Image Analysis of Xerosis and Atopic Dermatitis Following Prebiotic Skincare Regimen in Ethnically Diverse Patients.

Variations in the epidemiology, clinical presentation, and disease course in atopic dermatitis (AD) patients with Skin of Color (SOC) compared with white counterparts have been reported. In this study, we evaluated the capability of a new imaging device (SkinCam) in quantifying skin texture changes in diverse patients, presenting with AD or xerosis, after using a prebiotic skincare routine over 10 weeks.  A total of 39 subjects from diverse racial/ethnic backgrounds, aged 3 to 76 years old, with Fitzpatrick skin phototypes I to VI, presenting with mild AD and moderate to severe xerosis, were enrolled in the study. All subjects used a prebiotic cleanser on its own for 2 weeks, followed by a prebiotic moisturizer in conjunction for an additional 8 weeks. Standardized images of the subjects' legs were taken with SkinCam at several time points (baseline, week 2, and week 10), and analyzed for skin texture parameters. Our results demonstrate that both skin texture irregularity and skin color patterns significantly improve over time with a prebiotic skincare regimen in AD (n=12) and xerosis (n=24) subjects. Interestingly, image analyses showed more improvement over time in xerosis and AD SOC patients (n=18, Fitzpatrick IV-VI). Lastly, skin texture analyses from SkinCam imaging correlated with clinical assessments, showing significant improvement by prebiotic skincare regimen in all subjects by week 10. In summary, our results demonstrate that the SkinCam imaging device has the capability to effectively monitor skin texture parameters over time in both AD and xerosis patients with lightly and darkly pigmented skin. J Drugs Dermatol. 2024;23(7):557-563.  doi:10.36849/JDD.8371.

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.

Discovery and Optimization of Potent, Efficacious and Selective Inhibitors Targeting EGFR Exon20 Insertion Mutations.

Herein, we report the identification and optimization of a series of potent inhibitors of EGFR Exon20 insertions with significant selectivity over wild-type EGFR. A strategically designed HTS campaign, multiple iterations of structure-based drug design (SBDD), and tactical linker replacement led to a potent and wild-type selective series of molecules and ultimately the discovery of 36. Compound 36 is a potent and selective inhibitor of EGFR Exon20 insertions and has demonstrated encouraging efficacy in NSCLC EGFR CRISPR-engineered H2073 xenografts that carry an SVD Exon20 insertion and reduced efficacy in a H2073 wild-type EGFR xenograft model compared to CLN-081 (5), indicating that 36 may have lower EGFR wild-type associated toxicity.

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.

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.

Overcoming osimertinib resistance with AKT inhibition in EGFRm-driven Non-Small-Cell-Lung-Cancer with PIK3CA/PTEN alterations.

PURPOSE: Osimertinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) indicated for the treatment of EGFR mutated (EGFRm)-driven lung adenocarcinomas. Osimertinib significantly improves progression-free survival in first-line treated patients with EGFRm advanced NSCLC. Despite the durable disease control, the majority of patients receiving osimertinib eventually develop disease progression. EXPERIMENTAL DESIGN: ctDNA profiling analysis on-progression plasma samples from patients treated with osimertinib in both first (Phase 3, FLAURA trial) and second-line trials (Phase 3, AURA3 trial) revealed a high prevalence of PIK3CA/AKT/PTEN alterations. In vitro and in vivo evidence using CRISPR engineered NSCLC cell lines and PXD models support a functional role for PIK3CA and PTEN mutations in the development of osimertinib resistance. RESULTS: These alterations are functionally relevant as EGFRm NSCLC cells with engineered PIK3CA/AKT/PTEN alterations develop resistance to osimertinib and can be re-sensitized by treatment with the combination of osimertinib and the AKT inhibitor capivasertib. Moreover, xenograft and PDX in vivo models with PIK3CA/AKT/PTEN alterations display limited sensitivity to osimertinib relative to models without alteration, and in these double mutant models capivasertib and osimertinib combination elicits an improved anti-tumor effect versus osimertinib alone. CONCLUSIONS: Together, this approach offers a potential treatment strategy for patients with EGFRm-driven NSCLC that have a sub-optimal response, or develop resistance, to osimertinib through PIK3CA/AKT/PTEN alterations.

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.

How technical change has boosted fish aggregation device productivity in the Indian Ocean tuna fishery.

