Site-specific selection reveals selective constraints and functionality of tumor somatic mtDNA mutations.

BACKGROUND: Previous studies have indicated that tumor mitochondrial DNA (mtDNA) mutations are primarily shaped by relaxed negative selection, which is contradictory to the critical roles of mtDNA mutations in tumorigenesis. Therefore, we hypothesized that site-specific selection may influence tumor mtDNA mutations. METHODS: To test our hypothesis, we developed the largest collection of tumor mtDNA mutations to date and evaluated how natural selection shaped mtDNA mutation patterns. RESULTS: Our data demonstrated that both positive and negative selections acted on specific positions or functional units of tumor mtDNAs, although the landscape of these mutations was consistent with the relaxation of negative selection. In particular, mutation rate (mutation number in a region/region bp length) in complex V and tRNA coding regions, especially in ATP8 within complex V and in loop and variable regions within tRNA, were significantly lower than those in other regions. While the mutation rate of most codons and amino acids were consistent with the expectation under neutrality, several codons and amino acids had significantly different rates. Moreover, the mutations under selection were enriched for changes that are predicted to be deleterious, further supporting the evolutionary constraints on these regions. CONCLUSION: These results indicate the existence of site-specific selection and imply the important role of the mtDNA mutations at some specific sites in tumor development

Particle transfer and fusion cross-section for Super-heavy nuclei in dinuclear system

Within the dinuclear system (DNS) conception, instead of solving Fokker-Planck Equation (FPE) analytically, the Master equation is solved numerically to calculate the fusion probability of super-heavy nuclei, so that the harmonic oscillator approximation to the potential energy of the DNS is avoided. The relative motion concerning the energy, the angular momentum, and the fragment deformation relaxations is explicitly treated to couple with the diffusion process, so that the nucleon transition probabilities, which are derived microscopically, are time-dependent. Comparing with the analytical solution of FPE, our results preserve more dynamical effects. The calculated evaporation residue cross sections for one-neutron emission channel of Pb-based reactions are basically in agreement with the known experimental data within one order of magnitude.Comment: 19 pages, plus 6 figures, submitted to Phys. Rev.

Ivermectin induces apoptosis of esophageal squamous cell carcinoma via mitochondrial pathway

Background: Esophageal squamous cell carcinoma (ESCC) is the most predominant primary malignant tumor among worldwide, especially in China. To date, the successful treatment remains a mainly clinical challenge, it is imperative to develop successful therapeutic agents. Methods: The anti-proliferative effect of ivermectin on ESCC is investigated in cell model and in nude mice model. Cell apoptosis was assessed using flow cytometry, TUNEL assay and western blotting. Mitochondrial dysfunction was determined by reactive oxygen species accumulation, mitochondrial membrane potential and ATP levels. Results: Our results determined that ivermectin significantly inhibited the proliferation of ESCC cells in vitro and in vivo. Furthermore, we found that ivermectin markedly mediated mitochondrial dysfunction and induced apoptosis of ESCC cells, which indicated the anti-proliferative effect of ivermectin on ESCC cells was implicated in mitochondrial apoptotic pathway. Mechanistically, ivermectin significantly triggered ROS accumulation and inhibited the activation of NF-κB signaling pathway and increased the ratio of Bax/Bcl-2. Conclusions: These finding indicated that ivermectin has significant anti-tumour potential for ESSC and may be a potential therapeutic candidate against ESCC

Variation of Tensor Force due to Nuclear Medium Effect

The enhancement of $J^{\pi}(T)$=3$^{+}$(0) state with isospin $T=0$ excited by the tensor force in the free $^{6}$Li nucleus has been observed, for the first time, relative to a shrinkable excitation in the $^{6}$Li cluster component inside its host nucleus. Comparatively, the excitation of $J^{\pi}(T)$=0$^{+}$(1) state with isospin $T=1$ for these two $^{6}$Li formations take on an approximately equal excitation strength. The mechanism of such tensor force effect was proposed due to the intensive nuclear medium role on isospin $T$=0 state.Comment: 6 pages, 4 figure

Multi-alpha Boson Gas state in Fusion Evaporation Reaction and Three-body Force

The experimental evidence for the $\alpha$ Boson gas state in the $^{11}$C+$^{12}$C$\rightarrow$$^{23}$Mg$^{\ast}$ fusion evaporation reaction is presented. By measuring the $\alpha$ emission spectrum with multiplicity 2 and 3, we provide insight into the existence of a three-body force among $\alpha$ particles. The observed spectrum exhibited distinct tails corresponding to $\alpha$ particles emitted in pairs and triplets consistent well with the model-calculations of AV18-UX and chiral effective field theory of NV2-3-la*, indicating the formation of $\alpha$ clusters with three-body force in the Boson gas state.Comment: 7 pages, 6 figure

Aspect of Clusters Correlation at Light Nuclei Excited State

The correlation of $\alpha\alpha$ was probed via measuring the transverse momentum $p_{T}$ and width $\delta p_{T}$ of one $\alpha$, for the first time, which represents the spatial and dynamical essentialities of the initial coupling state in $^{8}$Be nucleus. The weighted interaction vertex of 3$\alpha$ reflected by the magnitudes of their relative momentums and relative emission angles proves the isosceles triangle configuration for 3$\alpha$ at the high excited energy analogous Hoyle states.Comment: 8 pages, 9 figure

A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci.

We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10⁻¹²) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10⁻¹¹) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10⁻⁷) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10⁻¹¹) and a tag SNP for NAT2 acetylation status (P = 4 × 10⁻¹¹), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis

A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci.

We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10⁻¹²) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10⁻¹¹) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10⁻⁷) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10⁻¹¹) and a tag SNP for NAT2 acetylation status (P = 4 × 10⁻¹¹), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis