Cost-benefit analysis of recombination and its application for understanding of chiasma interference.

A cost-benefit analysis of recombination was undertaken. The beneficial effects of crossing-over are proportional to the frequency of recombinant offspring, while its harmful effects (errors of crossing-over leading to mutations) are proportional to the number of crossover exchanges. An equilibrium point should exist where the beneficial effects of crossing-over are balanced by its harmful effects. It is suggested that natural selection sustains a number of crossover exchanges per meiosis at the level that provides highest benefit-cost difference. Chiasma interference prevents the arising of closely located exchanges which are less effective in the production of recombinants than exchanges separated by some "interference distance". Computer simulation shows that chiasma interference increases the recombination effectiveness of the multiple crossover exchanges as compared to the case without interference.     

Missense mutations in hMLH1 and hMSH2 are associated with exonic splicing enhancers

There is a critical need to understand why missense mutations are deleterious. The deleterious effects of missense mutations are commonly attributed to their impact on primary amino acid sequence and protein structure. However, several recent studies have shown that some missense mutations are deleterious because they disturb cis-acting splicing elements-so-called "exonic splicing enhancers" (ESEs). It is not clear whether the ESE-related deleterious effects of missense mutations are common. We have evaluated colocalization of pathogenic missense mutations (found in affected individuals) with high-score ESE motifs in the human mismatch-repair genes hMSH2 and hMLH1. We found that pathogenic missense mutations in the hMSH2 and hMLH1 genes are located in ESE sites significantly more frequently than expected. Pathogenic missense mutations also tended to decrease ESE scores, thus leading to a higher propensity for splicing defects. In contrast, nonpathogenic missense mutations (polymorphisms found in unaffected individuals) and nonsense mutations are distributed randomly in relation to ESE sites. Comparison of the observed and expected frequencies of missense mutations in ESE sites shows that pathogenic effects of >/=20% of mutations in hMSH2 result from disruption of ESE sites and disturbed splicing. Similarly, pathogenic effects of >/=16% of missense mutations in the hMLH1 gene are ESE related. The colocalization of pathogenic missense mutations with ESE sites strongly suggests that their pathogenic effects are splicing related.     

<Emphasis Type="Italic">Lactobacillus fermentum</Emphasis> 90 TC-4 taxonomic status confirmation using whole genome sequencing and MALDI TOF mass spectrum

With the use of whole genome sequencing, the taxonomic status of Lactobacillus fermentum 90 TC-4 strain from Russian collections were studied. Complex analysis of phenotypical and genetic properties was conducted using phenotypic and molecular genetic methods. The main characteristics of the genome and biochemical activity profile of the strain were determined. A comparative analysis of the mass spectrum of ribosomal proteins of the strain, its biochemical properties, a fragment of 16S rRNA gene sequencing, and the entire genome revealed that the present strain belongs to the species L. fermentum, confirming its taxonomic status in accordance with modern taxonomy.     

Use of liposomes for the association of foreign genetic material to spermatozoa]

The binding of liposomes of different composition with sperm cells and their effect on cell behaviour were studied. Experiments have demonstrated, that liposomes, containing positively charged phospholipids, had maximal degree of association with sperm cells. Besides, liposomes seem to be nontoxic for sperms and do not change the functional activity of the latter. Theoretically, sperm cells may serve as a natural vector for transfer of liposome-encapsulated DNA into the ovary cells of animals for obtaining transgenic animals.     

Modeling the Natural History and Detection of Lung Cancer Based on Smoking Behavior

In this study, we developed a method for modeling the progression and detection of lung cancer based on the smoking behavior at an individual level. The model allows obtaining the characteristics of lung cancer in a population at the time of diagnosis. Lung cancer data from Surveillance, Epidemiology and End Results (SEER) database collected between 2004 and 2008 were used to fit the lung cancer progression and detection model. The fitted model combined with a smoking based carcinogenesis model was used to predict the distribution of age, gender, tumor size, disease stage and smoking status at diagnosis and the results were validated against independent data from the SEER database collected from 1988 to 1999. The model accurately predicted the gender distribution and median age of LC patients of diagnosis, and reasonably predicted the joint tumor size and disease stage distribution.     

Genetic structure, subdivision, and differentiation in stankewiczii pine (Pinus stankewiczii (Sukacz.) Fomin) populations from mountainous Crimea

In order to analyze the genetic structure, subdivision and differentiation within and between two small isolated populations of the Crimea relict endemic, Pinus stankewiczii (Sukacz.) Fomin, electrophoretic analysis of the isozyme variation at nine enzymatic systems was carried out using 183 oldest trees. It was demonstrated that in populations of P. stankewiczii, 80% of the genes were in polymorphic state. Each tree was heterozygous at 19.1% loci, and at 21.6% loci in artificial 50-year-old plantation. The genetic structure of two populations was less differentiated (D _N = 0.006), compared to their individual localities (D _N = 0.008?0.009). Within-population subdivision of the diffusely dispersed populations was higher (F _ST -G _ST = 1.8–2.0%) than that of the populations themselves (0.8%).     

