Autoinflammation in patients with leukocytic CBL loss of heterozygosity is caused by constitutive ERK-mediated monocyte activation.

Patients heterozygous for germline CBL loss-of-function (LOF) variants can develop myeloid malignancy, autoinflammation, or both, if some or all of their leukocytes become homozygous for these variants through somatic loss of heterozygosity (LOH) via uniparental isodisomy. We observed an upregulation of the inflammatory gene expression signature in whole blood from these patients, mimicking monogenic inborn errors underlying autoinflammation. Remarkably, these patients had constitutively activated monocytes that secreted 10 to 100 times more inflammatory cytokines than those of healthy individuals and CBL LOF heterozygotes without LOH. CBL-LOH hematopoietic stem and progenitor cells (HSPCs) outgrew the other cells, accounting for the persistence of peripheral monocytes homozygous for the CBL LOF variant. ERK pathway activation was required for the excessive production of cytokines by both resting and stimulated CBL-LOF monocytes, as shown in monocytic cell lines. Finally, we found that about 1 in 10,000 individuals in the UK Biobank were heterozygous for CBL LOF variants and that these carriers were at high risk of hematological and inflammatory conditions.

Incontinentia pigmenti underlies thymic dysplasia, autoantibodies to type I IFNs, and viral diseases.

Human inborn errors of thymic T cell tolerance underlie the production of autoantibodies (auto-Abs) neutralizing type I IFNs, which predispose to severe viral diseases. We analyze 131 female patients with X-linked dominant incontinentia pigmenti (IP), heterozygous for loss-of-function (LOF) NEMO variants, from 99 kindreds in 10 countries. Forty-seven of these patients (36%) have auto-Abs neutralizing IFN-α and/or IFN-ω, a proportion 23 times higher than that for age-matched female controls. This proportion remains stable from the age of 6 years onward. On imaging, female patients with IP have a small, abnormally structured thymus. Auto-Abs against type I IFNs confer a predisposition to life-threatening viral diseases. By contrast, patients with IP lacking auto-Abs against type I IFNs are at no particular risk of viral disease. These results suggest that IP accelerates thymic involution, thereby underlying the production of auto-Abs neutralizing type I IFNs in at least a third of female patients with IP, predisposing them to life-threatening viral diseases.

A sensitive assay for measuring whole-blood responses to type I IFNs.

Human inborn errors of the type I IFN response pathway and auto-Abs neutralizing IFN-α, -ß, and/or -ω can underlie severe viral illnesses. We report a simple assay for the detection of both types of condition. We stimulate whole blood from healthy individuals and patients with either inborn errors of type I IFN immunity or auto-Abs against type I IFNs with glycosylated human IFN-α2, -ß, or -ω. As controls, we add a monoclonal antibody (mAb) blocking the type I IFN receptors and stimulated blood with IFN-γ (type II IFN). Of the molecules we test, IP-10 (encoded by the interferon-stimulated gene (ISG) CXCL10) is the molecule most strongly induced by type I and type II IFNs in the whole blood of healthy donors in an ELISA-like assay. In patients with inherited IFNAR1, IFNAR2, TYK2, or IRF9 deficiency, IP-10 is induced only by IFN-γ, whereas, in those with auto-Abs neutralizing specific type I IFNs, IP-10 is also induced by the type I IFNs not neutralized by the auto-Abs. The measurement of type I and type II IFN-dependent IP-10 induction therefore constitutes a simple procedure for detecting rare inborn errors of the type I IFN response pathway and more common auto-Abs neutralizing type I IFNs.

Evaluating the Frequency of Mole Checks by a Dermatologist and Correlated Variables in a Global Survey across 17 Countries: HELIOS Project.

