlands (4.4 cases per 100,000 population), the United States (3.7 cases per 100,000 population), and Denmark (2.8 cases per 100,000 population). Low rates (< 1.0 cases per 100,000 population) were found in Eastern Europe. The largest changes in incidence were reported in the Southern European countries, with an estimate of the average increase over six registries of 30% per year; in Australia, with an average increase of 23.5% per year; and in the United States, with an average increase of 20.6% per year. The rates of increase ranged from 8.7% to 17.5% on average in Northern Europe, Central Europe, and the United Kingdom. In Eastern Europe, at most, there was a minor rise in incidence. CONCLUSIONS In the Western industrialized nations, the analyzed data show that the incidence of AC of the esophagus has been rising rapidly in the last 20 years. The only exceptions to date are the countries of Eastern Europe. Cancer 2001;92:549–55. © 2001 American Cancer Society.

Solar UV irradiation and dermal photoaging

Abstract: The skin is increasingly exposed to ambient UV-irradiation thus increasing risks for photooxidative damage with long-term detrimental effects like photoaging, characterized by wrinkles, loss of skin tone and resilience. Photoaged skin displays alterations in the cellular component and extracellular matrix with accumulation of disorganized elastin and its microfibrillar component fibrillin in the deep dermis and a severe loss of interstitial collagens, the major structural proteins of the dermal connective tissue. The unifying pathogenic agents for these changes are UV-generated reactive oxygen species (ROS) which deplete and damage non-enzymatic and enzymatic antioxidant defense systems of the skin. As well as causing permanent genetic changes, ROS activate cytoplasmic signal transduction pathways in resident fibroblasts that are related to growth, differentiation, senescence and connective tissue degradation. This review focuses on the role of UV-induced ROS in the photodamage of the skin resulting in clinical and biochemical characteristics of photoaging. In addition, the relationship of photoaging to intrinsic aging of the skin will be briefly discussed. A decrease in the overall ROS load by efficient sunscreens or other protective agents may represent promising strategies to prevent or at least minimize ROS-induced photoaging.

Osmosensing and osmoregulatory compatible solute accumulation by bacteria

Abstract: Bacteria inhabit natural and artificial environments with diverse and fluctuating osmolalities, salinities and temperatures. Many maintain cytoplasmic hydration, growth and survival most effectively by accumulating kosmotropic organic solutes (compatible solutes) when medium osmolality is high or temperature is low (above freezing). They release these solutes into their environment when the medium osmolality drops. Solutes accumulate either by synthesis or by transport from the extracellular medium. Responses to growth in high osmolality medium, including biosynthetic accumulation of trehalose, also protect Salmonella typhimurium from heat shock. Osmotically regulated transporters and mechanosensitive channels modulate cytoplasmic solute levels in Bacillus subtilis, Corynebacterium glutamicum, Escherichia coli, Lactobacillus plantarum, Lactococcus lactis, Listeria monocytogenes and Salmonella typhimurium. Each organism harbours multiple osmoregulatory transporters with overlapping substrate specificities. Membrane proteins that can act as both osmosensors and osmoregulatory transporters have been identified (secondary transporters ProP of E. coli and BetP of C. glutamicum as well as ABC transporter OpuA of L. lactis). The molecular bases for the modulation of gene expression and transport activity by temperature and medium osmolality are under intensive investigation with emphasis on the role of the membrane as an antenna for osmo- and/or thermosensors.

Optimizing traffic lights in a cellular automaton model for city traffic.

Abstract: We study the impact of global traffic light control strategies in a recently proposed cellular automaton model for vehicular traffic in city networks. The model combines basic ideas of the Biham-Middleton-Levine model for city traffic and the Nagel-Schreckenberg model for highway traffic. The city network has a simple square lattice geometry. All streets and intersections are treated equally, i.e., there are no dominant streets. Starting from a simple synchronized strategy, we show that the capacity of the network strongly depends on the cycle times of the traffic lights. Moreover, we point out that the optimal time periods are determined by the geometric characteristics of the network, i.e., the distance between the intersections. In the case of synchronized traffic lights, the derivation of the optimal cycle times in the network can be reduced to a simpler problem, the flow optimization of a single street with one traffic light operating as a bottleneck. In order to obtain an enhanced throughput in the model, improved global strategies are tested, e.g., green wave and random switching strategies, which lead to surprising results.

Blow-up in a chemotaxis model without symmetry assumptions

Abstract: In this paper we prove the existence of solutions of the Keller–Segel model in chemotaxis, which blow up in finite or infinite time. This is done without assuming any symmetry properties of the solution.

