Showing papers by "University of Freiburg published in 2006"
TL;DR: It is argued that adaptation has taken place on a theme rather than via fundamentally different paths and similarities underlying the extensive diversity in the dormancy response to the environment that controls germination are identified.
Abstract: Seed dormancy is an innate seed property that defines the environmental conditions in which the seed is able to germinate. It is determined by genetics with a substantial environmental influence which is mediated, at least in part, by the plant hormones abscisic acid and gibberellins. Not only is the dormancy status influenced by the seed maturation environment, it is also continuously changing with time following shedding in a manner determined by the ambient environment. As dormancy is present throughout the higher plants in all major climatic regions, adaptation has resulted in divergent responses to the environment. Through this adaptation, germination is timed to avoid unfavourable weather for subsequent plant establishment and reproductive growth. In this review, we present an integrated view of the evolution, molecular genetics, physiology, biochemistry, ecology and modelling of seed dormancy mechanisms and their control of germination. We argue that adaptation has taken place on a theme rather than via fundamentally different paths and identify similarities underlying the extensive diversity in the dormancy response to the environment that controls germination.
2,411 citations
TL;DR: It is shown that influenza A virus infection does not generate dsRNA and that RIG-I is activated by viral genomic single-stranded RNA (ssRNA) bearing 5′-phosphates, and suggested that its ability to sense 5'-phosphorylated RNA evolved in the innate immune system as a means of discriminating between self and nonself.
Abstract: Double-stranded RNA (dsRNA) produced during viral replication is believed to be the critical trigger for activation of antiviral immunity mediated by the RNA helicase enzymes retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5). We showed that influenza A virus infection does not generate dsRNA and that RIG-I is activated by viral genomic single-stranded RNA (ssRNA) bearing 5'-phosphates. This is blocked by the influenza protein nonstructured protein 1 (NS1), which is found in a complex with RIG-I in infected cells. These results identify RIG-I as a ssRNA sensor and potential target of viral immune evasion and suggest that its ability to sense 5'-phosphorylated RNA evolved in the innate immune system as a means of discriminating between self and nonself.
2,133 citations
TL;DR: Application of this standardized QST protocol in patients and human surrogate models will allow to infer underlying mechanisms from somatosensory phenotypes as well as judge plus or minus signs in patients.
Abstract: The nationwide multicenter trials of the German Research Network on Neuropathic Pain (DFNS) aim to characterize the somatosensory phenotype of patients with neuropathic pain. For this purpose, we have implemented a standardized quantitative sensory testing (QST) protocol giving a complete profile for one region within 30 min. To judge plus or minus signs in patients we have now established age- and gender-matched absolute and relative QST reference values from 180 healthy subjects, assessed bilaterally over face, hand and foot. We determined thermal detection and pain thresholds including a test for paradoxical heat sensations, mechanical detection thresholds to von Frey filaments and a 64 Hz tuning fork, mechanical pain thresholds to pinprick stimuli and blunt pressure, stimulus/response-functions for pinprick and dynamic mechanical allodynia, and pain summation (wind-up ratio). QST parameters were region specific and age dependent. Pain thresholds were significantly lower in women than men. Detection thresholds were generally independent of gender. Reference data were normalized to the specific group means and variances (region, age, gender) by calculating z-scores. Due to confidence limits close to the respective limits of the possible data range, heat hypoalgesia, cold hypoalgesia, and mechanical hyperesthesia can hardly be diagnosed. Nevertheless, these parameters can be used for group comparisons. Sensitivity is enhanced by side-to-side comparisons by a factor ranging from 1.1 to 2.5. Relative comparisons across body regions do not offer advantages over absolute reference values. Application of this standardized QST protocol in patients and human surrogate models will allow to infer underlying mechanisms from somatosensory phenotypes.
2,030 citations
TL;DR: Fast Downward as discussed by the authors uses hierarchical decompositions of planning tasks for computing its heuristic function, called the causal graph heuristic, which is very different from traditional HSP-like heuristics based on ignoring negative interactions of operators.
