Miracle-dz/UniFAR-FTUs huggingface dataset:
The aryl hydrocarbon receptor suppresses immunity to oral squamous cell carcinoma through immune checkpoint regulation

Significance Immune checkpoint inhibitors have emerged as critical therapeutics for several cancer types, including head and neck squamous cell carcinoma. However, enthusiasm remains constrained by the fact that only a minority of patients benefit. Therefore, there is a need to identify new immunotherapy targets. Here, we provide evidence supporting our hypothesis that the aryl hydrocarbon receptor (AhR) influences multiple immune checkpoints in a model of oral squamous cell carcinoma (OSCC). Remarkably, transplant of AhR-deleted OSCC cells generates completely protective tumor immunity characterized by a decrease in multiple immune checkpoints (PD-L1, CD39, CTLA4, PD1, and Lag3) on malignant and/or immune cells. These results have important implications for understanding the biology of cancer immunosuppression and for targeting the AhR for cancer immunotherapy. Immune checkpoint inhibitors represent some of the most important cancer treatments developed in the last 20 y. However, existing immunotherapy approaches benefit only a minority of patients. Here, we provide evidence that the aryl hydrocarbon receptor (AhR) is a central player in the regulation of multiple immune checkpoints in oral squamous cell carcinoma (OSCC). Orthotopic transplant of mouse OSCC cells from which the AhR has been deleted (MOC1AhR-KO) results, within 1 wk, in the growth of small tumors that are then completely rejected within 2 wk, concomitant with an increase in activated T cells in tumor-draining lymph nodes (tdLNs) and T cell signaling within the tumor. By 2 wk, AhR+ control cells (MOC1Cas9), but not MOC1AhR-KO cells up-regulate exhaustion pathways in the tumor-infiltrating T cells and expression of checkpoint molecules on CD4+ T cells (PD-1, CTLA4, Lag3, and CD39) and macrophages, dendritic cells, and Ly6G+ myeloid cells (PD-L1 and CD39) in tdLNs. Notably, MOC1AhR-KO cell transplant renders mice 100% immune to later challenge with wild-type tumors. Analysis of altered signaling pathways within MOC1AhR-KO cells shows that the AhR controls baseline and IFNγ-induced Ido and PD-L1 expression, the latter of which occurs through direct transcriptional control. These observations 1) confirm the importance of malignant cell AhR in suppression of tumor immunity, 2) demonstrate the involvement of the AhR in IFNγ control of PD-L1 and IDO expression in the cancer context, and 3) suggest that the AhR is a viable target for modulation of multiple immune checkpoints.
Categories, components, and techniques in a modular construction of basket trials for application and further research

Basket trials have become a virulent topic in medical and statistical research during the last decade. The core idea of them is to treat patients, who express the same genetic predisposition—either personally or their disease—with the same treatment irrespective of the location of the disease. The location of the disease defines each basket and the pathway of the treatment uses the common genetic predisposition among the baskets. This opens the opportunity to share information among baskets, which can consequently increase the information of the basket‐wise response with respect to the investigated treatment. This further allows dynamic decisions regarding futility and efficacy of individual baskets during the ongoing trial. Several statistical designs have been proposed on how a basket trial can be conducted and this has left an unclear situation with many options. The different designs propose different mathematical and statistical techniques, different decision rules, and also different trial purposes. This paper presents a broad overview of existing designs, categorizes them, and elaborates their similarities and differences. A uniform and consistent notation facilitates the first contact, introduction, and understanding of the statistical methodologies and techniques used in basket trials. Finally, this paper presents a modular approach for the construction of basket trials in applied medical science and forms a base for further research of basket trial designs and their techniques.
Autoimmune Pancreatitis

