Transcription-associated mutation promotes RNA complexity in highly expressed genes - a major new source of selectable variation

Alternatively spliced transcript isoforms are thought to play a critical role for functional diversity. However, the mechanism generating the enormous diversity of spliced transcript isoforms remains unknown, and its biological significance remains unclear. We analyzed transcriptomes in saker falcons, chickens, and mice to show that alternative splicing occurs more frequently, yielding more isoforms, in highly expressed genes. We focused on hemoglobin in the falcon, the most abundantly expressed genes in blood, finding that alternative splicing produces 10-fold more isoforms than expected from the number of splice junctions in the genome. These isoforms were produced mainly by alternative use of de novo splice sites generated by transcription-associated mutation (TAM), not by the RNA editing mechanism normally invoked. We found that high expression of globin genes increases mutation frequencies during transcription, especially on nontranscribed DNA strands. After DNA replication, transcribed strands inherit these somatic mutations, creating de novo splice sites, and generating multiple distinct isoforms in the cell clone. Bisulfate sequencing revealed that DNA methylation may counteract this process by suppressing TAM, suggesting DNA methylation can spatially regulate RNA complexity. RNA profiling showed that falcons living on the high Qinghai–Tibetan Plateau possess greater global gene expression levels and higher diversity of mean to high abundance isoforms (reads per kilobases per million mapped reads ≥18) than their low-altitude counterparts, and we speculate that this may enhance their oxygen transport capacity under low-oxygen environments. Thus, TAM-induced RNA diversity may be physiologically significant, providing an alternative strategy in lifestyle evolution

The Role of Autophagy in Parkinson's Disease: Rotenone-Based Modeling

Background: Autophagy-mediated self-digestion of cytoplasmic inclusions may be protective against neurodegenerative diseases such as Parkinson’s disease (PD). However, excessive autophagic activation evokes autophagic programmed cell death. Methods: In this study, we aimed at exploring the role of autophagy in the pathogenesis of rotenone-induced cellular and animal models for PD. Results: Reactive oxygen species over-generation, mitochondrial membrane potential reduction or apoptosis rate elevation occurred in a dose-dependent fashion in rotenone-treated human neuroblastoma cell line SH-SY5Y. The time- and dose-dependent increases in autophagic marker microtubule-associated protein1 light chain 3 (LC3) expression and decreases in autophagic adaptor protein P62 were observed in this cellular model. LC3-positive autophagic vacuoles were colocalized with alpha-synuclein-overexpressed aggregations. Moreover, the number of autophagic vacuoles was increased in rotenone-based PD models in vitro and in vivo. Conclusions: These data, along with our previous finding showing rotenone-induced toxicity was prevented by the autophagy enhancers and was aggravated by the autophagy inhibitors in SH-SY5Y, suggest that autophagy contributes to the pathogenesis of PD, attenuates the rotenone toxicity and possibly represents a new subcellular target for treating PD

Glucocerebrosidase L444P Mutation Confers Genetic Risk for Parkinson’s Disease in Central China

Background: Mutations of the glucocerebrosidase (GBA) gene have reportedly been associated with Parkinson disease (PD) in various ethnic populations such as Singaporean, Japanese, Formosan, Canadian, American, Portuguese, Greek, Brazilian, British, Italian, Ashkenazi Jewish, southern and southwestern Chinese. The purpose of this study is to determine in central China whether or not the reported GBA mutations remain associated with PD. Methods: In this project, we conducted a controlled study in a cohort of 208 central Chinese PD patients and 298 controls for three known GBA mutations (L444P, N370S and R120W). Results: Our data reveals a significantly higher frequency of L444P mutation in GBA gene of PD cases (3.4%) compared with the controls (0.3%) (P = 0.007, OR = 10.34, 95% CI = 1.26 - 84.71). Specifically, the frequency of L444P mutation was higher in the late onset PD (LOPD) cases compared with that in control subjects. The N370S and R120W mutations were detected in neither the PD group nor the control subjects. Conclusions: Our observations demonstrated that the GBA L444P mutation confers genetic risk for PD, especially LOPD, among the population in the central China area

Population transcriptomes reveal synergistic responses of DNA polymorphism and RNA expression to extreme environments on the Qinghai-Tibetan Plateau in a predatory bird

Low oxygen and temperature pose key physiological challenges for endotherms living on the Qinghai–Tibetan Plateau (QTP). Molecular adaptations to high‐altitude living have been detected in the genomes of Tibetans, their domesticated animals and a few wild species, but the contribution of transcriptional variation to altitudinal adaptation remains to be determined. Here we studied a top QTP predator, the saker falcon, and analysed how the transcriptome has become modified to cope with the stresses of hypoxia and hypothermia. Using a hierarchical design to study saker populations inhabiting grassland, steppe/desert and highland across Eurasia, we found that the QTP population is already distinct despite having colonized the Plateau <2000 years ago. Selection signals are limited at the cDNA level, but of only seventeen genes identified, three function in hypoxia and four in immune response. Our results show a significant role for RNA transcription: 50% of upregulated transcription factors were related to hypoxia responses, differentiated modules were significantly enriched for oxygen transport, and importantly, divergent EPAS1 functional variants with a refined co‐expression network were identified. Conservative gene expression and relaxed immune gene variation may further reflect adaptation to hypothermia. Our results exemplify synergistic responses between DNA polymorphism and RNA expression diversity in coping with common stresses, underpinning the successful rapid colonization of a top predator onto the QTP. Importantly, molecular mechanisms underpinning highland adaptation involve relatively few genes, but are nonetheless more complex than previously thought and involve fine‐tuned transcriptional responses and genomic adaptation

