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Global fertilizer production and mismanagement significantly contribute to many harmful environmental impacts, revealing the need for a greater understanding of crop growth and nutrient uptake, which can be used to optimize fertilizer management. This study experimentally adapts first-principles microbial modeling techniques to the hydroponic cultivation of Bibb lettuce (Lactuca sativa) under nitrogen-limited conditions. Monod and Michaelis–Menten’s approaches are applied to predict biomass productivity and nutrient uptake and to evaluate the feasibility of reclaimed wastewater as a nutrient source of nitrogen. Experimental and modeling results reveal significantly different kinetic saturation constants (Ks = 1.331 and Km = 17.887 mg L−1) and a corresponding cell yield strongly dependent on nutrient concentration, producing visually and compositionally distinct tissue between treatments receiving ≤26.2 and ≥41.7 mgN L−1. The resulting Monod model overestimates dry mass predictions during low nutrient conditions, and the collective results support the development of a dynamic Monod curve that is temporally dependent during the plants’ lifecycle. Despite this shortcoming, these results support the feasibility of reclaiming nitrogen from wastewater in hydroponic agriculture, expecting to produce lesser biomass lettuce exhibiting healthy tissue. Furthermore, this study provides a mathematical foundation for agricultural simulations and nutrient management.

The Lightning Network (LN), a second-layer protocol built on top of the Bitcoin blockchain, is an innovative digital payment solution that offers increased convenience, speed, and cost-effectiveness to consumers and businesses alike. However, there is limited literature available on the characteristics of this nascent technology, the depth and breadth of the various business LN-related applications as well as relevant adoption/implementation challenges. This study aims to contribute to the understanding of the LN’s characteristics, its potential in enhancing business operations and its applicability across different sectors, while taking into account adoption and implementation challenges. We apply a narrative review methodology using a semi-systematic approach to examine new and emerging business models empowered by the LN and its characteristics, topology, performance, privacy and security. We analyze the data to identify key themes and trends in the literature, offering a critical analysis of the strengths and weaknesses of the existing literature. Based on the findings, we provide several clusters of fruitful areas for future research directions. This study not only provides crucial insights for businesses contemplating the adoption of LN to improve their operations and customer experience, but it also represents a substantial academic contribution, offering valuable knowledge and fostering further research in the fields of blockchain technology, FinTech and cryptocurrencies.

Background: The prevalence of metastatic melanoma is increasing, necessitating the identification of patients who do not benefit from immunotherapy. This study aimed to develop a radiomic biomarker based on the segmentation of all metastases at baseline and the first follow-up CT for the endpoints best overall response (BOR), progression-free survival (PFS), and overall survival (OS), encompassing various immunotherapies. Additionally, this study investigated whether reducing the number of segmented metastases per patient affects predictive capacity. Methods: The total tumour load, excluding cerebral metastases, from 146 baseline and 146 first follow-up CTs of melanoma patients treated with first-line immunotherapy was volumetrically segmented. Twenty-one random forest models were trained and compared for the endpoints BOR; PFS at 6, 9, and 12 months; and OS at 6, 9, and 12 months, using as input either only clinical parameters, whole-tumour-load delta radiomics plus clinical parameters, or delta radiomics from the largest ten metastases plus clinical parameters. Results: The whole-tumour-load delta radiomics model performed best for BOR (AUC 0.81); PFS at 6, 9, and 12 months (AUC 0.82, 0.80, and 0.77); and OS at 6 months (AUC 0.74). The model using delta radiomics from the largest ten metastases performed best for OS at 9 and 12 months (AUC 0.71 and 0.75). Although the radiomic models were numerically superior to the clinical model, statistical significance was not reached. Conclusions: The findings indicate that delta radiomics may offer additional value for predicting BOR, PFS, and OS in metastatic melanoma patients undergoing first-line immunotherapy. Despite its complexity, volumetric whole-tumour-load segmentation could be advantageous.

Breastfeeding is the most appropriate source of a newborn’s nutrition; among the plethora of its benefits, its modulation of circadian rhythmicity with melatonin as a potential neuroendocrine transducer has gained increasing interest. Transplacental transfer assures melatonin provision for the fetus, who is devoid of melatonin secretion. Even after birth, the neonatal pineal gland is not able to produce melatonin rhythmically for several months (with an even more prolonged deficiency following preterm birth). In this context, human breast milk constitutes the main natural source of melatonin: diurnal dynamic changes, an acrophase early after midnight, and changes in melatonin concentrations according to gestational age and during the different stages of lactation have been reported. Understudied thus far are the factors impacting on (changes in) melatonin content in human breast milk and their clinical significance in chronobiological adherence in the neonate: maternal as well as environmental aspects have to be investigated in more detail to guide nursing mothers in optimal feeding schedules which probably means a synchronized instead of mistimed feeding practice. This review aims to be thought-provoking regarding the critical role of melatonin in chrononutrition during breastfeeding, highlighting its potential in circadian entrainment and therefore optimizing (neuro)developmental outcomes in the neonatal setting.

Hairless (H) encodes the major antagonist in the Notch signaling pathway, which governs cellular differentiation of various tissues in Drosophila. By binding to the Notch signal transducer Suppressor of Hairless (Su(H)), H assembles repressor complexes onto Notch target genes. Using genome engineering, three new H alleles, HFA, HLLAA and HWA were generated and a phenotypic series was established by several parameters, reflecting the residual H-Su(H) binding capacity. Occasionally, homozygous HWA flies develop to adulthood. They were compared with the likewise semi-viable HNN allele affecting H-Su(H) nuclear entry. The H homozygotes were short-lived, sterile and flightless, yet showed largely normal expression of several mitochondrial genes. Typical for H mutants, both HWA and HNN homozygous alleles displayed strong defects in wing venation and mechano-sensory bristle development. Strikingly, however, HWA displayed only a loss of bristles, whereas bristle organs of HNN flies showed a complete shaft-to-socket transformation. Apparently, the impact of HWA is restricted to lateral inhibition, whereas that of HNN also affects the respective cell type specification. Notably, reduction in Su(H) gene dosage only suppressed the HNN bristle phenotype, but amplified that of HWA. We interpret these differences as to the role of H regarding Su(H) stability and availability.

Human patients with type 1 diabetes mellitus (T1DM) are susceptible to several long-term complications that are related to glycemic control and immune dysregulation. Immune function remains relatively unexplored in dogs with naturally occurring diabetes mellitus (NODM). Calcitriol improves various aspects of immune function in a variety of species, but its effect in diabetic dogs remains unexplored. Therefore, the objectives of this study were to (i) evaluate immune function in dogs with NODM and determine if differences exist based on the level of clinical control and (ii) assess the immunomodulatory effects of calcitriol. Twenty diabetic dogs (clinically controlled, n = ten, not controlled, n = ten) and 20 non-diabetic, healthy control dogs were included in this prospective, case–control study. Whole blood was incubated with calcitriol (10−7 M) or negative control, after which the samples were divided for phagocytosis and leukocyte cytokine response experiments. The phagocytosis of opsonized Escherichia coli (E. coli) was evaluated with flow cytometry. The samples for leukocyte cytokine response evaluations were stimulated with lipopolysaccharide (LPS), lipoteichoic acid (LTA), or phosphate buffer solution (PBS; negative control), and tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-8, and IL-10 were measured in supernatant using a canine-specific multiplex bead-based assay. The leukocytes from diabetic dogs produced higher concentrations of IL-10 (p = 0.01), IL-6 (p < 0.0001), and IL-8 (p < 0.0001) than the control dogs while controlling for the intervention and stimulant. Calcitriol decreased the supernatant concentrations of TNF-α (p < 0.001) and IL-8 (p = 0.04) with concomitant increases in IL-6 (p = 0.005). Diabetic dogs had a lower percentage of leukocytes undergoing phagocytosis (p < 0.0001) but a higher number of bacteria phagocytized per cell (p = 0.001) when compared to the control dogs. Calcitriol had no effect on phagocytic capacity. Lastly, the status of clinical control in diabetic dogs did not yield differences in immune function. These results support that dogs with NODM exhibit immune dysregulation and warrant additional investigation.

