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H3 K27M-altered diffuse midline gliomas (DMGs) are highly malignant tumours that arise in the midline structures of the CNS. Most DMGs carry an H3 K27M-mutation in one of the genes encoding for histone H3. Recent studies suggested that epigenetic subgroups of DMGs can be distinguished based on alterations in the MAPK-signalling pathway, tumour localisation, mutant H3-gene, or overall survival (OS). However, as these parameters were studied individually, it is unclear how they collectively influence survival. Hence, we analysed dependencies between different parameters, to define novel epigenetic, clinically meaningful subgroups of DMGs. We collected a multifaceted cohort of 149 H3 K27M-mutant DMGs, also incorporating data of published cases. DMGs were included in the study if they could be clearly allocated to the spinal cord (n = 31; one patient with an additional sellar tumour), medulla (n = 20), pons (n = 64) or thalamus (n = 33), irrespective of further known characteristics. We then performed global genome-wide DNA methylation profiling and, for a subset, DNA sequencing and survival analyses. Unsupervised hierarchical clustering of DNA methylation data indicated two clusters of DMGs, i.e. subtypes DMG-A and DMG-B. These subtypes differed in mutational spectrum, tumour localisation, age at diagnosis and overall survival. DMG-A was enriched for DMGs with MAPK-mutations, medullary localisation and adult age. 13% of DMG-A had a methylated MGMT promoter. Contrarily, DMG-B was enriched for cases with TP53-mutations, PDGFRA-amplifications, pontine localisation and paediatric patients. In univariate analyses, the features enriched in DMG-B were associated with a poorer survival. However, all significant parameters tested were dependent on the cluster attribution, which had the largest effect on survival: DMG-A had a significantly better survival compared to DMG-B (p < 0.001). Hence, the subtype attribution based on two methylation clusters can be used to predict survival as it integrates different molecular and clinical parameters. [ABSTRACT FROM AUTHOR]

Efficient cellular fusion of mononuclear precursors is the prerequisite for the generation of fully functional multinucleated bone-resorbing osteoclasts. However, the exact molecular factors and mechanisms controlling osteoclast fusion remain incompletely understood. Here we identify RANKL-mediated activation of caspase-8 as early key event during osteoclast fusion. Single cell RNA sequencing-based analyses suggested that activation of parts of the apoptotic machinery accompanied the differentiation of osteoclast precursors into mature multinucleated osteoclasts. A subsequent characterization of osteoclast precursors confirmed that RANKL-mediated activation of caspase-8 promoted the non-apoptotic cleavage and activation of downstream effector caspases that translocated to the plasma membrane where they triggered activation of the phospholipid scramblase Xkr8. Xkr8-mediated exposure of phosphatidylserine, in turn, aided cellular fusion of osteoclast precursors and thereby allowed generation of functional multinucleated osteoclast syncytia and initiation of bone resorption. Pharmacological blockage or genetic deletion of caspase-8 accordingly interfered with fusion of osteoclasts and bone resorption resulting in increased bone mass in mice carrying a conditional deletion of caspase-8 in mononuclear osteoclast precursors. These data identify a novel pathway controlling osteoclast biology and bone turnover with the potential to serve as target for therapeutic intervention during diseases characterized by pathologic osteoclast-mediated bone loss. [ABSTRACT FROM AUTHOR]

Efficient cellular fusion of mononuclear precursors is the prerequisite for the generation of fully functional multinucleated bone-resorbing osteoclasts. However, the exact molecular factors and mechanisms controlling osteoclast fusion remain incompletely understood. Here we identify RANKL-mediated activation of caspase-8 as early key event during osteoclast fusion. Single cell RNA sequencing-based analyses suggested that activation of parts of the apoptotic machinery accompanied the differentiation of osteoclast precursors into mature multinucleated osteoclasts. A subsequent characterization of osteoclast precursors confirmed that RANKL-mediated activation of caspase-8 promoted the non-apoptotic cleavage and activation of downstream effector caspases that translocated to the plasma membrane where they triggered activation of the phospholipid scramblase Xkr8. Xkr8-mediated exposure of phosphatidylserine, in turn, aided cellular fusion of osteoclast precursors and thereby allowed generation of functional multinucleated osteoclast syncytia and initiation of bone resorption. Pharmacological blockage or genetic deletion of caspase-8 accordingly interfered with fusion of osteoclasts and bone resorption resulting in increased bone mass in mice carrying a conditional deletion of caspase-8 in mononuclear osteoclast precursors. These data identify a novel pathway controlling osteoclast biology and bone turnover with the potential to serve as target for therapeutic intervention during diseases characterized by pathologic osteoclast-mediated bone loss. [ABSTRACT FROM AUTHOR]

Objective: The study objective was to assess the role of CCL19+ lymph node stromal cells of the joint‐draining popliteal lymph node (pLN) for the development of arthritis. Methods: CCL19+ lymph node stromal cells were spatiotemporally depleted for five days in the pLN before the onset of collagen‐induced arthritis (CIA) using Ccl19‐Cre × iDTR mice. In addition, therapeutic treatment with recombinant CCL19–immunoglobulin G (IgG), locally injected in the footpad, was used to confirm the results. RNA sequencing of lymph node stromal cells combined with T cell coculture assays using tropomyosin receptor kinase (Trk) family inhibitors together with in vivo local pLN small interfering RNA (siRNA) treatments were used to elucidate the pathway by which CCL19+ lymph node stromal cells initiate the onset of arthritis. Results: Spatiotemporal depletion of CCL19+ lymph node stromal cells prevented disease onset in CIA mice. These inhibitory effects could be mimicked by local CCL19‐IgG treatment. The messenger RNA sequencing analyses showed that CCL19+ lymph node stromal cells down‐regulated the expression of the tropomyosin receptor kinase A (TrkA) just before disease onset. Blocking TrkA in lymph node stromal cells led to increased T cell proliferation in in vitro coculture assays. Similar effects were observed with the pan‐Trk inhibitor larotrectinib in cocultures of lymph node stromal cells of patients with rheumatoid arthritis and T cells. Finally, local pLN treatment with TrkA inhibitor and TrkA siRNA led to exacerbated arthritis scores. Conclusion: CCL19+ lymph node stromal cells are crucially involved in the development of inflammatory arthritis. Therefore, targeting of CCL19+ lymph node stromal cells via TRK could provide a tool to prevent arthritis. [ABSTRACT FROM AUTHOR]

