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Genetic mechanisms that repress transposable elements (TEs) in young animals decline during aging, as reflected by increased TE expression in aged animals. Does increased TE expression during aging lead to more genomic TE copies in older animals? To address this question, we quantified TE Landscapes (TLs) via whole genome sequencing of young and aged Drosophila strains of wild-type and mutant backgrounds. We quantified TLs in whole flies and dissected brains and validated the feasibility of our approach in detecting new TE insertions in aging Drosophila genomes when small RNA and RNA interference (RNAi) pathways are compromised. We also describe improved sequencing methods to quantify extra-chromosomal DNA circles (eccDNAs) in Drosophila as an additional source of TE copies that accumulate during aging. Lastly, to combat the natural progression of aging-associated TE expression, we show that knocking down PAF1 , a conserved transcription elongation factor that antagonizes RNAi pathways, may bolster suppression of TEs during aging and extend lifespan. Our study suggests that in addition to a possible influence by different genetic backgrounds, small RNA and RNAi mechanisms may mitigate genomic TL expansion despite the increase in TE transcripts during aging.

Aim Real‐world data (RWD) for paliperidone palmitate (PP) three‐monthly (PP3M) is lacking based on Japan label requirements. This study evaluated the clinical effectiveness of PP3M versus PP once‐monthly (PP1M) in patients with schizophrenia administered according to Japan label requirements. Methods Retrospective analyses were conducted using RWD from Merative™ MarketScan® Multi‐State Medicaid (MDCD) claims database (June 2015–December 2022). Adult patients with schizophrenia switching from PP1M to PP3M were included. Patients transitioning to PP3M were matched with patients who continued with PP1M using propensity score matching (PSM) at 1:1 ratio. Primary hypothesis aimed to investigate non‐inferiority of PP3M versus PP1M in terms of relapse‐free status at 24 months from index PP injection. Outcome measures were proportions of relapse‐free patients at 24 months, time to relapse, treatment persistence, and adherence. Results Total 4252 eligible adult schizophrenia patients on PP (PP3M:582; PP1M:3670) were identified. After PSM, each PP cohort comprised 562 matched individuals. Estimated proportion of relapse‐free patients was higher in PP3M (85.7%) versus PP1M (77.9%), per Japan PP label. PP3M demonstrated superiority to PP1M after testing for non‐inferiority in terms of achieving relapse‐free status at 24 months, with an estimated difference of 7.8% (95% CI: 1.7%–13.9%). PP3M cohort had lower risk of relapse (HR: 0.605; CI: 0.427–0.856), longer treatment persistence, and higher treatment adherence versus PP1M cohort. Conclusions Findings suggests that patients who switched to PP3M might be able to reduce risk of relapse compared to those who continued PP1M after aligning particularly with Japan's label requirements. Japan's label requirements for PP3M prohibit the concurrent use of antipsychotic medication during the transition to PP3M and after initiating PP3M treatment. Analysis using the Merative™ MarketScan® Multi‐State Medicaid claims database revealed that adult patients with schizophrenia who switched to PP3M had a significantly lower risk of relapse compared to those who remained on PP1M. The risk difference at 24 months was 7.8% (95% CI: 1.7–13.9), with a hazard ratio (HR) of 0.605 (95% CI: 1.7–13.9), when using analytical methods consistent with Japan's label.

Drosophila Argonaute2 (AGO2) has been shown to regulate expression of certain loci in an RNA interference (RNAi)-independent manner, but its genome-wide function on chromatin remains unknown. Here, we identified the nuclear scaffolding protein LaminB as a novel interactor of AGO2. When either AGO2 or LaminB are depleted in Kc cells, similar transcription changes are observed genome-wide. In particular, changes in expression occur mainly in active or potentially active chromatin, both inside and outside LaminB-associated domains (LADs). Furthermore, we identified a somatic target of AGO2 transcriptional repression, no hitter (nht), which is immersed in a LAD located within a repressive topologically-associated domain (TAD). Null mutation but not catalytic inactivation of AGO2 leads to ectopic expression of nht and downstream spermatogenesis genes. Depletion of either AGO2 or LaminB results in reduced looping interactions within the nht TAD as well as ectopic inter-TAD interactions, as detected by 4C-seq analysis. Overall, our findings reveal coordination of AGO2 and LaminB function to dictate genome architecture and thereby regulate gene expression.

