The Effect of Granulometry of Carbonaceous Materials and Application Rates on the Availability of Soil-Bound Dichlorodiphenyltrichloroethane (DDT) and Its Metabolites.

Biochars (BCs) and activated carbons (ACs) are well-known carbon-rich materials that are being increasingly studied in environmental sciences for water treatment applications to remediate pollutant sequestration in soil. This study aimed to assess the impact of Sargasso BC particle size and amendment rate on the environmental availability of DDT and DDT metabolites in two distinct Kazakh soils. These two soils were collected in the vicinity of storehouse facilities in Kyzylkairat and Beskainar that store banned pesticides. They presented very distinct concentration levels of DDT and DDT metabolites. Three different types of carbonaceous matrices were tested: Sargasso BC and two commercial ACs (ORBOTM and DARCO©). For the granulometry effect, Sargasso BC was ground, and two particle sizes were tested (<150 µm, >150 µm) and compared to an unground material. Four distinct application rates were tested (0.25, 0.5, 1, and 2% (w/w)). After a three-month maturation period, environmental availability was assessed using an ISO/DIS 16751, part B-modified methodology. Interestingly, the best reductions in DDT environmental availability were obtained with the finest particle size (both ACs and Sargasso BC < 150 µm). More specifically, the effectiveness of the strategy seemed to depend on many factors. Firstly, a clear soil effect was demonstrated, suggesting that the more contaminated the soil, the more efficient this strategy may be. Secondly, the results showed that an increase in the amendment rate improves the immobilization of DDT and DDT metabolites. The sequestration material demonstrated different efficiency values (up to 58 ± 4% for Sargasso BC < 150 µm and 85 ± 4% for DARCO at a 2% application rate). Finally, a clear molecule effect was displayed, demonstrating the following immobilization order: p,p'-DDE > p,p'-DDD > p,p'-DDT > o,p'-DDT.

Association of Genetic Markers with the Risk of Early-Onset Breast Cancer in Kazakh Women.

Breast cancer is a global health problem. It is an age-dependent disease, but cases of early-onset breast cancer (eBC) are gradually increasing. There are many unresolved questions regarding eBC risk factors, mechanisms of development and screening. Only 10% of eBC cases are due to mutations in the BRCA1/BRCA2 genes, and 90% have a more complex genetic background. This poses a significant challenge to timely cancer detection in young women and highlights the need for research and awareness. Therefore, identifying genetic risk factors for eBC is essential to solving these problems. This study represents an association analysis of 144 eBC cases and 163 control participants to identify genetic markers associated with eBC risks in Kazakh women. We performed a two-stage approach in association analysis to assess genetic predisposition to eBC. First-stage genome-wide association analysis revealed two risk intronic loci in the CHI3L2 gene (p = 5.2 × 10-6) and MGAT5 gene (p = 8.4 × 10-6). Second-stage exonic polymorphisms haplotype analysis showed significant risks for seven haplotypes (p < 9.4 × 10-4). These results point to the importance of studying medium- and low-penetrant genetic markers in their haplotype combinations for a detailed understanding of the role of detected genetic markers in eBC development and prediction.

Case-Control Study of the Association between Single Nucleotide Polymorphisms of Genes Involved in Xenobiotic Detoxification and Antioxidant Protection with the Long-Term Influence of Organochlorine Pesticides on the Population of the Almaty Region.

