The effective integration of aerial remote sensing data and ground multi-source data has always been one of the difficulties of quantitative remote sensing. A new monitoring mode is designed which installs the hyperspectral imager on the UAV and places a buoy spectrometer on the river. Water samples are collected simultaneously to obtain in situ assay data of total phosphorus, total nitrogen, COD, turbidity and chlorophyll during data collection. The cross correlogram spectral matching (CCSM) algorithm is used to match the data of the buoy spectrometer with the UAV spectral data to reduce the UAV data noise significantly. An absorption characteristics recognition algorithm (ACR) is designed to realize a new method for comparing UAV data with laboratory data. This method takes into account the spectral characteristics and the correlation characteristics of test data synchronously. It is concluded that the most accurate water quality parameters can be calculated by using the regression method under five scales after the regression tests of multiple linear regression method (MLR), support vector machine method (SVM) and neural network (NN) method. This new working mode of integrating spectral imager data with point spectrometer data will become a trend in water quality monitoring.

As an extraordinarily diverse group of bacteria, lactobacilli are now placed in several genera which names still contain “lactobacillus” in their core. Despite the names, this group of the lactic acid bacteria comprises microorganisms which are very important for our life especially in early development of the human microbiota and immune system. The interactions of the lactobacilli with elements of the mucosal immunity leads to its shaping and development, which is recognized as a potential driving force in the evolution of the human immune system. Although most of the evidence supporting the idea of the leading role of lactobacilli in housekeeping of the human health derives from articles on probiotics aiming to elucidate mechanisms of their functional activities and studies on mucosal immunity on germ-free mice, it is justifiable to extend observations on properties of the individual probiotic Lactobacillus related to health benefits onto other strains sharing common characteristic of the species. In this review, we will discuss acquisition, presence and functions of lactobacilli in different human microbiota throughout the whole life including those arising in amnion and their interactions with mucosal and immune cells. Examples of immune system modulation by probiotic lactobacilli due to competition for available nutrients in the colon, colonization site interference, and competition for binding sites on gut epithelial cells, production of bacteriocin, lowering of colonic pH, and nonspecific stimulation of the immune system will be shown.

From their discovery in 2002, BRAF mutations have been identified as clear drivers of oncogenesis in several cancer types. Currently, their incidence rate is nearly 7% of all solid tumors with BRAF V600E constituting approximately 90% of these diagnoses [1]. In melanoma, thyroid cancer, and histiocytic neoplasms, BRAF hotspot mutations are found at a rate of about 50%, while in lung and colorectal cancers they range from 3 to 10% of reported cases [2-5]. Though present in other malignancies such as breast and ovarian cancers, they constitute a small portion of diagnoses (<1%). Given their frequency along with advancements in screening technologies, various methods are used for the detection of BRAF-mutant cancers. Among these are targeted next-generation sequencing (NGS) on tumor tissue or circulating tumor DNA (ctDNA) and immunohistochemistry (IHC)-based assays. With advancements in detection technologies, several approaches have been taken for the treatment of BRAF mutant cancers. In this review we retrace the milestones that led to the clinical development of targeted therapies currently available for these tumors.

Breast cancer represents the most frequent cancer and the leading cause of cancer death among women. Thus, the prevention and early diagnosis of breast cancer appears to be of primary urgency as well as the development of new treatments able to improve its prognosis. Nerve Growth Factor (NGF) is a neurotrophic factor that plays a key role in the regulation of neuronal functions thought the binding to the Tropomyosin receptor kinase A (TrkA) and the Nerve Growth Factor receptor or Pan-Neurotrophin Receptor 75 (NGFR/p75NTR). Also, its precursor (pro-NGF) can extert biological activity by forming a trimeric complex with NGFR/p75NTR and sortilin or by binding to TrkA receptors with low affinity. Both in vitro and in vivo studies showed that NGF is synthesized and released by breast cancer cells and has mitogen, antiapoptotic and angiogenic effects on these cells through the activation of different signaling cascades that involve TrkA and NGFR/p75NTR receptors. Conversely, pro-NGF signaling has been related to breast cancer invasion and metastasis. Other studies suggested that NGF and its receptors could represent a good diagnostic and prognostic tool, as well as promising therapeutic targets for breast cancer. Here, we comprehensively summarize and systematically review the current experimental evidence on this topic.

Discovery of inhibitors for endothelial-related transcription factors can contribute to the development of angiogenic therapies that treat diseases ranging from cardiovascular to cancer. The role of transcription factor Vezf1 in vascular development and regulation of angiogenesis has been defined by several earlier studies. Through construction of a computational model for Vezf1, work here has identified a novel small molecule drug capable of inhibiting Vezf1 from binding to its cognate DNA binding site. Using structure-based design and virtual screening of the NCI Diversity Compound Library, 12 shortlisted compounds were tested for their ability to interfere with the binding of Vezf1 to DNA using electrophoretic gel mobility shift assays. We identified one compound, T4, which has an IC50 of 20uM. Using murine endothelial cells, MSS31, we tested the effect of T4 on endothelial cell viability and angiogenesis by using tube formation assay. Our data show that addition of T4 in cell culture medium does not affect cell viability at concentrations lower or equal to its IC 50 but strongly inhibits the network formation by MSS31 in the tube formation assays. Given its potential efficacy, this inhibitor has significant therapeutic potential in several human diseases raging from wound healing to cancer.

Smart manufacturing encompasses a category of manufacturing that employs computer-integrated capabilities and technologies to enhance supply chain optimization, production efficiency, and recyclability. Yet limited studies have been conducted to optimize these prospects from the perspective of low resource countries where such innovative studies have not been adequately explored. This paper aims to examine the implications of smart manufacturing practices (Smart Procurement, Smart Supply Chain, Smart Production Planning and Control, Automation and Industrial Robot, and Supply Chain Configuration) on pro-environmental behaviour and develop a baseline moderated mediation model to explain the relationship between smart manufacturing and pro-environmental behaviour with a role of green dynamic capability, and environmental orientation. This study is anchored on quantitative research approach, deductive reasoning, and explanatory design. Cross – sectional survey data have been obtained from 382 manufacturing companies in Ghana. Our hypotheses have been tested using Structural Equation Modelling and SMART-PLS version 3.8.9. The study has revealed that smart manufacturing practices significantly and positively relate to pro-environmental behaviour. Moreover, green dynamic capability and environmental orientation moderate the relationship between smart manufacturing and pro-environmental behaviour. The implications of the study include the emergence of a baseline model to guide policymakers, practitioners, and academicians to explain the relationship between smart manufacturing and sustainable manufacturing in the context of developing countries. Again, the social implication of the study includes the realisation of decent job and economic growth, responsible consumption and production as well as actions taken to combat climate change.

Cancer is a leading cause of death worldwide. It is theorized that underlying genetic and epigenetic changes enable cells to proliferate out of control by escaping regulatory mechanisms. The progression of cancer is associated with increased cell proliferation, metabolic modifications, resistance to apoptosis, genetic instability, induction of angiogenesis and augmented migratory capability. Recent developments in DNA and RNA analysis have made it possible to study these genetic changes systematically. These advances have enabled us to possess a deeper knowledge of the signaling pathways and involved processes. In-depth studies of the pathways involved in carcinogenesis have led to the identification of pathways that may be targeted for therapeutic purposes. In this review, we provide an overview of the relevant mechanisms and pathways involved in the development and progression of cancer.

Matrix metalloproteinase 3 (MMP3) plays multiple roles in pro-tumorigenic proteolysis and in intracellular transcription. These include inducing connective tissue growth factor [CTGF, also known as cellular communication network factor 2 (CCN2)] and prompting a new definition of MMP3 as a moonlighting metalloproteinase. Members of the MMP family have been found within tumor-derived extracellular vesicles (EVs) such as oncosomes or exosomes. We here investigated the roles of MMP3-rich oncosomes in tumor progression, molecular transmission, and gene regulation. MMP3 and CCN2/CTGF were significantly co-expressed in tumor samples derived from patients suffering from colorectal adenocarcinoma. We found that oncosomes derived from a rapidly metastatic colon cancer cells (LuM1) were enriched in MMP3 and a C-terminal half fragment of CCN2/CTGF. MMP3-rich oncosomes were highly transmissive into recipient cells and were pro-tumorigenic in an allograft mouse model. Oncosome-derived MMP3 was transmissive into recipient cell nuclei, trans-activated CCN2/CTGF promoter, and induced CCN2/CTGF production at 1 to 6 hours after the addition of oncosomes to culture media. In addition, CRISPR/Cas9-mediated knockout of MMP3 showed significant anti-tumor effects, including inhibition of migration and invasion of LuM1 cells in vitro, inhibition of tumor growth in vivo, and reduction of CCN2/CTGF and its promoter activity in vitro. These data newly demonstrate that the oncosome-derived moonlighting metalloproteinase promotes metastasis and is pro-tumorigenic at distant sites as well as a transmissive trans-activator for the cellular communication network gene.

Background: Interleukins play dual roles in breast cancer, acting as both promoters and 11 inhibitors of tumorigenesis within the tumor microenvironment, which is shaped by their 12 inflammatory functions. This study analyzed the subtype-specific prognostic significance 13 of anti-inflammatory and pro-inflammatory signatures using microarray-based gene ex- 14 pression analysis. Correlations between these interleukin signatures and immune cell 15 markers (CD8, IgKC, CD20) and immune checkpoints (PD-1) were also evaluated. 16 Materials and Methods: The study investigated the prognostic significance of an anti- 17 inflammatory interleukin signature (IL-12, IL-21, IFN-γ) and a pro-inflammatory interleu- 18 kin signature (IL-4, IL-5, IL-10, IL-13, IL-17, CXCL1) for metastasis-free survival (MFS) 19 using Kaplan-Meier curves and Cox regression analyses in a cohort of 461 patients with 20 early breast cancer. Correlations were analyzed using the Spearman-Rho correlation coef- 21 ficient. 22 Results: Kaplan-Meier curves revealed that the prognostic significance of the anti-inflam- 23 matory signature was specifically pronounced in the basal-like subtype (p=0.004, Log 24 Rank). This signature retained independent prognostic significance in multivariate Cox 25 regression analysis (HR 0.463, 95% CI 0.290-0.741; p=0.001). Higher expression of the anti- 26 inflammatory interleukin signature was associated with longer MFS. The pro-inflamma- 27 tory interleukin signature showed a significant prognostic effect in the whole cohort, with 28 higher expression associated with shorter MFS (p=0.034). Strong correlations were found 29 between the anti-inflammatory signature and CD8 expression (ρ=0.391; p<0.001) and be- 30 tween the pro-inflammatory signature and PD-1 expression (ρ=0.627; p<0.001).

CD74 is a type II cell surface receptor found to be highly expressed in several hematological and solid cancers, due to its ability to activate pathways associated with tumor cell survival and proliferation. Over the past 16 years, CD74 is emerging as a commonly detected fusion partner in multiple oncogenic fusion proteins. Studies have found CD74 fusion proteins in a range of cancers including lung adenocarcinoma, inflammatory breast cancer, and pediatric acute lymphoblastic leukemia. To date, there are five known CD74 fusion proteins, CD74-ROS1, CD74-NTRK1, CD74-NRG1, CD74-NRG2a, and CD74-PDGFRB, with a total of 16 different variants, each with unique genetic signatures. Importantly, the occurrence of CD74 in the formation of fusion proteins has not been well explored despite the fact that ROS1 and NRG1 families utilize CD74 as the primary partner for the formation of oncogenic fusions. Fusion proteins known to be oncogenic drivers, including those of CD74, are typically detected, and targeted after standard chemotherapeutic plans fail and the disease relapses. The analysis reported herein provides insights into early intervention of CD74 fusions and highlight the need for improved routine assessment methods so that targeted therapies can be applied while they are most effective.

Lung cancer accounts for the majority of cancer cases. In recent years, checkpoint inhibitor immunotherapy (ICI) has emerged as a new treatment. A better understanding of the tumor microenvironment, or TMJ, or the immune system surrounding the tumor is needed. Cytokines are small proteins that carry messages between cells and are known to play an important role in the body's response to inflammation and infection. Cytokines are important for immunity in lung cancer. It promotes tumor growth (oncogenic cytokines) or inhibits tumor growth (anti-tumor cytokines) by controlling signaling pathways for growth, proliferation, metastasis, and apoptosis. The immune system relies heavily on cytokines. They can also be produced in the laboratory for therapeutic use. Cytokine therapy helps the immune system stop the growth or kill cancer cells. Interleukins and interferons are two types of cytokines used to treat cancer. This article begins by addressing the role of the tumor microenvironment (TMJ) and its components in lung cancer. This review also highlights the functions of various cytokines such as IL, TGF and TNF.

