Multiple genomic solutions for local adaptation in two closely related species (sheep and goats) facing the same climatic constraints.

The question of how local adaptation takes place remains a fundamental question in evolutionary biology. The variation of allele frequencies in genes under selection over environmental gradients remains mainly theoretical and its empirical assessment would help understanding how adaptation happens over environmental clines. To bring new insights to this issue we set up a broad framework which aimed to compare the adaptive trajectories over environmental clines in two domesticated mammal species co-distributed in diversified landscapes. We sequenced the genomes of 160 sheep and 161 goats extensively managed along environmental gradients, including temperature, rainfall, seasonality and altitude, to identify genes and biological processes shaping local adaptation. Allele frequencies at putatively adaptive loci were rarely found to vary gradually along environmental gradients, but rather displayed a discontinuous shift at the extremities of environmental clines. Of the 430 candidate adaptive genes identified, only 6 were orthologous between sheep and goats and those responded differently to environmental pressures, suggesting different putative mechanisms involved in local adaptation in these two closely related species. Interestingly, the genomes of the 2 species were impacted differently by the environment, genes related to signatures of selection were most related to altitude, slope and rainfall seasonality for sheep, and summer temperature and spring rainfall for goats. The diversity of candidate adaptive pathways may result from a high number of biological functions involved in the adaptations to multiple eco-climatic gradients, and a differential role of climatic drivers on the two species, despite their co-distribution along the same environmental gradients. This study describes empirical examples of clinal variation in putatively adaptive alleles with different patterns in allele frequency distributions over continuous environmental gradients, thus showing the diversity of genetic responses in adaptive landscapes and opening new horizons for understanding genomics of adaptation in mammalian species and beyond.

Response to treatment in NMOSD: the Australasian experience.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is associated with significant morbidity and mortality. Several therapies have been recommended for NMOSD and more recently clinical trials have demonstrated efficacy for three monoclonal antibody therapies. We present a retrospective observational study of treatment response in NMOSD. METHODS: This was a retrospective, unblinded, observational study of treatment efficacy for rituximab and traditional immunosuppressive therapy in patients with AQP4 antibody positive NMOSD. Treatment efficacy was assessed using annualised relapse rates (ARR), time to first relapse and expanded disability status scale (EDSS) scores. RESULTS: Complete relapse and treatment data were available for 43/68 (63%) of AQP4 antibody positive NMOSD cases covering 74 episodes of treatment. In a time to first relapse analysis rituximab showed a risk ratio of 0.23 (95% CI 0.08 - 0.65) when compared with no treatment and there was a non-significant reduction in ARR of 35% compared to pre-treatment. ß-interferon (p = 0.0002) and cyclophosphamide (p = 0.0034) were associated with an increased ARR compared to pre-treatment. Rituximab (median 4.0 [range 0.0 - 7.0]; p = 0.042) and traditional immunosuppressive therapy (median 4.0 [range 0.0 - 8.0]; p = 0.016) were associated with a lower final EDSS compared to ß-interferon (median 6.0 [range 4.0 - 7.5]). CONCLUSIONS: These data provide additional support for the use of rituximab in preference to traditional immunosuppressive agents and MS disease modifying therapies as first line treatment of NMOSD.

Expression Atlas update: gene and protein expression in multiple species.

The EMBL-EBI Expression Atlas is an added value knowledge base that enables researchers to answer the question of where (tissue, organism part, developmental stage, cell type) and under which conditions (disease, treatment, gender, etc) a gene or protein of interest is expressed. Expression Atlas brings together data from >4500 expression studies from >65 different species, across different conditions and tissues. It makes these data freely available in an easy to visualise form, after expert curation to accurately represent the intended experimental design, re-analysed via standardised pipelines that rely on open-source community developed tools. Each study's metadata are annotated using ontologies. The data are re-analyzed with the aim of reproducing the original conclusions of the underlying experiments. Expression Atlas is currently divided into Bulk Expression Atlas and Single Cell Expression Atlas. Expression Atlas contains data from differential studies (microarray and bulk RNA-Seq) and baseline studies (bulk RNA-Seq and proteomics), whereas Single Cell Expression Atlas is currently dedicated to Single Cell RNA-Sequencing (scRNA-Seq) studies. The resource has been in continuous development since 2009 and it is available at https://www.ebi.ac.uk/gxa.