The association of genetic polymorphisms with the individual sensitivity of humans to the action of pesticide pollution is being actively studied in the world. The aim of this study was a molecular epidemiological analysis of candidate polymorphisms of genes involved in pesticide metabolism, detoxification, and antioxidant protection. Some of the selected polymorphisms also relate to susceptibility to cancer and cardiovascular, respiratory, and immune system diseases in individuals exposed to pesticides for a long time. For a case-control study of a unique cohort of people exposed to organochlorine pesticides for 10 years or more were chosen, a control cohort was selected that matched with the experimental group by the main population characteristics. PCR-PRLF and genome-wide microarray genotyping (GWAS) methods were used. We identified 17 polymorphisms of xenobiotic detoxification genes and 27 polymorphisms of antioxidant defense genes, which had a significantly high statistical association with the negative impact of chronic pesticide intoxication on human health. We also found 17 polymorphisms of xenobiotic detoxification genes and 12 polymorphisms of antioxidant defense genes that have a protective effect. Data obtained added to the list of potential polymorphisms that define a group at high risk or resistant to the negative effects of pesticides.

Determination of genetic predisposition to early breast cancer in women of Kazakh ethnicity.

Breast cancer (BC) is the most common type of cancer among women in Kazakhstan. To date, little data are available on the spectrum of genetic variation in Kazakh women with BC. We aimed to identify population-specific genetic markers associated with the risk of developing early-onset BC and test their association with clinical and prognostic factors. The study included 224 Kazakh women diagnosed with BC (≤40 age). Entire coding regions (>1700 exons) and the flanking noncoding regions of 94 cancer-associated genes were sequenced from blood DNA using MiSeq platform. We identified 38 unique pathogenic variants (PVs) in 13 different cancer-predisposing genes among 57 patients (25.4%), of which 6 variants were novel. In total, 12 of the 38 distinct PVs were detected recurrently, including BRCA1 c.5266dup, c.5278-2del, and c.2T>C, and BRCA2 c.9409dup and c.9253del that may be founder in this population. BRCA1 carriers were significantly more likely to develop triple-negative BC (OR = 6.61, 95% CI 2.44-17.91, p = 0.0002) and have family history of BC (OR = 3.17, 95% CI 1.14-8.76, p = 0.03) compared to non-carriers. This study allowed the identification of PVs specific to early-onset BC, which may be used as a foundation to develop regional expertise and diagnostic tools for early detection of BC in young Kazakh women.

Homozygosity mapping in the Kazakh national dog breed Tazy.

The Tazy is a breed of sighthound common in Kazakhstan. The identification of runs of homozygosity (ROH) is an informative approach to assessing the history and possible patterns of directional selection pressure. To our knowledge, the present study is the first to provide an overview of the ROH pattern in the Tazy dogs from a genome-wide perspective. The ROH of the Tazy was found to be mainly composed of shorter segments (1-2 Mb), accounting for approximately 67% of the total ROH. The estimated ROH-based inbreeding coefficients (FROH) ranged from 0.028 to 0.058 with a mean of 0.057. Five genomic regions under positive selection were identified on chromosomes 18, 22, and 25. The regions on chromosomes 18 and 22 may be breed specific, while the region on chromosome 22 overlaps with regions of hunting traits in other hunting dog breeds. Among the 12 candidate genes located in these regions, the gene CAB39L may be a candidate that affects running speed and endurance of the Tazy dog. Eight genes could belong to an evolutionarily conserved complex as they were clustered in a large protein network with strong linkages. The results may enable effective interventions when incorporated into conservation planning and selection of the Tazy breed.

Individual Risk Assessment for Population Living on the Territories Long-Term Polluted by Organochlorine Pesticides.

The long-term storage of unutilized pesticides raised new problems of long-term environmental contamination. The study presents the results of surveying 151 individuals in 7 villages living close to pesticide-contaminated localities. All individuals have been surveyed concerning their consumption habits and lifestyle characteristics. An assessment of the general exposure risks of the local population was carried out using the analysis of pollutants in food products and the average levels of their consumption in the region. The cohort risk evaluation revealed that the greatest risk was associated with the regular consumption of cucumbers, pears, bell peppers, meat, and milk. The new model to estimate individual risks of long-term pesticide pollution was proposed as a calculation of the combined action of 9 risk factors, including individual genotypes, age, lifestyle, and personal pesticide consumption rates. The analysis of the predictive ability of this model showed that the final score for individual health risks corresponded to the development of chronic diseases. A high level of chromosomal aberrations was evidenced for individual genetic risk manifestations. The combined influence of all risk factors revealed contributions of 24.7% for health status and 14.2% for genetic status, while other impacts go to all unaccounted factors.