Abstract: Fast Downward is a classical planning system based on heuristic search. It can deal with general deterministic planning problems encoded in the propositional fragment of PDDL2.2, including advanced features like ADL conditions and effects and derived predicates (axioms). Like other well-known planners such as HSP and FF, Fast Downward is a progression planner, searching the space of world states of a planning task in the forward direction. However, unlike other PDDL planning systems, Fast Downward does not use the propositional PDDL representation of a planning task directly. Instead, the input is first translated into an alternative representation called multivalued planning tasks, which makes many of the implicit constraints of a propositional planning task explicit. Exploiting this alternative representation, Fast Downward uses hierarchical decompositions of planning tasks for computing its heuristic function, called the causal graph heuristic, which is very different from traditional HSP-like heuristics based on ignoring negative interactions of operators.
In this article, we give a full account of Fast Downward's approach to solving multivalued planning tasks. We extend our earlier discussion of the causal graph heuristic to tasks involving axioms and conditional effects and present some novel techniques for search control that are used within Fast Downward's best-first search algorithm: preferred operators transfer the idea of helpful actions from local search to global best-first search, deferred evaluation of heuristic functions mitigates the negative effect of large branching factors on search performance, and multiheuristic best-first search combines several heuristic evaluation functions within a single search algorithm in an orthogonal way. We also describe efficient data structures for fast state expansion (successor generators and axiom evaluators) and present a new non-heuristic search algorithm called focused iterative-broadening search, which utilizes the information encoded in causal graphs in a novel way.
Fast Downward has proven remarkably successful: It won the "classical" (i. e., propositional, non-optimising) track of the 4th International Planning Competition at ICAPS 2004, following in the footsteps of planners such as FF and LPG. Our experiments show that it also performs very well on the benchmarks of the earlier planning competitions and provide some insights about the usefulness of the new search enhancements.
1,400 citations
TL;DR: A simple local atomic structure optimization algorithm which is significantly faster than standard implementations of the conjugate gradient method and often competitive with more sophisticated quasi-Newton schemes typically used in ab initio calculations is introduced.
Abstract: We introduce a simple local atomic structure optimization algorithm which is significantly faster than standard implementations of the conjugate gradient method and often competitive with more sophisticated quasi-Newton schemes typically used in ab initio calculations. It is based on conventional molecular dynamics with additional velocity modifications and adaptive time steps. The surprising efficiency and especially the robustness and versatility of the method is illustrated using a variety of test cases from nanoscience, solid state physics, materials research, and biochemistry.
1,360 citations
TL;DR: The results suggest that gene therapy in combination with bone marrow conditioning can be successfully used to treat inherited diseases affecting the myeloid compartment such as CGD.
Abstract: Gene transfer into hematopoietic stem cells has been used successfully for correcting lymphoid but not myeloid immunodeficiencies. Here we report on two adults who received gene therapy after nonmyeloablative bone marrow conditioning for the treatment of X-linked chronic granulomatous disease (X-CGD), a primary immunodeficiency caused by a defect in the oxidative antimicrobial activity of phagocytes resulting from mutations in gp91(phox). We detected substantial gene transfer in both individuals' neutrophils that lead to a large number of functionally corrected phagocytes and notable clinical improvement. Large-scale retroviral integration site-distribution analysis showed activating insertions in MDS1-EVI1, PRDM16 or SETBP1 that had influenced regulation of long-term hematopoiesis by expanding gene-corrected myelopoiesis three- to four-fold in both individuals. Although insertional influences have probably reinforced the therapeutic efficacy in this trial, our results suggest that gene therapy in combination with bone marrow conditioning can be successfully used to treat inherited diseases affecting the myeloid compartment such as CGD.
1,172 citations
TL;DR: The Freiburg Mindfulness Inventory (FMI) as discussed by the authors ) is a psychometrically sound 30-item scale with an internal consistency of Cronbach alpha =.93 was able to demonstrate the increase in mindfulness after the retreat and to discriminate between experienced and novice meditators.
1,155 citations
TL;DR: A deeper understanding of the mechanism by which the P2X7 receptor triggers IL-1 maturation and exteriorization may suggest novel avenues for the treatment of inflammatory diseases and provide a deeper insight in the fundamental mechanism of protease activation and cellular export of proteins lacking a leader sequence.