Patient attitudes towards remote memory clinic assessment.

BACKGROUND: Due to demand on UK memory clinic services, most patients have limited consultant interaction before diagnosis/discharge. Technology offers an opportunity for remote assessment, from telephone/video-based consultations to fully digitised cognitive assessments with potential to track disease progression. Whilst many acute services utilise remote assessment, there are perceived barriers in memory clinic populations. However, COVID-19 and related national restrictions may have altered patients' attitudes towards and experience with remote assessment tools. We aimed to investigate attitudes including confidence and perceived challenges towards remote assessment as well as access and experience with technology amongst Oxfordshire memory clinic patients. METHOD: Between June and September 2020, all patients awaiting initial memory clinic assessment were asked to participate in a standardised semi-quantitative survey as part of an Oxford Health NHS Foundation Trust service evaluation. Designed with service-user input, questions aimed to capture availability, experience and confidence using technology and patients' comfort with assessment, diagnosis and future care discussions being conducted remotely, as well as any concerns or comments. RESULT: Amongst 73 respondents (average age=79.1 years), access to technology was high; 82% reported telephone access and 58% to a laptop, tablet, smartphone or combination of the three. 17% reported previous use of web-based video conferencing tools, and although confidence using these tools was 7%, this increased with written instruction or relative assistance. Similarly, whilst under half of the respondents felt comfortable with assessments, diagnosis or future care discussions occurring remotely, this increased to approximately two thirds with relative presence (67%, 69% and 66%, respectively). Qualitative analysis of patient's comments regarding remote assessment also revealed concerns over wait times/urgent need for assessment. However, 62% preferred to wait for an in-person visit, rather than an immediate remote appointment. CONCLUSION: This survey demonstrates availability of technology in this population but a disparity in willingness to engage in remote assessment. Consequently, there is a need to diverge from one-size-fits-all models to a tiered approach that helps facilitate individual choice based on the availability/confidence with technology and level of relative support. The Oxford Brain Health Centre, an integrated clinical-research service, provides an opportunity to research this tiered approach in clinical practice.

MRI Patterns Distinguish AQP4 Antibody Positive Neuromyelitis Optica Spectrum Disorder From Multiple Sclerosis.

Neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS) are inflammatory diseases of the CNS. Overlap in the clinical and MRI features of NMOSD and MS means that distinguishing these conditions can be difficult. With the aim of evaluating the diagnostic utility of MRI features in distinguishing NMOSD from MS, we have conducted a cross-sectional analysis of imaging data and developed predictive models to distinguish the two conditions. NMOSD and MS MRI lesions were identified and defined through a literature search. Aquaporin-4 (AQP4) antibody positive NMOSD cases and age- and sex-matched MS cases were collected. MRI of orbits, brain and spine were reported by at least two blinded reviewers. MRI brain or spine was available for 166/168 (99%) of cases. Longitudinally extensive (OR = 203), "bright spotty" (OR = 93.8), whole (axial; OR = 57.8) or gadolinium (Gd) enhancing (OR = 28.6) spinal cord lesions, bilateral (OR = 31.3) or Gd-enhancing (OR = 15.4) optic nerve lesions, and nucleus tractus solitarius (OR = 19.2), periaqueductal (OR = 16.8) or hypothalamic (OR = 7.2) brain lesions were associated with NMOSD. Ovoid (OR = 0.029), Dawson's fingers (OR = 0.031), pyramidal corpus callosum (OR = 0.058), periventricular (OR = 0.136), temporal lobe (OR = 0.137) and T1 black holes (OR = 0.154) brain lesions were associated with MS. A score-based algorithm and a decision tree determined by machine learning accurately predicted more than 85% of both diagnoses using first available imaging alone. We have confirmed NMOSD and MS specific MRI features and combined these in predictive models that can accurately identify more than 85% of cases as either AQP4 seropositive NMOSD or MS.