They were collected from plants with symptoms of yellowing and wilting in commercial chickpea fields in five municipalities in southern Guanajuato, Mexico. From these, the pathogens present in the stem and root were isolated and identified. Of the isolates obtained, those with morphological characteristics of Sclerotium rolfsii had their identity confirmed by sequencing the ITS fragments obtained with the oligonucleotides: NsiF and Nlb4R; the sequences obtained were compared with the NCBI database. Of the two isolates identified as S. rolfsii by both methodologies, the most virulent was identified, which was used to inoculate 181 chickpea genotypes of the kabuli and desi types. The results indicate that, according to the mortality percentage, the genotypes of the desi type ICC3287, ICC 4874, ICC1882, ICC 10259 and WR-315, and kabuli type CUGA 08-3160 presented moderate resistance to the pathogen. Of these resistant genotypes, ICC 10259 stands out, which has genetic resistance to four races of Fusarium oxysporum f. sp. ciceris and M. phaseolina. [ABSTRACT FROM AUTHOR]

In this study, eight invasive plant species were processed into botanical pesticides, and their bioefficacy was tested against the two-spotted spider mite, Tetranychus urticae. The evaluated botanical pesticides showed high toxicity against adult females of T. urticae, where the mortality ranged from 39.5–99.5% in the treatment groups, while the mortality was 0.5% in the control. Moreover, the oviposition deterrence activity of the botanical pesticides was reflected by the lower number of eggs laid in the treatment groups (9.1–255.5 eggs) compared to the control (504.8 eggs). The ovicidal activity bioassay revealed that the hatchability of eggs following the application of botanical pesticides was reduced to 63.5–95.5%, while the hatchability was 98.8% in the control. However, the ethanolic leaf extract of Mimosa pudica seemed to be the most efficacious botanical pesticide in all parameters observed since it showed high efficacy even when applied at a concentration of 7.5 g/L instead of 10 g/L. Through gas chromatography-mass spectrometry (GC/MS) analysis, 15 phytoconstituents that might be responsible for the anti-mite features were identified. The botanical pesticides used in this study have the potential to be used as environmentally friendly measures to manage T. urticae particularly in organic farming. [ABSTRACT FROM AUTHOR]

Staphylococcus aureus is a highly successful pathogen infecting various body parts and forming biofilms on natural and artificial surfaces resulting in difficult-to-treat and chronic infections. We investigated the secreted cytokines and proteomes of isolated peripheral blood mononuclear cells (PBMCs) from healthy volunteers exposed to methicillin-resistant S. aureus (MRSA) biofilms or planktonic bacteria. Additionally, the cytokine profiles in sera from patients with community-acquired pneumonia (CAP) caused by S. aureus were investigated. The aim was to gain insights into the immune response involved and differentiate between the planktonic and sessile MRSA forms. We identified 321 and 298 targets that were significantly differently expressed in PBMCs when exposed to planktonic or biofilm-embedded bacteria, respectively. PBMCs exposed to planktonic MRSA cells secreted increased levels of TNF-a, while IL-18 was elevated when exposed to the biofilm. The machine-learning analyses of the cytokine profiles obtained for the in vitro PBMCs and CAP sera distinguished between the two types of bacteria forms based on cytokines IL-18, IL12, and IL-17, and with a lower importance IL-6. Particularly, IL-18 which has not been correlated with S. aureus biofilms so far might represent a suitable marker for monitoring chronification during MRSA infection to individualize the therapy, but this hypothesis must be proved in clinical trials. [ABSTRACT FROM AUTHOR]

Starch derivatizations require harsh chemicals as solvents or catalysts, which can negate the green nature of starch-based materials. Often, these reaction systems require several hours to achieve moderate degrees of substitution (DS), drastically reduce molar mass and can result in undesired crosslinking compromising solubility. Here, we report an efficient and sustainable starch esterification with acetic anhydride (AA) and the optimization of the process avoiding initiators in terms of molar ratios, time, and temperature. Furthermore, chromatographic (HPSEC-MALS-dRI) and spectroscopic (FTIR, 1H NMR, 2D HSQC and HMBC, Solid State CP/MAS 13C NMR, TG-IR) tools were implemented to elucidate the chemical composition and structure of the resulting starch acetates and potential intermediate side reaction products over the course of the reaction. Different combinations of choline chloride (ChCl) with several hydrogen bond acceptors (urea, tartaric, malonic, and malic acids) were used as both chaotropic solvents and reaction promoters for starch acetylation. The reaction system comprising 1 : 1 molar ChCl : urea and AA showed good miscibility at 100 °C after 30 min, representing a seemingly homogeneous reaction system while better preserving starch molar mass. Side products emerging from solvent-reagent interactions, such as starch carbamate and acetylurea, were identified. Reaction optimization resulted in no side products, fast reaction rates (36 min), high DS (2.87) and starch loads (20 wt%), and increased reaction throughput and atom economy. Catalyst-free starch acetylation reduced hygroscopicity and increased glass transition and degradation temperatures (162 °C and 397 °C, respectively), while generally keeping a relatively higher molar mass (1.5–2.9 × 106 Da) than traditional starch acetates. [ABSTRACT FROM AUTHOR]

Progress in magnetoelectric materials is hindered by apparently contradictory requirements for time‐reversal symmetry broken and polar ferroelectric electronic structure in common ferromagnets and antiferromagnets. Alternative routes can be provided by recent discoveries of a time‐reversal symmetry breaking anomalous Hall effect (AHE) in noncollinear magnets and altermagnets, but hitherto reported bulk materials are not polar. Here, the authors report the observation of a spontaneous AHE in doped AgCrSe2, a layered polar semiconductor with an antiferromagnetic coupling between Cr spins in adjacent layers. The anomalous Hall resistivity 3 μΩcm$\mu \Omega \, \textnormal {cm}$ is comparable to the largest observed in compensated magnetic systems to date, and is rapidly switched off when the angle of an applied magnetic field is rotated to ≈80° from the crystalline c‐axis. The ionic gating experiments show that the anomalous Hall conductivity magnitude can be enhanced by modulating the p‐type carrier density. They also present theoretical results that suggest the AHE is driven by Berry curvature due to noncollinear antiferromagnetic correlations among Cr spins, which are consistent with the previously suggested magnetic ordering in AgCrSe2. The results open the possibility to study the interplay of magnetic and ferroelectric‐like responses in this fascinating class of materials. [ABSTRACT FROM AUTHOR]

