Clustering coefficient measures are key complex network analysis tools. We examine local and global clustering coefficient measures with respect to the lexicographic graph product. As a preliminary condition, we analyze the $K_3$ subgraph structure focused on vertex inclusion with respect to the product graph. From this structure, we determine both the clustering coefficient for the product graph vertices and the average clustering coefficient for the product graph.

Access to broadband communications in different parts of the world has become a priority for some governments and regulatory authorities around the world in recent years. Building new digital roads and pursuing a connected society includes looking for easier access to the Internet. In general, not all the areas where people congregate are fully covered, especially in rural zones, thus restricting access to data communications and bringing inequality. In the present review article, we have comprehensively surveyed the use of three platforms to deliver broadband services to such remote and low-income areas are proposed: Unmanned Aerial Vehicles (UAV), Altitude Platforms (APS), and Low-Earth Orbit (LEO) satellites. These novel strategies support the connected and accessible world hypothesis. Hence UAVs are considered a noteworthy solution since their efficient maneuverability can aboard the rural coverage issues or not-spots.

BACKGROUND Detecting total cholesterol in dried blood spots could aid in identifying individuals with a high likelihood of familial hypercholesterolemia and could be used as a screening measure. This study aims to assess the diagnostic accuracy of dried blood spots on Whatman 903 paper cards using a manual enzymatic technique. METHODS A total of 394 samples collected as serum and dried blood spots were compared. Cholesterol was determined in serum using the automated reference method, while cholesterol on paper was measured using a manual enzymatic method. Within- and between-day diagnostic variability were analyzed. The correlation between both methods was assessed using Passing-Bablok regression and Bland-Altman plot. Internal validation of our correlation formula was performed on 149 samples, along with external validation of the formula proposed by Corso et al. RESULTS The within- and between-day coefficient of variation was found to be lower than 10.14% and 14.09%, respectively. Method comparison yielded an area under the curve of 0.976, with a standard error of 0.009. Passing-Bablok regression indicated a precision of 0.803 and an accuracy of 0.96. Internal validation precision was measured at 0.716. Regarding internal validation, calculated cholesterol with our regression line did not differ from serum cholesterol analysis, while significant differences were observed in calculated cholesterol levels using the external formula. CONCLUSIONS Total cholesterol analysis in dot blood spots demonstrates high precision and reproducibility. This method reliably enables the incorporation of this biological marker into neonatal screening for familial hypercholesterolemia detection.

Dried blood spot (DBS) testing on confetti is one of the most common methods used to collect and extract DNA from field samples for molecular epidemiology of malaria studies. Here, we investigated whether ethanol or other solutions used to clean scissors are a source of sample contamination. DBS were prepared from 3 drops of blood from two Plasmodium falciparum cultures spotted on confetti, and 3 solutions (water, ethanol and DNase) were used to clean scissors between spots during DNA extraction. For each cleaning solution, two blank confetti were used as negative controls. Samples were analyzed by PCR-based genotyping of merozoite surface proteins 1 & 2 (msp-1 and msp-2), and P. falciparum chloroquine resistance transporter (Pfcrt). A total of 15 samples were analyzed. Based on msp-1 and msp-2 amplification, P. falciparum was detected on blank confetti when scissors were washed with ethanol. Based on Pfcrt amplification, DNA of P. falciparum was detected on blank confetti when scissors were cleaned with ethanol or water. No P. falciparum genes were detected on blank confetti when scissors were cleaned with DNase. Scissors cleaned with DNase prevented cross-contamination between samples during processing of dried blood spots, whereas ethanol (which is commonly used) fails to avert cross-contamination.

: The phenomenon of dark scleral spots postmortem is well-known in forensic pathology, first de-scribed by Sommers in 1833. Despite this, their presence is currently considered a nonspecific sign, and their pathogenesis has received little attention in forensic literature. In recent years, however, preliminary studies have suggested new mechanisms in their pathogenesis and links to specific types of death. This study aims to create a model for studying scleral spots using an animal model. Thirty-three sheep, already slaughtered for food, were used. After decapitation, the heads were transported to an environment with known temperature and humidity. The right eye underwent eyelid excision, while the left eye's eyelids were sutured. Continuous observation for approximately 24 hours was conducted, with brief interruptions to observe the closed eyes. Macroscopic obser-vation revealed dark scleral spots in 100% (20 out of 20) of the open eyes after an average of 240.96± 58,36 minutes. The spots did not appear in any of the closed eyes. Experimental data indicate that, despite the different location compared to human cadavers, this model serves as an excellent ex-perimental framework for studying postmortem scleral spots.

During recent years there is an on-going deployment of 5G base stations for radiofrequency (RF) communication in Sweden as well in many other countries. This is made without investigations on risks to human health and the environment. Since 2016 we have made several measurements of environmental exposure to RF radiation in Stockholm, Sweden, including previous generations and now also 5G. In the current study, performed in October 2023, the broadband meter Narda-550 with the probe EF-1891 was used. It gives results in the root mean square (RMS) mode, thus not peak levels. Both the International Commission on Non-Ionizing Radiation Protection (ICNIRP) and the US Federal Communications Commission (FCC) base their guidelines on RMS levels of RF radiation. Measurements were made in similar city areas as in our previous studies. Results show that the RF radiation has increased substantially. High maximum levels were found at e.g. the Central Railway Station (3 637 191 µW/m2), and popular walking streets such as Mäster Samuelsgatan (11 613 976 µW/m2), and Drottninggatan (5 271 555 µW/m2). The peak values would be much higher. These levels are in the same magnitude or even higher than those measured in homes of persons that rapidly developed symptoms of the microwave syndrome after installation of 5G, usually in combination with 4G+, in the neighborhood. They are also substantially higher than levels that have previously been linked to cancer and the microwave syndrome in studies of people living near base stations and masts from previous generations of telecommunications.

This Systematic Review examines studies focusing on tooth bleaching and its effect on healthy enamel or incipient caries and bacterial adhesion. The aim is to explore the impact of different bleaching agents on incipient caries lesions and healthy enamel. Randomized controlled trials, clinical trials, observational studies, and in vitro studies that compared at least two groups were included. A comprehensive search strategy was used to select studies from Pubmed and Scopus databases. Two evaluators performed data extraction, screening, and quality assessment independently. Only studies written in English were included. From 968 initial records, 28 studies were selected for a full-text evaluation. 7 studies were classified as cluster 1 (bacterial adherence on teeth), 12 studies as cluster 2 (no bacteria involved), 4 studies as cluster 3 (no teeth deployment), and 5 clinical studies were cluster 4. Of the selected studies, 6 (21.43%) supported increased bacterial attachment capacity and cariogenic dynamics, 4 (14.29%) decreased adhesion and cariogenic activity, 7 (25%) no difference, and 11 (39.28%) followed a differentiated methodological approach and could not be categorized. Due to different methodology strategies used in the studies of all clusters, the risk of bias was high. Thus, we cannot reach a confident conclusion.

This article proposes application of a new mathematical model of spots for solving inverse problems using a learning method, which is similar to using the deep learning. In general, the spots represent vague figures in abstract “information spaces” or crisp figures with lack of in-formation about their shapes and are adequate for representation human mental images and reasoning in Artificial Intelligence (AI). However, crisp figures are regarded as a special and limiting case of spots. A basic mathematical apparatus, basing on L4 numbers, has been developed for the representation and processing of qualitative information of elementary spatial relations between spots. Also, we defined L4 vectors, L4 matrices, and mathematical operations on them. Developed apparatus can be used in AI, in particular, for knowledge representation and for modeling qualitative reasoning and learning. Another application area is the solution of inverse problems by learning. For example, this can be applied to image reconstruction using ultrasound, X-ray, magnetic resonance, or radar scan data. The introduced apparatus was verified by solving problems of reconstruction of images, utilizing only qualitative data of its elementary relations with some scanning figures. This article also demonstrates application of spot-based inverse Radon algorithm for binary image reconstruction.

Spike (S) protein of Coronaviruses help in receptor attachment and virus entry into the host cells. While S protein is required for virus entry, it is also important as an immunogen as it is the most accessible part of the virus architecture. S protein form knob like structures (viral spikes) protruding outwards in the form of homotrimers containing an S1 and S2 as monomers. Mutations in structural proteins of virus play crucial role in determining virulence and also in many instances influencing emergence of antibody escape variants and cellular tropism. In this paper we have performed in depth analyses of spike protein sequences from various parts of the world and tried to correlate the data with possible functional relevance of such mutations.

The article presents the case of a 27-year-old female patient with idiopathic congenital complete heart block who was referred by her primary care physician for cardiological evaluation. The conduction disturbance was recognized at the age of 6 years and was asymptomatic. The disqualification from pacemaker implantation included detailed history of a patient’s symptoms, echocardiographic assessment of the heart, exercise testing and ECG Holter monitoring. The aid of salbutamol administered orally was also useful.

(1) Background: Several chronic respiratory diseases could be a risk factor for acquiring SARS-CoV-2 infection: among them, Primary Ciliary Dyskinesia (PCD) is a rare (about 1:10.000) inherited ciliopathy (MIM 242650) characterized by recurrent upper and lower respiratory tract infections due to a dysfunctioning of the respiratory cilia; We aimed to investigate if some polymorphisms of the TAS2R38 bitter taste receptor correlate with an increased prevalence of SARS-CoV-2 infection and severity of symptoms in a cohort of PCD subjects; (2) Methods: Patients answered several questions about possible SARS-CoV-2 infection, experienced symptoms and vaccinations; in case of infection, they also filled out a SNOT-22 and ARTIQ questionnaires; (3) Results: Forty PCD adult patients (mean age 36.6 ± 16.7 years, 23 females) participated to the study, out of which 30 % had tested positive for COVID-19 during the last four years; most of them reported a mildly symptomatic disease. We found no differences in age or sex, but a statistic significant difference (p=0.03) was observed in body mass index (BMI), that was higher in the COVID-acquired group (23.2 ± 3.3 vs 20.1 ± 4.1 kg/m2). Genotyping for TAS2R38 polymorphisms showed a prevalence of 28.6% PAV/PAV, 48.6% PAV/AVI and 22.8% AVI/AVI individuals in our cohort. In contrast to our hypothesis, we did not observe a protective role of PAV allele towards SARS-CoV-2 infection; (4) Conclusions: Our findings suggest that subjects with PCD may not be at increased risk of severe outcomes from COVID-19 and the TAS2R38 bitter taste receptor genotype type does not affect SARS-CoV-2 infection.

This paper deals with identifying the accident black spots and the influencing factors causing accidents using factored analysis in the medium-sized city (Tirunelveli) in India. From the literature review, the geospatial technique to identify the black spots and the factors causing accidents was used for analysis. The most influencing factors driving the accident were identified and ranked based on the repetitive occurrence of accidents in the black spot area. The spearman ranking system obtained the correlation among the factors causing accidents. The factor analysis technique was utilized to identify the key factors driving the repetitive accidents and group them. This study will help transportation planners to understand the factors causing accidents and take appropriate measures to reduce the casualties in the road construction planning stage and existing conditions.

Macrophages are well known for the involvement in the biocompatibility, as well as biodistribution, of nano(bio)materials. Although there are a number of rodent cell lines, they may not fully recapitulate primary cell responses; particularly for those of human cells. Isolation of tissue resident macrophages, from humans, is difficult and may result in insufficient cells with which to determine the possible interaction with nano(bio)materials. Isolation of primary human monocytes, and differentiation to monocyte-derived macrophages, may provide a useful tool with which to study, further, these interactions. To that end, we developed a standard operating procedure for this differentiation, as part of the REFINE project, and used it to measure the secretion of bioactive molecules from M1 and M2 differentiated monocytes in response to model nano(bio)materials, following an initial assessment of pyrogenic contamination which may confound, potential, observations. The SOP was deployed in two partner institutions with, broadly, similar results. The work presented here shows the utility of this assay but, highlights the relevance of donor variability in responses to nano(bio)materials. Whilst donor variability can provide some, logistical, challenges to application of such assays, this variability is much closer to the heterogeneous cells that are present in vivo, compared to homogeneous, non-human, cell lines.