Integrative Functional Genomic Analysis in Multiplex Autism Families from Kazakhstan.

The study of extended pedigrees containing autism spectrum disorder- (ASD-) related broader autism phenotypes (BAP) offers a promising approach to the search for ASD candidate variants. Here, a total of 650,000 genetic markers were tested in four Kazakhstani multiplex families with ASD and BAP to obtain data on de novo mutations (DNMs), common, and rare inherited variants that may contribute to the genetic risk for developing autistic traits. The variants were analyzed in the context of gene networks and pathways. Several previously well-described enriched pathways were identified, including ion channel activity, regulation of synaptic function, and membrane depolarization. Perhaps these pathways are crucial not only for the development of ASD but also for ВАР. The results also point to several additional biological pathways (circadian entrainment, NCAM and BTN family interactions, and interaction between L1 and Ankyrins) and hub genes (CFTR, NOD2, PPP2R2B, and TTR). The obtained results suggest that further exploration of PPI networks combining ASD and BAP risk genes can be used to identify novel or overlooked ASD molecular mechanisms.

Phytoremediation of Soil Contaminated by Organochlorine Pesticides and Toxic Trace Elements: Prospects and Limitations of Paulownia tomentosa.

Paulownia tomentosa (Thunb.) Steud is a drought-resistant, low-maintenance and fast-growing energy crop that can withstand a wide range of climatic conditions, provides a high biomass yield (approximately 50 t DM ha-1 yr-1), and develops successfully in contaminated sites. In Kazakhstan, there are many historically contaminated sites polluted by a mixture of xenobiotics of organic and inorganic origin that need to be revitalised. Pilot-scale research evaluated the potential of P. tomentosa for the phytoremediation of soils historically contaminated with organochlorine pesticides (OCPs) and toxic trace elements (TTEs) to minimise their impact on the environment. Targeted soils from the obsolete pesticide stockpiles located in three villages of Talgar district, Almaty region, Kazakhstan, i.e., Amangeldy (soil A), Beskainar (soil B), and Kyzylkairat (soil K), were subjected to research. Twenty OCPs and eight TTEs (As, Cr, Co, Ni, Cu, Zn, Cd, and Pb) were detected in the soils. The phytoremediation potential of P. tomentosa was investigated for OCPs whose concentrations in the soils were significantly different (aldrin, endosulfans, endrin aldehyde, HCB, heptachlor, hexabromobenzene, keltan, methoxychlor, and γ-HCH) and for TTEs (Cu, Zn, and Cd) whose concentrations exceeded maximum permissible concentrations. Bioconcentration (BCF) and translocation (TLF) factors were used as indicators of the phytoremediation process. It was ensured that the uptake and translocation of contaminants by P. tomentosa was highly variable and depended on their properties and concentrations in soil. Besides the ability to bioconcentrate Cr, Ni, and Cu, P. tomentosa demonstrated very encouraging results in the accumulation of endosulfans, keltan, and methoxychlor and the phytoextraction of γ-HCH (TLFs of 1.9-9.9) and HCB (BCFs of 197-571). The results of the pilot trials support the need to further investigate the potential of P. tomentosa for phytoremediation on a field scale.

The source of the Black Death in fourteenth-century central Eurasia.