Aim: Pilocytic astrocytomas (PA) in adults are rare and may be challenging to identify based only on histomorphology. Compared to their paediatric counterparts, they are reportedly molecularly more diverse and associated with a worse prognosis. We aimed to describe the characteristics of adult PAs more precisely by comprehensively profiling a series of 79 histologically diagnosed adult cases (≥18 years). Methods: We performed global DNA methylation profiling and DNA and RNA panel sequencing and integrated the results with clinical data. We further compared the molecular characteristics of adult and paediatric PAs that had a significant match to one of the established PA methylation classes in the Heidelberg brain tumour classifier. Results: The mean age in our cohort was 33 years, and 43% of the tumours were located supratentorially. Based on methylation profiling, only 39% of the cases received a significant match to a PA methylation class. Sixteen per cent matched a different tumour type, and 45% had a Heidelberg classifier score <0.9 with an affiliation to diverse established methylation classes in t‐SNE analyses. Although the KIAA1549::BRAF fusion was found in 98% of paediatric PAs, this was true for only 27% of histologically defined and 55% of adult PAs defined by methylation profiling. Conclusions: A particularly high fraction of adult tumours with histological features of PA do not match current PA methylation classes, indicating ambiguous histology and an urgent need for molecular profiling. Moreover, even in adult PAs with a match to a PA methylation class, the distribution of genetic drivers differs significantly from their paediatric counterparts (p < 0.01). [ABSTRACT FROM AUTHOR]

In the context of robust Bayesian analysis, studies mainly focus on computing the range of some quantities of interest when the prior distribution varies in a class. We use the concept of distorted bands to introduce a family of priors on the shape parameter of the Generalized Pareto distribution. We show how certain properties of the likelihood ratio order allow us to propose novel sensitivity measures for Value at Risk and Conditional Value at Risk, which are the most useful and reliable risk measures. Although we focus on the Generalized Pareto distribution, which is essential in Extreme Value Theory, the new sensitivity measures could be employed for all the distributions that verify certain conditions related to likelihood ratio order. A thorough simulation study was carried out to perform a sensitivity analysis, and two illustrative examples are also provided. [ABSTRACT FROM AUTHOR]

Enhanced osteoclastogenesis and osteoclast activity contribute to the development of osteoporosis, which is characterized by increased bone resorption and inadequate bone formation. As novel antiosteoporotic therapeutics are needed, understanding the genetic regulation of human osteoclastogenesis could help identify potential treatment targets. This study aimed to provide an overview of transcriptional reprogramming during human osteoclast differentiation. Osteoclasts were differentiated from CD14+ monocytes from eight female donors. RNA sequencing during differentiation revealed 8 980 differentially expressed genes grouped into eight temporal patterns conserved across donors. These patterns revealed distinct molecular functions associated with postmenopausal osteoporosis susceptibility genes based on RNA from iliac crest biopsies and bone mineral density SNPs. Network analyses revealed mutual dependencies between temporal expression patterns and provided insight into subtype-specific transcriptional networks. The donor-specific expression patterns revealed genes at the monocyte stage, such as filamin B (FLNB) and oxidized low-density lipoprotein receptor 1 (OLR1, encoding LOX-1), that are predictive of the resorptive activity of mature osteoclasts. The expression of differentially expressed G-protein coupled receptors was strong during osteoclast differentiation, and these receptors are associated with bone mineral density SNPs, suggesting that they play a pivotal role in osteoclast differentiation and activity. The regulatory effects of three differentially expressed G-protein coupled receptors were exemplified by in vitro pharmacological modulation of complement 5 A receptor 1 (C5AR1), somatostatin receptor 2 (SSTR2), and free fatty acid receptor 4 (FFAR4/GPR120). Activating C5AR1 enhanced osteoclast formation, while activating SSTR2 decreased the resorptive activity of mature osteoclasts, and activating FFAR4 decreased both the number and resorptive activity of mature osteoclasts. In conclusion, we report the occurrence of transcriptional reprogramming during human osteoclast differentiation and identified SSTR2 and FFAR4 as antiresorptive G-protein coupled receptors and FLNB and LOX-1 as potential molecular markers of osteoclast activity. These data can help future investigations identify molecular regulators of osteoclast differentiation and activity and provide the basis for novel antiosteoporotic targets. [ABSTRACT FROM AUTHOR]

Ependymomas encompass multiple clinically relevant tumor types based on localization and molecular profiles. Tumors of the methylation class “spinal ependymoma” (SP-EPN) represent the most common intramedullary neoplasms in children and adults. However, their developmental origin is ill-defined, molecular data are scarce, and the potential heterogeneity within SP-EPN remains unexplored. The only known recurrent genetic events in SP-EPN are loss of chromosome 22q and NF2 mutations, but neither types and frequency of these alterations nor their clinical relevance have been described in a large, epigenetically defined series. Transcriptomic (n = 72), epigenetic (n = 225), genetic (n = 134), and clinical data (n = 112) were integrated for a detailed molecular overview on SP-EPN. Additionally, we mapped SP-EPN transcriptomes to developmental atlases of the developing and adult spinal cord to uncover potential developmental origins of these tumors. The integration of transcriptomic ependymoma data with single-cell atlases of the spinal cord revealed that SP-EPN display the highest similarities to mature adult ependymal cells. Unsupervised hierarchical clustering of transcriptomic data together with integrated analysis of methylation profiles identified two molecular SP-EPN subtypes. Subtype A tumors primarily carried previously known germline or sporadic NF2 mutations together with 22q loss (bi-allelic NF2 loss), resulting in decreased NF2 expression. Furthermore, they more often presented as multilocular disease and demonstrated a significantly reduced progression-free survival as compared to SP-EP subtype B. In contrast, subtype B predominantly contained samples without NF2 mutation detected in sequencing together with 22q loss (monoallelic NF2 loss). These tumors showed regular NF2 expression but more extensive global copy number alterations. Based on integrated molecular profiling of a large multi-center cohort, we identified two distinct SP-EPN subtypes with important implications for genetic counseling, patient surveillance, and drug development priorities. [ABSTRACT FROM AUTHOR]