Supplemental digital content is available in the text. Objective The aim of this study was to critically analyze the surgical experience of managing autoimmune pancreatitis (AIP) in an era of modern diagnostics and compare these patients with those who were managed conservatively. Methods Two prospectively maintained databases were used to retrospectively identify patients with AIP who were either managed conservatively or underwent pancreatectomy. Results Eighty-eight patients were included in the study, of which 56 (63.6%) underwent resection and 32 (36.4%) were managed conservatively. Patients who underwent resection were more likely to present with jaundice (64.3% vs 18.1%, P < 0.001) and weight loss (53.6% vs 15.6%, P = 0.005). The cohort who underwent resection had a significantly higher median carbohydrate antigen 19-9 (40.0 vs 18.6 U/mL, P = 0.034) and was less likely to have elevated immunoglobulin G4 (26.1% vs 50.0%, P < 0.001). The most frequent initial diagnosis in the cohort who underwent resection was ductal adenocarcinoma (82.1%). Nine patients (28.1%) in the conservatively managed cohort experienced AIP relapse compared with 6 patients (10.7%) in the cohort who underwent resection. Conclusions The most frequent reason for surgical resection of AIP is concern for malignancy. Carbohydrate antigen 19-9 elevations were more common than immunoglobulin G4 in our cohort, suggesting that this laboratory profile is suboptimal for this population.
Evaluation of graded levels of Bacillus coagulans GBI-30, 6086 on apparent nutrient digestibility, stool quality, and intestinal health indicators in healthy adult dogs

Abstract Bacillus coagulans GBI-30, 6086 is a commercially available spore-forming non-toxigenic microorganism approved for use in dog foods with high resiliency to stresses associated with commercial manufacturing. The objectives of this research were to examine the effect of B. coagulans on stool quality, nutrient digestibility, and intestinal health markers in healthy adult dogs. Extruded diets containing graded levels of B. coagulans applied either to the base ration before extrusion or to the exterior of the kibble as a topical coating after extrusion were randomly assigned to 10 individually housed adult beagle dogs (7 castrated males and 3 spayed females) of similar age (5.75 ± 0.23 yr) and body weight (12.3 ± 1.5 kg). The study was designed as a 5 × 5 replicated Latin square with 16-d adaptation followed by 5-d total fecal collection for each period. Five dietary treatments were formulated to deliver a dose of 0-, 6-, 7-, 8-, and 9-log10 colony-forming units (CFU) per dog per day for the control (CON), extruded B. coagulans (PEX), and low, moderate, and high B. coagulans coating levels (PCL, PCM, and PCH), respectively. Food-grade TiO2 was added to all diets at a level of 0.4% to serve as an indigestible dietary marker for digestibility calculations. Data were analyzed using a mixed model through SAS (version 9.4, SAS Institute, Inc., Cary, NC) with treatment as a fixed effect and room (i.e., replicate), period, and dog(room) as random effects. Apparent total tract digestibility of organic matter, crude protein, crude fat, and gross energy calculated by the marker method were numerically greatest for dogs fed the 9-log10 dose treatment with increases (P < 0.05) observed in gross energy and organic matter digestibility compared with the negative control. No significant differences were observed in food intake, stool quality, fecal pH, fecal ammonia, fecal short-chain fatty acids, or branched-chain fatty acids for the extruded B. coagulans treatment (PEX) or the coated B. coagulans treatments (PCL, PCM, and PCH) compared with CON. These results suggest that B. coagulans has a favorable impact on nutrient digestibility and no apparent adverse effects when added to extruded diets at a daily intake level of up to 9-log10 CFU in healthy adult dogs.
Comparative Pathogenomics of Escherichia coli: Polyvalent Vaccine Target Identification through Virulome Analysis