The Escherichia coli Keio mutant collection has been a tool for assessing the role of specific genes and determining their role in E. coli physiology and uncovering novel functions. In this work, specific mutants in the DNA repair pathways and oxidative stress response were evaluated to identify the primary targets of silver nanoparticles (NPs) and their mechanism of action. The results presented in this work suggest that NPs mainly target DNA via double-strand breaks and base modifications since the recA, uvrC, mutL, and nfo mutants rendered the most susceptible phenotype, rather than involving the oxidative stress response. Concomitantly, during the establishment of the control conditions for each mutant, the katG and sodA mutants showed a hypersensitive phenotype to mitomycin C, an alkylating agent. Thus, we propose that KatG catalase plays a key role as a cellular chaperone, as reported previously for the filamentous fungus Neurospora crassa, a large subunit catalase. The Keio collection mutants may also be a key tool for assessing the resistance mechanism to metallic NPs by using their potential to identify novel pathways involved in the resistance to NPs.

Background: The electronic Freight Transport Information (eFTI) regulation is critical in modernizing freight transport (FT) within the European Union by establishing a framework for the electronic exchange of information. Despite its importance, there is a notable gap in the literature regarding the practical implementation challenges, especially from an empirical perspective. Methods: To address this gap, our study utilized a grounded theory approach, conducting interviews with a diverse group of logistics experts from Greece. The selection of experts was strategic to ensure a comprehensive range of knowledge and expertise, including insights at the policy level as well as practical experiences. Results: Our findings highlight several significant challenges in the implementation of eFTI, including the digital skill gap among the workforce, issues with system interoperability, and diverse capacities and resources of companies of different sizes. Economic factors, regulatory frameworks and the necessity for targeted training and leadership support were also identified as crucial for the digital transition. Conclusions: The study shows that uniform eFTI implementation may not work for all organizations, highlighting the necessity for customized strategies that address specific challenges in the FT chain. Our research deepens the understanding of these issues, providing actionable insights for successful eFTI adoption.

Pruritus has long been linked to hepatic dysfunction; however, there are limited data characterizing the association between liver disease and prurigo nodularis (PN), a chronic inflammatory skin disease featuring severe pruritis. We thus conducted a cross-sectional analysis of hepatic comorbidities in PN patients using TriNetX, a large global health research network. This analysis revealed that PN patients had a higher risk (p < 0.001) of developing liver cirrhosis, acute and subacute hepatic failure, inflammatory liver disease, chronic hepatitis, nonalcoholic steatohepatitis, portal hypertension, fatty liver, chronic passive congestion of the liver, and hepatocellular carcinoma compared with healthy controls. The cumulative incidence of liver disease was about three times higher in PN patients compared with healthy controls. These findings provided the basis for translational studies to investigate a genetic mechanism for this association. Cutaneous transcriptomic analysis performed on PN patients revealed the dysregulation of genes related to hepatic failure in lesional PN compared with both nonlesional PN and control skin. Similarly, gene set variation analysis (GSVA) revealed a significantly increased (p < 0.05) activation of liver metabolism, chronic hepatic failure, acute hepatic failure, cholestatic liver disease, polycystic liver disease, and hepatocellular carcinoma pathways in lesional PN compared with control skin. A subsequent genome-wide association study (GWAS) identified shared single-nucleotide polymorphisms (SNPs) in the genes AR, EDIL3, MACROD2, PCSK5, RUNX1T1, TENM4, and ZEB2 between PN and liver disease from the FinnGen cohort. Significant dysregulation of the skin–liver axis in PN patients may explain the increased incidence and severity of hepatic comorbidities and help identify future therapeutic targets for PN.

Land Suitability Analysis (LSA), under the impact of climate change, is a fundamental approach to the design of appropriate land management strategies for sustainable crop production and food security. In this study, the FAO framework was used to assess the impact of climate change on land suitability for maize in Flanders, Belgium. The current LSA revealed the marginal suitability for maize cultivation, characterizing most of the agricultural land in Flanders and identifying precipitation as the most limiting factor for maize suitability. The LSA, under two climate change scenarios, was based on climate projections from several CMIP5 Global Circulation Models, transformed into future land suitability projections and assembled into a multi-model ensemble (MME) of projected suitability changes. The results indicate an average reduction in projected suitability of approximately 7% by 2099 under the high-emission scenario. The potential of the Soil-Improving Cropping System (SICS) to mitigate the impacts of climate change on land suitability was statistically significant under both low- and high-emission scenarios. This research provides valuable insights into the MME modeling of climate change impacts on land suitability and its associated uncertainty, with the application of SICS as a potential long-term mitigation measure to promote sustainable agricultural practices.

Timely and accurate detection of diseases plays a significant role in attaining optimal growing conditions of olive crops. This study evaluated the use of two machine learning algorithms, Random Forest (RF) and XGBoost (XGB), in conjunction with the feature selection methods Recursive Feature Elimination (RFE) and Mutual Information (MI), for detecting stress in olive trees using hyperspectral data. The research was conducted in Halkidiki, Northern Greece, and focused on identifying stress caused by biotic and abiotic factors through the analysis of hyperspectral images. Both the RF and XGB algorithms demonstrated high efficacy in stress classification, achieving roc-auc scores of 0.977 and 0.955, respectively. The study also highlighted the effectiveness of RFE and MI in optimizing the classification process, with RF and XGB requiring a reduced number of hyperspectral features for an optimal performance of 1.00 on both occasions. Key wavelengths indicative of stress were identified in the visible to near-infrared spectrum, suggesting their strong correlation with olive tree stress. These findings contribute to precision agriculture by demonstrating the viability of using machine learning for stress detection in olive trees, and underscores the importance of feature selection in improving classifier performance.

Background: Model quality assessments via computational methods which entail comparisons of the modeled structures to the experimentally determined structures are essential in the field of protein structure prediction. The assessments provide means to benchmark the accuracies of the modeling techniques and to aid with their development. We previously described the ResiRole method to gauge model quality principally based on the preservation of the structural characteristics described in SeqFEATURE functional site prediction models. Methods: We apply ResiRole to benchmark modeling group performances in the Critical Assessment of Structure Prediction experiment, round 15. To gauge model quality, a normalized Predicted Functional site Similarity Score (PFSS) was calculated as the average of one minus the absolute values of the differences of the functional site prediction probabilities, as found for the experimental structures versus those found at the corresponding sites in the structure models. Results: The average PFSS per modeling group (gPFSS) correlates with standard quality metrics, and can effectively be used to rank the accuracies of the groups. For the free modeling (FM) category, correlation coefficients of the Local Distance Difference Test (LDDT) and Global Distance Test-Total Score (GDT-TS) metrics with gPFSS were 0.98239 and 0.87691, respectively. An example finding for a specific group is that the gPFSS for EMBER3D was higher than expected based on the predictive relationship between gPFSS and LDDT. We infer the result is due to the use of constraints imprinted by function that are a part of the EMBER3D methodology. Also, we find functional site predictions that may guide further functional characterizations of the respective proteins. Conclusion: The gPFSS metric provides an effective means to assess and rank the performances of the structure prediction techniques according to their abilities to accurately recount the structural features at predicted functional sites.

