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Aging is characterized by the accumulation of amyloid and prion-like proteins. However, the molecular mechanisms by which these proteins arise remain unclear. Here, we demonstrate that transcript errors generate amyloid and prion-like proteins in a wide variety of human cell types, including stem cells, brain organoids, and fully differentiated neurons. Intriguingly, some of these proteins are identical to proteins previously implicated in familial cases of amyloid diseases, raising the possibility that both familial and non-familial cases are caused by identical mutant proteins. However, transcript errors also generate amyloid proteins that have not been observed before, suggesting that aging cells are exposed to a second class of pathogenic proteins we are currently unaware of. Finally, we show that transcript errors are readily generated by DNA damage, a hallmark of human aging and a staple of multiple proteotoxic diseases, including Alzheimer’s disease. Together, these observations greatly expand our understanding of mutagenesis in human aging and disease and suggest a new mechanism by which amyloid diseases can develop.

To determine the error rate of transcription in human cells, we analyzed the transcriptome of H1 human embryonic stem cells with a circle-sequencing approach that allows for high-fidelity sequencing of the transcriptome. These experiments identified approximately 100,000 errors distributed over every major RNA species in human cells. Our results indicate that different RNA species display different error rates, suggesting that human cells prioritize the fidelity of some RNAs over others. Cross-referencing the errors that we detected with various genetic and epigenetic features of the human genome revealed that the in vivo error rate in human cells changes along the length of a transcript and is further modified by genetic context, repetitive elements, epigenetic markers, and the speed of transcription. Our experiments further suggest that BRCA1, a DNA repair protein implicated in breast cancer, has a previously unknown role in the suppression of transcription errors. Finally, we analyzed the distribution of transcription errors in multiple tissues of a new mouse model and found that they occur preferentially in neurons, compared to other cell types. These observations lend additional weight to the idea that transcription errors play a key role in the progression of various neurological disorders, including Alzheimer’s disease.

Building back coral reefs requires limiting greenhouse gas emissions, limiting local threats, and active restoration. Vessel noise pollution is a widespread threat acting at a local level impacting a broad range of species from cetaceans to cephalopods. Ultimate consequences of noise pollution include death due to injury or predation, failure to develop and reduced offspring quality and survival. We tested the hypothesis that protecting coral reefs from motorboat noise can improve reproductive output in fish on the Great Barrier Reef in Australia. Across an entire breeding season, we limited motorboat traffic at three separate reefs with breeding spiny chromis. We compared these protected nests with nests on three further reefs where motorboats drove regularly nearby. We replicated the breeding experiment in a laboratory setting to isolate noise as the stimulus. Protecting coral reefs from traffic noise was beneficial for breeding fish and their offspring: egg fanning and offpsring growth were enhanced with lower energetic resource use, and reproductive success was enhanced. Limiting traffic noise at the local level presents a valuable opportunity for enhancing resilience in coral reefs by improving reproductive success in fish. This could speed up recovery following climate related mass mortality events caused by bleaching and cyclones.

Frankia sp. strains CgS1, CcI156 and CgMI4 were isolated from Casuarina glauca and C. cunninghamiana nodules. Here, we report the 5.26-, 5.33- and 5.20-Mbp draft genome sequences of Frankia sp. strains CgS1, CcI156 and CgMI4, respectively. Analysis of the genome revealed the presence of high numbers of secondary metabolic biosynthetic gene clusters.

Frankia sp. strain B2 was isolated from Casuarina cunninghamiana nodules. Here, we report the 5.3-Mbp draft genome sequence of Frankia sp. strain B2 with a G+C content of 70.1 % and 4,663 candidate protein-encoding genes. Analysis of the genome revealed the presence of high numbers of secondary metabolic biosynthetic gene clusters.

Accurate transcription is required for the faithful expression of genetic information. Surprisingly though, little is known about the molecular mechanisms that control the fidelity of transcription, or the conservation of these mechanisms across the tree of life. To address this issue, we measured the error rate of transcription in five organisms of increasing complexity and identified various genes, alleles and processes that control transcriptional fidelity in multicellular organisms. In doing so, they highlight the evolutionary conservation of fidelity factors and open up new opportunities to probe the impact of transcription errors on intact organisms and human physiology. Finally, our experiments provide the first reasonable estimate of the error rate of transcription in human cells, identify the first disease associated with error-prone RNA polymerases and suggest that transcription errors may have contributed to the evolution of our genetic code.

