A longer time to relapse is associated with a larger increase in differences between paired primary and recurrent IDH wild-type glioblastomas at both the transcriptomic and genomic levels.

Glioblastoma (GBM) is the most common malignant brain tumor in adults, which remains incurable and often recurs rapidly after initial therapy. While large efforts have been dedicated to uncover genomic/transcriptomic alternations associated with the recurrence of GBMs, the evolutionary trajectories of matched pairs of primary and recurrent (P-R) GBMs remain largely elusive. It remains challenging to identify genes associated with time to relapse (TTR) and construct a stable and effective prognostic model for predicting TTR of primary GBM patients. By integrating RNA-sequencing and genomic data from multiple datasets of patient-matched longitudinal GBMs of isocitrate dehydrogenase wild-type (IDH-wt), here we examined the associations of TTR with heterogeneities between paired P-R GBMs in gene expression profiles, tumor mutation burden (TMB), and microenvironment. Our results revealed a positive correlation between TTR and transcriptomic/genomic differences between paired P-R GBMs, higher percentages of non-mesenchymal-to-mesenchymal transition and mesenchymal subtype for patients with a short TTR than for those with a long TTR, a high correlation between paired P-R GBMs in gene expression profiles and TMB, and a negative correlation between the fitting level of such a paired P-R GBM correlation and TTR. According to these observations, we identified 55 TTR-associated genes and thereby constructed a seven-gene (ZSCAN10, SIGLEC14, GHRHR, TBX15, TAS2R1, CDKL1, and CD101) prognostic model for predicting TTR of primary IDH-wt GBM patients using univariate/multivariate Cox regression analyses. The risk scores estimated by the model were significantly negatively correlated with TTR in the training set and two independent testing sets. The model also segregated IDH-wt GBM patients into two groups with significantly divergent progression-free survival outcomes and showed promising performance for predicting 1-, 2-, and 3-year progression-free survival rates in all training and testing sets. Our findings provide new insights into the molecular understanding of GBM progression at recurrence and potential targets for therapeutic treatments.

Influence of Inorganic Anions on the Chemical Stability of Molybdenum Disulfide Nanosheets in the Aqueous Environment.

Chemical stability is closely associated with the transformations and bioavailabilities of engineered nanomaterials and is a key factor that governs broader and long-term application. With the growing utilization of molybdenum disulfide (MoS2) nanosheets in water treatment and purification processes, it is crucial to evaluate the stability of MoS2 nanosheets in aquatic environments. Nonetheless, the effects of anionic species on MoS2 remain largely unexplored. Herein, the stability of chemically exfoliated MoS2 nanosheets (ceMoS2) was assessed in the presence of inorganic anions. The results showed that the chemical stability of ceMoS2 was regulated by the nucleophilicities and the resultant charging effects of the anions in aquatic systems. The anions promote the dissolution of ceMoS2 by triggering a shift in the chemical potential of the ceMoS2 surface as a function of the anion nucleophilicity (i.e., charging effect). Fast charging with HCO3- and HPO42-/H2PO4- was validated by a phase transition from 1T to 2H and the emergence of MoV, and it promoted oxidative dissolution of the ceMoS2. Additionally, under sunlight, ceMoS2 dissolution was accelerated by NO3-. These findings provide insight into the ion-induced fate of ceMoS2 and the durability and risks of MoS2 nanosheets in environmental applications.

FL-circAS: an integrative resource and analysis for full-length sequences and alternative splicing of circular RNAs with nanopore sequencing.