Comparative genomics of bacterial pathogens has been useful for revealing potential virulence factors. Escherichia coli is a significant cause of human morbidity and mortality worldwide but can also exist as a commensal in the human gastrointestinal tract. With many sequenced genomes, it has served as a model organism for comparative genomic studies to understand the link between genetic content and potential for virulence. ABSTRACT Comparative genomics of bacterial pathogens has been useful for revealing potential virulence factors. Escherichia coli is a significant cause of human morbidity and mortality worldwide but can also exist as a commensal in the human gastrointestinal tract. With many sequenced genomes, it has served as a model organism for comparative genomic studies to understand the link between genetic content and potential for virulence. To date, however, no comprehensive analysis of its complete “virulome” has been performed for the purpose of identifying universal or pathotype-specific targets for vaccine development. Here, we describe the construction of a pathotype database of 107 well-characterized completely sequenced pathogenic and nonpathogenic E. coli strains, which we annotated for major virulence factors (VFs). The data are cross referenced for patterns against pathotype, phylogroup, and sequence type, and the results were verified against all 1,348 complete E. coli chromosomes in the NCBI RefSeq database. Our results demonstrate that phylogroup drives many of the “pathotype-associated” VFs, and ExPEC-associated VFs are found predominantly within the B2/D/F/G phylogenetic clade, suggesting that these phylogroups are better adapted to infect human hosts. Finally, we used this information to propose polyvalent vaccine targets with specificity toward extraintestinal strains, targeting key invasive strategies, including immune evasion (group 2 capsule), iron acquisition (FyuA, IutA, and Sit), adherence (SinH, Afa, Pap, Sfa, and Iha), and toxins (Usp, Sat, Vat, Cdt, Cnf1, and HlyA). While many of these targets have been proposed before, this work is the first to examine their pathotype and phylogroup distribution and how they may be targeted together to prevent disease.
GABAA receptor β1‐subunit knock‐out mice show increased delta power in NREM sleep and decreased theta power in REM sleep

γ‐Aminobutyric acid (GABA) acting through heteropentameric GABAA receptors plays a pivotal role in the sleep‐promoting circuitry. Whereas the role of the different GABAA receptor α‐subunits in sleep regulation and in mediating the effect of benzodiazepines for treatment of insomnia is well‐described, the β‐subunits are less studied. Here we report the first study characterizing sleep in mice lacking the GABAA receptor β1‐subunit (β1−/− mice). We show that β1−/− mice have a distinct and abnormal sleep phenotype characterized by increased delta power in non‐rapid eye movement (NREM) sleep and decreased theta activity in rapid eye movement (REM) sleep compared to β1+/+ mice, without any change in the overall sleep‐wake architecture. From GABAA receptor‐specific autoradiography, it is further demonstrated that functional β1‐subunit‐containing GABAA receptors display the highest binding levels in the hippocampus and frontal cortex. In conclusion, this study suggests that the GABAA receptor β1‐subunit does not play an important role in sleep initiation or maintenance but instead regulates the power spectrum and especially the expression of theta rhythm. This provides new knowledge on the complex role of GABAA receptor subunits in sleep regulation. In addition, β1−/− mice could provide a useful mouse model for future studies of the physiological role of delta and theta rhythms during sleep.
Inherited retinal diseases are the most common cause of blindness in the working-age population in Australia

ABSTRACT Background: This study examined the frequency of inherited retinal diseases (IRDs) as the reason for blindness registrations over the last two decades and the demographic and clinical phenotypes of inherited retinal disease (IRD)-related registrations. Materials and methods: Retrospective, observational study of individuals registered with a state-wide blind and vision-impaired registry. Low-vision or blindness-only (≤20/200 or ≤20°) certificates issued to children (0-15 years), working-age (16-64 years) and older-age (65 and older) adults were assessed. Sex and age distributions were examined for the top 20 reasons for certification. Demographic and clinical features of specific phenotypes of IRDs listed in the registry were examined. Results: Amongst 11824 low-vision certificates issued between July 1995 and January 2017, 679 (5.7%) listed an IRD as the reason for registration. In individuals with blindness-only certification (N=4919), IRDs was the second most common diagnosis (8.3%), overtaking glaucoma (8.1%) and diabetic retinopathy (5.4%). IRD was the second most common reason for low-vision certification amongst children (11.6%) and the most common reason amongst working-age population (23.3%). The mean±SD age for IRD-related blindness-only certification was 46±20 years. The top three phenotypes of IRD-related low-vision certification were non-syndromic retinitis pigmentosa (54%), Stargardt disease (12%) and macular dystrophy (8%). Conclusion: Our findings of IRDs as a common cause of blindness in all ages justify continued funding for providing low-vision services and developing treatments for these conditions.
Incidence, individual, and macro level risk factors of severe binocular visual impairment and blindness in persons aged 50 and older

