Miracle-dz/UniFAR-FTUs huggingface dataset:
RAN translation of the expanded CAG repeats in the SCA3 disease context

Spinocerebellar ataxia type 3 (SCA3) is a progressive neurodegenerative disorder caused by a CAG repeat expansion in the ATXN3 gene encoding the ataxin-3 protein. Despite extensive research the exact pathogenic mechanisms of SCA3 are still not understood in depth. In the present study, to gain insight into the toxicity induced by the expanded CAG repeats in SCA3, we comprehensively investigated repeat-associated non-ATG (RAN) translation in various cellular models expressing translated or non-canonically translated ATXN3 sequences with an increasing number of CAG repeats. We demonstrate that two SCA3 RAN proteins, polyglutamine (polyQ) and polyalanine (polyA), are found only in the case of CAG repeats of pathogenic length. Despite having distinct cellular localization, RAN polyQ and RAN polyA proteins are very often coexpressed in the same cell, impairing nuclear integrity and inducing apoptosis. We provide for the first time mechanistic insights into SCA3 RAN translation indicating that ATXN3 sequences surrounding the repeat region have an impact on SCA3 RAN translation initiation and efficiency. We revealed that RAN translation of polyQ proteins starts at non-cognate codons upstream of the CAG repeats, whereas RAN polyA proteins are likely translated within repeats. Furthermore, integrated stress response activation enhances SCA3 RAN translation. We suggest that RAN translation in SCA3 is a common event substantially contributing to SCA3 pathogenesis and that the ATXN3 sequence context plays an important role in triggering this unconventional translation.
Metabolomic and Proteomic Stratification of Equine Osteoarthritis

Osteoarthritis (OA) is characterised by loss of articular cartilage, synovial membrane dysfunction and subchondral sclerosis. Few studies have used a global approach to stratify equine synovial fluid (SF) molecular profiles according to OA severity. SF was collected from 58 metacarpophalangeal (MCP) and metatarsophalangeal joints of racing Thoroughbred horses (Hong Kong Jockey Club; HKJC) and 83 MCP joints of mixed breed horses from an abattoir and equine hospital (biobank). Joints were histologically and macroscopically assessed for OA severity. For proteomic analysis, native SF and SF loaded onto ProteoMiner™ equalisation columns, to deplete high abundant proteins, were analysed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and label-free quantification. Validation of selected differentially expressed proteins was undertaken using clinical SF collected during diagnostic investigations. Native SF metabolites were analysed using 1D 1H Nuclear Magnetic Resonance (NMR). 1,834 proteins and 40 metabolites were identified in equine SF. Afamin levels decreased with synovitis severity and four uncharacterised proteins decreased with OA severity. Gelsolin and lipoprotein binding protein decreased with OA severity and apolipoprotein A1 levels increased for mild and moderate OA. Within the biobank, glutamate levels decreased with OA severity and for the HKJC cohort, 2-aminobutyrate, alanine and creatine increased with severity. Proteomic and metabolomic integration was undertaken using linear regression via Lasso penalisation modelling, incorporating 29 variables (R2=0.82) with principal component 2 able to discriminate advanced OA from earlier stages, predominantly driven by H9GZQ9, F6ZR63 and alanine. Combining biobank and HKJC datasets, discriminant analysis of principal components modelling prediction was good for mild OA (90%). This study has stratified equine OA using both metabolomic and proteomic SF profiles and identified a panel of markers of interest which may be applicable to grading OA severity. This is also the first study to undertake computational integration of NMR metabolomic and LC-MS/MS proteomic datasets of any biological system.
Teacher–student neural coupling during teaching and learning

