Synthesis and carbonic anhydrase inhibitory properties of novel bromophenols including natural products

(2-Bromo-3,4-dimethoxyphenyl) (3,4-dimethoxyphenyl)methanone (10) and its derivatives with Br, one dibromide and isomeric three tribromides, were synthesized. Demethylation of these compounds afforded a series of new bromophenols. Inhibition of human cytosolic carbonic anhydrase II (hCA II) isozyme by these new bromophenols and naturally occurring 3,4,6-tribromo-5-(2,5-dibromo-3,4-dihydroxybenzyl)benzene-1,2-diol (3), and 5,5'-methylenebis(3,4,6-tribromo-benzene-1,2-diol) (4) was investigated. The synthesized compounds showed carbonic anhydrase inhibitory capacities with IC(50) values in the range of 0.7-372 μM against hCA II. Some bromophenols investigated here showed effective hCA II inhibitory activity and might be used as leads for generating novel carbonic anhydrase inhibitors which are valuable drug candidates for the treatment of glaucoma, epilepsy, gastric and duodenal ulcers, neurological disorders, or osteoporosis.     

Replication and discrimination of limb movement velocity

It is well known that proprioception is composed of the senses of movement and position. Whereas tests of position sense are quite commonly used, tests of the acuity in perception of movement velocity are scarce. In the present study we examined some novel tests for assessing the sense of limb movement velocity, involving replication and discrimination of single-joint movement velocity. Specifically, we investigated: (1) whether replication of limb movement velocity is more accurate following active criterion movements as compared to passive; (2) whether antagonist muscle contraction during passive limb movement enhances velocity discrimination; (3) how criterion movement velocity influences response accuracy; (4) the relationship between movement velocity and movement extent during velocity replication; and (5) whether subjects really base discrimination of velocities on perceived velocity. Sixteen healthy subjects participated in four tests (I-IV). For each test, horizontal abductions were performed about the right glenohumeral joint from the sagittal plane. The subjects were required to actively replicate the velocity of either an active (Test I) or passive (Test II) criterion movement, or judge whether a passive/semipassive (passive during antagonist muscle contraction) movement was faster or slower than a previous passive/semipassive criterion movement (Test III/IV). The results revealed higher response accuracy for Test I compared to Test II and for slower movements compared to faster, but no difference in response accuracy between Test III and IV. For velocity discrimination, the analysis revealed that the subjects based their judgment on the difference between criterion and comparison velocity rather than time or extent cues.     

The Germinal Center Kinase TNIK Is Required for Canonical NF-κB and JNK Signaling in B-Cells by the EBV Oncoprotein LMP1 and the CD40 Receptor

The tumor necrosis factor-receptor-associated factor 2 (TRAF2)- and Nck-interacting kinase (TNIK) is a ubiquitously expressed member of the germinal center kinase family. The TNIK functions in hematopoietic cells and the role of TNIK-TRAF interaction remain largely unknown. By functional proteomics we identified TNIK as interaction partner of the latent membrane protein 1 (LMP1) signalosome in primary human B-cells infected with the Epstein-Barr tumor virus (EBV). RNAi-mediated knockdown proved a critical role for TNIK in canonical NF-κB and c-Jun N-terminal kinase (JNK) activation by the major EBV oncoprotein LMP1 and its cellular counterpart, the B-cell co-stimulatory receptor CD40. Accordingly, TNIK is mandatory for proliferation and survival of EBV-transformed B-cells. TNIK forms an activation-induced complex with the critical signaling mediators TRAF6, TAK1/TAB2, and IKKβ, and mediates signalosome formation at LMP1. TNIK directly binds TRAF6, which bridges TNIK's interaction with the C-terminus of LMP1. Separate TNIK domains are involved in NF-κB and JNK signaling, the N-terminal TNIK kinase domain being essential for IKKβ/NF-κB and the C-terminus for JNK activation. We therefore suggest that TNIK orchestrates the bifurcation of both pathways at the level of the TRAF6-TAK1/TAB2-IKK complex. Our data establish TNIK as a novel key player in TRAF6-dependent JNK and NF-κB signaling and a transducer of activating and transforming signals in human B-cells.     

Synthesis and potent antimicrobial activity of some novel methyl or ethyl 1H-benzimidazole-5-carboxylates derivatives carrying amide or amidine groups

A series of benzimidazole-5-carboxylic acid alkyl ester derivatives carrying amide or amidine substituted methyl or phenyl groups at the position C-2 were synthesised and evaluated for antibacterial and antifungal activities against S. aureus, methicillin resistant S. aureus (MRSA), S. faecalis, methicillin resistant S. epidermidis (MRSE), E. coli and C. albicans. The results showed that while all simple acetamides are essentially inactive, aromatic amides and amidines have potent antibacterial activities. Aromatic amidine derivatives 13 f-h exhibited the best inhibitory activity with 1.56-0.39 microg/mL MIC values against MRSA and MRSE.     

