Showing papers by "University of Würzburg published in 2000"
TL;DR: Sensory neurons from mice lacking VR1 are severely deficient in their responses to each of these noxious stimuli and are impaired in the detection of painful heat, and showed little thermal hypersensitivity in the setting of inflammation.
Abstract: The capsaicin (vanilloid) receptor VR1 is a cation channel expressed by primary sensory neurons of the "pain" pathway. Heterologously expressed VR1 can be activated by vanilloid compounds, protons, or heat (>43 degrees C), but whether this channel contributes to chemical or thermal sensitivity in vivo is not known. Here, we demonstrate that sensory neurons from mice lacking VR1 are severely deficient in their responses to each of these noxious stimuli. VR1-/- mice showed normal responses to noxious mechanical stimuli but exhibited no vanilloid-evoked pain behavior, were impaired in the detection of painful heat, and showed little thermal hypersensitivity in the setting of inflammation. Thus, VR1 is essential for selective modalities of pain sensation and for tissue injury-induced thermal hyperalgesia.
3,367 citations
TL;DR: In this paper, the spin-polarization effects of a current in a two-dimensional electron gas which is contacted by two ferromagnetic metals were calculated, and it was shown that for a typical device geometry, the degree of spin polarization of the current is limited to less than 0.1% only.
Abstract: We have calculated the spin-polarization effects of a current in a two-dimensional electron gas which is contacted by two ferromagnetic metals. In the purely diffusive regime, the current may indeed be spin-polarized. However, for a typical device geometry the degree of spin-polarization of the current is limited to less than 0.1% only. The change in device resistance for parallel and antiparallel magnetization of the contacts is up to quadratically smaller, and will thus be difficult to detect.
1,819 citations
TL;DR: Genomic islands are present in the majority of genomes of pathogenic as well as nonpathogenic bacteria and may encode accessory functions which have been previously spread among bacterial populations and are argued for the generation of pathogenicity islands by horizontal gene transfer.
Abstract: Virulence factors of pathogenic bacteria (adhesins, toxins, invasins, protein secretion systems, iron uptake systems, and others) may be encoded by particular regions of the prokaryotic genome termed pathogenicity islands. Pathogenicity islands were first described in human pathogens of the species Escherichia coli, but have recently been found in the genomes of various pathogens of humans, animals, and plants. Pathogenicity islands comprise large genomic regions [10-200 kilobases (kb) in size] that are present on the genomes of pathogenic strains but absent from the genomes of nonpathogenic members of the same or related species. The finding that the G+C content of pathogenicity islands often differs from that of the rest of the genome, the presence of direct repeats at their ends, the association of pathogenicity islands with transfer RNA genes, the presence of integrase determinants and other mobility loci, and their genetic instability argue for the generation of pathogenicity islands by horizontal gene transfer, a process that is well known to contribute to microbial evolution. In this article we review these and other aspects of pathogenicity islands and discuss the concept that they represent a subclass of genomic islands. Genomic islands are present in the majority of genomes of pathogenic as well as nonpathogenic bacteria and may encode accessory functions which have been previously spread among bacterial populations.
1,285 citations
TL;DR: This paper presents a meta-anatomy of the EMMARM, a probabilistic model of the immune response to EMT, which states that EMTs are more likely to attack the nervous system than the immune systems of mice.
Abstract: IP: 54.191.40.80 On: Sun, 20 Aug 2017 08:42:34 Journal of General Virology (2000), 81, 853–879. Printed in Great Britain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
929 citations
TL;DR: In this article, a mouse model of spinal muscular atrophy (SMA) was obtained using transgenic mice that express human SMN2 and mated these onto the null Smn (-/-)background.
Abstract: Proximal spinal muscular atrophy (SMA) is a common motor neuron disease in humans and in its most severe form causes death by the age of 2 years. It is caused by defects in the telomeric survival motor neuron gene ( SMN1 ), but patients retain at least one copy of a highly homologous gene, centromeric SMN ( SMN2 ). Mice possess only one survival motor neuron gene ( Smn ) whose loss is embryonic lethal. Therefore, to obtain a mouse model of SMA we created transgenic mice that express human SMN2 and mated these onto the null Smn (-/-)background. We show that Smn (-/-); SMN2 mice carrying one or two copies of the transgene have normal numbers of motor neurons at birth, but vastly reduced numbers by postnatal day 5, and subsequently die. This closely resembles a severe type I SMA phenotype in humans and is the first report of an animal model of the disease. Eight copies of the transgene rescues this phenotype in the mice indicating that phenotypic severity can be modulated by SMN2 copy number. These results show that SMA is caused by insufficient SMN production by the SMN2 gene and that increased expression of the SMN2 gene may provide a strategy for treating SMA patients.
