University of Marburg

About: University of Marburg is a education organization based out in Marburg, Germany. It is known for research contribution in the topics: Population & Gene. The organization has 23195 authors who have published 42907 publications receiving 1506069 citations. The organization is also known as: Philipps University of Marburg & Philipps-Universität.

Recent developments in structure-based drug design

Abstract: Structure-based design has emerged as a new tool in medicinal chemistry. A prerequisite for this new approach is an understanding of the principles of molecular recognition in protein-ligand complexes. If the three-dimensional structure of a given protein is known, this information can be directly exploited for the retrieval and design of new ligands. Structure-based ligand design is an iterative approach. First of all, it requires the crystal structure or a model derived from the crystal structure of a closely related homolog of the target protein, preferentially complexed with a ligand. This complex unravels the binding mode and conformation of a ligand under investigation and indicates the essential aspects determining its binding affinity. It is then used to generate new ideas about ways of improving an existing ligand or of developing new alternative bonding skeletons. Computational methods supplemented by molecular graphics are applied to assist this step of hypothesis generation. The features of the protein binding pocket can be translated into queries used for virtual computer screening of large compound libraries or to design novel ligands de novo. These initial proposals must be confirmed experimentally. Subsequently they are optimized toward higher affinity and better selectivity. The latter aspect is of utmost importance in defining and controlling the pharmacological profile of a ligand. A prerequisite to tailoring selectivity by rational design is a detailed understanding of molecular parameters determining selectivity. Taking examples from current drug development programs (HIV proteinase, t-RNA transglycosylase, thymidylate synthase, thrombin and, related serine proteinases), we describe recent advances in lead discovery via computer screening, iterative design, and understanding of selectivity discrimination.

Complications of implantable cardioverter defibrillator therapy in 440 consecutive patients.

Abstract: Background: Although more than 150,000 implantable cardioverter defibrillators (ICDs) are implanted yearly worldwide, only few studies systematically examined complications of ICD therapy in large patient cohorts. Methods: We prospectively analyzed ICD-related complications in 440 consecutive patients who underwent first implantation of an ICD system for primary or secondary prevention of sudden cardiac death within the last 10 years at our institution. All study patients received pectoral nonthoracotomy ICD lead systems with the exception of one patient who had an artificial tricuspid valve. Results: During 46 ± 37 months follow-up, 136 of 440 patients (31%) experienced at least one complication including implant procedure-related complications in 43 patients (10%), ICD generator-related complications in 28 patients (6%), lead-related complications in 52 patients (12%), and inappropriate shocks in 54 patients (12%). The most serious complications included one perioperative death due to heart failure (0.2%), two ICD system infections necessitating device removal (0.5%) and two perioperative cerebrovascular strokes (0.5%). Conclusions: We conclude that more than one quarter of ICD patients experience complications during a mean follow-up of almost 4 years, although serious complications such as intraoperative death or ICD system infections are rare in patients with nonthoracotomy ICD systems. Recognition of these complications is the prerequisite for advances in ICD technology and management strategies to avoid their recurrence.

Delayed recovery of movement-related cortical function in Parkinson's disease after striatal dopaminergic grafts

Abstract: Intrastriatal transplantation of dopaminergic neurones aims to repair the selective loss of nigrostriatal projections and the consequent dysfunction of striatocortical circuitries in Parkinson's disease (PD). Here, we have studied the effects of bilateral human embryonic dopaminergic grafts on the movement-related activation of frontal cortical areas in 4 PD patients using H2 15O positron emission tomography and a joystick movement task. At 6.5 months after transplantation, mean striatal dopamine storage capacity as measured by 18F-dopa positron emission tomography was already significantly elevated in these patients. This was associated with a modest clinical improvement on the Unified Parkinson's Disease Rating Scale, whereas the impaired cortical activation was unchanged. At 18 months after surgery, there was further significant clinical improvement in the absence of any additional increase in striatal 18F-dopa uptake. Rostral supplementary motor and dorsal prefrontal cortical activation during performance of joystick movements had significantly improved, however. Our data suggest that the function of the graft goes beyond that of a simple dopamine delivery system and that functional integration of the grafted neurones within the host brain is necessary to produce substantial clinical recovery in PD.

Effects of psychotherapy and other behavioral interventions on clinically depressed older adults: a meta-analysis.

Abstract: Objectives: The goal of the present study was to assess the effects of psychotherapy and other behavioral interventions on depressive symptoms in clinically depressed older patients. Methods: We used meta-analysis to examine the effects of 57 controlled intervention studies. Results: On average, self-rated depression improved by d=0.84 standard deviation units and clinician-rated depression improved by d=0.93. Effect sizes were large for cognitive and behavioral therapy (CBT) and reminiscence; and medium for psychodynamic therapy, psychoeducation, physical exercise and supportive interventions. Age differences in treatment effects were not observed. Weaker effects were found in studies that used an active control group and in studies of physically ill or cognitively impaired patients. Studies of samples comprised exclusively of patients suffering from major depression (versus other mood disorders) also yielded weaker intervention effects. On average, 18.9% of participants did not complete the intervention...

A fatal mitochondrial disease is associated with defective NFU1 function in the maturation of a subset of mitochondrial Fe-S proteins.

Abstract: We report on ten individuals with a fatal infantile encephalopathy and/or pulmonary hypertension, leading to death before the age of 15 months. Hyperglycinemia and lactic acidosis were common findings. Glycine cleavage system and pyruvate dehydrogenase complex (PDHC) activities were low. Homozygosity mapping revealed a perfectly overlapping homozygous region of 1.24 Mb corresponding to chromosome 2 and led to the identification of a homozygous missense mutation (c.622G>T) in NFU1, which encodes a conserved protein suggested to participate in Fe-S cluster biogenesis. Nine individuals were homozygous for this mutation, whereas one was compound heterozygous for this and a splice-site (c.545+5G>A) mutation. The biochemical phenotype suggested an impaired activity of the Fe-S enzyme lipoic acid synthase (LAS). Direct measurement of protein-bound lipoic acid in individual tissues indeed showed marked decreases. Upon depletion of NFU1 by RNA interference in human cell culture, LAS and, in turn, PDHC activities were largely diminished. In addition, the amount of succinate dehydrogenase, but no other Fe-S proteins, was decreased. In contrast, depletion of the general Fe-S scaffold protein ISCU severely affected assembly of all tested Fe-S proteins, suggesting that NFU1 performs a specific function in mitochondrial Fe-S cluster maturation. Similar biochemical effects were observed in Saccharomyces cerevisiae upon deletion of NFU1, resulting in lower lipoylation and SDH activity. Importantly, yeast Nfu1 protein carrying the individuals' missense mutation was functionally impaired. We conclude that NFU1 functions as a late-acting maturation factor for a subset of mitochondrial Fe-S proteins.