Urban lakes, especially those of natural origin, provide ecosystem services, recreation being one of the most important and highly valued by the city dwellers. Fulfilling the needs of city residents to relax and have contact with nature has become a priority in urbanized areas and has been proved to positively affect people’s health and well-being. The recreational potential of water bodies was identified to be most important aspect of ecosystem services to the residents of the neighboring areas. An assessment of recreational ecosystem services (RES) provisioning to society based on the real time spent by the citizens and housing values in the rural-urban gradient revealed that the economic benefits of lakes differ in urbanized, suburban and rural landscapes. The growth of cities has led to an increased population density in the surroundings of ecologically valuable areas, resulting in higher pressure from visitors seeking recreational areas. Along with urbanization, the impoverishment of ecosystem functions takes place, limiting their capability to provide ecosystem services. In this work provisioning of recreational ecosystem services of 28 floodplain lakes located along the urban-rural gradient of the Warsaw agglomeration was assessed. The relationship between the ecological value of the water bodies, measured using naturalness indices, and the recreational ecosystem services they can provide was assessed. The results showed that the floodplain lakes located along the urban-rural gradient are of a great importance to the citizens due to their recreational potential. The provisioning of recreational ecosystem services is poorly connected with the ecological characteristics of the floodplain lakes. Only hemeroby, was significantly correlated with provisioning, and there was no relationship with factors such as naturalness of vegetation or water quality, demonstrating that public preference was not generally influenced by high ecological quality. These data should be available to potential buyers and be integrated in spatial planning management plans in order to shape future housing policy.

The global warming has caused poor grape skin coloration and reduced the production of high-quality berries. To overcome these problems, the effect of synephrine (Syn) on anthocyanin accumulation was investigated. Syn treatment above 1 mM increased anthocyanin content in cultured grape cells in a molecular-structure-specific and concentration-dependent manner, and increased only the anthocyanin without affecting the sugar/acid ratio in grape bunches. It increased the expression of genes linked to anthocyanin synthesis after 24 h of treatment, without affecting phytohormone levels. Syn treatment induced the expression of SOD3, elevating hydrogen peroxide (H2O2) production from 3 to 24 h after treatment in cultured cells. Subsequent increases in CAT and APX6 expression occurred, which encode H2O2-eliminating enzymes. In cultured grape cells, Syn and H2O2 treatments upregulated the H2O2-responsive gene Chit4 and the anthocyanin-biosynthesis-related genes mybA1 and UFGT 4 days after the treatments and promoted anthocyanin accumulation 7 days after the treatments. In berries, both treatments enhanced anthocyanin accumulation after 9 days. These results suggest that Syn promotes anthocyanin accumulation through the production of H2O2 without the upregulation of phytohormone biosynthesis. Syn treatment is expected to improve poor grape coloration and contribute to higher-quality fruit production.

Diet-related diseases impact populations across the globe. While intertemporal preferences—a fundamental preference for the distribution of benefits across time—have been used to explain low-quality food choices, recent literature proposes another cause: inattention to future implications (or opportunity costs) of the options faced. Food choices tend to become habitual to conserve cognitive resources, rather than carefully modeling future health impacts. Both low discount rates for future benefits and attention to future health impacts predict healthier decisions. While intertemporal preferences are stable, attention may provide an opportunity to intervene in the decision process to promote healthier decisions. In this study, we test the impact of a simple message that highlights health during food choice on the healthiness of foods chosen and on health consideration and intertemporal preferences. Our results show that actively considering health outcomes and lower discount rates lead to healthier food choices. We find that messaging increases the consideration of health outcomes during food choice but does not affect intertemporal preferences, suggesting that simple prompts may be an effective way to promote decisions balancing short and long-term benefits by drawing attention to overlooked opportunity costs of choices.

Myelolipoma is a benign, typically inert neoplasm of uncertain aetiology that is rarely reported in cats. Although commonly asymptomatic, in some cases, myelolipomas can cause abdominal discomfort or present with rupture and haemorrhage. Here, we describe a rare case of a splenic myelolipoma in a Domestic Long Hair cat in which, after extensive diagnostic investigations, clinical signs of hyporexia and weight loss were attributable to the presence of an intra-abdominal mass. The patient was treated by splenectomy and unexpectedly died during the post-operative period. Although splenectomy appears to be a sensible intervention in symptomatic patients, the optimal management of splenic myelolipomas in cats remains unknown. The risk-benefit ratio of surgical management needs to be carefully considered, and therapeutic intervention should be tailored individually to each patient.

Background. Transferrin receptor 1 (TfR1), glucose transporter 1 (GLUT1), and CD98hc are candidates for targeted therapy at the blood-brain barrier (BBB). Our objective was to challenge the expression of TfR1, GLUT1, and CD98hc in brain capillaries by the histone deacetylase inhibitor (HDACi) valproic acid (VPA). Methods. Primary mouse brain capillary endothelial cells (BCECs) and brain capillaries isolated from mice injected intraperitoneally with VPA were examined using RT-qPCR and ELISA. Targeting to the BBB was performed by injecting monoclonal anti-TfR1 (Ri7217)-conjugated gold nanoparticles measured using ICP-MS. Results. In BCECs co-cultured with glial cells, Tfrc mRNA expression was significantly higher after 6 h VPA returning to baseline after 24 h. In vivo Glut1 mRNA expression was significantly higher in males, but not females', receiving VPA, whereas Cd98hc mRNA expression was unaffected by VPA. TfR1 increased significantly in vivo after VPA, whereas GLUT1 and CD98hc were unchanged. Uptake of anti-TfR1-conjugated nanoparticles was unaltered by VPA in spite upregulated TfR expression. Conclusions. VPA upregulates TfR1 in brain endothelium in vivo and in vitro. VPA does not increase GLUT1 and CD98hc proteins. The increase in TfR1 does not result in higher anti-TfR1 antibody targetability, suggesting targeting sufficiently occurs with available transferrin receptors without further contribution from accessory VPA-induced TfR1.

The study evaluated the regenerative responses of the lacrimal functional unit (LFU) after Lacrimal Gland (LG) ablation. The LG of Wistar rats were submitted to G1) partial LG ablation, G2) partial ablation and transplantation of an allogeneic LG, or G3) total LG ablation, (n=7-10/group). The eye wipe test, slit-lamp image, tear flow, and histology were evaluated. RT-PCR analyzed inflammatory and proliferation mediators. The findings were compared to naïve controls after 1 and 2 months (M1 and M2). G3 presented increased corneal sensitivity, and the 03 groups have shown corneal neovascularization. Histology revealed changes in LG, and corneal inflammation. In the LG, there was an increase in MMP-9 mRNA of G1 and G2 at M1 and M2 and RUNX-1 at M1 and M2 in G1 and RUNX-3 mRNA at M1 in G1, and in G2 at M2. TNF-α mRNA rose in the corneas of G1 and G2 at M2. There was an increase in the IL-1β mRNA in the Trigeminal Ganglion of G1 at M1. Without changes in tear flow or evidence of LG regeneration, LG ablation or grafting are unreliable models for dry eye or LG repair in rats. The surgical manipulation extended inflammation to the LFU.

There is a substantial lack of data relating to the hygrothermal traits of existing buildings and building materials. Moisture analysis in building envelopes is 1D (one-dimensional), and 2D and 3D effects and feedback can be neglected. Many European standards treat a moisture percentage in building envelopes as surface and interstitial moisture condensation, such as BS EN ISO 10211, BS EN ISO 13788, BS EN ISO 15148, and BS EN 15026. In this manuscript, there was a tendency to capture a relative quantity of superficial moisture, by metering spots on the inner and outer surface of wall lining systems with a moisture meter. The metering specimens were the buildings with different envelopes: a wooden hut-house, a masonry building and a building partially sheeted in stone. The referent heights on wall linings, for taking the moisture data were specified as 50 cm for a wooden and masonry building and 80 cm for a stone-sheeted building, from the ground. The obtained numeric results were palpable with no regard to the current state of the weather outside. The listed conclusions highlight the significance of a well-tailored building envelope, and its dependence on weather, junctions, gaskets, appropriate materials, etc.

Neurologic disorders such as traumatic brain injury, multiple sclerosis, Alzheimer’s disease, and drug-resistant epilepsy have a high socioeconomic impact around the world. Current therapies for these disorders are often not effective. This creates a demand for the development of new therapeutic approaches to treat these disorders. Recent data suggest that autoreactive naturally occurring immunoglobulins produced by subsets of B cells called B1 B cells combined with complement are actively involved in the processes of restoration of neuronal functions during pathological conditions and remyelination. The focus of this review is to discuss the possibility of creating specific therapeutic antibodies that can activate and fix complement to enhance neuronal survival and promote central nervous system repair after injuries associated with many types of neurodegenerative diseases.

The recent rise in ocean temperatures, accompanied by other environmental changes, has notably increased the occurrence and spread of diseases in Octocorallia, of which many species are integral to shallow tropical and subtropical coral reef ecosystems. This study focuses on the understanding of these diseases, which has been largely limited to symptomatic descriptions, with clear etiological factors identified in only a fraction of cases. A key example is the multifocal purple spots syndrome (MPSS) affecting the common Caribbean octocoral sea fan Gorgonia ventalina, linked to the gall-forming copepods of the genus Sphaerippe, a member of the widespread family Lamippidae. The specialized nature of these copepods as endoparasites in octocorals suggests the potential for the discovery of similar diseases across this host spectrum. Our investigation employed four molecular markers to study disease hotspots in Saint Eustatius, Curaçao, northwest and southwest Cuba, and Bonaire. This led to the discovery of a group of copepod species in these varied Caribbean locations. Importantly, these species are morphologically indistinguishable through traditional methods, challenging established taxonomic approaches. The observed diversity of symbionts, despite the host species' genetic uniformity, is likely due to variations in larval dispersal mechanisms. Our phylogenetic analyses confirmed that the Lamippidae copepods belong to the order Poecilostomatoida (Copepoda) and revealed their sister group relationship with the Anchimolgidae, Rhynchomolgidae, and Xarifiidae clades, known for their symbiotic relationships with scleractinian corals. These results add to our understanding of the evolutionary and ecological interactions of copepods and their hosts, and the diseases they cause, important data in a changing climate.

Plant biotechnology is dependent today on accessing broader plant genetic resources for food and agriculture (PGRFA) diversity for ensuring food security for our future. Heterogenous agricultural lands are considered today as hotspot for biodiversity, and they also exist in the hilly mountain areas of Romanian’s Carpathians. The scope of this review is to describe traditional home-hardens related to the land use of households and cultivated species from Moșna commune, Sibiu County, Romania. The survey was realized with the support of authorities and local stakeholders from 2010 up to 2019. The results of this survey revealed that maintenance of crop species structure and land use of traditional households is longer than 100 years. Consequently at least 15 traditional Saxon home-gardens of 120 taken into the study may be defined. Today these home-garden covers a media of 26% of the total area of a household and should be part of a surface ranging between 5,000 and 1,500 m2. The first Local Council Decision in Romania in 2019 supporting the recognition of landraces and home-gardens as heritage values was officially adopted supporting the need to more access bottom-up approaches for supporting biodiversity conservation.

Although heart failure with preserved ejection fraction (HFpEF) has become the predominant heart failure subtype, it remains clinically under-recognized. This, has been attributed to the complex pathophysiological mechanisms that accompany individuals with several co-morbidities and symptoms and signs of HFpEF. Natriuretic peptides have been recognized to have important role in the diagnosis and monitoring of patients with heart failure with reduced ejection fraction (HFrEF), but their role in HFpEF remains controversial. Its seems that the role of NtproBNP in the diagnosis of HFpEF, is mainly driven by the pathophysiological characteristics of the patients.

Citizen science substantially contributes to large-scale biodiversity monitoring and the enhancement of public literacy. While both of the contributions largely depend on the public’s self- regulated learning. In this study, we employed a mix- method approach, incorporating both a questionnaire survey of 133 participants and interviews with 12 volunteers, aiming to explore the feature of self- regulated learning in citizen science, as well as identify the main factors impacting it. The volunteers are all different ages, from different jobs, with varying educational backgrounds. The findings revealed that the educational background of volunteers did not significantly impact their self-regulated learning. However, an increased frequency of participation was linked to higher levels of self-regulated learning. Furthermore, achievement goal orientation mediates the prediction of self-regulation by scientific epistemology. These insights underscore the importance of enhancing citizen science's impact on scientific literacy by fostering self-regulated learning among participants. This can be achieved through explicit instruction in scientific epistemology and by fostering a sense of achievement to boost achievement goal orientations. Additionally, our study advocates for the promotion of social interaction between students and out- of- school citizen scientists in school-based citizen science projects. The main innovation of this study is to consider volunteers as learners, not merely as contributors of data.