729 citations
TL;DR: Depending on the cellular composition and tissue context of migration, diverse cellular and molecular migration strategies can be developed by different cell types.
Abstract: Cell migration in three-dimensional (3-D) extracellular matrix (ECM) is not a uniform event but rather comprises a modular spectrum of interdependent biophysical and biochemical cell functions. Haptokinetic cell migration across two-dimensional (2-D) surfaces consists of at least three processes: (i) the protrusion of the leading edge for adhesive cell-substratum interactions is followed by (ii) contraction of the cell body and (iii) detachment of the trailing edge. In cells of flattened morphology migrating slowly across 2-D substrate, contact-dependent clustering of adhesion receptors including integrins results in focal contact and stress fiber formation. While haptokinetic migration is predominantly a function of adhesion and deadhesion events lacking spatial barriers towards the advancing cell body, the biophysics of the tissues require a set of cellular strategies to overcome matrix resistance. Matrix barriers force the cells to adapt their morphology and change shape and/or enzymatically degrade ECM components, either by contact-dependent proteolysis or by protease secretion. In 3-D ECM, in contrast to 2-D substrate, the cell shape is mostly bipolar and the cytoskeletal organization is less stringent, frequently lacking discrete focal contacts and stress fibers. Morphologically large spindle-shaped cells (i.e., fibroblasts, endothelial cells, and many tumor cells) of high integrin expression and strong cytoskeletal contractility utilize integrin-dependent migration strategies that are coupled to the capacity to reorganize ECM. In contrast, a more dynamic ameboid migration type employed by smaller cells expressing low levels of integrins (i.e., T lymphocytes, dendritic cells, some tumor cells) is characterized by largely integrin-independent interaction strategies and flexible morphological adaptation to preformed fiber strands, without structurally changing matrix architecture. In tumor invasion and angiogenesis, migration mechanisms further comprise the migration of entire cell clusters or strands maintaining stringent cell-cell adhesion and communication while migrating. Lastly, cellular interactions, enzyme and cytokine secretion, and tissue remodeling provided by reactive stroma cells i.e. fibroblasts and macrophage contribute to cell migration. In conclusion, depending on the cellular composition and tissue context of migration, diverse cellular and molecular migration strategies can be developed by different cell types.
678 citations
TL;DR: The results support a model in which linker histones bind dynamically to chromatin in a stop-and-go mode, suggesting a higher rate of exchange upon chromatin remodelling.
Abstract: The linker histone H1 is believed to be involved in chromatin organization by stabilizing higher-order chromatin structure. Histone H1 is generally viewed as a repressor of transcription as it prevents the access of transcription factors and chromatin remodelling complexes to DNA. Determining the binding properties of histone H1 to chromatin in vivo is central to understanding how it exerts these functions. We have used photobleaching techniques to measure the dynamic binding of histone H1-GFP to unperturbed chromatin in living cells. Here we show that almost the entire population of H1-GFP is bound to chromatin at any one time; however, H1-GFP is exchanged continuously between chromatin regions. The residence time of H1-GFP on chromatin between exchange events is several minutes in both euchromatin and heterochromatin. In addition to the mobile fraction, we detected a kinetically distinct, less mobile fraction. After hyperacetylation of core histones, the residence time of H1-GFP is reduced, suggesting a higher rate of exchange upon chromatin remodelling. These results support a model in which linker histones bind dynamically to chromatin in a stop-and-go mode.
615 citations
TL;DR: Higher order unbinding forces, that increase with interaction time, indicate association of cadherins into complexes with cumulative binding strength, favor a model by which the inherently weak unit binding strength and affinity of Cadherin trans-interaction requires clustering and cytoskeletal immobilization for amplification.