Abstract: Human IL-1 family proteins are key mediators of the host response to infections, injury, and immunologic challenges. The mechanism by which IL-1 activates proinflammatory responses in target cells, and the plasma membrane receptors involved, is fairly well known. This has led to the development of innovative drugs that block IL-1 downstream to its synthesis and secretion. On the contrary, the mechanism of IL-1 and other IL-1 family members (e.g., IL-18) maturation and release is incompletely understood. Accruing evidence points to a plasma membrane receptor for extracellular ATP, the P2X(7) receptor, as a key player in both processes. A deeper understanding of the mechanism by which the P2X(7) receptor triggers IL-1 maturation and exteriorization may suggest novel avenues for the treatment of inflammatory diseases and provide a deeper insight in the fundamental mechanism of protease activation and cellular export of proteins lacking a leader sequence.
973 citations
TL;DR: The data suggest that brain reorganization during language recovery proceeds in three phases: a strongly reduced activation of remaining left language areas in the acute phase is followed by an upregulation with recruitment of homologue language zones, which correlates with language improvement.
Abstract: Previous functional imaging studies of chronic stroke patients with aphasia suggest that recovery of language occurs in a pre-existing, bilateral network with an upregulation of undamaged areas and a recruitment of perilesional tissue and homologue right language areas. The present study aimed at identifying the dynamics of reorganization in the language system by repeated functional MRI (fMRI) examinations with parallel language testing from the acute to the chronic stage. We examined 14 patients with aphasia due to an infarction of the left middle cerebral artery territory and an age-matched control group with an auditory comprehension task in an event-related design. Control subjects were scanned once, whereas patients were scanned repeatedly at three consecutive dates. All patients recovered clinically as shown by a set of aphasia tests. In the acute phase [mean: 1.8 days post-stroke (dps)], patients' group analysis showed little early activation of non-infarcted left-hemispheric language structures, while in the subacute phase (mean: 12.1 dps) a large increase of activation in the bilateral language network with peak activation in the right Broca-homologue (BHo) was observed. A direct comparison of both examinations revealed the strongest increase of activation in the right BHo and supplementary motor area (SMA). These upregulated areas also showed the strongest correlation between improved language function and increased activation (r(BHo) = 0.88, r(SMA) = 0.92). In the chronic phase (mean: 321 dps), a normalization of activation with a re-shift of peak activation to left-hemispheric language areas was observed, associated with further language improvement. The data suggest that brain reorganization during language recovery proceeds in three phases: a strongly reduced activation of remaining left language areas in the acute phase is followed by an upregulation with recruitment of homologue language zones, which correlates with language improvement. Thereafter, a normalization of activation is observed, possibly reflecting consolidation in the language system.
908 citations
TL;DR: Investigation of the presence and localization of ds RNA in cells infected with a range of viruses, employing a dsRNA-specific antibody for immunofluorescence analysis revealed that significant amounts ofdsRNA can be detected for viruses with a genome consisting of positive-strand RNA, dsRNAs, or DNA; Surprisingly, however, no DsRNA signals were detected for negative-stranded RNA viruses.
Abstract: Double-stranded RNA (dsRNA) longer than 30 bp is a key activator of the innate immune response against viral infections. It is widely assumed that the generation of dsRNA during genome replication is a trait shared by all viruses. However, to our knowledge, no study exists in which the production of dsRNA by different viruses is systematically investigated. Here, we investigated the presence and localization of dsRNA in cells infected with a range of viruses, employing a dsRNA-specific antibody for immunofluorescence analysis. Our data revealed that, as predicted, significant amounts of dsRNA can be detected for viruses with a genome consisting of positive-strand RNA, dsRNA, or DNA. Surprisingly, however, no dsRNA signals were detected for negative-strand RNA viruses. Thus, dsRNA is indeed a general feature of most virus groups, but negative-strand RNA viruses appear to be an exception to that rule.
886 citations
TL;DR: In this article, the contribution of street design, i.e. aspect ratio (or height-to-width ratio, H / W ) and solar orientation, towards the development of a comfortable microclimate at street level for pedestrians is discussed.
TL;DR: The guidelines for the use of oral nutritional supplements (ONS) and tube feeding (TF) in cancer patients were developed by an interdisciplinary expert group in accordance with officially accepted standards as discussed by the authors.
TL;DR: It is shown that the cytoplasmic tail of PC1 interacts with tuberin, and the mTOR pathway is inappropriately activated in cyst-lining epithelial cells in human ADPKD patients and mouse models, indicating that PC1 has an important function in the regulation of the m TOR pathway and that this pathway provides a target for medical therapy of AD PKD.
