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Rodolfo Kusch pertenece a esa generación de pensadores argentinos —y latinoamericanos— que se atrevió a abordar filosóficamente el problema de lo humano desde el pensamiento popular de nuestro subcontinente. Estas páginas proponen una breve presentación de su recuperación filosófica del saber contenido en los símbolos religiosos populares y del modo en que estos operan, centrándose en el análisis de dos obras tempranas: América profunda y El pensamiento indígena y popular en América . En estos escritos, Kusch elabora una primera aproximación al símbolo religioso popular como puesta en juego de una determinada configuración de la totalidad, es decir, de un horizonte de ultimidad en que se despliegan y reúnen las posibilidades de la existencia: el mundo, el dios y el hombre aparecen —en el mutuo darse de su “mero estar”— como el así , la ira y la indigencia.

El autor analiza en este artículo el influjo del Papa Inocencio III en la consecución de la visctoria cristiana en la batalla de Las Navas de Tolosa y la proyección que tomó en España en las ideas de batalla y reconquista. Los elementos esenciales fueron: reforma de la Iglesia, el estableciemiento de la Paz y la propagación del cristianismo.

Abstract Background Uveitis is the ophthalmic subfield dealing with a broad range of intraocular inflammatory diseases. With the raising importance of LLM such as ChatGPT and their potential use in the medical field, this research explores the strengths and weaknesses of its applicability in the subfield of uveitis. Methods A series of highly clinically relevant questions were asked three consecutive times (attempts 1, 2 and 3) of the LLM regarding current uveitis cases. The answers were classified on whether they were accurate and sufficient, partially accurate and sufficient or inaccurate and insufficient. Statistical analysis included descriptive analysis, normality distribution, non-parametric test and reliability tests. References were checked for their correctness in different medical databases. Results The data showed non-normal distribution. Data between subgroups (attempts 1, 2 and 3) was comparable (Kruskal-Wallis H test, p-value = 0.7338). There was a moderate agreement between attempt 1 and attempt 2 (Cohen’s kappa, ĸ = 0.5172) as well as between attempt 2 and attempt 3 (Cohen’s kappa, ĸ = 0.4913). There was a fair agreement between attempt 1 and attempt 3 (Cohen’s kappa, ĸ = 0.3647). The average agreement was moderate (Cohen’s kappa, ĸ = 0.4577). Between the three attempts together, there was a moderate agreement (Fleiss’ kappa, ĸ = 0.4534). A total of 52 references were generated by the LLM. 22 references (42.3%) were found to be accurate and correctly cited. Another 22 references (42.3%) could not be located in any of the searched databases. The remaining 8 references (15.4%) were found to exist, but were either misinterpreted or incorrectly cited by the LLM. Conclusion Our results demonstrate the significant potential of LLMs in uveitis. However, their implementation requires rigorous training and comprehensive testing for specific medical tasks. We also found out that the references made by ChatGPT 4.o were in most cases incorrect. LLMs are likely to become invaluable tools in shaping the future of ophthalmology, enhancing clinical decision-making and patient care.

Abstract Background Regional anaesthesia education, especially for ocular procedures, necessitates reliable surgical training models. While cadaveric models offer anatomical fidelity, conventional embalming methods may compromise tissue integrity. We aimed to assess the effectiveness of Thiel cadavers for training in sub-Tenon’s blocks by evaluating ocular tissues and measuring insertion forces. Methods Experimental design, using twenty eyes from ten Thiel cadaver heads. These cadavers were specifically prepared to test the administration of sub-Tenon’s blocks. The research was conducted in a controlled laboratory setting appropriate for handling cadaveric materials and conducting precise measurements. Each cadaver eye underwent an initial ultrasound examination, and its axial length was noted. An intravitreal injection of heptastarch solution followed, to re-establish the eye’s sphericity. After this volume injection, the axial length and intraocular pressure were measured again. Mock sub-Tenon’s blocks were administered in 2 separate quadrants of the eye, with insertion forces measured using a pressure gauge. These were compared to a data set of insertion forces measured in a series of isolated pig’s eyes on which STBs had been performed. Main outcome measurements were macroscopic assessment of the ocular tissue layers and the insertion forces required for the sub-Tenon’s blocks. In a second set of 10 Thiel cadaver heads, 5 ml of sodium chloride were injected as sub-Tenon’s blocks and the emergence of a periocular “T-sign” ascertained and measured by ultrasound. Results Four of twenty eyes (20%) retained near-natural sphericity, with the remaining requiring volume injection to approximate physiological shape and pressure. The conjunctiva and Tenon’s layer were intact, and correct cannula placement was achieved in all cases. In 16 of 20 eyes where T-signs could be measured, the median thickness of the T-sign amounted to 2.72 mm (range 1.34 mm–5.28 mm). The average maximum cannula insertion force was 2.92 Newtons. Insertion forces in intact Thiel cadaver heads were consistently higher than in isolated pig’s eyes (3.6 N vs 2.0 N). Conclusion These findings suggest that Thiel cadavers are a promising model for training in sub-Tenon’sblocks, despite the challenge of often desiccated and involuted eyes.

Abstract As hyperpolarized (HP) carbon-13 (13C) metabolic imaging is clinically translated, there is a need for easy-to-implement, fast, and robust imaging techniques. However, achieving high temporal resolution without decreasing spatial and/or spectral resolution, whilst maintaining the usability of the imaging sequence is challenging. Therefore, this study looked to accelerate HP 13C MRI by combining a well-established and robust sequence called two-dimensional Chemical Shift Imaging (2D CSI) with prospective under sampling and SENSitivity Encoding (SENSE) reconstruction. Due to the low natural abundance of 13C, the sensitivity maps cannot be pre-acquired for the reconstruction. As such, the implementation of sodium (23Na) sensitivity maps for SENSE reconstructed 13C CSI was demonstrated in a phantom and in vivo in the pig kidney. Results showed that SENSE reconstruction using 23Na sensitivity maps corrected aliased images with a four-fold acceleration. With high temporal resolution, the kidney spectra produced a detailed metabolic arrival and decay curve, useful for further metabolite kinetic modelling or denoising. Metabolic ratio maps were produced in three pigs demonstrating the technique’s ability for repeat metabolic measurements. In cases with unknown metabolite spectra or limited HP MRI specialist knowledge, this robust acceleration method ensures comprehensive capture of metabolic signals, mitigating the risk of missing spectral data.

Thorough biological safety testing of topical therapeutic compounds and antimicrobials is a critical prerequisite for appropriate cutaneous wound care. Increasing pathogen resistance rates to traditional antibiotics and antifungals are driving the development and registration of novel chemical entities. Although they are notably useful for animal testing reduction, the gold standard in vitro cytotoxicity assays in continuous cell lines (HaCaT keratinocytes, 3T3 fibroblasts) may be discussed from a translational relevance standpoint. The aim of this study was thus to establish and validate a sustainable primary cell banking model with a view to performing optimized in vitro cytotoxicity assay development. Primary dermal fibroblasts and adipose-derived stem cell (ASC) types were established from four infant polydactyly sources. A multi-tiered primary cell banking model was then applied to prepare highly sustainable and standardized dermal fibroblast and ASC working cell banks (WCBs), potentially allowing for millions of biological assays to be performed. The obtained cellular materials were then validated for use in cytotoxicity assays through in vitro biosafety testing of topical antiseptics (chlorhexidine, hypochlorous acid) and an antifungal compound (AR-12) of interest for optimized burn wound care. The experimental results confirmed that IC50 values were comparable between cytotoxicity assays, which were performed with cell lines and with primary cells. The results also showed that hypochlorous acid (HOCl) displayed an enhanced toxicological profile as compared to the gold standard chlorhexidine (CLX). Generally, this study demonstrated that highly sustainable primary cell sources may be established and applied for consistent topical compound biological safety assessments with enhanced translational relevance. Overall, the study underscored the safety-oriented interest of functionally benchmarking the products that are applied on burn patient wounds for the global enhancement of burn care quality.