Abstract: Single molecule atomic force microscopy was used to characterize structure, binding strength (unbinding force), and binding kinetics of a classical cadherin, vascular endothelial (VE)-cadherin, secreted by transfected Chinese hamster ovary cells as cis-dimerized full-length external domain fused to Fc-portion of human IgG. In physiological buffer, the external domain of VE-cadherin dimers is a ≈20-nm-long rod-shaped molecule that collapses and dissociates into monomers (V-shaped structures) in the absence of Ca2+. Trans-interaction of dimers is a low-affinity reaction (KD = 10−3–10−5 M, koff = 1.8 s−1, kon = 103–105 M−1·s−1) with relatively low unbinding force (35–55 pN at retrace velocities of 200–4,000 nm·s−1). Higher order unbinding forces, that increase with interaction time, indicate association of cadherins into complexes with cumulative binding strength. These observations favor a model by which the inherently weak unit binding strength and affinity of cadherin trans-interaction requires clustering and cytoskeletal immobilization for amplification. Binding is regulated by low-affinity Ca2+ binding sites (KD = 1.15 mM) with high cooperativity (Hill coefficient of 5.04). Local changes of free extracellular Ca2+ in the narrow intercellular space may be of physiological importance to facilitate rapid remodeling of intercellular adhesion and communication.
504 citations
TL;DR: In this paper, a consider-the-opposite strategy was proposed to reduce the effect of anchor-consistent knowledge on the assimilation of a numeric estimate to a previously considered standard.
Abstract: Anchoring effects—the assimilation of a numeric estimate to a previously considered standard—have proved to be remarkably robust. Results of two studies, however, demonstrate that anchoring can be reduced by applying a consider-the-opposite strategy. Based on the Selective Accessibility Model, which assumes that anchoring is mediated by the selectively increased accessibility of anchor-consistent knowledge, the authors hypothesized that increasing the accessibility of anchor-inconsistent knowledge mitigates the effect. Considering the opposite (i.e., generating reasons why an anchor is inappropriate) fulfills this objective and consequently proves to be a successful corrective strategy. In a real-world setting using experts as participants, Study 1 dem-onstrated that listing arguments that speak against a provided anchor value reduces the effect. Study 2 further revealed that the effects of anchoring and considering the opposite are additive.
481 citations
TL;DR: In this paper, a single-cell study was performed on 25 patients with Hodgkin and Reed-Sternberg (HRS) disease, with and without Epstein-Barr virus infection, for the presence of gene rearrangements.
468 citations
TL;DR: It is concluded that a tissue environment supports the accumulation of sequential signals, implicating a numeric or "digital" control mechanism for an ongoing primary immune response.
TL;DR: The existence of a yet-unknown family of intimin was suspected because several EHEC strains, isolated from human and cattle, did not react with any of the specific primer pairs, although these strains were eaepositive when primers amplifying the conserved 5′ end were used.
Abstract: Enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic E. coli (EHEC) produce the characteristic "attaching and effacing" (A/E) lesion of the brush border. Intimin, an outer membrane protein encoded by eae, is responsible for the tight association of both pathogens with the host cell. Several eae have been cloned from different EPEC and EHEC strains isolated from humans and animals. These sequences are conserved in the N-terminal region but highly variable in the last C-terminal 280 amino acids (aa), where the cell binding activity is localized. Based on these considerations, we developed a panel of specific primers to investigate the eae heterogeneity of the variable 3' region by using PCR amplification. We then investigated the distribution of the known intimin types in a large collection of EPEC and EHEC strains isolated from humans and different animal species. The existence of a yet-unknown family of intimin was suspected because several EHEC strains, isolated from human and cattle, did not react with any of the specific primer pairs, although these strains were eae positive when primers amplifying the conserved 5' end were used. We then cloned and sequenced the eae present in one of these strains (EHEC of serotype O103:H2) and subsequently designed a PCR primer that recognizes in a specific manner the variable 3' region of this new intimin type. This intimin, referred to as "epsilon," was present in human and bovine EHEC strains of serogroups O8, O11, O45, O103, O121, and O165. Intimin epsilon is the largest intimin cloned to date (948 aa) and shares the greatest overall sequence identity with intimin beta, although analysis of the last C-terminal 280 aa suggests a greater similarity with intimins alpha and gamma.
TL;DR: Since 1995, the European Association of Pathologists (EAHP) and the Society for Hematopathology (SH) have been developing a new World Health Organization (WHO) classification of haematological malignancies.
Abstract: Introduction
Since 1995, the European Association of Pathologists (EAHP) and the Society for Hematopathology (SH) have been developing a new World Health Organization (WHO) classification of haematological malignancies. The classification includes lymphoid, myeloid, histiocytic and mast cell neoplasms.