Delivering effective messages is critical to creating a more sustainable and resilient culture. The explosion of social media has enhanced information access but has often reinforced and polar-ized pre-existing viewpoints and norms. In contrast, digital signs are an “in your face in your space” technology that has the potential to deliver common content to a diverse local audience. Environmental Dashboard (ED) is a communications platform and set of content applications that combines information on current environmental conditions, real-time resource consumption, positive actions being taken by community members, and a community calendar. We conducted a longitudinal study to assess whether ED content delivered via digital signs in public locations would result in desirable psychological changes within a community. Participants completed surveys in six designated signage locations prior to installation (N = 174) and following two years of continuous exposure (N = 133). We observed: increases in pro-environmental social norms among people of color (a demographic emphasized); enhanced awareness of and sense of connection with the local community and ecology; increased self-reported electricity conservation; and increased perception of youth engagement (another demographic emphasized). Changes were mediated by exposure to digital signage. These findings support the hypothesis that content delivered through digital signs can strengthen pro-environmental and pro-social culture within communities.

(1) Background: The rapid development of information technology has changed the traditional concept of space, gradually shifting the "container space" to the "relational space" . The constraints of geographical spatial elements are diminishing, and the theory of virtual agglomeration is gaining attention. (2) Methods: In this study, we constructed an evaluation system for virtual agglomeration, comprising four primary indicators: virtual infrastructure level, virtual output level, virtual input level, and virtual service level. The TOPSIS method was used to calculate the virtual agglomeration level for each province, and the DEA-Malmquist method was employed to measure provincial total factor productivity (TFP) in China. Using panel data from 30 provincial regions in China from 2013 to 2021, we examined the mechanism and impact path of virtual agglomeration on TFP. (3) Result: There is an inverted U-shaped relationship between virtual agglomeration and TFP in China. The overall development level of virtual agglomeration is relatively low, within the range where the marginal effect of virtual agglomeration on TFP is positive but diminishing, indicating significant potential for further development. The impact of virtual agglomeration on TFP is stronger in the Yangtze River Economic Belt compared to non-Yangtze River areas, and the highest stable point of TFP is higher in central provinces than in eastern and western provinces. (4) Conclusions: This study provides a theoretical basis and practical reference for improving the level of virtual agglomeration.

Transcription factor activity of the nuclear respiratory factor 1 protein (NRF1) is increased in breast cancer. Whether this gain of NRF1 activity is directly involved in breast cancer remains unknown. Herein, we report a novel oncogenic function of NRF1 supporting its causative role in breast cancer development and progression. The gain of NRF1 and/or treatment with 17β-estradiol (E2) produced heterogeneous breast cancer stem cells (BCSCs) composed of more than ten distinct cell sub-populations. Flow sorting combined with confocal imaging of markers for pluripotency, epithelial mesenchymal transition (EMT), and BCSCs phenotypically confirmed that the sub-populations of BCSCs arise from cell re-programming. Thus, we determined the molecular actions of NRF1 on its target gene CXCR4 because of its known role in the acquisition of BCSCs through EMT. CXCR4 was activated by NRF1 in a redox dependent manner during malignant transformation. NRF1-induced BCSCs were able to form xenograft tumors in vivo, while inhibiting transcription of CXCR4 prevented xenograft tumor growth. Consistent with our observation of NRF1 driven breast tumorigenesis in the experimental model, higher levels of NRF1 protein expression were also found in human breast cancer tissue specimens. This highly novel role of NRF1 in the stochastic acquisition of BCSCs and their progression to a malignant phenotype may open an entirely new research direction targeting NRF1 signaling in invasive breast cancer. Additionally, the discovery of targeting transcriptional activation of CXCR4 to inhibit NRF1-induced oncogenic transformation provides a mechanistic explanation for estrogen-dependent breast carcinogenesis and opens the new avenues for mechanistic therapeutic strategy against breast cancer.

Research into lightweight structural concrete using volcanic tuff is of great importance to the construction industry. These materials have excellent thermal insulation properties, which helps improve the energy efficiency of buildings. A three-factor experimental design was used to build the statistical model. The test methods used were methods for determining the crushability of volcanic tuff, determining the average density, compressive strength and thermal conductivity of lightweight structural concrete. The influence of basalt fiber on the properties of lightweight structural concrete has been determined. The optimal compositions of lightweight structural concrete using tuff have been selected. The compressive strength of lightweight structural concrete reached 32.0 MPa. The average density range is 1754.6-2114.0 kg/m³. Good thermal conductivity values ​​were obtained in the range of 0.653-0.818 W/m·K. The article obtained the optimal compositions of lightweight structural concrete using volcanic tuff as a filler.

Spermatogenesis is critical for insect reproduction and is regulated by many different genes. In this study, we found that Forkhead transcription factor Fd59a functions as a key factor in spermatogenesis of Drosophila melanogaster. Fd59a contains a conversed Forkhead domain, and it is clustered to the FoxD subfamily with other FoxD members from some insect and vertebrate species. Mutation in Fd59a caused swelling in the apical region of the testis. More importantly, only a few mature sperm were present in the seminal vesicle of Fd59a mutant flies compared to the control flies, and the fertility of Fd59a2/2 mutant males was significantly lower than that of the control flies. Immunofluorescence staining showed that the homeostasis of testis stem cell niche in Fd59a2/2 mutant and Fd59a RNAi flies was disrupted, and apoptosis of sperm bundles was increased. Furthermore, results from RNA-sequencing and qRT-PCR suggest that Fd59a can regulate expression of genes related to reproductive process and cell death. Taken together, our results indicated that Fd59a plays a key role in the spermatogenesis of Drosophila.

In recent decades, reports of deforestation, mass extinctions, biodiversity loss, and emergencies like floods and droughts have clearly highlighted the impact of human activities on these outcomes. This underscores the need for significant lifestyle changes to mitigate this impact. Pro-environmental behavior (PEB) change involves adopting actions that protect the environment and reducing environmentally harmful activities. While qualitative research may provide unique insights into PEB barriers that are challenging to capture through quantitative methods, reports of qualitative studies are scattered across different literatures with little integration. With the present review, we bring together insights from qualitative studies on PEB barriers and examine whether those studies reveal barriers compatible with existing barrier frameworks from environmental psychology. We identified 38 qualitative studies on barriers to PEB change. Our analysis revealed that most of the barriers to individual pro-environmental action identified in qualitative studies align with environmental psychology frameworks. These barriers were experienced not only by individuals in their role as consumer or citizen, but also by community-level actors (e.g., seeking to implement pro-environmental policies) and industrial decision-makers (e.g., aiming to reduce the ecological footprint of their business activities). Our findings underscore the multifaceted nature of barriers to PEB change and emphasize the importance of addressing structural and institutional factors alongside individual-level interventions.

Muscle-enriched A-type lamin-interacting protein (MLIP) is an emerging protein involved in cellular homeostasis and stress adaptation. Eukaryotic cells regulate various cellular processes, including metabolism, DNA repair, and cell cycle progression, to maintain cellular homeostasis. Disruptions in this homeostasis can lead to diseases such as cancer, characterized by uncontrolled cell growth and division. This review aims to explore for the first time the unique role MLIP may play in cancer development and progression, given its interactions with the PI3K/Akt/mTOR pathway, p53, and FOXO transcription factors, all critical regulators of cellular homeostasis and tumor suppression. We discuss the current understanding of MLIP's involvement in pro-survival pathways and its potential implications in cancer cells' metabolic remodeling and dysregulated homeostasis. Additionally, we examine the potential of MLIP as a novel therapeutic target for cancer treatment. This review aims to shed light on MLIP's potential impact on cancer biology and contribute to developing innovative therapeutic strategies.

Long COVID, a name often given to the persistent symptoms following acute SARS-CoV-2 infection, poses a multifaceted challenge for health. This review explores the intrinsic relationship between comorbidities and autoimmune responses in shaping the trajectory of long COVID. Autoantibodies have emerged as significant players in COVID-19 pathophysiology, with implications for disease severity and progression. Studies show immune dysregulation persisting months after infection, marked by activated innate immune cells and high cytokine levels. The presence of autoantibodies against various autoantigens suggests their potential as comorbid factors in long COVID. Additionally, the formation of immune complexes may lead to severe disease progression, highlighting the urgency for early detection and intervention. Furthermore, long COVID is highly linked to cardiovascular complications and neurological symptoms, posing challenges in diagnosis and management. Multidisciplinary approaches, including vaccination, tailored rehabilitation, and pharmacological interventions, are used for mitigating long COVID's burden. However, numerous challenges persist, from evolving diagnostic criteria to addressing the psychosocial impact and predicting disease outcomes. Leveraging AI-based applications holds promise in enhancing patient management and improving our understanding of long COVID. As research continues to unfold, unravelling the complexities of long COVID remains paramount for effective intervention and patient care.

Based on research data from the renovation of old residential areas in Chengdu, China, this study provides empirical evidence regarding the causal relationship between urban renewal and the transformation of residents' pro-environmental behaviors. The research findings demonstrate a significant enhancement in residents' engagement in pro-environmental behaviors due to the renovation of old residential areas. Robustness tests based on replacement samples and two-stage difference-in-difference models also confirm the reliability of the conclusions. The preliminary mechanism test indicates that the mechanism of the impact of renovation of old residential areas on the transformation of residents' pro-environmental behaviors can be attributed to two main factors. Firstly, the improvement of environmental infrastructure provides residents with better conditions for participating in pro-environmental activities. Secondly, there is an elevation in residents' environmental protection awareness, prompting a more voluntary engagement in pro-environmental behavior. This study suggests that decision-makers should fully recognize that urban renewal activities nationwide are not only a process of improving urban hardware and functionality, but also a realistic and vivid "environmental education" course for the whole nation. Taking urban renewal as an opportunity to enhance citizens' awareness of environmental protection will effectively promote the transformation of pro-environmental behaviors among residents.

Genetic activation of the class I PI3K pathway is very common in cancer. This mostly results from oncogenic mutations in PIK3CA, the gene encoding the ubiquitously expressed PI3Kα catalytic subunit, or from inactivation of the PTEN tumour suppressor, a lipid phosphatase which opposes class I PI3K signalling. The clinical impact of PI3K inhibitors in solid tumours, aimed at dampening cancer-cell-intrinsic PI3K activity, has thus far been limited. Challenges include poor drug tolerance, incomplete pathway inhibition and pre-existing or inhibitor-induced resistance. The principle of pharmacologically targeting cancer-cell-intrinsic PI3K activity also assumes that all cancer-promoting effects of PI3K activation are reversible, which might not be the case. Emerging evidence suggests that genetic PI3K pathway activation can induce and/or allow cells to tolerate chromosomal instability, which – even if occurring in a low fraction of the cell population – might help to facilitate and/or drive tumour evolution. While it is clear that such genomic events cannot be reverted pharmacologically, a role for PI3K in the regulation of chromosomal instability could be exploited by using PI3K pathway inhibitors to prevent those genomic events from happening and/or reduce the pace at which they are occurring, thereby dampening cancer development or progression. Such an impact might be most effective in tumours with clonal PI3K activation and achievable at lower drug doses than the maximum-tolerated doses of PI3K inhibitors currently used in the clinic.

Chronic inflammatory diseases are considered the most significant cause of death worldwide. Current treatments for inflammatory diseases are limited due to the lack of understanding of the biological factors involved in early-stage disease progression. Nerve growth factor (NGF) is a neurotrophic factor directly associated with inflammatory and autoimmune diseases like osteoarthritis, multiple sclerosis, and rheumatoid arthritis. It has been shown that NGF levels are significantly upregulated at the site of inflammation and play a crucial role in developing a robust inflammatory response. However, little is known about NGF's temporal expression profile during the initial progressive phase of inflammation. This study aimed to determine the temporal expression pattern of NGF in rat skin during Adjuvant-Induced Arthritis (AIA). Sprague Dawley rats were randomly divided into control and Complete Freund's Adjuvant (CFA) treated groups. Levels of NGF were evaluated following unilateral AIA at different time points and it was found that peripheral inflammation due to AIA significantly upregulated the expression of NGF mRNA and Protein in a biphasic pattern. These results suggest that NGF signaling is crucial for initiating and maintaining peripheral neurogenic inflammation in rats during AIA.

