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Adult neurogenic decline, inflammation, and neurodegeneration are phenotypic hallmarks of Alzheimer’s disease (AD). Mobilization of transposable elements (TEs) in heterochromatic regions was recently reported in AD, but the underlying mechanisms are still underappreciated. Combining functional genomics with the differentiation of familial and sporadic AD patient derived-iPSCs into hippocampal progenitors, CA3 neurons, and cerebral organoids, we found that the upregulation of the AP-1 subunit, c-Jun, triggers decondensation of genomic regions containing TEs. This leads to the cytoplasmic accumulation of HERVK-derived RNA-DNA hybrids, the activation of the cGAS-STING cascade, and increased levels of cleaved caspase-3, suggesting the initiation of programmed cell death in AD progenitors and neurons. Notably, inhibiting c-Jun effectively blocks all these downstream molecular processes and rescues neuronal death and the impaired neurogenesis phenotype in AD progenitors. Our findings open new avenues for identifying therapeutic strategies and biomarkers to counteract disease progression and diagnose AD in the early, pre-symptomatic stages. It has recently been reported a link between Alzheimer’s disease and mobilization of transposable elements (TEs) in heterochromatic regions. Here the authors demonstrate that dysregulation of the pioneer transcription factor c-JUN (AP-1) underlies aberrant transposable element mobilization, associated innate immune 2 response, and impaired neurogenesis in Alzheimer’s disease.

While motor and cortical neurons are affected in C9orf72 amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD), it remains largely unknown if and how non-neuronal cells induce or exacerbate neuronal damage. We differentiated C9orf72 ALS/FTD patient-derived induced pluripotent stem cells into microglia (iPSC-MG) and examined their intrinsic phenotypes. Similar to iPSC motor neurons, C9orf72 ALS/FTD iPSC-MG mono-cultures form G 4 C 2 repeat RNA foci, exhibit reduced C9orf72 protein levels, and generate dipeptide repeat proteins. Healthy control and C9orf72 ALS/FTD iPSC-MG equally express microglial specific genes and perform microglial functions, including inflammatory cytokine release and phagocytosis of extracellular cargos, such as synthetic amyloid beta peptides and healthy human brain synaptoneurosomes. RNA sequencing analysis revealed select transcriptional changes of genes associated with neuroinflammation or neurodegeneration in diseased microglia yet no significant differentially expressed microglial-enriched genes. Moderate molecular and functional differences were observed in C9orf72 iPSC-MG mono-cultures despite the presence of C9orf72 pathological features suggesting that a diseased microenvironment may be required to induce phenotypic changes in microglial cells and the associated neuronal dysfunction seen in C9orf72 ALS/FTD neurodegeneration.

The C9ORF72 -linked diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are characterized by the nuclear depletion and cytoplasmic accumulation of TAR DNA-binding protein 43 (TDP-43). Recent studies have shown that the loss of TDP-43 function leads to the inclusion of cryptic exons (CE) in several RNA transcript targets of TDP-43. Here, we show for the first time the detection of CEs in a single-nuclei RNA sequencing (snRNA-seq) dataset obtained from frontal and occipital cortices of C9ORF72 patients that phenotypically span the ALS-FTD disease spectrum. We assessed each cellular cluster for detection of recently described TDP-43-induced CEs. Transcripts containing CEs in the genes STMN2 and KALRN were detected in the frontal cortex of all C9ORF72 disease groups with the highest frequency in excitatory neurons in the C9ORF72 -FTD group. Within the excitatory neurons, the cluster with the highest proportion of cells containing a CE had transcriptomic similarities to von Economo neurons, which are known to be vulnerable to TDP-43 pathology and selectively lost in C9ORF72 -FTD. Differential gene expression and pathway analysis of CE-containing neurons revealed multiple dysregulated metabolic processes. Our findings reveal novel insights into the transcriptomic changes of neurons vulnerable to TDP-43 pathology.