The origin of the medieval Black Death pandemic (AD 1346-1353) has been a topic of continuous investigation because of the pandemic's extensive demographic impact and long-lasting consequences1,2. Until now, the most debated archaeological evidence potentially associated with the pandemic's initiation derives from cemeteries located near Lake Issyk-Kul of modern-day Kyrgyzstan1,3-9. These sites are thought to have housed victims of a fourteenth-century epidemic as tombstone inscriptions directly dated to 1338-1339 state 'pestilence' as the cause of death for the buried individuals9. Here we report ancient DNA data from seven individuals exhumed from two of these cemeteries, Kara-Djigach and Burana. Our synthesis of archaeological, historical and ancient genomic data shows a clear involvement of the plague bacterium Yersinia pestis in this epidemic event. Two reconstructed ancient Y. pestis genomes represent a single strain and are identified as the most recent common ancestor of a major diversification commonly associated with the pandemic's emergence, here dated to the first half of the fourteenth century. Comparisons with present-day diversity from Y. pestis reservoirs in the extended Tian Shan region support a local emergence of the recovered ancient strain. Through multiple lines of evidence, our data support an early fourteenth-century source of the second plague pandemic in central Eurasia.

Stone Age Yersinia pestis genomes shed light on the early evolution, diversity, and ecology of plague.

The bacterial pathogen Yersinia pestis gave rise to devastating outbreaks throughout human history, and ancient DNA evidence has shown it afflicted human populations as far back as the Neolithic. Y. pestis genomes recovered from the Eurasian Late Neolithic/Early Bronze Age (LNBA) period have uncovered key evolutionary steps that led to its emergence from a Yersinia pseudotuberculosis-like progenitor; however, the number of reconstructed LNBA genomes are too few to explore its diversity during this critical period of development. Here, we present 17 Y. pestis genomes dating to 5,000 to 2,500 y BP from a wide geographic expanse across Eurasia. This increased dataset enabled us to explore correlations between temporal, geographical, and genetic distance. Our results suggest a nonflea-adapted and potentially extinct single lineage that persisted over millennia without significant parallel diversification, accompanied by rapid dispersal across continents throughout this period, a trend not observed in other pathogens for which ancient genomes are available. A stepwise pattern of gene loss provides further clues on its early evolution and potential adaptation. We also discover the presence of the flea-adapted form of Y. pestis in Bronze Age Iberia, previously only identified in in the Caucasus and the Volga regions, suggesting a much wider geographic spread of this form of Y. pestis. Together, these data reveal the dynamic nature of plague's formative years in terms of its early evolution and ecology.

Ecological risk assessment and long-term environmental pollution caused by obsolete undisposed organochlorine pesticides.

Obsolete organochlorine pesticides (OSPs) are currently prohibited as persistent organic pollutants that contaminate the environment. If undisposed, they continue to pollute soil and water, to accumulate in the food chain and to harm plants, animals and the human body. The aim of the study was to assess water and soil pollution around the storehouses of undisposed, banned OSPs and their possible genotoxic effect. The storehouses in four villages near Almaty, Kazakhstan were investigated. Chemical analysis confirmed contamination of water and soil around storehouses with OSPs. The genotoxic effect of water and soil samples was evaluated using model objects: S.typhymurium, D.melanogaster, sheep lymphocytes cultures and human lymphocytes cultures. It was found that water and soil samples caused mutagenic effect in all model systems. They increased the frequency of revertants in Salmonella, the frequency of lethal mutations in Drosophila chromosomes, and the frequency of chromosome aberrations in cultures of human and sheep lymphocytes. Although a genotoxic effect was demonstrated for each of these models, various models showed different sensitivity to the effects of pesticides and they varied degree of response. The association between the total content of OCPs in soil and the level of mutations for different model systems was discovered.

Ancient genomic time transect from the Central Asian Steppe unravels the history of the Scythians.

