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Crohn’s disease (CD) is a chronic inflammatory bowel disease marked by relapsing, transmural intestinal inflammation driven by innate and adaptive immune responses. Autophagy is a multi-step process that plays a critical role in maintaining cellular homeostasis by degrading intracellular components, such as damaged organelles and invading bacteria. Dysregulation of autophagy in CD is revealed by the identification of several susceptibility genes, including ATG16L1, IRGM, NOD2, LRRK2, ULK1, ATG4, and TCF4, that are involved in autophagy. In this review, the role of altered autophagy in the mucosal innate immune response in the context of CD is discussed, with a specific focus on dendritic cells, macrophages, Paneth cells, and goblet cells. Selective autophagy, such as xenophagy, ERphagy, and mitophagy, that play crucial roles in maintaining intestinal homeostasis in these innate immune cells, are discussed. As our understanding of autophagy in CD pathogenesis evolves, the development of autophagy-targeted therapeutics may benefit subsets of patients harboring impaired autophagy.

Epidermal barrier dysfunction can lead to xerotic skin and promote skin disorders like atopic dermatitis. Atopic skin is characterized by reduced water-retaining compounds, altered lipid composition and elevated skin pH. Against this background, a study was conducted to investigate the impact of a specific skin care product on epidermal barrier function in dry and atopic-prone skin. A marketed pH 4.5 cosmetic formulation containing 10% urea and specific plant oils was evaluated on 25 subjects with dry and atopic-prone skin. Measurements of skin hydration, pH, and barrier function were performed before and after 3 weeks of product usage. Additionally, visual scoring and stratum corneum lipid analysis using electron microscopy were conducted to investigate lipid composition. An improved skin hydration compared to the untreated area and a tendency to decrease the baseline elevated skin surface pH were observed. The visual scoring showed reduced dryness, roughness, and tension through the application. Furthermore, the stratum corneum lipid matrix was improved in terms of lipid content and organization. The combination of an acidic product’s pH, a relevant urea content and effective plant oils is shown to be beneficial in terms of improving the skin barrier function, structure and appearance and is recommended for dry and atopic-prone skin.

Background: Ultrahigh dose‐rate radiation (UHDR) produces less hydrogen peroxide (H2O2) in pure water, as suggested by some experimental studies, and is used as an argument for the validity of the theory that FLASH spares the normal tissue due to less reactive oxygen species (ROS) production. In contrast, most Monte Carlo simulation studies suggest the opposite. Purpose: We aim to unveil the effect of UHDR on H2O2 production in pure water and its underlying mechanism, to serve as a benchmark for Monte Carlo simulation. We hypothesized that the reaction of solvated electrons (eaq−${\mathrm{e}}_{{\mathrm{aq}}}^ - $) removing hydroxyl radicals (•OH), the precursor of H2O2, is the reason why UHDR leads to a lower G‐value (molecules/100 eV) for H2O2 (G[H2O2]), because: 1, the third‐order reaction between eaq−${\mathrm{e}}_{{\mathrm{aq}}}^ - $ and •OH is more sensitive to increased instantaneous ROS concentration by UHDR than a two‐order reaction of •OH self‐reaction producing H2O2; 2, eaq−${\mathrm{e}}_{{\mathrm{aq}}}^ - $ has two times higher diffusion coefficient and higher reaction rate constant than that of •OH, which means eaq−${\mathrm{e}}_{{\mathrm{aq}}}^ - $ would dominate the competition for •OH and benefit more from the inter‐track effect of UHDR. Meanwhile, we also experimentally verify the theory of long‐lived radicals causing lower G(H2O2) in conventional irradiation, which is mentioned in some simulation studies. Methods and materials: H2O2 was measured by Amplex UltraRed assay. 430.1 MeV/u carbon ions (50 and 0.1 Gy/s), 9 MeV electrons (600 and 0.62 Gy/s), and 200 kV x‐ray tube (10 and 0.1 Gy/s) were employed. For three kinds of water (real hypoxic: 1% O2; hypoxic: 1% O2 and 5% CO2; and normoxic: 21% O2), unbubbled and bubbled samples with N2O, the scavenger of eaq−${\mathrm{e}}_{{\mathrm{aq}}}^ - $, were irradiated by carbon ions and electrons with conventional and UHDR at different absolute dose levels. Normoxic water dissolved with sodium nitrate (NaNO3), another scavenger of eaq−${\mathrm{e}}_{{\mathrm{aq}}}^ - $, and bubbled with N2O was irradiated by x‐ray to verify the results of low‐LET electron beam. Results: UHDR leads to a lower G(H2O2) than conventional irradiation. O2 and CO2 can both increase G(H2O2). N2O increases G(H2O2) of both UHDR and conventional irradiation and eliminates the difference between them for carbon ions. However, N2O decreases G(H2O2) in electron conventional irradiation but increases G(H2O2) in the case of UHDR, ending up with no dose‐rate dependency of G(H2O2). Three‐spilled carbon UHDR does not have a lower G(H2O2) than one‐spilled UHDR. However, the electron beam shows a lower G(H2O2) for three‐spilled UHDR than for one‐spilled UHDR. Normoxic water with N2O or NaNO3 can both eliminate the dose rate dependency of H2O2 production for x‐ray. Conclusions: UHDR has a lower G(H2O2) than the conventional irradiation for both high LET carbon and low LET electron and x‐ray beams. Both scavengers for eaq−${\mathrm{e}}_{{\mathrm{aq}}}^ - $, N2O and NaNO3, eliminate the dose‐rate dependency of G(H2O2), which suggests eaq−${\mathrm{e}}_{{\mathrm{aq}}}^ - $ is the reason for decreased G(H2O2) for UHDR. Three‐spilled UHDR versus one‐spilled UHDR indicates that the assumption of residual radicals reducing G(H2O2) of conventional irradiation may only be valid for low LET electron beam. [ABSTRACT FROM AUTHOR]