Adult neurogenic decline, inflammation, and neurodegeneration are phenotypic hallmarks of Alzheimer's disease (AD). Mobilization of transposable elements (TEs) in heterochromatic regions was recently reported in AD, but the underlying mechanisms are still underappreciated. Combining functional genomics with differentiation of familial and sporadic AD patient derived-iPSCs into hippocampal progenitors, CA3 neurons, and cerebral organoids, we found that upregulation of the AP-1 subunit c-JUN triggers decondensation of genomic regions containing TEs. This leads to cytoplasmic accumulation of TE-derived RNA-DNA hybrids, activation of the cGAS-STING cascade, and increased cleaved caspase-3 levels, suggesting initiation of programmed cell death in progenitor cells and neurons. Notably, inhibiting c-JUN effectively blocks all the downstream molecular processes and rescues neuronal death and impaired neurogenesis in the AD progenitors. Our findings open new avenues for identifying therapeutic strategies and biomarkers to counteract disease progression and diagnose AD in the early, pre-symptomatic stages.Competing Interest StatementThe authors have declared no competing interest.

Adult neurogenic decline, inflammation, and neurodegeneration are phenotypic hallmarks of Alzheimer’s disease (AD). Mobilization of transposable elements (TEs) in heterochromatic regions was recently reported in AD, but the underlying mechanisms are still underappreciated. Combining functional genomics with differentiation of familial and sporadic AD patient derived-iPSCs into hippocampal progenitors, CA3 neurons, and cerebral organoids, we found that upregulation of the AP-1 subunit c-JUN triggers decondensation of genomic regions containing TEs. This leads to cytoplasmic accumulation of TE-derived RNA-DNA hybrids, activation of the cGAS-STING cascade, and increased cleaved caspase-3 levels, suggesting initiation of programmed cell death in progenitor cells and neurons. Notably, inhibiting c-JUN effectively blocks all the downstream molecular processes and rescues neuronal death and impaired neurogenesis in the AD progenitors. Our findings open new avenues for identifying therapeutic strategies and biomarkers to counteract disease progression and diagnose AD in the early, pre-symptomatic stages.

While motor and cortical neurons are affected in C9orf72 ALS/FTD, it remains still largely unknown if and how non-neuronal cells induce or exacerbate neuronal damage. We generated C9orf72 ALS/FTD patient-derived induced pluripotent stem cells differentiated into microglia (iPSC-MG) and examined their intrinsic phenotypes. Similar to iPSC motor neurons, C9orf72 ALS/FTD iPSC-MG mono-cultures form G4C2 repeat RNA foci, exhibit reduced C9orf72 protein levels and generate dipeptide repeat proteins. Healthy control and C9orf72 iPSC-MG equivalently express microglial specific genes and display microglial functions including inflammatory cytokine release and phagocytosis of extracellular toxic cargos such as synthetic amyloid beta peptides and healthy human brain synaptoneurosomes. Select C9orf72 iPSC-MG patient lines show inability to efficiently remove phagocytosed contents, suggesting dysfunction of the endosomal-lysosomal pathways. Finally, RNA sequencing revealed overall transcriptional changes in diseased microglia yet no significant differentially expressed microglial-enriched genes. These minimal differences in cellular, molecular and functional characteristics of microglial mono-cultures suggest that a diseased microenvironment is associated with microglial activation and subsequent regulation of neuronal dysfunction.

PurposeThis study was aimed to determine whether structured written and verbal education provided to patients by community pharmacists about high blood pressure (BP) and its treatment would be (a) better retained and (b) be associated with improved BP control as compared to patients receiving verbal advice only.MethodsThe study was designed as a randomised controlled trial and was conducted in the West Midlands, UK, between January 2014 and June 2014. The primary outcome measures were differences in systolic and diastolic BP from baseline and retention of information about high BP assessed with a questionnaire at 2-, 4- and 26-week follow-up points.ResultsA total of 64 adults were included in the study. At the week 26 follow-up, compared to participants in the control group, there was a significant improvement in the knowledge of intervention participants about the risks associated with high BP (p < 0.001) and awareness about potential adverse effects of the new BP medicine (p < 0.001). Similarly, there was a greater and more significant reduction in systolic BP in favour of the intervention group 8 mmHg (95% CI 2.1–13.3 p = 0.009) compared to 6 mmHg (95% CI 0.6–11.7 p = 0.02) in the control group at the week 4 follow-up. However, this greater effect of an intervention on BP was not sustained at the 26-week follow-up. For diastolic BP, there was no added effect of the intervention.ConclusionThis randomised controlled trial suggests that although written advice provided by community pharmacists in comparison to verbal advice was more effective in improving knowledge and understanding of patients about hypertension and its treatment, it did not lead to better blood pressure control.