Design
The WHO project involves 10 committees of pathologists, who have developed lists and definitions of disease entities. A Clinical Advisory Committee (CAC) of international haematologists and oncologists was formed to ensure that the classification will be useful to clinicians. A meeting was held in November 1997 to discuss clinical issues related to the classification.
Results
The WHO has adopted the ‘Revised European–American Classification of Lymphoid Neoplasms’ (REAL), published in 1994 by the International Lymphoma Study Group (ILSG), as the classification of lymphoid neoplasms. This approach to classification is based on the principle that a classification is a list of ‘real’ disease entities, which are defined by a combination of morphology, immunophenotype, genetic features and clinical features. The relative importance of each of these features varies among diseases, and there is no one ‘gold standard’. The WHO classification has applied the principles of the REAL classification to myeloid and histiocytic neoplasms. The classification of myeloid neoplasms recognizes distinct entities defined by a combination of morphology and cytogenetic abnormalities. The CAC meeting, which was organized around a series of clinical questions, was able to reach a consensus on most of the questions posed. The questions and the consensus are discussed in detail below. Among other things, the CAC concluded that clinical groupings of lymphoid neoplasms was neither necessary nor desirable. Patient treatment is determined by the specific type of lymphoma, with the addition of grade within the tumour type, if applicable, and clinical prognostic factors such as the international prognostic index (IPI).
Conclusion
The experience of developing the WHO classification has produced a new and exciting degree of cooperation and communication between oncologists and pathologists from around the world, which should facilitate progress in the understanding and treatment of haematological malignancies.
TL;DR: The Clinical Advisory Committee meeting, which was organized around a series of clinical questions, was able to reach a consensus on most of the questions posed and concluded that clinical grouping of lymphoid neoplasms was neither necessary nor desirable.
TL;DR: Combined, the two alternative reproductive tactics used by male O. taurus appear to favour opposite horn phenotypes, which may explain the paucity of intermediate morphologies in natural populations of O. Taurus.
TL;DR: The hypothesis that TrxR and extracellular thioredoxin play a pathophysiologic role in chronic diseases such as rheumatoid arthritis, Sjögren's syndrom, AIDS, and certain malignancies, is substantiated by biochemical, virological, and clinical evidence.
Abstract: Human cytosolic thioredoxin reductase (TrxR), a homodimeric protein containing 1 selenocysteine and 1 FAD per subunit of 55 kDa, catalyses the NADPH-dependent reduction of thioredoxin disulfide and of numerous other oxidized cell constituents. As a general reducing enzyme with little substrate specificity, it also contributes to redox homeostasis and is involved in prevention, intervention and repair of damage caused by H2O2-based oxidative stress. Being a selenite-reducing enzyme as well as a selenol-containing enzyme, human TrxR plays a central role in selenium (patho)physiology. Both dietary selenium deficiency and selenium oversupplementation, a lifestyle phenomenon of our time, appear to interfere with the activity of TrxR. Selenocysteine 496 of human TrxR is a major target of the anti-rheumatic gold-containing drug auranofin, the formal Ki for the stoichiometric inhibition being 4 nM. The hypothesis that TrxR and extracellular thioredoxin play a pathophysiologic role in chronic diseases such as rheumatoid arthritis, Sjogren's syndrom, AIDS, and certain malignancies, is substantiated by biochemical, virological, and clinical evidence. Reduced thioredoxin acts as an autocrine growth factor in various tumour diseases, as a chemoattractant, and it synergises with interleukins 1 and 2. The effects of anti-tumour drugs such as carmustine and cisplatin can be explained in part by the inhibition of TrxR. Consistently, high levels of the enzyme can support drug resistance. TrxRs from different organisms such as Escherichia coli, Mycobacterium leprae, Plasmodium falciparum, Drosophila melanogaster, and man show a surprising diversity in their chemical mechanism of thioredoxin reduction. This is the basis for attempts to develop specific TrxR inhibitors as drugs against bacterial infections like leprosy and parasitic diseases like amebiasis and malaria.
TL;DR: It is concluded that the balance between levels of activated matrix metalloproteinases and expression levels of their tissue inhibitors, and the coexpression of activates and adhesion molecules are important factors in determining melanoma cell invasion, tumor growth, and metastasis formation.