Our study investigates the impact of FGF23 overexpression on SaOS-2 cells to elucidate its role in cellular stress and morphology, contributing to the understanding of skeletal pathologies like X-linked hypophosphatemia (XLH). Using transmission electron microscopy and protein analysis (Western blot), we analyzed the rough endoplasmic reticulum (rER) and mitochondria in SaOS-2 cells with FGF23 overexpression compared to controls. We found significant morphological changes, including enlarged and elongated rER and mitochondria, with increased contact zones, suggesting enhanced interaction and adaptation to elevated protein synthesis and secretion demands. Additionally, we observed higher apoptosis rates of the cells after 24–72 h in vitro and upregulated proteins associated with ER stress and apoptosis, such as CHOP, XBP1 (spliced and unspliced), GRP94, eIF2α, and BAX. These findings indicate a robust activation of the unfolded protein response (UPR) and apoptotic pathways due to FGF23 overexpression. Our results highlight the critical role of ER and mitochondrial interactions in cellular stress responses and provide new insights into the mechanistic link between FGF23 signaling and cellular homeostasis. In conclusion, our study underscores the importance of analyzing UPR-related pathways in the development of therapeutic strategies for skeletal and systemic diseases and contributes to a broader understanding of diseases like XLH. [ABSTRACT FROM AUTHOR]

Grape berry moths, particularly Lobesia botrana Denis & Schiffermüller (Lepidoptera: Tortricidae), and vinegar flies, such as Drosophila melanogaster Meigen and Drosophila suzukii Matsumura (Diptera: Drosophilidae), are important vineyard pests, causing severe quality loss of grapes. Several arthropod taxa may be involved in the natural control of these pests. However, the role of arthropod predators in the natural control of vineyard pests remains unclear. We investigated 32 vineyards in the Palatinate region, southwest Germany, under organic and conventional management, which in both cases received either full or reduced fungicide applications (2 × 2 design). Predation of L. botrana eggs and pupae and D. melanogaster pupae on sentinel cards exposed in the vineyards was observed with infrared cameras. In total, nine predator taxa could be identified. The most dominant predator was the European earwig, Forficula auricularia L. (Dermaptera: Forficulidae), with 90% of all predation events. We conclude that F. auricularia is likely a key predator of vineyard pests, and that special attention should be paid to maintain it at high population densities. [ABSTRACT FROM AUTHOR]

Inequalities and discrimination based on gender identity, sexual orientation, and sex characteristics remain pervasive worldwide. Scholars have collaborated to address structural and social barriers in LGBTIQ+ research, creating a substantial literature base. However, much of this work focuses on specific segments of the population, overlooks resilience‐ and strengths‐based approaches, and is predominantly conducted in the U.S. and other Western countries. In this introduction article, we discuss how this special issue extends previous research by uniting scholars globally to collaboratively reimagine the lens through which scientists conduct LGBTIQ+ research. By exploring diverging needs across subgroups of LGBTIQ+ people, discussing the (dis)advantages of various methodological choices, and offering a better understanding of how unique legal and social landscapes affect LGBTIQ+ individuals globally, this special issue aims to provide a comprehensive picture of the current state of research combined with concrete directions for redress. Given that barriers to conducting LGBTIQ+ research differ significantly by nation, we conclude this introductory article by calling for a research community that is more aware of unequal power dynamics within academia, willing to take action to reduce disparities in the global academic system, and inclusive of voices from underrepresented groups. [ABSTRACT FROM AUTHOR]