Antecedentes: el disfrute es un estado afectivo promotor del ejercicio físico que involucra sentimientos de placer, agrado y diversión. La versión revisada de la escala de disfrute hacia la actividad física (PACES) reveló una estructura factorial unidimensional. No obstante, su adaptación en múltiples contextos culturales arrojó discordancias en su dimensionalidad. Objetivo: el presente estudio aporta evidencia sobre la estructura interna del PACES adaptado al contexto cultural argentino. Método: participaron 253 adultos residentes de la provincia de Buenos Aires. Se implementó la comparación de diferentes modelos de medición, incluyendo el análisis de un modelo bifactor. Para evaluar el ajuste de los diferentes modelos se utilizó el análisis factorial confirmatorio. Asimismo, se obtuvo evidencia de validez discriminante a partir del ejercicio físico autoinformado. Resultados: la exclusión de un ítem permitió un ajuste satisfactorio del modelo con una estructura de dos factores correlacionados. Asimismo, el modelo bifactor presentó un ajuste igualmente satisfactorio χ2(89) = 179.589 con CFI = .98, TLI = .97 y RMSEA = .074, con valores de ECV = .81 y PUC = .51. Conclusión: la evidencia indica buenas propiedades psicométricas, permitiendo calcular e interpretar una puntuación total que explique la variabilidad de los ítems, simultáneamente a los factores específicos.

Background/aims This study reports on the long-term functional and anatomical outcomes of patients with central retinal vein occlusion (CRVO) treated under the Bern treat-and-extend (T&E) protocol.Methods Observational study. Treatment-naive patients with CRVO and consecutive macular oedema treated with aflibercept were included. The T&E protocol involved 2 monthly injections followed by an extension based on individual assessments. At each visit, best-corrected visual acuity (BCVA), optical coherence tomography imaging and a 2 mg aflibercept injection were administered. Changes in BCVA, proportion of patients gaining ≥15 letters, central subfield thickness (CST) and treatment intervals were analysed.Results Out of 173 patients, 64 had a follow-up of at least 2 years. BCVA improved from 46.7±25.3 at baseline to 78.3±0.5 at year 9. The proportion of patients with ≥15 letters gained was 56%, 53%, 56%, 62%, 52%, 52%, 43%, 50% and 33% at years 1–9, respectively. CST decreased significantly from 660±242 µm at baseline to 359±63 µm at year 9. Treatment intervals extended from 4 weeks initially to an average of 13.0±4.1 weeks by year 8.Conclusions The T&E regimen for CRVO shows sustained visual improvements and reduced CST over time. Patients maintained stable visual gains for many years, demonstrating the effectiveness of this treatment approach. However, no control group was available to compare our T&E regimen with other strategies.

ABSTRACT Protein kinases are critical regulatory proteins in both prokaryotes and eukaryotes. Accordingly, protein kinases represent a common drug target for a wide range of human diseases. Therefore, understanding protein kinase function in human pathogens such as the fungus Candida albicans is likely to extend our knowledge of its pathobiology and identify new potential therapies. To facilitate the study of C. albicans protein kinases, we constructed a library of 99 non-essential protein kinase homozygous deletion mutants marked with barcodes in the widely used SN genetic background. Here, we describe the construction of this library and the characterization of the competitive fitness of the protein kinase mutants under 11 different growth and stress conditions. We also screened the library for protein kinase mutants with altered filamentation and biofilm formation, two critical virulence traits of C. albicans. An extensive network of protein kinases governs these virulence traits in a manner highly dependent on the specific environmental conditions. Studies on specific protein kinases revealed that (i) the cell wall integrity MAPK pathway plays a condition-dependent role in filament initiation and elongation; (ii) the hyper-osmolar glycerol MAPK pathway is required for both filamentation and biofilm formation, particularly in the setting of in vivo catheter infection; and (iii) Sok1 is dispensable for filamentation in hypoxic environments at the basal level of a biofilm but is required for filamentation in normoxia. In addition to providing a new genetic resource for the community, these observations emphasize the environmentally contingent function of C. albicans protein kinases.IMPORTANCECandida albicans is one of the most common causes of fungal disease in humans for which new therapies are needed. Protein kinases are key regulatory proteins and are increasingly targeted by drugs for the treatment of a wide range of diseases. Understanding protein kinase function in C. albicans pathogenesis may facilitate the development of new antifungal drugs. Here, we describe a new library of 99 protein kinase deletion mutants to facilitate the study of protein kinases. Furthermore, we show that the function of protein kinases in two virulence-related processes, filamentation and biofilm formation, is dependent on the specific environmental conditions.

Abstract Purpose Improved survival rates have been observed in castration‐resistant prostate cancer (CRPC) due to advancements in treatment options. However, individuals with brain metastases still have limited therapeutic options and an unfavorable prognosis. Therefore, there is an urgent need to explore new therapeutic avenues, such as antibody‐drug conjugates (ADCs), which have demonstrated significant clinical activity against active brain metastases in solid tumors. Our objective was to determine the expression levels of the ADC targets Trop‐2 and NECTIN‐4 in cerebral metastasized CRPC (mCRPC). Methods Immunohistochemical staining of Trop‐2 and NECTIN‐4 with evaluation of H‐score was performed in CRPC brain metastases (n = 31). Additionally, we examined Trop‐2 protein expression in prostate cancer cell lines and studied their responsiveness to the anti‐Trop‐2 ADC Sacituzumab govitecan (SG) in vitro. Results Our analysis revealed that most patients exhibited moderate to strong Trop‐2 expression [n = 27/31 with H‐score ≥100, median H‐score 220 (IQR 180–280)], while NECTIN‐4 was absent in all cerebral metastases. Mechanistically, we demonstrated that the efficacy of SG depends on Trop‐2 expression levels in vitro. Overexpression of Trop‐2 in Trop‐2‐negative PC‐3 cells led to sensitization to SG, whereas CRISPR‐Cas9‐mediated knockdown of Trop‐2 in Trop‐2‐expressing DU‐145 cells conferred resistance to SG. Conclusion The substantial expression of Trop‐2 in cerebral metastases, along with our preclinical in vitro results, supports the efficacy of SG in treating cerebral mCRPC. Thus, our results extend the understanding of the potential of ADCs in prostate cancer treatment and provide an additional treatment strategy for the challenging subset of patients with cerebral metastases.

The use of novel biomarkers to predict future atrial fibrillation (AF) risk may aid decision making with anti-coagulant therapy for stroke prevention. The purpose of our study was to determine whether quantitative echocardiography, blood tests, imaging, anthropometry are predictive of atrial fibrillation. Electrocardiography was not the scope of this review.Incremental increases in atrial volume and atrial diameter were most commonly associated with AF development. Likewise, incremental Brain Natriuretic Peptide (BNP) and N-terminal pro-(BNP) levels also correlate with AF risk. Anthropometric predictors such as BMI, lean mass and fat mass were also predictive of AF. Of studies reporting stroke topology, the presence of cortical infarcts, posterior circulation infarcts, multi-territory infarcts were independently predictive of AF.Newer echocardiographic techniques such as atrial and ventricular strain analysis were shown to be predictive of AF in multiple studies. Use of these biomarkers in composite scoring systems may accurately predict AF development and further help stratify patients that may benefit from anticoagulation for stroke prevention.