Increasing ionic conductivity within thermoplastics via commercial additives results in a dramatic decrease in fiber diameter from melt electrospinning.

Polyethylene melt conductivity was increased by adding a commercial anti-static agent, which resulted in a 20× decrease in electrospun fiber diameter and formation of a significant fraction of sub-micron diameter fibers. Two polyethylene formulations and varying additive concentrations were utilized to span the parameter space of conductivity and viscosity. The key role of conductivity in determining the jet radius (which sets the upper limit on the fiber size) is discussed in the context of fluid mechanics theory and previous simulations. Parameters which affect the conversion of the liquid jet to a solid fiber and the pertinent theory are outlined. An "unconfined" experimental configuration is utilized to both avoid potential needle clogging and enable direct observation of important characteristic length scales related to the interaction of the fluid and the applied electric field. In this approach, the fluid spontaneously forms an array of cone perturbations which act as stationary "nozzles" through which the mobile fluid flows to form the jet. The experimental data and theory considerations allow for a holistic discussion of the interaction between flow rate, viscosity, conductivity, and the resultant jet and fiber size. Information about the fluid viscosity and conductivity gained by observing the electrospinning process is highlighted. Schemes for theoretically predicting the cone-jet density, cone size, and flow rate are compared to experimental results.

Magnetic resonance imaging in neuromyelitis optica spectrum disorder.

Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory disease of the central nervous system (CNS) associated with antibodies to aquaporin-4 (AQP4), which has distinct clinical, radiological and pathological features, but also has some overlap with multiple sclerosis and myelin oligodendrocyte glycoprotein (MOG) antibody associated disease. Early recognition of NMOSD is important because of differing responses to both acute and preventive therapy. Magnetic resonance (MR) imaging has proved essential in this process. Key MR imaging clues to the diagnosis of NMOSD are longitudinally extensive lesions of the optic nerve (more than half the length) and spinal cord (three or more vertebral segments), bilateral optic nerve lesions and lesions of the optic chiasm, area postrema, floor of the IV ventricle, periaqueductal grey matter, hypothalamus and walls of the III ventricle. Other NMOSD-specific lesions are denoted by their unique morphology: heterogeneous lesions of the corpus callosum, 'cloud-like' gadolinium (Gd)-enhancing white matter lesions and 'bright spotty' lesions of the spinal cord. Other lesions described in NMOSD, including linear periventricular peri-ependymal lesions and patch subcortical white matter lesions, may be less specific. The use of advanced MR imaging techniques is yielding further useful information regarding focal degeneration of the thalamus and optic radiation in NMOSD and suggests that paramagnetic rim patterns and changes in normal appearing white matter are specific to MS. MR imaging is crucial in the early recognition of NMOSD and in directing testing for AQP4 antibodies and guiding immediate acute treatment decisions. Increasingly, MR imaging is playing a role in diagnosing seronegative cases of NMOSD.

Genetic perturbation of PU.1 binding and chromatin looping at neutrophil enhancers associates with autoimmune disease.

Neutrophils play fundamental roles in innate immune response, shape adaptive immunity, and are a potentially causal cell type underpinning genetic associations with immune system traits and diseases. Here, we profile the binding of myeloid master regulator PU.1 in primary neutrophils across nearly a hundred volunteers. We show that variants associated with differential PU.1 binding underlie genetically-driven differences in cell count and susceptibility to autoimmune and inflammatory diseases. We integrate these results with other multi-individual genomic readouts, revealing coordinated effects of PU.1 binding variants on the local chromatin state, enhancer-promoter contacts and downstream gene expression, and providing a functional interpretation for 27 genes underlying immune traits. Collectively, these results demonstrate the functional role of PU.1 and its target enhancers in neutrophil transcriptional control and immune disease susceptibility.

