Uncovering universal rules governing the selectivity of the archetypal DNA glycosylase TDG.

Thymine DNA glycosylase (TDG) is a pivotal enzyme with dual roles in both genome maintenance and epigenetic regulation. TDG is involved in cytosine demethylation at CpG sites in DNA. Here we have used molecular modeling to delineate the lesion search and DNA base interrogation mechanisms of TDG.

Discovery of selective inhibitors of tyrosyl-DNA phosphodiesterase 2 by targeting the enzyme DNA-binding cleft.

Tyrosyl-DNA phosphodiesterase 2 (TDP2) processes protein/DNA adducts resulting from abortive DNA topoisomerase II (Top2) activity. TDP2 inhibition could provide synergism with the Top2 poison class of chemotherapeutics. By virtual screening of the NCI diversity small molecule database, we identified selective TDP2 inhibitors and experimentally verified their selective inhibitory activity.

Secondary Interaction Interfaces with PCNA Control Conformational Switching of DNA Polymerase PolB from Polymerization to Editing.

Replicative DNA polymerases (Pols) frequently possess two distinct DNA processing activities: DNA synthesis (polymerization) and proofreading (3'-5' exonuclease activity). The polymerase and exonuclease reactions are performed alternately and are spatially separated in different protein domains. Thus, the growing DNA primer terminus has to undergo dynamic conformational switching between two distinct functional sites on the polymerase.

Distal substitutions drive divergent DNA specificity among paralogous transcription factors through subdivision of conformational space.

Many genomes contain families of paralogs--proteins with divergent function that evolved from a common ancestral gene after a duplication event. To understand how paralogous transcription factors evolve divergent DNA specificities, we examined how the glucocorticoid receptor and its paralogs evolved to bind activating response elements [(+)GREs] and negative glucocorticoid response elements (nGREs). We show that binding to nGREs is a property of the glucocorticoid receptor (GR) DNA-binding domain (DBD) not shared by other members of the steroid receptor family.

Unexpected Allosteric Network Contributes to LRH-1 Co-regulator Selectivity.

Phospholipids (PLs) are unusual signaling hormones sensed by the nuclear receptor liver receptor homolog-1 (LRH-1), which has evolved a novel allosteric pathway to support appropriate interaction with co-regulators depending on ligand status. LRH-1 plays an important role in controlling lipid and cholesterol homeostasis and is a potential target for the treatment of metabolic and neoplastic diseases. Although the prospect of modulating LRH-1 via small molecules is exciting, the molecular mechanism linking PL structure to transcriptional co-regulator preference is unknown.

Alkylpurine glycosylase D employs DNA sculpting as a strategy to extrude and excise damaged bases.

Alkylpurine glycosylase D (AlkD) exhibits a unique base excision strategy. Instead of interacting directly with the lesion, the enzyme engages the non-lesion DNA strand. AlkD induces flipping of the alkylated and opposing base accompanied by DNA stack compression.

Behaviour therapy for obesity treatment considering approved drug therapy.

Introduction: Obesity is a worldwide health problem whose prevalence is on the increase. Many obesity-associated diseases require intensive medical treatment and are the cause of a large proportion of health-related expenditures in Germany. Treatment of obesity includes nutritional, exercise and behaviour therapy, usually in combination.

Antioxidative vitamines for prevention of cardiovascular disease for patients after renal transplantation and patients with chronic renal failure.

Introduction: The mortality from cardiovascular disease in patients with chronic renal failure is much higher than in the general population. In particular, patients with chronic renal failure with replacement therapies (dialysis patients and patients with renal transplantation) show both increased traditional risk factors and risk factors due to the dysfunction of the renal system. In combination with necessary medication for renal insufficiency oxidative stress is elevated.

A study into the anti-microbial properties of an amino functionalised polymer using multi-parameter flow cytometry.

Fluorescent staining techniques were used to study the anti-microbial properties of aqueous suspensions of a novel, water insoluble amino functionalised polymer on three micro-organisms Pseudomonas fluorescens, Staphylococcus epidermidis and Saccharomyses cerevisiae. The mechanism of action was similar for each organism in that, after various contact times with the polymer, a progressive change in individual cell physiological state was measured using multi-parameter flow cytometry. The microbiocidal activity of this polymer may be similar to that of substances referred to as polycationic, amphipathic compounds (peptides, peptide derivatives and other polyamines).

Course of illness and pattern of recurrences in patients with affective disorders during long-term lithium prophylaxis: a retrospective analysis over 15 years.

We analysed the recurrences of 86 patients with monopolar and bipolar mood and schizoaffective disorders treated with lithium over a period of 8.2 years on average in a specialized out-patient clinic. Lithium medication was discontinued by 24% of patients.

[The behavior of plasma histamine levels following peridural morphine administration].

One of the frequently reported side effects following epidural morphine administration in clinical trials is a generalized pruritus of several hours duration. Since histamine can elicit pruritus we investigated the plasma histamine levels following epidurally applied morphine (0.05 mg/kg) in 10 urological patients.

[Catheter peridural anesthesia with bupivacaine HCI and bupivacaine CO2. A comparison and the effects of premedication].

A controlled prospective randomized study was carried out to compare the action of 0.5% bupivacaine-CO2 and 0.5% bupivacaine-HCI both with and without diazepam premedication.

[Post-traumatic metabolism--bases and clinical aspects].

In order to rationalize the nutritional therapy of polytraumatized patients we have developed a concept to explain the humoral response and subsequent metabolic reactions to trauma, which is based on current reports in the literature and our own investigations. Three separate phases should be defined. a) The acute phase: catecholamines dominate in the initial phase following severe trauma.

[Comparative studies on the side effects of morphine after peridural, spinal and intravenous administration].

A prospective randomized study was carried out on 29 patients undergoing transurethral prostatectomy. In addition to the regional anaesthetic given for the operation, the patients received either: 1 mg morphine intrathecally (spinal group), 0.05 mg/kg body weight of morphine i.

[Peridural morphine analgesia: effects and pharmacokinetics. A double-blind study in vaginal hysterectomy patients].

In a controlled prospective double-blind-study we were able to show that the analgesic duration of epidurally applied morphine is more than four fold longer lasting than intravenous morphine. We found similar pharmacokinetics in both groups, suggesting a rapid absorption of epidurally applied morphine into the vascular system. The identical pharmacokinetics of intravenous and epidurally applied morphine suggest that only small amounts of morphine diffuse across the dura to the spinal cord, where it produces a long lasting analgesia at the opiate receptors.

[Serum bupivacaine concentrations in patients with continuous peridural anesthesia administered by thoracic catheter].

Continuous infusion of a 0.2% solution of bupivacaine via a peridural catheter in a rate of 0.2 ml/kg x h is sufficient to make a patient pain-free for any time required following upper abdominal or abdomino-thoracic surgery.