Short Telomeres Initiate Telomere Recombination in Primary and Tumor Cells

Human tumors that lack telomerase maintain telomeres by alternative lengthening mechanisms. Tumors can also form in telomerase-deficient mice; however, the genetic mechanism responsible for tumor growth without telomerase is unknown. In yeast, several different recombination pathways maintain telomeres in the absence of telomerase—some result in telomere maintenance with minimal effects on telomere length. To examine non-telomerase mechanisms for telomere maintenance in mammalian cells, we used primary cells and lymphomas from telomerase-deficient mice (mTR−/− and Eμmyc+mTR−/−) and CAST/EiJ mouse embryonic fibroblast cells. These cells were analyzed using pq-ratio analysis, telomere length distribution outliers, CO-FISH, Q-FISH, and multicolor FISH to detect subtelomeric recombination. Telomere length was maintained during long-term growth in vivo and in vitro. Long telomeres, characteristic of human ALT cells, were not observed in either late passage or mTR−/− tumor cells; instead, we observed only minimal changes in telomere length. Telomere length variation and subtelomeric recombination were frequent in cells with short telomeres, indicating that length maintenance is due to telomeric recombination. We also detected telomere length changes in primary mTR−/− cells that had short telomeres. Using mouse mTR+/− and human hTERT+/− primary cells with short telomeres, we found frequent length changes indicative of recombination. We conclude that telomere maintenance by non-telomerase mechanisms, including recombination, occurs in primary cells and is initiated by short telomeres, even in the presence of telomerase. Most intriguing, our data indicate that some non-telomerase telomere maintenance mechanisms occur without a significant increase in telomere length

Recent progress in understanding and predicting Atlantic decadal climate variability

Recent Atlantic climate prediction studies are an exciting new contribution to an extensive body of research on Atlantic decadal variability and predictability that has long emphasized the unique role of the Atlantic Ocean in modulating the surface climate. We present a survey of the foundations and frontiers in our understanding of Atlantic variability mechanisms, the role of the Atlantic Meridional Overturning Circulation (AMOC), and our present capacity for putting that understanding into practice in actual climate prediction systems

Organ preservation surgery for laryngeal cancer

The principles of management of the laryngeal cancer have evolved over the recent past with emphasis on organ preservation. These developments have paralleled technological advancements as well as refinement in the surgical technique. The surgeons are able to maintain physiological functions of larynx namely speech, respiration and swallowing without compromising the loco-regional control of cancer in comparison to the more radical treatment modalities. A large number of organ preservation surgeries are available to the surgeon; however, careful assessment of the stage of the cancer and selection of the patient is paramount to a successful outcome. A comprehensive review of various organ preservation techniques in vogue for the management of laryngeal cancer is presented

Ontogeny of juvenile freshwater pearl mussels, Margaritifera margaritifera (Bivalvia: Margaritiferidae).

The gills of juvenile freshwater bivalves undergo a complex morphogenesis that may correlate with changes in feeding ecology, but ontogenic studies on juvenile mussels are rare. Scanning electron microscopy was used to examine the ultrastructure and ontogeny of 117 juvenile freshwater pearl mussels (Margaritifera margaritifera) ranging in age from 1–44 months and length from 0.49–8.90 mm. Three stages of gill development are described. In Stage 1 (5–9 inner demibranch filaments), only unreflected inner demibranch filaments were present. In Stage 2 (9–17 inner demibranch filaments), inner demibranch filaments began to reflect when shell length exceeded 1.13 mm, at 13–16 months old. Reflection began in medial filaments and then proceeded anterior and posterior. In Stage 3 (28–94 inner demibranch filaments), outer demibranch filaments began developing at shell length > 3.1 mm and about 34 months of age. The oral groove on the inner demibranch was first observed in 34 month old specimens > 2.66 mm but was never observed on the outer demibranch. Shell length (R2 = 0.99) was a better predictor of developmental stage compared to age (R2 = 0.84). The full suite of gill ciliation was present on filaments in all stages. Interfilamentary distance averaged 31.3 μm and did not change with age (4–44 months) or with size (0.75–8.9 mm). Distance between laterofrontal cirri couplets averaged 1.54 μm and did not change significantly with size or age. Labial palp primordia were present in even the youngest individuals but ciliature became more diverse in more developed individuals. Information presented here is valuable to captive rearing programmes as it provides insight in to when juveniles may be particularly vulnerable to stressors due to specific ontogenic changes. The data are compared with two other recent studies of Margaritifera development.N/

Comprehensive Evaluation of One-Carbon Metabolism Pathway Gene Variants and Renal Cell Cancer Risk