Human communication is remarkably versatile, enabling teachers to share highly abstracted and novel information with their students. What neural processes enable such transfer of information across brains during naturalistic teaching and learning? Here, we show that during lectures, wherein information transmission is unidirectional and flows from the teacher to the student, the student’s brain mirrors the teacher’s brain and that this neural coupling is correlated with learning outcomes. A teacher was scanned in fMRI giving an oral lecture with slides on a scientific topic followed by a review lecture. Students were then scanned watching either the intact lecture and review (N = 20) or a temporally scrambled version of the lecture (N = 20). Using intersubject correlation (ISC), we observed widespread teacher-student neural coupling spanning sensory cortex and language regions along the superior temporal sulcus as well as higher-level regions including posterior medial cortex (PMC), superior parietal lobule (SPL), and dorsolateral and dorsomedial prefrontal cortex. Teacher-student alignment in higher-level areas was not observed when learning was disrupted by temporally scrambling the lecture. Moreover, teacher-student coupling in PMC was significantly correlated with learning outcomes: the more closely the student’s brain mirrored the teacher’s brain, the more the student improved between behavioral pre-learning and post-learning assessments. Together, these results suggest that the alignment of neural responses between teacher and students may underlie effective communication of complex information across brains in classroom settings. Significance statement How is technical, non-narrative information communicated from one brain to another during teaching and learning? In this fMRI study, we show that the DMN activity of teachers and students are coupled during naturalistic teaching. This teacher-student neural coupling emerges only during intact learning and is correlated with learning outcomes. Together, these findings suggest that teacher-student neural alignment underlies effective communication during teaching.
A Chromosome-Scale Genome Assembly for the Fusarium oxysporum Strain Fo5176 To Establish a Model Arabidopsis-Fungal Pathosystem

Plant pathogens cause widespread yield losses in agriculture. Understanding the drivers of plant-pathogen interactions requires decoding the molecular dialog leading to either resistance or disease. However, progress in deciphering pathogenicity genes has been severely hampered by suitable model systems and incomplete fungal genome assemblies. Here, we report a significant improvement of the assembly and annotation of the genome of the Fusarium oxysporum (Fo) strain Fo5176. Fo comprises a large number of serious plant pathogens on dozens of plant species with largely unresolved pathogenicity factors. The strain Fo5176 infects Arabidopsis thaliana and, hence, constitutes a highly promising model system. We use high-coverage Pacific Biosciences Sequel long-read and Hi-C sequencing data to assemble the genome into 19 chromosomes and a total genome size of 67.98 Mb. The genome has a N50 of 4 Mb and a 99.1% complete BUSCO score. Phylogenomic analyses based on single-copy orthologs clearly place the Fo5176 strain in the Fo f sp. conglutinans clade as expected. We generated RNAseq data from culture medium and plant infections to train gene predictions and identified ∼18,000 genes including ten effector genes known from other Fo clades. We show that Fo5176 is able to infect cabbage and Brussel sprouts of the Brassica oleracea, expanding the usefulness of the Fo5176 model pathosystem. Finally, we performed large-scale comparative genomics analyses comparing the Fo5176 to 103 additional Fo genomes to define core and accessory genomic regions. In conjunction with the molecular tool sets available for A. thaliana, the Fo5176 genome and annotation provides a crucial step towards the establishment of a highly promising pathosystem.
Subcortical Volume Trajectories across the Lifespan: Data from 18,605 healthy individuals aged 3-90 years

Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalised on the resources of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to examine the age-related morphometric trajectories of the ventricles, the basal ganglia (caudate, putamen, pallidum, and nucleus accumbens), the thalamus, hippocampus and amygdala using magnetic resonance imaging data obtained from 18,605 individuals aged 3-90 years. All subcortical structure volumes were at their maximum early in life; the volume of the basal ganglia showed a gradual monotonic decline thereafter while the volumes of the thalamus, amygdala and the hippocampus remained largely stable (with some degree of decline in thalamus) until the sixth decade of life followed by a steep decline thereafter. The lateral ventricles showed a trajectory of continuous enlargement throughout the lifespan. Significant age-related increase in inter-individual variability was found for the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to derive risk predictions for the early identification of diverse clinical phenotypes.
Coding and regulatory variants affect serum protein levels and common disease

