Structure of the preholoproteasome reveals late steps in proteasome core particle biogenesis.

Assembly of the proteasome's core particle (CP), a barrel-shaped chamber of four stacked rings, requires five chaperones and five subunit propeptides. Fusion of two half-CP precursors yields a complete structure but remains immature until active site maturation. Here, using Saccharomyces cerevisiae, we report a high-resolution cryogenic electron microscopy structure of preholoproteasome, a post-fusion assembly intermediate.

DUB-le vision: snapshots of the proteasome during substrate processing.

Covalent modification by the small protein ubiquitin can target proteins for destruction by the proteasome, but the ubiquitin signal itself is recycled. Surprisingly, proteasomes contain three different deubiquitinating enzymes (DUBs). Recent work by Zhang and Zou et al.

Yeast PI31 inhibits the proteasome by a direct multisite mechanism.

Proteasome inhibitors are widely used as therapeutics and research tools, and typically target one of the three active sites, each present twice in the proteasome complex. An endogeneous proteasome inhibitor, PI31, was identified 30 years ago, but its inhibitory mechanism has remained unclear. Here, we identify the mechanism of Saccharomyces cerevisiae PI31, also known as Fub1.

Chaperone-mediated assembly of the proteasome core particle - recent developments and structural insights.

Much of cellular activity is mediated by large multisubunit complexes. However, many of these complexes are too complicated to assemble spontaneously. Instead, their biogenesis is facilitated by dedicated chaperone proteins, which are themselves excluded from the final product.

Mechanism of proteasome gate modulation by assembly chaperones Pba1 and Pba2.

The active sites of the proteasome are housed within its central core particle (CP), a barrel-shaped chamber of four stacked heptameric rings, and access of substrates to the CP interior is mediated by gates at either axial end. These gates are constitutively closed and may be opened by the regulatory particle (RP), which binds the CP and facilitates substrate degradation. We recently showed that the heterodimeric CP assembly chaperones Pba1/2 also mediate gate opening through an unexpected structural arrangement that facilitates the insertion of the N terminus of Pba1 into the CP interior; however, the full mechanism of Pba1/2-mediated gate opening is unclear.

[From acute coronary syndrome to zoster : Differential diagnostics in segmental and somatic dysfunction of the thoracic spine and ribs].

Background: Segmental and somatic dysfunction in the thoracic section can lead to various clinical symptoms. It is necessary to distinguish three variants.

Clinical Picture: 1.

[Manual medicine for the extremity joints : Successful treatment of complex symptom constellations].

One important field of manual medicine is the special diagnosis and treatment of the extremities. Biomechanical and neurophysiologic knowledge allows identification and treatment of so-called kinetic chain syndromes. The manual diagnosis of the extremities follows clear criteria and enables the diagnosis of myofascial or joint dysfunction.

[Segmental and somatic dysfunction : How does manual medicine work?].

Background: Manual medicine is based on neurophysiologic and biomechanical principles. Impaired senso-motor regulation causes segmental and somatic dysfunction. Via segmental mapping, somato-sensory and vegetative dysfunction arises.

Structures of chaperone-associated assembly intermediates reveal coordinated mechanisms of proteasome biogenesis.

The proteasome mediates most selective protein degradation. Proteolysis occurs within the 20S core particle (CP), a barrel-shaped chamber with an αββα configuration. CP biogenesis proceeds through an ordered multistep pathway requiring five chaperones, Pba1-4 and Ump1.

Reg1 and Snf1 regulate stress-induced relocalization of protein phosphatase-1 to cytoplasmic granules.

The compartmentalization of cellular function is achieved largely through the existence of membrane-bound organelles. However, recent work suggests a novel mechanism of compartmentalization mediated by membraneless structures that have liquid droplet-like properties and arise through phase separation. Cytoplasmic stress granules (SGs) are the best characterized and are induced by various stressors including arsenite, heat shock, and glucose deprivation.

Thiol-based direct threat sensing by the stress-activated protein kinase Hog1.

The yeast stress-activated protein kinase Hog1 is best known for its role in mediating the response to osmotic stress, but it is also activated by various mechanistically distinct environmental stressors, including heat shock, endoplasmic reticulum stress, and arsenic. In the osmotic stress response, the signal is sensed upstream and relayed to Hog1 through a kinase cascade. Here, we identified a mode of Hog1 function whereby Hog1 senses arsenic through a direct physical interaction that requires three conserved cysteine residues located adjacent to the catalytic loop.

Targeted Degradation of Glucose Transporters Protects against Arsenic Toxicity.

The abundance of cell surface glucose transporters must be precisely regulated to ensure optimal growth under constantly changing environmental conditions. We recently conducted a proteomic analysis of the cellular response to trivalent arsenic, a ubiquitous environmental toxin and carcinogen. A surprising finding was that a subset of glucose transporters was among the most downregulated proteins in the cell upon arsenic exposure.

Rapid induction of p62 and GABARAPL1 upon proteasome inhibition promotes survival before autophagy activation.

Proteasome inhibitors are used as research tools and to treat multiple myeloma, and proteasome activity is diminished in several neurodegenerative diseases. We therefore studied how cells compensate for proteasome inhibition. In 4 h, proteasome inhibitor treatment caused dramatic and selective induction of (but not other autophagy genes) and , which binds ubiquitinated proteins and GABARAPL1 on autophagosomes.

