Showing papers by "University of Göttingen published in 2006"
TL;DR: Rituximab added to six cycles of CHOP is an effective treatment for young patients with good-prognosis diffuse large-B-cell lymphoma and the definition of two prognostic subgroups allows for a more refined therapeutic approach for these patients.
Abstract: Summary Background The role of rituximab in combination with diff erent CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-like chemotherapy regimens in young patients with good-prognosis diff use large-B-cell lymphoma remains to be defi ned. We aimed to compare CHOP-like chemotherapy and rituximab with CHOP-like chemotherapy alone in these patients. Methods 824 patients who were from 18 countries; aged 18–60 years; and who had no risk factors or one risk factor according to age-adjusted International Prognostic Index (IPI), stage II–IV disease, or stage I disease with bulk were enrolled. These patients were randomly assigned to six cycles of CHOP-like chemotherapy and rituximab (n=413) or to six cycles of CHOP-like chemotherapy alone (n=411). Bulky and extranodal sites received additional radiotherapy. The primary endpoint was event-free survival; secondary endpoints were response, progression under therapy, progression-free survival, overall survival, and frequency of toxic eff ects. Analyses were done by intention to treat and per protocol. This trial is registered at http://www.clinicaltrials.gov, NCT 00064116. Findings After a median follow-up of 34 months (range 0·03–61), patients assigned chemotherapy and rituximab had increased 3-year event-free survival compared with those assigned chemotherapy alone (79% [95% CI 75–83] vs 59% [54–64]; diff erence between groups 20% [13–27], log-rank p<0·0001), and had increased 3-year overall survival (93% [90–95] vs 84% [80–88]; diff erence between groups 9% [3–13], log-rank p=0·0001). Event-free survival was aff ected by treatment group, presence of bulky disease, and age-adjusted IPI: after chemotherapy and rituximab, a favourable subgroup (ie, IPI=0, no bulk) could be defi ned from a less-favourable subgroup (ie, IPI=1 or bulk, or both). Groups did not diff er in the frequency of adverse events.
1,850 citations
University of California, Riverside1, University of Leeds2, University of Cambridge3, Max Planck Society4, National Institute of Standards and Technology5, Commonwealth Scientific and Industrial Research Organisation6, Imperial College London7, École Polytechnique Fédérale de Lausanne8, University of Göttingen9, Ford Motor Company10
TL;DR: The IUPAC Subcommittee on Gas Kinetic Data Evaluation for Atmospheric Chemistry (IUPAC-GKDE) as mentioned in this paper has published a series of data sheets for organic halogen species.
Abstract: This article, the fourth in the series, presents kinetic and photochemical data sheets evaluated by the IUPAC Subcommittee on Gas Kinetic Data Evaluation for Atmospheric Chemistry. It covers the gas phase and photochemical reactions of organic halogen species, which were last published in 1997, and were updated on the IUPAC website in 2006/07. The article consists of a summary sheet, containing the recommended kinetic parameters for the evaluated reactions, and four appendices containing the data sheets, which provide information upon which the recommendations are made.
1,623 citations
TL;DR: To the authors' knowledge, this is the first ab initio gene finder that can predict multiple transcripts and offers a motif searching facility, where user-defined regular expressions can be searched against putative proteins encoded by the predicted genes.
Abstract: AUGUSTUS is a software tool for gene prediction in eukaryotes based on a Generalized Hidden Markov Model, a probabilistic model of a sequence and its gene structure. Like most existing gene finders, the first version of AUGUSTUS returned one transcript per predicted gene and ignored the phenomenon of alternative splicing. Herein, we present a WWW server for an extended version of AUGUSTUS that is able to predict multiple splice variants. To our knowledge, this is the first ab initio gene finder that can predict multiple transcripts. In addition, we offer a motif searching facility, where user-defined regular expressions can be searched against putative proteins encoded by the predicted genes. The AUGUSTUS web interface and the downloadable open-source stand-alone program are freely available from http://augustus.gobics.de.
1,557 citations
TL;DR: A revised classification for extant ferns is presented, with emphasis on ordinal and familial ranks, and a synopsis of included genera is provided, reflecting recently published phylogenetic hypotheses based on both morphological and molecular data.