Epidemiologic studies suggest an inverse correlation between coffee consumption and the occurrence of neurodegenerative diseases, but the role of caffeine and roasting degree are still matter of debate. The objective of this work was to evaluate the effects of caffeinated (light, medium, and dark roast) and decaffeinated instant coffee samples in acetylcholinesterase inhibition and antioxidant assays, as well as in animal models of Parkinson’s disease. Caffeinated coffees inhibited the acetylcholinesterase in much smaller concentrations than decaffeinated coffee. All coffee samples showed antioxidant capacity without relation with the caffeine content. Dopaminergic-like activity in the haloperidol-induced catalepsy test was observed with caffeinated coffee, but not in the decaffeinated sample. The medium roast coffee reduced the number of rotations of rats after methamphetamine administration on the 6-hydroxydopamine unilateral lesion of the medial forebrain bundle. However, the coffee treatment did not avoid the loss of dopaminergic neurons on substantia nigra pars compact and only the smallest dose of coffee was able to avoid the decrease of dopamine levels in the lesioned side of the striatum. Altogether, these results suggest that coffee exerts moderate pro-cholinergic and pro-dopaminergic effects and caffeine seems to be the main responsible for these effects.

Abstract: Oncogenic RAS mutations drive more than half of human cancers, and RAS inhibition is the holy grail of oncology. Thirty years of relentless efforts and harsh disappointments have taught us about the intricacies of oncogenic RAS signalling that allow us to now get a pharmacological grip on this elusive protein. The inhibition of effector pathways, such as the RAF-MEK-ERK pathway, has largely proven disappointing. So far, most of these efforts were aimed at blocking the activation of ERK. Here, we discuss RAF dependent pathways that are regulated through RAF functions independent of catalytic activity and their potential role as targets to block oncogenic RAS signalling. We focus on the now well documented roles of RAF kinase independent functions in apoptosis, cell cycle progression and cell migration.

Despite advances in our understanding of molecular aspects of oncogenesis, cancer remains a leading cause of death. The malignant behavior of a cancer cell is driven by the inappropriate activation of transcription factors. In particular, signal transducers and activators of transcription (STATs), which regulate many critical cellular processes such as proliferation, apoptosis, and differentiation, are frequently activated inappropriately in a wide spectrum of human cancers. Multiple signaling pathways converge on the STATs, highlighting their importance in the development and progression of oncogenic diseases. STAT3 and STAT5 are two members of the STAT protein family that are the most frequently activated in cancers and can drive cancer pathogenesis directly. The development of inhibitors targeting STAT3 and STAT5 has been the subject of intense investigations in the last decade, although effective treatment options remain limited. In this review, we investigate the specific roles of STAT3 and STAT5 in normal physiology and cancer biology, discuss the opportunities and challenges in pharmacologically targeting STAT proteins and their upstream activators, and offer insights into novel therapeutic strategies to identify STAT inhibitors as cancer therapeutics.

Oncogenic fusion proteins, arising from chromosomal rearrangements, have emerged as prominent drivers of tumorigenesis and crucial therapeutic targets in cancer research. In recent years, the potential of small molecular inhibitors in selectively targeting fusion proteins has exhibited significant prospects, offering a novel approach to combat malignancies harboring these aberrant molecular entities. This review provides a comprehensive overview of the current state of small molecular inhibitors as therapeutic agents for oncogenic fusion proteins. We discuss the rationale for targeting fusion proteins, elucidate the mechanism of action of inhibitors, assess the challenges associated with their utilization, and provide a summary of the clinical progress achieved thus far. The objective is to provide the medicinal community with current and pertinent information and to expedite the drug discovery programs in this area.

The epidermal growth factor receptor (EGFR) plays vital roles in cellular processes including cell proliferation, survival, motility and differentiation. Dysregulated activation of the receptor is often implicated in human cancers. EGFR is synthesized as a single-pass transmembrane protein, which consists of an extracellular ligand-binding domain and an intracellular kinase domain separated by a single transmembrane domain. The receptor is activated by a variety of polypeptide ligands such as epidermal growth factor and transforming growth factor α. It has long been thought that EGFR is activated by ligand-induced dimerization of the receptor monomer, which brings intracellular kinase domains into close proximity for trans-autophosphorylation. An increasing number of diverse studies, however, demonstrate that EGFR is present as a pre-formed, yet inactive, dimer prior to ligand binding. Furthermore, recent progress in structural studies has provided insight into conformational changes during the activation of a pre-formed EGFR dimer. Upon ligand binding to the extracellular domain of EGFR, its transmembrane domains rotate or twist parallel to the plane of the cell membrane, resulting in reorientation of the intracellular kinase domain dimer from a symmetric inactive configuration to an asymmetric active form (the “rotation model”). This model is also able to explain how oncogenic mutations activate the receptor in the absence of ligand without assuming that the mutations induce receptor dimerization. In this review, we discuss mechanisms underlying ligand-induced activation of the preformed EGFR dimer, as well as how oncogenic mutations constitutively activate the receptor dimer, based on the rotation model.

This study presents a comprehensive approach to trim optimization as a energy efficiency improvement measure, focusing on reducing fuel consumption for one RO-RO car carrier. Utilizing Computational Fluid Dynamics (CFD) software, the methodology incorporates Artificial Neural Networks (ANN) to develop a mathematical model for estimating key parameters such as brake power, daily fuel oil consumption (DFOC) and propeller speed. The complex ANN model is then integrated into a user-friendly software tool for practical engineering applications. The research outlines a seven-phase trim optimization process and discusses its potential extension to other types of ships, aiming to establish a universal methodology for CFD-based engineering analyses. Based on trim optimization results, the biggest DFOC goes up to 10.5% at 7.5m draft and up to 8% for higher drafts. Generally, in every considered case, it is recommended to sail with the trim towards the bow, meaning that the ship’s weight (ballast) should be adjusted to tilt slightly forward.

Promoting green development has become an important way to optimize the ecological and economic structure and promote sustainable development. The Yangtze River Economic Belt is an important economic corridor in China, and it remains to be examined whether the implementation of environmental regulations has enhanced the green total factor productivity (GTFP) of cities. This paper calculates the green total factor productivity of 107 cities within the Yangtze River Economic Belt by using the super-efficient SBM model and the GML index with Chinese city panel data from 2007-2019 and measures the intensity of environmental regulations through textual analysis. The bidirectional fixed-effects model constructed in this paper suggests an inverted U-shaped relationship between environmental regulation and GTFP, which is confirmed by a series of robustness tests. Green technology innovation and advanced industrial structure play a mechanism role in this. In regions with lower levels of green technology and industrial structure, the inverted U-shaped relationship between environmental regulation and green total factor productivity is more significant. In addition, the phenomenon of GTFP rising and then falling because of environmental regulation is more obvious in cities in the middle and upper reaches of the Yangtze River and outside the urban agglomerations. Therefore, when formulating environmental regulation policies, it is necessary to balance the relationship between economic development and environmental protection and harmonize the environment and economic development of the entire Yangtze River Basin.

The aim of this work is to compare two softwares (MAUD and TOPAS) based on the Rietveld algorithm and to test the concept of tolerance factor using the dissolution at high temperature of yttrium into BaTiO₃. In general, both softwares give up different values of the crystalline parameters however the trends are similar in most cases but the analysis of the strain and crystallite size in the BaTiO₃ crystals suggests that, in this particular case, MAUD offered results more consistent with the expected behavior. Using the crystalline parameters calculated by Rietveld, the tolerance factor values were obtained and these data suggest even better stability in the crystalline structure than that expected using theoretical parameters. Tolerance factor concept also indicates that Ti⁴⁺ should be preferred.

The number of physical devices connected to the Internet such as vehicles, household appliances and other "things" has been steadily increasing in recent years, thus forming the basis for the Internet of Things (IoT). IoT ecosystem extends beyond country borders and application domains, combining thousands of versatile devices that differ in terms of their structures, capabilities, and available resources. It is therefore not surprising that the landscape of wireless communication technologies and the degree of IoT devices available today is excessively broad and diverse. Interference between networks leads to frame collisions and consequent packet loss. Frame collisions occur when two or more packets overlap in time and frequency and use the same Long Range (LoRa) parameters, i.e. the same Spreading Factor (SF), Bandwidth (BW) and Carrier Frequency (CF). When most devices use the same configuration, collision probability is higher. The probability of frame collisions is also affected by traffic characteristics, particularly the periodicity of the transmission and the payload size. Larger payload sizes and more frequent transmissions accumulate with higher Time on Air (ToA) and channel occupancy [1]. Transmission powers and the location of the gateways also influences this situation. The aim of this experimental work is to verify the effects of collisions and interference in Long Range Wide Area Network (LoRaWAN), regarding the periodicity of transmissions and the payload sizes in a context of an inter-SF interference scenario. And to validate measuring tools like Received Signal Strength Indicator (RSSI), ToA and Packet Delivery Ratio (PDR) in the reliability of a network. We validate our conclusions by analyzing ToA according with RSSI and different data sizes, the RSSI for different SFs and different data sizes and finally the packet loss through the PDR for a better understanding of the reliability of packet transmission in our link. In the end we conclude that in an environment with inter-SF interference, the choice of SFs and packet lengths impacts ToA. When dealing with multiple devices near gateways, different SFs and varying packet lengths can lead to increased latency and longer ToA. Consequently, the risk of packet loss becomes more significant, especially if the signal-to-interference ratio (SIR) is low. This limitation will therefore affect scalability, particularly in Non-Line-Of-Sight (NLOS) scenarios.

We have previously shown that the transmembrane protein ODZ1 promotes cytoskeletal remodelling of glioblastoma (GBM) cells and invasion of the surrounding parenchyma through activation of a RhoA-ROCK pathway. We also described that GBM cells can control the expression of ODZ1 through transcriptional mechanisms triggered by binding of IL-6 to its receptor and a hypoxic environment. Epidermal growth factor (EGF) plays a key role in the invasive capacity of GBM. However, the molecular mechanisms that enable tumor cells to acquire the morphological changes to migrate out from the tumor core have not been fully characterized. Here we show that EGF is able to induce the expression of ODZ1 in primary GBM cells. We analysed the levels of EGF receptor (EGFR) in 20 GBM primary cell lines and found expression in 19 of them by flow cytometry. We selected two cell lines that do or do not express EGFR and found that EGFR-expressing cells responded to EGF ligand by increasing ODZ1 at the mRNA and protein level. Moreover, blockade of EGF-EGFR binding by Cetuximab, inhibition of the p38 MAPK pathway or siRNA-mediated knockdown of MAPK11 (p38 MAPK) reduced the induction of ODZ1 in response to EGF. Overall, we show that EGF may activate an EGFR-mediated signalling pathway through p38 MAPK, to upregulate the invasion factor ODZ1, which may initiate morphological changes for tumor cells to invade the surrounding parenchyma. These data identify a new candidate of the EGF-EGFR pathway for novel therapeutic approaches.

Energy from biogas is one of the most promising renewable energy sources. Significant, for technical, economic, and environmental reasons, is the construction of agricultural microgas plants next to households specialising in cattle rearing. The availability of free substrate makes it possible not only to produce one's electricity and heat but also to produce a more environmentally and human-friendly manure. The operation of biogas plants is, unfortunately, associated with technical problems. This paper presents the results of a study of the quality of electricity generated in an agricultural biogas plant built at a farm specialising in dairy cows, where the owner reported a problem with the voltage in the power supply network. Therefore, selected power quality parameters occurring at the connection point of the biogas plant were analysed in detail. As the authors' research showed, in the case in question, the agricultural biogas plant was connected via a cable with too small a conductor cross-section, which resulted in significant voltage exceedances, making it impossible to switch on the second of the biogas plant's generators. Replacement of the feed-in cable has enabled both generators to run, but significant fluctuations in the feed-in voltage values were still noticeable. Analysis of the subsequent measurements revealed the need for changes in the design of the digester itself. The proposal for change is to replace the two current digester mixers (each rated at 9 kW) with more mixers of lower power. The new mixers would operate in an alternating system, where only one would always be activated.