Sarcoma can present as locally advanced disease involving pleura for which extra-pleural pneumonectomy (EPP) may be the only surgical option to ensure adequate local control. Data were collected on patients who underwent EPP between January 2009 and August 2021 at Princess Margret Hospital and SickKids (Toronto) using the CanSaRCC (Canadian Sarcoma Research and Clinical Collaboration). Ten patients with locally advanced sarcoma involving the pleura, aged 4 to 59 years (median 19.5 years) underwent EPP. Nine (90%) received pre-operative chemotherapy and eight (80%) achieved an R0 resection. Hemithoracic radiation was administered preoperatively (n = 6, 60%) or postoperatively (n = 4, 40%). Five (50%) patients were alive without disease at last follow-up (median 34.2 months) and time from EPP to last FU was median 29.2 months (range 2.2–87.5). Two patients (20%) had local recurrence, 4.3 and 5.8 months from EPP, and both died from progressive disease, 13.1 and 8.2 months from EPP, respectively. One patient died from brain metastasis (17 months), one died from radiation associated osteosarcoma (66 months), and one died from surgical complications (heart failure from constrictive pericarditis). EPP offers a feasible and life-prolonging surgical consideration for patients with locally advanced sarcoma involving the pleura in combination with chemotherapy and radiation. Consequently, EPP should be considered during multi-disciplinary tumor board discussions at high-volume centers.

Background: The aim of this study was to investigate whether the combination of radiomics and clinical parameters in a machine-learning model offers additive information compared with the use of only clinical parameters in predicting the best response, progression-free survival after six months, as well as overall survival after six and twelve months in patients with stage IV malignant melanoma undergoing first-line targeted therapy. Methods: A baseline machine-learning model using clinical variables (demographic parameters and tumor markers) was compared with an extended model using clinical variables and radiomic features of the whole tumor burden, utilizing repeated five-fold cross-validation. Baseline CTs of 91 stage IV malignant melanoma patients, all treated in the same university hospital, were identified in the Central Malignant Melanoma Registry and all metastases were volumetrically segmented (n = 4727). Results: Compared with the baseline model, the extended radiomics model did not add significantly more information to the best-response prediction (AUC [95% CI] 0.548 (0.188, 0.808) vs. 0.487 (0.139, 0.743)), the prediction of PFS after six months (AUC [95% CI] 0.699 (0.436, 0.958) vs. 0.604 (0.373, 0.867)), or the overall survival prediction after six and twelve months (AUC [95% CI] 0.685 (0.188, 0.967) vs. 0.766 (0.433, 1.000) and AUC [95% CI] 0.554 (0.163, 0.781) vs. 0.616 (0.271, 1.000), respectively). Conclusions: The results showed no additional value of baseline whole-body CT radiomics for best-response prediction, progression-free survival prediction for six months, or six-month and twelve-month overall survival prediction for stage IV melanoma patients receiving first-line targeted therapy. These results need to be validated in a larger cohort.

Combined BRAF/MEK-inhibition constitutes a relevant treatment option for BRAF-mutated advanced melanoma. The prospective, non-interventional COMBI-r study assessed the effectiveness and tolerability of the BRAF-inhibitor dabrafenib combined with the MEK-inhibitor trametinib in patients with advanced melanoma under routine clinical conditions. Progression-free survival (PFS) was the primary objective, and secondary objectives included overall survival (OS), disease control rate, duration of therapy, and the frequency and severity of adverse events. This study enrolled 472 patients at 55 German sites. The median PFS was 8.3 months (95%CI 7.1–9.3) and the median OS was 18.3 months (14.9–21.3), both tending to be longer in pre-treated patients. In the 147 patients with CNS metastases, PFS was similar in those requiring corticosteroids (probably representing symptomatic patients, 5.6 months (3.9–7.2)) compared with those not requiring corticosteroids (5.9 months (4.8–6.9)); however, OS was shorter in patients with brain metastases who received corticosteroids (7.8 (6.3–11.6)) compared to those who did not (11.9 months (9.6–19.5)). The integrated subjective assessment of tumor growth dynamics proved helpful to predict outcome: investigators’ upfront categorization correlated well with time-to-event outcomes. Taken together, COMBI-r mirrored PFS outcomes from other prospective, observational studies and confirmed efficacy and safety findings from the pivotal phase III COMBI-d/-v and COMBI-mb trials.

One of the major challenges for the Australian feedlot and meat sectors is to have accurate and robust long-term greenhouse gas (GHG) emissions data. Long-term measurements of methane (CH4) emissions (2015–2017) were made at two Australian beef feedlots having different climates, cattle types, and management practices. Emissions were measured using the inverse-dispersion model (IDM) micrometeorological technique, using CH4 concentrations measured at the feedlots with a closed-path Fourier transform infrared spectroscopic technique (CP-FTIR). The emissions data were used to evaluate methods used by the Department of Climate Change, Energy, the Environment and Water to estimate CH4 emissions from feedlots in Australian national inventory calculations. Expressed as a CH4 yield (emissions per unit dry matter intake, DMI), the two feedlots had emissions of 13.1 and 18.9 g CH4 kg−1 DMI. The lower-emitting feedlot had emissions that were 30% lower than the national inventory calculations based on feed intakes, while the second feedlot had emissions that were similar to the inventory calculations. The accurate quantification of emissions from feedlots, as demonstrated as part of this study, is important for validating the national accounting methods and therefore the sector’s GHG emissions profile.

As new phage-defense systems (PDs) are discovered, the overlap between their mechanisms and those of toxin/antitoxin systems (TAs) is becoming clear in that both use similar means to reduce cellular metabolism; for example, both systems have members that deplete energetic compounds (e.g., NAD+, ATP) and deplete nucleic acids, and both have members that inflict membrane damage. Moreover, both TAs and PDs are similar in that rather than altruistically killing the host to limit phage propagation (commonly known as abortive infection), both reduce host metabolism since phages propagate less in slow-growing cells, and slow growth facilitates the interaction of multiple phage-defense systems.

Constitutively active kinases play a crucial role in carcinogenesis, and their inhibition is a common target for molecular tumor therapy. We recently discovered the expression of two oncogenic isoforms of Bruton’s Tyrosine Kinase (BTK) in head and neck squamous cell carcinoma (HNSCC), Btk-p80 and BTK-p65. However, the precise role of BTK in HNSCC remains unclear. Analyses of a tissue microarray containing benign and malignant as well as inflammatory tissue samples of the head and neck region revealed the preferential expression of BTK-p80 in malignant tissue, whereas BTK-p65 expression was confirmed in over 80% of analyzed metastatic head and neck tumor cases. Therefore, processes associated with metastasis, like cancer stem cell (CSC) enrichment and the epithelial–mesenchymal transition (EMT), which in turn depend on an appropriate cytokine milieu, were analyzed. Treatment of HNSCC-derived cell lines cultured under 3D conditions with the BTK inhibitor AVL-292 caused reduced sphere formation, which was accompanied by reduced numbers of ALDH1A1+ CSCs as well as biological changes associated with the EMT. Moreover, we observed reduced NF-κB expression as well as altered NF-κB dependent pro-tumorigenic and EMT-associated cytokine release of IL-6, IFNγ, and TNFα when BTK activity was dampened. Therefore, an autocrine regulation of the oncogenic BTK-dependent process in HNSCC can be suggested, with BTK inhibition expected to be an effective treatment option for HNSCC.

Despite significant improvements in survival following preterm birth in recent years, the neurodevelopmental burden of prematurity, with its long-term cognitive and behavioral consequences, remains a significant challenge in neonatology. Neuroprotective treatment options to improve neurodevelopmental outcomes in preterm infants are therefore urgently needed. Alleviating inflammatory and oxidative stress (OS), melatonin might modify important triggers of preterm brain injury, a complex combination of destructive and developmental abnormalities termed encephalopathy of prematurity (EoP). Preliminary data also suggests that melatonin has a direct neurotrophic impact, emphasizing its therapeutic potential with a favorable safety profile in the preterm setting. The current review outlines the most important pathomechanisms underlying preterm brain injury and correlates them with melatonin’s neuroprotective potential, while underlining significant pharmacokinetic/pharmacodynamic uncertainties that need to be addressed in future studies.