International audience; Psoriasis has long been associated with inflammatory bowel disease (IBD); however, a causal link is yet to be established. Here, we demonstrate that imiquimod-induced psoriasis (IMQ-pso) in mice disrupts gut homeostasis, characterized by increased proportions of colonic CX3CR1hi macrophages, altered cytokine production, and bacterial dysbiosis. Gut microbiota from these mice produce higher levels of succinate, which induce de novo proliferation of CX3CR1hi macrophages ex vivo, while disrupted gut homeostasis primes IMQ-pso mice for more severe colitis with dextran sulfate sodium (DSS) challenge. These results demonstrate that changes in the gut environment in psoriasis lead to greater susceptibility to IBD in mice, suggesting a two-hit requirement, that is, psoriasis-induced altered gut homeostasis and a secondary environmental challenge. This may explain the increased prevalence of IBD in patients with psoriasis.

Mutation and recombination are the primary sources of genetic variation. To better understand the evolution of genetic variation, it is crucial to comprehensively investigate the processes involving mutation accumulation and recombination. In this study, we performed mutation accumulation experiments on four heterozygous diploid yeast species in the Saccharomycodaceae family to determine spontaneous mutation rates, mutation spectra, and losses of heterozygosity (LOH). We observed substantial variation in mutation rates and mutation spectra. We also observed high LOH rates (1.65–11.07×10−6 events per heterozygous site per cell division). Biases in spontaneous mutation and LOH together with selection ultimately shape the variable genome-wide nucleotide landscape in yeast species.

Frankia sp. strain BMG5.11, which was isolated from Elaeagnus angustifolia nodules, is able to infect other actinorhizal plants, including Elaeagnaceae, Rhamnaceae, Colletieae, Gymnostoma, and Myricaceae. Here, we report the 11.3-Mbp draft genome sequence of Frankia sp. strain BMG5.11, with a G+C content of 69.9% and 9,926 candidate protein-encoding genes.

Multimode fibres show great potential for use as miniature endoscopes for imaging deep in tissue with minimal damage. When used for coherent anti-Stokes Raman scattering (CARS) microscopy with femtosecond excitation sources, a high band-width probe is required to efficiently focus the broadband laser pulses at the sample plane. Although graded-index (GRIN) fibres have a large bandwidth, it is accompanied by a strong background signal from four-wave mixing and other non-linear processes occurring inside the fibre. We demonstrate that using a composite probe consisting of a GRIN fibre with a spliced on step-index fibre reduces the intensity of the non-linear background by more than one order of magnitude without significantly decreasing the focusing performance of the probe. Using this composite probe we acquire CARS images of biologically relevant tissue such as myelinated axons in the brain with good contrast.

Frankia sp. strain BMG5.30 was isolated from root nodules of a Coriaria myrtifolia seedling on soil collected in Tunisia and represents the second cluster 2 isolate. Frankia sp. strain BMG5.30 was able to re-infect C. myrtifolia generating root nodules. Here, we report its 5.8-Mbp draft genome sequence with a G + C content of 70.03% and 4509 candidate protein-encoding genes.

Background A discrete choice experiment (DCE) is a method used to elicit participants’ preferences and the relative importance of different attributes and levels within a decision-making process. DCEs have become popular in healthcare; however, approaches to identify the attributes/levels influencing a decision of interest and to selection methods for their inclusion in a DCE are under-reported. Our objectives were: to explore the development process used to select/present attributes/levels from the identified range that may be influential; to describe a systematic and rigorous development process for design of a DCE in the context of thrombolytic therapy for acute stroke; and, to discuss the advantages of our five-stage approach to enhance current guidance for developing DCEs. Methods A five-stage DCE development process was undertaken. Methods employed included literature review, qualitative analysis of interview and ethnographic data, expert panel discussions, a quantitative structured prioritisation (ranking) exercise and pilot testing of the DCE using a ‘think aloud’ approach. Results The five-stage process reported helped to reduce the list of 22 initial patient-related factors to a final set of nine variable factors and six fixed factors for inclusion in a testable DCE using a vignette model of presentation. Conclusions In order for the data and conclusions generated by DCEs to be deemed valid, it is crucial that the methods of design and development are documented and reported. This paper has detailed a rigorous and systematic approach to DCE development which may be useful to researchers seeking to establish methods for reducing and prioritising attributes for inclusion in future DCEs. Electronic supplementary material The online version of this article (10.1186/s12913-018-3305-5) contains supplementary material, which is available to authorized users.