Faced with increasing climate challenges, this pioneering study introduces groundbreaking approaches to ensure the resilience of potato crops in east-central Poland. Our research aimed to develop an innovative, cost-effective system tailored to the diverse local conditions of this region. Conducted between 2018 and 2020, the study analyzed integrated and organic production systems across different soil types and potato varieties. The experiment was conducted using a randomized block design with three replications in two locations. Integrated practices, enhanced by mineral fertilization and chemical protection, notably delayed the onset of late blight by 16 days and extended the critical infection period by 17% compared to their organic counterparts. Remarkably, the integrated systems resulted in a 49% increase in total production and a 52% increase in commercial yields, demonstrating their effectiveness in enhancing crop resilience. Different potato varieties exhibit varied responses to cultivation systems, influencing both yield and disease resistance. Further investigation into these varietal responses can help optimize cultivation practices, leading to improved efficiency and sustainability in potato farming. Location and soil conditions have a significant impact on potato yield and the spread of potato blight. Further research into specific soil properties and the adaptation of varieties to local conditions can contribute to increased productivity and stability in potato production. This study not only paves the way towards sustainable agriculture but also highlights the crucial role of soil diversity in shaping resilient farming practices.

The environmental exposure of human in the daily and occupational activities to plasticizers may adversely affect human health, and thus represents a global issue. The altered expression of MicroRNAs (miRNAs) exerts an important pathogenic role linked also to the exposure to plasticizers. This systematic review summarizes the recent findings showing modified ex-pression of miRNAs in cancer due to plasticizers exposures. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology, we performed a systematic review of the past ten years, focusing on the relationship between plasticizer exposures and expression of miRNAs cancer. Starting by 535 records, 17 articles were included. Results support the hypothesis that exposure to plasticizers cause changes or deregulation of a number of oncogenic miRNAs and showed that plasticizers interaction with several redundant miRNAs, such as let-7f, let-7g, miR-125b, miR-134, miR-146a, miR-22; miR-192, miR-222, miR-26a, miR-26b, miR-27b, miR-296, miR-324, miR-335, miR-122, miR-23b, miR-200, miR-29a and miR-21, might induce deep alterations. These genotoxic and oncogenic responses can eventually lead to abnormal cell signaling pathways and metabolisms that participate in many overlapped cellular processes, and miRNA level changes can be a useful tool for the toxicological assessment of environmental pollutants, including plastic additives and plasticizers

Cancer is a leading cause of death worldwide. It is theorized that underlying genetic and epigenetic changes enable cells to proliferate out of control by escaping regulatory mechanisms. The progression of cancer is associated with increased cell proliferation, metabolic modifications, resistance to apoptosis, genetic instability, induction of angiogenesis and augmented migratory capability. Recent developments in DNA and RNA analysis have made it possible to study these genetic changes systematically. These advances have enabled us to possess a deeper knowledge of the signaling pathways and involved processes. In-depth studies of the pathways involved in carcinogenesis have led to the identification of pathways that may be targeted for therapeutic purposes. In this review, we provide an overview of the relevant mechanisms and pathways involved in the development and progression of cancer.

Many anti-tumor effects of group-specific component-derived macrophage-activating factors (GcMAFs) have been reported; however, the specific mechanisms remain unclear. Controlling tumor-associated macrophages (TAMs) in the tumor microenvironment is essential for cancer treatment. This study assessed the role of GcMAF in macrophage activation, elucidated the mechanisms by which it exerts its anti-tumor effects, and determined its effects on TAMs in the tumor microenvironment. GcMAF-stimulated RAW264.7 macrophages and EMT6 breast tumor cells were co-cultured in a 0.4-µm pore cell culture insert, and gene and protein expression and cell viability were evaluated. DNA microarray analysis of GcMAF-stimulated RAW264.7 cells was conducted. The induction of M2 RAW264.7 cells by interleukin (IL)-4 and IL-13 was analyzed. GcMAF stimulation increased the tumor necrosis factor-α and inducible nitric oxide synthase mRNA and protein levels in RAW264.7 cells but decreased the viability of co-cultured EMT6 cells. These results were confirmed in the M2 RAW264M2.7 cells, suggesting that GcMAF exerts anti-tumor effects by inducing the differentiation of macrophages into the M1 type and reprogramming M2 macrophages to the M1 type. The anti-tumor activity of GcMAF via M2-to-M1 macrophage reprogramming could aid in developing novel cancer immunotherapies.

Neurosteroids are pleiotropic molecules involved in various neurodegenerative diseases with neuroinflammation. We assessed neurosteroids serum levels in a cohort of Parkinson’s Disease (PD) patients with heterozygous glucocerebrosidase (GBA) mutations (GBA-PD) compared with matched cohorts of consecutive non-mutated PD (NM-PD) patients, and healthy subjects with (GBA-C) and without (NM-HC) GBA mutations. A consecutive cohort of GBA-PD was paired for age, sex, disease duration, Hoehn &amp; Yahr stage, and comorbidities with a cohort of consecutive NM-PD. Two cohorts of GBA-C and HC were also considered. Clinical assessment included the MDS-UPDRS and the Montreal Cognitive Assessment (MoCA). Serum samples were processed and analyzed by liquid chromatography coupled with triple quadrupole mass spectrometry. Twenty-two GBA-PD (males: 11, age: 63.68), 22 NM-PD (males: 11, age: 63.05), 14 GBA-C (males: 8; age: 49.36), and 15 HC (males: 4; age: 60.60) were studied. Compared to NM-PD, GBA-PD showed more hallucinations and psychosis (p&lt;0.05, Fisher’s exact test) and higher MDS-UPDRS part-II (p&lt;0.05). Most of the serum neurosteroids were reduced in both GBA-PD and NM-PD compared to the respective control cohorts, except for 5α-DHP. Allopregnanolone was the only neurosteroid significantly lower (p&lt;0.01, Dunn’s test) in NM-PD compared to GBA-PD patients. Only in GBA-PD, allopregnanolone, and pregnanolone levels correlated (Spearman) with a more severe MDS-UPDRS part-III. Allopregnanolone levels also negatively correlated with MoCA scores, and pregnanolone levels correlated with more pronounced bradykinesia. This pilot study provides the first observation of changes in neurosteroid peripheral levels in GBA-PD. The involvement of the observed changes in the development of neuropsychological and motor symptoms of GBA-PD deserves further attention.

Abstract: Kiwifruit, a perennial horticultural crop known for its nutritional value, faces significant challenges due to biotic and abiotic stresses, affecting its yield and quality. Leucine-rich repeat receptor-like proteins (LRR-RLPs), a major group of receptor-like proteins in plants, have diverse functions in plant physiology, including growth, development, signal transduction, and stress responses. Despite their importance, the specific roles of kiwifruit LRR-RLPs in response to biotic and abiotic stresses remain poorly understood. In this study, we investigated the expression patterns of kiwifruit LRR-RLPs under various stress conditions, including pathogen stress, heat stress, waterlogging stress, and copper stress. Through genome and transcriptome analyses, we identified a total of 101, 164, and 105 LRR-RLPs in Actinidia Chinensis 'Hongyang', Actinidia eriantha 'Huate', and Actinidia chinensis 'Red5' kiwifruit, respectively, classified into 9 subgroups based on phylogenetic relationships. Synteny analysis revealed that the expansion of kiwifruit LRR-RLPs was primarily attributed to segmental duplication events. Using RNA-seq data from pathogen-infected kiwifruits, we identified specific LRR-RLP genes potentially involved in different stages of pathogen infection. Additionally, we observed the potential involvement of kiwifruit LRR-RLPs in abiotic stress responses, with upstream transcription factors possibly regulating their expression. Furthermore, protein interaction network analysis unveiled the participation of kiwifruit LRR-RLP genes in the regulatory network of abiotic stress responses. These findings highlight the crucial roles of LRR-RLPs in mediating both biotic and abiotic stress responses in kiwifruit, offering valuable insights for the breeding of stress-resistant kiwifruit varieties.

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related death worldwide. It is commonly diagnosed in advanced stages and therapeutic interventions are typically constrained to systemic chemotherapy, which yields only modest clinical outcomes. In this review, we examine recent developments in targeted therapy tailored to address distinct molecular pathway alteration required for PDAC. Our review delineates the principal signaling pathways and molecular mechanisms implicated in the initiation and progression of PDAC. Subsequently, we provide an overview of prevailing guidelines, ongoing investigations, and prospective research trajectories related to targeted therapeutic interventions, drawing insights from randomized clinical trials and other pertinent studies. This review focus on a comprehensive examination of preclinical and clinical data substantiating the efficacy of these therapeutic modalities, emphasizing the potential of combinatorial regimens and novel therapies to enhance the quality of life for individuals afflicted with PDAC. Lastly, the review delves into the contemporary application and ongoing research endeavors concerning targeted therapy for PDAC. This synthesis serves to bridge the molecular elucidation of PDAC with its clinical implications, the evolution of innovative therapeutic strategies, and the changing landscape of treatment approaches.

Suicide is a public health problem influenced by a variety of biological, psychological, social, and environmental factors. Recognizing the warning signs at each stage is crucial for prevention and helping those at risk. In this context, body awareness, especially interoceptive body awareness, emerges as a potentially relevant and underexplored factor. In this study, binary logistic regression and linear regression analyses were used to examine the relationship between interoceptive body awareness and suicidal orientation in Colombian university students. In addition, the bootstrap technique was used to resample and estimate the distribution of the data. The results support the idea that greater interoceptive awareness may protect against suicidal orientation by improving emotional regulation. An inverse relationship was found between interoceptive awareness and suicidal ideation. These findings are consistent with previous literature on the importance of body awareness for emotional well-being. Further longitudinal research is needed to explore this relationship in depth.

Chikungunya (CHIKV) and Mayaro (MAYV) viruses are arthritogenic alphaviruses that promote an incapacitating and long-lasting inflammatory muscle-articular disease. Despite studies pointing out the importance of skeletal muscle (SkM) in viral pathogenesis, the long-term consequences on its physiology after acute injury and the mechanism of persistence of symptoms are still poorly understood. Combining molecular, morphological, Nuclear Magnetic Resonance Imaging, and histological analysis, we conduct a temporal investigation of CHIKV and MAYV replication in a wild-type mice model, focusing on the impact on SkM composition, structure, and repair in the acute and late phases of infection. We found that viral replication and induced-inflammation promote fast loss of muscle mass and reduction of fibers cross sectional area, by inducing muscle-specific E3 ubiquitin ligases MuRF1 and Atrogin expression, that trigger protein breakdown, resulting in acute SkM fibers atrophy. After temporal reduction of inflammation and clearance of infectious viral particles, SkM atrophy persists until the late phase of infection. The genomic CHIKV and MAYV RNAs were still detected in SkM at the late phase, along with increased levels of chemokines and anti-inflammatory cytokines expression. In agreement with the involvement of inflammatory mediators on induced atrophy, neutralization of TNF and the reduction of oxidative stress using monomethyl fumarate, an agonist of Nrf2, decreases atrogens expression and atrophic fibers, while increasing weight gain in treated mice. Taken together, these data indicate that arthritogenic alphavirus infection could chronically impact body SkM composition and also harm repair machinery, contributing to a better understanding of mechanisms of arthritogenic alphaviruses pathogenesis and with description of potentially new targets of therapeutic intervention.

(1) Background: In this work, a series of benzimidazole derivatives containing colchicine-like and cathechol-like moieties with methyl group substitution in the benzimidazole ring were evaluated for their in vitro antiproliferative, pro-apoptotic and antioxidative activity against highly invasive breast cancer cell line MDA-MB-231 and related impairment of tubulin dynamics; (2) Methods: MTT assay was used to evaluate the antiproliferative activity. In vitro tubulin polymerization assay as well as docking analysis was applied to prove the alterations in tubulin polymerization. Immunofluorescent and DAPI staining reveal the pro-apoptotic potential of benzimidazole derivatives and the effect on tubulin’s dynamics in living cells. The antioxidant activity was evaluated by scavenging of H2O2 and hypochlorite ion and ortho-phenanthroline tests; (3) Results: The compounds containing colchicine-like moiety displayed significant growth inhibitory effect against cancer cell line as was highlighted the role of methyl functional group on the tubulin aggregation and blockage of mitosis. All compounds showed an ability to scavenge H2O2, while the compounds with cathecol-like moiety were more effective against hypochlorite ion and chelation of iron; (4) Conclusions: The benzimidazole derivative containing colchicine-like moiety and methyl group substitution in benzimidazole ring is a potential antiproliferative and microtubule destabilizing agent.

