Protein oxidative modifications in the ageing brain: consequence for the onset of neurodegenerative disease.

The free radical theory of ageing proposes the accumulation of altered, less active and toxic molecules of DNA, RNA, proteins and lipids caused by reactive oxygen species and reactive nitrogen species. Neurodegenerative disorders are characterized by an abnormal accumulation of oxidatively damaged macromolecules inside cells and in the extracellular space. Proteins involved in the formation of aggregates are β-amyloid, tau, α-synuclein, parkin, prion proteins and proteins containing polyglutamine.

MapSplice: accurate mapping of RNA-seq reads for splice junction discovery.

The accurate mapping of reads that span splice junctions is a critical component of all analytic techniques that work with RNA-seq data. We introduce a second generation splice detection algorithm, MapSplice, whose focus is high sensitivity and specificity in the detection of splices as well as CPU and memory efficiency. MapSplice can be applied to both short (<75 bp) and long reads (≥ 75 bp).

Specific disintegration of complex II succinate:ubiquinone oxidoreductase links pH changes to oxidative stress for apoptosis induction.

The formation of reactive oxygen species (ROS) and the change of the intracellular pH (pH(i)) are common phenomena during apoptosis. How they are interconnected, however, is poorly understood. Here we show that numerous anticancer drugs and cytokines such as Fas ligand and tumour necrosis factor α provoke intracellular acidification and cause the formation of mitochondrial ROS.

Selection and characterisation of affibody molecules inhibiting the interaction between Ras and Raf in vitro.

Development of molecules with the ability to selectively inhibit particular protein-protein interactions is important in providing tools for understanding cell biology. In this work, we describe efforts to select small Ras- and Raf-specific three-helix bundle affibody binding proteins capable of inhibiting the interaction between H-Ras and Raf-1, from a combinatorial library displayed on bacteriophage. Target-specific variants with typically high nanomolar or low micromolar affinities (K(D)) could be selected successfully against both proteins, as shown by dot blot, ELISA and real-time biospecific interaction analyses.

Electrophysiological evidence for the hierarchical organization of auditory change detection in the human brain.

Auditory change detection has been associated with mismatch negativity (MMN), an event-related potential (ERP) occurring at 100-250 ms after the onset of an acoustic change. Yet, single-unit recordings in animals suggest much faster novelty-specific responses in the auditory system. To investigate change detection in a corresponding early time range in humans, we measured the Middle Latency Response (MLR) and MMN during a controlled frequency oddball paradigm.

Early change detection in humans as revealed by auditory brainstem and middle-latency evoked potentials.

The ability to detect unexpected novel stimuli is crucial for survival, as it might urge a prompt adaptive response. Human auditory novelty detection has been associated to the mismatch negativity long-latency auditory-evoked potential, peaking at 100-200 ms. Yet, recent animal studies showing novelty responses at a very short latency (about 20-30 ms) in individual neurons already at the level of the midbrain and thalamus suggest that novelty detection might be a basic principle of the functional organization of the auditory system, expanding from lower levels in the brainstem along the auditory pathway up to higher-order areas of the cerebral cortex.

Cathepsin D is one of the major enzymes involved in intracellular degradation of AGE-modified proteins.

Oxidized and cross-linked modified proteins are known to accumulate in ageing. Little is known about whether the accumulation of proteins modified by advanced glycation end products (AGEs) is due to an affected intracellular degradation. Therefore, this study was designed to determine whether the intracellular enzymes cathepsin B, cathepsin D and the 20S proteasome are able to degrade AGE-modified proteins in vitro.

Oxidative protein damage and the proteasome.

Protein damage, caused by radicals, is involved in many diseases and in the aging process. Therefore, it is crucial to understand how protein damage can be limited, repaired or removed. To degrade damaged proteins, several intracellular proteolytic systems exist.

Tau protein degradation is catalyzed by the ATP/ubiquitin-independent 20S proteasome under normal cell conditions.

Tau is the major protein exhibiting intracellular accumulation in Alzheimer disease. The mechanisms leading to its accumulation are not fully understood. It has been proposed that the proteasome is responsible for degrading tau but, since proteasomal inhibitors block both the ubiquitin-dependent 26S proteasome and the ubiqutin-independent 20S proteasome pathways, it is not clear which of these pathways is involved in tau degradation.

Glioblastoma: a method for predicting response to antiangiogenic chemotherapy by using MR perfusion imaging--pilot study.

Purpose: To derive a magnetic resonance (MR)-based imaging metric that reflects local perfusion changes resulting from the administration of angiogenic-inhibiting chemotherapy in patients with recurrent glioblastoma multiforme (GBM).

Materials And Methods: In this retrospective Institutional Review Board-approved HIPAA-compliant study, 16 patients (12 men, four women; mean age, 51.8 years + or - 15.

The time-course of auditory and visual distraction effects in a new crossmodal paradigm.

Vision often dominates audition when attentive processes are involved (e.g., the ventriloquist effect), yet little is known about the relative potential of the two modalities to initiate a "break through of the unattended".

Expression and characterization of dog cytochrome P450 2A13 and 2A25 in baculovirus-infected insect cells.