Abstract: We present a revised classification for extant ferns, with emphasis on ordinal and familial ranks, and a synopsis of included genera. Our classification reflects recently published phylogenetic hypotheses based on both morphological and molecular data. Within our new classification, we recognize four monophyletic classes, 11 monophyletic orders, and 37 families, 32 of which are strongly supported as monophyletic. One new family, Cibotiaceae Korall, is described. The phylogenetic affinities of a few genera in the order Polypodiales are unclear and their familial placements are therefore tentative. Alphabetical lists of accepted genera (including common synonyms), families, orders, and taxa of higher rank are provided.
1,363 citations
Book•
11 Sep 2006TL;DR: It is shown that domino reactions initiated by oxidation or reduction or reduction, as well as other mechanisms, can be inhibited by various materials, such as Na6(CO3)(SO4), Na2SO4, Na2CO3, and so on.
Abstract: Introduction Cationic domino reactions Anionic domino reactions Radical domino reactions Pericyclic domino reactions Photochemically induced domino processes Transition metal catalysis Domino reactions initiated by oxidation or reduction Enzymes in domino reactions Multicomponent reactions Special techniques in domino reactions
1,337 citations
TL;DR: In ARDS, the percentage of potentially recruitable lung is extremely variable and is strongly associated with the response to PEEP, which may decrease ventilator-induced lung injury by keeping lung regions open that otherwise would be collapsed.
Abstract: Background In the acute respiratory distress syndrome (ARDS), positive end-expiratory pressure (PEEP) may decrease ventilator-induced lung injury by keeping lung regions open that otherwise would be collapsed. Since the effects of PEEP probably depend on the recruitability of lung tissue, we conducted a study to examine the relationship between the percentage of potentially recruitable lung, as indicated by computed tomography (CT), and the clinical and physiological effects of PEEP. Methods Sixty-eight patients with acute lung injury or ARDS underwent whole-lung CT during breath-holding sessions at airway pressures of 5, 15, and 45 cm of water. The percentage of potentially recruitable lung was defined as the proportion of lung tissue in which aeration was restored at airway pressures between 5 and 45 cm of water. Results The percentage of potentially recruitable lung varied widely in the population, accounting for a mean (±SD) of 13±11 percent of the lung weight, and was highly correlated with the percentage of lung tissue in which aeration was maintained after the application of PEEP (r 2 = 0.72, P<0.001). On average, 24 percent of the lung could not be recruited. Patients with a higher percentage of potentially recruitable lung (greater than the median value of 9 percent) had greater total lung weights (P<0.001), poorer oxygenation (defined as a ratio of partial pressure of arterial oxygen to fraction of inspired oxygen) (P<0.001) and respiratory-system compliance (P = 0.002), higher levels of dead space (P = 0.002), and higher rates of death (P = 0.02) than patients with a lower percentage of potentially recruitable lung. The combined physiological variables predicted, with a sensitivity of 71 percent and a specificity of 59 percent, whether a patient’s proportion of potentially recruitable lung was higher or lower than the median. Conclusions In ARDS, the percentage of potentially recruitable lung is extremely variable and is strongly associated with the response to PEEP.
1,260 citations
TL;DR: The structural basis for MHC restriction and signaling remains elusive as no structural features that define a common binding mode or signaling mechanism have yet been gleaned from the current set of TCR/pMHC complexes.
Abstract: Since the first crystal structure determinations of alphabeta T cell receptors (TCRs) bound to class I MHC-peptide (pMHC) antigens in 1996, a sizable database of 24 class I and class II TCR/pMHC complexes has been accumulated that now defines a substantial degree of structural variability in TCR/pMHC recognition. Recent determination of free and bound gammadelta TCR structures has enabled comparisons of the modes of antigen recognition by alphabeta and gammadelta T cells and antibodies. Crystal structures of TCR accessory (CD4, CD8) and coreceptor molecules (CD3epsilondelta, CD3epsilongamma) have further advanced our structural understanding of most of the components that constitute the TCR signaling complex. Despite all these efforts, the structural basis for MHC restriction and signaling remains elusive as no structural features that define a common binding mode or signaling mechanism have yet been gleaned from the current set of TCR/pMHC complexes. Notwithstanding, the impressive array of self, foreign (microbial), and autoimmune TCR complexes have uncovered the diverse ways in which antigens can be specifically recognized by TCRs.
1,195 citations
TL;DR: A robust approach to evaluate agri-environment schemes is described and it is used to evaluate the biodiversity effects of agri -environment schemes in five European countries and found marginal to moderately positive effects on biodiversity.
