Genomic hallmarks and therapeutic implications of G0 cell cycle arrest in cancer

BACKGROUND: Therapy resistance in cancer is often driven by a subpopulation of cells that are temporarily arrested in a non-proliferative G0 state, which is difficult to capture and whose mutational drivers remain largely unknown. RESULTS: We develop methodology to robustly identify this state from transcriptomic signals and characterise its prevalence and genomic constraints in solid primary tumours. We show that G0 arrest preferentially emerges in the context of more stable, less mutated genomes which maintain TP53 integrity and lack the hallmarks of DNA damage repair deficiency, while presenting increased APOBEC mutagenesis. We employ machine learning to uncover novel genomic dependencies of this process and validate the role of the centrosomal gene CEP89 as a modulator of proliferation and G0 arrest capacity. Lastly, we demonstrate that G0 arrest underlies unfavourable responses to various therapies exploiting cell cycle, kinase signalling and epigenetic mechanisms in single-cell data. CONCLUSIONS: We propose a G0 arrest transcriptional signature that is linked with therapeutic resistance and can be used to further study and clinically track this state

Genomic characterization of a novel group A lamb rotavirus isolated in Zaragoza, Spain

An ovine rotavirus (OVR) strain, 762, was isolated from a 30-day-old lamb affected with severe gastroenteritis, in Zaragoza, Spain, and the VP4, VP7, VP6, NSP4, and NSP5/NSP6 genes were subsequently characterized molecularly. Strain OVR762 was classified as a P[14] rotavirus, as the VP4 and VP8* trypsin-cleavage product of the VP4 protein revealed the highest amino acid (aa) identity (94% and 97%, respectively) with that of the P11[14] human rotavirus (HRV) strain PA169, isolated in Italy. Analysis of the VP7 gene product revealed that OVR762 possessed G8 serotype specificity, a type common in ruminants, with the highest degree of aa identity(95–98%) shared with serotype G8 HRV, bovine rotavirus, and guanaco (Lama guanicoe) rotavirus strains. Moreover, strain OVR762 displayed a bovine-like NSP4 (genotype E2) and NSP5/NSP6 (genotype H3), and a VP6 genotype I2, as well as a long electropherotype pattern. This is the first report of a lamb rotavirus with P[14] and G8 specificities, providing additional evidence for the wide genetic and antigenic diversity of group A rotaviruses

Age-related changes in eye lens biomechanics, morphology, refractive index and transparency

Life-long eye lens function requires an appropriate gradient refractive index, biomechanical integrity and transparency. We conducted an extensive study of wild-type mouse lenses 1-30 months of age to define common age-related changes. Biomechanical testing and morphometrics revealed an increase in lens volume and stiffness with age. Lens capsule thickness and peripheral fiber cell widths increased between 2 to 4 months of age but not further, and thus, cannot account for significant age-dependent increases in lens stiffness after 4 months. In lenses from mice older than 12 months, we routinely observed cataracts due to changes in cell structure, with anterior cataracts due to incomplete suture closure and a cortical ring cataract corresponding to a zone of compaction in cortical lens fiber cells. Refractive index measurements showed a rapid growth in peak refractive index between 1 to 6 months of age, and the area of highest refractive index is correlated with increases in lens nucleus size with age. These data provide a comprehensive overview of age-related changes in murine lenses, including lens size, stiffness, nuclear fraction, refractive index, transparency, capsule thickness and cell structure. Our results suggest similarities between murine and primate lenses and provide a baseline for future lens aging studies

Age-related changes in eye lens biomechanics, morphology, refractive index and transparency

Life-long eye lens function requires an appropriate gradient refractive index, biomechanical integrity and transparency. We conducted an extensive study of wild-type mouse lenses 1-30 months of age to define common age-related changes. Biomechanical testing and morphometrics revealed an increase in lens volume and stiffness with age. Lens capsule thickness and peripheral fiber cell widths increased between 2 to 4 months of age but not further, and thus, cannot account for significant age-dependent increases in lens stiffness after 4 months. In lenses from mice older than 12 months, we routinely observed cataracts due to changes in cell structure, with anterior cataracts due to incomplete suture closure and a cortical ring cataract corresponding to a zone of compaction in cortical lens fiber cells. Refractive index measurements showed a rapid growth in peak refractive index between 1 to 6 months of age, and the area of highest refractive index is correlated with increases in lens nucleus size with age. These data provide a comprehensive overview of age-related changes in murine lenses, including lens size, stiffness, nuclear fraction, refractive index, transparency, capsule thickness and cell structure. Our results suggest similarities between murine and primate lenses and provide a baseline for future lens aging studies

Dibaryons with Strangeness: their Weak Nonleptonic Decay using SU(3) Symmetry and how to find them in Relativistic Heavy-Ion Collisions

Weak SU(3) symmetry is successfully applied to the weak hadronic decay amplitudes of octet hyperons. Weak nonmesonic and mesonic decays of various dibaryons with strangeness, their dominant decay modes, and lifetimes are calculated. Production estimates for BNL's Relativistic Heavy-Ion Collider are presented employing wave function coalescence. Signals for detecting strange dibaryon states in heavy-ion collisions and revealing information about the unknown hyperon-hyperon interactions are outlined.Comment: 4 pages, 2 figures, uses RevTeX, discussion about the model of the weak decay and experimental signals extended, references update

Chiral dynamics in systems with strangeness

In this talk a brief review of several problems involving systems with strangeness is made. In the first place one shows how the Λ(1405), Λ(1670) and Σ(1620) states, for S=−1, and the Ξ(1620) for S=−2 are generated dynamically in the context of unitarized chiral perturbation theory. The results for the K¯N interaction are then used to evaluate the K−d scattering length. Results obtained for the kaon selfenergy in a nuclear medium within this approach, with application to K− atoms, are also mentioned. Finally a few words are said about recent developments in the weak decay of Λ hypernuclei and the puzzle of the Γn/Γp ratio

Strangeness nuclear physics: a critical review on selected topics

Selected topics in strangeness nuclear physics are critically reviewed. This includes production, structure and weak decay of $\Lambda$--Hypernuclei, the $\bar K$ nuclear interaction and the possible existence of $\bar K$ bound states in nuclei. Perspectives for future studies on these issues are also outlined.Comment: 63 pages, 51 figures, accepted for publication on European Physical Journal

Coincidence Measurement of the Nonmesonic Weak Decay of ^{12}_{Lambda}C

We have measured the angular correlation of the pair nucleons np and nn emitted from the nonmesonic weak decay (NMWD) of ^{12}_{Lambda}C produced via the (pi^+,K^+) reaction in coincidence measurement. The Lambda p -> np and Lambda n -> nn modes were clearly identified by measuring the back-to-back correlation of the emitted nucleon pairs which is the characteristic of two-body kinematics. From the measured nucleon pair numbers N_{nn} and N_{np}, the ratio Gamma_n/Gamma_p of the partial decay widths Gamma_n(Lambda n -> nn) and Gamma_p(Lambda p -> np) of ^{12}_{Lambda}C was extracted to be 0.51+-0.13(stat) +- 0.05(syst); this result is almost free from the ambiguity due to the nuclear final state interaction and 3-body decay process, which were inherent in the previous results. The obtained Gamma_n/Gamma_p ratio of ^{12}_{Lambda}C (p-shell) is close to that of ^5_{Lambda}He (s-shell). The results are consistent with those of recent theoretical calculations.Comment: 13 pages, 4figures, 1 table,re-submitted to Physics Letters