Abstract: Autosomal-dominant polycystic kidney disease (ADPKD) is a common genetic disorder that frequently leads to renal failure. Mutations in polycystin-1 (PC1) underlie most cases of ADPKD, but the function of PC1 has remained poorly understood. No preventive treatment for this disease is available. Here, we show that the cytoplasmic tail of PC1 interacts with tuberin, and the mTOR pathway is inappropriately activated in cyst-lining epithelial cells in human ADPKD patients and mouse models. Rapamycin, an inhibitor of mTOR, is highly effective in reducing renal cystogenesis in two independent mouse models of PKD. Treatment of human ADPKD transplant-recipient patients with rapamycin results in a significant reduction in native polycystic kidney size. These results indicate that PC1 has an important function in the regulation of the mTOR pathway and that this pathway provides a target for medical therapy of ADPKD.
TL;DR: The results suggest that the category CF at 30 cm can be replaced by 0.014, using ETDRS or FrACT, and one can even reproducibly quantify VA in the HM-range, yielding a mean VA of 0.02.
Abstract: Purpose The visual acuity (VA) of patients with very low vision is classified using the semiquantitative scale "counting fingers" (CF), "hand motion" (HM), "light perception" (LP), and "no light perception." More quantitative measures would be desirable, especially for clinical studies. The results of clinical VA measurements, Early Treatment Diabetic Retinopathy Study (ETDRS) charts, and the Freiburg Visual Acuity Test (FrACT) were compared. The FrACT is a computerized visual acuity test that can present very large Landolt C optotypes when necessary. Methods Examined were 100 eyes of 100 patients with various eye diseases (e.g., diabetic retinopathy, ARMD), covering a range of VAs from LP to decimal 0.32. The FrACT optotypes were presented on a 17-inch LCD monitor with random orientation. After extensive training, two ETDRS and FrACT measurements were obtained. The testing distance was 50 or 100 cm. Results ETDRS and FrACT coincided closely for VA > or = 0.02 (n = 80). ETDRS measures were successfully obtainable down to CF (at 30 cm; test-retest averaged over all patients, coefficient of variation [CV](ETDRS) = 9% +/- 8%), and FrACT provided reproducible measurements down to HM (test-retest CV(FrACT) =12% +/- 11%). For CF (n = 6), both ETDRS and FrACT resulted in a mean VA of 0.014 +/- 0.003 (range, 0.01-0.02). The VA results of FrACT for HM (n = 12) were 0.005 +/- 0.002 (range, 0.003-0.009); the individual values were highly reproducible. No results were obtainable for LP (n = 2). Conclusions The three acuity procedures concur above a VA of 0.02. The results suggest that the category CF at 30 cm can be replaced by 0.014, using ETDRS or FrACT. Using FrACT, one can even reproducibly quantify VA in the HM-range, yielding a mean VA of 0.005.
TL;DR: A genome-wide linkage search followed by mutational analysis of the candidate gene SCN9A, which encodes hNa(v)1.7, identified eight missense mutations in 11 families and 2 sporadic cases of PEPD mutants that revealed a reduction in fast inactivation, leading to persistent sodium current.
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 current view on the balancing act between virus-induced IFN responses and the viral counterplayers is discussed.
TL;DR: Microfracture is a minimal invasive method with good short-term results in the treatment of small cartilage defects but a deterioration of the results starts 18 months after surgery and is most evident in the ICRS-score.
TL;DR: To estimate outcome and discuss informed treatment decisions with AML patients of different age groups and different biologic risk categories, it is mandatory to consider that the outcome results reported in clinical trials were until now heavily biased toward younger patients, whereas the overall dismal prognosis documented in population‐based studies most likely reflects the exclusion of older patients from aggressive treatment.