Natural inert dust has been used as a grain protectant since the ancient Aztecs of Mexico to this modern era. Natural inert dust is divided into three groups: the first group includes sand, kaolin, paddy husk ash, wood ash, and clay; the second group includes mineral dust; and the third group includes natural silicas such as diatomaceous earth and zeolite. Natural inert dust has a unique mechanism for killing insect pests. Inert dust particles penetrate the insects' exoskeleton, causing dehydration through the cuticle. Relative humidity is a crucial factor affecting the efficacy of inert dust application. Inert dust has been traditionally used by farmers, which impacts the insects, such as decreasing population, no insect resistance, and being environmentally friendly. Problems of using inert dust include visible residues on grain, airborne dust, reduced flowability, bulk density reduction, and adverse effects on downstream processing machinery. Moreover, inert dust is a very light product, thus it may cause human respiratory illness. The inert dust can be applied to the smaller or larger storage containers. Natural silica can be readily integrated into modern agriculture as a pest management solution. [ABSTRACT FROM AUTHOR]

Defective modules that cause software execution failures are common in large software projects. Source code for a significant number of modules may be found in several software repositories. This software repository includes each module's software metrics and the module's faulty status. Software companies face a considerable problem detecting defects in sizeable and complex programming code. In addition, many international reports, such as the comprehensive human appraisal for originating (CHAOS) report, have mentioned that there are countless reasons for the failure of software projects, including the inability to detect errors and defects in the programming code of those projects at an early stage. This research employs a statistical analysis technique to reveal the characteristics that indicate the faulty status of software modules. It is recommended that statistical analysis models derived from the retrieved information be merged with existing project metrics and bug data to improve prediction. When all algorithms are merged with weighted votes, the results indicate enhanced prediction abilities. The proposed statistical analysis outperforms the state-of-the-art method (association rule, decision tree, Naive Bayes, and neural network) in terms of accuracy by 9.1%, 10.3%, 13.1%, and 13.1%, respectively. [ABSTRACT FROM AUTHOR]

Photochromic supramolecular hydrogels are versatile materials that show macroscopic effects upon irradiation, like liquefaction or shape changes. Here, we demonstrate a simple photochromic cyclic dipeptide (2,5‐diketopiperazine‐based) supergelator, composed of (S)‐lysine and an azobenzene analogue of phenylalanine, that forms supramolecular hydrogels even at 0.1 wt% loading. The gels can physically encapsulate cargo molecules and release them to the environment in a controllable manner upon irradiation with red light, thus working as a "molecular syringe". As the material is biocompatible and operational in the "therapeutic window" of light (>650 nm) that deeply penetrates soft human tissues, it is applicable to smart drug‐delivery systems. [ABSTRACT FROM AUTHOR]

Mucosal melanoma remains a rare cancer with high mortality and a paucity of therapeutic options. This is due in significant part to its low incidence leading to limited patient access to expert care and downstream clinical/basic science data for research interrogation. Clinical challenges such as delayed and at times inaccurate diagnoses, and lack of consensus tumor staging have added to the suboptimal outcomes for these patients. Clinical trials, while promising, have been difficult to activate and accrue. While individual institutions and investigators have attempted to seek solutions to such problems, international, national, and local partnership may provide the keys to more efficient and innovative paths forward. Furthermore, a mucosal melanoma coalition would provide a potential network for patients and caregivers to seek expert opinion and advice. The Melanoma Research Foundation Mucosal Melanoma Meeting (December 16, 2022, New York, USA) highlighted the current clinical challenges faced by patients, providers, and scientists, identified current and future clinical trial investigations in this rare disease space, and aimed to increase national and international collaboration among the mucosal melanoma community in an effort to improve patient outcomes. The included proceedings highlight the clinical challenges of mucosal melanoma, global clinical trial experience, basic science advances in mucosal melanoma, and future directions, including the creation of shared rare tumor registries and enhanced collaborations. [ABSTRACT FROM AUTHOR]

Neutrophils are critical phagocytic cells in innate immunity, playing a significant role in defending against invasive fungal pathogens. This study aimed to explore the transcriptional activation of human neutrophils in response to different fungal pathogens, including Candida albicans and Aspergillus fumigatus, compared to the bacterial pathogen Escherichia coli. We identified distinct transcriptional profiles and stress-related pathways in neutrophils during fungal infections, highlighting their functional diversity and adaptability. The transcriptional response was largely redundant across all pathogens in immune-relevant categories and cytokine pathway activation. However, differences in the magnitude of differentially expressed genes (DEGs) were observed, with A. fumigatus inducing a lower transcriptional effect compared to C. albicans and E. coli. Notably, specific gene signatures associated with cell death were differentially regulated by fungal pathogens, potentially increasing neutrophil susceptibility to autophagy, pyroptosis, and neutrophil extracellular trap (NET) formation. These findings provide valuable insights into the complex immunological responses of neutrophils during fungal infections, offering new avenues for diagnostic and therapeutic strategies, particularly in the management of invasive fungal diseases. [ABSTRACT FROM AUTHOR]

Algae are a rich but unexplored source of fibers with the potential to contribute to the next generation of prebiotics. The sulfated brown algae polysaccharide, fucoidan, is mainly composed of the deoxy-hexose L-fucose, which can be metabolized to 1,2-propanediol (1,2-PD) or lactate by gut microbes as precursors of propionate and butyrate. It was the aim of this study to investigate the impact of fucoidan on the fermentation capacity of the fecal microbiota and to compare to fucose. In batch fermentations of fecal microbiota collected from 17 donor samples, fucose promoted the production of propionate while no consistent effect was observed for commercial fucoidan and Fucus vesiculosus extract prepared in this study containing laminarin and fucoidan. H2S production was detected under all tested conditions, and levels were significantly lower in the presence of fucose in a dose-dependent manner. The addition of high fucose levels led to higher relative abundance of microbial 1,2-PD and lactate cross-feeders. Our results highlight that fucose and not fucoidan addition impacted fermentation capacity and increased the proportions of propionate and butyrate, which allows for precise modulation of intestinal microbiota activity. [ABSTRACT FROM AUTHOR]