Due to the discontinuation of routine smallpox vaccination after its eradication in 1980, a large part of the human population remains naïve against smallpox and other members of the orthopoxvirus genus. As a part of biosafety personnel protection programs, laboratory workers receive prophylactic vaccinations against diverse infectious agents, including smallpox. Here, we studied the levels of cross-protecting neutralizing antibodies as well as total IgG induced by either first- or third-generation smallpox vaccines against Monkeypox virus, using a clinical isolate from the 2022 outbreak. Serum neutralization tests indicated better overall neutralization capacity after vaccination with first-generation smallpox vaccines, compared to an attenuated third-generation vaccine. Results obtained from total IgG ELISA, however, did not show higher induction of orthopoxvirus-specific IgGs in first-generation vaccine recipients. Taken together, our results indicate a lower level of cross-protecting neutralizing antibodies against Monkeypox virus in recipients of third-generation smallpox vaccine compared to first-generation vaccine recipients, although total IgG levels were comparable.

As a by-product of wastewater treatment, sewage sludge can be used for natural, agricultural, or energy purposes. One method of preparing sludge for management and use is solar drying. To intensify the drying process, natural additives can be used to alter the structure of the sludge and accelerate the evaporation of water. This research aimed to evaluate the influences of different organic additives in sewage sludge mixtures on the physicochemical and energy parameters of briquettes. This research was carried out without thermal boosting in a 4 × 2.5 × 2 m plastic tunnel. The tunnel was equipped with three drying stations and control and measuring equipment. In two test series, sludge additives in the form of straw and lignocellulosic materials, sawdust, bark, woodchips, and walnut shells, were used. Briquettes were made from the resulting mixtures and then subjected to physical and chemical analyses. This research showed high variability in the contents of trace elements, nitrogen, and sulphur in relation to an increase in the amount of sludge in the briquettes, which, for the briquettes made from sewage sludge, was nearly twice as high as for the briquettes made from the mixtures. The results of the flue gas analysis for the briquettes with sawdust and wood chip additives were very similar. The briquettes made from sewage sludge with lignocellulosic materials (bark and wood chips) had fuel properties similar to woody biomass, with a calorific value and heat of combustion of 15–16 MJ/kg. Fibrous additives (straw) significantly increased the strength parameters of the briquettes, by more than 50% of the value. The compositions and properties of the mixtures affected the following briquetting parameters: temperature and compressive force. The briquettes made from sewage sludge and additives can be classified according to ISO 21640 as SRFs (solid recovered fuels). In most of the results, the net calorific value (NCV) was 3 to 4; the chlorine content (CL) was 2 to 1; and the mercury content (Hg) was 1. The sewage sludge mixtures facilitated the agricultural and energy use of the briquettes.

One method of preparing sludge for management and use is solar drying. To intensify the drying process, natural lignocellulosic additives can be used to alter the structure of the sludge and accelerate water evaporation. Light, hard materials with low absorption capacity are best suited for this purpose, e.g., walnut shells, which are unused waste. The aim of the study was to determine the impact of the evaluation of walnut shells on the sludge drying process and to assess the impact of the drying process on the chemical, physical, and fuel properties of the additive. The moisture content, crushing strength, chemical composition, and physical and fuel properties of mixtures were determined. A small addition of walnut shells (25%) was found to accelerate the drying process even in winter and spring (up to 30 days) compared to sludge without additives. Walnut shells retain their chemical composition and strength despite unfavourable conditions and a chemically aggressive environment, indicating they may be reused. The mixture containing sewage sludge and walnut shells has a calorific value of 15.6 MJ/kg, which is similar to wood; it is also fully biodegradable and suitable as a fertiliser to improve soil structure, as it contains approx. 80–90% DM (including approx. 40% carbon, 3% nitrogen, and other elements, such as phosphorus and potassium.)

Arginases are key enzymes that hydrolyze L-arginine to urea and L-ornithine in the urea cycle. The two arginase isoforms, arginase 1 (ARG1) and arginase 2 (ARG2), regulate the proliferation of cancer cells, migration, and apoptosis; affect immunosuppression; and promote the synthesis of polyamines, leading to the development of cancer. Arginases also compete with nitric oxide synthase (NOS) for L-arginine, and their participation has also been confirmed in cardiovascular diseases, stroke, and inflammation. Due to the fact that arginases play a crucial role in the development of various types of diseases, finding an appropriate candidate to inhibit the activity of these enzymes would be beneficial for the therapy of many human diseases. In this review, based on numerous experimental, preclinical, and clinical studies, we provide a comprehensive overview of the biological and physiological functions of ARG1 and ARG2, their molecular mechanisms of action, and affected metabolic pathways. We summarize the recent clinical trials’ advances in targeting arginases and describe potential future drugs.

We describe three cases of critical acute myositis with myocarditis occurring within 22 days of each other at a single institution, all within 1 month of receiving the initial cycle of the anti-PD-1 drug pembrolizumab. Analysis of T cell receptor repertoires from peripheral blood and tissues revealed a high degree of clonal expansion and public clones between cases, with several T cell clones expanded within the skeletal muscle putatively recognizing viral epitopes. All patients had recently received a COVID-19 mRNA booster vaccine prior to treatment and were positive for SARS-CoV2 Spike antibody. In conclusion, we report a series of unusually severe myositis and myocarditis following PD-1 blockade and the COVID-19 mRNA vaccination.

ABSTRACTCandida albicans is a common human fungal pathogen that is also a commensal of the oral cavity and gastrointestinal tract. C. albicans pathogenesis is linked to its transition from budding yeast to filamentous morphologies including hyphae and pseudohyphae. The centrality of this virulence trait to C. albicans pathobiology has resulted in extensive characterization of a wide range of factors associated with filamentation with a strong focus on transcriptional regulation. The vast majority of these experiments have used in vitro conditions to induce the yeast-to-filament transition. Taking advantage of in vivo approaches to quantitatively characterize both morphology and gene expression during filamentation during mammalian infection, we have investigated the dynamics of these two aspects of filamentation in vivo and compared them to in vitro filament induction with “host-like” tissue culture media supplemented with serum at mammalian body temperature. Although filamentation shares many common features in the two conditions, we have found two significant differences. First, alternative carbon metabolism genes are expressed early during in vitro filamentation and late in vivo, suggesting significant differences in glucose availability. Second, C. albicans begins a hyphae-to-yeast transition after 4-h incubation while we find little evidence of hyphae-to-yeast transition in vivo up to 24 h post-infection. We show that the low rate of in vivo hyphae-to-yeast transition is likely due to the very low expression of PES1, a key driver of lateral yeast in vitro and that heterologous expression of PES1 is sufficient to trigger lateral yeast formation in vivo.IMPORTANCECandida albicans filamentation is correlated with virulence and is an intensively studied aspect of C. albicans biology. The vast majority of studies on C. albicans filamentation are based on in vitro induction of hyphae and pseudohyphae. Here we used an in vivo filamentation assay and in vivo expression profiling to compare the tempo of morphogenesis and gene expression between in vitro and in vivo filamentation. Although the hyphal gene expression profile is induced rapidly in both conditions, it remains stably expressed over a 12-h time course in vivo while it peaks after 4 h in vitro and is reduced. This reduced hyphal gene expression in vitro correlates with reduced hyphae and increased hyphae-to-yeast transition. By contrast, there is little evidence of hyphae-to-yeast transition in vivo.