Abstract: Agri-environment schemes are an increasingly important tool for the maintenance and restoration of farmland biodiversity in Europe but their ecological effects are poorly known. Scheme design is partly based on non-ecological considerations and poses important restrictions on evaluation studies. We describe a robust approach to evaluate agri-environment schemes and use it to evaluate the biodiversity effects of agri-environment schemes in five European countries. We compared species density of vascular plants, birds, bees, grasshoppers and crickets, and spiders on 202 paired fields, one with an agri-environment scheme, the other conventionally managed. In all countries, agri-environment schemes had marginal to moderately positive effects on biodiversity. However, uncommon species benefited in only two of five countries and species listed in Red Data Books rarely benefited from agri-environment schemes. Scheme objectives may need to differentiate between biodiversity of common species that can be enhanced with relatively simple modifications in farming practices and diversity or abundance of endangered species which require more elaborate conservation measures.
1,000 citations
TL;DR: Critically discuss models of experimental autoimmune encephalomyelitis that reproduce specific features of the histopathology and neurobiology of multiple sclerosis and their shortcomings as tools to investigate emerging therapeutic approaches.
Abstract: In view of disease heterogeneity of multiple sclerosis and limited access to ex vivo specimens, different approaches must be undertaken to better understand disease pathogenesis and new therapeutic challenges. Here, we critically discuss models of experimental autoimmune encephalomyelitis (EAE) that reproduce specific features of the histopathology and neurobiology of multiple sclerosis and their shortcomings as tools to investigate emerging therapeutic approaches. By using EAE models we have understood mechanisms of T-cell mediated immune damage of the CNS, and the associated effector cascade of innate immunity. Also, the importance of humoral components of the immune system for demyelination has been delineated in EAE, before it was applied therapeutically to subtypes of multiple sclerosis. Yet, similar to multiple sclerosis, EAE is also heterogeneous and influenced by the selected autoantigen, species and the genetic background. In particular, the relevance of cytotoxic CD8 T cells for human multiple sclerosis has been underestimated in most EAE models, and no EAE model exists that mimics primary progressive disease courses of multiple sclerosis. Seventy years after the first description of EAE and the publication of >7000 articles, we are aware of the obvious limitations of EAE as a model of multiple sclerosis, but feel strongly that when used appropriately it will continue to provide a crucial tool for improving our understanding and treatment of this devastating disease.
995 citations
TL;DR: Sensitive probabilistic modeling of extrinsic evidence such as sequence database matches can increase gene prediction accuracy and be used to extend the ab initio gene prediction program AUGUSTUS to a versatile tool that is able to predict genes under user-defined constraints.
Abstract: Background
In order to improve gene prediction, extrinsic evidence on the gene structure can be collected from various sources of information such as genome-genome comparisons and EST and protein alignments. However, such evidence is often incomplete and usually uncertain. The extrinsic evidence is usually not sufficient to recover the complete gene structure of all genes completely and the available evidence is often unreliable. Therefore extrinsic evidence is most valuable when it is balanced with sequence-intrinsic evidence.
946 citations
TL;DR: The molecular definition of Burkitt's lymphoma clarifies and extends the spectrum of the WHO criteria for Burkitt’s lymphoma.
Abstract: Background The distinction between Burkitt’s lymphoma and diffuse large-B-cell lymphoma is unclear. We used transcriptional and genomic profiling to define Burkitt’s lymphoma more precisely and to distinguish subgroups in other types of mature aggressive B-cell lymphomas. Methods We performed gene-expression profiling using Affymetrix U133A GeneChips with RNA from 220 mature aggressive B-cell lymphomas, including a core group of 8 Burkitt’s lymphomas that met all World Health Organization (WHO) criteria. A molecular signature for Burkitt’s lymphoma was generated, and chromosomal abnormalities were detected with interphase fluorescence in situ hybridization and array-based comparative genomic hybridization. Results We used the molecular signature for Burkitt’s lymphoma to identify 44 cases: 11 had the morphologic features of diffuse large-B-cell lymphomas, 4 were unclassifiable mature aggressive B-cell lymphomas, and 29 had a classic or atypical Burkitt’s morphologic appearance. Also, five did not have a detectable IG-myc Burkitt’s translocation, whereas the others contained an IG-myc fusion, mostly in simple karyotypes. Of the 176 lymphomas without the molecular signature for Burkitt’s lymphoma, 155 were diffuse large-B-cell lymphomas. Of these 155 cases, 21 percent had a chromosomal breakpoint at the myc locus associated with complex chromosomal changes and an unfavorable clinical course. Conclusions Our molecular definition of Burkitt’s lymphoma clarifies and extends the spectrum of the WHO criteria for Burkitt’s lymphoma. In mature aggressive B-cell lymphomas without a gene signature for Burkitt’s lymphoma, chromosomal breakpoints at the myc locus were associated with an adverse clinical outcome.
