Meiotic DSB patterning: A multifaceted process

Meiosis is a specialized two-step cell division responsible for genome haploidization and the generation of genetic diversity during gametogenesis. An integral and distinctive feature of the meiotic program is the evolutionarily conserved initiation of homologous recombination (HR) by the developmentally programmed induction of DNA double-strand breaks (DSBs). The inherently dangerous but essential act of DSB formation is subject to multiple forms of stringent and self-corrective regulation that collectively ensure fruitful and appropriate levels of genetic exchange without risk to cellular survival. Within this article we focus upon an emerging element of this control—spatial regulation—detailing recent advances made in understanding how DSBs are evenly distributed across the genome, and present a unified view of the underlying patterning mechanisms employed

A Compromise between Neutrino Masses and Collider Signatures in the Type-II Seesaw Model

A natural extension of the standard $SU(2)_{\rm L} \times U(1)_{\rm Y}$ gauge model to accommodate massive neutrinos is to introduce one Higgs triplet and three right-handed Majorana neutrinos, leading to a $6\times 6$ neutrino mass matrix which contains three $3\times 3$ sub-matrices $M_{\rm L}$, $M_{\rm D}$ and $M_{\rm R}$. We show that three light Majorana neutrinos (i.e., the mass eigenstates of $\nu_e$, $\nu_\mu$ and $\nu_\tau$) are exactly massless in this model, if and only if $M_{\rm L} = M_{\rm D} M_{\rm R}^{-1} M_{\rm D}^T$ exactly holds. This no-go theorem implies that small but non-vanishing neutrino masses may result from a significant but incomplete cancellation between $M_{\rm L}$ and $M_{\rm D} M_{\rm R}^{-1} M_{\rm D}^T$ terms in the Type-II seesaw formula, provided three right-handed Majorana neutrinos are of ${\cal O}(1)$ TeV and experimentally detectable at the LHC. We propose three simple Type-II seesaw scenarios with the $A_4 \times U(1)_{\rm X}$ flavor symmetry to interpret the observed neutrino mass spectrum and neutrino mixing pattern. Such a TeV-scale neutrino model can be tested in two complementary ways: (1) searching for possible collider signatures of lepton number violation induced by the right-handed Majorana neutrinos and doubly-charged Higgs particles; and (2) searching for possible consequences of unitarity violation of the $3\times 3$ neutrino mixing matrix in the future long-baseline neutrino oscillation experiments.Comment: RevTeX 19 pages, no figure

Effect of smoking on physical and cognitive capability in later life: a multicohort study using observational and genetic approaches

Objectives: The observed associations between smoking and functional measures at older ages are vulnerable to bias and confounding. Mendelian randomisation (MR) uses genotype as an instrumental variable to estimate unconfounded causal associations. We conducted a meta-analysis of the observational associations and implemented an MR approach using the smoking-related single nucleotide polymorphism rs16969968 to explore their causal nature. Setting: 9 British cohorts belonging to the HALCyon collaboration. Participants: Individual participant data on N=26 692 individuals of European ancestry (N from earliest phase analysed per study) of mean ages 50-79 years were available for inclusion in observational meta-analyses of the primary outcomes. Primary outcomes: Physical capability, cognitive capability and cognitive decline. The smoking exposures were cigarettes per day, current versus ex-smoker, current versus never smoker and ever versus never smoker. Results: In observational analyses current and ever smoking were generally associated with poorer physical and cognitive capability. For example, current smokers had a general fluid cognition score which was 0.17 z-score units (95% CI -0.221 to -0.124) lower than ex-smokers in cross-sectional analyses. Current smokers had a walk speed which was 0.25 z-score units lower than never smokers (95% CI -0.338 to -0.170). An MR instrumental variable approach for current versus ex-smoker and number of cigarettes smoked per day produced CIs which neither confirmed nor refuted the observational estimates. The number of genetic associations stratified by smoking status were consistent with type I error. Conclusions: Our observational analysis supports the hypothesis that smoking is detrimental to physical and cognitive capability. Further studies are needed for a suitably powered MR approach

Influence of Anaesthesia on Mobilisation Following Hip Fracture Surgery : An Observational Study: 麻醉技術對髖部骨折病人術後活動能力的影響：一項觀察性研究

Background Anaesthetic technique can influence mortality and morbidity following hip fracture surgery. However, its influence on postoperative mobilisation is not clear. In this study, we evaluated the influence of anaesthetic technique on postoperative mobilisation. Methods In this prospective observational study, we included all consecutive patients who underwent surgery for hip fracture between 1 January 2012 and 31 December 2013 at our institution. Any patients who died prior to mobilisation or who could not be followed up after surgery were excluded. Data was collected on demographics, clinical characteristics, anaesthesia technique and surgical factors, and date and time of admission, operation, first mobilisation and discharge. Results Of the 1040 patients included in the analysis, 264 received general anaesthesia only (Group GA), 322 received general anaesthesia with regional anaesthesia (Group GARA), and 454 received central neuraxial blockade anaesthesia with or without sedation (Group CNB). There was no significant difference in age (p = 0.56), sex (p = 0.23), number of comorbidities (p = 0.06), residential status (p = 0.18), time to surgery (p = 0.10) and length of hospital stay (p = 0.30) between the three groups. There was a statistically significant difference in ASA grade (p = 0.01), implant type used (p = 0.04), grade of operating surgeon (p = 0.02) and grade of anaesthetist during surgery (p = 0.004) among the three groups. Patients in Group GARA had a median time-to-first mobilisation of 23.8 hours after surgery, compared to 24.1 hours in Group GA and 24.3 hours in Group CNB. This difference was not statistically significant after controlling for confounding factors (p = 0.45). Conclusion Our results show that anaesthetic technique does not influence time-to-first mobilisation after hip fracture surgery