Identification of novel genetic markers associated with clinical phenotypes of systemic sclerosis through a genome-wide association strategy

The aim of this study was to determine, through a genome-wide association study (GWAS), the genetic components contributing to different clinical sub-phenotypes of systemic sclerosis (SSc). We considered limited (lcSSc) and diffuse (dcSSc) cutaneous involvement, and the relationships with presence of the SSc-specific auto-antibodies, anti-centromere (ACA), and anti-topoisomerase I (ATA). Four GWAS cohorts, comprising 2,296 SSc patients and 5,171 healthy controls, were meta-analyzed looking for associations in the selected subgroups. Eighteen polymorphisms were further tested in nine independent cohorts comprising an additional 3,175 SSc patients and 4,971 controls. Conditional analysis for associated SNPs in the HLA region was performed to explore their independent association in antibody subgroups. Overall analysis showed that non-HLA polymorphism rs11642873 in IRF8 gene to be associated at GWAS level with lcSSc (P = 2.32×10⁻¹², OR = 0.75). Also, rs12540874 in GRB10 gene (P = 1.27 × 10⁻⁶, OR = 1.15) and rs11047102 in SOX5 gene (P = 1.39×10⁻⁷, OR = 1.36) showed a suggestive association with lcSSc and ACA subgroups respectively. In the HLA region, we observed highly associated allelic combinations in the HLA-DQB1 locus with ACA (P = 1.79×10⁻⁶¹, OR = 2.48), in the HLA-DPA1/B1 loci with ATA (P = 4.57×10⁻⁷⁶, OR = 8.84), and in NOTCH4 with ACA P = 8.84×10⁻²¹, OR = 0.55) and ATA (P = 1.14×10⁻⁸, OR = 0.54). We have identified three new non-HLA genes (IRF8, GRB10, and SOX5) associated with SSc clinical and auto-antibody subgroups. Within the HLA region, HLA-DQB1, HLA-DPA1/B1, and NOTCH4 associations with SSc are likely confined to specific auto-antibodies. These data emphasize the differential genetic components of subphenotypes of SSc.     

Initial medical attention on patients with early-stage non-small cell lung cancer

Background

Detection of early stage non-small cell lung cancer (NSCLC) is commonly believed to be incidental. Understanding the reasons that caused initial detection of these patients is important for early diagnosis. However, these reasons are not well studied.

Methods

We retrospectively reviewed medical records of patients diagnosed with stage I or II NSCLC between 2000 and 2009 at UT MD Anderson Cancer Center. Information on suggestive LC-symptoms or other reasons that caused detection were extracted from patients'' medical records. We applied univariate and multivariate analyses to evaluate the association of suggestive LC-symptoms with tumor size and patient survival.

Results

Of the 1396 early stage LC patients, 733 (52.5%) presented with suggestive LC-symptoms as chief complaint. 347 (24.9%) and 287 (20.6%) were diagnosed because of regular check-ups and evaluations for other diseases, respectively. The proportion of suggestive LC-symptom-caused detection had a linear relationship with the tumor size (correlation 0.96; with p<.0001). After age, gender, race, smoking status, therapy, and stage adjustment, the symptom-caused detection showed no significant difference in overall and LC-specific survival when compared with the other (non-symptom-caused) detection.

Conclusion

Symptoms suggestive of LC are the number one reason that led to detection in early NSCLC. They were also associated with tumor size at diagnosis, suggesting early stage LC patients are developing symptoms. Presence of symptoms in early stages did not compromise survival. A symptom-based alerting system or guidelines may be worth of further study to benefit NSCLC high risk individuals.     

Ecology of the ringed seal (Pusa hispida) from the Bering Strait in the late Holocene

The combined use of analysis of stable isotopes and archeozoological methods with respect to osteological material from an ancient Eskimo settlement (2370-810 yr BP) made it possible to reveal the main distinguishing features of ringed seal in the past. On the basis of the data obtained, we suppose that in the late Holocene in the Bering Strait, there were seals of two different ecotopes: those reproducing on fast ice and those on pack ice differing not only in habitats, but also in the proportion of various food items in the diet. The ringed seals caught by ancient Eskimos during their life had a mixed diet consisting of crustaceans and fish, but in most individuals, a shift towards fish eating was observed. No significant changes in the feeding related to individual age were recorded. The influence of feeding type on body size was shown: bigger, mature individuals occupied higher trophic positions.