IntroductionThe pupillary light reflex (PLR) is the constriction of the pupil in response to light. The PLR in response to a pulse of light follows a complex waveform that can be characterized by several parameters. It is a sensitive marker of acute neurological deterioration, but is also sensitive to the background illumination in the environment in which it is measured. To detect a pathological change in the PLR, it is therefore necessary to separate the contributions of neuro-ophthalmic factors from ambient illumination. Illumination varies over several orders of magnitude and is difficult to control due to diurnal, seasonal, and location variations.Methods and resultsWe assessed the sensitivity of seven PLR parameters to differences in ambient light, using a smartphone-based pupillometer (AI Pupillometer, Solvemed Inc.). Nine subjects underwent 345 measurements in ambient conditions ranging from complete darkness (

ABSTRACTCandida albicans is one of the most common causes of superficial and invasive fungal diseases in humans. Its ability to cause disease is closely linked to its ability to undergo a morphological transition from budding yeast to filamentous forms (hyphae and pseudohyphae). The extent to which C. albicans strains isolated from patients undergo filamentation varies significantly. In addition, the filamentation phenotypes of mutants involving transcription factors that positively regulate hyphal morphogenesis can also vary from strain to strain. Here, we characterized the virulence, in vitro and in vivo filamentation, and in vitro and in vivo hypha-associated gene expression profiles for four poorly filamenting C. albicans isolates and their corresponding deletion mutants of the repressor of filamentation NRG1. The two most virulent strains, 57055 and 78048, show robust in vivo filamentation but are predominately yeast phase under in vitro hypha induction; the two low-virulence strains (94015 and 78042) do not undergo filamentation well under either condition. In vitro, deletion of NRG1 increases hyphae formation in the SC5314 derivative SN250, but only pseudohyphae are formed in the clinical isolates. Deletion of NRG1 modestly increased the virulence of 78042, which was accompanied by increased expression of hypha-associated genes without an increase in filamentation. Strikingly, deletion of NRG1 in 78048 reduced filamentation in vivo, expression of candidalysin (ECE1), and virulence without dramatically altering establishment of infection. Thus, the function of the conserved repressor NRG1 in C. albicans shows strain-based heterogeneity during infection.IMPORTANCEClinical isolates of the human fungal pathogen Candida albicans show significant variation in their ability to undergo in vitro filamentation and in the function of well-characterized transcriptional regulators of filamentation. Here, we show that Nrg1, a key repressor of filamentation and filament specific gene expression in standard reference strains, has strain-dependent functions, particularly during infection. Most strikingly, loss of NRG1 function can reduce filamentation, hypha-specific gene expression such as the toxin candidalysin, and virulence in some strains. Our data emphasize that the functions of seemingly fundamental and well-conserved transcriptional regulators such as Nrg1 are contextual with respect to both environment and genetic backgrounds.

Abstract Cryptococcus spp. are environmental fungi that first must adapt to the host environment before they can cause life-threatening meningitis in immunocompromised patients. Host CO2 concentrations are 100-fold higher than the external environment and strains unable to grow at host CO2 concentrations are not pathogenic. Using a genetic screening and transcriptional profiling approach, we report that the TOR pathway is critical for C. neoformans adaptation to host CO2 partly through Ypk1-dependent remodeling of phosphatidylserine asymmetry at the plasma membrane. We also describe a C. neoformans ABC/PDR transporter (PDR9) that is highly expressed in CO2-sensitive environmental strains, suppresses CO2-induced phosphatidylserine/phospholipid remodeling, and increases susceptibility to host concentrations of CO2. Interestingly, regulation of plasma membrane lipid asymmetry by the TOR-Ypk1 axis is distinct in C. neoformans compared to S. cerevisiae. Finally, host CO2 concentrations suppress the C. neoformans pathways that respond to host temperature (Mpk1) and pH (Rim101), indicating that host adaptation requires a stringent balance among distinct stress responses.

Abstract The COVID-19 pandemic has had a major effect on HIV-related healthcare services. Zanzibar has experienced several interruptions of HIV services in the areas of testing and counselling, prevention of mother-to-child transmission of HIV, key population, care and treatment services as well due to the hospital operating at a reduced capacity and the strict visit restrictions with health care allocations to COVID 19 pandemic. The community HIV initiatives, such as index testing and ARVs medicine refills, were used to mitigate the consequences of the epidemic and can be applied in future emergencies. This report tries to reveal COVID-19’s unnoticed consequences on HIV services in Zanzibar.

Abstract The role of the immune microenvironment in maintaining disease remission in patients with multiple myeloma (MM) is not well understood. In this study, we comprehensively profile the immune system in patients with newly diagnosed MM receiving continuous lenalidomide maintenance therapy with the aim of discovering correlates of long-term treatment response. Leveraging single-cell RNA sequencing and T cell receptor β sequencing of the peripheral blood and CyTOF mass cytometry of the bone marrow, we longitudinally characterize the immune landscape in 23 patients before and one year after lenalidomide exposure. We compare patients achieving sustained minimal residual disease (MRD) negativity to patients who never achieved or were unable to maintain MRD negativity. We observe that the composition of the immune microenvironment in both the blood and the marrow varied substantially according to both MRD negative status and history of autologous stem cell transplant, supporting the hypothesis that the immune microenvironment influences the depth and duration of treatment response.

Abstract Background The balance of the intestinal commensal microbiome of fish and other animals plays an important role in the physiological processes of healthy animals, contributes to the defense against pathogens, stimulates the immune system and facilitates nutrient metabolism. In the last decade, the interest in the application of the insects in fish nutrition increased, although little is known regarding the effects of insect meals on the gastrointenstinal tract microbiome of the sea trout fingerlings. The aim of this study was to evaluate the effect of two diets containing mealworm (MW) and superworm (SW) on the microbiome of the digesta of sea trout fingerlings and the relative abundances of different taxa among communities under controlled conditions. Results The insect meals produced a similar weight gain and survival rate to sea trout fed fishmeal. The most abundant bacterial phylum in all the treatment groups was Firmicutes followed by Proteobacteria and Actinobacteria, and significant differences in the amount of Cyanobacteria were observed in the SW group. Conclusions The insect meals did not produce differences in the three most abundant phyla in the sea trout digesta. However, the effect of each type of meal on the lower taxonomic levels was evident, particularly in the case of the superworm meal. These microbiome differences indicated that mealworm meal was more related to fishmeal than superworm meal. Our results highlight the potential effects of insect meals, such as mealworm and superworm meals, on the microbiota of sea trout.

The article presents research results on the possibility of shaping the structure and properties of Co-Cr-W-C-Ti alloys (type Stellite 6) using laser cladding technology. Cobalt-based alloys are used in several industries because they are characterized by high erosion, abrasion, and corrosion resistance, retaining these properties at high temperatures. To further increase erosion resistance, it seems appropriate to reinforce material by in situ synthesis of hard phases. Among the transition metal carbides (TMCs), titanium carbide is one of the hardest and can have a positive effect on the extension of the lifetime of components made from cobalt-based alloys. In this article, concentration of C, W, and Ti due to the possibility of in situ synthesis of titanium carbides was subjected to detailed analysis. The provided research includes macrostructure and microstructure analysis, X-ray diffraction (XRD), microhardness, and penetrant tests. It was found that the optimal concentrations of Ti and C in the Co-Cr-W-C alloy allow the formation of titanium carbides, which significantly improves erosion resistance for low impact angles. Depending on the concentrations of titanium, carbon, and tungsten in the molten metal pool, it is possible to shape the alloy structure by influencing to morphology and size of the reinforcing phase in the form of the complex carbide (Ti,W)C.