Cholangiocellular carcinoma (CCA) is the second most common primary liver cancer, with increasing incidence worldwide and inadequate therapeutic options. Intra- and extrahepatic bile ducts have distinctly different embryonic origins and developmental behavior, and accordingly intra- and extrahepatic CCAs (ICC vs. ECC) are molecularly different. A promising strategy in oncotherapy is targeted therapy, targeting proteins that regulate cell survival and proliferation; such as the MAPK/ERK and PI3K/AKT/mTOR signaling pathways. Inhibitors of these pathways have been tested previously in CCA cell lines. However, these cell lines could not be clearly assigned to ICC or ECC, and results indicated apoptosis induction by targeted therapeutics. We tested targeted therapeutics (selumetinib, MK2206) in three defined ICC cell lines (HuH28, RBE, SSP25). We observed cooperative effects of dual inhibition of the two pathways, in accordance with inhibition of phospho-AKT and phospho-ERK1/2 expression. Proliferation was blocked more effectively with dual inhibition than with each single inhibition, but cell numbers did not drop below baseline. Accordingly, we observed G1-phase arrest, but not apoptosis (cleaved caspase-3, AIFM1 regulation, subG1-phase) or necroptosis (phospho-MLKL). We conclude that dual inhibition of MAPK/ERK and PI3K/AKT/mTOR pathways is highly effective to block proliferation of ICC cell lines, but therapy must certainly be supplemented with standard therapies.

The sudden onset of the Covid-19 pandemic disrupted the modern multi-national interconnected society and led the countries and societies to enforce unprecedented restrictions on movement. Among myriad containment measures, the policy of trace and quarantine found universal adoption among countries; the swift adoption of the policy was soon met with widespread criticism and opposition activists who questioned the utility and the risk associated with such a large scale collection of data and infringement on the movement of individuals. Consequently, one often tends to be either pro- or anti-trace and quarantine; the ensuing polarizing and politicized left little room for nuance. In this work, we undertake a methodology study to understand the nuances of the impact of different implementations of trace and quarantine. To this end, we design a user-friendly and intuitive tool that can be employed by experts to model the disease dynamics and societal structure. We focus on the study of the cost of policy with respect to quarantine degree, which captures the distance between the person required to quarantine after a person is detected to be infected. Our study results in a surprising conclusion: the cost is not necessarily monotone with respect to the degree of quarantine. Our analysis indicates that governments must curb the urge to adopt simplistic policy and the optimal policy of trace and quarantine for a country strongly depends on its societal structure and disease dynamics.

Stimulation of the alpha 7 nicotinic acetylcholine receptor (α7nAChR) has shown beneficial effects in several acute inflammatory disease models. This study aims to examine whether treatment with the selective α7nAChR agonist PHA 568487 can dampen inflammation and thereby improve cardiac function after myocardial infarction in mice. The possible anti-inflammatory properties of α7nAChR agonist PHA 568487 were tested in vivo using the air pouch model and in a permanent occlusion model of acute myocardial infarction in mice. Hematology parameters and cytokine levels were determined. Infarct size and cardiac function were assessed via echocardiography 24 h and one week after the infarction. Treatment with α7nAChR agonist PHA 568487 decreased 12 (CCL27, CXCL5, IL6, CXCL10, CXCL11, CXCL1, CCL2, MIP1a, MIP2, CXCL16, CXCL12 and CCL25) out of 33 cytokines in the air pouch model of acute inflammation. However, α7nAChR agonist PHA 568487 did not alter infarct size, ejection fraction, cardiac output or stroke volume at 24 h nor at 7 days after the myocardial infarction compared with control mice. In conclusion, despite promising immunomodulatory effects in the acute inflammatory air pouch model, α7nAChR agonist PHA 568487 did not affect infarct size or cardiac function after a permanent occlusion model of acute myocardial infarction in mice. Consequently, this study does not strengthen the hypothesis that stimulation of the α7nAChR is a future treatment strategy for acute myocardial infarction when reperfusion is lacking. However, whether other agonists of the α7nAChR can have different effects remains to be investigated.

The presence of mutated genes strongly correlates with the incidence of cancer. Decades of research, however, has not yielded any specific causative gene or set of genes for the vast majority of cancers. The Cancer Genome Atlas program was supposed to provide clarity but it only gave much more data without any accompanying insight into how the disease begins and progresses. It may be time to notice that epidemiological studies consistently show that the environment, not genes, has the principal role in causing cancer. Since carcinogenic chemicals in our food, drink, air and water are the primary culprits, we need to look at the biochemistry of cancer, with a focus on enzymes which invariably facilitate transformations in a cell. In particular, attention should be paid to the rate-limiting enzyme in DNA synthesis, ribonucleotide reductase (RnR) whose activity is tightly linked to tumor growth. Besides circumstantial evidence that cancer is induced at this enzyme’s vulnerable free-radical-containing active-site by various carcinogens, its role in initiating retinoblastoma and HPV-related cervical cancers is well documented. Blocking the activity of malignant RnR is a certain way to arrest cancer.

In two laboratory trials natural products, including freshly-picked leaves from spearmint, rosemary, and tansy plants; a water extract from soybean plants; peels from a common cucumber; and 1% peppermint oil in hexane were placed in a moist harborage preferred by Argentine ants, Linepithema humile, and the number of ants entering the harborage after two and four hours was counted. None of the recommended home remedies (tansy, cucumber, or soybean extract) deterred ants from an attractive, moist harborage in either trial even when the quantity of these treatments was increased 4- to 10-fold. Freshly picked leaves from rosemary and spearmint plants deterred ants from harboring, and the 1% peppermint oil was the most deterrent of all treatments.

Culex quinquefasciatus is an important target for vector control because of its ability to transmit pathogens that cause disease. Most populations are resistant to pyrethroids and often to organophosphates, the two most common classes of active ingredients used by public health agencies. A knockdown resistance (kdr) mutation, resulting in a change from a leucine to phenylalanine in the voltage gated sodium channel, is one mechanism contributing to the pyrethroid resistant phenotype. Enzymatic resistance has also been shown to play a very important role. Recent studies have shown strong resistance in populations even when kdr is relatively low which indicates factors other than kdr may be larger contributors to resistance. In this study, we examined on a statewide scale (over 70 populations), the strength of the correlation between resistance in the CDC bottle bioassay and the kdr genotypes and allele frequencies. Spearman correlation analysis showed only moderate (-0.51) and weak (-0.29) correlation between the kdr genotype and permethrin and deltamethrin respectively. The frequency of the kdr allele was an even weaker correlate. These results indicate, in contrast to Aedes aegypti, assessing kdr in populations of Culex quinquefasciatus is not a good surrogate for phenotypic resistance testing.

In South Sudan, three case-control studies found a positive association between Nodding Syn-drome (NS) and a Mansonella perstans infection. To investigate whether M. perstans could play the primary and sole causal role in the development of NS, we examined blood films of persons with and without epilepsy in rural villages affected by NS in Mahenge, Tanzania, to identify M. perstans infections. Study participants were also examined for onchocercal nodules and skin lesions and tested for the presence of anti-O. volvulus antibodies (Ov16 ELISA). One hundred and thirteen epilepsy cases and 132 controls were enrolled, with a mean age of 28.3 years (interquartile range 22 – 34 years); 125 (51%) were females. Of the persons with epilepsy, 43 (38.1%) met the probable NS criteria. M. perstans infection was absent in all participants, but Ov16 prevalence and oncho-cerciasis-associated skin manifestations were positively associated with epilepsy, including probable NS. Onchocercal nodules in the mothers of cases were also positively associated with epilepsy. In conclusion, in contrast with O. volvulus, M. perstans is likely not endemic in Mahenge and therefore cannot be a co-factor for NS in the area. Hence, this filaria cannot be the primary and sole causal factor in the development of NS.

When computers start to become a dominant part of technology around the 1950s, fundamental questions about reliable designs and robustness were of great relevance. Their development gave rise to the exploration of new questions such as what made brains reliable (since neurons can die) and how computers could get inspiration from neural systems. In parallel, the first Artificial Neural Networks came to life. Since then, the comparative view between brains and computers has been developed in new, sometimes unsuspected directions. With the rise of deep learning and the development of connectomics, an evolutionary look at how both hardware and neural complexity have evolved or designed is required. In this paper, we argue that important similarities have resulted both from convergent evolution (the inevitable outcome of architectural constraints) and inspiration of hardware and software principles guided by toy pictures of neurobiology. Moreover, dissimilarities and gaps originate from the lack of major innovations that have paved the way to biological computing (including brains) that are completely absent within the artificial domain. As it occurs within synthetic biocomputation, we can also ask whether alternative minds can emerge from A.I.\ designs. Here we take an evolutionary view of the problem and discuss the remarkable convergences between living and artificial designs and what are the pre-conditions to achieve artificial intelligence.

Decompression sickness (DCS) with neurological disorders is the leading cause of diving accidents. Exposure to high levels of CO2 during diving is a safety concern for occupational , groups at risk of DCS. However, the effects of prior exposure to CO2 have never been evaluated. The purpose of this study was to evaluate the effect of CO2 breathing prior to a provocative dive on the occurrence of DCS in mice. 50 mice were exposed to a maximum CO2 concentration of 70 hPa for one hour at atmospheric pressure. Another 50 mice breathing air under similar conditions served as controls. In the AIR group (controls), 22 out of 50 mice showed post-dive symptoms compared to 44 out of 50 in the CO2 group. We found that CO2 breathing is associated with a decrease in body temperature in mice and that CO2 exposure dramatically increases the incidence of DCS. More unexpectedly, it appears that a lower temperature of the animals even before exposure to the accident-prone protocol leads to an unfavorable prognosis. This study also suggests that the composition of the microbiota may influence thermogenesis and thus accidentology. Depending on prior exposure, some bacteria identified in this work could be perceived as protective or pathogenic.

Hereditary hemochromatosis (HH) is the main genetic cause of iron overload and is regarded as metal-related human toxicosis. HH may result from HFE and non-HFE gene mutations causing hepcidin deficiency or hepcidin resistance. The disorder has a high biochemical penetrance, but a low clinical prevalence. Unfortunately, the majority of patients with HH remain undiagnosed at their disease-curable stage. The main aim of HH therapy is to prevent iron overload in the early-phase disease and elimination of excess iron from the body by phlebotomy in its late stage. Raising global awareness of HH among health professionals, their training to pay attention to early HH signs and symptoms, and strict patient monitoring are critical management strategies for preventing treatment delays, upgrading its efficacy, and improving patient prognosis.

The Bacillus Calmette-Guérin (BCG) vaccine has been used for over one hundred years to protect against the most lethal infectious agent in human history, tuberculosis. Over four billion BCG doses have been given and, worldwide, most newborns receive BCG. A few countries, including the United States, did not adopt the WHO recommendation for routine use of BCG. Moreover, within the past several decades, most of Western Europe and Australia, having originally employed routine BCG, have discontinued its use. This review article articulates the impacts of those decisions. The associated consequences include increased tuberculosis, increased infections caused by non-tuberculous mycobacteria (NTM), increased autoimmune disease (autoimmune diabetes and multiple sclerosis) and increased neurodegenerative disease (Parkinson’s disease and Alzheimer’s disease). This review also offers an emerged zoonotic pathogen, Mycobacterium avium ss. paratuberculosis (MAP) as a mostly unrecognized NTM that may have a causal role in some, if not all, of these diseases. Current clinical trials with BCG for varied infectious, autoimmune and neurodegenerative diseases have brought this century-old vaccine to the fore due to its presumed immuno-modulating capacity. With its historic success and strong safety profile, the new and novel applications for BCG may lead to its universal use –putting the Western World back onto the road not taken.

The term low-resourced has been tossed around in the field of natural language processing to a degree that almost any language that is not English can be called "low-resourced"; sometimes even just for the sake of making a mundane or mediocre paper appear more interesting and insightful. In a field where English is a synonym for language and low-resourced is a synonym for anything not English, calling endangered languages low-resourced is a bit of an overstatement. In this paper, I inspect the relation of the endangered with the low-resourced from my own experiences.

In this paper we aim to help topical probiotics research and development achieve its potential as an incredible future solution for skin problems by investigating whether the current products on the market satisfy criteria for safe and effective use on the skin microbiome. As previously defined, this includes whether they use microbes known to be part of a healthy skin microbiome and in healthy amounts. In addition, we evaluate whether they contain live microbes, and therefore can be classified as probiotics according to the WHO’s definition. Using recent market analysis at least 84% of products do not contain live microbes. Of the products that appeared to use live microbes, they contained those used in research and development of probiotics for the gut. Due to the varying composition of each person’s microbiome, there is not a one size fits all probiotic solution. Personalisation of probiotics products is essential to satisfy the criteria for safe and effective use, but none of the products on the market, understandably, offer this. Upsetting the delicate ecosystem balance of the skin microbiome could have damaging effects and regulation could help to stop a loss of trust between consumers and cosmetics industry. Future work will perform an in-depth evaluation of the topical probiotics on the market in the EU, USA, and Canada. We will also investigate how to move the topic closer to achieving its potential by updating the criteria, including by discussing how to measure the success of a probiotic solution.