Vaccination strategies to lessen the impact of the spread of a disease are fundamental to public health authorities and policy makers. The socio-economic benefit of full return to normalcy is the core of such strategies. In this paper, a COVID-19 vaccination model with efficacy rate is developed and analyzed. The epidemiological parameters of the model are learned via a feed-forward neural network. A hybrid approach that combines residual neural network with variants of recurrent neural network is implemented and analyzed for reliable and accurate prediction of daily cases. The error metrics and a k-fold cross validation with random splitting reveal that a particular type of hybrid approach called residual neural network with gated recurrent unit is the best hybrid neural network architecture. The data-driven simulations confirm the fact that the vaccination rate with higher efficacy lowers the infectiousness and basic reproduction number. As a study case, COVID-19 data for the state of Tennessee in USA is used.

In future years, airline companies will be leaning more and more towards cryptocurrencies to implement their digital marketing strategies as leaders seek to gain an understanding of the factors affecting airlines’ visibility parameters. Cryptocurrency investment websites are currently experiencing rising demand, making them an appropriate site for paid advertisements. The above factors suggest the need for airlines to harvest cryptocurrency investment and platform users in their favour. To this end, it can be beneficial for airlines’ web promotions to link certain web analytics metrics to cryptocurrency trading site metrics. For research purposes, web analytics data were monitored and gathered for 2 consecutive years from 10 globally leading cryptocurrency trading companies and 10 airline websites. A three-stage model was adopted by the authors. In the first stage, statistical analysis was implemented using cryptocurrency and airline metrics, followed by fuzzy cognitive mapping and agent-based modelling stages. The findings of the study indicate that engagement with cryptocurrency trading websites has a positive impact on airline websites’ global ranking and visibility parameters. The outcomes of this research provide noteworthy digital marketing strategies which can be addressed by airline companies to increase their website visitors and optimise visibility parameters with the assistance of cryptocurrency trading websites.

Block Kriging (a spatial interpolation method) and log10 transformation were compared for their effectiveness in reducing relative variance (coefficient of variance: CV) and estimate mean values in all harvested maize plants grown in three randomly taken field plots and for harvested plants after removing the “edge or margin” ones. The results showed that log10 transformation reduced CVs of all harvested original fresh weight (FW) plant data in the three plots from 35.6–41.6% (original data) to 6.0–7.5%, while the respective CVs due to Block Kriging were reduced to 14.5–19.9%. The back-log10-transformed means of all harvested FW plant data were reduced by 6.8–9.4%, while the respective reduction for plants excluding the margin ones was 1.3–8.3%. The Block Kriging means for all harvested FW plant data were reduced only by 0.3–0.4%, while the respective means of the harvested plants excluding margin ones were increased by 0.4–4.3%. These findings strongly suggest that Block Kriging should be preferred over the log10 transformation method (used so far by agroscientists) as it managed to effectively reduce variability in crop data and estimate missing values that provide more precise and reliable estimates of corn yield for farmers.

Available 4- and 5-year updates for progression-free and for overall survival demonstrate a lasting clinical benefit for melanoma patients receiving anti-PD-directed immune checkpoint inhibitor therapy. However, at least one-half of the patients either do not respond to therapy or relapse early or late following the initial response to therapy. Little is known about the reasons for primary and/or secondary resistance to immunotherapy and the patterns of relapse. This review, prepared by an interdisciplinary expert panel, describes the assessment of the response and classification of resistance to PD-1 therapy, briefly summarizes the potential mechanisms of resistance, and analyzes the medical needs of and therapeutic options for melanoma patients resistant to immune checkpoint inhibitors. We appraised clinical data from trials in the metastatic, adjuvant and neo-adjuvant settings to tabulate frequencies of resistance. For these three settings, the role of predictive biomarkers for resistance is critically discussed, as well as are multimodal therapeutic options or novel immunotherapeutic approaches which may help patients overcome resistance to immune checkpoint therapy. The lack of suitable biomarkers and the currently modest outcomes of novel therapeutic regimens for overcoming resistance, most of them with a PD-1 backbone, support our recommendation to include as many patients as possible in novel or ongoing clinical trials.

In blood-oxygen-level-dependent (BOLD)-based resting-state functional (RS-fMRI) studies, usage of multi-echo echo-planar-imaging (ME-EPI) is limited due to unacceptable late echo times when high spatial resolution is used. Equipped with high-performance gradients, the compact 3T MRI system (C3T) enables a three-echo whole-brain ME-EPI protocol with smaller than 2.5 mm isotropic voxel and shorter than 1 s repetition time, as required in landmark fMRI studies. The performance of the ME-EPI was comprehensively evaluated with signal variance reduction and region-of-interest-, seed- and independent-component-analysis-based functional connectivity analyses and compared with a counterpart of single-echo EPI with the shortest TR possible. Through the multi-echo combination, the thermal noise level is reduced. Functional connectivity, as well as signal intensity, are recovered in the medial orbital sulcus and anterior transverse collateral sulcus in ME-EPI. It is demonstrated that ME-EPI provides superior sensitivity and accuracy for detecting functional connectivity and/or brain networks in comparison with single-echo EPI. In conclusion, the high-performance gradient enabled high-spatial-temporal resolution ME-EPI would be the method of choice for RS-fMRI study on the C3T.

Land degradation (LD) processes are widespread in drylands worldwide and are accelerated by climate change. As a result, food security and livelihoods are at risk. Thus, there is a need to monitor LD trends, especially in agricultural areas. Mediterranean countries, including Tunisia and Greece, are concerned due to the presence of drivers and pressures causing land degradation. Through the Trends.Earth plugin, the SDG 15.3.1 indicator can be implemented to map LD status. In this study, we mapped LD in Greece and Tunisia for the recommended baseline period of 2001–2015 and the selected reporting period of 2016–2020. The land productivity was assessed within Trends.Earth using the MODIS MOD13Q1 product, while the default datasets were used for the other sub-indicators. The main findings are: (i) the percentage of degraded land decreased from the baseline to the reporting period from 4.83% to 2.62% of total area in Greece and 9.97% to 6.26% in Tunisia—degradation rates that differ from those reported to the UNCCD (United Nations Convention to Combat Desertification) by the respective national authorities; (ii) the dominant land condition in Greece was improved, while in Tunisia, it was stable; (iii) land productivity presented a similar trend through the SDG 15.3.1 indicator over both countries, including the net land productivity dynamics over croplands; (iv) based on analysis using plant functional types performed with MODIS MCD12Q1, the highest portion of degraded land in Greece was located in grasslands and in Tunisia in cereal croplands (after desert areas); and (v) with a focus on LD over cereal croplands, the portion of degraded areas appeared to decrease in both Greece and Tunisia. The percentage was higher in Tunisia, representing 16.52% of the total degraded land during the reporting period compared to 10.83% in Greece. All the above stress the need to foster the adoption of sustainable land management practices, especially in Tunisia, and speed up the implementation of measures to achieve LD neutrality.

The terroir effect refers to the interactions between the grapes and their natural surroundings and has been recognized as an important factor in wine quality. The identification and mapping of viticultural terroir have long been relying on expert opinion coupled with land classification and soil/climate mapping. In this study, the data-driven approach has been implemented for mapping natural terroir units based on spatial modeling of public-access geospatial information regarding the three most important environmental factors that make up the terroir effect on different scales, climate, soil, and topography. K-means cluster analysis was applied to the comprehensive databases of relevant spatial information, and the optimum number of clusters was identified by the Dunn and CCC indices. The results have revealed ten clusters that cover the agricultural area of Drama (Greece), where it was applied, and displayed variable conditions on the climate, soil, and topographic factors. The implications of the resulting natural terroir units on the vini-viticultural management of the most common vine varieties are discussed. As more accurate and detailed input spatial data become available, the potential of such an approach is highlighted and paving the way toward a true understanding of the drivers of terroir.

