X-ray holographic imaging of magnetic surface spirals in FeGe lamellae

Isotropic helimagnets are known to host a diverse range of chiral magnetic states. In 2016, Rybakov et al., theorized the presence of a surface-pinned stacked spin spiral phase [F. N. Rybakov et al., New J. Phys. 18, 045002 (2016)], which has yet to be observed experimentally. The phase is characterized by surface spiral periods exceeding the host material's fundamental winding period L D . Here, we present experimental evidence for the observation of this state in lamellae of FeGe using resonant x-ray holographic imaging data and micromagnetic simulations. We find images of FeGe lamellae, exceeding a critical thickness of 300 nm ( 4.3 L D ), exhibit contrast modulations with a field-dependent periodicity of λ ≥ 1.4 L D , consistent with theoretical predictions of the stacked spiral state. The identification of this spiral state has significant implications for the stability of other coexisting spin textures, and will help complete our understanding of helimagnetic systems

History-dependent domain and skyrmion formation in 2D van der Waals magnet Fe3GeTe2

The discovery of two-dimensional magnets has initiated a new field of research, exploring both fundamental low-dimensional magnetism, and prospective spintronic applications. Recently, observations of magnetic skyrmions in the 2D ferromagnet Fe3GeTe2 (FGT) have been reported, introducing further application possibilities. However, controlling the exhibited magnetic state requires systematic knowledge of the history-dependence of the spin textures, which remains largely unexplored in 2D magnets. In this work, we utilise real-space imaging, and complementary simulations, to determine and explain the thickness-dependent magnetic phase diagrams of an exfoliated FGT flake, revealing a complex, history-dependent emergence of the uniformly magnetised, stripe domain and skyrmion states. The results show that the interplay of the dominant dipolar interaction and strongly temperature dependent out-of-plane anisotropy energy terms enables the selective stabilisation of all three states at zero field, and at a single temperature, while the Dzyaloshinksii-Moriya interaction must be present to realise the observed Néel-type domain walls. The findings open perspectives for 2D devices incorporating topological spin textures

Consensus-based statements for the management of mitochondrial stroke-like episodes

Background: Focal-onset seizures and encephalopathy are prominent features of a stroke-like episode, which is a severe neurological manifestation associated with subtypes of mitochondrial disease. Despite more than 30 years of research, the acute treatment of stroke-like episodes remains controversial.Methods: We used the modified Delphi process to harness the clinical expertise of a group of mitochondrial disease specialists from five European countries to produce consensus guidance for the acute management of stroke-like episodes and commonly associated complications.Results: Consensus on a new definition of mitochondrial stroke-like episodes was achieved and enabled the group to develop diagnostic criteria based on clinical features, neuroimaging and/or electroencephalogram findings. Guidelines for the management of strokelike episodes were agreed with aggressive seizure management strongly recommended at the outset of stroke-like episodes.Conclusions: Our consensus statement defines stroke-like episodes in terms of an epileptic encephalopathy and we have used this to revise both diagnostic criteria and guidelines for management. A prospective, multi-centre, randomised controlled trial is required for evaluating the efficacy of any compound on modifying the trajectory of stroke-like episodes.</p

Unlocking the transcriptomic potential of formalin-fixed paraffin embedded clinical tissues: Comparison of gene expression profiling approaches

Background: High-throughput transcriptomics has matured into a very well established and widely utilised research tool over the last two decades. Clinical datasets generated on a range of different platforms continue to be deposited in public repositories provide an ever-growing, valuable resource for reanalysis. Cost and tissue availability normally preclude processing samples across multiple technologies, making it challenging to directly evaluate performance and whether data from different platforms can be reliably compared or integrated. Methods: This study describes our experiences of nine new and established mRNA profiling techniques including Lexogen QuantSeq, Qiagen QiaSeq, BioSpyder TempO-Seq, Ion AmpliSeq, Nanostring, Affymetrix Clariom S or U133A, Illumina BeadChip and RNA-seq of formalin-fixed paraffin embedded (FFPE) and fresh frozen (FF) sequential patient-matched breast tumour samples. Results: The number of genes represented and reliability varied between the platforms, but overall all methods provided data which were largely comparable. Crucially we found that it is possible to integrate data for combined analyses across FFPE/FF and platforms using established batch correction methods as required to increase cohort sizes. However, some platforms appear to be better suited to FFPE samples, particularly archival material. Conclusions: Overall, we illustrate that technology selection is a balance between required resolution, sample quality, availability and cost