Double-Stranded RNA Attenuates the Barrier Function of Human Pulmonary Artery Endothelial Cells

Circulating RNA may result from excessive cell damage or acute viral infection and can interact with vascular endothelial cells. Despite the obvious clinical implications associated with the presence of circulating RNA, its pathological effects on endothelial cells and the governing molecular mechanisms are still not fully elucidated. We analyzed the effects of double stranded RNA on primary human pulmonary artery endothelial cells (hPAECs). The effect of natural and synthetic double-stranded RNA (dsRNA) on hPAECs was investigated using trans-endothelial electric resistance, molecule trafficking, calcium (Ca2+) homeostasis, gene expression and proliferation studies. Furthermore, the morphology and mechanical changes of the cells caused by synthetic dsRNA was followed by in-situ atomic force microscopy, by vascular-endothelial cadherin and F-actin staining. Our results indicated that exposure of hPAECs to synthetic dsRNA led to functional deficits. This was reflected by morphological and mechanical changes and an increase in the permeability of the endothelial monolayer. hPAECs treated with synthetic dsRNA accumulated in the G1 phase of the cell cycle. Additionally, the proliferation rate of the cells in the presence of synthetic dsRNA was significantly decreased. Furthermore, we found that natural and synthetic dsRNA modulated Ca2+ signaling in hPAECs by inhibiting the sarco-endoplasmic Ca2+-ATPase (SERCA) which is involved in the regulation of the intracellular Ca2+ homeostasis and thus cell growth. Even upon synthetic dsRNA stimulation silencing of SERCA3 preserved the endothelial monolayer integrity. Our data identify novel mechanisms by which dsRNA can disrupt endothelial barrier function and these may be relevant in inflammatory processes

Interpolated sequences and critical LL-values of modular forms

Recently, Zagier expressed an interpolated version of the Ap\'ery numbers for $\zeta(3)$ in terms of a critical $L$-value of a modular form of weight 4. We extend this evaluation in two directions. We first prove that interpolations of Zagier's six sporadic sequences are essentially critical $L$-values of modular forms of weight 3. We then establish an infinite family of evaluations between interpolations of leading coefficients of Brown's cellular integrals and critical $L$-values of modular forms of odd weight.Comment: 23 pages, to appear in Proceedings for the KMPB conference: Elliptic Integrals, Elliptic Functions and Modular Forms in Quantum Field Theor

The Suppressor of AAC2 Lethality SAL1 Modulates Sensitivity of Heterologously Expressed Artemia ADP/ATP Carrier to Bongkrekate in Yeast

The ADP/ATP carrier protein (AAC) expressed in Artemia franciscana is refractory to bongkrekate. We generated two strains of Saccharomyces cerevisiae where AAC1 and AAC3 were inactivated and the AAC2 isoform was replaced with Artemia AAC containing a hemagglutinin tag (ArAAC-HA). In one of the strains the suppressor of ΔAAC2 lethality, SAL1, was also inactivated but a plasmid coding for yeast AAC2 was included, because the ArAACΔsal1Δ strain was lethal. In both strains ArAAC-HA was expressed and correctly localized to the mitochondria. Peptide sequencing of ArAAC expressed in Artemia and that expressed in the modified yeasts revealed identical amino acid sequences. The isolated mitochondria from both modified strains developed 85% of the membrane potential attained by mitochondria of control strains, and addition of ADP yielded bongkrekate-sensitive depolarizations implying acquired sensitivity of ArAAC-mediated adenine nucleotide exchange to this poison, independent from SAL1. However, growth of ArAAC-expressing yeasts in glycerol-containing media was arrested by bongkrekate only in the presence of SAL1. We conclude that the mitochondrial environment of yeasts relying on respiratory growth conferred sensitivity of ArAAC to bongkrekate in a SAL1-dependent manner. © 2013 Wysocka-Kapcinska et al

Exoplanet phase curves: observations and theory

Phase curves are the best technique to probe the three dimensional structure of exoplanets' atmospheres. In this chapter we first review current exoplanets phase curve observations and the particular challenges they face. We then describe the different physical mechanisms shaping the atmospheric phase curves of highly irradiated tidally locked exoplanets. Finally, we discuss the potential for future missions to further advance our understanding of these new worlds.Comment: Fig.5 has been updated. Table 1 and corresponding figures have been updated with new values for WASP-103b and WASP-18b. Contains a table sumarizing phase curve observation