Crystal structure of the biologically active form of class Ib ribonucleotide reductase small subunit from Mycobacterium tuberculosis

Two nrdF genes of Mycobacterium tuberculosis code for different R2 subunits of the class Ib ribonucleotide reductase (RNR). The proteins are denoted R2F-1 and R2F-2 having 71% sequence identity. The R2F-2 subunit forms the biologically active RNR complex with the catalytic R1E-subunit. We present the structure of the reduced R2F-2 subunit to 2.2 A resolution. Comparison of the R2F-2 structure with a model of R2F-1 suggests that the important differences are located at the C-terminus. We found that within class Ib, the E-helix close to the iron diiron centre has two preferred conformations, which cannot be explained by the redox-state of the diiron centre. In the R2F-2 structure, we also could see a mobility of alphaE in between the two conformations.     

Identification of a cryptic lethal mutation in the mouse t(w73) haplotype

t haplotypes are naturally occurring, variant forms of the t complex on mouse chromosome 17, characterized by the presence of four inversions with respect to wild-type. They harbour mutations causing male sterility, male transmission ratio distortion (TRD) and embryonic lethality. Mice carrying t haplotypes have been found throughout the world, and genetic studies of the lethal mutations have identified at least 16 complementation groups. The embryonic lethal phenotypes of many t haplotypes have been characterized in detail, and are thought to be the consequence of homozygosity for single gene mutations. However, the existence of additional mutations in genes that function at later stages of development would be obscured. Here we investigated the possibility of multiple mutations in t haplotypes by screening the t(w73) haplotype for the presence of novel mutations. Since genetic analysis of t haplotype mutations is hindered by recombination suppression due to the inversions, deletion complexes covering the proximal two-thirds of the t complex were used to uncover the presence of any new lethal alleles. This analysis revealed a novel mutation between D17Jcs41 and D17Mit100, causing mice carrying both t(w73) and selected deletions to die at birth, prior to feeding. The finding of a new, cryptic lethal mutation in t haplotypes is an indication that these recombinationally isolated chromosomes, which already contain at least one lethal mutation that prevents homozygosity, may serve as sinks for the accumulation of additional recessive mutations.     

A preliminary study on the induction of dioestrous ovulation in the mare – a possible method for inducing prolonged luteal phase

Background  

Strong oestrous symptoms in the mare can cause problems with racing, training and handling. Since long-acting progesterone treatment is not permitted in mares at competition (e.g. according to FEI rules), there is a need for methods to suppress unwanted cyclicity. Spontaneous dioestrous ovulations in the late luteal phase may cause a prolongation of the luteal phase in mares.     

缺氧诱导因子与肺癌关系研究进展

缺氧诱导因子(Hypoxia-inducible factors,HIFs)是在缺氧条件下广泛存在于人和哺乳动物体内的一种转录因子,在细胞的增殖、存活、血管发生、新陈代谢、肿瘤侵袭和转移等过程中起着重要作用。缺氧是实体瘤的一个重要特征,缺氧诱导因子与肿瘤的发生、发展关系密切,通过分析缺氧诱导因子与肺癌的关系,为研发新靶点的肺癌药物奠定一定的理论基础。     

Identification of low molecular weight pyroglutamate A{beta} oligomers in Alzheimer disease: a novel tool for therapy and diagnosis

N-terminally truncated Aβ peptides starting with pyroglutamate (AβpE3) represent a major fraction of all Aβ peptides in the brain of Alzheimer disease (AD) patients. AβpE3 has a higher aggregation propensity and stability and shows increased toxicity compared with full-length Aβ. In the present work, we generated a novel monoclonal antibody (9D5) that selectively recognizes oligomeric assemblies of AβpE3 and studied the potential involvement of oligomeric AβpE3 in vivo using transgenic mouse models as well as human brains from sporadic and familial AD cases. 9D5 showed an unusual staining pattern with almost nondetectable plaques in sporadic AD patients and non-demented controls. Interestingly, in sporadic and familial AD cases prominent intraneuronal and blood vessel staining was observed. Using a novel sandwich ELISA significantly decreased levels of oligomers in plasma samples from patients with AD compared with healthy controls were identified. Moreover, passive immunization of 5XFAD mice with 9D5 significantly reduced overall Aβ plaque load and AβpE3 levels, and normalized behavioral deficits. These data indicate that 9D5 is a therapeutically and diagnostically effective monoclonal antibody targeting low molecular weight AβpE3 oligomers.     

An initial genetic linkage map of the rhesus macaque (Macaca mulatta) genome using human microsatellite loci

Rhesus macaques (Macaca mulatta) are the most widely used nonhuman primate species in biomedical research. To create new opportunities for genetic and genomic studies using rhesus monkeys, we constructed a genetic linkage map of the rhesus genome. This map consists of 241 microsatellite loci, all previously mapped in the human genome. These polymorphisms were genotyped in five pedigrees of rhesus monkeys totaling 865 animals. The resulting linkage map covers 2048 cM including all 20 rhesus autosomes, with average spacing between markers of 9.3 cM. Average heterozygosity among those markers is 0.73. This linkage map provides new comparative information concerning locus order and interlocus distances in humans and rhesus monkeys. The map will facilitate whole-genome linkage screens to locate quantitative trait loci (QTLs) that influence individual variation in phenotypic traits related to basic primate anatomy, physiology, and behavior, as well as QTLs relevant to risk factors for human disease.