Circular RNAs (circRNAs) are RNA molecules with a continuous loop structure characterized by back-splice junctions (BSJs). While analyses of short-read RNA sequencing have identified millions of BSJ events, it is inherently challenging to determine exact full-length sequences and alternatively spliced (AS) isoforms of circRNAs. Recent advances in nanopore long-read sequencing with circRNA enrichment bring an unprecedented opportunity for investigating the issues. Here, we developed FL-circAS (https://cosbi.ee.ncku.edu.tw/FL-circAS/), which collected such long-read sequencing data of 20 cell lines/tissues and thereby identified 884 636 BSJs with 1 853 692 full-length circRNA isoforms in human and 115 173 BSJs with 135 617 full-length circRNA isoforms in mouse. FL-circAS also provides multiple circRNA features. For circRNA expression, FL-circAS calculates expression levels for each circRNA isoform, cell line/tissue specificity at both the BSJ and isoform levels, and AS entropy for each BSJ across samples. For circRNA biogenesis, FL-circAS identifies reverse complementary sequences and RNA binding protein (RBP) binding sites residing in flanking sequences of BSJs. For functional patterns, FL-circAS identifies potential microRNA/RBP binding sites and several types of evidence for circRNA translation on each full-length circRNA isoform. FL-circAS provides user-friendly interfaces for browsing, searching, analyzing, and downloading data, serving as the first resource for discovering full-length circRNAs at the isoform level.

Large-scale benchmarking of circRNA detection tools reveals large differences in sensitivity but not in precision.

The detection of circular RNA molecules (circRNAs) is typically based on short-read RNA sequencing data processed using computational tools. Numerous such tools have been developed, but a systematic comparison with orthogonal validation is missing. Here, we set up a circRNA detection tool benchmarking study, in which 16 tools detected more than 315,000 unique circRNAs in three deeply sequenced human cell types. Next, 1,516 predicted circRNAs were validated using three orthogonal methods. Generally, tool-specific precision is high and similar (median of 98.8%, 96.3% and 95.5% for qPCR, RNase R and amplicon sequencing, respectively) whereas the sensitivity and number of predicted circRNAs (ranging from 1,372 to 58,032) are the most significant differentiators. Of note, precision values are lower when evaluating low-abundance circRNAs. We also show that the tools can be used complementarily to increase detection sensitivity. Finally, we offer recommendations for future circRNA detection and validation.

Detecting intragenic trans-splicing events from non-co-linearly spliced junctions by hybrid sequencing.

Trans-spliced RNAs (ts-RNAs) are a type of non-co-linear (NCL) transcripts that consist of exons in an order topologically inconsistent with the corresponding DNA template. Detecting ts-RNAs is often interfered by experimental artifacts, circular RNAs (circRNAs) and genetic rearrangements. Particularly, intragenic ts-RNAs, which are derived from separate precursor mRNA molecules of the same gene, are often mistaken for circRNAs through analyses of RNA-seq data. Here we developed a bioinformatics pipeline (NCLscan-hybrid), which integrated short and long RNA-seq reads to minimize false positives and proposed out-of-circle and rolling-circle long reads to distinguish between intragenic ts-RNAs and circRNAs. Combining NCLscan-hybrid screening and multiple experimental validation steps successfully confirmed that four NCL events, which were previously regarded as circRNAs in databases, originated from trans-splicing. CRISPR-based endogenous genome modification experiments further showed that flanking intronic complementary sequences can significantly contribute to ts-RNA formation, providing an efficient/specific method to deplete ts-RNAs. We also experimentally validated that one ts-RNA (ts-ARFGEF1) played an important role for p53-mediated apoptosis through affecting the PERK/eIF2a/ATF4/CHOP signaling pathway in breast cancer cells. This study thus described both bioinformatics procedures and experimental validation steps for rigorous characterization of ts-RNAs, expanding future studies for identification, biogenesis, and function of these important but understudied transcripts.

Recovery and repurposing of waste isopropanol with CO2-switchable deep eutectic solvents.

Large amounts of waste isopropanol (IPA) are generated in industry, rendering the recovery of IPA highly desirable due to the economic and environmental benefits. Because it forms an azeotropic mixture with water, IPA is difficult to separate from the waste stream. In the present work, a novel CO2-switchable monoethanolamine-butanol deep eutectic solvent (DES) ([MEA][BuOH]) was identified as a superior medium for separating IPA and water at ambient temperature by forming butanol-IPA mixtures. The switchable solvent system combines the advantages of homogeneous and heterogeneous systems, i.e., rapid mixing due to the low mass transfer limitations and facile product separation, respectively. The low viscosity of [MEA][BuOH], the similar physical features (polarity, dipole moment, and dielectric constant) of butanol and IPA, and the H-bonding interactions of [BuOH] with IPA are thought to enable effective IPA capture from water by the butanol. Recovery of the IPA and formation of a butanol-IPA mixture is appealing because the resultant mixture could serve as an additive or substitute for alternative fuels. The results suggest that the developed process will provide a low-cost, energy-saving, effective, and environmentally benign route to recycling and repurposing waste IPA, an environmental hazard, as a potential alternative fuel.