Frankia sp. strain KB5 was isolated from Casuarina equisetifolia and previous studies have shown both nitrogenase and uptake hydrogenase activities under free-living conditions. Here, we report 5.5-Mbp draft genome sequence with a G+C content of 70.03 %, 4,958 candidate protein-encoding genes, and 2 rRNA operons.

Frankia sp. strain CcI49 was isolated from Casuarina cunninghamiana nodules. However the strain was unable to re-infect Casuarina, but was able to infect other actinorhizal plants including Elaeagnaceae. Here, we report the 9.8-Mbp draft genome sequence of Frankia sp. strain CcI49 with a G+C content of 70.5 % and 7,441 candidate protein-encoding genes. Analysis of the genome revealed the presence of a bph operon involved in the degradation of biphenyls and polychlorinated biphenyls.

The horseshoe crab,Limulus polyphemus, exhibits robust circadian and circatidal rhythms, but little is known about the molecular mechanisms underlying those rhythms. In this study, horseshoe crabs were collected during the day and night as well as high and low tides, and their muscle and central nervous system tissues were processed for genome and transcriptome sequencing, respectively. The genome assembly resulted in7.4×105contigs with N50 of 4,736, while the transcriptome assembly resulted in9.3×104contigs and N50 of 3,497. Analysis of functional completeness by the identification of putative universal orthologs suggests that the transcriptome has three times more total expected orthologs than the genome. Interestingly, RNA-Seq analysis indicated no statistically significant changes in expression level for any circadian core or accessory gene, but there was significant cycling of several noncircadian transcripts. Overall, these assemblies provide a resource to investigate theLimulusclock systems and provide a large dataset for further exploration into the taxonomy and biology of the Atlantic horseshoe crab.

Massively parallel sequencing technologies have made it possible to generate large quantities of sequence data. However, as research-associated information is transferred into clinical practice, cost and throughput constraints generally require sequence-specific targeted analyses. Therefore, sample enrichment methods have been developed to meet the needs of clinical sequencing applications. However, current amplification and hybrid capture enrichment methods are limited in the contiguous length of sequences for which they are able to enrich. PCR based amplification also loses methylation data and other native DNA features. We have developed a novel technology (Negative Enrichment) where we demonstrate targeting long (>10 kb) genomic regions of interest. We use the specificity of CRISPR-Cas9 single guide RNA (Cas9/sgRNA) complexes to define 5′ and 3′ termini of sequence-specific loci in genomic DNA, targeting 10 to 36 kb regions. The complexes were found to provide protection from exonucleases, by protecting the targeted sequences from degradation, resulting in enriched, double-strand, non-amplified target sequences suitable for next-generation sequencing library preparation or other downstream analyses.

Background Ribosomal RNA (rRNA) comprises at least 90% of total RNA extracted from mammalian tissue or cell line samples. Informative transcriptional profiling using massively parallel sequencing technologies requires either enrichment of mature poly-adenylated transcripts or targeted depletion of the rRNA fraction. The latter method is of particular interest because it is compatible with degraded samples such as those extracted from FFPE and also captures transcripts that are not poly-adenylated such as some non-coding RNAs. Here we provide a cross-site study that evaluates the performance of ribosomal RNA removal kits from Illumina, Takara/Clontech, Kapa Biosystems, Lexogen, New England Biolabs and Qiagen on intact and degraded RNA samples. Results We find that all of the kits are capable of performing significant ribosomal depletion, though there are differences in their ease of use. All kits were able to remove ribosomal RNA to below 20% with intact RNA and identify ~ 14,000 protein coding genes from the Universal Human Reference RNA sample at >1FPKM. Analysis of differentially detected genes between kits suggests that transcript length may be a key factor in library production efficiency. Conclusions These results provide a roadmap for labs on the strengths of each of these methods and how best to utilize them. Keywords: RNAseqr; RNA depletion; Illumina; NGS; ABRF; Transcriptomics, National Cancer Institute (U.S.) (Grant P30-CA14051), National Institute of Environmental Health Sciences (Grant P30-ES002109)

The genus Mesorhizobium contains many species that are able to form nitrogen-fixing nodules on plants of the legume family. Here, we report the draft genome sequences for three Mesorhizobium strains. The genome sizes of strains LCM 4576, LCM 4577, and ORS3428 were 7.24, 7.02, and 6.55 Mbp, respectively.

The genus Mesorhizobium contains many species that are able to form nitrogen-fixing nodules on plants of the legume family. Here, we report the draft genome sequences for three Mesorhizobium strains. The genome sizes of strains LCM 4576, LCM 4577, and ORS3428 were 7.24, 7.02, and 6.55 Mbp, respectively.