Psoriasis is an inflammatory skin disease characterized by increased neo-vascularization, keratinocyte hyperproliferation, a pro-inflammatory cytokine milieu and immune cell infiltration. Diacerein is an anti-inflammatory drug, modulating immune cell functions, including expression and production of cytokines, in different inflammatory conditions. Therefore, we hypothesized that topical diacerein has beneficial effects on the course of psoriasis. The current study aimed to evaluate the effect of topical diacerein on imiquimod (IMQ)-induced psoriasis in C57BL/6 mice. Topical diacerein was observed to be safe without any adverse side effects in healthy or psoriatic animals. Our results demonstrated that diacerein significantly alleviated the psoriasiform-like skin inflammation over a 7-day period. Furthermore, diacerein significantly diminished the psoriasis-associated splenomegaly, indicating a systemic effect of the drug. Remarkably, we observed significantly reduced infiltration of CD11c+ dendritic cells (DCs) into the skin and spleen of psoriatic mice with diacerein treatment. As CD11c+ DCs play a pivotal role in psoriasis pathology, we consider diacerein to be a promising novel therapeutic candidate for psoriasis.

Here, we describe the expression of Bruton’s Tyrosine Kinase (BTK) in head and neck squamous cell carcinoma (HNSCC) cell lines as well as in primary HNSCC samples. BTK is a kinase initially thought to be expressed exclusively in cells of hematopoietic origin. Apart from the 77 kDa BTK isoform expressed in immune cells, particularly in B cells, we identified the 80 kDa and 65 kDa BTK isoforms in HNSCC, recently described as oncogenic. Importantly, we revealed that both isoforms are products of the same mRNA. By investigating the mechanism regulating oncogenic BTK-p80/p65 expression in HNSSC versus healthy or benign tissues, our data suggests that the epigenetic process of methylation might be responsible for the initiation of BTK-p80/p65 expression in HNSCC. Our findings demonstrate that chemical or genetic abrogation of BTK activity leads to inhibition of tumor progression in terms of proliferation and vascularization in vitro and in vivo. These observations were associated with cell cycle arrest and increased apoptosis and autophagy. Together, these data indicate BTK-p80 and BTK-p65 as novel HNSCC-associated oncogenes. Owing to the fact that abundant BTK expression is a characteristic feature of primary and metastatic HNSCC, targeting BTK activity appears as a promising therapeutic option for HNSCC patients.

Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous group of cancers and patients have limited therapy options if primary treatment fails. Therefore, additional information about the biology of the tumor is essential. Here we performed a feasibility study of concurrently applying two precision diagnostic tools in a consecutive series of HNSCC patients. We analyzed tumor samples of 31 patients using a genomic (oncomine) and a proteomic, immunohistochemical approach (oncopanel) and compared the result, also in the focus on their overlapping therapeutical targets. We found no strong correlation between the two approaches and observed a higher proportion of marker expression for the immunohistochemical panel. However, both panels show in our HNSCC cohort distinct patterns with druggable targets. The data suggest that both approaches complement one another and can be applied side-by-side to identify the best targets for the development of individual treatment options for HNSCC patients.

The bacterial archetypal adaptive immune system, CRISPR-Cas, is thought to be repressed in the best-studied bacterium, Escherichia coli K-12. We show here that the E. coli CRISPR-Cas system is active and serves to inhibit its nine defective (i.e., cryptic) prophages. Specifically, compared to the wild-type strain, reducing the amounts of specific interfering RNAs (crRNA) decreases growth by 40%, increases cell death by 700%, and prevents persister cell resuscitation. Similar results were obtained by inactivating CRISPR-Cas by deleting the entire 13 spacer region (CRISPR array); hence, CRISPR-Cas serves to inhibit the remaining deleterious effects of these cryptic prophages, most likely through CRISPR array-derived crRNA binding to cryptic prophage mRNA rather than through cleavage of cryptic prophage DNA, i.e., self-targeting. Consistently, four of the 13 E. coli spacers contain complementary regions to the mRNA sequences of seven cryptic prophages, and inactivation of CRISPR-Cas increases the level of mRNA for lysis protein YdfD of cryptic prophage Qin and lysis protein RzoD of cryptic prophage DLP-12. In addition, lysis is clearly seen via transmission electron microscopy when the whole CRISPR-Cas array is deleted, and eliminating spacer #12, which encodes crRNA with complementary regions for DLP-12 (including rzoD), Rac, Qin (including ydfD), and CP4-57 cryptic prophages, also results in growth inhibition and cell lysis. Therefore, we report the novel results that (i) CRISPR-Cas is active in E. coli and (ii) CRISPR-Cas is used to tame cryptic prophages, likely through RNAi, i.e., unlike with active lysogens, active CRISPR-Cas and cryptic prophages may stably co-exist.

Agricultural land use planning is based on the capacity of the soil to support different types of crops and is a prerequisite for better use of cultivated land. Land Suitability Analysis (LSA) is used to measure the level of suitability of growing a specific crop in the area and can also be used to evaluate future scenarios as a means for sustainable agriculture. LSA was employed to calculate current land suitability, as well as four scenarios of Soil-Improving Cropping Systems (SICS): (a) Conservation Tillage (CT), (b) Cover Crop (CC), (c) Crop Residue Management (CRM), and (d) Manure Application (MA). The scenarios of SICS were derived by increasing soil organic matter and cation exchange capacity values depending on the SICS hypothetically applied for a period of 100 years in the future. LSA was evaluated for maize in three sites: (a) Flanders (BE), (b) Somogy (HU), and (c) Hengshui (CH). LSA was performed using the Agricultural Land Use Evaluation System (ALUES) considering soil and climatic and topographic parameters. Weighing factors of input parameters were assigned using the Analytical Hierarchy Process (AHP). The results show that in Flanders, the highly suitable (S2) class covered 3.3% of the total area, and the best scenario for improving current LS was CRM, in which S2 expanded to 9.1%. In Somogy, the S2 class covered 18.3% of the total area, and the best scenarios for improving current land suitability were CT and CC, in both of which the S2 class expanded to 70.5% of the total area. In Hengshui, the S2 class covered 64.7% of the total area, and all SICS scenarios performed extremely well, converting almost all moderately suitable (S3) areas to S2. The main limiting factor that was recognized from a limiting factor analysis in all cases was the climatic conditions. This work proves that LSA can evaluate scenarios of management practices and recognize limiting factors. The proposed methodology is a novel approach that can provide land suitability maps to efficiently evaluate SICS scenarios by projecting soil characteristics and LSA in the future, thus facilitating management decisions of regional policy makers.

Software packages that use optimization to predict the motion of dynamic systems are powerful tools for studying human movement. These “predictive simulations” are gaining popularity in parameter optimization studies for designing assistive devices such as exoskeletons. The cost function is a critical component of the optimization problem and can dramatically affect the solution. Many cost functions have been proposed that are biologically inspired and that produce reasonable solutions, but which may lead to different conclusions in some contexts. We used OpenSim Moco to generate predictive simulations of human walking using several cost functions, each of which produced a reasonable trajectory of the human model. We then augmented the model with motors that generated hip flexion, knee flexion, or ankle plantarflexion torques, and repeated the predictive simulations to determine the optimal motor torques. The model was assumed to be planar and bilaterally symmetric to reduce computation time. Peak torques varied from 41.3 to 79.0 N·m for the hip flexion motors, from 48.0 to 94.2 N·m for the knee flexion motors, and from 42.6 to 79.8 N·m for the ankle plantarflexion motors, which could have important design consequences. This study highlights the importance of evaluating the robustness of results from predictive simulations.