Polypyrrole-induced active-edge-S and high-valence-Mo reinforced composites with boosted electrochemical performance for the determination of 2,4,6-trichlorophenol in the aquatic environment.

With the extensive application of halogenated aromatic compounds, including 2,4,6-Trichlorophenol (2,4,6-TCP), improper treatment or discharge contribute to persistently harmful effects on humans and the ecosystem, rendering the identification and monitoring of 2,4,6-TCP in the aquatic environment urgently required. In this study, a highly sensitive electrochemical platform was developed using active-edge-S and high-valence-Mo rich MoS2/polypyrrole composites. MoS2/PPy illustrates superior electrochemical performance and catalytic activity and has not been explored for detecting chlorinated phenols previously. The local environment of polypyrrole induces the richness of active edge S and a high oxidation state of Mo species in the composites, both of which endorse a sensitive anodic current response due to the favored oxidation of 2,4,6-TCP through nucleophilic substitution. Also, the higher complementarity between pyrrole and 2,4,6-TCP with respective electron-rich and electron-poor features through π-π stacking interactions enhances the specific detection capability of 2,4,6-TCP by the MoS2/polypyrrole-modified electrode. The MoS2/polypyrrole-modified electrode achieved a linear range of 0.1-260 µM with an ultralow limit of detection of 0.009 µM. Additionally, the structural stability boosted by the linkage of polypyrrole and MoS2 results in good resistance and satisfactory recovery in real water samples. The compiled results demonstrate that the proposed MoS2/polypyrrole composite opens up a new potential to advance a sensitive, selective, facile fabrication, and low-cost platform for the on-site determination of 2,4,6-TCP in aquatic systems. The sensing of 2,4,6-TCP is important to monitor its occurrence and transport, and can also serve to track the effectiveness and adjust subsequent remediation treatments applied to contaminated sites.

Assessing the impacts of various factors on circular RNA reliability.

Circular RNAs (circRNAs) are non-polyadenylated RNAs with a continuous loop structure characterized by a non-colinear back-splice junction (BSJ). Although millions of circRNA candidates have been identified, it remains a major challenge for determining circRNA reliability because of various types of false positives. Here, we systematically assess the impacts of numerous factors related to circRNA identification, conservation, biogenesis, and function on circRNA reliability by comparisons of circRNA expression from mock and the corresponding colinear/polyadenylated RNA-depleted datasets based on three different RNA treatment approaches. Eight important indicators of circRNA reliability are determined. The relative contribution to variability explained analyses reveal that the relative importance of these factors in affecting circRNA reliability in descending order is the conservation level of circRNA, full-length circular sequences, supporting BSJ read count, both BSJ donor and acceptor splice sites at the same colinear transcript isoforms, both BSJ donor and acceptor splice sites at the annotated exon boundaries, BSJs detected by multiple tools, supporting functional features, and both BSJ donor and acceptor splice sites undergoing alternative splicing. This study thus provides a useful guideline and an important resource for selecting high-confidence circRNAs for further investigations.

The role of transformation in the risks of chemically exfoliated molybdenum disulfide nanosheets to the aquatic environment.

While the effects of environmental factors (e.g., coexisting organic macromolecules and solar irradiation) on the phase transformation and oxidative dissolution of chemically exfoliated molybdenum nanosheets (ceMoS2) have been recognized, the effects of environmental processes on the subsequent biological impacts of ceMoS2 are still poorly understood. In this study, the bioavailability and transitions in chemical speciation occurring during the aging process are demonstrated to be key factors causing ceMoS2 to affect aquatic organisms. The lower survival rate of embryonic zebrafish with aged (i.e., sunlight-irradiated and dark-ambient-aged) ceMoS2, compared to that with freshly prepared ceMoS2, was due to the release of ionic aging products (mainly acidic Mo species) throughout the oxidative dissolution of ceMoS2. The released soluble molybdenum interacted with natural organic matter (NOM) depending on their functionality, and this attenuated the toxicity caused by ceMoS2 to different degrees. Toxicity triggered by aged ceMoS2 under both dark and irradiated conditions was significantly reduced by Suwannee River NOM due to the formation of complexes with ionic Mo species, which was established by Mo K-edge X-ray absorption spectroscopy. The findings provide useful insights for comprehending the impacts of ceMoS2 on aquatic organisms and guidance for the prevention measures necessary in the applications of MoS2 nanosheets.

