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Over the course of the COVID-19 pandemic, school students suffered from a reduction in opportunities to connect with higher education institutions, meet scientific role models in person, discuss scientific career options, and carry out hands-on practical laboratory activities. Current Chemistry Investigators (CCI) is a successful electrochemistry-based STEM career intervention program, developed and evaluated through a co-creation process with teachers and students. The goals of CCI are 2-fold: first, to provide school students with career advice through tangible scientific role models and, second, to provide real-world context for the fundamentals of electrochemistry through hands-on activities. Herein, the development of a novel electro-analytical workshop from concept through to delivery with over a thousand students having taken part to date is reported. Students are tasked with solving why a battery malfunctioned through quantitative and qualitative analyses of an electrolyte using conductivity meters. Student feedback is also gathered anonymously through the use of a classroom response system (also known as "clickers"). Together with feedback from teachers, a robust evaluation is presented to measure the impact of providing tangible scientific role models and the usefulness of the workshop.

Objectives: Lung squamous cell carcinoma (LUSC) is associated with a poor prognosis and a lack of specific treatment options. The dysregulation of activin A (ActA) has been reported in various malignancies. Herein, we investigated the diagnostic and prognostic significance of ActA in LUSC. Materials and methods: ActA concentrations were measured using ELISA in plasma samples of 128 LUSC patients (stage I-IV) and 73 controls, and correlated those values with clinicopathological parameters and survival. Results: ActA plasma levels were significantly higher in therapy-naive LUSC patients compared to controls (444.1 ± 310.9 pg/mL vs 338.9 ± 145.5 pg/mL, p = 0.010). ActA levels significantly correlated with advanced stage as well as with T and N factors. High circulating ActA levels were significantly increased in metastatic disease patients compared to M0 disease. Further, patients with ActA levels above a computationally established optimal cut-off value of 443.0 pg/mL had a significantly worse median overall (OS, 17.63 vs 64.77 months, HR 0.391, 95 % CI 0.200–0.762, p < 0.001) and median disease-/progression-free survival (DFS/PFS; 11.57 vs 30.20 months, HR 0.502, 95 % CI 0.248–1.019, p = 0.020). Multivariate analysis revealed that high ActA levels were an independent prognostic factor for shorter OS (p = 0.001) and DFS/PFS (p = 0.018). A newly developed score combining CRP and ActA levels was also an independent prognostic factor for OS and DFS/PFS. Conclusion: Measurement of circulating ActA levels may help identify advanced-stage LUSC patients, and this value could serve as a prognostic parameter in LUSC. Thus, ActA may be a novel blood-based biomarker for identifying LUSC patients with distant metastasis.

Fabry disease is a rare X-linked lysosomal condition that leads to the accumulation of glycosphingolipids in various tissues, causing cellular dysfunction, tissue remodeling, progressive fibrosis, and organ failure. The disease results from a deficiency in the human α-galactosidase A enzyme, responsible for breaking down glycosphingolipids like globotriaosylceramide (GL-3 or Gb3) into galactose and dihexose ceramides. In individuals diagnosed with Fabry disease, treatment from 2 years of age onwards typically involves agalsidase beta, the normal recombinant form of the defective enzyme. Agalsidase beta from Biosidus has been developed as a biosimilar to Sanofi-Genzyme's Fabrazyme®. In the molecule's clinical journey, a phase I trial was designed to establish its similarity in terms of pharmacokinetics, pharmacodynamics, and immunogenicity compared to the reference medication. The study was conducted on 24 healthy male volunteers, aged between 18 and 40 years. All volunteers received a single 1 mg/kg bw dose of Fabrazyme® or Biosidus Agalsidase beta by continuous intravenous (IV) infusion over 5 h. The 90 % confidence interval (CI) of the maximum concentration (Cmax), area under the plasma concentration-time curve from time 0 to 12 h (AUC0-12 h) and area under the plasma concentration-time curve extrapolated from time 0 to infinity (AUC0-∞) ratios fell within the accepted range of 80–125 %. No differences were detected in adverse effects or antibody induction. This indicates that Biosidus agalsidase beta meets the criteria for being considered similar to the reference formulation Sanofi Genzyme's Fabrazyme®.