Topoisomerases solve topological problems during DNA metabolism, but whether they participate in RNA metabolism remains unclear. Top3β represents a family of topoisomerases carrying activities for both DNA and RNA. Here we show that in Drosophila , Top3β interacts biochemically and genetically with the RNAi-induced silencing complex (RISC) containing AGO2, p68 RNA helicase, and FMRP. Top3β and RISC mutants are similarly defective in heterochromatin formation and transcriptional silencing by position-effect variegation assay. Moreover, both Top3β and AGO2 mutants exhibit reduced levels of heterochromatin protein HP1 in heterochromatin. Furthermore, expression of several genes and transposable elements in heterochromatin is increased in the Top3β mutant. Notably, Top3β mutants defective in either RNA binding or catalytic activity are deficient in promoting HP1 recruitment and silencing of transposable elements. Our data suggest that Top3β may act as an RNA topoisomerase in siRNA-guided heterochromatin formation and transcriptional silencing. Topoisomerases solve topological problems during DNA metabolism, but their role in RNA metabolism remains unclear. Here the authors provide evidence that in Drosophila , Topoisomerase 3β interacts biochemically and genetically with the RNAi-induced silencing complex (RISC) to promote heterochromatin formation and transcriptional silencing.

Aim To examine treatment persistence rates of paliperidone palmitate 3‐month (PP3M) for schizophrenia in Japan because evidence in real‐world settings is limited. Methods A retrospective population‐based cohort study was conducted using the Japan Medical Data Center claims database. The overall cohort comprised schizophrenia patients aged ≥ 18 years, who received paliperidone palmitate 1‐month (PP1M) within 180 days before initiating PP3M. Of patients in the overall cohort, those who received PP1M ≥ 4 times within 180 days at 21–42‐day intervals with the same dosage strength as the last two PP1M doses before switching to PP3M initiated PP3M with a dose equivalent to 3.5‐fold the last PP1M dose and took no other concomitant antipsychotics within 112 days before initiating PP3M were included in the per protocol cohort (PPC). The Kaplan–Meier method was used to calculate PP3M persistence rates in the overall cohort and PP3M monotherapy persistence rates in the PPC. Results In the overall cohort and PPC, 121 patients and 87 patients, with a mean age of 41.5 years and 48%–53% being employed, were followed up for ≤ 27 months. At 365 days and 730 days, the PP3M persistence rate was 76.9% and 71.7% in the overall cohort, and that for PP3M monotherapy was 73.1% and 64.6% in the PPC. Conclusion Treatment persistence rates for PP3M in Japan were relatively high among schizophrenia patients transitioned from PP1M. High persistence rates can be achieved with PP3M monotherapy in patients who have been sufficiently stabilized with PP1M monotherapy prior to initiating PP3M. In Japan, schizophrenia patients need to be stabilized with paliperidone palmitate 1‐month (PP1M) monotherapy prior to switching to paliperidone palmitate 3‐month (PP3M) treatment. However, evidence for the treatment persistence rates of PP3M in real‐world settings is limited. Our results demonstrated high persistence rates for PP3M monotherapy, indicating that such rates can be achieved in patients who have been sufficiently stabilized with PP1M monotherapy before initiating PP3M.

Spinal muscular atrophy (SMA) is an autosomal recessive genetic neuromuscular disorder with progressive muscle weakness and atrophy, mainly caused by lower motor neuron degeneration resulting from decreased levels of the survival motor neuron protein. Recently, 3 disease-modifying therapies for SMA (nusinersen, onasemnogene abeparvovec, and risdiplam) were approved in Japan that are expected to improve the prognosis of patients with SMA. Long-term clinical follow-up of adult patients treated with disease-modifying therapies and the natural history of SMA are essential to assess the real-world effectiveness of available treatments. Until recently, nusinersen was the only treatment option for patients with SMA in Japan; however, because Japanese approval of nusinersen was based on global clinical trials in infants and children aged 0-15 years with SMA, the effectiveness of nusinersen in adult patients has not been fully assessed in Japan. In addition, longitudinal clinical data of adult patients have not been systematically collected in Japan. This longitudinal observational study of adult patients with SMA who have been diagnosed with 5q-SMA in Japan aims to gain a better understanding of the natural history of SMA, as well as the long-term effectiveness of disease-modifying therapies. Here, we describe the protocol for the study. The Japan Registry for Adult Subjects of Spinal Muscular Atrophy (jREACT-SMA) study is a longitudinal (prospective and retrospective) observational study with a 60-month prospective follow-up being conducted at 19 investigational sites using the newly established jREACT-SMA registry. Patients aged ≥18 years with genetically confirmed 5q-SMA were planned to be enrolled in the registry from December 2020 to May 2022. The planned enrollment was 100 patients. The protocol was approved on September 28, 2020 (approval 2020-0289) by the ethical review committee of Nagoya University. Registration, demographics, genetic diagnosis, motor functions, patient-reported outcomes/quality-of-life outcomes, and other clinical data have been or will be collected. As of May 2022, 113 patients had been enrolled, and the completion of patient registration has been extended from May 2022 to December 2022. Data at registration and during the follow-up period were and will be prospectively collected at least once a year until November 2025 (maximum 60 months). Data analyses will be conducted when all data have been collected. Results are expected to be available in 2026 and the study is expected to be completed by March 2027. This jREACT-SMA study will provide longitudinal prospective follow-up data in adult patients with SMA in Japan, including data on the natural history of the disease and data on the long-term effectiveness of disease-modifying therapies. University Hospital Medical Information Network Center Clinical Trials Registry UMIN000042015; https://rctportal.niph.go.jp/en/detail?trial_id=UMIN000042015. DERR1-10.2196/38878.