The corrosion behavior of two different Cu–Al–Mn–Ni alloys, pseudoelastic and pseudoplastic, was studied in a 0.6 M sodium chloride aqueous solution by monitoring the open circuit potential for 100 h and characterizing the resulting corrosion products. Electrochemical impedance spectroscopy analysis detected three processes related to the electrochemical double layer, a passive film and a diffusive contribution associated with the dissolution/precipitation of corrosion products. Potentiodynamic scans revealed a cathodically controlled corrosion mechanism and the presence of active–passive behavior at anodic potentials for both alloys studied. Polarization of the samples at selected potentials in the anodic branch allowed the investigation of the reactions involved, highlighting an improved corrosion resistance of the pseudoelastic alloy. The corrosion rates of the pseudoelastic and pseudoplastic alloys, after 100 h of immersion, were determined to be 0.007 and 0.011 mmpy, respectively. The post‐experiment characterization was carried out by means of scanning electron microscopy, micro‐Raman spectroscopy and X‐ray diffraction, supporting the electrochemical results. [ABSTRACT FROM AUTHOR]

Research on LGBTIQ+ populations has focused primarily on identifying problems in the community (e.g., health disparities) and their predictors (e.g., minority stressors, discrimination). Scholars have argued that the approach of highlighting "damage" or deficits has been helpful for advocacy but has also harmed this community by perpetuating stereotypes (e.g., LGBTIQ+ individuals are unhealthy), ignoring or devaluing positive LGBTIQ+ experiences, and contributing to negative interactions in healthcare settings. To evaluate the extent to which a damage‐centered approach dominates the body of available research, the authors of this article conducted a content analysis of articles related to LGBTIQ+ health published in the Journal of Social Issues (JSI). The content analysis of 45 years of published manuscripts (1978–2023) revealed a strong emphasis on damage‐centered themes. In response, this article advocates for structural changes that may lead to an increase in research that focuses LGBTIQ+ experiences more holistically, with the overarching goal of reimaging LGBTIQ+ research. Such suggested changes include concentrated research funding and publishing opportunities, medical training that emphasizes a strengths‐based focus, and function‐oriented and autonomy‐promoting LGBTIQ+ research. This article suggests strategies to improve patient‐provider interactions in healthcare and enhance the overall well‐being of LGBTIQ+ communities. It advocates for a deliberate expansion towards a more holistic, less damage‐centered body of research in LGBTIQ+ psychology. [ABSTRACT FROM AUTHOR]

Abstract Lithium salts are used as mood-balancing medication prescribed to patients suffering from neuropsychiatric disorders, such as bipolar disorder and major depressive disorder. Lithium salts cross the blood-brain barrier and reach the brain parenchyma within few hours after oral application, however, how lithium influences directly human neuronal function is unknown. We applied patch–clamp and microelectrode array technology on human induced pluripotent stem cell (iPSC)-derived cortical neurons acutely exposed to therapeutic (1 mM) of lithium chloride (LiCl) to assess how therapeutically effective and overdose concentrations of LiCl directly influence human neuronal electrophysiological function at the synapse, single-cell, and neuronal network level. We describe that human iPSC-cortical neurons exposed to lithium showed an increased neuronal activity under all tested concentrations. Furthermore, we reveal a lithium-induced, concentration-dependent, transition of regular synchronous neuronal network activity using therapeutically effective concentration (1 mM LiCl). The overdose concentration lithium-induced epileptiform-like activity was similar to the epileptiform-like activity caused by the GABAA-receptor antagonist. Patch–clamp recordings reveal that lithium reduces action potential threshold at all concentrations, however, only overdose concentration causes increased frequency of spontaneous AMPA-receptor mediated transmission. By applying the AMPA-receptor antagonist and anti-epileptic drug Perampanel, we demonstrate that Perampanel suppresses lithium-induced epileptiform-like activity in human cortical neurons. We provide insights in how therapeutically effective and overdose concentration of lithium directly influences human neuronal function at synapse, a single neuron, and neuronal network levels. Furthermore, we provide evidence that Perampanel suppresses pathological neuronal discharges caused by overdose concentrations of lithium in human neurons.

Abstract A key predictor of morbidity and mortality for patients with a bloodstream infection is time to appropriate antimicrobial therapy. Accelerating antimicrobial susceptibility testing from positive blood cultures is therefore key to improving patient outcomes, yet traditional laboratory approaches can require 2–4 days for actionable results. The eQUANT—a novel instrument utilizing electrical biosensors—produces a standardized inoculum equivalent to a 0.5 McFarland directly from positive blood cultures. This proof-of-concept study demonstrates that eQUANT inocula prepared from clinically significant species of Enterobacterales were comparable to 0.5 McF inocula generated from bacterial colonies in both CFU/ml concentration and performance in antimicrobial susceptibility testing, with ≥ 95% essential and categorical agreement for VITEK2 and disk diffusion. The eQUANT, combined with a rapid, direct from positive blood culture identification technique, can allow the clinical laboratory to begin antimicrobial susceptibility testing using a standardized inoculum approximately 2–3 h after a blood culture flags positive. This has the potential to improve clinical practice by accelerating conventional antimicrobial susceptibility testing and the resulting targeted antibiotic therapy.