Novel ZNF proteins such as ZNF671 that are located on chromosome 19q13 are known to be hypermethylated at a high frequency in HNSCC as well as in other epithelial solid tumors. Their function is largely unknown. Here, we show that ZNF671 is epigenetically silenced in HNSCC primary tumors compared to matched adjacent normal tissue. Moreover, low expression of ZNF671 is significantly associated with decreased survival in HNSCC patients. Over-expression of ZNF671 in UM-SCC-1 oral cancer cells resulted in a significant reduction in tumor cell mobility and invasion compared to the empty-vector control cells. Transcriptomic analysis showed that ZNF671 re-expression resulted in a significant decrease in the expression of a major oncogenic long non-coding RNA LINC00665. Together, these results suggest that epigenetic silencing of ZNF671 may activate multiple oncogenic signaling pathways via the resulting up-regulation of LINC00665.

The insulin-regulated aminopeptidase (IRAP; oxytocinase) is part of the M1 aminopeptidase family and is highly expressed in many tissues, including the neocortex and hippocampus of the brain. IRAP is involved in various physiological functions and has been identified as a receptor for the endogenous hexapeptide Angiotensin IV (Ang IV). Binding of Ang IV inhibits the enzymatic activity of IRAP and has proven to enhance learning and memory in animal models. The macrocyclic compound 9 (C9) is a potent synthetic IRAP inhibitor developed from the previously reported inhibitor HA08. In this study, we have examined compound C9 and its effects on cognitive markers drebrin, microtubule-associated protein 2 (MAP2), and glial fibrillary acidic protein (GFAP) in primary hippocampal and cortical cultures. Cells from Sprague Dawley rats were cultured for 14 days before treatment with C9 for 4 consecutive days. The cells were analysed for protein expression of drebrin, MAP2, GFAP, glucose transporter type 4 (GLUT4), vesicular glutamate transporter 1 (vGluT1), and synapsin I using immunocytochemistry. The gene expression of related proteins was determined using qPCR, and viability assays were performed to evaluate toxicity. The results showed that protein expression of drebrin and MAP2 was increased, and the corresponding mRNA levels were decreased, after treatment with C9 in the hippocampal cultures. The ratio of MAP2 positive neurons and GFAP positive astrocytes was altered in both hippocampal and cortical cultures, and there were no toxic effects observed. In conclusion, IRAP inhibitor compound C9 enhance the expression of pro-cognitive markers drebrin and MAP2 which further confirms IRAP as a relevant pharmaceutical target and C9 as a promising candidate for further investigation.

Identification of recurrent driver mutations in genes encoding tyrosine kinases has resulted in the development of molecularly targeted strategies designed to improve the outcomes for patients diagnosed with acute myeloid leukemia (AML). The receptor tyrosine kinase FLT3, is the most commonly mutated gene in AML, with internal tandem duplications within the juxtamembrane domain (FLT3-ITD) or missense mutations in the tyrosine kinase domain (FLT3-TKD), present in 30%-35% of AML patients at diagnosis. An established driver mutation and marker of poor prognosis, the FLT3 tyrosine kinase has emerged as an attractive therapeutic target, and thus has encouraged the development of FLT3 tyrosine kinase inhibitors (TKIs). However, the therapeutic benefit of FLT3 inhibition, particularly as monotherapy, frequently results in the development of treatment resistance and disease relapse. Commonly, FLT3 inhibitor resistance is induced by the emergence of secondary lesions in the FLT3 gene, particularly in the second tyrosine kinase domain at residue Asp835 (D835) to form a ‘dual mutation’ (ITD-D835). Individual FLT3-ITD and FLT3-TKD mutations influence independent signaling cascades however, currently little is known which divergent signaling pathways are controlled by each of these FLT3 specific mutations, particularly in the context of patients harboring dual ITD-D835 mutations. This review provides a comprehensive analysis of the known discrete and cooperative signaling pathways regulated by each of the FLT3 specific mutations, as well as the therapeutic approaches that hold the most promise for development of more durable and personalized therapeutic approaches targeting mutant FLT3, to improve the treatment of AML.

Aortic stenosis (AS) is a prevalent valvular disorder that often requires surgical aortic valve replacement (SAVR) to alleviate symptoms and improve survival. However, the selection of an appropriate prosthetic valve size is crucial to avoid patient-prosthesis mismatch (PPM), which can lead to suboptimal hemodynamic outcomes. Von Willebrand factor (VWF), a key component of hemostasis, has been shown to be altered in AS patients and may contribute to the hemostatic imbalance observed following valve replacement. This prospective study aimed to investigate the impact of PPM on postprocedural VWF levels in patients undergoing SAVR for severe AS. The study included 31 consecutive patients diagnosed with severe AS who underwent SAVR. By focusing on the relationship between PPM and VWF dynamics, this study sought to provide valuable insights into the potential role of VWF as a marker for hemostatic changes associated with PPM, ultimately informing strategies for optimal valve selection and perioperative management to minimize complications.

In this study, we provided an empirical testability of the FF3FM against the co-moment-augmented FF3FM using the Newey–West GMM methods to account for potential endogeneity. The results showed that value risk is not significantly priced, and systematic skewness and systematic kurtosis play more important roles in explaining asset return than market and size factors. We discovered that there is much to gain in moving from the incumbent FF3FM to the co-moment-augmented FF3FM. By extending this study to Nigeria and using out-of-sample data that span across the recent COVID-19 period, the study has contributed to existing knowledge significantly. The study concludes that the co-moment-augmented FF3FM is superior to the incumbent FF3FM in pricing assets, and the anomalies associated with the return-size risk factor relationship are reduced by accounting for systematic skewness and systematic kurtosis in the FF3FM. Therefore, we recommend that investors should take a long position in size-hedged portfolios and hold systematic skewness and kurtosis as constant, and vice visa.

In view of the fact that the field monitoring information can more intuitively and accurately reflect the stability state of slopes, this paper takes the warning threshold of slope deformation rate monitoring as the slope stability evaluation standard, and puts forward a method for solving the safety coefficient of rocky slopes. The discrete element method 3DEC, which is suitable for rocky slopes, is selected as the numerical calculation tool, and the convergence criterion of its strength reduction method is modified to the slope deformation rate threshold, and the method is realized by the bifurcation method through its built-in FISH programming language. The results of the classical case show that, by selecting the slope deformation rate threshold in the appropriate interval, the results of this paper's method are very close to those of the finite unit stress method and the limit equilibrium method, which verifies the reliability of this paper's method. Further, the method of this paper is applied to an open-pit mine slope project, based on the slope deformation on-site monitoring data, through the time series prediction method to determine the slope deformation rate warning threshold, using the threshold as an evaluation criterion to solve the slope's coefficient of safety, the calculation results show that: the slope's coefficient of safety in natural working conditions is 1.086, basically stable, suffered from continuous rainfall, the slope body is gradually saturated, the slope's coefficient of safety is reduced to 0.987, the slope's safety is reduced to 0.987. After continuous rainfall and gradual saturation of the slope, the coefficient of safety decreased to 0.987, destabilizing and destroying, which is consistent with the site conditions.

Recently, microfluidics deformability cytometry has emerged as a powerful tool for high throughput mechanical phenotyping of large populations of cells. These methods characterize cells by their mechanical fingerprints through exerting hydrodynamic forces and monitoring the resulting deformation. These devices have shown great promise for label free cytometry, yet there is a critical need to improve their accuracy and reconcile any discrepancies with other methods, such as atomic force microscopy. In this study, we employ computational fluid dynamics simulations and uncover how the elasticity of frequently used carrier fluids such as methyl-cellulose dissolved in phosphate-buffered saline is significantly influential to the resulting cellular deformation. We conducted CFD simulations that are conventionally used within the deformability cytometry field, which neglect fluid elasticity. Subsequently, we incorporated a more comprehensive model that simulates the viscoelastic nature of the carrier fluid. A comparison of the predicted stresses between these two approaches underscores the significance of the emerging elastic stresses in addition to the well-recognized viscous stresses along the channel. Furthermore, we utilize a two-phase flow model to predict the deformation of a promyelocyte (i.e. HL-60 cell type) within a hydrodynamic constriction channel. The obtained results highlight a substantial impact of the elasticity of carrier fluid on cellular deformation and raise questions about the accuracy of mechanical property estimates derived by neglecting elastic stresses.

Arboviruses are infections caused by arboviruses that may be either symptomatic or asymptomatic, according to individuals' resistance and immune response, which dietary patterns can influence. Thus, this study aimed to investigate the possible association between the occurrence of clinical manifestations of arboviruses and the dietary pattern of the population studied. The study was conducted in a rural population in the metropolitan area of Belém, Pará State, Brazil. The sampling consisted of 95 individuals during a febrile outbreak. Two investigations were conducted: clinical-epidemiological-dietary and laboratory investigation based on blood samples taken for arbovirus analysis. Out of the 95 individuals studied, more than half (57.89%) showed clinical manifestations. Following the laboratory serology (HI and IgM ELISA) analyses, viral isolation in C6/36 cells, and viral genome detection (RT-qPCR), the final diagnosis of the cases was 47.37% Oropouche Fever, 2.11% Oropouche Fever and Chikungunya Fever, and 1.05% Mayaro Fever. Regarding dietary pattern, as for the comparison analyses, statistical significance was observed between dietary pattern and classification regarding the presence of symptoms (p<0.05); after the correspondence analysis, symptomatic cases were more associated with a bad dietary pattern, while asymptomatic cases were more associated with a good dietary pattern.

The number of physical devices connected to the Internet such as vehicles, household appliances and other "things" has been steadily increasing in recent years, thus forming the basis for the Internet of Things (IoT). IoT ecosystem extends beyond country borders and application domains, combining thousands of versatile devices that differ in terms of their structures, capabilities, and available resources. It is therefore not surprising that the landscape of wireless communication technologies and the degree of IoT devices available today is excessively broad and diverse. Interference between networks leads to frame collisions and consequent packet loss. Frame collisions occur when two or more packets overlap in time and frequency and use the same LoRa parameters, i.e. the same spreading factor (SF), bandwidth (BW) and carrier frequency (CF). When most devices use the same configuration, collision probability is higher. The probability of frame collisions is also affected by traffic characteristics, particularly the periodicity of the transmission and the payload size. Larger payload sizes and more frequent transmissions accumulate with higher time on air (ToA) and channel occupancy [1]. Transmission powers and the location of the gateways also influences this situation. The aim of this experimental work is to verify the effects of collisions and interference in LoRaWAN, regarding the periodicity of transmissions and the payload sizes. The hardware used is an Arduino board programmed in C/C++, a LoRa Bee module operating at a frequency of 868 MHz and a LoRaWAN LG02 gateway. Different scenarios were tested in an outdoor environment, with Line of Sight and Non-Line of Sight, and different variables such as: SFs equal to 7, 9 and 12; distances of 20, 40 and 60 meters and different data sizes of 14, 32 and 51 bytes, over the same channel. The packets with different SF’s and different data sizes were transmitted in a (pseudo) random way, one after the other, overlapping different SFs in the same channel and testing this way (theoretical) orthogonality among them. By fixing the bandwidth in 125 kHz, and testing different SFs we intend to increase the probability of cause packet loss by applying to our connection a combination of emitted power/short distance that leaves an interference power received, strong enough [2] for the effect. We validate our conclusions by analyzing ToA according with RSSI and different data sizes, the RSSI for different SFs and different data sizes and finally the packet loss through the PDR-Packet Delivery Ratio for a better understanding of the reliability of packet transmission in our link.

Glutamate functions as the major excitatory neurotransmitter for primary sensory neurons and has a crucial role in sensitizing peripheral nociceptor terminals producing sensitization. Glutaminase (GLS) is the synthetic enzyme that converts glutamine to glutamate. GLS-immunoreactivity (-ir) and enzyme activity are elevated in dorsal root ganglion (DRG) neuronal cell bodies during chronic peripheral inflammation, but the mechanism for this GLS elevation is yet to be fully characterized. It has been well established that, after nerve growth factor (NGF) binds to its high-affinity receptor tropomyosin receptor kinase A (TrkA), a retrograde signaling endosome is formed. This endosome contains the late endosomal marker Rab7GTPase and is retrogradely transported via axons to the cell soma located in DRG. This complex is responsible for regulating the transcription of several critical nociceptive genes. Here, we show that this retrograde NGF signaling mediates the expression of GLS in DRG neurons during the process of peripheral inflammation. We disrupted the normal NGF/TrkA signaling in adjuvant-induced arthritic (AIA) Sprague Dawley rats by pharmacological inhibition of TrkA or blockade of Rab7GTPase, which significantly attenuated the expression of GLS in DRG cell bodies. These results indicate that NGF/TrkA signaling is crucial for the production of glutamate and has a vital role in the development of neurogenic inflammation. In addition, our pain behavioural data suggest that Rab7GTPase can be a potential target for attenuating peripheral inflammatory pain.