This study investigated subclinical atherosclerosis progression in low-risk, middle-aged adults (N=141; mean age 49.6±4.7 years) using a 5-year ultrasound follow-up. We compared in-volvement of the carotid and femoral arteries. Methods: Clinical data, risk factors, and carotid/femoral intima-media thickness (IMT) and plaque presence were analyzed. Results: Cardiovascular risk factors and scores increased significantly at follow-up. Both carotid and femoral IMT increased (p<0.001) but remained within the normal range. While plaque prev-alence rose and was similar in both arteries (carotid: 4.8% to 17.9%, femoral: 3.6% to 17.7%, p<0.001 for both), the progression of plaque burden was greater in femorals. Notably, carotid IMT demonstrated a faster yearly progression rate compared to femoral IMT. The age- and sex-adjusted increase in IMT was also more frequent in the carotids (52.9% to 78.8%, p<0.001) compared to femorals (23.2% to 44.7%, p<0.001). Conclusions: This study demonstrates significant subclinical atherosclerosis progression in low-risk middle-aged adults during 5 years. Carotid arteries showed a faster progression rate and higher prevalence of increased age- and sex-adjusted IMT compared to the femoral arteries. However, plaque burden was similar in both territories, with greater progression in femorals. Identifying carotid and femoral atherosclerosis burden may be a valuable tool for risk stratification in this population.

Previous evidence in support of a slowly acting (scale of 100s of seconds) and volume-transmitted component of cholinergic signaling was based largely on studies using measures of extracellular brain acetylcholine (ACh) levels which required several minutes to generate a single data point and typically employed AChEsterase inhibitors (AChEIs) to foster the measurement of ACh. Moreover, collecting such data points in correlation with relatively stable behavioral states has supported the view that extracellular ACh levels vary at a relatively slow rate. Here we argue that forebrain cholinergic signaling is exclusively phasic (milliseconds to perhaps seconds), unlikely to be volume-transmitted, and that previous neurochemical evidence and associated behavioral correlates may be re-interpreted in terms of integrated phasic cholinergic activity and specific behavioral and cognitive operations. The highly potent catalytic enzyme for ACh, AChE, limits the presence of an ambient extracellular ACh level and thus renders it unlikely that ACh influences target regions via relatively slow changes in extracellular ACh concentrations. Real-time amperometric recordings of cholinergic signaling have suggested a specific function of rapid, phasic or transient cholinergic signaling in attentional contexts. Optogenetic studies support a causal relationship between these transients on behavior. Combined electrochemical and neurophysiological recordings revealed that the powerful behavioral control by cholinergic transients involves the generation of high-frequency oscillations. Such oscillations are thought to recruit efferent circuitry to (re)activate dormant task sets. Evidence showing the impact of genetic variations of the capacity of cholinergic synapses likewise can be interpreted in terms of their impact on the ability to sustain generation of repeated phasic cholinergic signals, as opposed to effects on ambient ACh levels. Further, while notions of slowly-changing, sleep stage-associated variations in extracellular ACh levels and their functions are widely accepted, the evidence is in fact limited. An alternative hypothesis offers a role for high-frequency cholinergic transient signaling during REM sleep. By employing a theoretical framework that focuses on the phasic and causative characteristics and functions of cholinergic signaling, results from human cognitive neuroscience studies of cholinergic function may be substantially clarified and simplified. Compared to the current treatment of cholinergic deficits using AChEIs, the conceptualization of forebrain cholinergic signaling as wired, phasic, and causative predicts that drugs that either rescue transient presynaptic signaling or amplify or rescue the postsynaptic impact of phasic signals will be more efficacious in treating age- and dementia-related cognitive and cognitive-motor disorders.

We consider a constrained optimal control problem and an extension of it, in which the set of strict-sense trajectories is enlarged. Extension is a common procedure in optimal control, used to derive necessary and sufficient optimality conditions for the original problem from the extended one, which usually admits a minimizer and has a more regular structure. However, this procedure fails if the two problems have different infima. It is therefore relevant to identify such situations. Following on from earlier work by Warga but adopting perturbation techniques developed in non-smooth analysis, we investigate the relation between the occurrence of an infimum gap and abnormality of necessary conditions. For a notion of local minimizer based on control distance and an extension including the impulsive one, we prove that (i) a local extended minimizer which is not a local minimizer of the original problem and (ii) a local strict-sense minimizer which is not a local minimizer of the extended problem, both satisfy the extended maximum principle in abnormal form. The main novelty is result (ii), as until now it had only been shown that a strict-sense minimizer which is not an extended minimizer is abnormal for an `averaged version’ of the maximum principle.

Epistaxis, particularly in Hereditary Hemorrhagic Telangiectasia (HHT) patients, is a common otolaryngological emergency, often requiring complex management. A hierarchy of increasingly invasive interventions, from external compression of the nasal pyramid to nostril closure, is typically proposed and applied. We conducted a retrospective study on HHT patients to assess the effectiveness and longevity of invasive procedures postoperatively. Data were collected using the Epistaxis Severity Score (ESS) questionnaire. The primary focus was on changes in the frequency and intensity of epistaxis, while the secondary focus was on the overall quality of life. The study found that invasive procedures initially improved the frequency and intensity of epistaxis in HHT patients. However, within one to 9 months postoperatively, these benefits often diminished, with hemorrhagic symptoms recurring at similar or worsened levels. Facial trauma further negated the advantages of these procedures. The findings suggest a need for a gradual and increasingly invasive approach to managing epistaxis in HHT patients. Highly invasive procedures should be reserved for cases where less invasive methods fail, due to their limited temporal effectiveness and the risk of causing anatomical-functional changes in the rhino-sinus area, complicating future management of severe epistaxis.

This study checked whether vitamin D (Vit-D) supplementation improves the efficacy of resistance training (RT) in terms of increasing muscle strength and lean body mass (LBM) and influencing cardiorespiratory fitness (VO2max) in Vit-D insufficient middle-aged healthy men. Participants (n = 28) were quasi‐randomly assigned to one of the two groups, which, in a double‐blind manner, supplemented their diet daily with either Vit‐D (8000 IU; VD) or placebo (PLC) during participation in a 12‐week supervised RT program. During the intervention, serum Vit‐D concentrations increased 2.6‐fold (p < 0.001) in the VD group, while no changes occurred in the PLC group. Muscle strength gains (p < 0.001) as measured in seven exercises performed on RT equipment and increases (p < 0.001) in LBM were similar in the two groups. Total fat mass, percent total fat, and percent android fat decreased (p < 0.05) to a similar extent in both groups, but there was no change in VO2max in either group. In conclusion, in healthy Vit‐D insufficient middle-aged men engaged in resistance training, Vit‐D supplementation increases serum 25(OH)D levels but does not enhance gains in muscle strength and LBM or decreases in fat mass and fat percentage and does not affect cardiorespiratory fitness.

Type I contextuality or inconsistent connectedness is a fundamental feature of both the classical as well as the quantum realms. Type II contextuality (true contextuality or CHSH type contextuality) is frequently asserted to be specific to the quantum realm. Nevertheless, evidence for Type II contextuality in classical settings is slowly emerging (at least in the psychological realm). An example is given here of Type II contextuality involving a simple cooperative game. This arises due to the cooperative nature of the game which results in sign intransitivity for expectation values while individual random variables remain consistently connected. This shows that the conditions attributed uniquely to quantum systems may occur in classical settings as well. Sign intransitivity can be observed in preference relations in the setting of decision making and so intransitivity in decision making may also yield examples of Type II contextuality. Previously it was suggested that a fruitful setting in which to search for such contextuality is that of decision making by collective intelligence systems. An experiment was conducted using a detailed simulation of nest emigration by workers of the ant Temnothorax albipennis. In spite of intransitivity, these simulated colonies came close to but failed to violate Dzhafarov’s inequality for a 4-cyclic system. Further research using more sophisticated simulations and experimental paradigms is required

After defeating and pushing aside the Carthaginians, the Romans named the territory of north Africa Mauretania and its population, Mauri. Later on, historians have had to reflect on the origin of the term mauri to designate the population or Mauretania to name the territory. Besides the signification of the Latin/Greek word « mauri » which means « black », it is admitted, as well, that the word Mauri is a transcription, into Latin alphabet, of a punic word meaning « the west » or « the westerners ». If the latter meaning is 2000 years old, the other approbation is relatively modern and suspected of ideological biases. The punic word maġaribis, transcribed mauri/ma’ari/mahauri, really makes sense since it means the west in Punic - the 15 century-long North African lingua franca.

The article derives the probability for lethal recessive alleles in the case of recessive disadvantage or advantage. It is shown that the recessive advantage of a lethal gene can be detected by the ratio of heterozygotes and homozygotes. This demonstrates that the higher IQ of certain ethnic groups cannot be explained by the recessive advantage of lethal genes. The article shows that lethal genes can survive in the population if some lineages of families have much more children than the average.

Hyperuricemia is a risk factor for gout. It has been well observed that a large proportion of hyperuricemia individuals have never had a gout attack(s), while some patients with gout can have a normuricemia. This raises a puzzle of the real role of serum uric acid (SUA) in the occurrence of gout attacks. As the molecule of uric acid has its dual effects in vivo with antioxidant property as well as being an inflammatory promoter, it has been placed in a delicate position in balancing metabolisms. Gout seems to be a multifactorial metabolic disease and its pathogenesis should not rely solely on hyperuricemia or MSU crystal. This critical review aims to unfold the mechanisms of the SUA role participating in gout development. It also discusses some key elements which are prerequisite for the formation of gout in association with the current therapeutic regime. The compilation should be helpful in precisely fighting for a cure of gout clinically and pharmaceutically.

The growing interest related to the proposal of formal definition of a new geological period that has being called “Anthropocene” has introduced a buzzing dynamics in the scientific community, but its conduct is perhaps due to various interests involved in a discussion that has long surpassed the contours of the so-called “Geosciences”. Themes such as “Climate Change or Drift”, “Global Warming”, “Massive Extinction of Species” and “Loss of bio and geodiversity”, among others, are the wheel of a geomorphogenetic dynamics of anthropocentric origin, which leads the debate. But are the conditions for the formal establishment of a new morphosedimentary cycle following the Meghalayanian (Upper Holocene) Age? This work pursues a line of thought that seeks to answer these and other questions, based on the official position of the institutes that have the scientific competence for the formalization under consideration, and the formal criteria that should be considered for this purpose.

The spike protein of SARS coronavirus (SARS-CoV) attaches the virus to its cellular receptor, angiotensin-converting enzyme 2 (ACE2), which is mediated by the receptor binding domain (RBD) of the spike protein. Recently, an analysis based on decade-long structural studies of SARS was reported to illustrate with atomic-level details receptor recognition by the novel coronavirus from Wuhan, i.e., 2019-nCoV. Here, this article reports a comprehensive set of structural electrostatic analysis of all SARS-CoV spike protein RBD-related structures as of February 13, 2020, aiming at identifying the electrostatic hot spots for SARS-CoV spike protein to be complexed with ACE2 and its neutralizing antibodies. First, this article identified a structural action mechanism of the F26G19 antibody (of SARS-CoV spike protein), where its Asp56 residue binds to the Arg426 of the SARS-CoV spike protein RBD against the formation of the interfacial Arg426-Glu329 salt bridges between ACE2 and the SARS-CoV spike protein RBD. Second, a hypothesis is reported that a pair of electrostatic clips exist at the interface between ACE2 and the SARS-CoV spike protein RBD, including both Arg426-Glu329 and His445-Glu23-Lys447 salt bridges. Last, this article reports a structurally identified interfacial Glu35-Arg479 salt bridge which helps stabilize the complex structure of ACE2 and the SARS-CoV spike protein RBD. Overall, the structurally identified electrostatic hot spots reported here may be useful for the design of SARS-CoV-neutralizing antibodies in future.