Folate and one-carbon metabolism are linked to cancer risk through their integral role in DNA synthesis and methylation. Variation in one-carbon metabolism genes, particularly MTHFR, has been associated with risk of a number of cancers in epidemiologic studies, but little is known regarding renal cancer.Tag single nucleotide polymorphisms (SNPs) selected to produce high genomic coverage of 13 gene regions of one-carbon metabolism (ALDH1L1, BHMT, CBS, FOLR1, MTHFR, MTR, MTRR, SHMT1, SLC19A1, TYMS) and the closely associated glutathione synthesis pathway (CTH, GGH, GSS) were genotyped for 777 renal cell carcinoma (RCC) cases and 1,035 controls in the Central and Eastern European Renal Cancer case-control study. Associations of individual SNPs (n = 163) with RCC risk were calculated using unconditional logistic regression adjusted for age, sex and study center. Minimum p-value permutation (Min-P) tests were used to identify gene regions associated with risk, and haplotypes were evaluated within these genes.The strongest associations with RCC risk were observed for SLC19A1 (P(min-P) = 0.03) and MTHFR (P(min-P) = 0.13). A haplotype consisting of four SNPs in SLC19A1 (rs12483553, rs2838950, rs2838951, and rs17004785) was associated with a 37% increased risk (p = 0.02), and exploratory stratified analysis suggested the association was only significant among those in the lowest tertile of vegetable intake.To our knowledge, this is the first study to comprehensively examine variation in one-carbon metabolism genes in relation to RCC risk. We identified a novel association with SLC19A1, which is important for transport of folate into cells. Replication in other populations is required to confirm these findings

Analysis of SNPs and Haplotypes in Vitamin D Pathway Genes and Renal Cancer Risk

In the kidney vitamin D is converted to its active form. Since vitamin D exerts its activity through binding to the nuclear vitamin D receptor (VDR), most genetic studies have primarily focused on variation within this gene. Therefore, analysis of genetic variation in VDR and other vitamin D pathway genes may provide insight into the role of vitamin D in renal cell carcinoma (RCC) etiology. RCC cases (N = 777) and controls (N = 1,035) were genotyped to investigate the relationship between RCC risk and variation in eight target genes. Minimum-p-value permutation (Min-P) tests were used to identify genes associated with risk. A three single nucleotide polymorphism (SNP) sliding window was used to identify chromosomal regions with a False Discovery Rate of <10%, where subsequently, haplotype relative risks were computed in Haplostats. Min-P values showed that VDR (p-value = 0.02) and retinoid-X-receptor-alpha (RXRA) (p-value = 0.10) were associated with RCC risk. Within VDR, three haplotypes across two chromosomal regions of interest were identified. The first region, located within intron 2, contained two haplotypes that increased RCC risk by approximately 25%. The second region included a haplotype (rs2239179, rs12717991) across intron 4 that increased risk among participants with the TC (OR = 1.31, 95% CI = 1.09–1.57) haplotype compared to participants with the common haplotype, TT. Across RXRA, one haplotype located 3′ of the coding sequence (rs748964, rs3118523), increased RCC risk 35% among individuals with the variant haplotype compared to those with the most common haplotype. This study comprehensively evaluated genetic variation across eight vitamin D pathway genes in relation to RCC risk. We found increased risk associated with VDR and RXRA. Replication studies are warranted to confirm these findings

A role of the Atlantic Ocean in predicting summer surface air temperature over North East Asia?

We assess the ability of the DePreSys3 prediction system to predict the summer (JJAS) surface-air temperature over North East Asia. DePreSys3 is based on a high resolution ocean–atmosphere coupled climate prediction system (~ 60 km in the atmosphere and ~ 25 km in the ocean), which is full-field initialized from 1960 to 2014 (26 start-dates). We find skill in predicting surface-air temperature, relative to a long-term trend, for 1 and 2–5 year leadtimes over North East Asia, the North Atlantic Ocean and Eastern Europe. DePreSys3 also reproduces the interdecadal evolution of surface-air temperature over the North Atlantic subpolar gyre and North East Asia for both lead times, along with the strong warming that occurred in the mid-1990s over both areas. Composite analysis reveals that the skill at capturing interdecadal changes in North East Asia is associated with the propagation of an atmospheric Rossby wave, which follows the subtropical jet and modulates surface-air temperature from Europe to Eastern Asia. We hypothesise that this ‘circumglobal teleconnection’ pattern is excited over the Atlantic Ocean and is related to Atlantic multi-decadal variability and the associated changes in precipitation over the Sahel and the subtropical Atlantic Ocean. This mechanism is robust for the 2–5 year lead-time. For the 1 year lead-time the Pacific Ocean also plays an important role in leading to skill in predicting SAT over Northeast Asia. Increased temperatures and precipitation over the western Pacific Ocean was found to be associated with a Pacific-Japan like-pattern, which can affect East Asia’s climate

The G-Quadruplex Ligand Telomestatin Impairs Binding of Topoisomerase IIIα to G-Quadruplex-Forming Oligonucleotides and Uncaps Telomeres in ALT Cells

In Alternative Lengthening of Telomeres (ALT) cell lines, specific nuclear bodies called APBs (ALT-associated PML bodies) concentrate telomeric DNA, shelterin components and recombination factors associated with telomere recombination. Topoisomerase IIIα (Topo III) is an essential telomeric-associated factor in ALT cells. We show here that the binding of Topo III to telomeric G-overhang is modulated by G-quadruplex formation. Topo III binding to G-quadruplex-forming oligonucleotides was strongly inhibited by telomestatin, a potent and specific G-quadruplex ligand. In ALT cells, telomestatin treatment resulted in the depletion of the Topo III/BLM/TRF2 complex and the disruption of APBs and led to the segregation of PML, shelterin components and Topo III. Interestingly, a DNA damage response was observed at telomeres in telomestatin-treated cells. These data indicate the importance of G-quadruplex stabilization during telomere maintenance in ALT cells. The function of TRF2/Topo III/BLM in the resolution of replication intermediates at telomeres is discussed