Behavior analysis is a widely used non-invasive tool in the practical production routine, as the animal acts as a biosensor capable of reflecting its degree of adaptation and discomfort to some environmental challenge. Predominantly, conventional statistics use occurrence data for behavioral evaluation and well-being estimation, disregarding the temporal sequence of events. The Generalized Sequential Pattern (GSP) algorithm is a data mining method that identifies recurrent sequences that exceed a user-specified support threshold, whose potential has not yet been investigated for broiler chickens in enriched environments. Enrichment aims to increase environmental complexity with promising effects on animal welfare, stimulating priority behaviors and potentially reducing the deleterious effects of heat stress. The objective was to validate the application of the GSP algorithm to identify temporal correlations between heat stress and the behavior of broiler chickens in enriched environments through proof of concept. Video image collection was carried out automatically for 48 continuous hours, analyzing a continuous period of seven hours, from 12:00 PM to 6:00 PM, during two consecutive days of tests for chickens housed in enriched and non-enriched environments under comfort and stress temperatures. Chickens at comfort temperature showed high motivation to perform the behaviors of Preening (P), Foraging (F), Lying down (Ld), Eating (E), and Walking (W) whose sequences &lt;{Ld,P}&gt;; &lt;{Ld,F}&gt;; &lt;{P,F,P}&gt;; &lt;{Ld,P,F}&gt; and &lt;{E,W,F}&gt; were the only ones observed in both treatments. All other sequential patterns (comfort and stress) were distinct, suggesting that environmental enrichment alters the behavioral pattern of broiler chickens. Heat stress drastically reduced the sequential patterns found at the 20% threshold level in the tested environments. The behavior of lying laterally "Ll" is a strong indicator of heat stress in broilers and was only frequent in the non-enriched environment, which may suggest that environmental enrichment provides the animal with better opportunities to adapt to stress-inducing challenges, such as heat.

Background: Population studies have shown that prehypertension is associated with adverse cardiometabolic risk profile even among apparently healthy populations. Although associations between serum triglyceride (TG) concentrations and the risk of atherosclerotic cardiovascular disease have been reported, there are lack of data on the association of hypertriglyceridemia with cardiovascular risk (CVR) in a low risk prehypertensive population. Aim: Our aim was to analyze the cardiorenometabolic characteristics of prehypertensives (PHT) compared to normotensives (NT) and untreated hypertensives (HT) and its associations with CVR. Materials and methods: In our cross-sectional study we included 323 apparently healthy untreated subjects 18-45 years who underwent basic anthropometric and standardized blood pressure measurement, fasting blood sampling, spot urine collection and transthoracic echocardiogram. Results: Higher BMI, waist circumference, HOMA-IR, LDL-cholesterol, TG, uric acid and LVMI contribute to higher CVR in PHT compared to true NT (p

Background: Despite a range of available treatments, there is a remaining unmet need for patients with severe post-partum hemorrhage (sPPH). Objective: This manuscript evaluated efficacy and safety of recombinant activated factor VIIa (rFVIIa) in sPPH management. Methods: An open-label, multi-center, randomized controlled trial (RCT; NCT00370877) and four observational studies (OS; OS-1 [NCT04723979], OS-2, OS-3 and OS-4) were analyzed regarding efficacy (need for subsequent invasive procedures, including uterine compression sutures, uterine or iliac artery ligation, arterial embolization or hysterectomy) and safety (incidence of thromboembolic events [TE] and maternal mortality) of rFVIIa for sPPH. The RCT, and OS-1 and OS-2, included a control group of women who did not receive rFVIIa (with propensity score-matching used in OS-1 and OS-2), whereas OS-3 and OS-4 provided descriptive data for rFVIIa exposed women only. Results: A total of 446 women exposed to rFVIIa and 1,717 non-exposed controls were included. In the RCT, fewer rFVIIa exposed women (50% [21/42]) had an invasive procedure versus non-exposed women (91% [38/42]; odds ratio 0.11, 95% confidence interval 0.03–0.35). In OS-1, more rFVIIa exposed women (58% [22/38]) had an invasive procedure versus non-exposed women (35% [13.3/38]; odds ratio 2.46, 95% confidence interval 1.06–5.99). In OS-2, 17% (3/18) of rFVIIa exposed women and 32% (5.6/17.8) of non-exposed women had an invasive procedure (odds ratio 0.33, 95% confidence interval 0.03–1.75). Across all included women, TEs occurred in 1.5% (0.2% arterial and 1.2% venous) of rFVIIa exposed women and 1.6% (0.2% arterial and 1.4% venous) of non-exposed women with available data. Conclusions: The positive treatment effect of rFVIIa in the RCT was not confirmed in the OS. However, the safety analysis did not show any increased incidence of TEs with rFVIIa treatment.

Despite recent advancements, therapies remain ineffective against advanced oral squamous cell carcinoma (OSCC), resulting in unsatisfactory therapeutic outcomes. Cold atmospheric plasma (CAP) offers a promising approach in the treatment of malignant neoplasms. Yet, the exact mechanisms driving CAP-induced cancer cell death are not fully understood. This study revealed a significant reduction in the viability of OSCC cell lines, inactivation of AKT and ERK, and the downregulation of the miR-21, miR-31, miR-134, miR-146a and miR-211 expression followed the CAP treatment. Pretreatment with ZVAD, 3-MA, and Fer-1 synergistically reduced CAP-induced cell death, indicating a combined induction of variable death pathways by CAP. Activation of AKT and ERK, alongside combined treatments using death inhibitors and miRNA mimics, counteracted the cell mortality associated with CAP. CAP-induced downregulation of miR-21, miR-31, miR-187 and miR-211 expression was rescued by AKT and ERK activation. Additionally, CAP treatments notably inhibited the growth of SAS cell xenografts on nude mice. The reduced expression of oncogenic miRNAs in vivo aligned with in vitro findings. In conclusion, our study indicates that CAP jet treatment diminishes OSCC cell viability by abrogating survival signals and oncogenic miRNA expression.

Diffuse type of gastric cancer (GC) has an increasing prevalence worldwide, especially in Western countries, is usually diagnosed at advanced stages, and has no efficacious treatment options. Epidemiological studies have reported an increased mortality from GC after occupational exposure to well-studied pro-carcinogen that are metabolically activated by Cyp P450 enzymes through aryl hydrocarbon receptor (AhR). Substantial studies support the involvement of AhR in gastric carcinogenesis. However, little is known about the role of AhR in diffuse GC, as compared to intestinal GC. In a cohort of 29 gastric tumors, we described a significantly increased AhR protein and mRNA expression levels in GCs, independently of subtypes and clinical parameters. AhR and RhoA mRNA expression were correlated in diffuse GC. Further, our study characterized how AhR affects gene expression in diffuse GC. Using qRT-PCR, we compared the expression levels of AhR, Cyp1A1 and Cyp1B1 to the expression of genes in a panel previously described. In diffuse GC, Cyp1A1 expression correlated with genes involved in IGF signalling, EMT (VIM), migration (MMP2). In an in vitro assay using the poorly differentiated KATOIII epithelial cell line, two well-known ligands for AhR (TCDD and BaP) induced mRNA expression of CYP1A1, IL1b, as well as UGT1, NQO1 and AhRR to a lower extent. We also observed a strong increase in Cyp1B1 expression in diffuse GC, along with a lower TCDD-increased Cyp1B1 expression as compared to Cyp1A1 in KATOIII cells, and immunostaining in stromal cells. In intestinal GC, Cyp1B1 inversely correlated with several genes including IDO1 (generating endogenous kynurenin-e AhR ligand). Our data provide evidence for a major role of AhR in GC, as an environmental xenobiotics receptor, through different mechanisms and pathways in diffuse and intestinal GC. Our results support continued efforts to clarify the identities of exogenous AhR ligands in diffuse GC in order to define new therapeutic strategies.

PURPOSE: Breast cancer tumors frequently have intratumor heterogeneity. Tumors with high intratumor heterogeneity have caused therapeutic resistance and have human epidermal growth factor receptor 2 (HER2) heterogeneity in response to HER2-targeted therapies. This study aimed to investigate whether high HER2 heterogeneity levels were clinically related to poor prognosis for HER2-targeted adjuvant therapies resistance in primary breast cancers. METHODS: This study included patients with primary breast cancer (n = 251) treated with adjuvant HER2-targeted therapies. HER2 heterogeneity was manifested by the shape of HER2 fluorescence in situ hybridization amplification (FISH) distributed histograms with HER2 gene copy number within a tumor sample. Those heterogeneity classified each tumor into the biphasic grade graph (high heterogeneity [HH]) group and the monophasic grade graph (low heterogeneity [LH]) group. Both groups were evaluated for disease-free survival (DFS) and overall survival (OS) for a median of ten years of annual follow-up. RESULTS: Of 251 patients with HER2-positive breast cancer, 46 (18.3%) and 205 (81.7%) were classified into the HH and LH groups, respectively. The HH group had more distant metastases and a poorer prognosis than the LH group (DFS: P < 0.001 (HH:63% vs LH:91% at 10 years), and OS: P = 0.012 (HH:78% vs LH:95% at 10 years). CONCLUSION: High HER2 heterogeneity is a poor prognostic factor in patients with HER2-positive breast cancer. A novel approach of heterogeneity, which is manifested by the shape of HER2 FISH distributions, might be clinically useful in the prognosis prediction of patients after HER2 adjuvant therapy.

Deuterium is a heavy nonradioactive isotope of hydrogen, having a neutron as well as a proton, making it twice as heavy. It is a natural element, present at 156 parts per million in seawater. The ATPase pumps in the mitochondria utilize proton motive force to drive ATP synthesis, and deuterons damage the pumps, producing a stutter that can cause reactive oxygen release and inefficiencies in ATP synthesis. Cellular metabolism incorporates several novel mechanisms to assure low deuterium content in the mitochondria and other organelles. Nicotinamide adenine dinucleotide (NAD) is a major carrier of deuterium depleted (deupleted) protons to supply the mitochondria. Many enzymes, especially flavoproteins, are able to use proton tunneling to fractionate out deuterium. In this paper, we argue that the amino acid proline is able to trap and sequester deuterium, and that peptidyl prolyl isomerases (PPIases) play a central role in facilitating deuterium trapping in proline-rich proteins, most notably collagen. The endothelial glycocalyx also sequesters deuterium in gelled water lining the blood vessels, creating a battery and promoting low deuterium in the circulation. Excess deuterium promotes cancer growth, and cancer cells release large quantities of lactate via aerobic glycolysis to help reverse deuterium overload, systemically.

The early 2-factor (E2F) family of transcription factors, including E2F1-8, plays a critical role in apoptosis, metabolism, proliferation, and angiogenesis within glioblastoma (GBM). However, the specific functions of E2F transcription factors (E2Fs) and their impact on the malignancy of Bevacizumab (BVZ)-responsive GBM subtypes remain unclear. This study used data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) to explore the impact of eight E2F family members on the clinical characteristics of BVZ-responsive GBM subtypes and possible mechanisms of recurrence after BVZ treatment.To predict the possibility of GBM patient survival and progression, we classified and comparedthe expression of E2Fs according to BVZ-responsive subtypes and employed a machine learning method-TreeBagger, one random forest algorithm. Multiple bioinformatics analyses have shown that the significant increased E2F8 post BVZ treatment may enhance the function of angiogenesis and stem cell proliferation, indicating one of the mechanisms of GBM recurrence after treatment. In addition, BVZ treatment in unresponsive GBM patients may potentially worsen disease progression. Our findings suggest that E2F family members play important roles in GBM malignancy and BVZ treatment response, highlighting their potential as prognostic biomarkers and therapeutic targets and recommending precise BVZ treatment for GBM patients.