TL;DR: Maintenance chemotherapy would seem to be more effective in low-risk medulloblastoma, especially in patients older than 6 years of age, and quality control of radiotherapy revealed correct treatment in more than 88% for dose prescription, more than 90% for coverage of target volume, and 98% for field matching.
Abstract: Purpose: The German Society of Pediatric Hematology and Oncology (GPOH) conducted a randomized, prospective, multicenter trial (HIT ’91) in order to improve the survival of children with medulloblastoma by using postoperative neoadjuvant chemotherapy before radiation therapy as opposed to maintenance chemotherapy after immediate postoperative radiotherapy.
Methods and Materials: Between 1991 and 1997, 158 patients were enrolled and 137 patients randomized. Seventy-two patients were allocated to receive neoadjuvant chemotherapy before radiotherapy (arm I, investigational). Chemotherapy consisted of ifosfamide, etoposide, intravenous high-dose methotrexate, cisplatin, and cytarabine given in two cycles. In arm II (standard arm), 65 patients were assigned to receive immediate postoperative radiotherapy, with concomitant vincristine followed by 8 cycles of maintenance chemotherapy consisting of cisplatin, CCNU, and vincristine (“Philadelphia protocol”). All patients received radiotherapy to the craniospinal axis (35.2 Gy total dose, 1.6 Gy fractionated dose / 5 times per week followed by a boost to posterior fossa with 20 Gy, 2.0 Gy fractionated dose).
Results: During chemotherapy Grade III/IV infections were predominant in arm I (40%). Peripheral neuropathy and ototoxicity were prevailing in arm II (37% and 34%, respectively). Dose modification was necessary in particular in arm II (63%). During radiotherapy acute toxicity was mild in the majority of patients and equally distributed in both arms. Myelosuppression led to a mean prolongation of treatment time of 11.5 days in arm I and 7.5 days in arm II, and interruptions in 35% of patients in arm I. Quality control of radiotherapy revealed correct treatment in more than 88% for dose prescription, more than 88% for coverage of target volume, and 98% for field matching. At a median follow-up of 30 months (range 1.4–62 months), the Kaplan-Meier estimates for relapse-free survival at 3 years for all randomized patients were 0.70 ± 0.08; for patients with residual disease: 0.72 ±0.06; without residual disease: 0.68 ± 0.09; M0: 0.72 ± 0.04; M1: 0.65 ± 0.12; and M2/3: 0.30 ± 0.15. For all randomized patients without M2/3 disease: 0.65± 0.05 (arm I) and 0.78 ± 0.06 (arm II) (p < 0.03); patients between 3 and 5.9 years: 0.60 ± 0.13 and 0.64 ± 0.14, respectively, but patients between 6 and 18 years: 0.62 ± 0.09 and 0.84 ± 0.08, respectively (p < 0.03). In a univariate analysis the only negative prognostic factors were M2/3 disease (p < 0.002) and an age of less than 8 years (p < 0.03).
Conclusions: Maintenance chemotherapy would seem to be more effective in low-risk medulloblastoma, especially in patients older than 6 years of age. Neoadjuvant chemotherapy was accompanied by increased myelotoxicity of the subsequent radiotherapy, causing a higher rate of interruptions and an extended overall treatment time. Delayed and/or protracted radiotherapy may therefore have a negative impact on outcome. M2/3 disease was associated with a poor survival in both arms, suggesting the need for a more intensive treatment. Young age and M2/3 stage were negative prognostic factors in medulloblastoma, but residual or M1 disease was not, suggesting a new stratification system for risk subgroups. High quality of radiotherapy may be a major contributing factor for the overall outcome.
TL;DR: It is demonstrated that the incorporation of these coil parameters into a localized Fourier transform allows reconstruction of full FOV images in each of the component coils from data sets acquired with a reduced number of phase encoding steps compared to conventional imaging techniques.