With the term neuroinflammation has defined the typical inflammatory response of the brain closely related to the onset of many neurological diseases. Neuroinflammation is well known, but its mechanisms and pathways are not entirely comprehended. Currently, some progress has been achieved through many efforts and research. Consequently, new cellular and molecular mecha-nisms, diverse from conventional ones, are emerging. In listing some of those that will be the sub-ject of our description and discussion, essential are the important role of peripheral and infiltrated monocytes and clonotypic cells, alterations in gut/brain axis, dysregulation of the apelinergic sys-tem, as well as changes in the endothelial glycocalyx of blood-brain barrier, variation in expres-sion of some genes and levels of the encoding molecules by microRNAs (miRNAs), or other epige-netic factors and distinctive transcriptional factors, as well as the role of autophagy, ferroptosis, sex differences and modifications in the circadian cycle. Such mentioned mechanisms can add significant pieces in understanding the complex etiological puzzle of neuroinflammation. In addi-tion, they could represent biomarkers and targets of neurodegenerative diseases, in increase in our old populations.

We present the detailed calculations of social distancing requirement. A comparative study of the growth pattern and death tolls in different communities indicates that the growth pattern of infected patients and death rate follow the similar distribution with different parametrizations. Every distribution follows an exponential growth pattern curve, like other microbes, then reaches the saturation point an d eventually decay s However, the argument for the exponential function depends on several parameters unbeknownst, as of yet. However, the slope varies different ial ly for various epicenter s and seems to have a relationship with parameters such as accessibi lity to healthcare facilities, pre existing medical conditions socio economic conditions and lifestyle. The mismatch of the growth pattern is also linked with the impact of various other factors and a premature interpretation of limit ed data. Novel behavi or of the virus brought many surprises, opened up new venues for medical research, and the need for the more detailed study of pathogens in the light of the interaction of RNA and DNA The adaptability to diverse ecological condition s and the relevant modification in the structure is also worth investigation The genetic modification can be studied using quantum mechanical probabilistic approach.

Background: The risk to physicians who worked with patients without confirmed COVID-19 testing during the pandemic has been little studied. However, they were at high risk. Methods: A total of 1285 Romanian physicians completed an online survey. We performed Mann-Whitney comparisons between physicians who reported that they knowingly had direct contact with COVID patients and those who didn't regarding their willingness to work. Results: Compared with their colleagues, physicians who reported not knowingly having direct contact with COVID patients reported less access to protective equipment, less overall willingness to respond when asked to work with infected patients, more likely to work out of fear of losing their jobs, and fear of legal repercussions. They received less training in the use of protective equipment. Conclusions: Physicians who worked with patients not yet diagnosed with COVID-19 were significantly less willing to work. The perception of invisible risk may explain the observed differences.

Analysis of tRNA sequence structural features from forty mammals proves neither isoacceptors nor isodecoders are degenerate, and model organisms are inadequate representatives for multiple aspects of the translational process. It is proposed tRNA participate in protein construction beyond mere transport of amino acids to ribosomes: specifically, to facilitate amino acid modification and promote development of protein folding characteristics.

A toy model for the distribution of the impact factor (IF) of a journal is proposed. The model demonstrates the presence of a heavy tail for the IF distribution, which occurs due to some random non-scientific circumstances. Therefore, the use of IF as an indicator of the quality of scientific papers seems to be inadequate.

This research aims to determine the influence of the independent commissioners, audit committee, institutional ownership, firm size and leverage against the integrity of the financial reporting information. This research is quantitative research with the causal approach. This study uses secondary data and panel data regression analysis method. The research results prove that audit committee, institutional ownership and leverage effect on the integrity of the financial reporting information. But it does not prove that the independent commissioner and firm size effect on the integrity of the financial reporting information.

Dengue is the most prevalent arthropod-borne disease globally and affects approximately 2.5 billion people living in over 100 countries. The increasing geographic expansion of Aedes aegypti mosquitoes which transmit the virus has made dengue fever a global health concern. There are currently no approved antivirals available to treat dengue, and the only approved vaccine used in some countries is limited to seropositive patients. Treatment of dengue therefore remains largely supportive to date; hence research efforts are being intensified for the development of antivirals against dengue. The NS3 and NS5 nonstructural proteins have been the major targets for dengue antiviral development due to their indispensable enzymatic and biological functions in the viral replication process. NS5 is the largest and most conserved nonstructural protein encoded by flaviviruses including dengue. Its multifunctionality makes it an attractive target for antiviral development against dengue, but research efforts are hindered due to its limited structural characterization compared to the NS5 of other flaviviruses like the Zika virus. Increase in structural insights into the dengue NS5 protein will accelerate drug discovery efforts focused on NS5 as an antiviral target. In this review, we will give an overview of the current state of therapeutic development against dengue.

Mathematical modelling of bioprocesses has a long and notable history, with eminent contributions from fields including microbiology, ecology, biophysics, chemistry, statistics, control theory and mathematical theory. This richness of ideas and breadth of concepts provide great motivation for inquisitive engineers and intrepid scientists to try their hand at modelling, and this collaboration of disciplines has also delivered significant milestones in the quality and application of models for both theoretical and practical interrogation of engineered biological systems. The focus of this review is the anaerobic digestion process, which, as a technology that has come in and out of fashion, still remains a fundamental process for addressing the global climate emergency. Whether with conventional anaerobic digestion systems, biorefineries, or other anaerobic technologies, mathematical models are important tools that are used to design, monitor, control and optimise the process. Both highly structured, mechanistic models and data-driven approaches have been used extensively over half a decade, but recent advances in computational capacity, scientific understanding and diversity and quality of process data, presents an opportunity for the development of new modelling paradigms, augmentation of existing methods, or even incorporation of tools from other disciplines, to ensure that anaerobic digestion research can remain resilient and relevant in the face of emerging and future challenges.

Even despite rapid advances in colorectal surgery, morbidity and mortality rates in elective gastrointestinal surgery play a significant role. For decades, there have been tempestuous discussions on preventive measures to minimize the risk of anastomotic dehiscence. When mechanical bowel preparation before elective procedure, one of the key hypotheses, has been introduced into practice, it was assumed that it would decrease number of infectious complications and anastomotic dehiscence. The advancements in antibiotic treatment supported concomitant administration of oral antibiotics and mechanical bowel preparation. In the prospective study conducted at our clinic, we performed left-side colorectal procedures without the prior mechanical preparation. All patients enrolled in the study underwent the surgery and had been observed in the 3rd Surgical Clinic, Faculty of Medicine, Comenius University in Bratislava, Slovakia, from January 2019 to January 2020. As a control group we used similar group of patients with MBP. Our observed group included 87 patients with tumors in the left part of their large intestine (lineal flexure, descendent colon, sigmoid colon, and rectum). Dixon laparoscopic resection was performed in 26 patients. Sigmoid laparoscopic resection was performed in 27 patients. In 12 patients, the procedure was started laparoscopically but had to be converted due to adverse anatomical conditions. The conservative approaches mostly included Dixon resections (19 patients), sigmoid colon resection (5 patients) and left side hemicolectomy (6 patients), and Miles´ tumor resection with rectal amputation (4 patients). Our study highlighted the fact that MBP does not have the unequivocal benefit for patients with colorectal infection, which has an impact on development of anastomotic dehiscence.

Background: Measuring vital signs has always been a central task for Critical Care Nurse´s (CCNs) and Registered Nurse Anesthetist`s (RNAs) providing care in the post-anesthesia care unit (PACU) and a prerequisite for their decision-making. Properly measuring and understanding pediatric vital signs is a challenge in younger pediatric patients up to 36 months old. Purpose: gain a greater understanding of CCNs' and RNAs' perceptions of decision-making regarding the level of vital sign monitoring children require in the PACU. Method: A qualitative study design involving the critical-incident technique was used. Interviews were carried out with a purposeful sample of CCNs and RNAs (n=17) from two different hospitals. Findings: According to the nurses' experience, grounds for decisions concerning children’s need of vital-sign monitoring were both adequate and inadequate. They used actions to adjust the monitoring of vital signs to optimise conditions for assessment and the prospects of a safe recovery for the child. Conclusions: Evidence-based care and safety are compromised when the technology has limitations and is not adapted for children. Its use means that experience and clinical assessment are relied on to a greater extent. This not only makes experience important for reliable assessment, but also means that greater risks are accepted.

Castration of stallions is traditionally performed after puberty around the age of 2 years old. No studies have focused on the effects of early castration on osteoarticular metabolism. Thus, we sought to compare early castration (3 days after birth) with traditional castration (18 months of age) in horses. Testosterone and estradiol levels were monitored from birth to 33 months in these two groups. We quantified the levels of biomarkers of cartilage and bone anabolism (CPII and N-MID) and catabolism (CTX-I and CTX-II), of osteoarthritis (HA and COMP) and inflammation (IL-6 and PGE2). We revealed a lack of parallelism between testosterone and estradiol syntheses after birth and during puberty in both groups. An extra-gonadal synthesis of steroids was observed around the 28 month-mark, regardless of the castration age. We found the expression of estrogen receptor (ESR1) in cartilage and bone, whereas androgen receptor (AR) expression appeared to be restricted to bone. Nevertheless, with regards to osteoarticular metabolism, steroid hormone deprivation resulting from early castration showed no discernable impact on the levels of biomarkers related to bone and cartilage metabolism, nor on those associated with OA and inflammation. Consequently, our research demonstrated that early castration does not disrupt bone and cartilage homeostasis.

Two anisotropic exact Bianchi type I solutions of Einstein’s field equations that generalize the isotropic ΛCDM universe model, are used to investigate the Hubble tension. It is shown that the cosmic anisotropy as deduced from the Planck measurements of the fluctuations in the temperature of the cosmic microwave background radiation, is ten billion times too small to solve the Hubble tension.

A paper in this journal on decamethylcyclopentasiloxane (D5) used unreliable methods to reach unreliable conclusions. The authors concluded that D5 exposure should be viewed as causing human reproductive disorders and should be considered a developmental toxicant, that is, toxic to the developing embryo. The inadequate methods could not have answered the authors' research questions, and the paper should be withdrawn.

Descartes believed that there was a logical path from doubting the existence of the body to affirming mind-body dualism. In the 20th and 21st centuries, a critique of Cartesian reasoning first made by Arnauld in 1641 has been revived and widely accepted. Several writers including Paul Churchland and Gary Hatfield make the case that the argument for dualism commits the masked man fallacy; that the Cartesian argument relies on mere ignorance of the body to reach its conclusion. In this paper, I show that the argument from Cartesian doubt to mind-body dualism does not depend on mere ignorance. It depends on reliable knowledge about what can and can not be known. Descartes’ method of doubt leads to the conclusion that the body can never under any circumstance be known as the mind is known. The argument for dualism rests on that knowledge, not on ignorance. This paper reveals a viable Cartesian argument for mind-body dualism and explicates the missteps of Descartes’ contemporaneous and present-day critics.

This paper describes an image processing method that makes use of image parts instead of neural parts. Neural networks excel at image or pattern recognition and they do this by constructing complex networks of weighted values that can cover the complexity of the pattern data. These features however are integrated holistically into the network, which means that they can be difficult to use in an individual sense. A different method might scan individual images and use a more local method to try to recognise the features in it. This paper suggests such a method, where a trick during the scan process can not only recognise separate image parts, as features, but it can also produce an overlap between the parts. It is therefore able to produce image parts with real meaning and also place them into a positional context. Tests show that it can be quite accurate, on some handwritten digit datasets, but not as accurate as a neural network, for example. The fact that it offers an explainable interface could make it interesting however. It also fits well with an earlier cognitive model, and an ensemble-hierarchy structure in particular.

Abstract: Giant Cell Arteritis (GCA) is an autoimmune/autoinflammatory disease affecting large vessels in patients over 50 years old. The disease presents as an acute inflammatory response with two phenotypes, cranial-GCA and Large Vessel Vasculitis (LV)-GCA, involving the thoracic aor-ta and its branches. 18F-fluorodeoxyglucose positron emission tomography-computed tomogra-phy (18F-FDG PET-CT) is among the imaging techniques contributing to diagnosis of patients with systemic disease. However, its association with soluble inflammatory markers is still elu-sive. This proof-of-concept study aims to identify novel soluble serum biomarkers in PET/CT pos-itive patients with LV-GCA and associate them with active (0 months) and inactive disease (6 months following treatment), in sequential samples. The Most-Disease-Segment Target-to-Background Ratio (TBRMDS) was calculated for 9 LV-GCA patients, while 12 cranial-GCA and 7 Polymyalgia Rheumatica patients with negative initial PET/CT served as disease controls. Serum macrophage-related cytokines were evaluated by Cytometric Bead Array (CBA). Finally, previously published NMR-metabolomics data acquired at the same blood sampling were associated with PET/CT findings. TBRMDS was significantly increased in active versus inactive disease (3.45 vs. 2.55, p=0.008). The analysis identified 6 serum metabolites, as more sensitive to change from the active to inactive state. Among them, choline levels were exclusively altered in the LV-GCA group, but not the disease controls. Cytokine levels were not associated with PET/CT activity. Combining with CRP, ESR, and TBRMDS a composite index was generated to depict well the differences between active and inactive systemic LV-GCA (25.45 vs 11.45, p=0.0039). These preliminary results could pave the way for more extensive studies integrating serum metabolomic parameters with PET/CT imaging data to extract sensitive composite disease indexes useful for the everyday clinical practice.