Gains to species diversity in organically farmed fields are not propagated at the farm level

Organic farming is promoted to reduce environmental impacts of agriculture, but surprisingly little is known about its effects at the farm level, the primary unit of decision making. Here we report the effects of organic farming on species diversity at the field, farm and regional levels by sampling plants, earthworms, spiders and bees in 1470 fields of 205 randomly selected organic and nonorganic farms in twelve European and African regions. Species richness is, on average, 10.5% higher in organic than nonorganic production fields, with highest gains in intensive arable fields (around +45%). Gains to species richness are partly caused by higher organism abundance and are common in plants and bees but intermittent in earthworms and spiders. Average gains are marginal +4.6% at the farm and +3.1% at the regional level, even in intensive arable regions. Additional, targeted measures are therefore needed to fulfil the commitment of organic farming to benefit farmland biodiversity

Primrose syndrome: Characterization of the phenotype in 42 patients

Primrose syndrome (PS; MIM# 259050) is characterized by intellectual disability (ID), macrocephaly, unusual facial features (frontal bossing, deeply set eyes, down-slanting palpebral fissures), calcified external ears, sparse body hair and distal muscle wasting. The syndrome is caused by de novo heterozygous missense variants in ZBTB20. Most of the 29 published patients are adults as characteristics appear more recognizable with age. We present 13 hitherto unpublished individuals and summarize the clinical and molecular findings in all 42 patients. Several signs and symptoms of PS develop during childhood, but the cardinal features, such as calcification of the external ears, cystic bone lesions, muscle wasting, and contractures typically develop between 10 and 16 years of age. Biochemically, anemia and increased alpha-fetoprotein levels are often present. Two adult males with PS developed a testicular tumor. Although PS should be regarded as a progressive entity, there are no indications that cognition becomes more impaired with age. No obvious genotype-phenotype correlation is present. A subgroup of patients with ZBTB20 variants may be associated with mild, nonspecific ID. Metabolic investigations suggest a disturbed mitochondrial fatty acid oxidation. We suggest a regular surveillance in all adult males with PS until it is clear whether or not there is a truly elevated risk of testicular cancer.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.published version, accepted version (12 month embargo) submitted versio

TLR7 gain-of-function genetic variation causes human lupus

Although circumstantial evidence supports enhanced Toll-like receptor 7 (TLR7) signalling as a mechanism of human systemic autoimmune disease1-7, evidence of lupus-causing TLR7 gene variants is lacking. Here we describe human systemic lupus erythematosus caused by a TLR7 gain-of-function variant. TLR7 is a sensor of viral RNA8,9 and binds to guanosine10-12. We identified a de novo, previously undescribed missense TLR7Y264H variant in a child with severe lupus and additional variants in other patients with lupus. The TLR7Y264H variant selectively increased sensing of guanosine and 2',3'-cGMP10-12, and was sufficient to cause lupus when introduced into mice. We show that enhanced TLR7 signalling drives aberrant survival of B cell receptor (BCR)-activated B cells, and in a cell-intrinsic manner, accumulation of CD11c+ age-associated B cells and germinal centre B cells. Follicular and extrafollicular helper T cells were also increased but these phenotypes were cell-extrinsic. Deficiency of MyD88 (an adaptor protein downstream of TLR7) rescued autoimmunity, aberrant B cell survival, and all cellular and serological phenotypes. Despite prominent spontaneous germinal-centre formation in Tlr7Y264H mice, autoimmunity was not ameliorated by germinal-centre deficiency, suggesting an extrafollicular origin of pathogenic B cells. We establish the importance of TLR7 and guanosine-containing self-ligands for human lupus pathogenesis, which paves the way for therapeutic TLR7 or MyD88 inhibition.Grant J. Brown, Pablo F. Cañete, Hao Wang, Arti Medhavy, Josiah Bones, Jonathan A. Roco, Yuke He, Yuting Qin, Jean Cappello, Julia I. Ellyard, Katharine Bassett, Qian Shen, Gaetan Burgio, Yaoyuan Zhang, Cynthia Turnbull, Xiangpeng Meng, Phil Wu, Eun Cho, Lisa A. Miosge, T. Daniel Andrews, Matt A. Field, Denis Tvorogov, Angel F. Lopez, Jeffrey J. Babon, Cristina Aparicio López, África Gónzalez-Murillo, Daniel Clemente Garulo, Virginia Pascual, Tess Levy, Eric J. Mallack, Daniel G. Calame, Timothy Lotze, James R. Lupski, Huihua Ding, Tomalika R. Ullah, Giles D. Walters, Mark E. Koina, Matthew C. Cook, Nan Shen, Carmen de Lucas Collantes, Ben Corry, Michael P. Gantier, Vicki Athanasopoulos, Carola G. Vinues