Performance of bioelectrochemical systems in treating exhaust gas with power generation: Effects of shock-load, shut-down episodes and microbial community.

A diffusive packed anode-bioelectrochemical (Dpa-Bes) system was constructed by feeding waste gas from the cathode to the anode tank in DPa-Bes through a proton exchange membrane (PEM). The high removal of oxygen by the PEM and the effective combination of the two packing materials reduced the electron loss and enhanced the proton transfer capacity, promoting the removal of acetone from the exhaust gas and increasing the output power. The maximum acetone removal efficiency of the modified Dpa-Bes reached ∼99 % after seven days of closed-circuit operation, with a 3.2-fold increase in maximum power density and a 2.27-fold increase in closed-circuit voltage relative to those of the unmodified Dpa-Bes. When the acetone concentration was 2400 ppm, the removal efficiency was 73.22 % and the elimination capacity was at its highest value of 290.21 g/m3/h. Microbial analysis revealed that the conductive filter contained abundant facultative and anaerobic bacteria, whereas the non-conductive filter was rich in aerobic bacteria. The abundance of anaerobic and facultative microorganisms in Dpa-Bes was much higher than in the unmodified Dpa-Bes, and the dominant bacteria were Flavobacterium and Ferruginibacter.

Trans-genetic effects of circular RNA expression quantitative trait loci and potential causal mechanisms in autism.

Genetic risk variants and transcriptional expression changes in autism spectrum disorder (ASD) were widely investigated, but their causal relationship remains largely unknown. Circular RNAs (circRNAs) are abundant in brain and often serve as upstream regulators of mRNAs. By integrating RNA-sequencing with genotype data from autistic brains, we assessed expression quantitative trait loci of circRNAs (circQTLs) that cis-regulated expression of nearby circRNAs and trans-regulated expression of distant genes (trans-eGenes) simultaneously. We thus identified 3619 circQTLs that were also trans-eQTLs and constructed 19,804 circQTL-circRNA-trans-eGene regulatory axes. We conducted two different types of approaches, mediation and partial correlation tests (MPT), to determine the axes with mediation effects of circQTLs on trans-eGene expression through circRNA expression. We showed that the mediation effects of the circQTLs (trans-eQTLs) on circRNA expression were positively correlated with the magnitude of circRNA-trans-eGene correlation of expression profile. The positive correlation became more significant after adjustment for the circQTLs. Of the 19,804 axes, 8103 passed MPT. Meanwhile, we performed causal inference test (CIT) and identified 2070 circQTL-trans-eGene-ASD diagnosis propagation paths. We showed that the CIT-passing genes were significantly enriched for ASD risk genes, genes encoding postsynaptic density proteins, and other ASD-relevant genes, supporting the relevance of the CIT-passing genes to ASD pathophysiology. Integration of MPT- and CIT-passing axes further constructed 352 circQTL-circRNA-trans-eGene-ASD diagnosis propagation paths, wherein the circRNA-trans-eGene axes may act as causal mediators for the circQTL-ASD diagnosis associations. These analyses were also successfully applied to an independent dataset from schizophrenia brains. Collectively, this study provided the first framework for systematically investigating trans-genetic effects of circQTLs and inferring the corresponding causal relations in diseases. The identified circQTL-circRNA-trans-eGene regulatory interactions, particularly the internal modules that were previously implicated in the examined disorders, also provided a helpful dataset for further investigating causative biology and cryptic regulatory mechanisms underlying the neuropsychiatric diseases.

Upcycling fruit peel waste into a green reductant to reduce graphene oxide for fabricating an electrochemical sensing platform for sulfamethoxazole determination in aquatic environments.