Abstract: Acute myeloid leukemias (AMLs) are infrequent, yet highly malignant neoplasms responsible for a large number of cancer-related deaths. The incidence has been near stable over the last years. It continuously shows 2 peaks in occurrence in early childhood and later adulthood. With an incidence of 3.7 per 100,000 persons and an age-dependent mortality of 2.7 to nearly 18 per 100,000 persons, there is a rising awareness in the Western world of AML's special attributes resulting from an ever-aging population. To objectively describe epidemiologic data on this patient population, recent publications were evaluated to make transparent the current trends and facts. A review of the literature is presented, reflecting highlights of current research with respect to AML etiology. To estimate outcome and discuss informed treatment decisions with AML patients of different age groups and different biologic risk categories, it is mandatory to consider that the outcome results reported in clinical trials were until now heavily biased toward younger patients, whereas the overall dismal prognosis documented in population-based studies most likely reflects the exclusion of older patients from aggressive treatment. The etiology for most cases of AML is unclear, but a growing knowledge concerning leukemogenenic agents within chemotherapy regimens for other malignancies is already available. This includes specific associations of the most frequent balanced translocations in AML, including the "good-risk" abnormalities comprised by the core binding factor leukemias (i.e., AML with the translocation (8;21) and inversion of chromosome 16, and acute promyelocytic leukemia with the translocation (15;17)). In contrast to these genetic alterations, epigenetic lesions, e.g., promoter silencing by hypermethylation of the p15/INK4b and other genes, are increasingly recognized as important in the pathogenesis of AML.
TL;DR: This work identifies WNT and its inhibitor DKK as primary determinants of murine hair follicle spacing, using a combined experimental and computational modeling approach and provides in vivo corroboration of the reaction-diffusion mechanism for epidermal appendage formation.
Abstract: Mathematical reaction-diffusion models have been suggested to describe formation of animal pigmentation patterns and distribution of epidermal appendages. However, the crucial signals and in vivo mechanisms are still elusive. Here we identify WNT and its inhibitor DKK as primary determinants of murine hair follicle spacing, using a combined experimental and computational modeling approach. Transgenic DKK overexpression reduces overall appendage density. Moderate suppression of endogenous WNT signaling forces follicles to form clusters during an otherwise normal morphogenetic program. These results confirm predictions of a WNT/DKK-specific mathematical model and provide in vivo corroboration of the reaction-diffusion mechanism for epidermal appendage formation.
TL;DR: The level of platelet aggregation immediately before elective coronary stenting in patients pre-treated with a high loading dose of clopidogrel is correlated with early outcome after the procedure, and this is a significant independent predictor of 30-day MACE.
University of Michigan1, Newcastle University2, University of Cologne3, Simon Fraser University4, Harvard University5, University of Hyogo6, Max Planck Society7, Peking University8, University of California, San Diego9, University of Zurich10, University of Washington11, Hannover Medical School12, University of Freiburg13
TL;DR: These findings help establish the link between centrosome function, tissue architecture and transcriptional control in the pathogenesis of cystic kidney disease, retinal degeneration, and central nervous system development.
Abstract: The molecular basis of nephronophthisis, the most frequent genetic cause of renal failure in children and young adults, and its association with retinal degeneration and cerebellar vermis aplasia in Joubert syndrome are poorly understood. Using positional cloning, we here identify mutations in the gene CEP290 as causing nephronophthisis. It encodes a protein with several domains also present in CENPF, a protein involved in chromosome segregation. CEP290 (also known as NPHP6) interacts with and modulates the activity of ATF4, a transcription factor implicated in cAMP-dependent renal cyst formation. NPHP6 is found at centrosomes and in the nucleus of renal epithelial cells in a cell cycle-dependent manner and in connecting cilia of photoreceptors. Abrogation of its function in zebrafish recapitulates the renal, retinal and cerebellar phenotypes of Joubert syndrome. Our findings help establish the link between centrosome function, tissue architecture and transcriptional control in the pathogenesis of cystic kidney disease, retinal degeneration, and central nervous system development.
TL;DR: Future directions of research should focus on the creation of microvascular networks within 3D tissue constructs in vitro before implantation or by co-stimulation of angiogenesis and parenchymal cell proliferation to engineer the vascularized tissue substitute in situ.