Crystal structure of human protein kinase CK2: insights into basic properties of the CK2 holoenzyme

Abstract: The crystal structure of a fully active form of human protein kinase CK2 (casein kinase 2) consisting of two C-terminally truncated catalytic and two regulatory subunits has been determined at 3.1 A resolution. In the CK2 complex the regulatory subunits form a stable dimer linking the two catalytic subunits, which make no direct contact with one another. Each catalytic subunit interacts with both regulatory chains, predominantly via an extended C-terminal tail of the regulatory subunit. The CK2 structure is consistent with its constitutive activity and with a flexible role of the regulatory subunit as a docking partner for various protein kinases. Furthermore it shows an inter-domain mobility in the catalytic subunit known to be functionally important in protein kinases and detected here for the first time directly within one crystal structure.

The prevalence of Peyronie's disease: results of a large survey.

Abstract: Objectives To determine the prevalence of Peyronie's disease, a localized connective tissue disorder of the penile tunica albuginea, the symptoms of which include palpable plaque, painful erections and curvature of the penis, in a large sample of men in Germany. Subjects and methods A standardized questionnaire was sent to 8000 male inhabitants (age range 30–80 years) of the greater Cologne area (≈ 1.5 million inhabitants). Three questions about the self-diagnosis of Peyronie's disease were previously assessed for validity on 158 healthy men and 24 patients with confirmed Peyronie's disease. To optimize the response rate, the questionnaire was mailed three times to all the men. Results The response rate after the third mailing was 55.4% (4432 men); 142 men (3.2%, mean age 57.4 years, sd 13.4) reported the new appearance of a palpable plaque which, from the previous validation, was the most sensitive question and the main symptom of the disease. In men aged 30–39 years only 1.5% reported localized penile induration, compared with 3.0% in those 40–49 and 50–59 years, 4.0% in those 60–69 years and 6.5% of those > 70 years old. Newly occurring angulation was reported by 119 of the 142 men (84%) and painful erection by 66 (46.5%). The combination of the three symptoms (plaque, deviation and painful erection) was reported by 46 of the 4432 respondents (1.04%), i.e. 32% of the 142 men with penile induration; 58 of the 142 men (41%) reported erectile dysfunction. Conclusions This is the first large cross-sectional, community-based study to examine the prevalence of Peyronie's disease. Using previously validated questions the prevalence of Peyronie's disease in the sample was 3.2%; this is much higher than indicated in previous reports. A comparably high prevalence is reported for diabetes and urolithiasis, suggesting that this ‘rare’ disease is more widespread than previously thought.

Thermophilic adaptation of proteins.

Abstract: Hyperthermophilic organisms optimally grow close to the boiling point of water. As a consequence, their macromolecules must be much more thermostable than those from mesophilic species. Here, proteins from hyperthermophiles and mesophiles are compared with respect to their thermodynamic and kinetic stabilities. The known differences in amino acid sequences and three-dimensional structures between intrinsically thermostable and thermolabile proteins will be summarized, and the crucial role of electrostatic interactions for protein stability at high temperatures will be highlighted. Successful attempts to increase the thermostability of proteins, which were either based on rational design or on directed evolution, are presented. The relationship between high thermo-stability of enzymes from hyperthermophiles and their low catalytic activity at room temperature is discussed. Not all proteins from hyperthermophiles are thermostable enough to retain their structures and functions at the high physiological temperatures. It will be shown how this shortcoming can be surpassed by extrinsic factors such as large molecular chaperones and small compatible solutes. Finally, the potential of thermostable enzymes for biotechnology is discussed.

DNA Hypomethylation Perturbs the Function and Survival of CNS Neurons in Postnatal Animals

Abstract: DNA methyltransferase I (Dnmt1), the maintenance enzyme for DNA cytosine methylation, is expressed at high levels in the CNS during embryogenesis and after birth. Because embryos deficient for Dnmt1 die at gastrulation, the role of Dnmt1 in the development and function of the nervous system could not be studied by using this mutation. We therefore used the cre/loxP system to produce conditional mutants that lack Dnmt1 in neuroblasts of embryonic day 12 embryos or in postmitotic neurons of the postnatal animal. Conditional deletion of the Dnmt1 gene resulted in rapid depletion of Dnmt1 proteins, indicating that the enzyme in postmitotic neurons turns over quickly. Dnmt1 deficiency in postmitotic neurons neither affected levels of global DNA methylation nor influenced cell survival during postnatal life. In contrast, Dnmt1 deficiency in mitotic CNS precursor cells resulted in DNA hypomethylation in daughter cells. Whereas mutant embryos carrying 95% hypomethylated cells in the brain died immediately after birth because of respiratory distress, mosaic animals with 30% hypomethylated CNS cells were viable into adulthood. However, these mutant cells were eliminated quickly from the brain within 3 weeks of postnatal life. Thus, hypomethylated CNS neurons were impaired functionally and were selected against at postnatal stages.