The Scythians were a multitude of horse-warrior nomad cultures dwelling in the Eurasian steppe during the first millennium BCE. Because of the lack of first-hand written records, little is known about the origins and relations among the different cultures. To address these questions, we produced genome-wide data for 111 ancient individuals retrieved from 39 archaeological sites from the first millennia BCE and CE across the Central Asian Steppe. We uncovered major admixture events in the Late Bronze Age forming the genetic substratum for two main Iron Age gene-pools emerging around the Altai and the Urals respectively. Their demise was mirrored by new genetic turnovers, linked to the spread of the eastern nomad empires in the first centuries CE. Compared to the high genetic heterogeneity of the past, the homogenization of the present-day Kazakhs gene pool is notable, likely a result of 400 years of strict exogamous social rules.

Genetic Relationship Among the Kazakh People Based on Y-STR Markers Reveals Evidence of Genetic Variation Among Tribes and Zhuz.

Ethnogenesis of Kazakhs took place in Central Asia, a region of high genetic and cultural diversity. Even though archaeological and historical studies have shed some light on the formation of modern Kazakhs, the process of establishment of hierarchical socioeconomic structure in the Steppe remains contentious. In this study, we analyzed haplotype variation at 15 Y-chromosomal short-tandem-repeats obtained from 1171 individuals from 24 tribes representing the three socio-territorial subdivisions (Senior, Middle and Junior zhuz) in Kazakhstan to comprehensively characterize the patrilineal genetic architecture of the Kazakh Steppe. In total, 577 distinct haplotypes were identified belonging to one of 20 haplogroups; 16 predominant haplogroups were confirmed by SNP-genotyping. The haplogroup distribution was skewed towards C2-M217, present in all tribes at a global frequency of 51.9%. Despite signatures of spatial differences in haplotype frequencies, a Mantel test failed to detect a statistically significant correlation between genetic and geographic distance between individuals. An analysis of molecular variance found that ∼8.9% of the genetic variance among individuals was attributable to differences among zhuzes and ∼20% to differences among tribes within zhuzes. The STRUCTURE analysis of the 1164 individuals indicated the presence of 20 ancestral groups and a complex three-subclade organization of the C2-M217 haplogroup in Kazakhs, a result supported by the multidimensional scaling analysis. Additionally, while the majority of the haplotypes and tribes overlapped, a distinct cluster of the O2 haplogroup, mostly of the Naiman tribe, was observed. Thus, firstly, our analysis indicated that the majority of Kazakh tribes share deep heterogeneous patrilineal ancestries, while a smaller fraction of them are descendants of a founder paternal ancestor. Secondly, we observed a high frequency of the C2-M217 haplogroups along the southern border of Kazakhstan, broadly corresponding to both the path of the Mongolian invasion and the ancient Silk Road. Interestingly, we detected three subclades of the C2-M217 haplogroup that broadly exhibits zhuz-specific clustering. Further study of Kazakh haplotypes variation within a Central Asian context is required to untwist this complex process of ethnogenesis.

Comprehensive assessment of unutilized and obsolete pesticides impact on genetic status and health of population of Almaty region.

