Widespread exon skipping triggers degradation by nuclear RNA surveillance in fission yeast

Exon skipping is considered a principal mechanism by which eukaryotic cells expand their transcriptome and proteome repertoires, creating different splice variants with distinct cellular functions. Here we analyze RNA-seq data from 116 transcriptomes in fission yeast (Schizosaccharomyces pombe), covering multiple physiological conditions as well as transcriptional and RNA processing mutants. We applied brute-force algorithms to detect all possible exon-skipping events, which were widespread but rare compared to normal splicing events. Exon-skipping events increased in cells deficient for the nuclear exosome or the 5'-3' exonuclease Dhp1, and also at late stages of meiotic differentiation when nuclear-exosome transcripts decreased. The pervasive exon-skipping transcripts were stochastic, did not increase in specific physiological conditions, and were mostly present at less than one copy per cell, even in the absence of nuclear RNA surveillance and during late meiosis. These exon-skipping transcripts are therefore unlikely to be functional and may reflect splicing errors that are actively removed by nuclear RNA surveillance. The average splicing rate by exon skipping was ∼ 0.24% in wild type and ∼ 1.75% in nuclear exonuclease mutants. We also detected approximately 250 circular RNAs derived from single or multiple exons. These circular RNAs were rare and stochastic, although a few became stabilized during quiescence and in splicing mutants. Using an exhaustive search algorithm, we also uncovered thousands of previously unknown splice sites, indicating pervasive splicing; yet most of these splicing variants were cryptic and increased in nuclear degradation mutants. This study highlights widespread but low frequency alternative or aberrant splicing events that are targeted by nuclear RNA surveillance

A modified vaccinia Ankara vaccine expressing spike and nucleocapsid protects rhesus macaques against SARS-CoV-2 Delta infection

SARS-CoV-2 vaccines should induce broadly cross-reactive humoral and T cell responses to protect against emerging variants of concern (VOCs). Here, we inactivated the furin cleavage site (FCS) of spike expressed by a modified vaccinia Ankara (MVA) virus vaccine (MVA/SdFCS) and found that FCS inactivation markedly increased spike binding to human ACE2. After vaccination of mice, the MVA/SdFCS vaccine induced eightfold higher neutralizing antibodies compared with MVA/S, which expressed spike without FCS inactivation, and protected against the Beta variant. We next added nucleocapsid to the MVA/SdFCS vaccine (MVA/SdFCS-N) and tested its immunogenicity and efficacy via intramuscular (IM), buccal (BU), or sublingual (SL) routes in rhesus macaques. IM vaccination induced spike-specific IgG in serum and mucosae (nose, throat, lung, and rectum) that neutralized the homologous (WA-1/2020) and heterologous VOCs, including Delta, with minimal loss (<2-fold) of activity. IM vaccination also induced both spike- and nucleocapsid-specific CD4 and CD8 T cell responses in the blood. In contrast, the SL and BU vaccinations induced less spike-specific IgG in secretions and lower levels of polyfunctional IgG in serum compared with IM vaccination. After challenge with the SARS-CoV-2 Delta variant, the IM route induced robust protection, the BU route induced moderate protection, and the SL route induced no protection. Vaccine-induced neutralizing and non-neutralizing antibody effector functions positively correlated with protection, but only the effector functions correlated with early protection. Thus, IM vaccination with MVA/SdFCS-N vaccine elicited cross-reactive antibody and T cell responses, protecting against heterologous SARS-CoV-2 VOC more effectively than other routes of vaccination

Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat

Subcortical brain volume, regional cortical thickness, and cortical surface area across disorders: findings from the ENIGMA ADHD, ASD, and OCD Working Groups

Objective Attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD) are common neurodevelopmental disorders that frequently co-occur. We aimed to directly compare all three disorders. The ENIGMA consortium is ideally positioned to investigate structural brain alterations across these disorders. Methods Structural T1-weighted whole-brain MRI of controls (n=5,827) and patients with ADHD (n=2,271), ASD (n=1,777), and OCD (n=2,323) from 151 cohorts worldwide were analyzed using standardized processing protocols. We examined subcortical volume, cortical thickness and surface area differences within a mega-analytical framework, pooling measures extracted from each cohort. Analyses were performed separately for children, adolescents, and adults using linear mixed-effects models adjusting for age, sex and site (and ICV for subcortical and surface area measures). Results We found no shared alterations among all three disorders, while shared alterations between any two disorders did not survive multiple comparisons correction. Children with ADHD compared to those with OCD had smaller hippocampal volumes, possibly influenced by IQ. Children and adolescents with ADHD also had smaller ICV than controls and those with OCD or ASD. Adults with ASD showed thicker frontal cortices compared to adult controls and other clinical groups. No OCD-specific alterations across different age-groups and surface area alterations among all disorders in childhood and adulthood were observed. Conclusion Our findings suggest robust but subtle alterations across different age-groups among ADHD, ASD, and OCD. ADHD-specific ICV and hippocampal alterations in children and adolescents, and ASD-specific cortical thickness alterations in the frontal cortex in adults support previous work emphasizing neurodevelopmental alterations in these disorders