JUK-8 ([Zn(oba)(pip)]n, oba2– = 4,4′-oxybis(benzenedicarboxylate), pip = 4-pyridyl-functionalized benzene-1,3-dicarbohydrazide) is a hydrolytically stable flexible metal-organic framework. Owing to its unusual adsorptive properties, JUK-8 can be considered as a promising sensing material for construction of detectors of volatile organic compounds (VOCs) in air. Quasi-equilibrated temperature-programmed desorption and adsorption (QE-TPDA) is a versatile method dedicated to characterization of porous materials. In this work, QE-TPDA was employed to study co-adsorption of water and selected alcohols in JUK-8. For the first time an infrared detector sensitive to organic compounds was used in the QE-TPDA measurements, allowing the study of the influence of water vapor on sorption of VOCs. The QE-TPDA profiles of the studied alcohols, exhibiting two desorption maxima and two adsorption minima, are consistent with the standard sorption isotherms, revealing a two-step adsorption–desorption mechanism. The profiles recorded in the presence of water are noticeably changed in different ways for different alcohols. While at low relative humidity (RH) (ca. 20%) the low temperature adsorption states of ethanol and 1-propanol were only slightly destabilized, for 2-propanol almost complete suppression of adsorption was observed. The results found for moderate RH levels (ca. 50%) indicated that the opening of the JUK-8 structure, responsible for its breathing behavior, was followed by the filling of the just generated pores with a water–alcohol mixture.

This study investigates the application of steganography for enhancing network security by detecting and promptly eliminating malicious packets to prevent flooding and consequent denial of service attacks while also identifying malicious equipment. The paper discusses foundational concepts such as the prisoner’s dilemma, covert channels, qualitative metrics, and existing steganography techniques in computer communications. An architecture was developed to assess the effectiveness of this solution, and experiments were conducted, with their results presented. This contribution leverages established steganographic principles and seamlessly integrates with widely adopted IPsec protocols, offering a solution to improve covert communication within computer networks.

Abstract Background Inducible T cell costimulator ICOS is an emerging target in immuno-oncology. The aim of this study was to investigate the epigenetic regulation of ICOS in melanoma by DNA methylation. Methods We comprehensively investigate ICOS DNA methylation of specific CpG sites and expression pattern within the melanoma microenvironment with regard to immune correlates, differentiation, clinical outcomes, and immune checkpoint blockade (ICB) response. Results Our study revealed a sequence-contextual CpG methylation pattern consistent with an epigenetically regulated gene. We found a cell type-specific methylation pattern and locus-specific correlations and associations of CpG methylation with ICOS mRNA expression, immune infiltration, melanoma differentiation, prognosis, and response to ICB. High ICOS mRNA expression was identified as a surrogate for enriched immune cell infiltration and was associated with favorable overall survival (OS) in non-ICB-treated patients and predicted response and a prolonged progression-free survival (PFS) following ICB therapy initiation. ICOS hypomethylation, however, significantly correlated with poor OS in non-ICB patients but predicted higher response and prolonged PFS and OS in ICB-treated patients. Moreover, we observed cytoplasmic and sporadically nuclear tumor cell-intrinsic ICOS protein expression. Tumor cell-intrinsic ICOS protein and mRNA expression was inducible by pharmacological demethylation with decitabine. Conclusion Our study identified ICOS DNA methylation and mRNA expression as promising prognostic and predictive biomarkers for immunotherapy in melanoma and points towards a hitherto undescribed role of ICOS in tumor cells.

Abstract The study aimed to evaluate the impact of selected exerkines concentration induced by folk-dance and balance training on physical performance, insulin resistance, and blood pressure in older adults. Participants (n = 41, age 71.3 ± 5.5 years) were randomly assigned to folk-dance (DG), balance training (BG), or control group (CG). The training was performed 3 times a week for 12 weeks. Physical performance tests—time up and go (TUG) and 6-min walk test (6MWT), blood pressure, insulin resistance, and selected proteins induced by exercise (exerkines) were assessed at baseline and post-exercise intervention. Significant improvement in TUG (p = 0.006 for BG and 0.039 for DG) and 6MWT tests (in BG and DG p = 0.001), reduction of systolic blood pressure (p = 0.001 for BG and 0.003 for DG), and diastolic blood pressure (for BG; p = 0.001) were registered post-intervention. These positive changes were accompanied by the drop in brain-derived neurotrophic factor (p = 0.002 for BG and 0.002 for DG), the increase of irisin concentration (p = 0.029 for BG and 0.022 for DG) in both groups, and DG the amelioration of insulin resistance indicators (HOMA-IR p = 0.023 and QUICKI p = 0.035). Folk-dance training significantly reduced the c-terminal agrin fragment (CAF; p = 0.024). Obtained data indicated that both training programs effectively improved physical performance and blood pressure, accompanied by changes in selected exerkines. Still, folk-dance had enhanced insulin sensitivity.

Abstract Biofilm production plays a clinically significant role in the pathogenicity of many bacteria, limiting our ability to apply antimicrobial agents and contributing in particular to the pathogenesis of chronic infections. Bacteriophage depolymerases, leveraged by these viruses to circumvent biofilm mediated resistance, represent a potentially powerful weapon in the fight against antibiotic resistant bacteria. Such enzymes are able to degrade the extracellular matrix that is integral to the formation of all biofilms and as such would allow complementary therapies or disinfection procedures to be successfully applied. In this manuscript, we describe the development and application of a machine learning based approach towards the identification of phage depolymerases. We demonstrate that on the basis of a relatively limited number of experimentally proven enzymes and using an amino acid derived feature vector that the development of a powerful model with an accuracy on the order of 90% is possible, showing the value of such approaches in protein functional annotation and the discovery of novel therapeutic agents.

Motivation:31P magnetic resonance spectroscopic imaging (31P MRSI) is a powerful technique for investigating the metabolic effects of treatments for heart failure in vivo, allowing a better understanding of their mechanism of action in patient cohorts. Unfortunately, cardiac 31P MRSI is fundamentally limited by low SNR, which leads to compromises in acquisition, such as no cardiac or respiratory gating or low spatial resolution, in order to achieve reasonable scan times. Spectroscopy with linear algebra modeling (SLAM) reconstruction may be able to address these challenges and therefore improve repeatability by incorporating a segmented localizer into the reconstruction.Methods: Six healthy volunteers were scanned twice in a test–retest procedure to allow quantification of repeatability. Each scan consisted of anatomical localizers and two acquisition-weighted (AW) 31P MRSI acquisitions, which were acquired with and without cardiac gating. Five patients with heart failure with a preserved ejection fraction were then scanned with the same 31P MRSI sequence without cardiac gating. All 31P MRSI datasets were reconstructed with both conventional Fourier transform (FT)-based reconstruction and SLAM reconstruction, which were compared statistically. The effect of shifting the 31P MRSI acquisition field of view was also investigated.Results: In the healthy volunteer cohort, the spectral fit of the SLAM reconstructions had significantly improved Cramer–Rao lower bounds (CRLBs) compared to the FT-based reconstruction of non-cardiac gated data, as well as improved coefficients of variability and repeatability. The SLAM reconstruction found a significant difference in the PCr/ATP ratio between the healthy volunteer and patient cohorts, which the FT-based reconstruction did not find. Furthermore, the SLAM reconstruction was less influenced by the placement of the field of view (FOV) of the 31P MRSI acquisition in post hoc analysis.Discussion: The experimental benefits of the SLAM reconstruction for AW data were demonstrated by the improvements in fit confidence and repeatability seen in the healthy volunteer cohort and post hoc FOV analysis. The benefit of SLAM reconstruction of AW data for clinical studies was then illustrated by the patient cohort, which suggested improved sensitivity to clinically significant changes in the PCr/ATP ratio.