Equine herpesvirus type 1 (EHV-1) causes rhinopneumonitis, abortion and neurological outbreaks (equine herpesvirus myeloencephalopathy, EHM) in horses. EHV-1 also causes lethal encephalitis in laboratory small animals such as mice and hamsters experimentally. EHV-1 ORF76 is a homologue of HSV-1 US9, which is a herpesvirus kinase. Starting with an EHV-1 bacterial artificial chromosome clone of neuropathogenic strain Ab4p (pAb4p BAC), we constructed an ORF76 deletion mutant (Ab4p∆ORF76) by replacing ORF76 with the rpsLneo gene. Deletion of ORF76 had no influence on replication, cell-to-cell spread in cultured cells or replication in primary neuronal cells. In western blots of EHV-1-infected cell lysates, an EHV-1 Us9-specific polyclonal antibody detected multiple bands ranging from 35 to 42-kDa. In a CBA/N1 mouse infection model following intranasal inoculation, the parent and Ab4p∆ORF76 revertant caused the same histopathology in the brain and olfactory bulbs. The parent, Ab4p∆ORF76 and revertant mutant replicated similarly in the olfactory mucosa, although Ab4p∆ORF76 was not transported to the olfactory bulbs and was unable to infect the CNS. These results indicated that the ORF76 (US9) plays an essential role in the anterograde spread EHV-1.

Cardiovascular (CV) morbidity and mortality are markedly increased in non-dialysis patients with chronic kidney disease (CKD). Thus, the precise management of CV risk factors involved in CKD is crucial to improving outcomes. Serum phosphate (Pi) and FGF-23 levels have been linked with a higher risk of CV events in CKD. However, the exact thresholds of Pi and FGF-23, at which the risk of adverse events increases, remain unknown. We evaluated the expression of intact FGF-23 (iFGF-23) and Pi in a non-dialysis CKD patient population (n=82; 42M:40F; median age 61 years) and investigated their association with CV and renal outcomes, in a 5-year follow-up period. At baseline, the median estimated glomerular filtration rate (eGFR), iFGF-23, and Pi were 45 ml/min/1.73m² (IQ 26.6-73.1), 69.9 µg/ml (IQ 33-117) and 3.4 mg/dL (IQ 3.3-3.9), respectively. Univariate analysis showed a strong association of both iFGF-23 and Pi with age, Charlson Comorbidity Index, hypertension, and diabetes. In addition, iFGF-23 and Pi were both associated with the composite outcome (major CV and cerebrovascular events – MACCEs, hospitalizations, and all-cause mortality) during follow-up. Moreover, Pi was independently associated with all-cause mortality during follow-up. The segmentation of the population in terciles, according to Pi (<3mg/dL; 3-3.6 mg/dL; ≥3.7 mg/dL) within reference serum levels, showed a distribution of the fatality of 0%, 20% and 80% (p =0.034), respectively. Our results reinforce the association of both iFGF-23 and Pi with composite CV outcomes in non-dialysis CKD patients and further suggest that Pi, within current reference levels, may behave as an independent risk factor for mortality in this population. It is suggested that a reassessment of Pi reference levels for early therapeutic intervention in this population may be justified.

While the two primary risk factors for head and neck squamous cell carcinoma (HNSCC) are alcohol and tobacco, viruses account for an important and significant upward trend in HNSCC incidence. Human papillomavirus (HPV) is the causative agent for a subset of oropharyngeal squamous cell carcinoma (OPSCC)—a cancer that is impacting a rapidly growing group of typically middle-aged non-smoking white males. While HPV is a ubiquitously present virus (with about 7% of the population having oral HPV infection at any one time), only 1% of those infected develop OPSCC— suggesting that additional cofactors or coinfections may be required. Epstein-Barr virus (EBV) is a similarly ubiquitous virus that is strongly linked to nasopharyngeal carcinoma (NPC). Both of these viruses cause cellular transformation and chronic inflammation. While dysbiosis of the human microbiome has been associated with similar chronic inflammation and the pathogenesis of mucosal diseases (including OPSCC and NPC), a significant knowledge gap remains in understanding the role of bacterial-viral interactions in the initiation, development, and progression of head and neck cancers. In this review, we utilize the known associations of HPV with OPSCC and EBV with NPC to investigate these interactions. We thoroughly review the literature and highlight how perturbations of the pharyngeal microbiome may impact host-microbiome-tumor-viral interactions—leading to tumor growth.

We conduct a thematic analysis of a U.S. adult sample’s self-reported motives and perception of environmental activists’ motives to engage in pro-environmental behavior via a qualitative online survey. We identified themes using a two-stage coding procedure, whereby the research team first helped to code all content into one or more of 17 inductive content categories, then the lead investigator examined themes in each of the categories and created 5 themes based on both inductive and theoretical (e.g., moral foundations theory) considerations: a) harm and care, b) purity, c) waste and efficiency, d) spreading awareness, and e) self-interest (mostly non-financial). Endorsement of themes were qualitatively similar across individuals’ own self-described motives and perceptions of environmental activists’ motives.

Inflammation is an essential protective response against injury or infection. Physiological inflammation eliminates the pathogen, promotes tissue repair and healing. An exaggerated, out of control inflammation, however, can become pathological. Inflammation can generate secondary cell damage, inflame the vessels (endothelitis), activate coagulation processes. Among these pathogenetic factors (cell damage, inflammation, endothelitis, coagulopathies), self-amplification mechanisms can be created, spreading beyond the initial site, up to Multiple Organ Failure (MOF) and host death. If the inflammation does not resolve in a physiological way, the remodeling of the tissues can be maladaptive and lead to the onset of chronic inflammatory degenerative diseases. Diseases such as sepsis, burns, polytrauma, severe forms of influenza or COVID-19, are characterized by a condition of hyperinflammation, associated with a condition of immunosuppression. The initial events triggered by the pathogen (cell damage, interferon response in the case of viruses) ignite the inflammation by activating the inflammasome, the transcription factor NFkB, the release of pro-inflammatory eicosanoids (Prostaglandins, Leukotrienes, Thromboxanes) by neutrophils and macrophages. Hence, the cells of the innate immune system produce pro-inflammatory cytokines. Indeed, the ‘’eicosanoid storm’’ precedes the ‘’cytokine storm’’. Eicosanoids are a group of potent endogenous lipid mediators derived from omega-6 fatty acids Arachidonic Acid (AA). Eicosanoids include a group of molecules with pro-inflammatory (Prostaglandins, Leukotriens) and pro-coagulant (Thromboxanes) action. In addition, Arachidonic Acid (AA) is the source of Lipoxins (LXs). Lipoxins belong to a group of molecules collectively referred to as specialized pro-solving mediators (SPMs) which also include molecules derived from w-3 eicosapentaenoic acid (EPA): Resolvins (ReV-E sieres) and w-3 docohexanoic (DHA): Resolvins D-series (ReV D-series); Protectins (PTs); Maresins (MaRs). SPMs are important for the resolution phase of inflammation to take place properly. Their deficiency could be involved in both acute uncontrolled inflammation and chronic inflammation. The active regulation of the acute inflammatory process, integrating the precursors of Specialized Pro-resolving Mediators (SPMs), such as ⍵-6 and ⍵-3 in balanced ratio, or the SPMs themselves, could be a complementary therapeutic approach useful for taming the "storm of cytokines '' which characterizes exaggerated forms of inflammation. ⍵-3 and ⍵-6 are part of already widely used, readily available, inexpensive and safe supplements. Resolvins have already been included in clinical trials for various other inflammatory diseases (eye diseases, periodontal diseases).

Newton's kinetic energy equation delineates the laws of motion for objects travelling at speeds much less than the speed of light, an equation extensively validated at these lower velocities. Any new, more complete formulation of kinetic energy must approximate Newton's kinetic energy equation under these conditions. Einstein's special relativity, utilizing the Lorentz factor, introduces a new perspective on spacetime, adhering to the requirement that the Newtonian kinetic energy equation serves as an approximation at low velocities. In this paper, we identify all factor expressions satisfying the condition that their approximate solutions at low velocities align with Newton's kinetic energy equation. We introduce the Yuyunrui factor, incorporating two real number hyperparameters, $\alpha$ and $\beta$, encompassing all potentially correct factors, with the Lorentz factor as a specific instance where $(\alpha=0$, $\beta=1)$. We classify all potentially correct $(\alpha, \beta)$ combinations into six categories based on their distinct scaling effects and present the corresponding scaling effects. The combinations of $(\alpha, \beta)$ values applicable in the real world are necessarily included within these candidates, with the precise values requiring rigorous experimental validation. This work aims to refine our understanding of special relativity beyond the Lorentz factor.

Aim: To analysis the relationship between healthy adults right ventricular diameter (RVD) and geographical factors. Location: China’s 22 provinces, municipalities and autonomous regions. Methods: Using correlation analysis the relationship between RVD and nine geographic factors, build predictive models by factor analysis. Results: There is significant correlation between RVD and geographical factors, and the annual average temperature is most relevant geographical factors, a predictive model was built by factor analysis: Ŷ = 19.46 + 0.0007072X1 + 0.001034X2 -0.05412X3 -0.001405X4 -0.0006351X5 + 0.02903X6 + 0.01243X7 -0.01033X8 + 0.03816X9 ± 0.63. Then using Kriging interpolation interpolate the geographical distribution of Chinese healthy adult right ventricular diameter reference value in ArcGIS software. Main Conclusion: If geographic factors can be derived in anywhere of China, RVD can be calculated by the model, you can also get RVD from geographical distribution.

Background: Human papillomavirus is a common pathogen that infects the skin and mucosal epithelium, is transmitted sexually; causes condylomas or squamous cell carcinomas. Two (16 and 18) of the 150 HPV serotypes are oncogenic types. Studies have been done on the infection by oncogenic human papillomavirus 16/18 and associated factors are found to be very limited in Ethiopia. Objective: This study aimed to assess the prevalence of oncogenic human papillomavirus infection (HPV 16/18) and associated factors among women. Methods: An institutional-based cross-sectional study was conducted among 337 women screened for cervical cancer in two hospitals in East Gojjam Zone from February to April 2021 G.C. Four BSc-qualified nurses who worked in the chosen hospitals collected the data using pretested questionnaire and an HPV test (OncoE6TM Cervical Test) specific to HPV16/18 in cervical swabs. Descriptive analysis was performed to determine the prevalence and a multivariate logistic regression model was used to identify the associated factors of HPV16/18 infection. Finally, statistical significance was declared at P < 0.05.Results: The prevalence of HPV infection was 14.2% (95% CI: 10.7% -18.1%). The mean age of the respondents was 36.7±9.1 years. Women with the age group of 55-65 years (AOR = 7.91, 95% CI: 1.95-32.09), early initiation of sexual intercourse (AOR = 5.36, 95% CI: 1.58-18.13), history of sexually transmitted infection (STI) (AOR = 3.52, 95% CI: 1.27-9.72), human immunodeficiency virus (HIV) positive status (AOR = 6.8, 95% CI: 1.99-23.54), and number of lifetime sexual partners (AOR = 4.37, 95% CI: 1.15-17.3) were important independent factors associated with the presence of oncogenic HPV infection. Conclusion and Recommendation: We found a relatively low prevalence of high-risk HPV infection. Age, early initiation of sexual intercourse at less than 18 years, STI of women, being HIV seropositive, and a number of sexual partners were important factors for high-risk HPV infection. Women aged > 46 years, women with early initiation of sex, a history of STI, being HIV positive, and a history of multiple sexual partners should be encouraged to be screened and vaccinated for HPV infection. Wider-ranging studies are also needed in HPV-infected women in association with the cervical lesion.

Cotton fiber is the leading natural textile material, and fiber elongation plays an essential role in the formation of cotton yield and quality. Although a wealth of components in the molecular network controlling cotton fiber elongation have been reported, a lot of players still need to be functionally dissected to understand the regulatory mechanism of fiber elongation comprehensively. In the present study, an R2R3-MYB transcription factor gene, GhMYB201, was characterized and functionally verified via CRISPR/Cas9 mediated gene editing. GhMYB201 was homologous to Arabidopsis AtMYB60, and both coding genes (GhMYB201At and Dt) were preferentially expressed in elongating cotton fibers. Knocking-out of GhMYB201 significantly reduced the rate and duration of fiber elongation, resulting in shorter and coarser mature fibers. It was found that GhMYB201 could bind and activate the transcription of cell wall loosening genes (GhRDLs), and also β-ketoacyl-CoA synthase (GhKCSs) genes to enhance very-long-chain fatty acid (VLCFA) levels in elongating fibers. Taken together, our data demonstrated that the transcription factor GhMYB201s play essential roles in promoting fiber elongation via activating genes related to cell wall loosening and VLCFA biosynthesis.