The group of persistent organic pollutants (POPs) are particularly dangerous for the environment and by consequence for human health because of the risk to be transmitted in the food chain. Among them, the urgent problem of obsolete and forbidden organochlorinated pesticides (OCPs) needs a rigorous management in many countries, including Kazakhstan. The aim of our study was to evaluate the effect of pesticides content in food products on the genetic status and health of the population living on the contaminated areas near destroyed warehouses for OCPs (4 villages of Talgar district and 1 control site, Almaty region). The food products sampled in Taukaraturyk (control site), and in 4 villages where non-utilized obsolete pesticides were discovered: Beskainar, Kyzylkairat, Amangeldy, and Belbulak. The contents of 24 pesticides in food products from plant (apples, pears, tomatoes, cucumbers, sweet peppers) and animal (beef meat, cow milk, honey) origin, that grown in places of localization of non-utilized OCPs, were determined, sometimes in high and unacceptably high concentrations (before 2500 times over MRL). In pears, the pesticides content (especially DDT, γ-HCH, ß-HCH, endosulfan, and aldrin pesticide group), was higher than in other fruits. Among vegetables, the highest levels of all groups of pesticide were found in cucumbers. Beef meat samples demonstrated increased contents of ß-HCH, γ-HCH, endrin and dieldrin. In cow milk samples only the high concentration of dieldrin was found. The content of pesticides in meat was 4-5 times higher than in milk. The medical examinations, carried out among the cohorts living around the polluted by pesticides territories and control cohort from ecologically favorable village, showed that there were more individuals with high and middle levels of somatic health in the control group than in groups exposed to OCPs. The long-term effect of the pesticide contamination of the environment on genetic status of the population was assessed by chromosomal aberration (CA) frequencies. The highest level of chromosomal aberrations was identified for the examined residents of Kyzylkairat (41%) and Belbulak (38%), a high level in Amangeldy (12%), and middle level in Beskainar (6.5%). The association between the CA frequency, health status and the pesticides contents in food were assessed by a Spearman rank correlation. The low indicators of somatic health status were strictly associated with high levels of CA, and good health status indicates that the CA rates did not exceed the spontaneous level of mutagenesis. The strongest correlation was shown between high levels of chromosomal aberrations and the content of different pesticides in pears (Cr = 0.979-0.467), tomatoes (Cr = 0.877-0.476), cucumbers (Cr = 0.975-0.553) and meat (Cr = 0.839-0.368). The obtained results highlight the need to improve health protection by increasing the public awareness to the security of the storage of obsolete OCPs in order to strengthen food safety by efficient control services.

The effects of DNA repair polymorphisms on chromosome aberrations in the population of Kazakhstan.

Purpose: To analyze the effects of DNA repair polymorphism and other factors on the frequency chromosome aberrations in an irradiated cohort of subjects living around the Semipalatinsk nuclear test site and non-exposed group of subjects from ecologically favorable zones of Kazakhstan.Materials and methods: Blood samples were collected in the rural areas of the East Kazakhstan district around the Semipalatinsk nuclear test site and ecologically favorable zones of Almaty region of Kazakhstan. Chromosome aberrations in the fresh and cryopreserved peripheral blood lymphocyte cultures were analyzed by Giemsa staining. Single nucleotide polymorphisms at eight DNA repair genes (XRCC1 rs1799782, XRCC1 rs25487, XRCC3 rs861539, ATM rs1801516, XPD rs1799793, XPD rs13181, APEX1 rs1130409, and hOGG1 rs1052133) were determined by PCR-RFLP method.Results: The age of donors and smoking significantly affected the frequency of chromosome aberrations among the irradiated and control subjects. In the irradiated and control cohorts, the frequency of chromosome aberrations was significantly increased in the heterozygous ATM rs1801516 (1853 Asp/Asn) individuals; for the rest of the loci no significant associations between polymorphism and the frequency of chromosome aberrations were detected.Conclusions: The age of donors, smoking, and the ATM rs1801516 polymorphism significantly affect the frequency of chromosome aberrations among individuals inhabiting contaminated area around the Semipalatinsk nuclear weapon test site, as well as among those inhabiting ecologically favorable zones of Kazakhstan.

Mutation Spectrum of Cancer-Associated Genes in Patients With Early Onset of Colorectal Cancer.