Background: Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease characterized by the loss of motor neurons in cerebral cortex, brainstem and spinal cord. Numerous studies have demonstrated signs of oxidative stress in postmortem neuronal tissue, cerebrospinal fluid, plasma and urine of ALS patients, without focusing on the specific processes within motor neurons. Thus, we aimed to investigate the relevance of reactive oxygen species (ROS) detoxification mechanisms and its consequences on the formation of toxic/lethal DNA double strand breaks (DSBs) in the ALS model of the Wobbler mouse.Methods: Live cell imaging in dissociated motor neuronal cultures was used to investigate the production of ROS using Dihydroethidium (DHE). The expression levels of ROS detoxifying molecules were investigated by qPCR as well as Western blots. Furthermore, the expression levels of DNA damage response proteins p53bp1 and H2ax were investigated using qPCR and immunofluorescence staining. Proof-of-principle experiments using ROS scavengers were performed in vitro to decipher the influence of ROS on the formation of DNA double strand breaks quantifying the γH2ax spots formation.Results: Here, we verified an elevated ROS-level in spinal motor neurons of symptomatic Wobbler mice in vitro. As a result, an increased number of DNA damage response proteins p53bp1 and γH2ax in dissociated motor neurons of the spinal cord of Wobbler mice was observed. Furthermore, we found a significantly altered expression of several antioxidant molecules in the spinal cord of Wobbler mice, suggesting a deficit in ROS detoxification mechanisms. This hypothesis could be verified by using ROS scavenger molecules in vitro to reduce the number of γH2ax foci in dissociated motor neurons and thus counteract the harmful effects of ROS.Conclusion: Our data indicate that maintenance of redox homeostasis may play a key role in the therapy of the neurodegenerative disease ALS. Our results underline a necessity for multimodal treatment approaches to prolong the average lifespan of motor neurons and thus slow down the progression of the disease, since a focused intervention in one pathomechanism seems to be insufficient in ALS therapy.

Journals exert considerable control over letters, commentaries and online comments that criticize prior research (post-publication critique). We assessed policies (Study One) and practice (Study Two) related to post-publication critique at 15 top-ranked journals in each of 22 scientific disciplines (N = 330 journals). Two-hundred and seven (63%) journals accepted post-publication critique and often imposed limits on length (median 1000, interquartile range (IQR) 500–1200 words) and time-to-submit (median 12, IQR 4–26 weeks). The most restrictive limits were 175 words and two weeks; some policies imposed no limits. Of 2066 randomly sampled research articles published in 2018 by journals accepting post-publication critique, 39 (1.9%, 95% confidence interval [1.4, 2.6]) were linked to at least one post-publication critique (there were 58 post-publication critiques in total). Of the 58 post-publication critiques, 44 received an author reply, of which 41 asserted that original conclusions were unchanged. Clinical Medicine had the most active culture of post-publication critique: all journals accepted post-publication critique and published the most post-publication critique overall, but also imposed the strictest limits on length (median 400, IQR 400–550 words) and time-to-submit (median 4, IQR 4–6 weeks). Our findings suggest that top-ranked academic journals often pose serious barriers to the cultivation, documentation and dissemination of post-publication critique.

A prática da agressividade fiscal visa amenizar o alto custo com impostos ocasionado pela complexidade da legislação tributária, mira diminuir gastos tributários e maximizar o desempenho das organizações. O presente estudo analisa o impacto da agressividade fiscal na rentabilidade das empresas de capital aberto listadas na B3 no período de 2016 a 2020, posto que no contexto brasileiro, as evidências sobre a relação entre essa prática e a rentabilidade das empresas ainda são limitadas. A amostra final do estudo foi composta por 204 empresas brasileiras e as proxies utilizadas para a mensuração da agressividade fiscal foram o Book Tax Difference total (BTD) e Effective Tax Rate (ETR). Em relação às variáveis de rentabilidade, observou-se o retorno de investimentos, retorno para acionistas e atividades operacionais. A análise foi feita por meio de estatísticas descritivas, regressões múltiplas (com efeitos aleatórios) e quantílicas, sendo que os resultados encontrados não apresentaram consenso entre as proxies. Enquanto a BTD aponta que quanto maior a agressividade fiscal maior a rentabilidade, a ETR demonstra relação inversa. Em virtude de as proxies de agressividade fiscal não demonstrarem consenso nos resultados, não foi possível afirmar que maiores níveis de agressividade fiscal aumentam a rentabilidade das companhias abertas listadas na B3. Nesse sentido, as evidências empíricas permitem reflexões sobre o uso da agressividade fiscal no Brasil e a tomada de decisão dos gestores.