TL;DR: Discovery of hybrid peptide-polyketide genotoxins in E. coli will change the view on pathogenesis and commensalism and open new biotechnological applications.
Abstract: Transient infection of eukaryotic cells with commensal and extraintestinal pathogenic Escherichia coli of phylogenetic group B2 blocks mitosis and induces megalocytosis. This trait is linked to a widely spread genomic island that encodes giant modular nonribosomal peptide and polyketide synthases. Contact with E. coli expressing this gene cluster causes DNA double-strand breaks and activation of the DNA damage checkpoint pathway, leading to cell cycle arrest and eventually to cell death. Discovery of hybrid peptide-polyketide genotoxins in E. coli will change our view on pathogenesis and commensalism and open new biotechnological applications.
TL;DR: Guan et al. as discussed by the authors used genetic selection to isolate adult spermatogonial stem cells (SSCs) from adult mouse testis using a success rate of 27%.
Abstract: Some cells in newborn mouse testis are — like embryonic stem cells — able to generate many different tissue types. Guan et al. have discovered that these cells persist in the adult. Sperm-producing stem cells from mouse adult testis can grow as heart, nerve or muscle cells in the right conditions. If similar multipotent adult germline stem cells (maGSCs) can be isolated from humans — perhaps by simple testicular biopsy — they might provide an alternative source of genetically matched therapeutic cells. Stem cells isolated from the testis of adult mice show similar characteristics to embryonic stem cells — suggesting that stem cells capable of forming many different tissues may be accessible from testicular biopsies. Embryonic germ cells as well as germline stem cells from neonatal mouse testis are pluripotent and have differentiation potential similar to embryonic stem cells1,2, suggesting that the germline lineage may retain the ability to generate pluripotent cells. However, until now there has been no evidence for the pluripotency and plasticity of adult spermatogonial stem cells (SSCs), which are responsible for maintaining spermatogenesis throughout life in the male3. Here we show the isolation of SSCs from adult mouse testis using genetic selection, with a success rate of 27%. These isolated SSCs respond to culture conditions and acquire embryonic stem cell properties. We name these cells multipotent adult germline stem cells (maGSCs). They are able to spontaneously differentiate into derivatives of the three embryonic germ layers in vitro and generate teratomas in immunodeficient mice. When injected into an early blastocyst, SSCs contribute to the development of various organs and show germline transmission. Thus, the capacity to form multipotent cells persists in adult mouse testis. Establishment of human maGSCs from testicular biopsies may allow individual cell-based therapy without the ethical and immunological problems associated with human embryonic stem cells. Furthermore, these cells may provide new opportunities to study genetic diseases in various cell lineages.
TL;DR: The MIPI as discussed by the authors is the first prognostic index particularly suited for mantle cell lymphoma patients and may serve as an important tool to facilitate risk-adapted treatment decisions in patients with advanced stage MCL.
Journal Article•
TL;DR: In this paper, the authors used genetic selection to isolate adult spermatogonial stem cells (SSCs) from adult mouse testis using a success rate of 27% and found that these isolated SSCs respond to culture conditions and acquire embryonic stem cell properties.