Abstract: Long-term function of three-dimensional (3D) tissue constructs depends on adequate vascularization after implantation. Accordingly, research in tissue engineering has focused on the analysis of angiogenesis. For this purpose, 2 sophisticated in vivo models (the chorioallantoic membrane and the dorsal skinfold chamber) have recently been introduced in tissue engineering research, allowing a more detailed analysis of angiogenic dysfunction and engraftment failure. To achieve vascularization of tissue constructs, several approaches are currently under investigation. These include the modification of biomaterial properties of scaffolds and the stimulation of blood vessel development and maturation by different growth factors using slow-release devices through pre-encapsulated microspheres. Moreover, new microvascular networks in tissue substitutes can be engineered by using endothelial cells and stem cells or by creating arteriovenous shunt loops. Nonetheless, the currently used techniques are not sufficient to induce the rapid vascularization necessary for an adequate cellular oxygen supply. Thus, future directions of research should focus on the creation of microvascular networks within 3D tissue constructs in vitro before implantation or by co-stimulation of angiogenesis and parenchymal cell proliferation to engineer the vascularized tissue substitute in situ.
TL;DR: Connectivity analysis identified placebo dependent contributions of rACC activity with bilateral amygdalae and the periaqueductal gray, which supports the view that placebo analgesia depends on the enhanced functional connectivity of the rACC with subcortical brain structures that are crucial for conditioned learning and descending inhibition of nociception.
Abstract: Placebo analgesia is one of the most striking examples of the cognitive modulation of pain perception and the underlying mechanisms are finally beginning to be understood. According to pharmacological studies, the endogenous opioid system is essential for placebo analgesia. Recent functional imaging data provides evidence that the rostral anterior cingulate cortex (rACC) represents a crucial cortical area for this type of endogenous pain control. We therefore hypothesized that placebo analgesia recruits other brain areas outside the rACC and that interactions of the rACC with these brain areas mediate opioid-dependent endogenous antinociception as part of a top-down mechanism. Nineteen healthy subjects received and rated painful laser stimuli to the dorsum of both hands, one of them treated with a fake analgesic cream (placebo). Painful stimulation was preceded by an auditory cue, indicating the side of the next laser stimulation. BOLD-responses to the painful laser-stimulation during the placebo and no-placebo condition were assessed using event-related fMRI. After having confirmed placebo related activity in the rACC, a connectivity analysis identified placebo dependent contributions of rACC activity with bilateral amygdalae and the periaqueductal gray (PAG). This finding supports the view that placebo analgesia depends on the enhanced functional connectivity of the rACC with subcortical brain structures that are crucial for conditioned learning and descending inhibition of nociception.
Hannover Medical School1, University of California, San Diego2, University of Giessen3, University of Bologna4, Columbia University5, Leipzig University6, Dresden University of Technology7, University of Michigan8, University of California, Los Angeles9, University of Greifswald10, Saarland University11, University of Freiburg12
TL;DR: When performed in experienced centers, right heart catheter procedures in patients with pulmonary hypertension are associated with low morbidity and mortality rates.
University of Michigan1, University of Cologne2, Harvard University3, Medical University of Vienna4, University of Marburg5, Hacettepe University6, Rabin Medical Center7, Tel Aviv University8, University of Freiburg9, Technische Universität München10, Dokuz Eylül University11, Charité12, Hannover Medical School13, State University of New York Upstate Medical University14, University of Rochester15
TL;DR: These findings, together with the zebrafish model of human nephrotic syndrome generated by plce1 knockdown, open new inroads into pathophysiology and treatment mechanisms of nephrotsic syndrome.
Abstract: Nephrotic syndrome, a malfunction of the kidney glomerular filter, leads to proteinuria, edema and, in steroid-resistant nephrotic syndrome, end-stage kidney disease. Using positional cloning, we identified mutations in the phospholipase C epsilon gene (PLCE1) as causing early-onset nephrotic syndrome with end-stage kidney disease. Kidney histology of affected individuals showed diffuse mesangial sclerosis (DMS). Using immunofluorescence, we found PLCepsilon1 expression in developing and mature glomerular podocytes and showed that DMS represents an arrest of normal glomerular development. We identified IQ motif-containing GTPase-activating protein 1 as a new interaction partner of PLCepsilon1. Two siblings with a missense mutation in an exon encoding the PLCepsilon1 catalytic domain showed histology characteristic of focal segmental glomerulosclerosis. Notably, two other affected individuals responded to therapy, making this the first report of a molecular cause of nephrotic syndrome that may resolve after therapy. These findings, together with the zebrafish model of human nephrotic syndrome generated by plce1 knockdown, open new inroads into pathophysiology and treatment mechanisms of nephrotic syndrome.