Objective: In this study, we aimed to decipher the gut microbiome (GM) and serum metabolic characteristic of individuals at high risk for rheumatoid arthritis (RA) and to investigate the causative effect of GM on the mucosal immune system and its involvement in the pathogenesis of arthritis. Methods: Fecal samples were collected from 38 healthy individuals and 53 high‐risk RA individuals with anti–citrullinated protein antibody (ACPA) positivity (Pre‐RA), 12 of 53 Pre‐RA individuals developed RA within 5 years of follow‐up. The differences in intestinal microbial composition between the healthy controls and Pre‐RA individuals or among Pre‐RA subgroups were identified by 16S ribosomal RNA sequencing. The serum metabolite profile and its correlation with GM were also explored. Moreover, antibiotic‐pretreated mice that received GM from the healthy control or Pre‐RA groups were then evaluated for intestinal permeability, inflammatory cytokines, and immune cell populations. Collagen‐induced arthritis (CIA) was also applied to test the effect of fecal microbiota transplantation (FMT) from Pre‐RA individuals on arthritis severity in mice. Results: Stool microbial diversity was lower in Pre‐RA individuals than in healthy controls. The bacterial community structure and function significantly differed between healthy controls and Pre‐RA individuals. Although there were differences to some extent in the bacterial abundance among the Pre‐RA subgroups, no robust functional differences were observed. The metabolites in the serum of the Pre‐RA group were dramatically different from those in the healthy controls group, with KEGG pathway enrichment of amino acid and lipid metabolism. Moreover, intestinal bacteria from the Pre‐RA group increased intestinal permeability in FMT mice and zonula occludens‐1 expression in the small intestine and Caco‐2 cells. Moreover, Th17 cells in the mesenteric lymph nodes and Peyer's patches were also increased in mice receiving Pre‐RA feces compared to healthy controls. The changes in intestinal permeability and Th17‐cell activation prior to arthritis induction enhanced CIA severity in PreRA‐FMT mice compared with HC‐FMT mice. Conclusion: Gut microbial dysbiosis and metabolome alterations already occur in individuals at high risk for RA. FMT from preclinical individuals triggers intestinal barrier dysfunction and changes mucosal immunity, further contributing to the development of arthritis. [ABSTRACT FROM AUTHOR]

This paper provides a presentation of differential calculus involving fourth-order tensors in consideration of the cyclic class-based tensor operations introduced in an earlier paper on fourth-order tensor algebraic operations. Three classes of cyclic second-order tensor operators, denoted by dot, cross, and star, with separate definitions for double contraction, quadruple contraction, and tensor products were recognized. The present paper examines the differentiation of second-order isotropic tensor functions with respect to a second-order tensor, taking into account the three classes of second-order tensor operators. Product rules, chain rules, and identities necessary to maintain consistency are defined. In combining the proposed calculus rules with the second-order tensor operators, a comprehensive set of proofs for the power derivatives is first presented. A closed-form solution for the second-order tensor derivative of an isotropic tensor function is also detailed. Some of the new solutions are an outcome of capabilities offered by new operators and identities provided in the literature. The paper is arranged so as to be a useful reference work with regard to the mathematics of fourth-order tensors in absolute notation, particularly for application in the field of continuum mechanics in engineering. [ABSTRACT FROM AUTHOR]

Vinasse is a by-product of the sugar and alcohol industry with high toxicity and crop fertilization capacity. The bioconversion of vinasse to high-value products could represent an opportunity to reduce operating costs and environmental footprints. In this study, exopolysaccharides (EPSs) and fungal biomass were produced by different species of the genus Pleurotus (Pleurotus sajor-caju CCB 020, Pleurotus florida, Pleurotus ostreatoroseus, Pleurotus flabellatus, Pleurotus sp. CCB 068, and Pleurotus spleurotus) in submerged culture supplemented with different vinasse medium formulations. The highest yield of EPSs (about 7 g/L) was observed in the P. florida strain and the highest biomass in Pleurotus sp. CCB 068 with 28.8 g/L, after 14 days of fermentation. Results revealed that 100% vinasse is a suitable medium to achieve increased protein-rich biomass, exopolysaccharide content and minerals accumulation in the fungal biomass. Sugars predominant in the exopolysaccharide matrix were glucose, galactose, and mannose. Furthermore, the treatment of vinasse with Pleurotus provided efficient removal of color (98.8%) and turbidity (99%). The biomass following vinasse treatment can then be utilized for animal feed and human food supplementation, thus adding economic value to vinasse production. [ABSTRACT FROM AUTHOR]

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Background We sought to determine the prevalence of germline pathogenic variants (gPVs) in unselected patients with endometrial cancer (EC), define biallelic gPVs within tumors, and describe their associations with clinicopathologic features. Methods Germline assessment of at least 76 cancer predisposition genes was performed in patients with EC undergoing clinical tumor-normal Memorial Sloan Kettering–Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) sequencing from January 1, 2015, to June 30, 2021. In patients with gPVs, biallelic alterations in ECs were identified through analysis of loss of heterozygosity and somatic PVs. Clinicopathologic variables were compared using nonparametric tests. Results Of 1625 patients with EC, 216 (13%) had gPVs, and 15 patients had 2 gPVs. There were 231 gPVs in 35 genes (75 [32%] high penetrance; 39 [17%] moderate penetrance; and 117 [51%] low, recessive, or uncertain penetrance). Compared with those without gPVs, patients with gPVs were younger (P  = .002), more often White (P  = .009), and less obese (P  = .025) and had differences in distribution of tumor histology (P  = .017) and molecular subtype (P  < .001). Among 231 gPVs, 74 (32%) exhibited biallelic inactivation within tumors. For high-penetrance gPVs, 63% (47 of 75) of ECs had biallelic alterations, primarily affecting mismatch repair (MMR) and homologous recombination related genes, including BRCA1, BRCA2 , RAD51D , and PALB2. Biallelic inactivation varied across molecular subtypes with highest rates in microsatellite instability-high (MSI-H) or copy-number (CN)–high subtypes (3 of 12 [25%] POLE, 30 of 77 [39%] MSI-H, 27 of 60 [45%] CN-high, 9 of 57 [16%] CN-low; P  < .001). Conclusions Of unselected patients with EC, 13% had gPVs, with 63% of gPVs in high-penetrance genes (MMR and homologous recombination) exhibiting biallelic inactivation, potentially driving cancer development. This supports germline assessment in EC given implications for treatment and cancer prevention. [ABSTRACT FROM AUTHOR]