IntroductionComplete macroscopic cytoreduction represents the most important prognostic parameter for overall survival in ovarian cancer. This dogma remains tenacious despite significant improvements in adjuvant systemic treatment. Hence, optimization of surgical therapy is an overarching goal to improve patients’ outcomes. In this context, intraoperative tumor-specific imaging might facilitate optimized cytoreduction. In neurosurgery, intraoperative 5-aminolevulinic acid (5-ALA) guided imaging is applied in clinical routine to assess surgical resection margins. Here, we report the case of a patient with ovarian cancer in whom intraoperative 5-ALA tumor visualization led to optimized complete cytoreduction.ObjectiveIntraoperative administration of 5-ALA led to improved complete cytoreduction by identification and resection of additional ovarian cancer tumor manifestations.CaseThe 39-year-old patient, Jehovah`s witness, presented to our department with a left sided ovarian mass, suspicious of ovarian cancer, based on clinical examination, sonographic suspicious features and a CA12-5 elevation. The patient’s medical history and family history was unremarkable. Preoperative CT imaging of the thorax and abdomen showed no pathology besides the adnexal mass. Surgery was performed by a midline laparotomy with hysterectomy, bilateral adnexectomy, pelvic peritonectomy, omentectomy, ureterolysis, diaphragm stripping, adhesiolysis and the collection of peritoneal and rectal samples. Intraoperative 5-ALA imaging using a dedicated excitation and detection loupe system (Reveal, DVI) led to tumor detection at the diaphragm, the omentum and the rectum that was not detectable by palpation and visualization using white light. The pathology results revealed that the 5-ALA positive samples (diaphragm, rectum and omentum) obtained by intraoperative 5-ALA were positive for ovarian cancer.ConclusionIntraoperative administration of 5-ALA represents a promising approach to improve complete cytoreduction in ovarian cancer surgery thereby improving clinical outcomes. Hence, further research and clinical trials are required to investigate the potential of intraoperative 5-ALA imaging in ovarian cancer debulking surgery and its impact on long-term clinical outcomes.

ABSTRACTPD-L1 status assessed by immunohistochemistry (IHC) has failed to reliably predict outcomes for patients with metastatic urothelial carcinoma (mUC) on immune checkpoint blockade (ICB). PD-L1 promoter methylation is an epigenetic mechanism that has been shown to regulate PD-L1 mRNA expression in various malignancies. The aim of our present study was to evaluate the predictive potential of PD-L1 promoter methylation status (mPD-L1) in ICB-treated mUC compared to conventional IHC-based PD-L1 assessment. We quantified mPD-L1 in formalin-fixed and paraffin-embedded tissue sections using an established quantitative methylation-specific PCR assay (qMSP) in a well-characterized multicenter ICB-treated cohort comprising N = 107 patients with mUC. Additionally, PD-L1 protein expression in tumor tissues was assessed using regulatory approved IHC protocols. The effect of pharmacological hypomethylation by the DNA methyltransferase inhibitor decitabine in combination with interferon-γ stimulation in urothelial carcinoma cell lines was investigated by IHC and FACS. mPD-L1 hypomethylation predicted objective response rate at the first staging on ICB. Patients with tumors categorized as PD-L1 hypomethylated (lower quartile) showed significantly prolonged progression-free (PFS) and overall survival (OS) after ICB initiation. In contrast, PD-L1 protein expression status neither correlated with response nor survival. In multivariable Cox regression analyses, PD-L1 promoter hypermethylation remained an independent predictor of unfavorable PFS and OS. In urothelial carcinoma cell lines, pharmacological demethylation led to an upregulation of membranous PD-L1 expression and an enhanced inducibility of PD-L1 expression by interferon γ. Hypomethylation of the PD-L1 promoter is a promising predictive biomarker for response to ICB in patients with mUC.

Accurate recording of forensically important information on bruises is vital in child protection proceedings (Royal College of Paediatrics and Child Health (RCPCH)). An online survey was distributed to the RCPCH child protection committees to assess compliance with guidance. 56 individuals were contacted by email, 47 (84%) completed the survey. Results showed that the paediatricians always record size (n=41; 87%), site (n=45; 96%), shape (n=32; 68%) and colour (n=36; 77%); n=10; 22% of the paediatricians stated that they ‘always’ used a ranking system for likelihood of abuse; n=12; 35% of those surveyed ‘sometimes’ estimated the size of the bruise. Results showed that paediatric bruise reporting is inconsistent and incomplete for some fields compared with national guidance.

Background Cell culture conditions during manufacturing can impact the clinical efficacy of chimeric antigen receptor (CAR) T cell products. Production methods have not been standardized because the optimal approach remains unknown. Separate CD4+ and CD8+ cultures offer a potential advantage but complicate manufacturing and may affect cell expansion and function. In a phase 1/2 clinical trial, we observed poor expansion of separate CD8+ cell cultures and hypothesized that coculture of CD4+ cells and CD8+ cells at a defined ratio at culture initiation would enhance CD8+ cell expansion and simplify manufacturing.Methods We generated CAR T cells either as separate CD4+ and CD8+ cells, or as combined cultures mixed in defined CD4:CD8 ratios at culture initiation. We assessed CAR T cell expansion, phenotype, function, gene expression, and in vivo activity of CAR T cells and compared these between separately expanded or mixed CAR T cell cultures.Results We found that the coculture of CD8+ CAR T cells with CD4+ cells markedly improves CD8+ cell expansion, and further discovered that CD8+ cells cultured in isolation exhibit a hypofunctional phenotype and transcriptional signature compared with those in mixed cultures with CD4+ cells. Cocultured CAR T cells also confer superior antitumor activity in vivo compared with separately expanded cells. The positive impact of CD4+ cells on CD8+ cells was mediated through both cytokines and direct cell contact, including CD40L-CD40 and CD70-CD27 interactions.Conclusions Our data indicate that CD4+ cell help during cell culture maintains robust CD8+ CAR T cell function, with implications for clinical cell manufacturing.

Abstract In public opinion, social and digital media provide means for influence as well as sorting according to pre-existing values. Here we consider types of media usage versus opinion using new polling results in the former Soviet republics (FSRs) of Belarus, Ukraine, and Georgia. Over 1000 individuals in each country were asked about a news event (the January 6 riot at the U.S. Capitol) and about the long-term future of their country. We find that year of birth and country of residence, rather than self-reported media reliance, consistently predicted the respondents’ views, particularly on the future of their country. The timing of these differences suggests a cultural difference between generations growing up in the Soviet Union (likely more pro-Russian) versus afterward, in an FSR (more pro-Western). Whereas digital media choice is somewhat correlated with perceptions of a recent, international news event, the more predictive factors are longer-term cultural values and age cohorts within each nation.