Cell type-specific novel long non-coding RNA and circular RNA in the BLUEPRINT hematopoietic transcriptomes atlas.

Transcriptional profiling of hematopoietic cell subpopulations has helped to characterize the developmental stages of the hematopoietic system and the molecular bases of malignant and non-malignant blood diseases. Previously, only the genes targeted by expression microarrays could be profiled genome-wide. High-throughput RNA sequencing, however, encompasses a broader repertoire of RNA molecules, without restriction to previously annotated genes. We analyzed the BLUEPRINT consortium RNA-sequencing data for mature hematopoietic cell types. The data comprised 90 total RNA-sequencing samples, each composed of one of 27 cell types, and 32 small RNA-sequencing samples, each composed of one of 11 cell types. We estimated gene and isoform expression levels for each cell type using existing annotations from Ensembl. We then used guided transcriptome assembly to discover unannotated transcripts. We identified hundreds of novel non-coding RNA genes and showed that the majority have cell type-dependent expression. We also characterized the expression of circular RNA and found that these are also cell type-specific. These analyses refine the active transcriptional landscape of mature hematopoietic cells, highlight abundant genes and transcriptional isoforms for each blood cell type, and provide a valuable resource for researchers of hematologic development and diseases. Finally, we made the data accessible via a web-based interface: https://blueprint.haem.cam.ac.uk/bloodatlas/.

Relapse Patterns in NMOSD: Evidence for Earlier Occurrence of Optic Neuritis and Possible Seasonal Variation.

Neuromyelitis optica spectrum disorders (NMOSD) and multiple sclerosis (MS) show overlap in their clinical features. We performed an analysis of relapses with the aim of determining differences between the two conditions. Cases of NMOSD and age- and sex-matched MS controls were collected from across Australia and New Zealand. Demographic and clinical information, including relapse histories, were recorded using a standard questionnaire. There were 75 cases of NMOSD and 101 MS controls. There were 328 relapses in the NMOSD cases and 375 in MS controls. Spinal cord and optic neuritis attacks were the most common relapses in both NMOSD and MS. Optic neuritis (p < 0.001) and area postrema relapses (P = 0.002) were more common in NMOSD and other brainstem attacks were more common in MS (p < 0.001). Prior to age 30 years, attacks of optic neuritis were more common in NMOSD than transverse myelitis. After 30 this pattern was reversed. Relapses in NMOSD were more likely to be treated with acute immunotherapies and were less likely to recover completely. Analysis by month of relapse in NMOSD showed a trend toward reduced risk of relapse in February to April compared to a peak in November to January (P = 0.065). Optic neuritis and transverse myelitis are the most common types of relapse in NMOSD and MS. Optic neuritis tends to occur more frequently in NMOSD prior to the age of 30, with transverse myelitis being more common thereafter. Relapses in NMOSD were more severe. A seasonal bias for relapses in spring-summer may exist in NMOSD.

Examining a Group Acceptance and Commitment Therapy Intervention for Music Performance Anxiety in Student Vocalists.

Music performance anxiety (MPA) is a distressing and persistent anxious apprehension related to musical performance. The experience of MPA forces many musicians to give up performing or develop maladaptive coping mechanisms (e.g., avoidance or substance use), which can impact their career and wellbeing. High levels of MPA in students and vocalists are reported in the literature. Vocalists present a unique challenge for clinicians in that vocal and breathing mechanisms, required for performance, are negatively impacted when anxious. Acceptance and commitment therapy (ACT) has demonstrated efficacy for the treatment of a range of psychological problems including social anxiety disorder (of which MPA may be indicated as a subtype). This study sought to investigate whether group-based ACT may be a feasible and effective intervention for MPA in Australian student vocalists and aimed to design an intervention that could be adopted by music education providers. Potential participants (N = 31) completed an online survey including demographic questions and outcome measures. Six vocal students (four females; two males; aged M = 20.33 years) with elevated MPA scores participated in the ACT for MPA group program and 3-month follow-up. Group sessions were 2 h each week for six consecutive weeks. Participants were followed up 3 months post-intervention via online survey. There was a significant increase in psychological flexibility and significant decreases in MPA and psychological inflexibility. Gains were maintained at 3-month follow-up. The current study offers preliminary evidence for the feasibility and effectiveness of a group-based ACT protocol for musicians with performance anxiety which may be incorporated into tertiary performance training curricula.