Objective This study aims to estimate the incidence of severe binocular vision impairment and blindness (SVI/B) and to identify eye diseases and regional risk factors of persons with SVI/B at ages 50 years and older. Methods We designed an observational cohort study based on longitudinal, multifactorial, and administrative information of a random sample of 250,000 persons at ages 50+. All individuals were included in the process-produced health claims register of the Allgemeine Ortskrankenkasse in 2004, and were followed until 2015. We analyzed ten selected eye diseases and regional characteristics as risk factors for SVI/B using Cox models, adjusting for demographic characteristics and multi-morbidity. Results The age-standardized incidence was 79 new diagnoses of SVI/B per 100,000 person-years (95%-CI: 76-82); 77 for males (72-82) and 81 for females (77-85). By adjusting for multiple factors, the model revealed and confirmed that individuals who were very old (Hazard ratio90+: 6.67; 3.59-12.71), male (1.18; 1.01-1.38), had multi-morbidities (three+ diseases: 3.36; 2.51-4.49), or had diabetes (1.26; 1.07-1.49) had an increased risk of SVI/B. Compared to persons without the particular eye disease (all p<0.001), persons diagnosed with secondary glaucoma had a multiple-adjusted 4.66 times (3.17-6.85) higher risk, those with retinal vascular occlusion had a 4.51 times (3.27-6.23) higher risk, and those with angle-closure glaucoma had a 4.22 times (2.60-6.85) higher risk. Population density was not a risk factor, while persons living in wealthier regions had 0.75 times (p=0.003) to 0.70 times (p<0.001) the risk of SVI/B than persons in the least wealthy regions of Germany. Conclusion The study revealed and confirmed some profound risk factors of SVI/B at both the individual and the macro level. The sizes of the effects of the characteristics of the living context were smaller than those of the individual characteristics, especially for some severe eye diseases. While urbanity and access to health services had no effect, regional economic wealth was a risk factor for SVI/B. Future health care measures and advice by physicians should take these dimensions of inequalities in SVI/B into account.
Progress in tumour-targeted drug delivery based on cell-penetrating peptides

Abstract Since the discovery of cell-penetrating peptides (CPP) in the 1980s, they have played a unique role in various fields owing to their excellent and unique cell membrane penetration function. In particular, in the treatment of tumours, CPPS have been used to deliver several types of ‘cargos’ to cancer cells. To address the insufficient targeting ability, non-selectivity, and blood instability, activatable cell-penetrating peptides, which can achieve targeted drug delivery in tumour treatment, enhance curative effects, and reduce toxicity have been developed. This study reviews the application of different cell-penetrating peptides in tumour-targeted delivery, overcoming multidrug resistance, organelle targeting, tumour imaging, and diagnosis, and summarises the different mechanisms of activatable cell-penetrating peptides in detail.
Balance of salts and growth of papaya cultivars irrigated with saline water = Balanço de sais e crescimento de cultivares de mamoeiro irrigadas com água salina

The papaya crop has great socio-economic expression in the Brazil and is mainly grown in the northeastern region, which is facing serious problems of water shortage, particularly in its qualitative aspect, due to high concentration of salts in water. For best performance of a crop it is necessary to adopt managements strategies, such as the use of tolerant cultivars, thus, aimed to assess the balance of salts in the substrate, growth and partition of biomass of varieties of papaya irrigated with saline water. The experiment was conducted in a randomized complete block design with treatments arranged in a 2 x 4 factorial arrangement , consisting of two cultivars of papaya (Sunrise Solo and Tainung - 01) and four levels of water salinity (1.2, 2.4, 3.6 and 4.8 dS m -1 ) with three replications. The balance of salts in the substrate, growth rate and the dry matter partitioning were evaluated to determine crops’ tolerance to salinity in the initial growth phase. The water salinity increased linearly electrical conductivity, sodium absorption ratio and exchangeable sodium percentage of the substrate, and reduced growth and the biomass of varieties of papaya, in which reductions in biomass accumulation followed the order leaves > roots > stem. Salinity reduced the percentage of dry weight of stem and leaves and increased the dry weight of roots.
Structure and Activity of Microbial Communities in Sediments