Background: Chronic exposure to severe hypoxia causes an increase in hematocrit (Hct) and hemoglobin concentration ([Hb]), which can lead to Excessive Erythrocytosis (EE), which could impact physical performance. This work aims to determine the differences in the six-minute walking test (6MWT) outputs between EE and healthy subjects residing at more than 5000 meters. Methods: A prospective, cross-sectional study was performed on 71 men (36 healthy and 25 suffering EE) living in La Rinconada, Peru (5100 m). Basal levels of [Hb] and Hct were obtained. All the subjects per-formed the 6MWT, and distance reached, vital signs, dyspnea, and fatigue (Borg scale) at the end of the test were recorded. Results: The average [Hb] and Hct levels in the control group were 18.7 ± 1.2 g/dL and 60.4 ± 7.1%, respectively, contrasting with EE subjects who showed 23.4 ± 1.6 g/dL and 73.6 ± 5.9% (p < 0.001). However, no statistically significant differences were observed in BMI or other anthropometric parameters. At the end of the 6MWT, the distance traveled, and vital constants were similar between both groups, except for arterial oxygen saturation which was consistently lower in subjects with EE along the test. Conclusion: EE does not significantly affect 6MWT performance at high altitudes nor the hemodynamic control during moderate aerobic exercise of subjects who live permanently in a severe hypoxic environment.

In this tutorial review, we compare and contrast the chemical mechanisms of electrophile/oxidant sensing, and the molecular mechanisms of signal propagation. We critically analyze biological systems in which these different pathways are believed to be manifest and what the data really mean. Finally, we discuss applications of this knowledge to disease treatment and drug development.

A partial mitochondrial DNA Cytochrome Oxidase subunit I (mtCOI) gene haplotype variant of the coconut rhinoceros beetle (CRB) Oryctes rhinoceros classed as ‘CRB-G (clade I)’ has been the focus of much research since 2007 with reports of invasions into new Pacific Island locations (e.g., Guam, Hawaii, Solomons Islands). For numerous invasive species, inference of invasion biology via whole genome is superior to assessments via the partial mtCOI gene. Here, we explore CRB draft mitochondrial genomes (mitogenomes) from historical and recent collections, with assessment focused on individuals associated within the CRB-G (clade I) classification. We found that all Guam CRB individuals possessed the same mitogenome across all 13 protein coding genes and differed from individuals collected elsewhere, including ‘non-Guam’ individuals designated as CRB-G (clade I) by partial mtCOI assessment. Two alternative ATP6 and COIII partial gene primer sets were developed to enable distinction between CRB (clade I) that invaded Guam and CRB-G (Clade I) individuals collected elsewhere. Phylogenetic analyses based on concatenated ATP6-COIII genes showed that only Guam CRB-G (clade I) individuals clustered together, and therefore Guam was not the source of the CRB that invaded the other locations in the Pacific assessed in this study. The use of the mtCOI and/or mtCOIII genes for initial molecular diagnosis of CRB remained crucial, and assessment of more native CRB populations will further advance our ability to identify the provenance of CRB invasions being reported within the Pacific and elsewhere

There is a need to develop tools for mastitis management in goats and to measure the effects of milking machines on teats. Infrared thermography (IRT), as shown in cows, was a good candidate for early detection of mastitis and focusing on milking equipment and settings implicated in potential problems. The aim of this study was to test IRT to detect udder inflammation and the effects of mechanical milking on teats in relation to inflammation status, udder balance and teat shape in Alpine goats. IRT spectra were compared before and after milking in 551 goats from three commercial herds compared to their individual SCC (somatic cell count). We found no regression or trend between logSCC and IRT measurement or response to milking, even in highly inflamed goat udders. The effect of milking was significant (P

The apple leaf-curling midge, Dasineura mali Kieffer (Diptera: Cecidomyiidae), is an invasive pest of apple. To provide crucial information for its pest risk analysis, forecast and management, we investigated the effects of temperatures (5, 10, 15, 20 and 25°C) and daylengths (10, 11, 12, 13, 14 and 15 hrs) on its development and survival. The midge could not complete its development at 10°C or lower. After transferred from 20°C to 10°C, mature larvae could survive for about two months and develop to adults. Pupation and emergence rates were significantly higher at 20°C than at 10°C and 25°C. Daylength had no effect on these parameters. The low temperature threshold and thermal requirement to complete development from eggs to adults were 3.7°C and 627 degree-days, respectively. The midge had significantly lower thermal requirement for completion of its lifecycle at 20°C (614.5 degree-days) than at 15°C (650.1 degree-days) and 25°C (634.8 degree-days). The thermal model developed in this study provided accurate predictions of the number of D. mali generations and adult emergence time in each generation in different regions of New Zealand. We suggest that the model could be used to predict population dynamics of this pest in other parts of the world.

The ongoing exponential growth of human population poses a risk to sustainable development goals (SDGs). Unless we understand the drivers of this growth and inform policy development accordingly, SDGs would remain a dream. One of the old theories of population growth known as the Malthusian theory predicts that resource availability drives population growth to a certain time when population growth outrun resource availability, leading to all sort of crises known as Malthusian crisis. Although the link between economic growth and population has been widely investigated while testing the theory, little is known about environmental and social factors po-tentially driving population growth. Here, because of various crises of our time recalling the Malthusian crisis, we revisited the theory by fitting structural equation models to environmental, social and economic data collected over 30-year period in South Africa. None of the social varia-bles tested predicts population growth. Instead, we found that biodiversity (species protection index) correlates positively with population growth. Biodiversity provides various resources through ecosystem goods and services to human, thus supporting population growth as pre-dicted in the Malthusian theory. However, we also found that this population growth may lead to conservation conflict as we found that biodiversity habitat (wetland area) correlates negatively with population growth, thus raising the compromising effect of population growth on life on earth. What’s more, we found a significant link between economic growth measured as GDP and population growth, further supporting the Malthusian prediction. Overall, our study re-affirms the value of biodiversity to human and suggests that the Malthusian theory should continuously be tested with predictors other than economic.

Ordinary computing machines prohibit self-reference because it leads to logical inconsistencies and undecidability. In contrast, the human mind can understand self-referential statements without necessitating physically impossible brain states. Why can the brain make sense of self-reference? Here, we address this question by defining the Strange Loop Model, which features causal feedback between two brain modules, and circumvents the paradoxes of self-reference and negation by unfolding the inconsistency in time. We also argue that the metastable dynamics of the brain inhibit and terminate unhalting inferences. Finally, we show that the representation of logical inconsistencies in the Strange Loop Model leads to causal incongruence between brain subsystems in Integrated Information Theory.

Antibiotic-sparing treatments are required to prevent the further emergence of anti-microbial resistance in Neisseria gonorrhoeae. Commensal Neisseria species have previously been found to inhibit the growth of pathogenic Neisseria species. For example, a previous study found that 3 out of 5 historical isolates of Neisseria mucosa could inhibit the growth of N. gonorrhoeae. In this study, we used agar overlay assays to assess if 24 circulating and historical isolates of Neisseria mucosa could inhibit the growth of 28 circulating and historical isolates of N. gonorrhoeae. Although pitting around each colony of N. mucosa created an optical illusion of decreased growth of N. gonorrhoeae, we found no evidence of inhibition (n=24). In contrast, positive controls of Streptococcus pneumoniae and Escherichia coli demonstrated a strong inhibitory effect against the growth of N. gonorrhoeae.

Coronaviruses are pathogens recognized for having an animal origin, commonly associated with terrestrial environments. However, although in a few cases, there are reports of their presence in aquatic organisms like fish, frogs, waterfowls and marine mammals. None of these cases has led to human health effects when contact with these infected organisms has taken place, whether they are alive or dead. Aquatic birds seem to be the main group carrying and circulating these types of viruses among healthy bird populations. Although the route of infection for CoVID-19 by water or aquatic organisms has not yet been observed in the wild, the relevance of its study is highlighted because there are cases of other viral infections known to have been transferred to humans by aquatic biota. It is encouraging to know that aquatic species, such as fish, marine mammals, and amphibians, shows very few cases of coronaviruses and that some other aquatic animals may also be a possible source of cure or treatment against then, as some evidence with algae and marine sponges suggest.

Global teacher shortage is a serious concern with grave implications for the future of education. This calls for novel ways of addressing teacher roles. The economic benefits of tireless labour inspires the need for teachers who are unlimited by natural human demands, highlighting consideration for the affordances of robotics and Artificial Intelligence in Education (AIED) as currently obtainable in other areas of human life. This however demands designing robotic personalities that can take on independent teacher roles despite strong opinions that robots will not be able to fully replace humans in the classroom of the future. In this paper, we argue for a future classroom with independent robot teachers, highlighting the minimum capabilities required of such personalities in terms of personality, instructional delivery, social interaction and affect. We describe our project on the design of a robot teacher based on these. Possible directions for future system development and studies are highlighted.

Dual-energy CT (DECT) imaging has broadened the potential of CT imaging by offering multiple postprocessing datasets with a single acquisition at more than one energy level. DECT shows profound capabilities to improve diagnosis based on its superior material differentiation and its quantitative value. However, the potential of dual energy imaging remains relatively untapped, possibly due to its intricate workflow and intrinsic technical limitations of DECT. Knowing the clinical advantages of dual-energy imaging and recognizing its limitations and pitfalls is neces-sary for an appropriate clinical use. The aims of this paper are to review physical and technical basis of DECT acquisition and analysis, to discuss advantages and limitations of DECT in dif-ferent clinical scenarios, to review technical constraints in material labeling and quantification, and to evaluate cutting-edge applications of DECT imaging, including artificial intelligence, qualitative and quantitative imaging biomarkers, and DECT-derived radiomics and radioge-nomics

Hypoxia can induce pulmonary edema (PE) and inflammation. Furthermore, hypoxia depresses left ventricular (LV) inotropy despite sympathetic activation. Here, we investigated the role of nitrosative stress and cardiovascular dysfunction in hypoxic lung injury. Additionally, we studied effects of adrenergic blockade (AB) on hypoxia-induced pulmonary injury. Eighty-six female rats were exposed for 72 h to normoxia or normobaric hypoxia and received infusions with NaCl, prazosin, propranolol or prazosin-propranolol combination. We evaluated hemodynamic function and performed histological and immunohistochemical analyses of the lung. Hypoxia significantly depressed LV but not right ventricular (RV) inotropic and lusitropic functions. AB significantly decreased LV function both in normoxia and hypoxia. AB effects on RV were weaker. Hypoxic rats showed signs of moderate PE and inflammation. This was accompanied by elevated levels of tumor necrosis factor (TNF)  and nitrotyrosine, a marker of nitrosative stress in the lungs. In hypoxia, all types of AB significantly reduced both TNF and nitrotyrosine to normoxic levels. However, AB did not attenuate PE. Results suggest that hypoxia-induced sympathetic activation contributes to inflammation and nitrosative stress in the lungs but not to PE. We suggest that AB in hypoxia aggravates hypoxia-induced inotropic LV dysfunction and backlog into pulmonary circulation, thus promoting PE.

The glycosaminoglycan, heparan sulphate (HS), orchestrates many developmental processes. Yet its biological role has not yet fully been elucidated. Small molecule chemical inhibitors can be used to perturb HS function and these compounds pro-vide cheap alternatives to genetic manipulation methods. However, existing chemical inhibition methods for HS also interfere with chondroitin sulphate (CS), complicating data interpretation of HS function. Herein, a simple method for the selective inhibition of HS biosynthesis is described. Using endogenous metabolic sugar pathways, Ac4GalNAz produces UDP-GlcNAz, which can target HS synthesis. Cell treatment with Ac4GalNAz resulted in defective chain elongation of the polymer and decreased HS expression. Conversely, no adverse effect on CS production was observed. The inhibition was transient and dose-dependent, affording rescue of HS expression after removal of the unnatural azido sugar. The utility of inhibition is demonstrated in cell culture and in whole or-ganisms, demonstrating that this small molecule can be used as a tool for HS inhibition in biological systems.