Circulating proteins are prognostic for human outcomes including cancer, heart failure, brain trauma and brain amyloid plaque burden. A deep serum proteome survey recently revealed close associations of serum protein networks and common diseases. The present study reveals unprecedented number of individual serum proteins that overlap genetic signatures of diseases emanating from different tissues of the body. Here, 54,469 low-frequency and common exome-array variants were compared with 4782 protein measurements in the serum of 5343 individuals of the deeply annotated AGES Reykjavik cohort. Using a study-wide significant threshold, 2019 independent exome array variants affecting levels of 2135 serum proteins were identified. These variants overlapped genetic loci for hundreds of complex disease traits, emphasizing the emerging role for serum proteins as biomarkers of and potential causative agents of multiple diseases.
Repeated genomic signatures of adaptation to urbanisation in a songbird across Europe

Urbanisation is currently increasing worldwide, and there is now ample evidence of phenotypic changes in wild organisms in response to this novel environment, but the extent to which this adaptation is due to genetic changes is poorly understood. Current evidence for evolution is based on localised studies, and thus lacking replicability. Here, we genotyped great tits (Parus major) from nine cities across Europe, each paired with a rural site, and provide evidence of repeated polygenic responses to urban habitats. In addition, we show that selective sweeps occurred in response to urbanisation within the same genes across multiple cities. These genetic responses were mostly associated with genes related to neural function and development, demonstrating that genetic adaptation to urbanisation occurred around the same pathways in wildlife populations across a large geographical scale.
Genetic structure and molecular diversity of Brazilian grapevine germplasm: Management and use in breeding programs

The management of germplasm banks is complex, especially when many accessions are involved. Microsatellite markers are an efficient tool for assessing the genetic diversity of germplasm collections, optimizing their use in breeding programs. This study genetically characterizes a large collection of 410 grapevine accessions maintained at the Agronomic Institute of Campinas (IAC) (Brazil). The accessions were genotyped with 17 highly polymorphic microsatellite markers. Genetic data were analyzed to determine the genetic structure of the germplasm, quantify its allelic diversity, suggest the composition of a core collection, and discover cases of synonymy, duplication, and misnaming. A total of 304 alleles were obtained, and 334 unique genotypes were identified. The molecular profiles of 145 accessions were confirmed according to the literature and databases, and the molecular profiles of more than 100 genotypes were reported for the first time. The analysis of the genetic structure revealed different levels of stratification. The primary division was between accessions related to Vitis vinifera and V. labrusca, followed by their separation from wild grapevine. A core collection of 120 genotypes captured 100% of all detected alleles. The accessions selected for the core collection may be used in future phenotyping efforts, in genome association studies, and for conservation purposes. Genetic divergence among accessions has practical applications in grape breeding programs, as the choice of relatively divergent parents will maximize the frequency of progeny with superior characteristics. Together, our results can enhance the management of grapevine germplasm and guide the efficient exploitation of genetic diversity to facilitate the development of new grape cultivars for fresh fruits, wine, and rootstock.
Cortical Thickness Trajectories across the Lifespan: Data from 17,075 healthy individuals aged 3-90 years

Delineating age-related cortical trajectories in healthy individuals is critical given the association of cortical thickness with cognition and behaviour. Previous research has shown that deriving robust estimates of age-related brain morphometric changes requires large-scale studies. In response, we conducted a large-scale analysis of cortical thickness in 17,075 individuals aged 3-90 years by pooling data through the Lifespan Working group of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium. We used fractional polynomial (FP) regression to characterize age-related trajectories in cortical thickness, and we computed normalized growth centiles using the parametric Lambda, Mu, and Sigma (LMS) method. Inter-individual variability was estimated using meta-analysis and one-way analysis of variance. Overall, cortical thickness peaked in childhood and had a steep decrease during the first 2-3 decades of life; thereafter, it showed a gradual monotonic decrease which was steeper in men than in women particularly in middle-life. Notable exceptions to this general pattern were entorhinal, temporopolar and anterior cingulate cortices. Inter-individual variability was largest in temporal and frontal regions across the lifespan. Age and its FP combinations explained up to 59% variance in cortical thickness. These results reconcile uncertainties about age-related trajectories of cortical thickness; the centile values provide estimates of normative variance in cortical thickness, and may assist in detecting abnormal deviations in cortical thickness, and associated behavioural, cognitive and clinical outcomes.
From sea surface to seafloor: a benthic allochthonous eDNA survey for the abyssal ocean