Secondary prevention of skin cancer consists in early detection of malignant lesions through patients' mole self-examination and medical examination. The objective of this study was to assess the self-reported  frequency of mole examination in a large, representative sample of the adult general population of 17 countries from all continents. Of a total of 17,001 participants, 4.8% had their moles checked by a dermatologist more than once a year, 11.3% once a year, 8.4% every 2-3 years, 12.4% once in a while, 10.3% once in lifetime, and 52.6% of participants had never performed a mole examination. Egypt was the country with the highest prevalence of people who performed a moles check more than once a year (15.9%), followed by Brazil and the USA. A higher frequency of mole checks was associated with sex (man vs woman), higher education, higher income, fair phototype, history of skin cancer, medical insurance, and sun-protective behaviours. Despite recommendations by health providers, it appears that the frequency of mole checks in the general population is still low. It is necessary for dermatologists to keep informing at-risk populations about the importance of moles check, with particular care regarding categories that less frequently adhere to secondary prevention measures.

The cepacian-like exopolysaccharide of Paraburkholderia ultramafica STM10279T enhances growth and metal adaptation of Tetraria comosa on New Caledonian ultramafic soil.

Paraburkholderia ultramafica STM10279T is a metal-tolerant rhizobacterium that promotes plant growth. It was isolated from the roots of Tetraria arundinaceae, a pioneer endemic tropical herb growing on ultramafic soils in New Caledonia. We have recently shown that the main mechanism of metal tolerance of P. ultramafica is related to the production of an acidic exopolysaccharide (EPS). To explore the potential role of this EPS in the plant's environmental adaptation, we first elucidated its structure by employing a combination of chromatography and mass spectrometry techniques. These analyses revealed that the EPS is highly branched and composed of galactosyl (35.8%), glucosyl (33.2%), rhamnosyl (19.5%), mannosyl (7.2%), and glucuronosyl residues (4.4%), similar to the EPS of the Burkholderia cepacia complex known as cepacian. We subsequently conducted greenhouse experiments on Tetraria comosa plantlets inoculated with P. ultramafica or a solution of its EPS during transplanting onto ultramafic substrate. The data showed that the dry weight of T. comosa shoots was 2.5 times higher in the plants treated with the EPS compared to the unexposed plants. In addition, inductively coupled plasma-optical emission spectrometry (ICP-OES) analysis revealed that exposure to the EPS significantly increased Ca, Mg, K, and P uptake as well as K content in roots. In vitro experiments using the Pikovskaya method showed that the EPS was able to solubilize phosphorus. Consistent with the retention of metals in roots and a reduction in shoots, our data revealed a significant decrease in metal translocation factors (TFs) in the plants inoculated with the EPS. These results suggest a beneficial effect of the rhizobacterial EPS on plant growth and abiotic stress mitigation. In addition, the data suggest that the reduced levels of trace metals in plants exposed to P. ultramafica STM10279T are due to metal chelation by the EPS. Further investigations are needed to firmly demonstrate whether this EPS could be used as a biostimulant for plant growth and adaptation to ultramafic soils.

Attitudes and behaviors regarding sun exposure in Japan compared to Europe and North America.

The objective of our study was to assess the attitudes and behaviors in Japan regarding sun exposure and compare them to those in Europe and North America. The study population was a representative sample of individuals aged >18 years from Ipsos panels in Japan (N = 1000), North America (N = 1000), and Europe (N = 6000) using the quota method. Questionnaires covered habits, practices, and perceptions regarding sun exposure. Results revealed that the majority of people (80.1%) believed that the sun gives them energy, and 61.1% considered that being tanned made them look healthier. However, there was a significant difference between men and women regarding the appeal of tanned skin, with 54.95% of men versus 34.67% (p < 0.001) of women seeing a tan as an aesthetic asset. People aged <40 years were less likely to find a tan attractive (30.3%) compared to those aged ≥40 years (48.9%) (p < 0.001). Of those questioned, 45.70% of used sunscreen with a much higher use among women (70.10%) than men (18.74%) (p < 0.001). Almost 54% of people said they stayed in the shade to protect themselves from the sun with this behavior being more prevalent among women (67.05%) and fair-skinned individuals (56.13%). Fear of the risks of sun exposure was more common among women, with 84.8% fearing premature skin aging, compared to 71.8% of men (p < 0.001). In Japan, 44.30% of those questioned said tanned skin was attractive (p < 0.001); for Europeans and North Americans the proportions were 81.1% and 77.6%, respectively. Only a quarter (25.80%) thought it essential to return from vacation with a tan. On the other hand, Europeans showed a strong recognition of the energy the sun brings (83.18%), and widely believed that tanned skin is attractive (82.32%) and healthy (73.15%). In North America, attitudes were similar to those in Europe regarding the attractiveness of tanned skin (77.65%) and the importance of returning tanned from vacation (48.15%). Compared to Europeans and North Americans, the Japanese seemed to be more cautious about sun-induced hazards and considered lighter skin to be more attractive.