Blood‐brain‐barrier (BBB) disruption has been associated with a variety of central‐nervous‐system diseases. In vitro BBB models enable to investigate how the barrier reacts to external injury events, commonly referred to as insults. Here, a human‐cell‐based BBB platform with integrated, transparent electrodes to monitor barrier tightness in real time at high resolution is presented. The BBB model includes human cerebral endothelial cells and primary pericytes and astrocytes in a 3D arrangement within a pump‐free, open‐microfluidic platform. With this platform, this study demonstrates that oxygen‐glucose deprivation (OGD), which mimics the characteristics of an ischemic insult, induces a rapid remodeling of the cellular actin structures and subsequent morphological changes in the endothelial cells. High‐resolution live imaging shows the formation of large actin stress‐fiber bundles in the endothelial layer during OGD application, which ultimately leads to cell shrinkage and barrier breakage. Simultaneous electrical measurements evidence a rapid decrease of the barrier electrical resistance before the appearance of stress fibers, which indicates that the barrier function is compromised already before the appearance of drastic morphological changes. The results demonstrate that the BBB platform recapitulates the main barrier functions in vitro and can be used to investigate rapid reorganization of the BBB upon application of external stimuli. [ABSTRACT FROM AUTHOR]

Exposure of human monocytes to lipopolysaccharide (LPS) or other pathogenassociated molecular pattern (PAMPs) induces a temporary insensitivity to subsequent LPS challenges, a cellular state called endotoxin tolerance (ET), associated with the pathogenesis of sepsis. In this study, we aimed to characterize the cellular state of human monocytes from healthy donors stimulated with Staphylococcus aureus in comparison to TLR2-specific ligands. We analyzed S. aureus induced gene expression changes after 2 and 24 hours by amplicon sequencing (RNA-AmpliSeq) and compared the proinflammatory response after 2 hours with the response in re-stimulation experiments. In parallel, glycoprotein expression changes in human monocytes after 24 hours of S. aureus stimulation were analyzed by proteomics and compared to stimulation experiments with TLR2 ligands Malp-2 and Pam3Cys and TLR4 ligand LPS. Finally, we analyzed peripheral blood monocytes of patients with S. aureus bloodstream infection for their ex vivo inflammatory responses towards S. aureus stimulation and their glycoprotein expression profiles. Our results demonstrate that monocytes from healthy donors stimulated with S. aureus and TLR ligands of Gram-positive bacteria entered the tolerant cell state after activation similar to LPS treatment. In particular reduced gene expression of pro-inflammatory cytokines (TNF, IL1b) and chemokines (CCL20, CCL3, CCL4, CXCL2, CXCL3 and CXCL8) could be demonstrated. Glycoprotein expression changes in monocytes tolerized by the different TLR agonists were highly similar while S. aureus-stimulated monocytes shared some of the PAMP-induced changes but also exhibited a distinct expression profile. 11 glycoproteins (CD44, CD274, DSC2, ICAM1, LAMP3, LILRB1, PTGS2, SLC1A3, CR1, FGL2, and HP) were similarly up- or downregulated in all four comparisons in the tolerant cell state. Monocytes from patients with S. aureus bacteremia revealed preserved pro-inflammatory responsiveness to S. aureus stimulation ex vivo, expressed increased CD44 mRNA but no other glycoprotein of the tolerance signature was differentially expressed. [ABSTRACT FROM AUTHOR]

Liver cancer is a malignancy developed from underlying liver disease that encompasses liver injury and metabolic disorders. The progression from these underlying liver disease to cancer is accompanied by chronic inflammatory conditions in which liver macrophages play important roles in orchestrating the inflammatory response. During this process, bioactive lipids produced by hepatocytes and macrophages mediate the inflammatory responses by acting as pro-inflammatory factors, as well as, playing roles in the resolution of inflammation conditions. Here, we review the literature discussing the roles of bioactive lipids in acute and chronic hepatic inflammation and progression to cancer. [ABSTRACT FROM AUTHOR]

Socio-ecological systems (SESs) hinge on human groups and ecosystems, promoting interdependence and resilience to environmental disturbances. Climate change effects propagate from organism to biomes, likely influencing SES. In southern and relict patches in southeastern Brazil, Araucaria Forest is a typical SES due to the historical interaction between humans and biodiversity. We thus aimed to evaluate empirically and theoretically how climate change could disrupt this system by interviewing 97 smallholders and assessing their traditional ecological knowledge (TEK). We evaluated and measured the following: (i) socioeconomic impact of araucaria's nut-like seed (pinhão) trade; (ii) ethnoecological knowledge about climate change; and (iii) generated an ecosystem services network. We projected these empiric data with a projected loss of 50–70% of the Araucaria Forest due to climate change to quantify the risks of the potential disruption of this socioecological system. We found evidence that to avoid the disruption of the Araucaria Forests is paramount to value TEK holders, safeguard the historical socioecological interaction, and promote non-mutually exclusive measures in an integrative response to maintain the Araucaria Forests resilient to future disturbances. [ABSTRACT FROM AUTHOR]

The authors provided a novel explicit expression for the dot derivative of an isotropic tensor function in the work by Kellermann et al. An alternate proof is provided in this addendum without the power series assumption. [ABSTRACT FROM AUTHOR]