Abstract Background Expanding pre-exposure prophylaxis (PrEP) among transgender women in the United States is an important strategy to meet national HIV prevention goals, however self-reported use of PrEP is low in this group. Methods This study reports the findings of a cross-sectional analysis of the relationship of barriers as well as facilitators to recent PrEP use among transgender women enrolled in an evaluation of the TransLife Care project (Chicago, Illinois), a structural intervention designed to meet basic needs. We computed multivariable prevalence ratios for barriers, facilitators and recent PrEP use, controlling for demographics. Results Findings suggest that psychosocial and structural barriers, including moderate/high alcohol use, stimulant use, and history of incarceration were all positively associated with recent PrEP use among urban transgender women. In addition, a psychosocial facilitator, gender affirmation, was positively associated with recent PrEP use, while, while collective self-esteem, a was negatively associated with it. Finally, common indications for PrEP have high sensitivity, but low specificity and predictive value for identifying those on PrEP. Conclusion We conclude that despite a large gap in PrEP use among those with indications, individuals experiencing psychosocial and structural barriers are more likely to use PrEP, and facilitators, such as psychological sense of affirmed gender may support its use. Trial registration N/A.

Digestate from a biogas plant can be a valuable organic and mineral fertilizer. Quantitative proportions of co-substrates used in three agricultural biogas plants in Poland were analyzed. The composition of digestates was examined and large differences in the content of macronutrients were found, especially N and K. On the basis of the factors used to calculate emissions from the production and use of artificial fertilizers, the GHG reduction resulting from replacing mineral fertilizers with digestate was calculated. In terms of 1 Mg of fresh digestate, this reduction may not seem large, as it amounts to 27.9-61.6 kg of CO2 eq, but it should be taken into account that digestate contains little dry matter. The annual amount of digestate used on an area of 1 ha allows avoiding GHG emissions of 25.8-44.5 Mg CO2 eq.

The microstructure of the in situ TiC-reinforced composite surface layers developed during laser surface alloying of a ductile cast iron substrate with titanium was related to the solidification conditions in the molten pool. The solidification conditions were estimated using infrared thermography. It was found that the cooling rates of the melt up to about 700 °C/s enable the complete reaction between carbon and the entire amount of titanium introduced into the molten pool. In turn, the cooling rate of about 280 °C/s for the melt containing 8.0 wt% Ti allows the TiC particles to grow in the dendritic form with well-developed secondary arms and a total size of up to 30 µm. For a constant Ti content, the cooling rate of the melt had no effect on the TiC fraction. The increase in the cooling rate elevated the retained austenite fraction in the matrix material, lowering its hardness.

Enzymatic solid-state fermentation can improve the nutritional quality of feed materials. The current study aimed to determine the effect of the solid-state fermentation of rapeseed meal (RSM) with carbohydrase/s and phytases in various combinations. RSM was fermented for 24 h at 25 °C with eight commercial preparations and mixtures thereof to prepare eleven products (PHYL—liquid-6-phytase; RON NP—6-phytase; RON HI—6-phytase; RON R—α-amylase; RON WX—β-xylanase; RON VP—β-glucanase; RON A—α-amylase, β-glucanase; RON M—xylanase, β-glucanase; RON NP+M; RON NP+A; RON NP+M+R). Afterward, the enzymes were deactivated at 70 °C within 15 min, and the biomass was dried for 24 h at 55 °C. Carbohydrase and/or phytase additives did not positively affect crude or true protein content or reduce crude fiber (p > 0.05). Among the products after fermentation, a significant reduction in the content of the raffinose family oligosaccharides, glucosinolates, and phytate was found. In the presence of phytase, the phytate reduction was more significant (p < 0.01) than that in the presence of carbohydrases only. The addition of carbohydrases together with phytases did not improve the results in comparison with phytases alone (p > 0.05). The most valuable effect was found for liquid-6-phytase (PHYL).

ABSTRACT Candida albicans is a diploid human fungal pathogen that displays significant genomic and phenotypic heterogeneity over a range of virulence traits and in the context of a variety of environmental niches. Here, we show that the effect of Rob1 on biofilm and filamentation virulence traits is dependent on both the specific environmental condition and the clinical strain of C. albicans. The C. albicans reference strain SC5314 is a ROB1 heterozygote with two alleles that differ by a single nucleotide polymorphism at position 946, resulting in a serine- or proline-containing isoform. An analysis of 224 sequenced C. albicans genomes indicates that SC5314 is the only ROB1 heterozygote documented to date and that the dominant allele contains a proline at position 946. Remarkably, the ROB1 alleles are functionally distinct, and the rare ROB1946S allele supports increased filamentation in vitro and increased biofilm formation in vitro and in vivo, suggesting it is a phenotypic gain-of-function allele. SC5314 is among the most highly filamentous and invasive strains characterized to date. Introduction of the ROB1946S allele into a poorly filamenting clinical isolate increases filamentation, and conversion of an SC5314 laboratory strain to a ROB1946S homozygote increases in vitro filamentation and biofilm formation. In a mouse model of oropharyngeal infection, the predominant ROB1946P allele establishes a commensal state while the ROB1946S phenocopies the parent strain and invades into the mucosae. These observations provide an explanation for the distinct phenotypes of SC5314 and highlight the role of heterozygosity as a driver of C. albicans phenotypic heterogeneity. IMPORTANCE Candida albicans is a commensal fungus that colonizes the human oral cavity and gastrointestinal tract but also causes mucosal as well as invasive disease. The expression of virulence traits in C. albicans clinical isolates is heterogeneous and the genetic basis of this heterogeneity is of high interest. The C. albicans reference strain SC5314 is highly invasive and expresses robust filamentation and biofilm formation relative to many other clinical isolates. Here, we show that SC5314 derivatives are heterozygous for the transcription factor Rob1 and contain an allele with a rare gain-of-function SNP that drives filamentation, biofilm formation, and virulence in a model of oropharyngeal candidiasis. These findings explain, in part, the outlier phenotype of the reference strain and highlight the role heterozygosity plays in the strain-to-strain variation of diploid fungal pathogens.

IntroductionAn attractive, yet unrealized, goal in cancer therapy is repurposing psychiatric drugs that can readily penetrate the blood-brain barrier for the treatment of primary brain tumors and brain metastases. Phenothiazines (PTZs) have demonstrated anti-cancer properties through a variety of mechanisms. However, it remains unclear whether these effects are entirely separate from their activity as dopamine and serotonin receptor (DR/5-HTR) antagonists.MethodsIn this study, we evaluated the anti-cancer efficacy of a novel PTZ analog, CWHM-974, that was shown to be 100-1000-fold less potent against DR/5-HTR than its analog fluphenazine (FLU).ResultsCWHM-974 was more potent than FLU against a panel of cancer cell lines, thus clearly demonstrating that its anti-cancer effects were independent of DR/5-HTR signaling. Our results further suggested that calmodulin (CaM) binding may be necessary, but not sufficient, to explain the anti-cancer effects of CWHM-974. While both FLU and CWHM-974 induced apoptosis, they induced distinct effects on the cell cycle (G0/G1 and mitotic arrest respectively) suggesting that they may have differential effects on CaM-binding proteins involved in cell cycle regulation. DiscussionAltogether, our findings indicated that the anti-cancer efficacy of the CWHM-974 is separable from DR/5-HTR antagonism. Thus, reducing the toxicity associated with phenothiazines related to DR/5-HTR antagonism may improve the potential to repurpose this class of drugs to treat brain tumors and/or brain metastasis

