High-resolution cryo-EM structure of the F-actin-fimbrin/plastin ABD2 complex

Many actin binding proteins have a modular architecture, and calponin-homology (CH) domains are one such structurally conserved module found in numerous proteins that interact with F-actin. The manner in which CH-domains bind F-actin has been controversial. Using cryo-EM and a single-particle approach to helical reconstruction, we have generated 12-A-resolution maps of F-actin alone and F-actin decorated with a fragment of human fimbrin (L-plastin) containing tandem CH-domains. The high resolution allows an unambiguous fit of the crystal structure of fimbrin into the map. The interaction between fimbrin ABD2 (actin binding domain 2) and F-actin is different from any interaction previously observed or proposed for tandem CH-domain proteins, showing that the structural conservation of the CH-domains does not lead to a conserved mode of interaction with F-actin. Both the stapling of adjacent actin protomers and the additional closure of the nucleotide binding cleft in F-actin when the fimbrin fragment binds may explain how fimbrin can stabilize actin filaments. A mechanism is proposed where ABD1 of fimbrin becomes activated for binding a second actin filament after ABD2 is bound to a first filament, and this can explain how mutations of residues buried in the interface between ABD2 and ABD1 can rescue temperature-sensitive defects in actin.     

Coumarins permeability in Caco‐2 cell model

Objectives The presence of coumarins in human diet, their multiple pharma***?ological properties and occurrence in various herbal remedies represent significant reasons to explore their membrane permeability, as a first event contributing to coumarins oral bioavailability. Thus, we evaluated the permeability and cytotoxicity of 18 coumarins, with different substitution patterns involving OH, OCH₃ and CH₃ groups. Methods A modified Caco‐2 permeability model was used, in which the permeability test is performed with a robotic workstation and cells are grown on 96‐well plates for 7 days. Key findings All studied coumarins were highly permeable, with calculated P_app values that varied within 4.1 times 10^?5 to 2.1 times 10^?4 in apical to basolateral studies and within 1.8 times 10^?5 to 7.0 times 10^?5 in basolateral to apical studies. The efflux ratio remained in all cases below 1. It was demonstrated that the type and position of substituents contributed more to the permeability than the number of substituents. Conclusions The results allowed us to predict that these coumarins are well absorbed in the gut lumen and efflux is not limiting the absorption. Five coumarins had an influence on the mitochondrial function of Caco‐2 cells (1 < 80%, 4 > 120%), according to the WST‐1 cytotoxicity test, but this does not seem to affect the permeability of the compounds.     

Osteotomie als Methode der operativen Behandlung der Spasmophilie und Tetanie

Zusammenfassung 3 Beobachtungen, welche die Beeinflu\barkeit tetanischer und spasmophiler Zust?nde durch einfache operative Knochentraumen zeigen sollen.      

CyberKnife stereotactic radiotherapy for mass lesions of the spinal cord and spine

Introduction of a novel technology of stereotactic radiation treatment using linear accelerators, refining of systems for visualization and guidance provided rapid development of extracranial radiosurgery. Nowadays there is a possibility of precise stereotactic irradiation of lesions with different size and localization. One of the most actual and promising indications for radiosurgery are different primary and metastatic lesions and arteriovenous malformations of spinal cord and spine. Radiosurgery and hypofractionated radiotherapy with precise dose delivery during one or several sessions allow effective and safe treatment of neoplasms with any degree of radioresistance. This paper contains analysis of the first Russian experience of stereotactic radiation treatment of lesions of spinal cord and spine using robotized system CyberKnife (Accuray Inc., USA).     

CyberKnife stereotactic radiosurgery in the treatment of patients with trigeminal neuralgia

Trigeminal neuralgia (TN) is a disabling disease with severe impairment of quality of life and everyday activity of patients. Range of treatment modalities is wide and includes conservative therapy, surgical methods and stereotactic radiosurgery (SRS). SRS is a minimally invasive technique which provides good results and minimal rate of complications. High geometrical and clinical precision of frameless SRS using CyberKnife system allows its application in TN when high dose is delivered to a small volume. The given paper focuses on the first Russian experience of frameless SRS of TN using robotized system CyberKnife. Since April 2009 till June 2011 4 patients with TN were treated in department for radiation therapy of Burdenko Neurosurgical Institute using CyberKnife system. Mean age was 63 years. Mean and maximal target dose reached 70 and 90 Gy, respectively. Data of catamnestic clinical examination were available in all 4 patients. Follow-up period reached 8 months. Response to treatment was observed in all cases. In 2 (50%) patients full effect was reached while in the rest only partial effect was present. No complications were encountered. Effectiveness and safety of SRS using CyberKnife system is comparable with framed SRS.     

Cortical connections of area V4 in the macaque

To determine the locus, full extent, and topographic organization of cortical connections of area V4 (visual area 4), we injected anterograde and retrograde tracers under electrophysiological guidance into 21 sites in 9 macaques. Injection sites included representations ranging from central to far peripheral eccentricities in the upper and lower fields. Our results indicated that all parts of V4 are connected with occipital areas V2 (visual area 2), V3 (visual area 3), and V3A (visual complex V3, part A), superior temporal areas V4t (V4 transition zone), MT (medial temporal area), and FST (fundus of the superior temporal sulcus [STS] area), inferior temporal areas TEO (cytoarchitectonic area TEO in posterior inferior temporal cortex) and TE (cytoarchitectonic area TE in anterior temporal cortex), and the frontal eye field (FEF). By contrast, mainly peripheral field representations of V4 are connected with occipitoparietal areas DP (dorsal prelunate area), VIP (ventral intraparietal area), LIP (lateral intraparietal area), PIP (posterior intraparietal area), parieto-occipital area, and MST (medial STS area), and parahippocampal area TF (cytoarchitectonic area TF on the parahippocampal gyrus). Based on the distribution of labeled cells and terminals, projections from V4 to V2 and V3 are feedback, those to V3A, V4t, MT, DP, VIP, PIP, and FEF are the intermediate type, and those to FST, MST, LIP, TEO, TE, and TF are feedforward. Peripheral field projections from V4 to parietal areas could provide a direct route for rapid activation of circuits serving spatial vision and spatial attention. By contrast, the predominance of central field projections from V4 to inferior temporal areas is consistent with the need for detailed form analysis for object vision.