Vertebrate and fly rhodopsins are prototypical GPCRs that have served for a long time as model systems for understanding GPCR signaling. Although all rhodopsins seem to become phosphorylated at their C-terminal region following activation by light, the role of this phosphorylation is not uniform. Two major functions of rhodopsin phosphorylation have been described: (1) inactivation of the activated rhodopsin either directly or by facilitating binding of arrestins in order to shut down the visual signaling cascade and thus eventually enabling a high-temporal resolution of the visual system. (2) Facilitating endocytosis of activated receptors via arrestin binding that in turn recruits clathrin to the membrane for clathrin-mediated endocytosis. In vertebrate rhodopsins the shutdown of the signaling cascade may be the main function of rhodopsin phosphorylation, as phosphorylation alone already quenches transducin activation and, in addition, strongly enhances arrestin binding. In the Drosophila visual system rhodopsin phosphorylation is not needed for receptor inactivation. Its role here may rather lie in the recruitment of arrestin 1 and subsequent endocytosis of the activated receptor. In this review, we summarize investigations of fly rhodopsin phosphorylation spanning four decades and contextualize them with regard to the most recent insights from vertebrate phosphorylation barcode theory.

Crohn’s disease (CD), is an inflammatory bowel disease that can affect any part of the gastro-intestinal tract (GI) and is associated with an increased risk of gastro-intestinal cancer. In the current study, we determined the role of genetic and small-molecule modulation of STAT3 in a mouse model of CD. STAT3 has 2 isoforms (α, β) which are expressed in most cells in a 4:1 ratio (α: β). STAT3α has pro-inflammatory and anti-apoptotic functions, while STAT3β has contrasting roles. We used an animal model of CD consisting of intrarectal administration of 2,4,6-trinitrobenzene sulfonic acid and examined the severity of CD in transgenic-mice that express only STAT3α (∆β/∆β), as well as in wild-type (WT) mice administered TTI-101 (formerly C188-9), a small molecule STAT3 inhibitor. We determined that clinical manifestations of CD, such as mortality, rectal-bleeding, colonic bleeding, diarrhea, and colon shortening, were exacerbated in ∆β/∆β transgenic versus cage-control WT mice, while they were markedly decreased by TTI-101 treatment of WT mice. TTI-101 treatment also increased apoptosis of pathogenic CD4+ T cells and reduced colon levels of IL-17-positive cells. Our results indicate that STAT3 contributes to CD and that targeting of STAT3 with TTI-101 may be a useful approach to treating CD.

We present the Pharmacorank search tool as an objective means to obtain prioritized protein drug targets and their associated medications according to user-selected diseases. This tool could be used to obtain prioritized protein targets for the creation of novel medications or to predict novel indications for medications that already exist. To prioritize the proteins associated with each disease, a gene similarity profiling method based on protein functions is implemented. The priority scores of the proteins are found to correlate well with the likelihoods that the associated medications are clinically relevant in the disease’s treatment. When the protein priority scores are plotted against the percentage of protein targets that are known to bind medications currently indicated to treat the disease, which we termed the pertinency score, a strong correlation was observed. The correlation coefficient was found to be 0.9978 when using a weighted second-order polynomial fit. As the highly predictive fit was made using a broad range of diseases, we were able to identify a general threshold for the pertinency score as a starting point for considering drug repositioning candidates. Several repositioning candidates are described for proteins that have high predicated pertinency scores, and these provide illustrative examples of the applications of the tool. We also describe focused reviews of repositioning candidates for Alzheimer’s disease. Via the tool’s URL, https://protein.som.geisinger.edu/Pharmacorank/, an open online interface is provided for interactive use; and there is a site for programmatic access.

Diabetes mellitus is a common endocrinopathy in dogs and in most cases is analogous to type 1 diabetes mellitus (T1DM) in humans. Candida spp. is a common commensal fungi with higher prevalence and magnitude of growth in humans with T1DM. There is currently no published information about the fungal microbiome in diabetic dogs. Therefore, the objectives of this study were to (i) determine whether diabetic dogs were more likely to have Candida spp. or other types of fungi from feces compared to non-diabetic controls, and (ii) identify variables associated with fungi colonization. Fourteen diabetic dogs and 14 age, sex, and breed matched non-diabetic healthy control dogs were included in this prospective case–control study. Matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) was used for fungal identification. Diabetic dogs had greater quantitative fungal growth compared to controls (p = 0.004). Moreover, female dogs were more likely to have fungi colonization than males (p = 0.02). All instances of Candida spp. and Aspergillus spp. colonization were exclusively identified in diabetic dogs. Serum fructosamine concentration was higher in diabetic dogs with fecal colonization of Candida spp. compared to diabetic dogs without growth (p = 0.03). Our results indicate that the fungal microbiome in feces is altered in diabetic dogs, which seem to favor an increased prevalence of Candida spp. and higher quantitative fungal growth. Moreover, female sex and glycemic control could affect the intestinal mycobiome.

The development of direct pulp-capping materials with favorable biological and structural properties is an important goal in restorative dentistry. Fucoidan is a sulfated, fucose-containing polysaccharide obtained from brown seaweed, with a wide range of applications; however, its use as a direct pulp-capping material has not been examined. This study aimed to evaluate the mechanical, physical, and biological effects of fucoidan combined with conventional mineral trioxide aggregate (MTA) for direct pulp capping. The capping materials were created using Portland cement (80 wt%) and zirconium oxide (20 wt%) as base components, compared with base components plus 5 wt% fucoidan (PZF5) and base components plus 10 wt% fucoidan (PZF10). The initial and final setting time, compressive strength, chemical components, cell viability, adhesion, migration, osteogenesis, and gene expression were analyzed. Fucoidan significantly reduced the initial and final setting time, regardless of quantity. However, the compressive strength was lower for PZF5. Sulfur levels increased with fucoidan. The biological activity improved, especially in the PZF5 group. Cell migration, Alizarin Red S staining, and alkaline phosphatase activity were upregulated in the PZF5 group. Fucoidan is a useful regenerative additive for conventional pulp-capping materials because it reduces the setting time and improves cell migration and osteogenic ability.

Due to ethical and practical reasons, a knowledge gap exists on the pharmacokinetics (PK) of inflammatory bowel disease (IBD)-related drugs in pregnant women with IBD. Before evidence-based dosing can be proposed, insight into the PK has to be gained to optimize drug therapy for both mother and fetus. This systematic review aimed to describe the effect of pregnancy and IBD on the PK of drugs used for IBD. One aminosalicylate study, two thiopurine studies and twelve studies with biologicals were included. Most drugs within these groups presented data over multiple moments before, during and after pregnancy, except for mesalazine, ustekinumab and golimumab. The studies for mesalazine, ustekinumab and golimumab did not provide enough data to demonstrate an effect of pregnancy on concentration and PK parameters. Therefore, no evidence-based dosing advice was given. The 6-thioguanine nucleotide levels decreased during pregnancy to 61% compared to pre-pregnancy levels. The potentially toxic metabolite 6-methylmercaptopurine (6-MMP) increased to maximal 209% of the pre-pregnancy levels. Although the PK of the thiopurines changed throughout pregnancy, no evidence-based dosing advice was provided. One study suggested that caution should be exercised when the thiopurine dose is adjusted, due to shunting 6-MMP levels. For the biologicals, infliximab levels increased, adalimumab stayed relatively stable and vedolizumab levels tended to decrease during pregnancy. Although the PK of the biologicals changed throughout pregnancy, no evidence-based dosing advice for biologicals was provided. Other drugs retrieved from the literature search were mesalazine, ustekinumab and golimumab. We conclude that limited studies have been performed on PK parameters during pregnancy for drugs used in IBD. Therefore, more extensive research to determine the values of PK parameters is warranted. After gathering the PK data, evidence-based dosing regimens can be developed.

