The Human Homolog of Insect-Derived Growth Factor, CECR1, Is a Candidate Gene for Features of Cat Eye Syndrome

Cat eye syndrome (CES) is a developmental disorder with multiple organ involvement, associated with the duplication of a 2-Mb region of 22q11.2. Using exon trapping and genomic sequence analysis, we have isolated and characterized a gene, CECR1, that maps to this critical region. The protein encoded by CECR1 is similar to previously identified novel growth factors: IDGF from Sarcophaga peregrina (flesh fly) and MDGF from Aplysia californica (sea hare). The CECR1 gene is alternatively spliced and expressed in numerous tissues, with most abundant expression in human adult heart, lung, lymphoblasts, and placenta as well as fetal lung, liver, and kidney. In situ hybridization of a human embryo shows specific expression in the outflow tract and atrium of the developing heart, the VII/VIII cranial nerve ganglion, and the notochord. The location of this gene in the CES critical region and its embryonic expression suggest that the overexpression of CECR1 may be responsible for at least some features of CES, particularly the heart defects.     

Scaffold-hopping with zwitterionic CCR3 antagonists: Identification and optimisation of a series with good potency and pharmacokinetics leading to the discovery of AZ12436092

The discovery and optimisation of a series of zwitterionic CCR3 antagonists is described. Optimisation of the structure led to AZ12436092, a compound with excellent selectivity over activity at hERG and outstanding pharmacokinetics in preclinical species.     

Toward a unified theory of visual area V4

Visual area V4 is a midtier cortical area in the ventral visual pathway. It is crucial for visual object recognition and has been a focus of many studies on visual attention. However, there is no unifying view of V4's role in visual processing. Neither is there an understanding of how its role in feature processing interfaces with its role in visual attention. This review captures our current knowledge of V4, largely derived from electrophysiological and imaging studies in the macaque monkey. Based on recent discovery of functionally specific domains in V4, we propose that the unifying function of V4 circuitry is to enable selective extraction of specific functional domain-based networks, whether it be by bottom-up specification of object features or by top-down attentionally driven selection.     

Complete Genome Sequence Analysis of Leuconostoc kimchii IMSNU 11154

Leuconostoc kimchii IMSNU 11154, isolated from kimchi, a traditional Korean fermented food, is known to be an important antimicrobial lactic acid bacterium with probiotic potential. Here we announce the complete genome sequence of L. kimchii IMSNU 11154 consisting of a 2,101,787-bp chromosome and five plasmids. The strain has genes for dextran formation from sucrose and for mannitol formation from fructose. Antimicrobial and antioxidative functions of L. kimchii IMSNU 11154 could be attributed to a leucosin B-like peptide and multiple enzymes to reduce hydrogen peroxide and oxidized thiols, respectively.Kimchi is a traditional Korean pickled vegetable dish with varied seasonings, and it is known to be an important source of vitamins, minerals, and dietary fiber as well as a good dietary source of lactic acid bacteria (LAB) for humans (2, 3). An exopolysaccharide (EPS)-producing LAB, designated IMSNU 11154, was isolated from kimchi made of cabbage and subsequently classified as a novel species, Leuconostoc kimchii (6). The strain and its culture broth showed antimicrobial activities against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Bacillus cepacia, Candida albicans, and Aspergillus niger. Here we report the genome sequence of Leuconostoc kimchii IMSNU 11154 using a whole-genome shotgun sequencing strategy (4). The complete sequences of one chromosome and five plasmids were obtained. The circular chromosome of strain IMSNU 11154 was 2,101,787 bp in length (37.9% G+C), and the five plasmids were LkipL48 (3,196 bp; 37.1% G+C), LkipL4701 (21,055 bp; 34.3% G+C), LkipL4704 (23,285 bp; 35.6% G+C), LkipL4719 (21,924 bp; 39.1% G+C), and LkipL4726 (29,616 bp; 35.5% G+C). The number of predicted open reading frames (ORFs) is 2,205, covering 89.5% (1,880,952 bp) of the genome. Noncoding RNA regions were identified as 68 tRNAs and 4 copies of rRNA operons. A small gene encoding a leucosin B-like peptide was identified.Strain IMSNU 11154 was missing the fructose 1,6-bisphosphatase enzyme of the Embden-Meyerhof-Parnas pathway and transaldolase of the 6-phosphogluconate/phosphoketolase pathway. Tricarboxylic cycle enzymes were also absent, except for cytochrome oxidase bd-I subunits. The strain metabolized sucrose by invertase, sucrose phosphorylase, and dextransucrase. Formation of EPS and fructose from sucrose by dextransucrase could enhance the probiotic function as well as improve the taste and flavor of kimchi. Strain IMSNU 11154 had a mannitol dehydrogenase gene (mdh) identical to mdh of Leuconostoc mesenteroides (1). By producing mannitol, it maintains its turgor and stabilizes membrane lipids and proteins at low water activity as well as scavenges free reactive oxygen radicals as previously observed for mannitol fermenters (10). Like other Leuconostoc spp., strain IMSNU 11154 does not bear any catalase or superoxide dismutase (SOD) enzymes but has six thioredoxins and four thioredoxin reductases that were shown to be important in coping with acid and oxidative stress (9, 11). Harboring thioredoxin systems on plasmids is a common feature for both L. kimchii IMSNU 11154 and Leuconostoc citreum KM20 (7). Glutathione protected some lactic acid bacteria against oxidative stress (8), but gamma-glutamylcysteine (γ-GC) is the major low-molecular-weight thiol in Leuconostoc spp., including IMSNU 11154 (5). Genes for γ-GC synthesis and reduction are present in strain IMSNU 11154 (5), and there are genes for putative peroxiredoxins that can reduce hydrogen peroxide via small thiols or thioredoxins. Thus, multiple antioxidative systems reduce thiols in strain IMSNU 11154.In conclusion, the genome of Leuconostoc kimchii IMSNU 11154 revealed that its carbohydrate metabolism has adapted to the formation of dextran, fructose, and mannitol from sucrose. The antimicrobial activity of strain IMSNU 11154 could be due to a leucosin B-like peptide, and it contains multiple antioxidative systems to manage acid and oxidative stresses independent of SOD and catalase.