In the summer of 1838, Arnold Guyot was asked by Louis Agassiz to gather information on Alpine glaciers, with the aim of reporting their findings in September, at the annual gathering of the French Geological Society. Guyot's observations of the internal structure of the ice and interpretations on glacier movements, reported orally at the conference, were new to science. Unfortunately, because of purported illness, Guyot did not send his manuscript to be published and missed his first opportunity to be recognized as a pioneer in glacier studies. During the years 1841 to 1847, Guyot published a series of notes, detailing results of his field work in tracing erratic blocks in the central Alpine region, in the Alpine foreland and in the Jura Mountains. The level of detail in his work was unprecedented and has not been replicated since. Recognizing that erratic blocks of similar lithology could be followed along organized paths of deposition, Guyot could invalidate those theories that sought to explain their deposition by chaotic means, such as floods, debacles or drifting icebergs loaded with rock debris. Only moraines, composed of material transported by glaciers, could explain the mapped arrangements of erratic blocks. Geological proofs for extensive glaciations in central Europe had just been found, and Guyot could demonstrate them on his hand-drawn map. But, in 1848, a revolution broke out in Neuchâtel. The local academy where Guyot was engaged as a professor shut down and all staff were left without pay. Answering a call from Agassiz who had emigrated to the USA in 1846, Guyot departed Switzerland and joined his friend there in the fall of 1848. In his luggage were all the papers on his unfinished project, including his map, and a full collection of erratic rock specimens. After arrival in the USA, Guyot had to begin a new professional life and could not devote significant attention to the subject of erratic blocks. In 1849, he showed his map of the erratic basins of Switzerland and discussed his results with various members of the American Association for the Advancement of Science (AAAS); he also shared his novel ideas about the climatic conditions required for the formation of large glaciers; however, he did not formally publish the results of his work in the Alps, and he thus lost his second opportunity for wider peer recognition and for driving the acceptance of the glacial theory. Only in 1874, 26 years after his arrival in the USA and a year after Agassiz's death, did Guyot open his boxes of alpine rock specimens and display his unpublished map in the Museum of the College of New Jersey (later Princeton University), where he was engaged as a professor. In 1883, at age 77, his memory of the unpublished 1838 report on glaciers was still in his conscience which finally pushed him to submit it for printing at Neuchâtel. It passed largely unnoticed, however, and Guyot died one year later without recognition attached to his name for his original, innovative work. This paper reviews Guyot's work and analyses his relationship with Agassiz while both were working in Neuchâtel. It seeks to evaluate his pioneering work on glaciers and on erratic blocks. It includes a copy of Guyot's map of the erratic basins of Switzerland, kept to this day in the archives of Princeton University. [ABSTRACT FROM AUTHOR]

Ambrosia beetles are the largest group of beetles living mutualistically with ambrosia fungi. Increased global shipments of forest and agricultural products have expanded the distribution of some species of ambrosia beetle. We investigated the partitioning diversity of the ambrosia beetle community on teak plantations in Indonesia's Java, Sumbawa, and Sulawesi Islands. The ambrosia beetles were collected on the twelve sites of teak plantations with different managements (un-thinned and thinned) in Java, Sulawesi, and Sumbawa Islands. Ambrosia beetles were collected ten times at 7-day intervals. The diversity of ambrosia beetles recorded in teak plantations across twelve sites in Java, Sumbawa, and Sulawesi Islands were 17 species and 6154 individuals. Xyleborus affinis (47.17%), Xylosandrus crassiusculus (27.64%), and Hypothenemus sp. (12.33%) were the three dominant species. The highest and lowest species richness were found in the teak plantations in Java and Sumbawa Islands, respectively. The highest and lowest populations of ambrosia beetles were in Sulawesi and Sumbawa islands, respectively. Three factors contribute to the species richness of ambrosia beetles, i.e., temperature, rainfall, and altitude. Stand age, temperature, rainfall, altitude, and teak management contribute to ambrosia beetle abundance. Ambrosia beetle communities among islands show differences between each group, as confirmed by analysis of variance based on homogeneity of multivariate dispersion (sig. 0.001) and permutation test for homogeneity of multivariate dispersions (sign. 0.001). For the group of teak managements, there are differences between both teak managements, as confirmed by analysis of variance based on homogeneity of multivariate dispersion (sig. 0.001) and permutation test for homogeneity of multivariate dispersions (sign. 0.01). Based on the eigenvalues for PCoA axes by the Bray–Curtis method, Sulawesi Island is separate from both Java, and Sumbawa islands. However, Java and Sumbawa islands overlap each other. For groups of teak managements (thinning and non-thinning), there are overlap with each other based on the eigenvalues for PCoA axes by the Bray–Curtis method. The β-1 (Within bottle trap/local scale) contributes the highest to γ-diversity (42.46%). The relative contribution of species replacement (β-sim) in multiple sites across Java, Sumbawa, and Sulawesi Islands (regional scale) provides a high contribution (85%) to overall beta diversity, and the relative contribution of β-nes to the β-sor among sites is 14.03%. [ABSTRACT FROM AUTHOR]

Background: Esophageal cancer and gastric cancer are two important causes of upper GI malignancies. Literature has shown that minimally invasive esophagectomies (MIE) and gastrectomies (MIG), have shorter length of stay and fewer complications. However, limited literature exists about the association between race and access to MIE and MIG. This study aims to identify the racial disparities in the different approaches to esophagectomy and gastrectomy. We further evaluate the relationship between the race and postoperative complications. Methods: This IRB-approved retrospective study utilized data from the American College of Surgeons National Quality Improvement Program. All recorded cases of MIE, MIG, open gastrectomy, and esophagectomy between 2012 and 2019 were isolated. Propensity score matching and univariate analysis was performed to assess the independent effect of black self-identified race on access and outcomes. p < 0.05 was required to achieve statistical significance. Results: 7891 cases of esophagectomy and 5,132 cases of gastrectomy cases were identified. Using Propensity and logistic regression, we identified that black self-reported race is an independent predictor of open approach to gastrectomy (OR 1.6871943, 95% CI 1.431464–1.989829, p < 0.001). Black self-reported race was not predictive of operative approach among esophagectomy patients (OR 0.7942576, 95% CI 0.5698645–1.124228, p = 0.183). In contrast, black self-reported is an independent predictor of postoperative complications among esophagectomy patients only. Esophagectomy patients of black self-reported race were more likely to experience any complication (OR 1.4373437, 95% CI 1.1129239–1.8557096, p = 0.00537), severe complications (OR 1.3818966, 95% CI 1.0653087–1.7888454, p = 0.0144), and death (OR 2.00779762, 95% CI 1.08034921–3.56117535, p = 0.0211) within 30 days of their surgeries. Conclusion: Our analysis revealed a significant racial disparity in access to MIG and a higher incidence of post-operative complications amongst esophagectomy patients. Minimally invasive techniques are underutilized in racial minorities. The findings herein warrant further investigation to eliminate barriers and disparities. [ABSTRACT FROM AUTHOR]