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers

Growth Mechanism and Photoluminescence Properties of In2O3 Nanotowers

To elucidate the growth mechanism of In2O3 nanotowers synthesized via a Au-catalyzed vapor transport process, the structural evolution of In2O3 nanotowers was carefully examined during the synthesis process. It was found that Au catalysts only play a role at the initial stage, where they facilitate the formation of In2O3 nanoparticles and nanorods. After the Au atoms are consumed by the formation of Au-In compound(s), the liquid In droplets will form on the tips of In2O3 nanoparticles or nanorods, and the self-catalytic vapor-liquid-solid (VLS) growth mechanism will dominate the subsequent one-dimensional (1D) growth of In2O3 nanopillars. Since the supply of In2O may not be sufficient for the continuous 1D growth, the lateral growth of In2O3 nanopillars governed by the vapor-solid (VS) mechanism will occur. The periodical axial and continuous lateral growth leads to the formation of In2O3 nanotowers with a truncated octahedron structure of 4-fold symmetry {111} accumulated planes along the [100] direction. The photoluminescence (PL) spectrum of In2O3 nanotowers exhibited an intense green-yellow luminescence at the wavelength of 580 nm, which can be ascribed to the possible recombination of electrons on singly ionized oxygen vacancies and holes on the valence band or doubly ionized oxygen vacancies

Growth mechanism and cathodoluminescence properties of indium hydroxide nanocubes synthesized from a simple aqueous solution

Single-crystalline In(OH)(3) nanocubes were synthesized in a simple aqueous solution, without using a surfactant, at a temperature as low as 90 degrees C. To elucidate the growth mechanism, the structural evolution of In(OH)(3) nanocubes during the synthesis process were carefully examined. The experimental results showed that the formation of the In(OH)(3) nanocubes is primarily guided by the oriented attachment mechanism, following a zero-dimensional (0D) -> one-dimensional (1D) -> three-dimensional (3D) mode. The 0D In(OH)(3) nanoparticles will first assemble to form 1D nanorods, then the nanorods will orientedly attach to form 3D nanorod bundles and finally the In(OH)(3) nanorod bundles will fuse into strip-like or square nanocubes. Small strip-like or square nanocubes can further orientedly attach and fuse into big single-crystalline strip-like or square nanocubes. However, the growth of strip-like and square nanocubes may also occur based on the Ostwald ripening. The cathodoluminescence (CL) spectra at room temperature of the as-synthesized In(OH)(3) nanocubes exhibited a weak ultraviolet luminescence at 350 nm (3.54 eV) and a strong blue luminescence at 450 nm (2.75 eV), which can be attributed to the hydroxy ion defects generated by the incomplete reaction of the In(3+) ions with OH(-) radicals during the synthesis process

Synthesis of Sb-additivated SnO2 nanostructures and dependence of photoluminescence properties on Sb additivation concentration

Single crystalline Sb-additivated SnO2 nanorods, beaklike nanorods, and nanoribbons were synthesized by an in situ catalyst-assisted thermal evaporation process on single-crystal Si substrates. As the Sb:Sn weight ratios were increased, the morphologies of Sb-additivated SnO2 nanostructures would progressively transform from nanorods to beaklike nanorods and to the mixture of nanowires and nanoribbons. The SnO2 nanorods grow along the [0 (2) over bar0] direction and with lateral facets defining a square column consisting of {100} and {001} planes. The Sb-additivated SnO2 beaklike nanorods initially grow along the [0 (1) over tilde(1) over bar] direction and then switch to the [03 (1) over tilde] direction to form the beak, while the nanoribbons grow along the [110] direction. The Sb atoms were found to uniformly distribute over the whole Sb-additivated SnO2 nanostructures and that it would not affect the single crystallinity of SnO2 nanostructures. The photoluminescence spectra of the nonadditivated and Sb-additivated SnO2 nanostructures exhibited multipeaks with peak positions centered at 403, 453, 485, 557, and 622 nm. When Sb atoms were additivated into SnO2 nanostructures, the luminescence intensities would significantly decrease and photoluminescence at 557 and 622 nm would almost disappear. These can be explained by the replacements of the six- and fivefold coordinated Sn atoms on low-index facets by five- and fourfold coordinated Sb atoms, respectively, leading to the cancellation of 100 degrees tin coordinated on-plane oxygen bridging vacancies and 130 degrees tin coordinated in-plane oxygen vacancies. (c) 2009 American Institute of Physics. [DOI: 10.1063/1.3068487

Positron measurements in 2H-TaSe/sub 2/ crystals

Temperature-dependent positron annihilation lifetime and Doppler broadening experiments are reported on single crystals of 2H-TaSe/sub 2/ to search for effects from known charge-density-wave (CDW) phase transitions. The positron lifetime in the perfect lattice and in positron trapping sites were found to be 0.173 and 0.378 ns, respectively. The apparent activation energy for the thermally generated trapping sites was found to be 0.12 eV. Doppler broadening spectra exhibited no response to the known CDW phase transitions, nor any significant overall anisotropy in their temperature dependence