FLT3L governs the development of partially overlapping hematopoietic lineages in humans and mice.

FMS-related tyrosine kinase 3 ligand (FLT3L), encoded by FLT3LG, is a hematopoietic factor essential for the development of natural killer (NK) cells, B cells, and dendritic cells (DCs) in mice. We describe three humans homozygous for a loss-of-function FLT3LG variant with a history of various recurrent infections, including severe cutaneous warts. The patients' bone marrow (BM) was hypoplastic, with low levels of hematopoietic progenitors, particularly myeloid and B cell precursors. Counts of B cells, monocytes, and DCs were low in the patients' blood, whereas the other blood subsets, including NK cells, were affected only moderately, if at all. The patients had normal counts of Langerhans cells (LCs) and dermal macrophages in the skin but lacked dermal DCs. Thus, FLT3L is required for B cell and DC development in mice and humans. However, unlike its murine counterpart, human FLT3L is required for the development of monocytes but not NK cells.

A magnetar giant flare in the nearby starburst galaxy M82.

Magnetar giant flares are rare explosive events releasing up to 1047 erg in gamma rays in less than 1 second from young neutron stars with magnetic fields up to 1015-16 G (refs. 1,2). Only three such flares have been seen from magnetars in our Galaxy3,4 and in the Large Magellanic Cloud5 in roughly 50 years. This small sample can be enlarged by the discovery of extragalactic events, as for a fraction of a second giant flares reach luminosities above 1046 erg s-1, which makes them visible up to a few tens of megaparsecs. However, at these distances they are difficult to distinguish from short gamma-ray bursts (GRBs); much more distant and energetic (1050-53 erg) events, originating in compact binary mergers6. A few short GRBs have been proposed7-11, with different amounts of confidence, as candidate giant magnetar flares in nearby galaxies. Here we report observations of GRB 231115A, positionally coincident with the starburst galaxy M82 (ref. 12). Its spectral properties, along with the length of the burst, the limits on its X-ray and optical counterparts obtained within a few hours, and the lack of a gravitational wave signal, unambiguously qualify this burst as a giant flare from a magnetar in M82.

The immunopathological landscape of human pre-TCRα deficiency: From rare to common variants.

We describe humans with rare biallelic loss-of-function PTCRA variants impairing pre-α T cell receptor (pre-TCRα) expression. Low circulating naive αß T cell counts at birth persisted over time, with normal memory αß and high γδ T cell counts. Their TCRα repertoire was biased, which suggests that noncanonical thymic differentiation pathways can rescue αß T cell development. Only a minority of these individuals were sick, with infection, lymphoproliferation, and/or autoimmunity. We also report that 1 in 4000 individuals from the Middle East and South Asia are homozygous for a common hypomorphic PTCRA variant. They had normal circulating naive αß T cell counts but high γδ T cell counts. Although residual pre-TCRα expression drove the differentiation of more αß T cells, autoimmune conditions were more frequent in these patients compared with the general population.

Molecular Phylogeny, Morphology, Growth and Toxicity of Three Benthic Dinoflagellates Ostreopsis sp. 9, Prorocentrum lima and Coolia monotis Developing in Strait of Gibraltar, Southwestern Mediterranean.