RNA-Puzzles Round IV:3D structure predictions of four ribozymes and two aptamers

International audienceRNA-Puzzles is a collective endeavor dedicated to the advancement and improvement of RNA 3D structure prediction. With agreement from crystallographers, the RNA structures are predicted by various groups before the publication of the crystal structures. We now report the prediction of 3D structures for six RNA sequences: four nucleolytic ribozymes and two riboswitches. Systematic protocols for comparing models and crystal structures are described and analyzed. In these six puzzles, we discuss (i) the comparison between the automated web servers and human experts; (ii) the prediction of coaxial stacking; (iii) the prediction of structural details and ligand binding; (iv) the development of novel prediction methods; and (v) the potential improvements to be made. We show that correct prediction of coaxial stacking and tertiary contacts is essential for the prediction of RNA architecture, while ligand binding modes can only be predicted with low resolution and simultaneous prediction of RNA structure with accurate ligand binding still remains out of reach. All the predicted models are available for the future development of force field parameters and the improvement of comparison and assessment tools

High Performance Direct-Current Generator Based on Dynamic PN Junctions

After the electromagnetic generator, searching for novel electric generators without strong magnetic field is highly demanded. The generator without strong magnetic field calls for a physical picture distinct from the traditional generators. As the counterpart of the static PN junction has been widely used in the integrated circuits, we develop an electric generator named dynamic PN generator with a high current density and voltage output, which converts mechanical energy into electricity by sliding two semiconductors with different Fermi level. A dynamic N-GaAs/SiO2/P-Si generator with the open-circuit voltage of 3.1 V and short-circuit density of 1.0 A/m2 have been achieved. The physical mechanism of the dynamic PN generator is proposed based on the built-in electric field bounding back diffusing carriers in dynamic PN junctions, which breaks the equilibrium between drift and diffusion current in the PN junction. Moreover, the dynamic MoS2/AlN/Si generator with the open-circuit voltage of 5.1 V and short-circuit density of 112 A/m2 (11.2 mA/cm2) have also been achieved, which can effectively output a direct-current and light up a blue light-emitting diode directly. This dynamic MoS2/AlN/Si generator can continuously work for hours without obvious degradation, demonstrating its unique mechanism and potential applications in many fields where the mechanical energy is available

Bitsliced Implementations of the PRINCE, LED and RECTANGLE Block Ciphers on AVR 8-bit Microcontrollers

Due to the demand for low-cost cryptosystems from industry, there spring up a lot of lightweight block ciphers which are excellent for some different implementation features. An innovative design is the block cipher PRINCE. To meet the requirement for low-latency and instantaneously encryption, NXP Semiconductors and its academic partners cooperate and design the low-latency block cipher PRINCE. Another good example is the block cipher LED which is very compact in hardware, and whose designers also aim to maintain a reasonable software performance. In this paper, we demonstrate how to achieve high software performance of these two ciphers on the AVR 8-bit microcontrollers using bitslice technique. Our bitsliced implementations speed up the execution of these two ciphers several times with less memory usage than previous work. In addition to these two nibble-oriented ciphers, we also evaluate the software performance of a newly proposed lightweight block cipher RECTANGLE, whose design takes bitslicing into consider. Our results show that RECTANGLE has very high performance ranks among the existing block ciphers on 8-bit microcontrollers in the real-world usage scenarios

Wave-graphene: a full-auxetic carbon semiconductor with high flexibility and optical UV absorption

The abundant bonding possibilities of Carbon stimulate the design of numerous carbon allotropes, promising the foundation for exploring structure-functionality relationships. Herein, utilizing the space bending strategy, we successfully engineered a two-dimensional carbon allotrope with pure sp2 hybridization, named "Wave-graphene" from the unique wave-like ripple structure. The novel Wave-graphene exhibits full-auxetic behavior due to anisotropic mechanical response, possessing both negative and zero Poisson's ratios. The fundamental mechanism can be attributed to the fact that highly buckled out-of-plane structures lead to anisotropic responses of in-plane nonlinear interactions, which further lead to anisotropy of lattice vibrations. In addition, Wave-graphene is found having quasi-direct wide bandgap of 2.01 eV, the excellent optical transparency and the high flexibility. The successful design of Wave-graphene with excellent outstanding multifunctional properties shows that the utilization of space bending strategies can provide more degrees of freedom for designing novel materials, further enriching the carbon material family and supplementing its versatility