Dog CYP2A13 and CYP2A25 were coexpressed with dog NADPH-cytochrome P450 reductase (OR) in baculovirus-infected Sf9 insect cells. CYP2A13 effectively catalyzed 7-ethoxycoumarin (7EC) deethylation and coumarin hydroxylation with apparent K(m) values of 4.8 and 2.

A temporal constraint for automatic deviance detection and object formation: A mismatch negativity study.

The automatic detection of deviations within a constant sine wave tone is confined to the initial part of approximately 350 ms. When a deviation occurs beyond this critical limit, the mismatch negativity (MMN) - a deviance-related component of the event-related potential - is largely attenuated or even absent. However, for time-variant acoustic stimuli such as speech sounds or tonal patterns, MMN is also obtained for deviations beyond the initial 350 ms.

Light-induced cytotoxicity after aminolevulinic acid treatment is mediated by heme and not by iron.

Photodynamic therapy (PDT) is a promising antitumor treatment strategy. However, effectiveness of PDT is limited due to an initiation of rescue responses in tumor cells, including the induction of heme oxygenase-1 (HO-1). Furthermore, the main sources of free radical production in PDT-induced oxidative stress are not clear.

Diagnostic yield of ink-jet prints from digital radiographs for the assessment of approximal carious lesions: ROC-analysis.

Aims: To investigate the diagnostic quality of different quality, individually calibrated ink-jet printers for the very challenging dental radiographic task of approximal carious lesion detection.

Materials And Methods: A test-pattern evaluating resolution, contrast and homogeneity of the ink-jet prints was developed. 50 standardized dental radiographs each showing two neighbouring teeth in natural contact were printed on glossy paper with calibrated, randomly selected ink-jet printers (Canon S520 and iP4500, Epson Stylus Photo R2400).

Anticancer genes: inducers of tumour-specific cell death signalling.

Recent studies have revealed a new class of genes encoding proteins with specific anticancer activity. Upon ectopic expression, these factors cause cell death specifically in tumour cells by apoptosis, autophagy or mitotic catastrophe, yet normal cells are spared. Some of these genes or their encoded proteins are in clinical development and show promising results, and their signalling pathways are currently under intense investigation.

Role of human UGT2B10 in N-glucuronidation of tricyclic antidepressants, amitriptyline, imipramine, clomipramine, and trimipramine.

The role of human UDP glucuronosyltransferase (UGT) 2B10 in the N-glucuronidation of a number of tricyclic antidepressants was investigated and compared with that of UGT1A4 in both the Sf9 expressed system and human liver microsomes. The apparent K(m) (S(50)) values for the formation of quaternary N-glucuronides of amitriptyline, imipramine, clomipramine, and trimipramine were 2.60, 16.

Lipofuscin-bound iron is a major intracellular source of oxidants: role in senescent cells.

Aging is accompanied by an intracellular accumulation of lipofuscin, a hydrophobic yellow-brownish material that accumulates especially in the lysosomal compartment, where it can be neither degraded nor exocytosed from the cell. The intracellular effects of accumulating lipofuscin are still a subject of speculation. In addition to the demonstrated inhibition of the proteasome, it was proposed that lipofuscin is cytotoxic because of its ability to incorporate transition metals such as copper and iron, resulting in a redox-active surface, able to catalyze the Fenton reaction.

Lorazepam modulates orbitofrontal signal changes during emotional processing in catatonia.

Objective: Catatonia is a psychomotor syndrome characterized by concomitant emotional, behavioural and motor symptoms. In many cases clinical symptoms disappear almost immediately with administration of lorazepam, which acts on GABA(A) receptors.

Methods: Using functional magnetic resonance imaging (fMRI) we investigated prefrontal activation patterns during emotion processing in catatonic patients with and without lorazepam in a double-blind study design.

Chromatin repair after oxidative stress: role of PARP-mediated proteasome activation.

Oxidative stress is an inevitable process in the nucleus, especially in antitumor chemotherapy, and adaptation by defense mechanisms seems to be one element in the development of long-term resistance to many chemotherapeutic drugs. In this study, a potential chromatin repair mechanism during oxidative stress was investigated in HT22 cells. The 20S proteasome has been shown to be largely responsible for the degradation of oxidatively modified histone proteins in the nucleus.

Efficacy of vagus nerve stimulation in the treatment of depression.

Major depressive disorder is a disease with prominent individual, medical and economic impacts. A relevant proportion of depressive patients suffering from a therapy-resistant course are increasingly being treated with antidepressant brain stimulation techniques. One of these interventions is the vagus nerve stimulation that has recently been tested in a number of clinical trials.

Adult primary spinal cord tumors.

Primary spinal cord tumors represent 2-4% of all neoplasms of the CNS. Primary spinal cord tumors are anatomically separable into two broad categories: intradural intramedullary and intradural extramedullary. Intramedullary tumors are comprised predominantly of gliomas (infiltrative astrocytomas and ependymomas).

Rapid cerebral hemodynamic modulation during set shifting: evidence of time-locked associations with cognitive control in females.

Set shifting provokes specific alterations of cerebral hemodynamics in basal cerebral arteries. However, no gender differences have been reported. In the following functional transcranial Doppler study, we introduced cerebral hemodynamic modulation to the aspects of set shifting during Wisconsin Card Sorting Test (WCST).