The inverse base-rate effect is a robust irrational bias that arises when people face ambiguity. The most prominent theories of this irrational bias depend on prediction error. In this study, we gradually removed elements of a predictive learning design to test the extent to which error-driven processes underlie this bias. In our first experiment, we removed explicit feedback by implementing the inverse base-rate effect in an observational learning procedure. In our second study, we further removed any causal relationship between stimulus features and category labels by moving towards an unsupervised learning procedure. This removed any information participants could use to identify category labels. In both experiments, the inverse base-rate effect persisted and remained robust. This outcome suggests that this irrational bias is independent of supervised learning procedures. We propose that any theories and models of the inverse base-rate effect must manage information encoding and connection updates without explicit prediction error.

Pleural mesothelioma (PM) is characterized by rapid growth, local invasion, and limited therapeutic options. The multifunctional oncoprotein Y‐box‐binding protein‐1 (YB‐1) is frequently overexpressed in cancer and its inhibition reduces aggressive behavior in multiple tumor types. Here, we investigated the effects of YB‐1 on target gene regulation and PM cell behavior. Whereas siRNA‐mediated YB‐1 knockdown reduced cell motility, YB‐1 overexpression resulted in scattering, increased migration, and intravasation in vitro. Furthermore, YB‐1 stimulated PM cell spreading in zebrafish. Combined knockdown and inducible overexpression of YB‐1 allowed bidirectional control and rescue of cell migration, the pattern of which was closely followed by the mRNA and protein levels of EGFR and the protein level of snail, whereas the mRNA levels of MMP1, EPHA5, and PARK2 showed partial regulation by YB‐1. Finally, we identified snail as a critical regulator of YB‐1‐mediated cell motility in PM. This study provides insights into the mechanism underlying the aggressive nature of PM and highlights the important role of YB‐1 in this cancer. In this context, we found that YB‐1 closely regulates EGFR and snail, and, moreover, that YB‐1‐induced cell migration depends on snail.

Abstract Developing synchronous bilateral Wilms tumor suggests an underlying (epi)genetic predisposition. Here, we evaluate this predisposition in 68 patients using whole exome or genome sequencing (n = 85 tumors from 61 patients with matched germline blood DNA), RNA-seq (n = 99 tumors), and DNA methylation analysis (n = 61 peripheral blood, n = 29 non-diseased kidney, n = 99 tumors). We determine the predominant events for bilateral Wilms tumor predisposition: 1)pre-zygotic germline genetic variants readily detectable in blood DNA [WT1 (14.8%), NYNRIN (6.6%), TRIM28 (5%), and BRCA-related genes (5%)] or 2)post-zygotic epigenetic hypermethylation at 11p15.5 H19/ICR1 that may require analysis of multiple tissue types for diagnosis. Of 99 total tumor specimens, 16 (16.1%) have 11p15.5 normal retention of imprinting, 25 (25.2%) have 11p15.5 copy neutral loss of heterozygosity, and 58 (58.6%) have 11p15.5 H19/ICR1 epigenetic hypermethylation (loss of imprinting). Here, we ascertain the epigenetic and genetic modes of bilateral Wilms tumor predisposition.