Abstract: Some cells in newborn mouse testis are — like embryonic stem cells — able to generate many different tissue types Guan et al have discovered that these cells persist in the adult Sperm-producing stem cells from mouse adult testis can grow as heart, nerve or muscle cells in the right conditions If similar multipotent adult germline stem cells (maGSCs) can be isolated from humans — perhaps by simple testicular biopsy — they might provide an alternative source of genetically matched therapeutic cells Stem cells isolated from the testis of adult mice show similar characteristics to embryonic stem cells — suggesting that stem cells capable of forming many different tissues may be accessible from testicular biopsies Embryonic germ cells as well as germline stem cells from neonatal mouse testis are pluripotent and have differentiation potential similar to embryonic stem cells1,2, suggesting that the germline lineage may retain the ability to generate pluripotent cells However, until now there has been no evidence for the pluripotency and plasticity of adult spermatogonial stem cells (SSCs), which are responsible for maintaining spermatogenesis throughout life in the male3 Here we show the isolation of SSCs from adult mouse testis using genetic selection, with a success rate of 27% These isolated SSCs respond to culture conditions and acquire embryonic stem cell properties We name these cells multipotent adult germline stem cells (maGSCs) They are able to spontaneously differentiate into derivatives of the three embryonic germ layers in vitro and generate teratomas in immunodeficient mice When injected into an early blastocyst, SSCs contribute to the development of various organs and show germline transmission Thus, the capacity to form multipotent cells persists in adult mouse testis Establishment of human maGSCs from testicular biopsies may allow individual cell-based therapy without the ethical and immunological problems associated with human embryonic stem cells Furthermore, these cells may provide new opportunities to study genetic diseases in various cell lineages
TL;DR: It is shown that deletion mutant mice lacking neuroligin expression die shortly after birth due to respiratory failure, and that neuroligins are required for proper synapse maturation and brain function, but not for the initial formation of synaptic contacts.
TL;DR: These studies establish germline KRAS mutations as a cause of human disease and infer that the constellation of developmental abnormalities seen in Noonan syndrome spectrum is, in large part, due to hyperactive Ras.
Abstract: Noonan syndrome (MIM 163950) is characterized by short stature, facial dysmorphism and cardiac defects. Heterozygous mutations in PTPN11, which encodes SHP-2, cause approximately 50% of cases of Noonan syndrome. The SHP-2 phosphatase relays signals from activated receptor complexes to downstream effectors, including Ras. We discovered de novo germline KRAS mutations that introduce V14I, T58I or D153V amino acid substitutions in five individuals with Noonan syndrome and a P34R alteration in a individual with cardio-facio-cutaneous syndrome (MIM 115150), which has overlapping features with Noonan syndrome. Recombinant V14I and T58I K-Ras proteins show defective intrinsic GTP hydrolysis and impaired responsiveness to GTPase activating proteins, render primary hematopoietic progenitors hypersensitive to growth factors and deregulate signal transduction in a cell lineage-specific manner. These studies establish germline KRAS mutations as a cause of human disease and infer that the constellation of developmental abnormalities seen in Noonan syndrome spectrum is, in large part, due to hyperactive Ras.
TL;DR: The results of this study suggest that this new approach of cortical stimulation can be effective to control pain in patients with spinal cord lesion, and potential mechanisms for pain amelioration after tDCS, such as a secondary modulation of thalamic nuclei activity.
Abstract: Past evidence has shown that motor cortical stimulation with invasive and non-invasive brain stimulation is effective to relieve central pain. Here we aimed to study the effects of another, very safe technique of non-invasive brain stimulation--transcranial direct current stimulation (tDCS)--on pain control in patients with central pain due to traumatic spinal cord injury. Patients were randomized to receive sham or active motor tDCS (2mA, 20 min for 5 consecutive days). A blinded evaluator rated the pain using the visual analogue scale for pain, Clinician Global Impression and Patient Global Assessment. Safety was assessed with a neuropsychological battery and confounders with the evaluation of depression and anxiety changes. There was a significant pain improvement after active anodal stimulation of the motor cortex, but not after sham stimulation. These results were not confounded by depression or anxiety changes. Furthermore, cognitive performance was not significantly changed throughout the trial in both treatment groups. The results of our study suggest that this new approach of cortical stimulation can be effective to control pain in patients with spinal cord lesion. We discuss potential mechanisms for pain amelioration after tDCS, such as a secondary modulation of thalamic nuclei activity.
TL;DR: This review provides an overview of mechanisms of stimulus perception for members of all three groups of bacterial signal-transducing histidine kinases.