Background: Colorectal cancer (CRC) incidence is rising worldwide, as well as in the Republic of Kazakhstan, while its occurrence is also increasing in the younger population. Hereditary forms associated with the development of colon and rectal cancer and early-onset CRC have never been studied in the population of Kazakhstan. The aim of this research was to investigate the spectrum of CRC-related gene mutations to determine which mutations cause early onset of CRC in the Kazakhstan population. Methods: The study included 125 unrelated patients from Kazakhstan (range 17-50 years in age) with early onset CRC. Genomic DNA was obtained from peripheral blood of the patients. Next-generation sequencing was performed using the TruSightCancer Kit on the MiSeq platform. The Studio Variant was used to annotate and interpret genetic variants. Results: Bioinformatics analysis of Next-generation sequencing data revealed 11,152 variants from 85 genes, of them, 3,790 missense, 6,254 synonymous variants, 44 3'UTR variants, 10 frameshift variants, five stop-gain variants, four in-frame deletions, two splice donors, one splice acceptor variant, and 1,042 intron or non-coding variants. APC, BRCA2/1, ALK, BRIP1, EGFR, FANCA, FANCD2, FANCI, HNF1A, MEN1, NSD1, PMS2, RECQL4, RET, SLX4, WRN, and XPC genes mutated most often. According to the ACMG guidelines and LOVD/ClinVar databases, 24 variants were pathogenic (10 frameshifts, five missenses, five stop-gain, one in-frame deletion, and three splice-site mutations), and 289 were VUS with population frequency <1%, 131 of them were attributed as deleterious. In the study, 50% of all pathogenic mutations found in Kazakhstani patients with early CRC onset were identified in the subgroups with a family history of CRC and primary multiple tumors. In APC, pathogenic mutations were most often (21%). Conclusion: Pathogenic and likely pathogenic mutations were found in 20 (16%) out of 125 patients. Eight novel pathogenic mutations detected in FANCI, APC, BMPR1, ATM, and DICER1 genes have not been reported in previous literature. Given the high frequency and wide spectrum of mutations, NGS analysis must be carried out in families with a history of CRC/CRC-related cancers with the purpose to identify cause-effective mutations, clarify the clinical diagnosis, and prevent the development of the disease in other family members.

No Association between the rs1799836 Polymorphism of the Monoamine Oxidase B Gene and the Risk of Autism Spectrum Disorders in the Kazakhstani Population.

Autism spectrum disorders (ASDs) are heterogeneous diseases that are triggered by a number of environmental and genetic factors. The aim of the current study was to investigate an association of the rs1799836 genetic variant of the neurotransmitter-related gene MAOB with ASDs. In total, 262 patients diagnosed with ASDs and their 126 healthy siblings were included in the present study. All individuals represented a Kazakhstani population. The distributions of the rs1799836 genotype were in accordance with the Hardy-Weinberg equilibrium among both cases and controls. No statistically significant differences were found in the allelic distributions of this polymorphism between ASD and control subjects (A/G: for males OR = 1.11, 95% 0.59-2.06, p = 0.75; for females OR = 1.14, 95% 0.70-1.86, p = 0.76). However, the increased score in the overall CARS was significantly associated with the A allele of rs1799836 MAOB for females (OR = 2.31, 95% 1.06-5.04, p = 0.03). The obtained results suggest that the rs1799836 polymorphism of the MAOB gene may have little contribution to the development of ASDs but may be involved in pathways contributing to ASD symptom severity in females. Further large-scale investigations are required to uncover possible relationships between rs1799836 MAOB and ASD progression in a gender-specific manner and their possible application as a therapeutic target.

The genetic history of admixture across inner Eurasia.

The indigenous populations of inner Eurasia-a huge geographic region covering the central Eurasian steppe and the northern Eurasian taiga and tundra-harbour tremendous diversity in their genes, cultures and languages. In this study, we report novel genome-wide data for 763 individuals from Armenia, Georgia, Kazakhstan, Moldova, Mongolia, Russia, Tajikistan, Ukraine and Uzbekistan. We furthermore report additional damage-reduced genome-wide data of two previously published individuals from the Eneolithic Botai culture in Kazakhstan (~5,400 BP). We find that present-day inner Eurasian populations are structured into three distinct admixture clines stretching between various western and eastern Eurasian ancestries, mirroring geography. The Botai and more recent ancient genomes from Siberia show a decrease in contributions from so-called 'ancient North Eurasian' ancestry over time, which is detectable only in the northern-most 'forest-tundra' cline. The intermediate 'steppe-forest' cline descends from the Late Bronze Age steppe ancestries, while the 'southern steppe' cline further to the south shows a strong West/South Asian influence. Ancient genomes suggest a northward spread of the southern steppe cline in Central Asia during the first millennium BC. Finally, the genetic structure of Caucasus populations highlights a role of the Caucasus Mountains as a barrier to gene flow and suggests a post-Neolithic gene flow into North Caucasus populations from the steppe.