Diverse and remote deep-sea communities are critically under-sampled and increasingly threatened by anthropogenic impacts. Environmental DNA (eDNA) metabarcoding could facilitate rapid and comprehensive biotic surveys in the deep ocean, yet many aspects of the sources and distribution of eDNA in the deep sea are still poorly understood. In order to examine the influence of the water column on benthic eDNA surveys in regions targeted for deep-sea polymetallic nodule mining, we investigated the occurrence of pelagic eDNA across: (1) two different deep-sea habitat types, abyssal plains and seamounts, (2) benthic sample types, including nodules, sediment, and seawater within the benthic boundary layer (BBL), and (3) sediment depth horizons (0-2 cm, 3-5 cm). Little difference was observed between seamounts and the adjacent abyssal plains in the proportion of legacy pelagic eDNA sampled in the benthos, despite an > 1000 m depth difference for these habitats. In terms of both reads and amplicon sequence variants (ASVs), pelagic eDNA was minimal within sediment and nodule samples (< 2%), and is unlikely to affect benthic surveys that monitor resident organisms at the deep seafloor. However, pelagic eDNA was substantial within the BBL (up to 13 % ASVs, 86% reads), deriving both from the high biomass upper ocean as well as deep pelagic residents. While most pelagic eDNA found in sediments and on nodules could be sourced from the epipelagic for metazoans, protist legacy eDNA sampled on these substrates appeared to originate across a range of depths in the water column. Some evidence of eDNA degradation across a vertical sediment profile was observed for protists, with higher diversity in the 0-2 cm layer and a significantly lower proportion of legacy pelagic eDNA in deeper sediments (3-5 cm). Study-wide, our estimated metazoan sampling coverage ranged from 40% to 74%, despite relatively large sample size. Future deep-sea eDNA surveys should examine oceanographic influences on eDNA transport and residence times, consider habitat heterogeneity at a range of spatial scales in the abyss, and aim to process large amounts of material per sample (with replication) in order to increase the sampling coverage in these diverse deep ocean communities.
Light affects behavioral despair involving the clock gene Period 1

Light at night has strong effects on physiology and behavior of mammals. It affects mood in humans, which is exploited as light therapy, and has been shown to reset the circadian clock in the suprachiasmatic nuclei (SCN). This resetting is paramount to align physiological and biochemical timing to the environmental light-dark cycle. Here we provide evidence that light affects mood-related behaviors also in mice by activating the clock gene Period1 (Per1) in the lateral habenula (LHb), a brain region known to modulate mood-related behaviors. A light pulse given at ZT22 to wild type mice caused profound changes of gene expression in the mesolimbic dopaminergic system including the nucleus accumbens (NAc). Sensory perception of smell and G-protein coupled receptor signaling was affected the most in this brain region. Interestingly, most of these genes were not affected in Per1 knock-out animals, indicating that induction of Per1 by light serves as a filter for light-mediated gene induction in the brain. Taken together we show that light affects mood-related behavior in mice at least in part via induction of Per1 in the LHb with consequences on signaling mechanisms in the mesolimbic dopaminergic system.
Levels of lactoferrin, lysozyme and albumin in the tear film of keratoconus patients and their correlations with important parameters of the disease