To assess AR’s role in TNBC treatment, various existing and completed clinical trials targeting AR or co-targeting AR with other pertinent signaling molecules were analyzed. Cyclin-dependent kinase 4/6 (CDK4/6), cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17 lyase), and the phosphatidylinositol 3kinase (PI3K)/protein kinase B (AKT) signaling pathway were some of the most prevalent biomarkers used in combination therapy with AR inhibitors in these trials. Studying how AR functions in tandem with these molecules can have increasing breakthroughs in the treatment options for TNBC. Previous studies have been largely unsuccessful in utilizing AR as the sole drug target for systemic targeted treatment in TNBC. However, there is a lack of other commonly used drug target biomarkers in the treatment of this disease, as well. Thus, analyzing the clinical benefit rate (CBR) within clinical trials that are using combination therapy can prove to be imperative to the progression of improving treatment options and prognoses.

Intracortical microelectrode arrays (MEAs) can be used in a range of applications, from basic neuroscience research to providing an intimate interface with the brain as part of a Brain-Computer Interface (BCI) system aimed to restore function for people living with neurological disorders or injuries. Unfortunately, MEAs tend to fail prematurely, leading to a loss in functionality for many applications. An important contributing factor in MEA failure is oxidative stress resulting from chronically inflammatory-activated microglia and macrophages releasing reactive oxygen species (ROS) around the implant site. Antioxidants offer a means for mitigating oxidative stress and improving tissue health and MEA performance. Here, we investigate using the clinically available antioxidant dimethyl fumarate (DMF) to reduce the neuroinflammatory response and improve MEA performance in a rat MEA model. Daily treatment of DMF for 16 weeks resulted in a significant improvement in the recording capabilities of MEA devices during the sub-chronic (Weeks 5-11) phase (42% active electrode yield vs. 35% for control). However, these sub-chronic improvements were lost in the chronic implantation phase, as a more exacerbated neuroinflammatory response occurs in DMF-treated animals by 16 weeks post-implantation. Yet, neuroinflammation was indiscriminate between treatment and control groups during the sub-chronic phase. Although worse for chronic use, a temporary improvement (&lt;12 weeks) in MEA performance is meaningful. Providing short-term improvement to MEA devices using DMF can allow for improved use for limited-duration studies. Further efforts should be taken to explore the mechanism behind a worsened neuroinflammatory response at the 16-week time point for DMF-treated animals to assess its usefulness to specific applications.

The aim of the present study was to investigate the acute effect of caffeine supplementation on performance in official soccer matches. In double-blind, randomized crossover design, 13 professional soccer players performed two complete matches, with Caffeine (CAF) (6 mg/kg) and placebo (PLA) supplementation. Two-way repeated measures ANOVA showed that there was no effect of supplementation on the total distance covered (p = 0.536; ŋp² =0.033) or the total distance covered at different speeds (p = 0.453; ŋp² = 0.048), acceleration or deceleration (p = 0.387; ŋp² = 0.063) number of sprints (p = 0.521; µ² = 0.035) Heart Rate mean (p = 0.484; ŋp² = 0.042) Heart Rate maximum (p = 0.110; ŋp² = 0.199), Rate Perceived Effort (p = 0.151) or efficiency index (p = 0.480). Therefore, acute caffeine supplementation not effective to increase the performance of soccer players in official matches.

All life on Earth uses three integrated molecular systems in which genetic information contained in DNA base sequences is transmitted to ribosomes by RNA and a genetic code, then translated into the amino acid sequences of structural and catalytic proteins. Therefore, the most important point for understanding the origin of life is to determine how such systems could emerge from random processes on the early Earth. In this review, two alternatives are compared: the RNA world hypothesis and the [GADV]-protein world hypothesis. [GADV] refers to four amino acids, Gly [G], Ala [A], Asp [D] and Val [V] that are conserved in the amino acid sequences of many common proteins. Here I will argue that the origins of the three primary processes required for life to begin can be better explained by the GADV hypothesis than the RNA world hypothesis. The GADV hypothesis also incorporates a conversion process by which random polymers can evolve into proteins with ordered sequences.

Entheseal spinal inflammation and new bone formation with progressive ankylosis may occur in ankylosing spondylitis (AS) and psoriatic arthritis (PsA). This study evaluated whether JAK inhibition with tofacitinib modulated the key disease associated cytokines, TNF and IL-17A and whether tofacitinib also modulated bone marrow stromal cell-derived mesenchymal stem cells (MSCs) function including osteogenesis, since post inflammation new bone formation occurs in these conditions. Methods: Conventional entheseal derived αβ CD4+ and CD8+ T-cells were in-vestigated following anti-CD3/CD28 bead stimulation to determine IL-17A and TNF levels in Tofacitinib treated (1000nM) peri-entheseal bone (PEB) and peripheral blood mononuclear cells (PBMC) following ELISA. Bone marrow stromal cell-derived mesenchymal stem cells (MSCs) colony forming unit (CFU-F) and multilineage potential was evaluated using tofacitinib (dosag-es ranging between 100, 500, 1000 and 10000nM). Results: Induced IL-17A and TNF cytokine production from both entheseal CD4+ T-cells and CD8+ T-cells were effectively inhibited by to-facitinib. Tofacitinib treatment did not impact on CFU-F potential or in vitro chondro- and oste-ogenesis. However, tofacitinib stimulation increased MSC adipogenic potential with greater Oil Red O stained area. Conclusion: Inducible IL-17A and TNF production by healthy human enthe-seal CD4+ and CD8+ T-cells was robustly inhibited in vitro by tofacitinib. However, tofacitinib did not impact on MSC osteogenesis but stimulated in vitro MSC adipogenesis, the rele-vance of which needs further evaluation given the adipocytes are associated with new bone formation in SpA.

Neurodegeneration with brain iron accumulation (NBIA) is a group of rare neurogenetic dis-orders frequently associated with iron accumulation in the basal nuclei of the brain. Among NBIA subtypes, β -propeller protein-associated neurodegeneration (BPAN) is associated with mutations in the autophagy gene WDR45. The aim of this study was to demonstrate autophagic defects and secondary pathological con-sequences in cellular models derived from two patient harboring WDR45 mutations. Both protein and mRNA expression levels of WDR45 were decreased in patient-derived fibro-blasts. In addition, the increase of LC3B upon treatments with autophagy inducers or inhibitors was lower in mutant cells compared to control cells, suggesting decreased autophagosome formation and impaired autophagic flux. Transmission electron microscopy (TEM) analysis showed mitochondrial vacuolization associated with accumulation of lipofuscin-like aggregates containing undegraded material. Autophagy dysregulation was also associated with iron ac-cumulation and lipid peroxidation. In addition, mutant fibroblasts showed altered mitochon-drial bioenergetics. Antioxidants such as pantothenate, vitamin E and α-lipoic prevented lipid peroxidation and iron accumulation. However, antioxidants were not able to correct the ex-pression levels of WDR45 neither the autophagy defect nor cell bioenergetics. Our study demonstrated that WDR45 mutations in BPAN cellular models impaired autophagy, iron metabolism and cell bioenergetics. Antioxidant partially improved cell physiopathology, however autophagy and cell bioenergetics remained affected.

Introduction & Objectives: Blood cells-(BC)count derived parameters have been inves-tigated in systemic inflammation, cancer, and various cutaneous diseases. Little is known about their usefulness in trichology, especially as prognostic and therapeutic biomarkers. We conducted a retrospective study on patients with not-cicatricial alopecia to assess differences in BC-count. Materials & Methods: Patients with alopecia areata (AA), telogen effluvium (TE), androgenic alopecia (AGA), psoriasis and hidradenitis suppurativa (HS) were included in the study. Baseline complete BC-count and derived parameters (i.e. NLR, PLR, MLR, SII; PIV) were recorded and analyzed for each patient and at different timepoints for AA patients on systemic agents. Results: 170 patients fulfilled inclusion criteria. BC-count and derived values were similar across the not-cicatricial alopecia groups, while general differences were observed compared to psoriasis and HS. TE displayed a closer inflammatory signature to psoriasis with respect to CRP, NLR, MLR, SII and PIV. We also found a significant reduction in RBCs in severe versus patchy-AA and an increase of SII in acute versus chronic AA. Modulation of platelet number and volume could be used as therapeutic marker in AA. Conclusions: In our experience, the BC-count and its derived parameters could represent potential tools in AA and TE.

Soil sodicity is a major constraint to seedling emergence and crop production, potentially reducing plant growth due to physical and chemical constraints. Examining responses to ion imbalances may assist in the identification of genotypes tolerant to chemical constraints in sodic soils and improve productivity. We evaluated the performance of four wheat (Triticum aestivum. L) genotypes in solutions with five sodium adsorption ratios (SARs) ranging from 0 to 60. For all four genotypes, seedling emergence and shoot dry matter (DM) decreased significantly with increasing SAR. A significant positive correlation was observed between Ca concentration in roots, as well as both root and shoot DM for all genotypes. At SAR values &gt;20, a more tolerant genotype (EGA Gregory), had higher Ca concentrations in root tissues, while a more sensitive genotype (Baxter) exhibited Na-induced Ca deficiency. Thus, selection for genotypes that are able to accumulate Ca in roots in sodic conditions may be a useful trait for selecting genotypes tolerant of soils with high ESP values. However, for soils that restrict plant growth at ESP (SAR) values of 6-10%, it is likely that growth is restricted by physical constraints rather than by a Na-induced Ca deficiency.

This study assessed the acute effects of oral methylliberine (DynamineTM) supplementation on cognitive function and indices of well-being. This was a double-blind, randomized, within-subject crossover trial. 25 healthy men and women (33.5±10.7yr, 172.7±8.6cm, 73.3±11.0kg) underwent pretesting before ingesting methylliberine (100mg) or placebo (PLA) for 3 days. On the fourth day participants were tested before their 4th dose (baseline) and every hour post-ingestion for 3 hours. After a one-week washout period, participants repeated testing with the alternate investigational product. The testing battery consisted of vitals, Stroop test and Trail Making Test-B, and visual analog scales that assessed various indices of well-being. Mixed factorial ANOVA with repeated measures were used to assess all variables. There were significant (p≤0.050) interactions in concentration, motivation, and mood. Methylliberine improved concentration 1- and 3-hours, motivation 3 hours, and mood 1-, 2-, and 3 hours (p≤0.050). Methylliberine improved energy, sustained energy, and mood in all participants to a greater extent than PLA at 1-hour and 3-hours relative to baseline (p≤0.050). PLA improved motivation at 1- and 2-hours and mood at 2-hours (p≤0.050). Methylliberine improved concentration, well-being, and the ability to tolerate stress to a greater extent than PLA at 3-hours relative to baseline (p≤0.050). Women observed elevations in sustained energy 1- and 3-hours (p≤0.050) in methylliberine vs. PLA. Methylliberine had negligible influence on cognitive function, vitals (p>0.050), and no adverse events were reported. Methylliberine significantly improved subjective feelings of energy, concentration, motivation, and mood, but not cognitive function. PLA improved motivation and mood at hours 1 and 2, while methylliberine sustained benefits for longer. Methylliberine also improved concentration, well-being, and the ability to tolerate stress to a greater degree than PLA while having no detrimental effects on vital signs. Methylliberine also seems to have a positive impact on sustained energy in women.

Background: The frequency of visits to restaurants has been suggested to contribute to the pandemic of obesity. However, few studies have examined how individual use of these restaurants is related to BMI using new technology of reminding to avoid memory error. Aim: To investigate the association between the usage of different types of food outlets and BMI among adults in Scotland. Method: The study was cross-sectional. Participants (n = 681) completed an online survey for seven consecutive days where all food purchased at food outlets was reported each day. We explored the relationship between BMI and usage of these restaurants using auto-reminder text system. Results: Body Mass Index (BMI) of both males and females was not related to frequency of use of Full-Service Restaurants (FSRs), Fast Food Restaurants (FFRs), delivery or takeaways, when assessed individually, or combined (TFO= Total Food Outlet). Conclusion: These data do not support the widespread belief that consumption of food out of the home at fast-food and full-service restaurants, combined with that derived from deliveries and takeaways, is a major driver of obesity in UK.

Sexual Issues played a significant role in Judaism’s engagement with its Greco-Roman world. This paper will examine that engagement in the Hellenistic Greco-Roman era to the end of the first century CE. In part sexual issues were a key element of demarcation between Jews and the wider community, alongside such matters as circumcision, food laws, sabbath keeping and idolatry. Jewish writers, such as Philo of Alexandria, make much of the alleged sexual profligacy of their Gentile contemporaries, not least in association with wild drunken parties, same-sex relations and pederasty. Jews, including the emerging Christian movement, claimed the moral high ground. In part, however, matters of sexuality were also areas where intercultural influence is evident, such as in the shift in Jewish tradition from polygyny to monogyny, but also in the way Jewish and Christian writers adapted the suspicion and sometimes rejection of passions characteristic of some popular philosophies of their day, seeing them as allies in their moral crusade.