TL;DR: In this paper, the authors developed a psychological tax contract that goes beyond the traditional deterrence model and explains tax morale as a complicated interaction between taxpayers and the government, and discussed the impact of deterrence and rewards on tax morale.
Abstract: In this paper, we develop the concept of a psychological tax contract that goes beyond the traditional deterrence model and explains tax morale as a complicated interaction between taxpayers and the government. Based on crowding theory, the impact of deterrence and rewards on tax morale is discussed. As a contractual relationship implies duties and rights for each contract partner, sticking to the fiscal exchange paradigm between citizens and the state increases tax compliance. Citizens are willing to honestly declare income even if they do not receive a full public good equivalent to their tax payments as long as the political process is perceived to be fair and legitimate. At the procedural level, a friendly treatment of taxpayers by the tax office in auditing processes increases tax compliance.
TL;DR: In this paper, four LEP collaborations, ALEPH, DELPHI, L3 and OPAL, have searched for the neutral Higgs bosons which are predicted by the minimal supersymmetric standard model (MSSM).
Abstract: The four LEP collaborations, ALEPH, DELPHI, L3 and OPAL, have searched for the neutral Higgs bosons which are predicted by the Minimal Supersymmetric standard model (MSSM). The data of the four collaborations are statistically combined and examined for their consistency with the background hypothesis and with a possible Higgs boson signal. The combined LEP data show no significant excess of events which would indicate the production of Higgs bosons. The search results are used to set upper bounds on the cross-sections of various Higgs-like event topologies. The results are interpreted within the MSSM in a number of “benchmark” models, including CP-conserving and CP-violating scenarios. These interpretations lead in all cases to large exclusions in the MSSM parameter space. Absolute limits are set on the parameter cosβ and, in some scenarios, on the masses of neutral Higgs bosons.
TL;DR: A combined approach of clinical lesion studies and functional imaging is a promising tool for identifying the cerebral regions involved in the process of motor learning and provides insight into the mechanisms underlying the generalisation of actions.
Abstract: This chapter reviews results of clinical and functional imaging studies which investigated the time-course of cortical and subcortical activation during the acquisition of motor a skill. During the early phases of learning by trial and error, activation in prefrontal areas, especially in the dorsolateral prefrontal cortex, is has been reported. The role of these areas is presumably related to explicit working memory and the establishment of a novel association between visual cues and motor commands. Furthermore, motor associated areas of the right hemisphere and distributed cerebellar areas reveal strong activation during the early motor learning. Activation in superior-posterior parietal cortex presumably arises from visuospatial processes, while sensory feedback is coded in the anterior-inferior parietal cortex and the neocerebellar structures. With practice, motor associated areas of the left-hemisphere reveal increased activity. This shift to the left hemisphere has been observed regardless of the hand used during training, indicating a left-hemispheric dominance in the storage of visuomotor skills. Concerning frontal areas, learned actions of sequential character are represented in the caudal part of the supplementary motor area (SMA proper), whereas the lateral premotor cortex appears to be responsible for the coding of the association between visuo-spatial information and motor commands. Functional imaging studies which investigated the activation patterns of motor learning under implicit conditions identified for the first, a motor circuit which includes lateral premotor cortex and SMA proper of the left hemisphere and primary motor cortex, for the second, a cognitive loop which consists of basal ganglia structures of the right hemisphere. Finally, activity patterns of intermanual transfer are discussed. After right-handed training, activity in motor associated areas maintains during performance of the mirror version, but is increased during the performance of the original-oriented version with the left hand. In contrary, increased activity during the mirror reversed action, but not during the original-oriented performance of the untrained right hand is observed after left-handed training. These results indicate the transfer of acquired right-handed information which reflects the mirror symmetry of the body, whereas spatial information is mainly transferred after left-handed training. Taken together, a combined approach of clinical lesion studies and functional imaging is a promising tool for identifying the cerebral regions involved in the process of motor learning and provides insight into the mechanisms underlying the generalisation of actions.
TL;DR: It is suggested that phy-induced phosphorylation of proteins such as PIF3 may represent the primary intermolecular signaling transaction of the activated photoreceptor, tagging the target protein for proteosomal degradation, possibly in nuclear speckles.