BackgroundThe COVID-19 pandemic has been a devastating and enduring mass-bereavement event, with uniquely difficult sets of circumstances experienced by people bereaved at this time. However, little is known about the long-term consequences of these experiences, including the prevalence of Prolonged Grief Disorder (PGD) and other conditions in pandemic-bereaved populations.MethodsA longitudinal survey of people bereaved in the UK between 16 March 2020 and 2 January 2021, with data collected at baseline (n = 711), c. 8 (n = 383), 13 (n = 295), and 25 (n = 185) months post-bereavement. Using measures of Prolonged Grief Disorder (PGD) (Traumatic Grief Inventory), grief vulnerability (Adult Attitude to Grief Scale), and social support (Inventory of Social Support), this analysis examines how participant characteristics, characteristics of the deceased and pandemic-related circumstances (e.g., restricted visiting, social isolation, social support) are associated with grief outcomes, with a focus on symptoms of PGD.ResultsAt baseline, 628 (88.6%) of participants were female, with a mean age of 49.5 (SD 12.9). 311 (43.8%) deaths were from confirmed/suspected COVID-19. Sample demographics were relatively stable across time points. 34.6% of participants met the cut-off for indicated PGD at c. 13 months bereaved and 28.6% at final follow-up. Social isolation and loneliness in early bereavement and lack of social support over time strongly contributed to higher levels of prolonged grief symptoms, while feeling well supported by healthcare professionals following the death was associated with reduced levels of prolonged grief symptoms. Characteristics of the deceased most strongly associated with lower levels of prolonged grief symptoms, were a more distant relationship (e.g., death of a grandparent), an expected death and death occurring in a care-home. Participant characteristics associated with higher levels of prolonged grief symptoms included low level of formal education and existence of medical conditions.ConclusionResults suggest higher than expected levels of PGD compared with pre-pandemic times, with important implications for bereavement policy, provision and practice now (e.g., strengthening of social and specialist support) and in preparedness for future pandemics and mass-bereavement events (e.g., guidance on infection control measures and rapid support responses).

Summary: Kynurenine monooxygenase (KMO) blockade protects against multiple organ failure caused by acute pancreatitis (AP), but the link between KMO and systemic inflammation has eluded discovery until now. Here, we show that the KMO product 3-hydroxykynurenine primes innate immune signaling to exacerbate systemic inflammation during experimental AP. We find a tissue-specific role for KMO, where mice lacking Kmo solely in hepatocytes have elevated plasma 3-hydroxykynurenine levels that prime inflammatory gene transcription. 3-Hydroxykynurenine synergizes with interleukin-1β to cause cellular apoptosis. Critically, mice with elevated 3-hydroxykynurenine succumb fatally earlier and more readily to experimental AP. Therapeutically, blockade with the highly selective KMO inhibitor GSK898 rescues the phenotype, reducing 3-hydroxykynurenine and protecting against critical illness and death. Together, our findings establish KMO and 3-hydroxykynurenine as regulators of inflammation and the innate immune response to sterile inflammation. During critical illness, excess morbidity and death from multiple organ failure can be rescued by systemic KMO blockade.

Abstract Hyperpolarized carbon-13 magnetic resonance imaging is a promising technique for in vivo metabolic interrogation of alterations between health and disease. This study introduces a formalism for quantifying the metabolic information in hyperpolarized imaging. This study investigated a novel perfusion formalism and metabolic clearance rate (MCR) model in pre-clinical stroke and in the healthy human brain. Simulations showed that the proposed model was robust to perturbations in T1, transmit B1, and k PL. A significant difference in ipsilateral vs contralateral pyruvate derived cerebral blood flow (CBF) was detected in rats (140 ± 2 vs 89 ± 6 mL/100 g/min, p

Due to the greater importance put on the environment in the construction industry, wood, being a natural building material, has become more popular. It is of particular importance in the case of making elements with high aesthetic value and resistant to chemical corrosion. Due to high strength and, at the same time low weight, composite materials, especially fibrous composites, are also increasingly used. Among the fibrous composites, basalt fiber materials that are of natural origin and are ecological deserve attention. Therefore, the possible benefits resulting from the combination of two ecological materials was considered. In Ansys 16.1, a numerical model was created for parametric tests, assuming various construction configurations. In the ANSYS program, beams made of glued laminated timber, reinforced with BFRP bars, were modeled in various configurations of beam height, bar length, and bar distance from the lower and upper edge of the cross-section. The best results were obtained for the highest-height reinforced beams.

The aim of this review is to present and discuss the most recent literature about the processing of insect biomass and its impact on nutritive value, further implementation of meals and fats derived from invertebrates to livestock (poultry and swine), aquaculture (salmonids), and companion animal diets and their impact on growth performance, metabolic response, and gastrointestinal microbiota shifts. Additionally, the most important barriers to obtaining unified products in terms of their nutritive value are considered, i.e., to define insects' nutrient requirements, including various technological groups and further biomass processing (slaughtering, drying, and storage). Due to the current limitation in the insect production process consisting of the lack of infrastructure, there is stress on the relatively small amount of insect products added to the animal diets as a functional feed additive. Currently, only in the case of pet nutrition may insects be considered a full replacement for commonly used environmentally harmful and allergenic products. Simultaneously, the least information has been published on this topic. Thus, more scientific data are needed, particularly when the pet food branch and insect-based diets are rapidly growing.

Abstract Background During the COVID-19 pandemic, many children and young people have experienced the death of close family members, whilst also facing unprecedented disruption to their lives. This study aimed to investigate the experiences and support needs of bereaved children and young people from the perspective of their parents and guardians. Methods We analysed cross-sectional qualitative free-text data from a survey of adults bereaved in the UK during the pandemic. Participants were recruited via media, social media, national associations and community/charitable organisations. Thematic analysis was conducted on free text data collected from parent/guardian participants in response to a survey question on the bereavement experiences and support needs of their children. Results Free-text data from 104 parent/guardian participants was included. Three main themes were identified: the pandemic-related challenges and struggles experienced by children and young people; family support and coping; and support from schools and services. Pandemic-challenges include the impacts of being separated from the relative prior to their death, isolation from peers and other family members, and disruption to daily routines and wider support networks. Examples were given of effective family coping and communication, but also of difficulties relating to parental grief and children’s existing mental health problems. Schools and bereavement organisations’ provision of specialist support was valued, but there was evidence of unmet need, with some participants reporting a lack of access to specialist grief or mental health support. Conclusion Children and young people have faced additional strains and challenges associated with pandemic bereavement. We recommend resources and initiatives that facilitate supportive communication within family and school settings, adequate resourcing of school and community-based specialist bereavement/mental health services, and increased information and signposting to the support that is available.

How does auditory information influence the perception and evaluation of complex skills? Especially in technical compositional sports, such as gymnastics, the visual information perceived by the judges (and coaches) is the subject of an immediate evaluation. Various factors influence the judges’ performances. The impact of auditory information on the evaluation of complex skills is predominantly unexplored. Therefore, the study aimed to investigate floor music’s role in female gymnastics routines. Participants with different gymnastics expertise were asked to rate acrobatic series on the floor in three different audio-visual conditions (original, inter-beat, matched-beat). The current study results show that participants (irrespective of the group) rated acrobatic series in the matched-beat higher than in the original condition. In conclusion, it would be interesting to investigate if an effect on the participants’ perception is given for other gymnastics skills (gymnastic jumps and leaps) or the overall (execution) score on the floor.