Taxonomic review and phylogenetic inference elucidate the evolutionary history of Mesozoic Procercopidae,with new data from the Cretaceous Jehol Biota of NE China (Hemiptera,Cicadomorpha)

The Mesozoic family Procercopidae is widely treated as the ancient group of Cercopoidea and a transitional unit to recent lineages, but its evolution and diversity are vague due to fragmentary fossil record and confusing taxonomic history. Herein, an extensive taxonomic review of Procercopidae is presented and some new fossils are reported from the Lower Cretaceous Yixian Formation of NE China. As a result, Chengdecercopis Hong, 1983 is transferred from Procercopidae to Sinoalidae; Procercopis longipennis Becker-Migdisova, 1962 and P shawanensis Zhang, Wang and Zhang, 2003 are transferred to Procercopina Martynov, 1937, resulting in Procercopina longipennis (Becker-Migdisova, 1962), comb. n. and P shawanensis (Zhang, Wang and Zhang, 2003), comb. n.; Luanpingia senjituensis Hong, 1984 is transferred to Stellularis Chen, Yao and Ren, 2015, leading to Stellulari senjituensis (Hong, 1984), comb. n.; Anthoscytina macula Hu, Yao and Ren, 2014 is transferred to Sinocercopis Hong, 1982, and Sunoscytinopteris (Scytinopteridae) and Cathaycixius (Cixiidae) are treated as junior homonym names of Sinocercopis, leading to Sinocercopis macula (Hu, Yao and Ren, 2014), comb. n., S lushangfenensis (Hong, 1984), comb. n., S pustulosis (Ren, 1995), comb. n., and S trinervis (Ren, 1995), comb. n. Additionally, two new species are erected: Stellularis bineuris Chen and Wang, sp. n. and S minutus Chen and Wang, sp. n. Our cladistic analysis based on wing (tegmen and hind wing) characteristics recovers the high-level relationships within Cercopoidea: Sinoalidae + (Procercopidae + (Cercopionidae + modern cercopoids)). Within the family Procercopidae, the cladistic analysis reveals that the Middle to Late Jurassic Titanocercopis and Jurocercopis and the Cretaceous Cretocercopis occupy the basal position, and a gradual change in wing venation can be recognized from the Early Jurassic Procercopis and Procercopina to the Jurassic Anthoscytina, and then to the Cretaceous Stellularis and Sinocercopis. The two Cretaceous genera, sharing wing traits with extant cercopoids, likely represent transitional forms between Procercopidae and recent Cercopoidea; however, they are very similar to their Jurassic relatives in body structures, suggesting it is applicable to attribute them to Procercopidae. Furthermore, our analysis suggests that the extinction of Procercopidae and the origin and early diversification of modern Cercopoidea approximately coincided with the rise and explosive radiation of angiosperms in the late Early Cretaceous and onwards.     

Conventional and Molecular Identification of Bacteria with Magnesite Enrichment Potential from Local Quarries in Erzurum

In this study, the bacteria having ore enrichment potential were isolated from three different magnesite quarries located in Erzurum-Askale borderlines. The obtained isolates were identified and characterized according to the conventional (morphological, physiological and biochemical tests) and molecular techniques (fatty acid methyl ester profiles (FAME), BOX PCR and 16S rDNA). According to sequence analysis, they were determined as Exiguobacterium aurantiacum (4), Exiguobacterium sibiricum (2), Bacillus sp. (2), Staphylococcus epidermidis (2), Staphylococcus haemolyticus (1), Shewanella baltica (1) and Klebsiella oxytoca (1), respectively.     

Mutations in Either TUBB or MAPRE2 Cause Circumferential Skin Creases Kunze Type

Circumferential skin creases Kunze type (CSC-KT) is a specific congenital entity with an unknown genetic cause. The disease phenotype comprises characteristic circumferential skin creases accompanied by intellectual disability, a cleft palate, short stature, and dysmorphic features. Here, we report that mutations in either MAPRE2 or TUBB underlie the genetic origin of this syndrome. MAPRE2 encodes a member of the microtubule end-binding family of proteins that bind to the guanosine triphosphate cap at growing microtubule plus ends, and TUBB encodes a β-tubulin isotype that is expressed abundantly in the developing brain. Functional analyses of the TUBB mutants show multiple defects in the chaperone-dependent tubulin heterodimer folding and assembly pathway that leads to a compromised yield of native heterodimers. The TUBB mutations also have an impact on microtubule dynamics. For MAPRE2, we show that the mutations result in enhanced MAPRE2 binding to microtubules, implying an increased dwell time at microtubule plus ends. Further, in vivo analysis of MAPRE2 mutations in a zebrafish model of craniofacial development shows that the variants most likely perturb the patterning of branchial arches, either through excessive activity (under a recessive paradigm) or through haploinsufficiency (dominant de novo paradigm). Taken together, our data add CSC-KT to the growing list of tubulinopathies and highlight how multiple inheritance paradigms can affect dosage-sensitive biological systems so as to result in the same clinical defect.     

Ligand- and species-dependent activation of PPARalpha.

Peroxisome proliferator-activated receptor alpha (PPARalpha) is mainly expressed in liver and involved in lipid metabolism. Oxidation of certain fatty acids in peroxisomes is under PPARalpha control. A wide variety of lipid molecules activate PPARalpha as well as the fibric acid derivative clofibrate. In the present study, we evaluated the differential activation of PPARalpha with several agonist ligands through its expression and DNA binding in both rat (McA-RH7777) and human (HepG2) hepatoma cell lines. In McA-RH7777 cells, clofibrate alone mediated a higher induction of PPARalpha expression than linoleic acid. In contrast, linoleic acid was the most effective ligand in HepG2 cells and treatment with clofibrate plus linoleic acid did not further increase PPARalpha expression. PPRE-binding activity of PPARalpha in ligand-treated cells was also increased in a parallel manner. We suggest that ligand-induced PPARalpha activation might give rise to differential species-dependent responses.