Mineralization of organic matter in sediments are driven by a dense microbial population. Large chemical concentration gradients perpendicular to the interface are developed. Concentration profiles at the sediment-water interface can be measured in situ with miniaturized ion-selective electrodes and fluxes, and reaction rates can be calculated with this information. Direct flux measurements in benthic chambers are performed with isotope tracers to investigate the cycling of nutrients such as nitrogen and sulfur. With the development of molecular genetics new tools have become available to obtain information on the location and activity of microbial communities in the sediment. This opens a fascinating field for collaboration between geochemists and microbiologists. Flux measurements based on microsensors and in situ incubation techniques can now be related to microbiological information. In this contribution we give an overview of the current state of research in sensor development, incubation techniques, and molecular genetics at EAWAG.
Anisotropic Crystal Growth in Flat and Nonflat Systems: The Important Influence of van der Waals Contact Molecular Stacking on Crystal Growth and Dissolution

The crystal structures and crystal morphology of the mono-semicarbazone of 9,10-phenanthraquinone and nine of its solvates were examined to probe the mechanism of crystal growth of flat molecules. Three of the solvates were isomorphous, did not have stacked structures, and grew as blocks. Six of the solvates had stacked structures and grew as needles. A centroid distance based method for the detection of van der Waals (vdW) contact stacking is described. Nonflat carbamazepine (CBZ) forms I, III, and VI, 4-hydroxy-N-phenylbenzenesulfonamide, and a polymorph of 1,4-diphenyl-2H-cyclopenta[d]pyridazine all exhibited needle growth and have structures which maximize vdW contact stacking in the needle growth direction. The experimentally reported anisotropic dissolution of CBZ form I has been simulated using molecular dynamics. The intermolecular interactions have been analyzed using Gavezzotti’s PIXEL program. Dispersion force interactions between the molecules are most important within the stacks. A crystal gr.
Strategic asset allocation considerations for German pension insurance funds: theoretical analysis and empirical evidence : applying stochastic time-series simulations and dynamic, multiperiod investment strategies to determine optimal portfolio structures

Our research project analyses the suitability of social responsible investments (SRI) and alternative asset classes (in particular commodities, hedge fund investments, high-yield bonds) for the portfolio management of German Pension Insurance Funds (Pensionskassen), the largest external occupational pension scheme in Germany. The research objective is to determine optimal portfolio allocations for varying asset classes and investment strategies. The empirical methodology applied in our analysis will consist of stochastic time series simulations in combination with dynamic, multi-period asset allocation strategies. To our knowledge, our research proposal is to date the first of its kind and will provide valuable results to the academic research community as well as represent a useful reference for finance practitioners.
Synthesis and characterization of novel polyimides derived from 3,6-bis(4-aminophenoxy)pyridazine

Pyridazine-containing aromatic diamine monomer, 3,6-bis(4-aminophenoxy)pyridazine (APPD), was successfully synthesized by a nucleophilic substitution reaction of 3,6-dichloropyridazine with para-aminophenol. The aromatic heterocyclic diamine was employed to synthesize a series of polyimides (PIs) by polycondensation with various commercially available aromatic dianhydrides in N,N-dimethylacetamide via the conventional two-step method and further thermal imidization forming polyimides. The inherent viscosities of the resulting poly (amic acid)s were in the range of 0.47–1.51 dL g−1. Meanwhile, strong and flexible PI films were obtained, which had good thermal resistance, with the glass transition temperatures of 214–305°C and the temperature at 5% weight loss of 421–463°C under nitrogen atmosphere, as well as outstanding mechanical properties with tensile strengths of 61–102 MPa and elongations at break of 2.8–64.7%. The cutoff wavelength of the PI films were ranged in 357–413 nm.
Pollution studies on Nigerian rivers: heavy metals in surface water of warri river, Delta State

Surface water samples from Warri river in Delta State of Nigeria were analyzed quantitatively for the concentration of nine heavy metals, namely: Cadmium, Chromium, Copper, Iron, Lead, Manganese, Nickel, Vanadium and Zinc, using Atomic Absorption Spectrophotometer. Iron (Fe) recorded the highest mean value of 1.9304mgl-1 while Lead (Pb), had the least mean concentration of 0.0001mgl-1. Warri river receives effluents from industrial, agricultural and domestic sources. Cadmium, Chromium, Manganese and Nickel had higher concentrations than values in standard guidelines for potable water, pointing to the existence of risks to public health. There is need, therefore for a constant monitoring of the heavy metals concentrations in the surface water as well as a comprehensive conservation efforts by relevant organizations.