Abstract Background: Despite the fact that keratoconus has been tipically defined as a noninflammatory condition, recent research has promoted the role of inflammatory factors and protein changes of tear film in disease progression. Aims: to determine the level of serum albumin, lactoferrin and lyzozyme in tears of keratoconic patients and their correlations with corneal biomechanical properties. Subjects and methods: 16 eyes of keratoconus patients and 14 eyes of control cases were enrolled in an observational prospective study. We performed a complete ophthalmological examination on all participants. In order to determine the concentration of tear film proteins, a minimum of 20 microlitres of tears from the lower conjunctival fornix were collected from each subject and measured by enzyme-linked immunosorbent assay (ELISA) analysis. Results: The level of lactoferrin measured in the tear film was significantly decreased in the keratoconus group compared to the normal subjects in all cases (p<0.05). We also found an increased level of lyzozyme and albumin in the keratoconus patients when compared to the controls, only the lyzozyme beeing statistically significant. In the keratoconus group, the correlations between proteins and important parameters such as keratometry, pachymetry and corneal biomechanics were statistically relevant in our study. Conclusions: We can state that the protein composition of tears is modified in keratoconus by increased levels of protein with inflammatory properties such as albumin or by decreased levels of protein with anti-inflammatory properties such as lactoferrin.
Intrinsic defects in lymph node stromal cells underpin poor germinal center responses during aging

The failure to generate enduring humoral immunity after vaccination is a hallmark of advancing age. This can be attributed to a reduction in the germinal center response, which generates long-lived antibody-secreting cells that provide protection against (re)infection. Despite intensive investigation into the effect of age on the lymphoid compartment, the primary cellular defect that causes impaired germinal centers in aging has not been identified. Herein we demonstrate that aging reduces the capacity of germinal center-associated stromal cells to respond to vaccination. Heterochronic parabiosis and mathematical modeling demonstrate that a poor stromal cell response limits the size of the germinal center. This study reveals that age-associated defects in stromal cells are a significant barrier to efficacious vaccine responses in older individuals.
Splicing variation of BMP2K balances endocytosis, COPII trafficking and autophagy in erythroid cells

Intracellular transport undergoes remodeling upon cell differentiation, which involves cell type-specific regulators. Bone morphogenetic protein 2-inducible kinase (BMP2K) has been potentially implicated in endocytosis and cell differentiation but its molecular functions remained unknown. We discovered that its longer (L) and shorter (S) splicing variants regulate erythroid differentiation in a manner unexplainable by their involvement in AP-2 adaptor phosphorylation and endocytosis. However, both variants interacted with SEC16A whose silencing in K562 erythroid leukemia cells affected generation of COPII assemblies and induced autophagic degradation. Variant-specific depletion approach showed that BMP2K isoforms constitute a BMP2K-L/S regulatory system. Therein, L promotes while S restricts recruitment of SEC31A to SEC24B-containing COPII structures forming at SEC16A-positive ER exit sites. Finally, we found L to promote and S to restrict autophagic degradation. Hence, we propose that BMP2K-L favors SEC16A-dependent intracellular processes important for erythroid maturation, such as COPII trafficking and autophagy, in a manner inhibited by BMP2K-S.
Detailed temporal dissection of an enhancer cluster reveals two distinct roles for individual elements

Many genes are regulated by multiple enhancers that often simultaneously activate their target gene. Yet, how individual enhancers collaborate to activate transcription is not well understood. Here, we dissect the functions and interdependencies of five enhancer elements that form a previously identified enhancer cluster and activate the Fgf5 locus during exit from naïve murine pluripotency. Four elements are located downstream of the Fgf5 gene and form a super-enhancer. Each of these elements contributes to Fgf5 induction at a distinct time point of differentiation. The fifth element is located in the first intron of the Fgf5 gene and contributes to Fgf5 expression at every time point by amplifying overall Fgf5 expression levels. This amplifier element strongly accumulates paused RNA Polymerase II but does not give rise to a mature Fgf5 mRNA. By transplanting the amplifier to a different genomic position, we demonstrate that it enriches for high levels of paused RNA Polymerase II autonomously. Based on our data, we propose a model for a mechanism by which RNA Polymerase II accumulation at a novel type of enhancer element, the amplifier, contributes to enhancer collaboration.