Excess harvesting power can threaten the long-term sustainability of fisheries. Indicators of excess harvesting capacity must include input-output-based estimates of economic production efficiency. The increasing use of drifting Fish-Aggregating-Devices (DFADs) has boosted fishing productivity in high-seas tuna fisheries, perhaps beyond the biological capacity of the stocks, and is an object of global debate. We carried out a Data Envelopment Analysis (DEA) of relative changes in production efficiencies of the French purse-seine fleet targeting tropical tuna in the western Indian Ocean using two fishing strategies: (1) on floating objects (FOB) and (2) free swimming schools (FSC) using tuna catch and effort data spanning 1992-2019. We show that FOB fishing evolved dramatically through time with an estimated change of 3.6%yr-1 (8.0%yr-1 2007-2019), in contrast to 2.1%yr-1 for FSC. While the efficiency level in combining and using inputs has barely changed for FOB fishing, it means that all the growth in productivity comes from technical change for this strategy. The dynamics is different for the FSC with a mixture of innovation and higher efficiency. Immediate plans to improve input-based management in this region are needed to prevent further risks of overfishing to yellowfin (Thunnus albacares) and skipjack (Katsuwonus pelamis) tunas.

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.

Effect of the supplementation with a combination of plant extracts on sow and piglet performance and physiology during lactation and around weaning.

Weaning is a critical period for pigs. Some plant extracts showing antioxidant, anti-inflammatory or antibacterial properties, provided to piglets and/or their dam, may improve piglets' robustness at weaning, thus reducing the need for antobiotics. This study investigated the effects of a maternal and/or a direct supplementation of piglets with a combination of plant extracts on sow and piglet performance and their metabolic, immune, inflammatory, and oxidative status during lactation and around weaning. Sixty-four sows were assigned to the control or treated group. Treated sows were supplemented with a powdered plant extracts supplement daily top-dressed on feed from day of gestation (DG) 106 to day of lactation (DL) 28 and a liquid solution top-dressed on feed on DG109. Within each sow group, litters were divided into two groups: a control piglet group and a treated piglet group. A single dose of a liquid solution was orally given to piglets in the treated piglet group. Piglets were weaned on DL28. Blood samples were collected from sows on DG94, DG112, and DL26 and from 2 piglets per litter on DL3, DL14, DL25, and 5 d postweaning to analyze indicators of metabolic, immune, inflammatory, and oxidative status. Colostrum and milk samples were collected at farrowing, DL6, and 26. Maternal supplementation had no effect on sow metabolic, immune, inflammatory, and oxidative status except for fewer lymphocytes on DG112 (P < 0.05) and a lower plasma concentration of non-esterified fatty acids on DL26 (P < 0.05). Maternal supplementation tended to decrease dry matter and gross energy (P < 0.10) and reduced fat and haptoglobin concentrations (P < 0.01) in milk on DL26. Maternal supplementation had no effect on piglets' growth performance and blood indicators during lactation and around weaning. On DL25, the direct supplementation of piglets decreased their neutrophils proportion (P < 0.05), increased the expression of genes encoding pro- and anti-inflammatory cytokines in whole blood culture in response to lipopolysaccharide (P < 0.05) and tended to decrease the oxidative stress index (P = 0.06). After weaning, these beneficial effects were no longer observed but the supplementation improved piglets' growth performance during the postweaning period (P < 0.05). Plant extract supplementation could thus modify the composition of mammary secretions and improve postweaning performance of piglets potentially related to the modification of their immune and oxidative status before weaning.

Weaning is a critical period for piglets. Some plant extracts, known to exhibit antioxidant, anti-inflammatory, or antibacterial properties, may improve piglets' robustness at weaning. This study investigated the effects of a maternal and/or a direct supplementation of piglets with a combination of plant extracts on sow and piglet metabolic, immune, inflammatory, and oxidative status during lactation and around weaning. The maternal supplementation corresponded to a powdered supplement top-dressed on sow diet during late gestation and lactation and a liquid solution administered once 1 wk before parturition. The piglet supplementation was a liquid solution administered once on day 3 of age. The most concentrated components of the powder were extracts of fenugreek, Siberian ginseng, and cat's claw. The liquid solutions contained mostly oregano and eucalyptus essential oils. The maternal supplementation had few effects on sow immune, inflammatory, and oxidative status but modified milk composition at the end of lactation. It did not improve growth performance and the immune, inflammatory, and oxidative blood parameters of piglets around weaning. The direct supplementation of piglets modified their immune and oxidative status before weaning and increased their growth performance during the postweaning period, showing the potential of plant extracts as part of preventive strategies dedicated to improve piglets' robustness during the suckling and postweaning periods.