The clinical profile of NMOSD in Australia and New Zealand.

Neuromyelitis optica spectrum disorders (NMOSD) are an inflammation of the central nervous system associated with autoantibodies to aquaporin-4. We have undertaken a clinic-based survey of NMOSD in the Australia and New Zealand populations with the aim of characterising the clinical features and establishing the value of recently revised diagnostic criteria. Cases of possible NMOSD and age and sex-matched controls with multiple sclerosis (MS) were referred from centres across Australia and New Zealand. Cases were classified as NMOSD if they met the 2015 IPND criteria and remained as suspected NMOSD if they did not. Clinical and paraclinical data were compared across the three groups. NMOSD was confirmed in 75 cases and 89 had suspected NMOSD. There were 101 controls with MS. Age at onset, relapse rates and EDSS scores were significantly higher in NMOSD than in MS. Lesions and symptoms referable to the optic nerve were more common in NMOSD whereas brainstem, cerebellar and cerebral lesions were more common in MS. Longitudinally extensive spinal cord lesions were seen in 48/71 (68%) of cases with NMOSD. Elevations of CSF, white cell count and protein were more common in NMOSD. We have confirmed a clinical pattern of NMOSD that has been seen in several geographical regions. We have demonstrated the clinical utility of the current diagnostic criteria. Distinct patterns of disease are evident in NMOSD and MS, but there remains a large number of patients with NMOSD-like features who do not meet the current diagnostic criteria for NMOSD and remain a diagnostic challenge.

Nanoparticle-based photothermal heating to drive chemical reactions within a solid: using inhomogeneous polymer degradation to manipulate mechanical properties and segregate carbonaceous by-products.

Photothermal heating via metal nanoparticles is utilized to degrade polyethylcyanoacrylate (PECA), which undergoes a thermally-driven depolymerization process, resulting in (i) monomer loss from the sample, (ii) repolymerization to form shorter chains (oligomer), and (iii) formation of carbonaceous by-products which are graphene-like and luminescent. These unique PECA properties are used to demonstrate the heterogeneous temperature distribution present during photothermal processing and the results are compared to degradation via conventional methods where a uniform temperature is present. Photothermal heating results in formation of pockets of depolymerized material around each nanoscale heating site. The characteristic size of these photothermally-generated mechanical defects is determined from changes in the material's tensile strength. Changes in mass loss and molecular weight are utilized to determine the fraction of the sample that has depolymerized: distributing this volume equally to each heating site (based on the nanoparticle concentration) results in a volume that matches the defect size from independent mechanical measurements. In this way, macroscopic measurements elucidate the mesoscopic pattern of photothermal degradation. Sample morphology on scales from millimeters to nanometers is assessed via optical and electron microscopy. The carbonaceous by-products of degradation form in the hot region around each nanoparticle during photothermal heating, as revealed by transmission electron microscopy studies. Heterogeneous heating is also evident from optical images where starch granules, employed as an inert dilute additive to enhance PECA mechanical properties, also become luminescent due to degradation in "hot spots" created by the overlap of warm regions from nearby nanoparticle sites. Beyond the fundamental knowledge gained by these studies, the results demonstrate the ability to manipulate the connection between mechanical properties and chemical degradation which is important for developing new strategies for management of polymeric waste.