Epoxy resin-based sealers are commonly used for successful endodontic treatment. This study aimed to evaluate the cytotoxicity and genotoxicity of epoxy resin-based sealers under unset and set conditions. Three epoxy resin-based sealers were used: Adseal, AH Plus, and Dia-Proseal. To test cytotoxicity, an agar overlay test and a 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay were performed using unset and set sealers on L929 mouse fibroblasts. The genotoxicity test of the comet assay was performed using the same cell line. Extract dilutions in the culture media were used as test materials for the MTT and comet assays. The comet tail produced by the damaged DNA was calculated by image analyses. Statistical analyses were performed using one-way analysis of variance and Tukey’s post hoc test. Unset sealers did not show defined decolorized areas. Hardened specimens of resin-based sealers showed circular discolored zones in the agar overlay test. Dia-Proseal was the least cytotoxic after hardening. These results were confirmed in the MTT assay. Cell viability was significantly higher in cells treated with hardened sealers in both groups than that in cells treated with freshly mixed sealers in the MTT assay. Unset AH Plus® and Dia-Proseal™ significantly increased cell viability with decreasing dilution. Adseal™ was the least cytotoxic. Freshly mixed Adseal™ was more genotoxic when freshly mixed than when set. Unset epoxy resin-based sealers were generally more cytotoxic and genotoxic than set materials. Cytotoxicity does not always match the genotoxicity results; therefore, various test tools are required to test toxicity. It is necessary to properly evaluate the toxic effects to establish a biocompatibility test that mimics clinical conditions.

Melanoma incidence rates are high among individuals with fair skin and multiple naevi. Established prognostic factors are tumour specific, and less is known about prognostic host factors. A total of 556 stage I to stage IV melanoma patients from Germany with phenotypic and disease-specific data were analysed; 64 of these patients died of melanoma after a median follow-up time of 8 years. Germline DNA was assessed by the HumanCoreExome BeadChip and data of 356,384 common polymorphisms distributed over all 23 chromosomes were used for a genome-wide analysis. A suggestive genome-wide significant association of the intronic allele rs7551288*A with diminished melanoma-specific survival was detected (p = 2 × 10−6). The frequency of rs7551288*A was 0.43 and was not associated with melanoma risk, hair and eye colour, tanning and total naevus count. Cox regression multivariate analyses revealed a 5.31-fold increased risk of melanoma-specific death for patients with the rs7551288 A/A genotype, independent of tumour thickness, ulceration and stage of disease at diagnoses. The variant rs7551288 belongs to the DHCR24 gene, which encodes Seladin-1, an enzyme involved in the biosynthesis of cholesterol. Further investigations are needed to confirm this genetic variant as a novel prognostic biomarker and to explore whether specific treatment strategies for melanoma patients might be derived from it.

The tensile bond strength between zirconia subjected to different surface-pretreatment methods and methacryloyloxydecyl-dihydrogen-phosphate (MDP)-containing self-adhesive resin cement was evaluated herein. Eighty-eight cylindrical zirconia specimens were randomly divided into the following four groups based on the pretreatment method: (1) no treatment, (2) air abrasion, (3) HNO3/HF etching, and (4) zirconia-nanoparticle coating. The tensile bond strength of the zirconia–resin-cement complexes was investigated. One-way ANOVA and post hoc tests were performed at a 95% significance level, and the Weibull modulus was calculated. Fracture patterns were visualized by SEM. The surface roughness of the specimens without resin bonding was evaluated by AFM. The tensile bond strength of the specimens decreased as follows: Groups 3 > 4 > 2 > 1 (28.2 ± 6.6, 26.1 ± 5.7, 16.6 ± 3.3, and 13.9 ± 3.0 MPa, respectively). Groups 3 and 4 had significantly higher tensile bond strengths (p < 0.05) and lower fracture probabilities than those of Groups 1 and 2. They also showed both mixed failure and resin-cement cohesive failure, whereas Groups 1 and 2 showed mixed failure exclusively. The zirconia–resin tensile bond was stronger after HNO3/HF etching or ZrO2-nanoparticle coating than after air abrasion or no treatment. The estimated surface roughness decreased as follows: Groups 3 > 4 > 2 > 1. The combination of zirconia pretreated with HNO3/HF etching or ZrO2-nanoparticle coating and an MDP-containing self-adhesive resin cement can increase the clinical longevity of zirconia restorations by preventing their decementation.

Cone beam computed tomography (CBCT) is increasingly used for dental and maxillofacial imaging. The occurrence of incidental findings has been reported, but clinical implications of these findings remain unclear. The study’s aim was to identify the frequency and clinical impact of incidental findings in CBCT. A total of 374 consecutive CBCT examinations of a 3 year period were retrospectively evaluated for the presence, kind, and clinical relevance of incidental findings. In a subgroup of 54 patients, therapeutic consequences of CBCT incidental findings were queried from the referring physicians. A total of 974 incidental findings were detected, involving 78.6% of all CBCT, hence 2.6 incidental findings per CBCT. Of these, 38.6% were classified to require treatment, with an additional 25.2% requiring follow-up. Incidental findings included dental pathologies in 55.3%, pathologies of the paranasal sinuses and airways in 29.2%, osseous pathologies in 14.9% of all CBCT, and findings in the soft tissue or TMJ in few cases. Clinically relevant dental incidental findings were detected significantly more frequently in CBCT for implant planning compared to other indications (60.7% vs. 43.2%, p < 0.01), and in CBCT with an FOV ≥ 100 mm compared to an FOV < 100 mm (54.7% vs. 40.0%, p < 0.01). Similar results were obtained for paranasal incidental findings. In a subgroup analysis, 29 of 54 patients showed incidental findings which were previously unknown, and the findings changed therapeutical management in 19 patients (35%). The results of our study highlighted the importance of a meticulous analysis of the entire FOV of CBCT for incidental findings, which showed clinical relevance in more than one in three patients. Due to a high number of clinically relevant incidental findings especially in CBCT for implant planning, an FOV of 100 × 100 mm covering both the mandible and the maxilla was concluded to be recommendable for this indication.

Adenoid cystic carcinoma (ACC) is a rare malignancy in the head and neck. The prognosis remains poor and late recurrences often occur after 5 years and later. To date, there are no reliable prognostic markers for ACC. In several solid tumors, tertiary lymphoid structures (TLS) are associated with improved survival. This study aims to investigate the role of distribution patterns of tumor infiltrating immune cells (TIL) in ACC. A cohort of 50 patients from three different cancer centers was available for analysis. Sections were stained for CD3, CD4, CD8 and CD20 and evaluated with regard to their distribution of TIL. Patterns were determined as infiltrated-excluded, infiltrated-inflamed and presence of tertiary lymphoid structures. About half of the cases showed an infiltrated-excluded TIL pattern and only a minority of six cases had TLS present within the tumor. Within the inflamed phenotype CD3+ cells were by far the most abundant lymphocyte subtype, and within this compartment, CD8+ T cells were predominant. There was no influence on overall or disease-free survival by any of the TIL patterns. This indicates that ACC is a tumor with very low immunogenicity and even abundance of lymphocytes does not seem to improve prognosis for this disease. Therefore, the observed lack of response towards immunotherapy is not surprising and other methods to induce recognition of ACC by the immune system must be found.

Background: Two-stage exchange arthroplasty remains the gold standard in the United States for treatment of chronic periprosthetic joint infection (PJI). Long-term reinfection rates and clinical outcomes with sufficient subject numbers remain limited. The purpose was to evaluate the long-term outcomes following two-stage exchange following hip arthroplasty. Methods: Retrospective review of 221 patients who underwent two-stage exchange hip arthroplasty for chronic PJI at three large tertiary referral institutions from 1990–2015. Outcomes including reinfection, mortality, and all-cause revision were calculated. Cumulative incidence of reinfection with death as competing factor was also calculated. Risk factors for reinfection were determined using Cox multivariate regression analysis. Results: Rate of infection eradication and all-cause revision was 88.24% and 22.6%, respectively. Overall mortality rate was 40.72%. Patients with minimum five-year follow-up (n = 129) had a success rate of 91.47% with mortality rate of 41.1%. Major risk factors for reinfection included polymicrobial infection (HR = 2.36, 95% CI: 1.08–5.14) and antibiotic resistant organism (HR = 2.36, 95% CI: 1.10–5.04). Conclusion: This is the largest series with greater than 5-year follow-up evaluating outcomes of two-stage exchange hip arthroplasty. This technique resulted in a relatively high infection eradication, however, the mortality rate is alarmingly high. Antibiotic resistant organisms appear to be highest risk factor for failure.