In fission yeast, the formation of centromeric heterochromatin is induced through the RNA interference (RNAi)-mediated pathway. Some pre-mRNA splicing mutants (prp) exhibit defective formation of centromeric heterochromatin, suggesting that splicing factors play roles in the formation of heterochromatin, or alternatively that the defect is caused by impaired splicing of pre-mRNAs encoding RNAi factors. Herein, we demonstrate that the splicing factor spPrp16p is enriched at the centromere, and associates with Cid12p (a factor in the RNAi pathway) and the intron-containing dg ncRNA. Interestingly, removal of the dg intron, mutations of its splice sites, or replacement of the dg intron with an euchromatic intron significantly decreased H3K9 dimethylation. We also revealed that splicing of dg ncRNA is repressed in cells and its repression depends on the distance from the transcription start site to the intron. Inefficient splicing was also observed in other intron-containing centromeric ncRNAs, dh and antisense dg, and splicing of antisense dg ncRNA was repressed in the presence of the RNAi factors. Our results suggest that the introns retained in centromeric ncRNAs work as facilitators, co-operating with splicing factors assembled on the intron and serving as a platform for the recruitment of RNAi factors, in the formation of centromeric heterochromatin.

Genetic mechanisms that repress transposable elements (TEs) in young animals decline during aging, as reflected by increased TE expression in aged animals. Does increased TE expression during aging lead to more genomic TE copies in older animals? To address this question, we quantified TE Landscapes (TLs) via whole genome sequencing of young and aged Drosophila strains of wild-type and mutant backgrounds. We quantified TLs in whole flies and dissected brains and validated the feasibility of our approach in detecting new TE insertions in aging Drosophila genomes when small RNA and RNA interference (RNAi) pathways are compromised. We also describe improved sequencing methods to quantify extra-chromosomal DNA circles (eccDNAs) in Drosophila as an additional source of TE copies that accumulate during aging. Lastly, to combat the natural progression of aging-associated TE expression, we show that knocking down PAF1, a conserved transcription elongation factor that antagonizes RNAi pathways, may bolster suppression of TEs during aging and extend lifespan. Our study suggests that in addition to a possible influence by different genetic backgrounds, small RNA and RNAi mechanisms may mitigate genomic TL expansion despite the increase in TE transcripts during aging. Author summary Transposable elements, also called transposons, are genetic parasites found in all animal genomes. Normally, transposons are compacted away in silent chromatin in young animals. But, as animals age and transposon-silencing defense mechanisms break down, transposon RNAs accumulate to significant levels in old animals like fruit flies. An open question is whether the increased levels of transposon RNAs in older animals also correspond to increased genomic copies of transposons. This study approached this question by sequencing the whole genomes of young and old wild-type and mutant flies lacking a functional RNA interference (RNAi) pathway, which naturally silences transposon RNAs. Although the wild-type flies with intact RNAi activity had little new accumulation of transposon copies, the sequencing approach was able to detect several transposon accumulation occurrences in some RNAi mutants. In addition, we found that some fly transposon families can also accumulate as extra-chromosomal circular DNA copies. Lastly, we showed that genetically augmenting the expression of RNAi factors can counteract the rising transposon RNA levels in aging and promote longevity. This study improves our understanding of the animal host genome relationship with transposons during natural aging processes.

ABSTRACT Genetic mechanisms that repress transposable elements (TEs) in young animals decline during aging, as reflected by increased TE expression in aged animals. Does increased TE expression during aging lead to more genomic TE copies in older animals? To answer this question, we quantified TE Landscapes (TLs) via whole genome sequencing of young and aged Drosophila strains of wild-type and mutant backgrounds. We quantified TLs in whole flies and dissected brains and validated the feasibility of our approach in detecting new TE insertions in aging Drosophila genomes when natural defenses like RNA interference (RNAi) pathways are compromised. By also incorporating droplet digital PCR to validate genomic TE loads, we confirm TL changes can occur in a single lifespan of Drosophila when TEs are not suppressed. We also describe improved sequencing methods to quantify extra-chromosomal DNA circles (eccDNAs) in Drosophila as an additional source of TE copies that accumulate during aging. Lastly, to combat the natural progression of aging-associated TE expression, we show that knocking down PAF1, a conserved transcription elongation factor that antagonizes RNAi pathways, may bolster suppression of TEs during aging and extend lifespan. Our study suggests that RNAi mechanisms generally mitigate genomic TL expansion despite the increase in TE transcripts during aging.