Abstract: In this study a novel partially parallel acquisition method is presented, which can be used to accelerate image acquisition using an RF coil array for spatial encoding. In this technique, Parallel Imaging with Localized Sensitivities (PILS), it is assumed that the individual coils in the array have localized sensitivity patterns, in that their sensitivity is restricted to a finite region of space. Within the PILS model, a detailed, highly accurate RF field map is not needed prior to reconstruction. In PILS, each coil in the array is fully characterized by only two parameters: the center of coil's sensitive region in the FOV and the width of the sensitive region around this center. In this study, it is demonstrated that the incorporation of these coil parameters into a localized Fourier transform allows reconstruction of full FOV images in each of the component coils from data sets acquired with a reduced number of phase encoding steps compared to conventional imaging techniques. After the introduction of the PILS technique, primary focus is given to issues related to the practical implementation of PILS, including coil parameter determination and the SNR and artifact power in the resulting images. Finally, in vivo PILS images are shown which demonstrate the utility of the technique.
TL;DR: With accelerated radiotherapy, the efficiency of simultaneously given chemotherapy may be not as high as expected when compared to standard fractionated RT and should be given in radiotherapy regimen only with strong hematologic indication.
Abstract: Purpose: To demonstrate the efficacy of radiochemotherapy (RCT) as the first choice of treatment for advanced unresectable head-and-neck cancer. To prove an expected benefit of simultaneously given chemotherapy, a two-arm randomized study with hyperfractionated accelerated radiochemotherapy (HF-ACC-RCT) vs. hyperfractionated accelerated radiotherapy (HF-ACC-RT) was initiated. The primary endpoint was 1-year survival with local control (SLC). Methods and Materials: Patients with Stage III and IV (UICC) unresectable oro- and hypopharyngeal carcinomas were randomized for HF-ACC-RCT with 2 cycles of 5-FU (600 mg/m2/day)/carboplatinum (70 mg/m2) on days 1–5 and 29–33 (arm A) or HF-ACC-RT alone (arm B). In both arms, there was a second randomization for testing the effect of prophylactically given G-CSF (263 μg, days 15–19) on mucosal toxicity. Total RT dose in both arms was 69.9 Gy in 38 days, with a concomitant boost regimen (weeks 1–3: 1.8 Gy/day, weeks 4 and 5: b.i.d. RT with 1.8 Gy/1.5 Gy). Between July 1995 and May 1999, 263 patients were randomized (median age 56 years; 96% Stage IV tumors, 4% Stage III tumors). Results: This analysis is based on 240 patients: 113 patients with RCT and 127 patients with RT, qualified for protocol and starting treatment. There were 178 oropharyngeal and 62 hypopharyngeal carcinomas. Treatment was tolerable in both arms, with a higher mucosal toxicity after RCT. Restaging showed comparable nonsignificant different CR + PR rates of 92.4% after RCT and 87.9% after RT (p = 0.29). After a median observed time of 22.3 months, l- and 2-year local-regional control (LRC) rates were 69% and 51% after RCT and 58% and 45% after RT (p = 0.14). There was a significantly better 1-year SLC after RCT (58%) compared with RT (44%, p = 0.05). Patients with oropharyngeal carcinomas showed significantly better SLC after RCT (60%) vs. RT (40%, p = 0.01); the smaller group of hypopharyngeal carcinomas had no statistical benefit of RCT (p = 0.84). For both tumor locations, prophylactically given G-CSF was a poor prognostic factor (Cox regression), and resulted in reduced LRC (log-rank test: ± G-CSF, p = 0.0072). Conclusion: With accelerated radiotherapy, the efficiency of simultaneously given chemotherapy may be not as high as expected when compared to standard fractionated RT. Oropharyngeal carcinomas showed better LRC after HF-ACC-RCT vs. HF-ACC-RT; hypopharyngeal carcinomas did not. Prophylactic G-CSF resulted in an unexpected reduced local control and should be given in radiotherapy regimen only with strong hematologic indication.
TL;DR: This contribution reviews studies of major gene effects in inbred and knockout strains of mice with increased aggression-related behavior and discusses the relevance of several serotonergic gene variations in humans which include high aggressiveness as part of the phenotype.
Abstract: The expression of aggressiveness, which constitutes many facets of behavior, is influenced by a complex interaction of biologic, psychologic, and social variables. Even though individual differences in impulsivity and the behavioral consequences, such as aggression, addiction, and suicidality, are substantially heritable, they ultimately result from an interplay between genetic variations and environmental factors. While formation and integration of multiple neural networks is dependent on the actions of neurotransmitters, such as serotonin (5HT), converging lines of evidence indicate that genetically determined variability in serotonergic gene expression influences complex traits including that of inappropriately aggressive behavior. This contribution reviews studies of major gene effects in inbred and knockout strains of mice with increased aggression-related behavior and discusses the relevance of several serotonergic gene variations in humans which include high aggressiveness as part of the phenotype. Although special emphasis is given to the molecular psychobiology of 5HT in aggression-related behavior in rodents, nonhuman primates, and humans, relevant conceptual and methodological issues in the search for candidate genes for impulsivity and aggressiveness and for the development of mouse models of aggressive and antisocial behavior in humans are also considered.