Dialect Variation Influences the Phonological and Lexical-Semantic Word Processing in Sentences. Electrophysiological Evidence from a Cross-Dialectal Comprehension Study.

This event-related potential (ERP) study examines the influence of dialectal competence differences (merged vs. unmerged dialect group) on cross-dialectal comprehension between Southern German dialects. It focuses on the question as to whether certain dialect phonemes (/[Formula: see text]/, /[Formula: see text]/), which are attributed to different lexemes in two dialect areas (Central Bavarian, Bavarian-Alemannic transition zone) evoke increased neural costs during sentence processing.

Effects of Stomach Inflation on Cardiopulmonary Function and Survival During Hemorrhagic Shock: A Randomized, Controlled, Porcine Study.

Background: Ventilation of an unprotected airway may result in stomach inflation. The purpose of this study was to evaluate the effect of clinically realistic stomach inflation on cardiopulmonary function during hemorrhagic shock in a porcine model.

Methods: Pigs were randomized to a sham control group (n = 9), hemorrhagic shock (35 mL kg over 15 min [n = 9]), and hemorrhagic shock combined with stomach inflation (35 mL kg over 15 min and 5 L stomach inflation [n = 10]).

Functions of genes and enzymes involved in phenalinolactone biosynthesis.

Phenalinolactones are novel terpene glycoside antibiotics produced by Streptomyces sp. Tü6071. Inactivation of three oxygenase genes (plaO2, plaO3 and plaO5), two dehydrogenase genes (plaU, plaZ) and one putative acetyltransferase gene (plaV) led to the production of novel phenalinolactone derivatives (PL HS6, PL HS7, PL HS2 and PL X1).

Capture of endothelial progenitor cells by a bispecific protein/monoclonal antibody molecule induces reendothelialization of vascular lesions.

Tissue injury is inevitably accompanied by disruption of the endothelium and exposure of the subendothelial matrix. To generate a guidance molecule directing progenitor cells to sites of vascular lesions, we designed a bifunctional protein. The protein consists of the soluble platelet collagen receptor glycoprotein VI and an antibody to CD133 (hereafter called GPVI-CD133).

Heterologous expression and genetic engineering of the phenalinolactone biosynthetic gene cluster by using red/ET recombineering.

The heterologous expression of natural product biosynthetic pathways is of increasing interest in biotechnology and drug discovery. This approach enables the production of complex metabolites in more amenable host organisms and provides the basis for the generation of novel analogues through genetic engineering. Here we describe a straightforward strategy for the heterologous expression of the highly complex phenalinolactone biosynthetic pathway, which was recently cloned from Streptomyces sp.

Cooling extensive burns: sprayed coolants can improve initial cooling management - a thermography-based study.

This pilot study was designed to verify whether the spraying of coolant improves initial cooling in extensive burns. The cooling effects of 1l of sprayed water and 5l of poured water (at 22 degrees C) were tested; 53 healthy participants were cooled for 15 min over 18% of their total body surface, twice. Thermographic imaging measured the loss of skin temperature and assessed the homogeneity of cooling.

Biosynthesis of the terpene phenalinolactone in Streptomyces sp. Tü6071: analysis of the gene cluster and generation of derivatives.

Phenalinolactones are terpene glycosides with antibacterial activity. A striking structural feature is a highly oxidized gamma-butyrolactone of elusive biosynthetic origin. To investigate the genetic basis of the phenalinolactones biosynthesis, we cloned and sequenced the corresponding gene cluster from the producer strain Streptomyces sp.

Occurrence and regulation of the ferric citrate transport system in Escherichia coli B, Klebsiella pneumoniae, Enterobacter aerogenes, and Photorhabdus luminescens.

In Escherichia coli K-12, transcription of the ferric citrate transport genes fecABCDE is initiated by binding of diferric dicitrate to the outer membrane protein FecA which elicits a signaling cascade from the cell surface to the cytoplasm. The FecI sigma factor is only active in the presence of FecR, which transfers the signal across the cytoplasmic membrane. In other bacteria, fecIRA homologues control iron transport gene transcription by siderophores other than citrate.

Separation and quantitation of alkylphosphocholines and analogues of different liposome formulations by HPTLC.

High-performance thin-layer chromatographic (HPTLC) analysis of non UV-active phospholipids in biological matrixes is a common method for separation, detection, and quantitation. Liposomes containing new alkylphosphocholines and analogues with enhanced cytostatic activity had been prepared. The liposomal formulations were designed to enable the intravenous application of the alkylphosphocholines and analogues and to reduce dose-limiting toxicities observed after oral administration.

Preparation and analysis of styrene oligomers containing migrates from various polystyrenes used in food packaging.

An oligostyrene-like product (F2L5250) was reported to have estrogen-like activity (statistically significant increases in means for absolute uterine weight and the ratios of the uterine weight to terminal body weight) in juvenile female rats provided a dietary concentration of 100 ppm F2L5250 for four consecutive days. The highest no-effect-level (NOEL) for estrogenic activity was 80 ppm in the diet, corresponding to a daily intake of 13.3 mg F2L5250/kg.

[Ectopic gastric mucosa in the duodenal bulb].

The radiological and clinical findings of 12 patients with ectopic gastric mucosa in the duodenal bulb are presented. This is a defined disease with characteristic radiological features: multiple small nodular defects of the contrast medium of 1-3 mm diameter. Histology shows complete heterotopia.