Background Plant cell walls are interwoven structures recalcitrant to degradation. Native and adapted microbiomes can be particularly effective at plant cell wall deconstruction. Although most understanding of biological cell wall deconstruction has been obtained from isolates, cultivated microbiomes that break down cell walls have emerged as new sources for biotechnologically relevant microbes and enzymes. These microbiomes provide a unique resource to identify key interacting functional microbial groups and to guide the design of specialized synthetic microbial communities. Results To establish a system assessing comparative microbiome performance, parallel microbiomes were cultivated on sorghum ( Sorghum bicolor L. Moench) from compost inocula. Biomass loss and biochemical assays indicated that these microbiomes diverged in their ability to deconstruct biomass. Network reconstructions from gene expression dynamics identified key groups and potential interactions within the adapted sorghum-degrading communities, including Actinotalea , Filomicrobium , and Gemmatimonadetes populations. Functional analysis demonstrated that the microbiomes proceeded through successive stages that are linked to enzymes that deconstruct plant cell wall polymers. The combination of network and functional analysis highlighted the importance of cellulose-degrading Actinobacteria in differentiating the performance of these microbiomes. Conclusions The two-tier cultivation of compost-derived microbiomes on sorghum led to the establishment of microbiomes for which community structure and performance could be assessed. The work reinforces the observation that subtle differences in community composition and the genomic content of strains may lead to significant differences in community performance. 3Ck-Q-KzsX1uPWsLmUjZUv Video Abstract

Engineered polyketide synthases (PKSs) have great potential as biocatalysts. These unnatural enzymes are capable of synthesizing molecules that are either not amenable to biosynthesis or are extremely challenging to access chemically. PKSs can thus be a powerful platform to expand the chemical landscape beyond the limits of conventional metabolic engineering. Here we employ a retrobiosynthesis approach to design and construct PKSs to produce δ-valerolactam (VL) and three enantiopure α-substituted VL analogues that have no known biosynthetic route. We introduce the engineered PKSs and pathways for various malonyl-CoA derivatives into Pseudomonas putida and use proteomics, metabolomics and culture condition optimization to improve the production of our target compounds. These α-substituted VLs are polymerized into polyamides (nylon-5) or converted into their N -acryloyl derivatives. RAFT polymerization produces bio-derived polymers with potential biomedical applications. Overall, this interdisciplinary effort highlights the versatility and effectiveness of a PKS-based retrobiosynthesis approach in exploring and developing innovative biomaterials. Engineered polyketide synthases (PKSs) have great potential as biocatalysts for the synthesis of chemically challenging molecules. Here the authors show a retrobiosynthesis approach to design and construct PKSs to produce a series of valerolactams for biopolymer production.

Background Multiple long-term conditions (MLTCs; commonly referred to as multimorbidity) are highly prevalent among people admitted to hospital and are therefore of critical importance to hospital-based healthcare systems. To date, most research on MLTCs has been conducted in primary care or the general population with comparatively little work undertaken in the hospital setting. Purpose To describe the rationale and content of ADMISSION: a four-year UK Research and Innovation and National Institute of Health and Care Research funded interdisciplinary programme that seeks, in partnership with public contributors, to transform care for people living with MLTCs admitted to hospital. Research design Based across five UK academic centres, ADMISSION combines expertise in clinical medicine, epidemiology, informatics, computing, biostatistics, social science, genetics and care pathway mapping to examine patterns of conditions, mechanisms, consequences and pathways of care for people with MLTCs admitted to hospital. Data collection The programme uses routinely collected electronic health record data from large UK teaching hospitals, population-based cohort data from UK Biobank and routinely collected blood samples from The Scottish Health Research Register and Biobank (SHARE). These approaches are complemented by focused qualitative work exploring the perspectives of healthcare professionals and the lived experience of people with MLTCs admitted to hospital. Conclusion ADMISSION will provide the necessary foundations to develop novel ways to prevent and treat MLTCs and their consequences in people admitted to hospital and to improve care systems and the quality of care for this underserved group.