Fruit and vegetable wastes contribute to a substantial proportion of global food waste. While these wastes could potentially be repurposed for a wide range of applications, the majority of them are discarded without effective utilization. To address the current challenges of fruit waste accumulation and sustainable nanomaterial synthesis, natural reductants derived from discarded dragon fruit (Hylocereus polyrhizus) peels are proposed as an alternative to conventional hazardous reductants for graphene-based material synthesis. Given that the chemical reduction of graphene oxide (GO) is the major route for graphene production, the effectiveness of the proposed reductants derived from peels of dragon fruit on graphene oxide reduction was evaluated. The reducing constituents (i.e., betanin substances) were recovered from dragon fruit peel wastes using facile aqueous extraction processes, where suitable extraction treatments (e.g., pH conditions) were found to be critical for boosting the reducing power of the obtained reductants. The compiled results indicated that the proposed fruit waste-derived reducing agents demonstrated great promise for GO reduction through SN2 nucleophilic reactions, mainly driven by the extracted betanin. The obtained reduced GO serves as a promising platform for electrochemical determination of sulfamethoxazole in aquatic environments, realizing both food waste valorization and environmentally benign material synthesis.

Comparative Analyses of Single-Cell Transcriptomic Profiles between In Vitro Totipotent Blastomere-like Cells and In Vivo Early Mouse Embryonic Cells.

The developmental potential within pluripotent cells in the canonical model is restricted to embryonic tissues, whereas totipotent cells can differentiate into both embryonic and extraembryonic tissues. Currently, the ability to culture in vitro totipotent cells possessing molecular and functional features like those of an early embryo in vivo has been a challenge. Recently, it was reported that treatment with a single spliceosome inhibitor, pladienolide B (plaB), can successfully reprogram mouse pluripotent stem cells into totipotent blastomere-like cells (TBLCs) in vitro. The TBLCs exhibited totipotency transcriptionally and acquired expanded developmental potential with the ability to yield various embryonic and extraembryonic tissues that may be employed as novel mouse developmental cell models. However, it is disputed whether TBLCs are 'true' totipotent stem cells equivalent to in vivo two-cell stage embryos. To address this question, single-cell RNA sequencing was applied to TBLCs and cells from early mouse embryonic developmental stages and the data were integrated using canonical correlation analyses. Differential expression analyses were performed between TBLCs and multi-embryonic cell stages to identify differentially expressed genes. Remarkably, a subpopulation within the TBLCs population expressed a high level of the totipotent-related genes Zscan4s and displayed transcriptomic features similar to mouse two-cell stage embryonic cells. This study underscores the subtle differences between in vitro derived TBLCs and in vivo mouse early developmental cell stages at the single-cell transcriptomic level. Our study has identified a new experimental model for stem cell biology, namely 'cluster 3', as a subpopulation of TBLCs that can be molecularly defined as near totipotent cells.

Pathways of emotional autonomy, problem-solving ability, self-efficacy, and self-management on the glycemic control of adolescents with type 1 diabetes: A prospective study.

This prospective study tested a model to depict associations between a number of individual characteristics and 6-month glycated hemoglobin (HbA1c) levels in adolescents with type 1 diabetes (T1D). Adolescents (N = 232) aged 10-19 years with T1D were recruited from a medical center in Taiwan. Demographic characteristics, emotional autonomy, problem-solving ability, self-efficacy at baseline, and self-management information three months after baseline were collected using a self-reported questionnaire. HbA1c levels 6 months after study commencement were obtained from medical records. Structural equation modeling was used to test the model. Higher baseline self-efficacy and self-management at 3 months were directly associated with lower 6-month HbA1c levels. Higher baseline problem-solving ability and self-efficacy were directly associated with higher 3-month self-management, and higher baseline problem-solving ability was directly associated with higher baseline self-efficacy. Higher baseline emotional autonomy was directly associated with lower 6-month HbA1c levels but indirectly associated with higher 6-month HbA1c levels through the mediation of lower problem-solving ability, self-efficacy, and 3-month self-management. Findings indicate that improving self-management is essential to improving subsequent glycemic control, which might be achieved by enhancing problem-solving ability and self-efficacy. Strengthening problem-solving ability could diminish the negative impact of emotional autonomy on subsequent glycemic control in adolescents with T1D.