Photothermally-driven thermo-oxidative degradation of low density polyethylene: heterogeneous heating plus a complex reaction leads to homogeneous chemistry.

Photothermal heating from embedded nanoparticles, a process whereby visible light is converted into heat resulting in a high temperature in each particle's immediate vicinity, was utilized to degrade low density polyethylene (LDPE) via thermo-oxidation. The spatially-varying steady-state photothermal temperature field is a potential mechanism by which ambient light (e.g. sunlight) could be used to drive chemical reactions within solid materials and may result in a non-uniform pattern of products, an advantage or disadvantage depending on application. Novel approaches to control polymer degradation are of interest because of the goal of remediating plastic waste, including autonomous means to minimize its effect when unconfined in the environment. For thermoplastic auto-oxidation, heterogeneous degradation would likely enhance deleterious micro-fragmentation however, the multi-step, multi-site nature of the reaction mitigated the temperature non-uniformity. A photothermally-heated LDPE nanocomposite with silver nanoparticle and cobalt-stearate additives showed degradation, characterized by ultraviolet-visible and Fourier-transform infrared absorption spectroscopy, electron microscopy, and mechanical testing, nearly identical to that resulting from uniform conventional treatment at the same average temperature.

An evaluation of sequencing coverage and genotyping strategies to assess neutral and adaptive diversity.

Whole genome sequences (WGS) greatly increase our ability to precisely infer population genetic parameters, demographic processes, and selection signatures. However, WGS may still be not affordable for a representative number of individuals/populations. In this context, our goal was to assess the efficiency of several SNP genotyping strategies by testing their ability to accurately estimate parameters describing neutral diversity and to detect signatures of selection. We analysed 110 WGS at 12× coverage for four different species, i.e., sheep, goats and their wild counterparts. From these data we generated 946 data sets corresponding to random panels of 1K to 5M variants, commercial SNP chips and exome capture, for sample sizes of five to 48 individuals. We also extracted low-coverage genome resequencing of 1×, 2× and 5× by randomly subsampling reads from the 12× resequencing data. Globally, 5K to 10K random variants were enough for an accurate estimation of genome diversity. Conversely, commercial panels and exome capture displayed strong ascertainment biases. Besides the characterization of neutral diversity, the detection of the signature of selection and the accurate estimation of linkage disequilibrium (LD) required high-density panels of at least 1M variants. Finally, genotype likelihoods increased the quality of variant calling from low coverage resequencing but proportions of incorrect genotypes remained substantial, especially for heterozygote sites. Whole genome resequencing coverage of at least 5× appeared to be necessary for accurate assessment of genomic variations. These results have implications for studies seeking to deploy low-density SNP collections or genome scans across genetically diverse populations/species showing similar genetic characteristics and patterns of LD decay for a wide variety of purposes.

Correction to: Functional variation in allelic methylomes underscores a strong genetic contribution and reveals novel epigenetic alterations in the human epigenome.

Following publication of the original article [1], the authors reported an error in Additional file 1.

Multi-platform discovery of haplotype-resolved structural variation in human genomes.

The incomplete identification of structural variants (SVs) from whole-genome sequencing data limits studies of human genetic diversity and disease association. Here, we apply a suite of long-read, short-read, strand-specific sequencing technologies, optical mapping, and variant discovery algorithms to comprehensively analyze three trios to define the full spectrum of human genetic variation in a haplotype-resolved manner. We identify 818,054 indel variants (<50 bp) and 27,622 SVs (≥50 bp) per genome. We also discover 156 inversions per genome and 58 of the inversions intersect with the critical regions of recurrent microdeletion and microduplication syndromes. Taken together, our SV callsets represent a three to sevenfold increase in SV detection compared to most standard high-throughput sequencing studies, including those from the 1000 Genomes Project. The methods and the dataset presented serve as a gold standard for the scientific community allowing us to make recommendations for maximizing structural variation sensitivity for future genome sequencing studies.