Rising air temperatures have the capacity to impact rice yields in future climates. Studies in large temperature-controlled field chambers were established to examine the responses of four contrasting rice genotypes to elevated daytime temperatures (ET) during reproductive development under paddy conditions. Field chambers were effective in raising mean above-canopy maximum daytime temperatures from 29.9 to 41.1°C during 12 d of ET treatment (68–80 d after emergence, DAE), while increased transpiration under ET resulted in lowering of mean lower-canopy maximum temperature to 33.2°C. Nevertheless, the earliest genotype Vandana encountered a hot spell of 37.0°C at 68–74 DAE in the lower canopy at its late reproductive stage, which exceeded the spikelet sterility threshold of 33.7°C, so its spikelet fertility, grain number and grain yield were reduced under ET. Genotypes differed in the extent of canopy cooling, with less reduction in Vandana and IR64 than in N22 and Takanari. For canopy cooling to be effective, stratification of air layers must occur within the canopy, which was more effective under the shorter and denser canopy of N22 and Takanari (plant height of 70–80 ​cm) than under IR64 (90–110 ​cm) and Vandana (115–130 ​cm). Genotypes with appropriate canopy structures should be chosen for high vapour pressure deficit (VPD) conditions. Both maximum canopy temperature and VPD need to be specified to define the critical threshold for heat tolerance. Takanari was notable for greater leaf area retention and greater leaf photosynthetic capacity due to the maintenance of a higher internal leaf CO2 concentration, which led to higher spikelet and grain numbers and higher yield potential under ET conditions.

La leche de cabra suplementada con aceites de girasol y pescado presenta un aumento en el porcentaje de ácidos grasos poliinsaturados (LAGPI) respecto a la leche de cabra no suplementada (LC), una disminución en el porcentaje de ácidos grasos saturados y la consecuente baja del índice aterogénico que le otorga mayor valor nutracéutico. El objetivo del trabajo fue caracterizar y comparar las propiedades físico-químicas que determinan la calidad tecnológica para la elaboración de quesos de LAGPI y LC, con énfasis en las proteínas. Ambas leches se obtuvieron en una granja comercial de cabras raza Saanen ubicada en el Sudeste Bonaerense. Una vez confirmados los perfiles de ácidos grasos se analizaron: 1) componentes principales: grasa butirosa (GB), proteína bruta, lactosa, sólidos no grasos y sólidos totales (ST), 2) composición porcentual de la caseína y tamaño de las micelas, 3) tamaño de los glóbulos grasos, 4) composición físico-química: contenido de humedad, densidad, pH y acidez y 5) calidad higiénica (bacterias aeróbicas mesófilas totales). Los contenidos de GB, lactosa y ST fueron significativamente mayores en LAGPI (P

Abstract Background Pleural mesothelioma (PM) is a relatively rare malignancy with limited treatment options and dismal prognosis. We have previously found elevated FGF18 expression in PM tissue specimens compared with normal mesothelium. The objective of the current study was to further explore the role of FGF18 in PM and evaluate its suitability as a circulating biomarker. Methods FGF18 mRNA expression was analyzed by real‐time PCR in cell lines and in silico in datasets from the Cancer Genome Atlas (TCGA). Cell lines overexpressing FGF18 were generated by retroviral transduction and cell behavior was investigated by clonogenic growth and transwell assays. Plasma was collected from 40 PM patients, six patients with pleural fibrosis, and 40 healthy controls. Circulating FGF18 was measured by ELISA and correlated to clinicopathological parameters. Results FGF18 showed high mRNA expression in PM and PM‐derived cell lines. PM patients with high FGF18 mRNA expression showed a trend toward longer overall survival (OS) in the TCGA dataset. In PM cells with low endogenous FGF18 expression, forced overexpression of FGF18 resulted in reduced growth but increased migration. Surprisingly, despite the high FGF18 mRNA levels observed in PM, circulating FGF18 protein was significantly lower in PM patients and patients with pleural fibrosis than in healthy controls. No significant association of circulating FGF18 with OS or other disease parameters of PM patients was observed. Conclusions FGF18 is not a prognostic biomarker in PM. Its role in PM tumor biology and the clinical significance of decreased plasma FGF18 in PM patients warrant further investigation.