TL;DR: Artificial electronic structure is investigated by injecting optically a controlled number of electrons and holes into an isolated single quantum dot, which forms complexes that are artificial analogues of hydrogen, helium, lithium, beryllium, boron and carbon excitonic atoms.
Abstract: Quantum dots1,2,3,4,5,6,7 or ‘artificial atoms’ are of fundamental and technological interest—for example, quantum dots8,9 may form the basis of new generations of lasers The emission in quantum-dot lasers originates from the recombination of excitonic complexes, so it is important to understand the dot's internal electronic structure (and of fundamental interest to compare this to real atomic structure) Here we investigate artificial electronic structure by injecting optically a controlled number of electrons and holes into an isolated single quantum dot The charge carriers form complexes that are artificial analogues of hydrogen, helium, lithium, beryllium, boron and carbon excitonic atoms We observe that electrons and holes occupy the confined electronic shells in characteristic numbers according to the Pauli exclusion principle In each degenerate shell, collective condensation of the electrons and holes into coherent many-exciton ground states takes place; this phenomenon results from hidden symmetries (the analogue of Hund's rules for real atoms) in the energy function that describes the multi-particle system Breaking of the hidden symmetries leads to unusual quantum interferences in emission involving excited states
TL;DR: A combination of six polymorphisms in neurotransmitter-receptor-related genes resulted in 76.7% success in the prediction of clozapine response and a sensitivity of 95% (+/- 0.04) for satisfactory response in schizophrenic patients.
TL;DR: The proposed role for ABCA4 in age-related macular degeneration (AMD), a common cause of late-onset blindness, is assessed by studying 200 affected individuals with late-stage disease and using a screening strategy based primarily on denaturing gradient gel electrophoresis.
Abstract: Stargardt disease (STGD) is a common autosomal recessive maculopathy of early and young-adult onset and is caused by alterations in the gene encoding the photoreceptor-specific ATP-binding cassette (ABC) transporter (ABCA4). We have studied 144 patients with STGD and 220 unaffected individuals ascertained from the German population, to complete a comprehensive, population-specific survey of the sequence variation in the ABCA4 gene. In addition, we have assessed the proposed role for ABCA4 in age-related macular degeneration (AMD), a common cause of late-onset blindness, by studying 200 affected individuals with late-stage disease. Using a screening strategy based primarily on denaturing gradient gel electrophoresis, we have identified in the three study groups a total of 127 unique alterations, of which 90 have not been previously reported, and have classified 72 as probable pathogenic mutations. Of the 288 STGD chromosomes studied, mutations were identified in 166, resulting in a detection rate of ∼58%. Eight different alleles account for 61% of the identified disease alleles, and at least one of these, the L541P-A1038V complex allele, appears to be a founder mutation in the German population. When the group with AMD and the control group were analyzed with the same methodology, 18 patients with AMD and 12 controls were found to harbor possible disease-associated alterations. This represents no significant difference between the two groups; however, for detection of modest effects of rare alleles in complex diseases, the analysis of larger cohorts of patients may be required.
TL;DR: In this paper, two theories about how honeybees estimate the distance to food sources were tested by observing dances of bees that have flown through a short, narrow tunnel to collect a food reward.
Abstract: There are two theories about how honeybees estimate the distance to food sources. One theory proposes that distance flown is estimated in terms of energy consumption. The other suggests that the cue is visual, and is derived from the extent to which the image of the world has moved on the eye during the trip. Here the two theories are tested by observing dances of bees that have flown through a short, narrow tunnel to collect a food reward. The results show that the honeybee's "odometer" is visually driven. They also provide a calibration of the dance and the odometer in visual terms.
TL;DR: The occurrence of a new Stx2 variant in STEC from pigeons enlarges the pool of Stx 2 variants and raises the question whether horizontal gene transfer to E. coli pathogenic to humans may occur.
