Loss of transglutaminase 2 sensitizes for diet-induced obesity-related inflammation and insulin resistance due to enhanced macrophage c-Src signaling.

Transglutaminase 2 (TG2) is a multifunctional protein that promotes clearance of apoptotic cells (efferocytosis) acting as integrin ß3 coreceptor. Accumulating evidence indicates that defective efferocytosis contributes to the development of chronic inflammatory diseases. Obesity is characterized by the accumulation of dead adipocytes and inflammatory macrophages in the adipose tissue leading to obesity-related metabolic syndrome. Here, we report that loss of TG2 from bone marrow-derived cells sensitizes for high fat diet (HFD)-induced pathologies. We find that metabolically activated TG2 null macrophages express more phospho-Src and integrin ß3, unexpectedly clear dying adipocytes more efficiently via lysosomal exocytosis, but produce more pro-inflammatory cytokines than the wild type ones. Anti-inflammatory treatment with an LXR agonist reverts the HFD-induced phenotype in mice lacking TG2 in bone marrow-derived cells with less hepatic steatosis than in wild type mice proving enhanced lipid clearance. Thus it is interesting to speculate whether LXR agonist treatment together with enhancing lysosomal exocytosis could be a beneficial therapeutic strategy in obesity.

Benzodiazines: recent synthetic advances.

Benzodiazines (diazonaphthalenes with both nitrogens in the same ring) - cinnolines (1,2-benzodiazine), quinazolines (1,3-benzodiazine), phthalazines (2,3-benzodiazine) and quinoxalines (1,4-benzodiazine) - are important class of compounds with broad biological properties and wide application in pharmaceutical as well as agrochemical arenas. These diazaheterocycles are present in a wide variety of bioactive natural products as well as synthetic molecules that are good drug candidates constituting key structural units responsible for their pronounced therapeutic activities. Their rapidly growing uses and applications in medicinal and agrochemical arenas prompt the researchers for further studies on this important group of compounds. In this review, we hope to provide a brief overview of the important general methodologies and recent developments towards their synthesis and open the door for further progress in this area.

Synthesis of 3-substituted isoindolin-1-ones via a tandem desilylation, cross-coupling, hydroamidation sequence under aqueous phase-transfer conditions.

A simple and expedient method for the synthesis of 3-methylene-isoindolin-1-ones 4 under aqueous phase-transfer conditions has been developed. Starting from 2-iodobenzamides 1 and (silyl)alkynes, the products are obtained in high yields and short reaction times (30 min) with the use of inexpensive CuCl/PPh3 catalyst system in the presence of n-Bu4NBr (TBAB) as a phase-transfer agent. Terminal alkynes are conveniently "unmasked" upon in situ desilylation under the reaction conditions. Alkynes possessing heterocyclic moieties were also found as amenable substrates. Furthermore, a one-pot process starting from 2-iodobenzamides 1, aryl halides (bromides or iodides) and trimethylsilylacetylene (TMSA) as a convenient acetylene surrogate was also shown to be feasible under Pd/Cu catalysis.

Lewis Acid Catalyzed Condensation-Cyclization Cascade: Direct Synthesis of Di/Trifluoromethyl-1,2,3,4-tetrahydroquinazolines.

Condensed heterocycles such as quinazolines constitute the framework of many promising drugs. The great impact of the dramatic fluorine effect in pharmaceuticals prompted a great surge in the quest for fluorinated drug design resulting in over 20 % fluorine-containing drugs in the market today. Therefore, finding an efficient and cost-effective method for the direct synthesis of fluorine-tagged quinazoline systems is of great significance in the pharmaceutical arena. For the first time, a one-pot sequential condensation-cyclization reaction to form selectively the difluoro/trifluoromethylated tetrahydroquinazolines from simple components difluoro/trifluoroacetaldehyde hemiacetal and aromatic amines is reported. Our recent studies using difluoro/trifluoroacetaldehyde hemiacetal as simple and elegant difluoro/trifluoromethyl synthons and metal triflates such as gallium triflate as safe and stable Lewis acid catalysts led us to this direct synthesis protocol for the expedient and convenient synthesis of fluorinated quinazolines. DFT calculations at PCM/B3LYP/6-31++G** were carried out for evaluating a possible reaction mechanism for this cyclization. According to the DFT calculations, product stereochemistry is thermodynamically driven, favoring the cis isomer as the major product, which is also confirmed experimentally.

Modelling pathology from autolog fresh cadaver organs as a novel concept in neurosurgical training.

BACKGROUND: The aim of neurosurgical cadaver training for residents and fellows is not only to obtain a high level of skills, but also to keep the number of complications during the learning curve as low as possible. To move this process forward, we have worked out a novel method in further training. METHODS: Tumours can be modelled from the autolog organs. We can then implant the modelled tumour from the opposite direction and a colleague can remove the pathology from the correct approach. RESULTS: We have experienced improving skills in difficult microsurgical operations. CONCLUSION: We have performed more than 800 fresh cadaver operations over the last 6 years. The last 70 cases have been performed with modelling pathology. In our department, we introduce a regular weekly program in our cadaver operating theatre. The consideration could be useful not only for the young neurosurgeons but also for experienced colleagues.

Straight needle with fingertip support technique reduces exclusion time during bypass (in vitro, in vivo animal study): a technical note.

BACKGROUND: The duration of exclusion time of recipient artery is an important factor in bypass surgery of cerebral revascularization. The longest period of exclusion is the suturing time. The fingertip support technique (first published in 2006) reduced the physiological tremor to speed up this extra-precise microsurgical procedure. The use of a straight needle proved to further decrease suturing time during the bypass procedure. METHODS: A straight micro needle was added to the fingertip support method for further reduction of exclusion time. A comparative study, measuring the duration of suturing time in vitro and in vivo for animal cases, was performed. This was a golden opportunity to examine how to simplify vascular transposition, using the fingertip support technique and straight needle. RESULTS: The average time of the bypass procedure by the novel considerations (fingertip support and straight needle) was significantly less than the average time by traditional microsurgical support. CONCLUSION: This in vitro/in vivo animal study provides evidence of the reduction of the suturing time, and thus the exclusion time, by using the fingertip support technique with a straight needle in the bypass procedure.

Organically modified Pd-silica catalysts applied in Heck coupling.

Pd-silica catalysts prepared by depositing Pd onto silica precursors modified by surface methyl or phenyl groups through the reduction of Pd2+ ions with surface Si-H functions exhibit high activity and selectivity in Heck coupling.