Abstract: Two-component signal-transducing systems are ubiquitously distributed communication interfaces in bacteria. They consist of a histidine kinase that senses a specific environmental stimulus and a cognate response regulator that mediates the cellular response, mostly through differential expression of target genes. Histidine kinases are typically transmembrane proteins harboring at least two domains: an input (or sensor) domain and a cytoplasmic transmitter (or kinase) domain. They can be identified and classified by virtue of their conserved cytoplasmic kinase domains. In contrast, the sensor domains are highly variable, reflecting the plethora of different signals and modes of sensing. In order to gain insight into the mechanisms of stimulus perception by bacterial histidine kinases, we here survey sensor domain architecture and topology within the bacterial membrane, functional aspects related to this topology, and sequence and phylogenetic conservation. Based on these criteria, three groups of histidine kinases can be differentiated. (i) Periplasmic-sensing histidine kinases detect their stimuli (often small solutes) through an extracellular input domain. (ii) Histidine kinases with sensing mechanisms linked to the transmembrane regions detect stimuli (usually membrane-associated stimuli, such as ionic strength, osmolarity, turgor, or functional state of the cell envelope) via their membrane-spanning segments and sometimes via additional short extracellular loops. (iii) Cytoplasmic-sensing histidine kinases (either membrane anchored or soluble) detect cellular or diffusible signals reporting the metabolic or developmental state of the cell. This review provides an overview of mechanisms of stimulus perception for members of all three groups of bacterial signal-transducing histidine kinases.
TL;DR: In this paper, anodal transcranial direct current stimulation (tDCS) is associated with a change in a working memory task performance in patients with Parkinson's disease, and the results showed a significant improvement in working memory as indexed by task accuracy.
TL;DR: In unmedicated schizophrenic patients, a high striatal dopamine turnover may increase the "noise" in the reward system, thus interfering with the neuronal processing of reward-predicting cues by phasic dopamine release, which may contribute to negative symptoms as such as anhedonia, apathy, and loss of drive and motivation.
TL;DR: The complete genome sequence of the two chromosomes of R. eutropha H16 is reported, offering the genetic basis for exploiting the biotechnological potential of this organism and providing insights into its remarkable metabolic versatility.
Abstract: The H2-oxidizing lithoautotrophic bacterium Ralstonia eutropha H16 is a metabolically versatile organism capable of subsisting, in the absence of organic growth substrates, on H2 and CO2 as its sole sources of energy and carbon. R. eutropha H16 first attracted biotechnological interest nearly 50 years ago with the realization that the organism's ability to produce and store large amounts of poly[R-(–)-3-hydroxybutyrate] and other polyesters could be harnessed to make biodegradable plastics. Here we report the complete genome sequence of the two chromosomes of R. eutropha H16. Together, chromosome 1 (4,052,032 base pairs (bp)) and chromosome 2 (2,912,490 bp) encode 6,116 putative genes. Analysis of the genome sequence offers the genetic basis for exploiting the biotechnological potential of this organism and provides insights into its remarkable metabolic versatility.
TL;DR: It is suggested that spillover of agriculturally subsidized insect natural enemies may be an important process affecting prey populations in natural habitat fragments, based on the ubiquity of agricultural-natural edges in human dominated landscapes and the clear importance of the landscape matrix in influencing predator impacts in agroecosystems.
Abstract: The cross-edge spillover of subsidized predators from anthropogenic to natural habitats is an important process affecting wildlife, especially bird, populations in fragmented landscapes. However, the importance of the spillover of insect natural enemies from agricultural to natural habitats is unknown, despite the abundance of studies examining movement in the opposite direction. Here, we synthesize studies from various ecological sub-disciplines to suggest that spillover of agriculturally subsidized insect natural enemies may be an important process affecting prey populations in natural habitat fragments. This contention is based on (1) the ubiquity of agricultural–natural edges in human dominated landscapes; (2) the substantial literature illustrating that crop and natural habitats share important insect predators; and (3) the clear importance of the landscape matrix, specifically distance to ecological edges, in influencing predator impacts in agroecosystems. Further support emerges from theory on the importance of cross-boundary subsidies for within site consumer– resource dynamics. In particular, high productivity and temporally variable resource abundance in agricultural systems are predicted to result in strong spillover effects. More empirical work examining the prevalence and significance of such natural enemy spillover will be critical to a broader understanding of fragmentation impacts on insect predator–prey interactions.
TL;DR: Otoferlin is essential for a late step of synaptic vesicle exocytosis and may act as the major Ca(2+) sensor triggering membrane fusion at the IHC ribbon synapse.