Photorhabdus temperata strain Hm is an entomopathogenic bacterium that forms a symbiotic association with Heterorhabditis nematodes. Here, we report a 5.0-Mbp draft genome sequence for P. temperata strain Hm with a G+C content of 44.1% and containing 4,226 candidate protein-encoding genes.

Frankia sp. strain CcI49 was isolated from Casuarina cunninghamiana nodules. However the strain was unable to re-infect Casuarina, but was able to infect other actinorhizal plants including Elaeagnaceae. Here, we report the 9.8-Mbp draft genome sequence of Frankia sp. strain CcI49 with a G+C content of 70.5 % and 7,441 candidate protein-encoding genes. Analysis of the genome revealed the presence of a bph operon involved in the degradation of biphenyls and polychlorinated biphenyls.

Frankia sp. strain Cc1.17 is a member of the Frankia lineage 3, the organisms of which are able to reinfect plants of the Eleagnaceae, Rhamnaceae, and Myricaceae families and the genera Gynmnostoma and Alnus . Here, we report the 8.4-Mbp draft genome sequence, with a G+C content of 72.14% and 6,721 candidate protein-coding genes.

The genus Rhizobium contains many species that are able to form nitrogen-fixing nodules on plants of the legume family. Here, we report the 5.5-Mb draft genome sequence of the salt-tolerant Rhizobium sp. strain LCM 4573, which has a G+C content of 61.2% and 5,356 candidate protein-encoding genes.

The genus Rhizobium contains many species that are able to form nitrogen-fixing nodules on plants of the legume family. Here, we report the 5.5-Mb draft genome sequence of the salt-tolerant Rhizobium sp. strain LCM 4573, which has a G+C content of 61.2% and 5,356 candidate protein-encoding genes.

Here, we present draft genome sequences for three atypical Frankia strains (lineage 4) that were isolated from root nodules but are unable to reinfect actinorhizal plants. The genome sizes of Frankia sp. strains EUN1h, BMG5.36, and NRRL B16386 were 9.91, 11.20, and 9.43 Mbp, respectively.

The genus Rhizobium contains many species able to form nitrogen-fixing nodules on plants of the legume family. Here, we report the 6.9-Mbp draft genome sequence of Rhizobium sp. strain RSm-3, with a G+C content of 61.4% and 6,511 candidate protein-coding genes.

Here, we present draft genome sequences for three atypical Frankia strains (lineage 4) that were isolated from root nodules but are unable to reinfect actinorhizal plants. The genome sizes of Frankia sp. strains EUN1h, BMG5.36, and NRRL B16386 were 9.91, 11.20, and 9.43 Mbp, respectively.

The genus Rhizobium contains many species able to form nitrogen-fixing nodules on plants of the legume family. Here, we report the 6.9-Mbp draft genome sequence of Rhizobium sp. strain RSm-3, with a G+C content of 61.4% and 6,511 candidate protein-coding genes.

Frankia sp. strain BR is a member of Frankia lineage Ic and is able to reinfect plants of the Casuarinaceae family. Here, we report a 5.2-Mbp draft genome sequence with a G+C content of 70.0% and 4,777 candidate protein-encoding genes.

Frankia sp. strain EI5c is a member of Frankia lineage III, which is able to reinfect plants of the Eleagnaceae , Rhamnaceae , Myricaceae , and Gymnostoma , as well as the genus Alnus . Here, we report the 6.6-Mbp draft genome sequence of Frankia sp. strain EI5c with a G+C content of 72.14 % and 5,458 candidate protein-encoding genes.

Frankia strain CeD is a member of Frankia lineage Ib that is able to reinfect plants of the Casuarina families. Here, we report a 5.0-Mbp draft genome sequence with a G+C content of 70.1% and 3,847 candidate protein-encoding genes.

Photorhabdus luminescens subsp. laumondii HP88 is an entomopathogenic bacterium that forms a symbiotic association with Heterorhabditis nematodes. We report here a 5.27-Mbp draft genome sequence for P. luminescens subsp. laumondii HP88, with a G+C content of 42.4% and containing 4,243 candidate protein-coding genes.

Frankia stains CpI1-S and CpI1-P are members of Frankia lineage Ia that are able to reinfect plants of the Betulaceae and Myricaceae families. Here, we report two 7.6-Mbp draft genome sequences with 6,396 and 6,373 candidate protein-coding genes for CpI1-S and CpI1-P, respectively.