Abstract: We have isolated Shiga toxin (Stx)-producing Escherichia coli (STEC) strains from the feces of feral pigeons which contained a new Stx2 variant gene designated stx(2f). This gene is most similar to sltIIva of patient E. coli O128:B12 isolate H.I.8. Stx2f reacted only weakly with commercial immunoassays. The prevalence of STEC organisms carrying the stx(2f) gene in pigeon droppings was 12.5%. The occurrence of a new Stx2 variant in STEC from pigeons enlarges the pool of Stx2 variants and raises the question whether horizontal gene transfer to E. coli pathogenic to humans may occur.
TL;DR: The comparative pharmacological characterization of all four human adenosine receptor subtypes revealed that some of the compounds thought to be selective from data in other species have unexpected potencies at human receptors.
Abstract: The regulatory actions of adenosine are mediated via four subtypes of G protein-coupled receptors distinguished as A1, A2A, A2B and A3 receptors Their presence on basically every cell makes them an interesting target for the pharmacological intervention in many pathophysiological situations A large number of ligands have been synthesized over the last two decades and provide agonists and antagonists that are more or less selective for the known receptor subtypes In addition, many radioligands are available in tritiated or radioiodinated form The comparative pharmacological characterization of all four human adenosine receptor subtypes revealed that some of the compounds thought to be selective from data in other species have unexpected potencies at human receptors As a result, compounds that exhibit high affinity to only one subtype are an exception Although the selection of ligands is immense, it is less than satisfying for most subtypes of adenosine receptors
TL;DR: The model reveals the structural basis for discrimination between type I and type II receptors and the variability of receptor–ligand interactions that is seen in BMP–TGF-β systems.
Abstract: Bone morphogenetic proteins (BMPs) belong to the large transforming growth factor-beta (TGF-beta) superfamily of multifunctional cytokines. BMP-2 can induce ectopic bone and cartilage formation in adult vertebrates and is involved in central steps in early embryonal development in animals. Signaling by these cytokines requires binding of two types of transmembrane serine/threonine receptor kinase chains classified as type I and type II. Here we report the crystal structure of human dimeric BMP-2 in complex with two high affinity BMP receptor IA extracellular domains (BRIAec). The receptor chains bind to the 'wrist' epitopes of the BMP-2 dimer and contact both BMP-2 monomers. No contacts exist between the receptor domains. The model reveals the structural basis for discrimination between type I and type II receptors and the variability of receptor-ligand interactions that is seen in BMP-TGF-beta systems.
TL;DR: Assaying reactivity to BP180 should be a helpful guide for the therapeutic management of patients with this disease and underline the pathogenic relevance of autoantibodies to human BP180.
Abstract: Objective To investigate the possible correlation of levels of circulating anti-BP180 autoantibodies with disease activity in bullous pemphigoid (BP). Design Diagnostic study. Setting Regional referral center at a university dermatology department. Patients Fifteen patients with typical clinical, histologic, and immunofluorescence findings of BP who had not received prior systemic treatment. Interventions Initially, 6 consecutive patients with BP were treated with oral doxycycline and niacinamide. Subsequently, 9 consecutive patients with BP received a combination of oral dapsone and prednisolone. Main Outcome Measures Disease activity, serum levels of autoantibodies to BP180, and titers of anti–basement membrane zone autoantibodies were assayed before initiation of treatment and 4 and 8 weeks later. Reactivity to BP180 was analyzed by enzyme-linked immunosorbent assay using a recombinant form of BP180 NC16A. Titers of anti–basement membrane zone autoantibodies were assayed by indirect immunofluorescence on 1-mol/L sodium chloride–split human skin. Results In both treatment groups, disease activity correlated with serum levels of autoantibodies to BP180 NC16A ( P = .004 [dapsone-prednisolone] and .007 [doxycycline-niacinamide]). No correlation was seen between disease activity and indirect immunofluorescence reactivity ( P = .18 and .16, respectively). In patients receiving dapsone plus prednisolone, the dose of corticosteroids necessary to suppress new blister formation correlated with anti-BP180 reactivity ( P = .002). Conclusions In contrast to indirect immunofluorescence reactivity that reflects reactivity to both BP180 and BP230, serum levels of autoantibodies to BP180 correlate with disease activity in BP. Assaying reactivity to BP180 should be a helpful guide for the therapeutic management of patients with this disease. Our results underline the pathogenic relevance of autoantibodies to human BP180.