King's College London1, Trinity College, Dublin2, Radboud University Nijmegen3, Memorial Hospital of South Bend4, University of Göttingen5, Ghent University6, Shaare Zedek Medical Center7, University of Valencia8, University Medical Center Groningen9, University of Zurich10, VU University Amsterdam11, University of Southampton12, State University of New York Upstate Medical University13
TL;DR: In this article, the authors examined 1038 single-nucleotide polymorphisms (SNPs) spanning 51 candidate genes involved in the regulation of neurotransmitter pathways, particularly dopamine, norepinephrine and serotonin pathways, in addition to circadian rhythm genes.
Abstract: Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder, starting in early childhood and persisting into adulthood in the majority of cases. Family and twin studies have demonstrated the importance of genetic factors and candidate gene association studies have identified several loci that exert small but significant effects on ADHD. To provide further clarification of reported associations and identify novel associated genes, we examined 1038 single-nucleotide polymorphisms (SNPs) spanning 51 candidate genes involved in the regulation of neurotransmitter pathways, particularly dopamine, norepinephrine and serotonin pathways, in addition to circadian rhythm genes. Analysis used within family tests of association in a sample of 776 DSM-IV ADHD combined type cases ascertained for the International Multi-centre ADHD Gene project. We found nominal significance with one or more SNPs in 18 genes, including the two most replicated findings in the literature: DRD4 and DAT1. Gene-wide tests, adjusted for the number of SNPs analysed in each gene, identified associations with TPH2, ARRB2, SYP, DAT1, ADRB2, HES1, MAOA and PNMT. Further studies will be needed to confirm or refute the observed associations and their generalisability to other samples.
TL;DR: The findings provide initial evidence of a beneficial effect of tDCS in fibromyalgia, thus encouraging further trials.
Abstract: Objective. Recent evidence suggests that fibromyalgia is a disorder characterized by dysfunctional brain activity. Because transcranial direct current stimulation (tDCS) can modulate brain activity noninvasively and can decrease pain in patients with refractory central pain, we hypothesized that tDCS treatment would result in pain relief in patients with fibromyalgia. Methods. Thirty-two patients were randomized to receive sham stimulation or real tDCS with the anode centered over the primary motor cortex (M1) or the dorsolateral prefrontal cortex (DLPFC) (2 mA for 20 minutes on 5 consecutive days). A blinded evaluator rated the patient’s pain, using the visual analog scale for pain, the clinician’s global impression, the patient’s global assessment, and the number of tender points. Other symptoms of fibromyalgia were evaluated using the Fibromyalgia Impact Questionnaire and the Short Form 36 Health Survey. Safety was assessed with a battery of neuropsychological tests. To assess potential confounders, we measured mood and anxiety changes throughout the trial. Results. Anodal tDCS of the primary motor cortex induced significantly greater pain improvement compared with sham stimulation and stimulation of the DLPFC (P < 0.0001). Although this effect decreased after treatment ended, it was still significant after 3 weeks of followup (P 0.004). A small positive impact on quality of life was observed among patients who received anodal M1 stimulation. This treatment was associated with a few mild adverse events, but the frequency of these events in the active-treatment groups was similar to that in the sham group. Cognitive changes were similar in all 3 treatment groups. Conclusion. Our findings provide initial evidence of a beneficial effect of tDCS in fibromyalgia, thus encouraging further trials.
TL;DR: In this paper, the combined effects of soil compaction and soil moisture on the emission of N2O, N2 and CO2 from undisturbed soil cores fertilized with N 15 O 3 − (150 kilograms N ǫ−1) in a potato field were analyzed.
Abstract: Soil compaction and soil moisture are important factors influencing denitrification and N2O emission from fertilized soils. We analyzed the combined effects of these factors on the emission of N2O, N2 and CO2 from undisturbed soil cores fertilized with N 15 O 3 − (150 kg N ha−1) in a laboratory experiment. The soil cores were collected from differently compacted areas in a potato field, i.e. the ridges (ρD=1.03 g cm−3), the interrow area (ρD=1.24 g cm−3), and the tractor compacted interrow area (ρD=1.64 g cm−3), and adjusted to constant soil moisture levels between 40 and 98% water-filled pore space (WFPS). High N2O emissions were a result of denitrification and occurred at a WFPS≥70% in all compaction treatments. N2 production occurred only at the highest soil moisture level (≥90% WFPS) but it was considerably smaller than the N2O–N emission in most cases. There was no soil moisture effect on CO2 emission from the differently compacted soils with the exception of the highest soil moisture level (98% WFPS) of the tractor-compacted soil in which soil respiration was significantly reduced. The maximum N2O emission rates from all treatments occurred after rewetting of dry soil. This rewetting effect increased with the amount of water added. The results show the importance of increased carbon availability and associated respiratory O2 consumption induced by soil drying and rewetting for the emissions of N2O.