Multi-system neurological disease is common in patients with OPA1 mutations

Additional neurological features have recently been described in seven families transmitting pathogenic mutations in OPA1, the most common cause of autosomal dominant optic atrophy. However, the frequency of these syndromal ‘dominant optic atrophy plus’ variants and the extent of neurological involvement have not been established. In this large multi-centre study of 104 patients from 45 independent families, including 60 new cases, we show that extra-ocular neurological complications are common in OPA1 disease, and affect up to 20% of all mutational carriers. Bilateral sensorineural deafness beginning in late childhood and early adulthood was a prominent manifestation, followed by a combination of ataxia, myopathy, peripheral neuropathy and progressive external ophthalmoplegia from the third decade of life onwards. We also identified novel clinical presentations with spastic paraparesis mimicking hereditary spastic paraplegia, and a multiple sclerosis-like illness. In contrast to initial reports, multi-system neurological disease was associated with all mutational subtypes, although there was an increased risk with missense mutations [odds ratio = 3.06, 95% confidence interval = 1.44–6.49; P = 0.0027], and mutations located within the guanosine triphosphate-ase region (odds ratio = 2.29, 95% confidence interval = 1.08–4.82; P = 0.0271). Histochemical and molecular characterization of skeletal muscle biopsies revealed the presence of cytochrome c oxidase-deficient fibres and multiple mitochondrial DNA deletions in the majority of patients harbouring OPA1 mutations, even in those with isolated optic nerve involvement. However, the cytochrome c oxidase-deficient load was over four times higher in the dominant optic atrophy + group compared to the pure optic neuropathy group, implicating a causal role for these secondary mitochondrial DNA defects in disease pathophysiology. Individuals with dominant optic atrophy plus phenotypes also had significantly worse visual outcomes, and careful surveillance is therefore mandatory to optimize the detection and management of neurological disability in a group of patients who already have significant visual impairment

SARS-CoV-2-specific nasal IgA wanes 9 months after hospitalisation with COVID-19 and is not induced by subsequent vaccination

BACKGROUND: Most studies of immunity to SARS-CoV-2 focus on circulating antibody, giving limited insights into mucosal defences that prevent viral replication and onward transmission. We studied nasal and plasma antibody responses one year after hospitalisation for COVID-19, including a period when SARS-CoV-2 vaccination was introduced. METHODS: In this follow up study, plasma and nasosorption samples were prospectively collected from 446 adults hospitalised for COVID-19 between February 2020 and March 2021 via the ISARIC4C and PHOSP-COVID consortia. IgA and IgG responses to NP and S of ancestral SARS-CoV-2, Delta and Omicron (BA.1) variants were measured by electrochemiluminescence and compared with plasma neutralisation data. FINDINGS: Strong and consistent nasal anti-NP and anti-S IgA responses were demonstrated, which remained elevated for nine months (p < 0.0001). Nasal and plasma anti-S IgG remained elevated for at least 12 months (p < 0.0001) with plasma neutralising titres that were raised against all variants compared to controls (p < 0.0001). Of 323 with complete data, 307 were vaccinated between 6 and 12 months; coinciding with rises in nasal and plasma IgA and IgG anti-S titres for all SARS-CoV-2 variants, although the change in nasal IgA was minimal (1.46-fold change after 10 months, p = 0.011) and the median remained below the positive threshold determined by pre-pandemic controls. Samples 12 months after admission showed no association between nasal IgA and plasma IgG anti-S responses (R = 0.05, p = 0.18), indicating that nasal IgA responses are distinct from those in plasma and minimally boosted by vaccination. INTERPRETATION: The decline in nasal IgA responses 9 months after infection and minimal impact of subsequent vaccination may explain the lack of long-lasting nasal defence against reinfection and the limited effects of vaccination on transmission. These findings highlight the need to develop vaccines that enhance nasal immunity. FUNDING: This study has been supported by ISARIC4C and PHOSP-COVID consortia. ISARIC4C is supported by grants from the National Institute for Health and Care Research and the Medical Research Council. Liverpool Experimental Cancer Medicine Centre provided infrastructure support for this research. The PHOSP-COVD study is jointly funded by UK Research and Innovation and National Institute of Health and Care Research. The funders were not involved in the study design, interpretation of data or the writing of this manuscript