Background Cognitive stimulation therapy (CST) is a well-established group psychosocial intervention for people with dementia. There is evidence that home-based programmes of cognitive stimulation delivered by family caregivers may benefit both the person and the caregiver. However, no previous studies have evaluated caregiver-delivered CST. This study aimed to evaluate the effectiveness of a home-based, caregiver-led individual cognitive stimulation therapy (iCST) program in (i) improving cognition and quality of life (QoL) for the person with dementia and (ii) mental and physical health (well-being) for the caregiver. Methods and findings A single-blind, pragmatic randomised controlled trial (RCT) was conducted at eight study sites across the United Kingdom. The intervention and blinded assessment of outcomes were conducted in participants’ homes. Three hundred fifty-six people with mild to moderate dementia and their caregivers were recruited from memory services and community mental health teams (CMHTs). Participants were randomly assigned to iCST (75, 30-min sessions) or treatment as usual (TAU) control over 25 wk. iCST sessions consisted of themed activities designed to be mentally stimulating and enjoyable. Caregivers delivering iCST received training and support from an unblind researcher. Primary outcomes were cognition (Alzheimer’s Disease Assessment Scale–cognitive [ADAS-Cog]) and self-reported QoL (Quality of Life Alzheimer’s Disease [QoL-AD]) for the person with dementia and general health status (Short Form-12 health survey [SF-12]) for the caregiver. Secondary outcomes included quality of the caregiving relationship from the perspectives of the person and of the caregiver (Quality of the Carer Patient Relationship Scale) and health-related QoL (European Quality of Life–5 Dimensions [EQ-5D]) for the caregiver. Intention to treat (ITT) analyses were conducted. At the post-test (26 wk), there were no differences between the iCST and TAU groups in the outcomes of cognition (mean difference [MD] = −0.55, 95% CI −2.00–0.90; p = 0.45) and self-reported QoL (MD = −0.02, 95% CI −1.22–0.82; p = 0.97) for people with dementia, or caregivers’ general health status (MD = 0.13, 95% CI −1.65–1.91; p = 0.89). However, people with dementia receiving iCST rated the relationship with their caregiver more positively (MD = 1.77, 95% CI 0.26–3.28; p = 0.02), and iCST improved QoL for caregivers (EQ-5D, MD = 0.06, 95% CI 0.02–0.10; p = 0.01). Forty percent (72/180) of dyads allocated to iCST completed at least two sessions per week, with 22% (39/180) completing no sessions at all. Study limitations include low adherence to the intervention. Conclusions There was no evidence that iCST has an effect on cognition or QoL for people with dementia. However, participating in iCST appeared to enhance the quality of the caregiving relationship and caregivers’ QoL. Trial registration The iCST trial is registered with the ISRCTN registry (identified ISRCTN 65945963, URL: DOI 10.1186/ISRCTN65945963)., In a randomized controlled trial, Martin Orrell and colleagues investigate the impact of individual cognitive stimulation therapy (iCST) on cognition, quality of life, caregiver health, and family relationships for people with dementia., Author summary Why was this study done? Cognitive stimulation therapy (CST) is a structured group activity programme for people with dementia that has been shown to improve quality of life (QOL) and cognition. This therapy is recommended by organisations such as the Alzheimer’s Disease International (ADI) and the UK National Institute for Health and Care Excellence. Although CST is becoming more widely available both in the UK and internationally, some people may not have access to groups because groups are not available near their home, they are not able to get to centres offering groups because of transport, health, or mobility problems, or they would prefer not to do group activities. This study aimed to look at the potential use and benefits of an adapted version of CST called individual CST (iCST) delivered by a family carer or friend at the person with dementia’s home for 30 min ideally two or three times a week. What did the researchers do and find? The research team produced the iCST programme (including a manual, activity workbook, and materials such as maps and dominoes) in collaboration with people with dementia, carers, health care professionals, and experts. In a randomised controlled trial (RCT), 356 pairs of people with dementia and carers were split between two groups; 180 pairs received iCST, and 176 pairs continued with activities, treatments, and services offered as part of usual care but did not receive iCST, to test whether iCST benefits cognition and QOL for people with dementia and mental and physical health for carers. The study found that people with dementia receiving iCST did not benefit in terms of cognition or QOL, and neither was there evidence to suggest iCST improved carers’ mental or physical health. However, people with dementia in the iCST group reported better relationship quality with their family carer at 26 wk, and carers delivering iCST had better QOL at 26 wk. What do these findings mean? We did not find that iCST improves cognition or QOL for people with dementia. Given that iCST appears to have a positive effect on the caregiving relationship and carer well-being, the programme might be a useful part of personally tailored home care packages.