Abstract Background Major depressive disorder (MDD) is a leading cause of disability and premature mortality. This study compared the overall survival (OS) between patients with MDD and non-MDD controls stratified by gender, age, and comorbidities. Methods This nationwide population-based cohort study utilized longitudinal patient data (01/01/2010 – 12/31/2020) from the Hungarian National Health Insurance Fund database, which contains healthcare service data for the Hungarian population. Patients with MDD were selected and matched 1:1 to those without MDD using exact matching. The rates of conversion from MDD to bipolar disorder (BD) or schizophrenia were also investigated. Results Overall, 471,773 patients were included in each of the matched MDD and non-MDD groups. Patients with MDD had significantly worse OS than non-MDD controls (hazard ratio [HR] = 1.50; 95% CI: 1.48−1.51; males HR = 1.69, 95% CI: 1.66–1.72; females HR = 1.40, 95% CI: 1.38–1.42). The estimated life expectancy of patients with MDD was 7.8 and 6.0 years less than that of controls aged 20 and 45 years, respectively. Adjusted analyses based on the presence of baseline comorbidities also showed that patients with MDD had worse survival than non-MDD controls (adjusted HR = 1.29, 95% CI: 1.28–1.31). After 11 years of follow-up, the cumulative conversions from MDD to BD and schizophrenia were 6.8 and 3.4%, respectively. Converted patients had significantly worse OS than non-converted patients. Conclusions Compared with the non-MDD controls, a higher mortality rate in patients with MDD, especially in those with comorbidities and/or who have converted to BD or schizophrenia, suggests that early detection and personalized treatment of MDD may reduce the mortality in patients diagnosed with MDD.

Due to the high variance in response rates concerning anti-PD1 immunotherapy (IT), there is an unmet need to discover innovative biomarkers to predict immune checkpoint inhibitor (ICI)-efficacy. Our study included 62 Caucasian advanced-stage non-small cell lung cancer (NSCLC) patients treated with anti-PD1 ICI. Gut bacterial signatures were evaluated by metagenomic sequencing and correlated with progression-free survival (PFS), PD-L1 expression and other clinicopathological parameters. We confirmed the predictive role of PFS-related key bacteria with multivariate statistical models (Lasso- and Cox-regression) and validated on an additional patient cohort (n = 60). We find that alpha-diversity showed no significant difference in any comparison. However, there was a significant difference in beta-diversity between patients with long- (>6 months) vs. short (≤6 months) PFS and between chemotherapy (CHT)-treated vs. CHT-naive cases. Short PFS was associated with increased abundance of Firmicutes (F) and Actinobacteria phyla, whereas elevated abundance of Euryarchaeota was specific for low PD-L1 expression. F/Bacteroides (F/B) ratio was significantly increased in patients with short PFS. Multivariate analysis revealed an association between Alistipes shahii, Alistipes finegoldii, Barnesiella visceriola, and long PFS. In contrast, Streptococcus salivarius, Streptococcus vestibularis, and Bifidobacterium breve were associated with short PFS. Using Random Forest machine learning approach, we find that taxonomic profiles performed superiorly in predicting PFS (AUC = 0.74), while metabolic pathways including Amino Acid Synthesis and Fermentation were better predictors of PD-L1 expression (AUC = 0.87). We conclude that specific metagenomic features of the gut microbiome, including bacterial taxonomy and metabolic pathways might be suggestive of ICI efficacy and PD-L1 expression in NSCLC patients.

There is a growing interest in alternative explanations to the dual-system account of how people learn category structures varying in their optimal decision bounds (unidimensional and information-integration structures). Recognition memory performance and hippocampal activation patterns in these tasks are two interesting findings, which have not been formally explained. Here, we carry out a formal simulation with SUSTAIN (Love, Medin, & Gureckis, 2004), an adaptive model of category learning, which had great success in accounting for recognition memory performance and fMRI activity patterns. We show, for the first time, that a formal single-system model of category learning can accommodate recognition performance after learning and is consistent with fMRI data obtained while participants learned these structures.