Roles of Emotional Autonomy, Problem-Solving Ability and Parent-Adolescent Relationships on Self-Management of Adolescents with Type 1 Diabetes in Taiwan.

BACKGROUND: High emotional autonomy has a negative association, whereas good problem-solving ability and parent-adolescent relationships have positive association with self-management in adolescents with type 1 diabetes (T1D). Exploring roles of these variables is crucial to design specific interventions to improve self-management in such afflicted adolescents. PURPOSE: To explore the roles of emotional autonomy, problem-solving ability and parent-adolescent relationships on self-management in adolescents with T1D. DESIGN AND METHODS: Cross-sectional design was used in this study. A total of 242 adolescents with T1D were recruited from an outpatient clinic of a medical center by convenience sampling in Taiwan. Self-reported questionnaires were used to collect personal characteristics, self-management, emotional autonomy, problem-solving ability, and parent-adolescent relationships. RESULTS: Hierarchical multiple regressions indicated that body mass index, problem-solving ability, father-adolescent relationship, and emotional autonomy were significant factors associated with self-management. The interactions of emotional autonomy with problem-solving ability and with parent-adolescents relationship were not significantly associated with self-management. The overall model explained 47.5% variance of self-management. CONCLUSIONS: High emotional autonomy was significantly associated with poor self-management. Problem-solving ability and father-adolescent relationships could not moderate, but were independently and significantly associated with self-management in adolescents with T1D. PRACTICE IMPLICATION: Healthcare providers should evaluate emotional autonomy earlier and provide more timely help to reduce any negative impact on self-management in adolescents with T1D. Improving problem-solving ability and encouraging fathers to develop optimal father-adolescents relationship might be promising strategies to enhance self-management in adolescents with T1D.

Genome-wide, integrative analysis of circular RNA dysregulation and the corresponding circular RNA-microRNA-mRNA regulatory axes in autism.

Circular RNAs (circRNAs), a class of long noncoding RNAs, are known to be enriched in mammalian neural tissues. Although a wide range of dysregulation of gene expression in autism spectrum disorder (ASD) have been reported, the role of circRNAs in ASD remains largely unknown. Here, we performed genome-wide circRNA expression profiling in postmortem brains from individuals with ASD and controls and identified 60 circRNAs and three coregulated modules that were perturbed in ASD. By integrating circRNA, microRNA, and mRNA dysregulation data derived from the same cortex samples, we identified 8170 ASD-associated circRNA-microRNA-mRNA interactions. Putative targets of the axes were enriched for ASD risk genes and genes encoding inhibitory postsynaptic density (PSD) proteins, but not for genes implicated in monogenetic forms of other brain disorders or genes encoding excitatory PSD proteins. This reflects the previous observation that ASD-derived organoids show overproduction of inhibitory neurons. We further confirmed that some ASD risk genes (NLGN1, STAG1, HSD11B1, VIP, and UBA6) were regulated by an up-regulated circRNA (circARID1A) via sponging a down-regulated microRNA (miR-204-3p) in human neuronal cells. Particularly, alteration of NLGN1 expression is known to affect the dynamic processes of memory consolidation and strengthening. To the best of our knowledge, this is the first systems-level view of circRNA regulatory networks in ASD cortex samples. We provided a rich set of ASD-associated circRNA candidates and the corresponding circRNA-microRNA-mRNA axes, particularly those involving ASD risk genes. Our findings thus support a role for circRNA dysregulation and the corresponding circRNA-microRNA-mRNA axes in ASD pathophysiology.

Chemical Stability and Transformation of Molybdenum Disulfide Nanosheets in Environmental Media.