TL;DR: It is concluded that CaMKII associates with and phosphorylates cardiac Na(+) channels and alters I( Na) gating to reduce availability at high heart rate, while enhancing late I(Na) (which could prolong action potential duration) in mice.
Abstract: In heart failure (HF), Ca2+/calmodulin kinase II (CaMKII) expression is increased. Altered Na+ channel gating is linked to and may promote ventricular tachyarrhythmias (VTs) in HF. Calmodulin regulates Na+ channel gating, in part perhaps via CaMKII. We investigated effects of adenovirus-mediated (acute) and Tg (chronic) overexpression of cytosolic CaMKIIδC on Na+ current (INa) in rabbit and mouse ventricular myocytes, respectively (in whole-cell patch clamp). Both acute and chronic CaMKIIδC overexpression shifted voltage dependence of Na+ channel availability by –6 mV (P < 0.05), and the shift was Ca2+ dependent. CaMKII also enhanced intermediate inactivation and slowed recovery from inactivation (prevented by CaMKII inhibitors autocamtide 2–related inhibitory peptide [AIP] or KN93). CaMKIIδC markedly increased persistent (late) inward INa and intracellular Na+ concentration (as measured by the Na+ indicator sodium-binding benzofuran isophthalate [SBFI]), which was prevented by CaMKII inhibition in the case of acute CaMKIIδC overexpression. CaMKII coimmunoprecipitates with and phosphorylates Na+ channels. In vivo, transgenic CaMKIIδC overexpression prolonged QRS duration and repolarization (QT intervals), decreased effective refractory periods, and increased the propensity to develop VT. We conclude that CaMKII associates with and phosphorylates cardiac Na+ channels. This alters INa gating to reduce availability at high heart rate, while enhancing late INa (which could prolong action potential duration). In mice, enhanced CaMKIIδC activity predisposed to VT. Thus, CaMKII-dependent regulation of Na+ channel function may contribute to arrhythmogenesis in HF.
TL;DR: This approach provides an accessible in vitro model system for studies of mammalian gametogenesis, as well as for the development of new strategies for the generation of transgenic mice and treatment of infertility.
TL;DR: In this article, the authors explored the influence of farming system, landscape context and regional differences on the relative impact of organic farming on farmland biodiversity and ecosystem services such as pollination.
Abstract: 1. Agri-environment schemes promote organic farming in an attempt to reduce the negative effects of agricultural intensification on farmland biodiversity and ecosystem services such as pollination. Farming system, landscape context and regional differences may all influence biodiversity, but their relative impact and possible interactions have been little explored. 2. The study was performed in three regions (150 km apart, 400-500 km(2) per region) differing in land use intensity. Within each region, seven pairs of conventionally and organically cultivated wheat fields (mean size 4 ha, 42 study fields) were selected to encompass a gradient from heterogeneous to homogeneous landscapes within a 1-km radius around each field. 3. Farming system had the greatest influence on biodiversity. Higher bee diversity, flower cover and diversity of flowering plants were recorded in organic compared with conventional fields. Bee diversity was related both to flower cover and diversity of flowering plants, suggesting plant-mediated effects of the farming system. 4. Differences in bee diversity between organic and conventional fields increased with the proportion of arable crops in the surrounding landscape, indicating that processes at the landscape level modified the effectiveness of organic farming in promoting biodiversity. Similar patterns for flower cover and diversity of flowering plants suggested that landscape effects on bee diversity were mainly resource-mediated. After statistically removing the variance explained by flower parameters, residual bee diversity increased with increasing landscape heterogeneity. 5. Bee diversity differed between the three regions, but the effects of farming systems and landscape context were independent of regional differences. 6. Synthesis and applications. Bee diversity in wheat fields was mainly influenced by farming system, but an understanding of local bee diversity needs to incorporate both landscape and regional perspectives. The consistency of the results in three regions provides a reliable basis for management decisions. Agri-environment schemes that promote organic farming in homogeneous landscapes where there are few remaining flower-rich habitats could have the highest relative impact. However, while organic farming could help to sustain pollination services by generalist bees in agricultural landscapes, other measures are required to conserve more specialized bee species in semi-natural habitats.