In this video, we review the steps of uterine transposition, emphasizing robotic trocar placement and docking, how to optimize organ manipulation and tissue handling, and our pearls for successful perioperative management. The patient is a 27-year-old woman with T2 node-positive rectal cancer. Uterine transposition is a new surgical procedure with limited information regarding outcomes. Although evolving over time, we present our preferred patient selection criteria and identify key stakeholders, which include colorectal surgeons, radiation oncologists, fertility specialists, social workers, and radiologists. [ABSTRACT FROM AUTHOR]

In this surgical teaching video, we demonstrate the technique of robot-assisted uterine anastomosis combined with low anterior resection in a 27-year-old patient with T2 node-positive rectal cancer. The patient had undergone uterine transposition for fertility preservation prior to upfront chemotherapy and radiation therapy for rectal cancer. In this video, we review the key steps of both surgical procedures. We emphasize robot trocar placement and docking, demonstrate optimal organ manipulation and tissue handling, and include key operative modifications and pearls for successful perioperative management. [ABSTRACT FROM AUTHOR]

Obesity confers an independent risk for carcinogenesis. Classically viewed as a genetic disease, owing to the discovery of tumor suppressors and oncogenes, genetic events alone are not sufficient to explain the progression and development of cancers. Tumor development is often associated with metabolic and immunological changes. In particular, obesity is found to significantly increase the mortality rate of liver cancer. As its role is not defined, a fundamental question is whether and how metabolic changes drive the development of cancer. In this review, we will dissect the current literature demonstrating that liver lipid dysfunction is a critical component driving the progression of cancer. We will discuss the involvement of inflammation in lipid dysfunction driven liver cancer development with a focus on the involvement of liver macrophages. We will first discuss the association of steatosis with liver cancer. This will be followed with a literature summary demonstrating the importance of inflammation and particularly macrophages in the progression of liver steatosis and highlighting the evidence that macrophages and macrophage produced inflammatory mediators are critical for liver cancer development. We will then discuss the specific inflammatory mediators and their roles in steatosis driven liver cancer development. Finally, we will summarize the molecular pattern (PAMP and DAMP) as well as lipid particle signals that are involved in the activation, infiltration and reprogramming of liver macrophages. We will also discuss some of the therapies that may interfere with lipid metabolism and also affect liver cancer development. [ABSTRACT FROM AUTHOR]

Tauopathies such as progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) exhibit characteristic neuronal and glial inclusions of hyperphosphorylated Tau (pTau). Although the astrocytic pTau phenotype upon neuropathological examination is the most guiding feature in distinguishing both diseases, regulatory mechanisms controlling their transitions into disease-specific states are poorly understood to date. Here, we provide accessible chromatin data of more than 45,000 single nuclei isolated from the frontal cortex of PSP, CBD, and control individuals. We found a strong association of disease-relevant molecular changes with astrocytes and demonstrate that tauopathy-relevant genetic risk variants are tightly linked to astrocytic chromatin accessibility profiles in the brains of PSP and CBD patients. Unlike the established pathogenesis in the secondary tauopathy Alzheimer disease, microglial alterations were relatively sparse. Transcription factor (TF) motif enrichments in pseudotime as well as modeling of the astrocytic TF interplay suggested a common pTau signature for CBD and PSP that is reminiscent of an inflammatory immediate-early response. Nonetheless, machine learning models also predicted discriminatory features, and we observed marked differences in molecular entities related to protein homeostasis between both diseases. Predicted TF involvement was supported by immunofluorescence analyses in postmortem brain tissue for their highly correlated target genes. Collectively, our data expand the current knowledge on risk gene involvement (e.g., MAPT, MAPK8, and NFE2L2) and molecular pathways leading to the phenotypic changes associated with CBD and PSP. [ABSTRACT FROM AUTHOR]

As a recently explored agricultural practice, the controlled elicitation of plants offers high potential in multiple crop needs as growth promotion, activation of defenses and the production of specific metabolites. Extracellular DNA has been identified as a plant immune system elicitor but some aspects of the plant response have not been explored. In the present work, five DNA treatments were applied in tomato plants and the response of catalase, superoxide dismutase, phenylalanine ammonia lyase activities, hydrogen peroxide, total phenolics and flavonoid contents in leaves were spectrophotometrically measured. Treatments differed by the source and concentration of DNA and plant phenological stage of application. Furthermore, mathematical modeling and principal component analysis were performed to explore the behavior of each variable and their interaction. The most effective treatment was the self-DNA application in young plants based on the intensity and duration of immune system activation. The information given by the measured variables correlated positively with the phenylpropanoid pathway markers and negatively with catalase and superoxide dismutase activities. Results reported here propose an easy way to evaluate plant immune response activation by DNA and any other elicitor and provide useful information for future development of controlled elicitation strategies in crop production. [ABSTRACT FROM AUTHOR]

Summary: We report a case of a 47‐year‐old woman with a history of acral lentiginous melanoma, left great toe subungual primary, metastatic to the lungs, brain, and spleen, presenting with lower urinary tract symptoms. She had also palpated and removed a dark mass from her vaginal canal. Magnetic resonance imaging (MRI) showed polypoidal lesions within the urinary bladder and the endometrium. The suspected differential diagnosis was endometrial and bladder melanoma metastases, based on her cancer history and MRI findings. The patient underwent cystoscopy with transurethral resection of the bladder tumor and endometrial biopsy, and pathology was consistent with metastatic melanoma. Bladder and endometrial metastatic lesions are exceedingly rare. Herein, we describe an unusual case of metastatic melanoma concurrent to the urinary bladder and endometrium. [ABSTRACT FROM AUTHOR]