Layered transition metal dichalcogenides, including molybdenum disulfide (MoS2), have previously been considered stable in the ambient environment due to the absence of dangling bonds in the electron-filled shells of the end chalcogen atoms. Here, we evaluate the chemical stability of MoS2 nanosheets fabricated by chemical exfoliation (ceMoS2) and surfactant dispersion (sMoS2). The results demonstrate that sMoS2 exhibits greater long-term persistence. Contrarily, ceMoS2 underwent progressive deterioration, in which preferential oxidation of the 1T of a mixture of 1T and 2H phases was observed. The oxidative degradation of ceMoS2 was retarded in the presence of natural organic matter (NOM), including Suwannee River natural organic matter (SRNOM) and Aldrich humic acid (ALHA), in the dark ambient condition, while the aging process of MoS2 with co-occurring ALHA was accelerated under sunlight exposure. The observed inhibition effect on the deterioration of ceMoS2 by NOM was mainly attributed to slower dissolution kinetics with rapid initial oxidation (i.e., forming Mo-O bonding) or carbon grafting, rather than prevention of the formation of secondary small suspended Mo-containing particles. The compiled results highlight that the environmental fate of MoS2 nanosheets will be regulated by the combined effects of exfoliating agents and environmentally relevant factors including organic macromolecules and sunlight exposure.

Transcriptomopathies of pre- and post-symptomatic frontotemporal dementia-like mice with TDP-43 depletion in forebrain neurons.

TAR DNA-binding protein (TDP-43) is a ubiquitously expressed nuclear protein, which participates in a number of cellular processes and has been identified as the major pathological factor in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Here we constructed a conditional TDP-43 mouse with depletion of TDP-43 in the mouse forebrain and find that the mice exhibit a whole spectrum of age-dependent frontotemporal dementia-like behaviour abnormalities including perturbation of social behaviour, development of dementia-like behaviour, changes of activities of daily living, and memory loss at a later stage of life. These variations are accompanied with inflammation, neurodegeneration, and abnormal synaptic plasticity of the mouse CA1 neurons. Importantly, analysis of the cortical RNA transcripts of the conditional knockout mice at the pre-/post-symptomatic stages and the corresponding wild type mice reveals age-dependent alterations in the expression levels and RNA processing patterns of a set of genes closely associated with inflammation, social behaviour, synaptic plasticity, and neuron survival. This study not only supports the scenario that loss-of-function of TDP-43 in mice may recapitulate key behaviour features of the FTLD diseases, but also provides a list of TDP-43 target genes/transcript isoforms useful for future therapeutic research.

NCLcomparator: systematically post-screening non-co-linear transcripts (circular, trans-spliced, or fusion RNAs) identified from various detectors.

BACKGROUND: Non-co-linear (NCL) transcripts consist of exonic sequences that are topologically inconsistent with the reference genome in an intragenic fashion (circular or intragenic trans-spliced RNAs) or in an intergenic fashion (fusion or intergenic trans-spliced RNAs). On the basis of RNA-seq data, numerous NCL event detectors have been developed and detected thousands of NCL events in diverse species. However, there are great discrepancies in the identification results among detectors, indicating a considerable proportion of false positives in the detected NCL events. Although several helpful guidelines for evaluating the performance of NCL event detectors have been provided, a systematic guideline for measurement of NCL events identified by existing tools has not been available. RESULTS: We develop a software, NCLcomparator, for systematically post-screening the intragenic or intergenic NCL events identified by various NCL detectors. NCLcomparator first examine whether the input NCL events are potentially false positives derived from ambiguous alignments (i.e., the NCL events have an alternative co-linear explanation or multiple matches against the reference genome). To evaluate the reliability of the identified NCL events, we define the NCL score (NCLscore) based on the variation in the number of supporting NCL junction reads identified by the tools examined. Of the input NCL events, we show that the ambiguous alignment-derived events have relatively lower NCLscore values than the other events, indicating that an NCL event with a higher NCLscore has a higher level of reliability. To help selecting highly expressed NCL events, NCLcomparator also provides a series of useful measurements such as the expression levels of the detected NCL events and their corresponding host genes and the junction usage of the co-linear splice junctions at both NCL donor and acceptor sites. CONCLUSION: NCLcomparator provides useful guidelines, with the input of identified NCL events from various detectors and the corresponding paired-end RNA-seq data only, to help users selecting potentially high-confidence NCL events for further functional investigation. The software thus helps to facilitate future studies into NCL events, shedding light on the fundamental biology of this important but understudied class of transcripts. NCLcomparator is freely accessible at https://github.com/TreesLab/NCLcomparator .