Few works have been carried out on benthic harmful algal blooms (BHAB) species in the southern Mediterranean and no data are available for the highly dynamic Strait of Gibraltar (western Mediterranean waters). For the first time, Ostreopsis sp. 9, Prorocentrum lima and Coolia monotis were isolated in this key region in terms of exchanges between the Atlantic Ocean and the Mediterranean and subject to intense maritime traffic. Ribotyping confirmed the morphological identification of these three dinoflagellates species. Monoclonal cultures were established and the maximum growth rate and cell yield were measured at a temperature of 24 °C and an irradiance of 90 µmol photons m-2 s-1, for each species: 0.26 ± 0.02 d-1 (8.75 × 103 cell mL-1 after 28 days) for Ostreopsis sp. 9, 0.21 ± 0.01 d-1 (49 × 103 cell mL-1 after 145 days) for P. lima and 0.21 ± 0.01 d-1 (10.02 × 103 cell mL-1 after 28 days) for C. monotis. Only P. lima was toxic with concentrations of okadaic acid and dinophysistoxin-1 measured in optimal growth conditions ranging from 6.4 pg cell-1 to 26.97 pg cell-1 and from 5.19 to 25.27 pg cell-1, respectively. The toxin content of this species varied in function of the growth phase. Temperature influenced the growth and toxin content of P. lima. Results suggest that future warming of Mediterranean coastal waters may lead to higher growth rates and to increases in cellular toxin levels in P. lima. Nitrate and ammonia affected the toxin content of P. lima but no clear trend was noted. In further studies, we have to isolate other BHAB species and strains from Strait of Gibraltar waters to obtain more insight into their diversity and toxicity.

Human inherited CCR2 deficiency underlies progressive polycystic lung disease.

We describe a human lung disease caused by autosomal recessive, complete deficiency of the monocyte chemokine receptor C-C motif chemokine receptor 2 (CCR2). Nine children from five independent kindreds have pulmonary alveolar proteinosis (PAP), progressive polycystic lung disease, and recurrent infections, including bacillus Calmette Guérin (BCG) disease. The CCR2 variants are homozygous in six patients and compound heterozygous in three, and all are loss-of-expression and loss-of-function. They abolish CCR2-agonist chemokine C-C motif ligand 2 (CCL-2)-stimulated Ca2+ signaling in and migration of monocytic cells. All patients have high blood CCL-2 levels, providing a diagnostic test for screening children with unexplained lung or mycobacterial disease. Blood myeloid and lymphoid subsets and interferon (IFN)-γ- and granulocyte-macrophage colony-stimulating factor (GM-CSF)-mediated immunity are unaffected. CCR2-deficient monocytes and alveolar macrophage-like cells have normal gene expression profiles and functions. By contrast, alveolar macrophage counts are about half. Human complete CCR2 deficiency is a genetic etiology of PAP, polycystic lung disease, and recurrent infections caused by impaired CCL2-dependent monocyte migration to the lungs and infected tissues.

Fiber orientation and crimp level might control the auxetic effect of biological tissues.

We propose an analytical micromechanical model for studying the lamellar-composite-like structure of fibrous soft tissue. The tissue under consideration is made up of several lamellae, and is designed to resemble the annulus fibrosus (AF) tissue or media layer of arterial tissue, for example. The collagen fibers are arranged in parallel in each lamella and the fiber orientation differs from one lamella to its neighbors. The parallel fibers in each lamella of AF tissue, for example, have been observed to have a crimped microstructure. The proposed model incorporates this quality, considering fiber waviness as a sinusoidal shape and taking into account the fiber dispersion in different layers, where both fiber and matrix are considered as solid phases. We find that collagen-fiber waviness and layer orientation have a significant influence on Poisson's ratio. The effective Poisson's ratio predicted by the proposed model demonstrates that the crimped collagen fiber microstructure might weaken the auxetic effect of fibrous soft tissue, which might explain why, as the literature suggests, the auxetic behavior is more difficult to observe than large Poisson's ratios. As opposed to the many studies that use the well-known hyperelastic fiber-based constitutive model, in which out-of-plane expansion is often observed, the present work explains the auxetic response found in modeling and in experimental data from the perspective of collagen fiber microstructure.