Association of GCLM -588C/T and GCLC -129T/C Promoter Polymorphisms of Genes Coding the Subunits of Glutamate Cysteine Ligase with Ischemic Heart Disease Development in Kazakhstan Population.

BACKGROUND: Glutamate cysteine ligase (GCL) is a rate-limiting enzyme in synthesis of glutathione. Evidence suggests that genetic variations in the promoter region of genes coding a catalytic subunit (GCLC -129T/C) and a modifier subunit (GCLM -588C/T) of GCL have a functional impact on their transcriptional activity and were associated with various disorders. Hence, we hypothesize whether these two polymorphic variants of GCLM and GCLC genes are associated with the risk of ischemic heart disease (IHD) development in the population of Kazakhstan. METHODS: We evaluated 360 patients with IHD and 341 control subjects. Allele frequencies of studied promoters' polymorphisms were detected by PCR-RFLP analysis. Multiple logistic regression analysis was applied to assess the risk for different genotypes obtained. RESULTS: The presence of -588T allele in GCLM and -129T allele in GCLC gene genotypes was associated with an increased risk of IHD (GCLM -588T: OR = 3.92, p = 0.003; GCLC -129T: OR = 3.22, p = 0.03) for general ethnically mixed group. Analysis of each ethnical groups separately showed the higher risk tendency for Kazakhs as for GCLM -588T (OR = 4.79; p = 0.03) and as for GCLC -129T (OR = 4.79, p = 0.03). For Russians, statistically differences for two polymorphisms were not observed. CONCLUSION: The two promoter polymorphisms of GCLM (-588C/T) and GCLC (-128T/C) are associated with an increased risk of IHD in Kazakhstan population.

Cancer cell death induced by nanomagnetolectin.

Magnetic nanoparticles represent a new paradigm for molecular targeting therapy in cancer. However, the transformative targeting potential of magnetic nanoparticles has been stymied by a key obstacle-safe delivery to specified target cells in vivo. As cancer cells grow under nutrient deprivation and hypoxic conditions and decorate cell surface with excessive sialoglycans, sialic acid binding lectins might be suitable for targeting cancer cells in vivo. Here we explore the potential of magnetic nanoparticles functionalized with wheat germ lectin (WGA) conjugate, so-called nanomagnetolectin, as apoptotic targetable agents for prostate cancer. In the presence of magnetic field (magnetofection) for 15min, 2.46nM nanomagnetolectin significantly promoted apoptosis (∼12-fold, p value <0.01) of prostate cancer cells (LNCaP, PC-3, DU-145) compared to normal prostate epithelial cells (PrEC, PNT2, PZ-HPV-7), when supplemented with 10mM sialic acid under nutrient deprived condition. Nanomagnetolectin targets cell-surface glycosylation, particularly sialic acid as nanomagnetolectin induced apoptosis of cancer cells largely diminished (only 2 to 2.5-fold) compared to normal cells. The efficacy of magnetofected nanomagnetolectin was demonstrated in orthotopically xenografted (DU-145) mice, where tumor was not only completely arrested, but also reduced significantly (p value <0.001). This was further corroborated in subcutaneous xenograft model, where nanomagnetolectin in the presence of magnetic field and photothermal heating at ∼42°C induced apoptosis of tumor by ∼4-fold compared to tumor section heated at ∼42°C, but without magnetic field. Taken all together, the study demonstrates, for the first time, the utility of nanomagnetolectin as a potential cancer therapeutic.