A new mycoheterotrophic species, Thismia kenyirensis Siti-Munirah & Dome from Peninsular Malaysia, is described and illustrated. Thismia kenyirensis differs from other previously described species in the following characteristics: the flower tube is completely orange, with alternating darker and paler-coloured longitudinal lines on the outer and inner surfaces, the outer tepals are ovate (petaloid), the inner tepals are narrowly lanceolate, each ending with a long appendage. According to the IUCN Red List categories and criteria, T. kenyirensis is provisionally classified as Least Concern.

ABSTRACT Fungal infections are of mounting global concern, and the current limited treatment arsenal poses challenges when treating such infections. In particular, infections by Cryptococcus neoformans are associated with high mortality, emphasizing the need for novel therapeutic options. Calcineurin is a protein phosphatase that mediates fungal stress responses, and calcineurin inhibition by the natural product FK506 blocks C. neoformans growth at 37°C. Calcineurin is also required for pathogenesis. However, because calcineurin is conserved in humans and inhibition with FK506 results in immunosuppression, the use of FK506 as an anti-infective agent is precluded. We previously elucidated the structures of multiple fungal calcineurin-FK506-FKBP12 complexes and implicated the C-22 position on FK506 as a key point for differential modification of ligand inhibition of mammalian versus fungal target proteins. Through in vitro antifungal and immunosuppressive testing of FK520 (a natural analog of FK506) derivatives, we identified JH-FK-08 as a lead candidate for further antifungal development. JH-FK-08 exhibited significantly reduced immunosuppressive activity and both reduced fungal burden and prolonged survival of infected animals. JH-FK-08 exhibited additive activity in combination with fluconazole in vivo. These findings further advance calcineurin inhibition as an antifungal therapeutic approach. IMPORTANCE Fungal infections cause significant morbidity and mortality globally. The therapeutic armamentarium against these infections is limited, and the development of antifungal drugs has been hindered by the evolutionary conservation between fungi and the human host. With rising resistance to the current antifungal arsenal and an increasing at-risk population, there is an urgent need for the development of new antifungal compounds. The FK520 analogs described in this study display potent antifungal activity as a novel class of antifungals centered on modifying an existing orally active FDA-approved therapy. This research advances the development of much-needed newer antifungal treatment options with novel mechanisms of action.

Over the past decade, mRNA-based therapy has displayed significant promise in a wide range of clinical applications. The most striking example of the leap in the development of mRNA technologies was the mass vaccination against COVID-19 during the pandemic. The emergence of large-scale technology and positive experience of mRNA immunization sparked the development of antiviral and anti-cancer mRNA vaccines as well as therapeutic mRNA agents for genetic and other diseases. To facilitate mRNA delivery, lipid nanoparticles (LNPs) have been successfully employed. However, the diverse use of mRNA therapeutic approaches requires the development of adaptable LNP delivery systems that can control the kinetics of mRNA uptake and expression in target cells. Here, we report effective mRNA delivery into cultured mammalian cells (HEK293T, HeLa, DC2.4) and living mouse muscle tissues by liposomes containing either 1,26-bis(cholest-5-en-3β-yloxycarbonylamino)-7,11,16,20-tetraazahexacosane tetrahydrochloride (2X3) or the newly applied 1,30-bis(cholest-5-en-3β-yloxycarbonylamino)-9,13,18,22-tetraaza-3,6,25,28-tetraoxatriacontane tetrahydrochloride (2X7) cationic lipids. Using end-point and real-time monitoring of Fluc mRNA expression, we showed that these LNPs exhibited an unusually delayed (of over 10 h in the case of the 2X7-based system) but had highly efficient and prolonged reporter activity in cells. Accordingly, both LNP formulations decorated with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] (DSPE-PEG2000) provided efficient luciferase production in mice, peaking on day 3 after intramuscular injection. Notably, the bioluminescence was observed only at the site of injection in caudal thigh muscles, thereby demonstrating local expression of the model gene of interest. The developed mRNA delivery systems hold promise for prophylactic applications, where sustained synthesis of defensive proteins is required, and open doors to new possibilities in mRNA-based therapies.