The purpose of this study is to examine the self-esteem levels of visually handicapped individuals who do sports and do’t do sports. There were 106 sportsmen and 94 persons with visual handicapped (200 in total) who participated in the research clubs in the province of Izmir. As the sub-problems, the relationship between the genders of participant who visually handicapped and not visually handicapped was investigated. The study consists of two parts. In the first part, the demographic characteristics of the participants were determined; in the second part Rosenberg Self Value scale consisting of 10 questions was used. Data were analyzed with SPSS 18.00 package program. T test, correlation analysis, descriptive statistics were applied to test hypotheses of the study. The research found that there is a significant difference between the self-esteem levels of individuals with and without visually handicapped sports (P <0.05). No statistically significant difference was found between the self-esteem levels of the sportsmen and the sportswomen (P> 0,05). There was no significant difference in the self-esteem levels of visually handicapped individuals who played individual sports and team sports (P> 0,05). As a result, it has been seen that sports have a positive effect on self-esteem in visually handicapped individuals and they contribute and hold to life more meaningful.

Then the purposes of this study were to compare and correlate the aerobic threshold (TH_aer) and anaerobic threshold (TH_anaer) measured during a new single judo specific incremental test and Treadmill Test for aerobic demand evaluation. Eight well-trained male competitive judo players (24.3±7.9 years; height of 169.3±6.7cm; fat mass of 12.7±3.9%) performed a maximal incremental specific test for judo mimicking the UchiKomi drills and on treadmill in different days. There was difference between specific and general TH_aer (P=0.0006) as well as weak correlation for TH_aer (r=0.32; R²=0.1; P=0.2) and TH_anaer (rs=-0.31; R²=0.1; P=0.12). When correlation was applied with normalized data (percentage of peak load) we observed moderate correlation for TH_aer (r=0.76; R²=0.58; P=0.027), but the same was not observed for TH_anaer. We conclude that there is a need of TH_aer and TH_anaer evaluation through a specific test for Judo.

Overactive bladder (OAB) is characterized by urinary urgency and increased urinary frequency, and can impact quality of life significantly. Tamsulosin and mirabegron combination therapy has been studied as a safe and effective treatment option for patients with OAB. This study evaluated the effects of combining these two drugs on their pharmacokinetics and safety profiles in healthy Korean males. In this open-label, fixed-sequence, 3-period, drug-drug interaction phase 1 study, a total of 36 male participants were administered multiple doses of tamsulosin alone (0.2 mg once daily), mirabegron alone (50 mg once daily), and a combination of both drugs. The results showed that the combination of tamsulosin and mirabegron increased tamsulosin exposure in the plasma by approximately 40%. In contrast, the maximum plasma concentration of mirabegron reduced by approximately 17%, when administered along with tamsulosin. No clinically significant changes in safety profiles, vital signs, or clinical laboratory test results were observed in this study. In conclusion, there were no clinically relevant drug-drug interactions between tamsulosin and mirabegron in terms of pharmacokinetics, safety, and tolerability, suggesting that their combination therapy could be a promising treatment option for patients with OAB.

Reactive oxygen species (ROS) play an important role in biological processes and offer hope for the development of effective treatments for ROS-dependent diseases, including cancer. The interaction of hydrogen peroxide with proteins stimulates the creation of chemical molecules that can weaken or stop the pathological process in cancer. However, reliable drugs have not yet been described. To understand the reason for the failure, we studied the behavior of ROS-containing compounds in cancer cells. The epidermal growth factor receptor (EGFR) is activated by interaction with a ligand protein, as well as by binding the chemical structure of hydrogen peroxide to the catalytic cysteine in the intracellular domain. Both mechanisms trigger signaling pathways in cells. The EGFR can be inactivated by protein tyrosinase phosphatase PTP-1B, which itself is activated by hydrogen peroxide. A simple in-gel fluorescence technique was used to demonstrate the rapid binding of hydrogen peroxide to a large number of proteins, including both activating and inactivating target proteins. Natural defense systems take longer to action and apparently cannot prevent hydrogen peroxide from binding to protect cells from exposure to unwanted proteins. Therefore, superoxide dismutase, which produces hydrogen peroxide, is not a suitable target for disease therapy.

Machine learning models are increasingly being used in critical domains, but their complexity, lack of transparency, and poor interpretability remain problematic. Decision trees (DTs) and rule-based approaches are well-known examples of interpretable models, and numerous studies have investigated techniques for approximating tree ensembles using DTs or rule sets; however, tree ensemble approximators do not consider interpretability. These methods are known to generate three main types of rule sets: DT-based, unordered-based, and decision list-based. However, no known metric has been devised to distinguish and compare these rule sets. Therefore, the present study proposes an interpretability metric to allow comparisons of interpretability between different rule sets, such as decision list- and DT-based rule sets, and investigates the interpretability of the rules generated by the tree ensemble approximators. To provide new insights into the reasons why decision list-based and inspired classifiers do not work well for categorical datasets consisting of mainly nominal attributes, we compare objective metrics and rule sets generated by the tree ensemble approximators and the \textit{Recursive-Rule eXtraction algorithm (Re-RX) with J48graft}. The results indicated that \textit{Re-RX with J48graft} can handle categorical and numerical attributes separately, has simple rules, and achieves high interpretability, even when the number of rules is large.

Background: Neuromuscular electrical stimulation (NMES) has beneficial effects on physical functions in Multiple Sclerosis (MS) patients. However, the neurophysiological mechanisms underlying these functional improvements are still unclear. This study aims at comparing acute responses in spinal excitability, as measured by soleus Hoffmann reflex (H-reflex), between MS patients and healthy individuals, following three experimental conditions involving the ankle planta flexor muscles: 1) passive NMES (pNMES); 2) NMES superimposed to isometric voluntary contraction (NMES+); and 3) isometric voluntary contraction (ISO). Methods: 20 MS patients (MSp) and 20 healthy individuals as control group (CG) took part in a single experimental session. During each condition, participants performed 15 repetitions of 6 seconds at 20% of maximal voluntary isometric contraction, with 6 seconds of recovery between repetitions. Before and after each condition, H-reflex amplitudes were recorded. Results: In MSp, H-reflex amplitude did not change following any experimental condition (ISO: p = 0.506; pNMES: p = 0.068; NMES+: p = 0.126). In CG, H-reflex amplitude significantly increased following NMES+ (p = 0.01), decreased after pNMES (p = 0.000) and was unaltered following ISO (p = 0.829). Conclusion: the different H-reflex responses between MS and CG might reflect a reduced ability of MS patients in modulating spinal excitability.

Cardiac development is a complex developmental process that results in the formation of the four-chambered organ from a single linear heart tube. In the early stages of development, the linear heart tube is composed of only two tissue layers, an external myocardium that is internally lined by the endocardium. Subsequently, the proepicardium emerges at the septum transversum and soon thereafter proepicardial cells will migrate into the naked myocardium, leading to the formation of the embryonic epicardium. As cardiac development proceeds, epicardial-derived cells migrate into the subepicardial space and subsequently invade the developing ventricular chambers leading to the contribution of distinct cardiovascular cell types such as the cardiac fibroskeleton and different components of coronary vasculature. At present, the molecular mechanisms that regulate the transitional process from the proepicardium to the embryonic myocardium are largely unexplored. In this study we have implemented an ex vivo proepicardium/septum transversum (PE/ST)-embryonic myocardium explant model and we demonstrated that miR-223, but not miR-195, is capable of modulating PE/ST migration, a process that seems to be mediated by Slug expression. Thus, our study demonstrates for the first time the implication of distinct microRNAs in the PE/ST to embryonic myocardium transition in chicken embryonic hearts.

Hepatic hemangiomas (HH) are the most frequent benign tumors of the liver. They are usually asymptomatic and small in size. However, others can present as large tumors and can be symptomatic. In this case surgical resection is recomemend. We present a case report for treatment in our hospital. A 48 years old male, who was brought to the emergency room complaining of vomiting and pain in the right upper quadrant that had been going on for 8 years. The examination showed a firm mass in the right hypochondrium that extended below the umbilicus. The ultrasound (US) reported severe hepatomegaly secondary to giant hypoechoic lesions. The study was completed with a computed tomography scan (CT-scan) or Magnetic resonance imaging (MRI). This case was evaluated by a multi - disciplinary team, who decided to do a liver transplant. After three months signed up on the waiting list,the patient finally received a new liver from a matched brain - dead organ donor. In this case the surgery was completed with caval - preserving Piggy - back implant technique, without the need of a classic technique nor a veno - venous bypass. He received a transfusion of 8 units of packed red blood cells during the operation. The postoperative time passed with good evaluation. Patient went back home after 14 days in the hospital. The pathology report showed a giant multifocal hemangioma, with a size of 28 x 19 x 15 cms. Some HH needs surgery, there are different options: simple enucleation to complete hepatectomy associating liver transplant as our case. The correct treatment is too important, and these case have to be tried with multi - disciplinary team. This group is composed of hepatobiliary surgeons, hepatologists and anesthetists. The bleeding massive risk is large, so it is necessary to know the clasic surgery technique.

Global research on the Covid-19 vaccine’s effectiveness is using methods that are misleading the scientific community and public opinion. There is a golden rule in medicine: to measure the effectiveness of an experimental medicine you need to have two groups. The group that will take medicine and the group that will not take medicine. You follow the health status of both groups for a few months and you will get objective results. This is the only proper methodology to verify the effectiveness of a new medicine. Articles cited from 1-5 did not use the gold rule. They develop different kinds of methodologies that all have no statistical significance. On the basis of their methodologies, they conclude that Covid-19 vaccines have a positive effect on public health. By comparing graphs of the intensity of vaccination and the rate of mortality we see that after the period of intense vaccination follows the period of higher excess mortality. Basic statistical data are confirming that Covid-19 vaccines increased the mortality rate.

The endomembrane system in plant cells enables the cell to manage and coordinate a variety of membranous compartments so that they and their contents arrive at the right location. The secretory pathway takes part in this complex network and has its gateway at the Endoplasmic Reticulum. Therefore, alterations at the Endoplasmic reticulum level could condition how protein trafficking takes place or, at least, influence how such cargo leaves this organelle. With this work, we intended to assess how abnormalities at the Endoplasmic Reticulum would interfere with protein sorting and trafficking. Thus, we used a novel Arabidopsis mutant - leb-2 GFP-h -, presenting ER morphology alterations. Our results show that alterations in the leb-2 GFP-h mutant did not disrupt PSI A/B–mCherry transport to the vacuole but influences the expression of endogenous aspartic proteinases. Furthermore, the study of key-endomembrane genes expression revealed an upregulation of the SNAREs AtVAMP722 and AtVAMP723. As a whole, the leb-2 mutant seems not to interfere with vacuolar routes but may be implicated in secretion events.

Glyphosate (G)-based herbicidal formulations, such as the most commonly used one, Roundup (R), are major pesticides used worldwide on food and feed. Pregnant women may thus be frequently exposed to R compounds. These are composed of G, which is declared as the active principle, and other products contained in formulations, named formulants, which have been declared as inerts and diluents by the manufacturers. These formulants have, in fact, been demonstrated to be much more toxic than G, in particular to placental and embryonic human cells. In this work, we thus compared the effect of G and R, using placental perfusion ex vivo. R, but not G alone, was demonstrated to alter the placental permeability of a known small model molecule, antipyrine. Similar results were observed for the fetal venous flow rate. The transfer of G alone increases with time, but is significantly decreased in presence of its formulants. The perfusion of R provokes a destruction of fetal vessels, as demonstrated by immunohistochemistry. Formulants obviously alter the fetal-placental circulation and placental integrity according to time of exposure. Therefore, G does not appear to be the main toxic agent of R. Formulants, although undeclared, include polyoxyethanolamines, PAHs, or heavy metals, and may be responsible for this toxicity. These compounds are also present in other pesticides. The progressive blood flow reduction due to the toxic compounds of formulations may diminish the nutrient supply to the fetus, alter the development, and may enhance the poisoning effects. Although these are preliminary results, they could at least partially explain some adverse pregnancy outcomes in mothers exposed to pesticides or other environmental pollutants. The debate on glyphosate alone is proven insufficient for the understanding of the toxicity.