Soil surveys with line-scanning platforms appear to have great advantages over the traditional methods used to collect soil information for the development of field-scale soil mapping and applications. These carry VNIR (visible and near infrared) spectrometers and have been used in recent years extensively for the assessment of soil fertility at the field scale, and the delineation of site-specific management zones (MZ). A challenging feature of VNIR applications in precision agriculture (PA) is the massiveness of the derived datasets that contain point predictions of soil properties, and the interpolation techniques involved in incorporating these data into site-specific management plans. In this study, fixed-rank kriging (FRK) geostatistical interpolation, which is a flexible, non-stationary spatial interpolation method especially suited to handling huge datasets, was applied to massive VNIR soil scanner data for the production of useful, smooth interpolated maps, appropriate for the delineation of site-specific MZ maps. Moreover, auxiliary Sentinel-2 data-based biophysical parameters NDVI (normalized difference vegetation index) and fAPAR (fraction of photosynthetically active radiation absorbed by the canopy) were included as covariates to improve the filtering performance of the interpolator and the ability to generate uniform patterns of spatial variation from which it is easier to receive a meaningful interpretation in PA applications. Results from the VNIR prediction dataset obtained from a pivot-irrigated field in Albacete, southeastern Spain, during 2019, have shown that FRK variants outperform ordinary kriging in terms of filtering capacity, by doubling the noise removal metrics while keeping the computation cost reasonably low. Such features, along with the capacity to handle a large volume of spatial information, nominate the method as ideal for PA applications with massive proximal and remote sensing datasets.

The origin of life might be sparked by the polymerization of the first RNA molecules in Darwinian ponds during wet-dry cycles. The key life-building block ribose was found in carbonaceous chondrites. Its exogenous delivery onto the Hadean Earth could be a crucial step toward the emergence of the RNA world. Here, we investigate the formation of ribose through a simplified version of the formose reaction inside carbonaceous chondrite parent bodies. Following up on our previous studies regarding nucleobases with the same coupled physico-chemical model, we calculate the abundance of ribose within planetesimals of different sizes and heating histories. We perform laboratory experiments using catalysts present in carbonaceous chondrites to infer the yield of ribose among all pentoses (5Cs) forming during the formose reaction. These laboratory yields are used to tune our theoretical model that can only predict the total abundance of 5Cs. We found that the calculated abundances of ribose were similar to the ones measured in carbonaceous chondrites. We discuss the possibilities of chemical decomposition and preservation of ribose and derived constraints on time and location in planetesimals. In conclusion, the aqueous formose reaction might produce most of the ribose in carbonaceous chondrites. Together with our previous studies on nucleobases, we found that life-building blocks of the RNA world could be synthesized inside parent bodies and later delivered onto the early Earth.

Cross-laminated timber (CLT) slabs in residential buildings need additional weight, e.g., in the form of screeds or gravel layers, to fulfill the criterion for the highest impact-sound class. The additional mass is, however, not exploited for the load bearing behavior, but adds additional weight and leads to an increased height of the floor construction. In this study, such a CLT floor construction with a construction height of 380 mm is compared with a composite slab consisting of a CLT plate with a concrete layer on top with a floor construction height of 330 mm. The timber concrete composite (TCC) slab has a different creep behavior than the CLT slab. Thus, the development of the time-dependent deflections over the service life are of interest. A straightforward hybrid approach is developed, which exploits advanced multiscale-based material models for the individual composite layers and a standardized structural analysis method for the structural slab to model its linear creep behavior. The introduced approach allows to investigate load redistribution between the layers of the composite structure and the evolution of the deflection of the slab during the service life. The investigated slab types show a similar deflection after 50 years, while the development of the deflections over time are different. The CLT slab has a smaller overall stiffness at the beginning but a smaller decrease in stiffness over time than the investigated TCC slab.

Predator-prey dynamics are fundamental in shaping and regulating wildlife communities; however, these relationships are often altered by urbanization. An urban predation paradox, where predation rates are lower in urban areas despite an increase in predator abundance, has been observed in some predator communities. We looked for evidence of an urban predation paradox in a raptor community in a large urban forest fragment in north Texas, USA. From May–August 2019, we conducted weekly raptor surveys and deployed prey mimics along an urban-to-rural gradient within the forest fragment. We examined relationships between predation rates on mimics, predator abundance, and urbanization intensity using a variety of statistical tests. We detected 161 raptors representing eight species and found that raptor activity was significantly higher in our low urbanization sites. Of the 732 prey mimics deployed, 61 were attacked, and we found no relationship between predation rates and urbanization. Furthermore, we found no relationship between raptor activity and depredation events. Although we failed to find evidence for an urban predation paradox, our results showed a decoupling of the relationship between the abundance of predators and prey in this urban setting. The use of prey mimics is a useful tool for assessing predator-prey dynamics, and more research is necessary to fully understand the impacts of urbanization on this important ecological process.

Vaccine hesitancy, which potentially leads to the refusal or delayed acceptance of COVID-19 vaccines, is considered a key driver of the increasing death toll from the pandemic in the EU. The European Commission and several member states’ governments are either planning or have already directly or indirectly announced mandatory vaccination for individuals aged over 60, the group which has repeatedly proved to be the most vulnerable. In this paper, an assessment of this strategy’s benefits is attempted by deriving a metric for the potential gains of vaccination mandates that can be used to compare EU member states. This is completed by examining the reduction in Standard Expected Years of Life Lost (SEYLL) per person for the EU population over 60 as a function of the member states’ vaccination percentage in these ages. The publicly available data and results of the second iteration of the SHARE COVID-19 survey on the acceptance of COVID-19 vaccines, conducted during the summer of 2021, are used as inputs.

Colorectal cancer (CRC) is a major public health burden and one of the leading causes of cancer-related deaths worldwide. Screening programs facilitate early diagnosis and can help to reduce poor outcomes. Serum metabolomics can extract vital molecular information that may increase the sensitivity and specificity of colonoscopy in combination with histopathological examination. The present study identifies serum metabolite patterns of treatment-naïve patients, diagnosed with either advanced adenoma (AA) or CRC in colonoscopy screenings, in the framework of the SAKKOPI (Salzburg Colon Cancer Prevention Initiative) program. We used a targeted flow injection analysis and liquid chromatography-tandem mass spectrometry metabolomics approach (FIA- and LC-MS/MS) to characterise the serum metabolomes of an initial screening cohort and two validation cohorts (in total 66 CRC, 76 AA and 93 controls). The lipidome was significantly perturbed, with a proportion of lipid species being downregulated in CRC patients, as compared to AA and controls. The predominant alterations observed were in the levels of lyso-lipids, glycerophosphocholines and acylcarnitines, but additionally, variations in the quantity of hydroxylated sphingolipids could be detected. Changed amino acid metabolism was restricted mainly to metabolites of the arginine/dimethylarginine/NO synthase pathway. The identified metabolic divergences observed in CRC set the foundation for mechanistic studies to characterise biochemical pathways that become deregulated during progression through the adenoma to carcinoma sequence and highlight the key importance of lipid metabolites. Biomarkers related to these pathways could improve the sensitivity and specificity of diagnosis, as well as the monitoring of therapies.