This review article discusses the involvement of the Brain-Derived Neurotrophic Factor (BDNF) in the control of pain. BDNF, a neurotrophin known for its essential role in neuronal survival and plasticity, has garnered significant attention for its potential implications as a modulator of nociception and pain. This comprehensive review aims to provide insights into the multifaceted interactions between BDNF and pain pathways, encompassing both physiological and pathological pain conditions. I delve into the molecular mechanisms underlying BDNF's involvement in pain processing and discuss potential therapeutic applications of BDNF and its mimetics in managing pain. Furthermore, I highlight recent advancements and challenges in translating BDNF-related research into clinical practice.

The object of study in the article is the auxiliary variable-frequency electric drive onboard of an AC electric locomotive, and more precisely, the structure and parameters of the control system of the active corrector of power factor (ACPF), which is part of the electric drive, as a unit that ensures electromagnetic compatibility of the electric drive with other equipment on board the electric locomotive and catenary and its energy efficiency. The topic of the article's research is the substantiation of the structure of the ACPF control system, the choice of types (transfer functions) of controllers and the calculation of their parameters. The research method chosen was the calculation of the transfer functions of the controllers of the cascaded loops control system, followed by computer simulation using the OrCAD software. The results of simulating a cascaded two loops control system of an ACPF with different types of controllers are presented and analytically compared. It is concluded that it is advisable to use a cascaded two loops control system, containing a voltage control loop and a current control loop. The best results show the simulation when using an aperiodic current controller (A-controller) and a proportional-integral voltage controller (PI-controller). The data obtained serve as the basis for further improvement of the operation of the ACPF by enhancing and optimizing the settings, structure and algorithms of the control system, which, with the selected hardware of power converter unit, will allow the ACPF to perform its functions with a high degree of reliability in an entire range of disturbing and control influences.

Macrophages are the key effector cells of innate immunity which show two polarized states: M1, classically activated and M2, alternatively activated. Tumor-associated macrophages (TAMs) which usually show M2 polarization, are immunosuppressive cells that enhance tumor metastasis and invasion. Also, enrichment of TAMs is known to be closely associated with poor prognosis of cancer patients. Therefore, TAMs are considered to be promising targets for immunotherapy. Importantly, tumor-derived exosomes emerged as a crucial player in immune regulation which can remodel the tumor microenvironment towards immunosuppressive state. Of note, few studies have shown that exosomes could induce polarization of macrophages towards M2 type in tumor condition, while others showed activation of M1 or mixed phenotype. Considering the role of TAMs in cancer, there is an urgent need to decipher the exosome-mediated cross-talk between tumor cells and macrophages.For this, we used murine model of Dalton’s lymphoma (DL), wherein, firstly, we evaluated increased exosome burden by assessing exosome level in serum as well as in various tissues of tumor-bearing host. Next, proteomic profiling of lymphoma-derived exosomes was done which revealed the presence of immunomodulatory proteins. Of note, these proteins were known to alter the macrophage polarization. In order to assess the effect of these exosomes on macrophages, we performed in vitro study using RAW264.7 cells. In vitro study revealed that frequent uptake of exosomes mediated a morphological change in macrophages which reduced their phagocytic activity. In parallel, exosomes increased reactive oxygen species (ROS) level and inhibited LPS-induced nitric oxide (NO) level in macrophages. Also, exosomes upregulated the expression of arginase-1 (an M2 marker) in macrophages but decreased the LPS-induced nitric oxide synthase 2 (NOS2) (an M1 marker) expression. Moreover, we observed a pro-tumoral cytokine profile in macrophages incubated with exosomes. Our study suggests that exosome load increases in lymphoma-bearing hosts systemically. Importantly, lymphoma-derived exosomes mediate the activation of macrophages towards pro-tumoral M2 type. Our results give an insight into the exosome-mediated tumor and immune cell cross-talk which could serve as an important prospect for targeting in cancer immunotherapy.

Dysregulation of cartilage homeostasis and the changes in the density and the architecture of the subchondral bone were postulated as a potent mechanically pathological activity contributing to osteoarthritis (OA) pathogenesis. Extracorporeal shockwave therapy (ESWT) is a new, none invasive and effective method in the treatment of animal OA model. In the current study, we demonstrated that shockwave induced the expression of protein-disulfide isomerase-associated 3 (Pdia-3) which is a multifunctional protein hypothesized to be a significant mediator for 1α,25-Dihydroxyvitamin D3 (1α,25(OH)₂D₃) signaling pathway using two-dimensional electrophoresis. Histological analysis and quantitative polymerase chain reaction (qPCR) were verified and observed that the expression of Pdia-3 at 2 weeks was significantly higher than that of any other group at 4 weeks, 8 weeks, and 12 weeks post-shockwave treatment in early OA knee of rat. The other factors of the 1α,25(OH)₂D₃ rapid membrane signaling pathway including extracellular signal-regulated protein kinases 1 (ERK1), osteopontin (OPG), alkaline phosphatase (ALP), and matrix metallopeptidase 13 (MMP13) were measured and significantly increased by qPCR at 2 weeks post-shockwave treatment in early OA knee. Our proteomic data revealed significant Pdia-3 expression in microenvironments of joint tissue that could be actively responded to ESWT, which may potentially regulate biological function of chondrocytes and osteoblasts in the treatment of OA knee.

Helicobacter pylori cytotoxin-associated gene A protein (CagA) has been associated with the increase in virulence and risk of cancer. It has been demonstrated that CagA's translocation is dependent on its interaction with phosphatidylserine. We evaluated the variability of the N-terminal CagA in 127 sequences reported in NCBI, by referring to molecular interaction forces with the Phosphatidylserine and the docking of 3 mutations chosen from variations in specific positions. The major sites of conservation of the residues involved in CagA-Phosphatidylserine interaction were 617, 621 and 626 which had no amino acid variation. Position 636 had the lowest conservation score, so mutations in this position were evaluated to observe the differences in intermolecular forces of the CagA-Phosphatidylserine complex. We evaluated the docking of 3 mutations: K636A, K636R and K636N. The models of the crystal and mutations presented a ΔG of −8.919907, −8.665261, −8.701923, −8.515097 Kcal/mol, respectively, while mutations K636A, K636R, K636N and the crystal structure presented 0, 3, 4 and 1 H-bonds, respectively. Likewise, the bulk effect of the ΔG and amount of H-bonds was estimated in all of the docking models. The type of mutation affected both the ΔG (χ²(1) = 93.82, p-value < 2.2 × 10⁻¹⁶) and the H-bonds (χ²(1) = 91.93, p-value < 2.2 × 10⁻¹⁶). In all the data, 76.9% of the strains that exhibit the K636N mutation produced a severe pathology. The average H-bond count diminished when comparing the mutations with the crystal structure of all the docking models, which means that other molecular forces are involved in the CagA-Phosphatidylserine complex interaction.

Microglial cells are highly specialized central nervous system (CNS) cells that can promote the inflammation and neurodegeneration seen in Multiple Sclerosis (MS). MS is a neurodegenerative autoimmune disease characterized by inflammation, demyelination, and axonal degeneration. In MS patients, demyelination is associated with activated microglia. Endothelin-1 (ET-1) is a potent vasoconstrictor that induces severe and prolonged cerebral vasoconstriction and inflammation. However, the mechanism of how ET-1 activates a proinflammatory response in the CNS is unknown. To investigate ET-1’s role in microglia activation, HMC3 cells were treated with ET-1 in the presence or absence of endothelin receptor B antagonist, BQ788. TNFα and IL-6 levels were measured using ELISA. Nitric Oxide (NO) production was measured using Griess Reagent. Reactive oxygen species (ROS) production was measured using the MUSE Oxidative Stress kit. ET-1 increases TNFα levels by 56% (p= 0.0003) and IL-6 levels by 86% (p= 0.0111) in HMC3 cells, and it was decreased to basal levels in the presence of BQ788. NO and ROS production is induced by ET-1 (p&lt;0.05), and treatment with BQ788 was able to decrease them. ET-1 increases STAT-1 activation by 3.5 folds compared to control (p &lt;0.0001) in microglia cells. Moreover, to study ET-1 levels in MS, we used C57BL/6 mice brains with or without induced experimental autoimmune encephalomyelitis (EAE). The brain ET-1 levels were measured by qPCR and ELISA. We found that the ET-1 gene and protein were upregulated by 1.5 folds (p= 0.0199) in EAE mice compared to the control. These data suggest that in vitro administration of ET-1-activated microglia significantly increased inflammatory cytokine levels and NO and ROS formation. This novel mechanism of microglial cell activation will provide key information to understand MS pathogenesis.

Climate changes challenges people’s life and sustainability. Environmental problems seem to derive from human behavior. Dentistry has a high environmental footprint that needs to be controlled worldwide. Thus, the change of behavior of dentists is a necessary condition to improve the environmental situation. In this study we use a system dynamics approach to analyze pro-environmental behavior in dentists. Systemic modelling in this case, allow us to make a clear prediction of how the population of non-eco dentists will change in the future if certain factors will be affected and how much time will be needed by the system of a group of dental professionals to become eco- dentists. The ECODENT model was designed with Vensim software. It was based on the influence of WOM (word of mouth) spread of information among colleagues and stakeholders (e.g. patients, auxiliary staff and community) and other factors such as dental income, state support, CaPex and OpEx, education hours, level of urbanization and time to react. By changing each one of them we can observe the changes in the groups of non-eco and eco dentists as well as the flow of the phenomenon. It is tested that by augmenting WOM parameter, state economic support or education hours, while diminishing CaPex and OpEx, changes in pro-environmental behaviors of dentist will be reported in a shorter time. The ECODENT model can be used to further study pro-environmentalism in different dental groups and associations and design relevant eco-friendly educational programs.

LSM4 is an essential yeast gene encoding a component of different LSM complexes involved in the regulation of mRNA splicing, stability and translation. In previous papers we reported that the expression in S. cerevisiae of the K. lactis Lsm4 gene lacking the C-terminal Q/N-rich domain in a Lsm4 null strain S. cerevisiae (Sclsm4D1) restored cell viability. Nevertheless, in this transformed strain we observed some phenotypes which are typical markers of regulated cell death, Reactive Oxygen Species and oxidated RNA accumulation. In this paper we report that a similar truncation operated in the S. cerevisiae LSM4 gene confers to cells the same phenotypes observed with the K.lactis LSM4D1 gene. Up to now there was no evidence on the direct involvement of LSM4 in autophagy. Here we found that the Sclsm4D1 mutant showed defects in the induction of autophagy and it was very sensitive to nitrogen starvation or treatment with low doses of rapamycin, an inducer of autophagy. Moreover, both during nitrogen starvation and ageing, the Sclsm4D1 mutant accumulated cytoplasmic autophagy-related structures, suggesting a role of Lsm4 in Phagophore Assembly Site (PAS) processing and/or vacuolar autophagosome internalization

The prevalence of food allergy has increased in recent years, especially in children. Food allergen avoidance and symptomatic drugs in case of an allergic reaction remain the standard of care in food allergy. Nevertheless, increasing attention has been given to the possibility to treat food allergy, through immunotherapy, particularly oral immunotherapy (OIT). Several OIT protocols and clinical trials have been published. Most of them focus on children allergic to milk, egg, or peanuts, although recent studies developed protocols for other foods, such as wheat and different nuts. OIT efficacy in randomized controlled trials is usually evaluated as the possibility for patients to achieve desensitization, while the issue of a possible long-term sustained unresponsiveness has not been completely addressed. Here, we evaluated current OIT knowledge, focusing on the results of clinical trials and current guidelines. Specifically, we wanted to highlight what is known in terms of OIT efficacy and effectiveness, safety, and impact on quality of life. For each aspect, we reported the pros and the cons, inferable from published literature. In conclusion, even though many protocols, reviews and meta-analysis have been published on this topic, OIT remains a controversial therapy and no definitive generalized conclusion may be drawn so far. It should be an option provided by specialized teams, when both patients and their families are prone to adhere to the proposed protocol. Efficacy, long-term effectiveness, possible role of adjuvant therapies, risk of severe reactions including anaphylaxis or eosinophilic esophagitis, and impact on the quality of life of both children and caregivers are all aspects that should be discussed before starting OIT. Future studies are needed to provide firm clinical and scientific evidence, which should also consider patient reported outcomes.

Indoor dusts are collectively formed from anthropogenic and atmospheric activities. Particle matter 10 (PM10) is inhalable and causes significant inflammation by interaction with the pulmonary epithelial barrier. The mediators involved in bronchial epithelial cells response to dust are remined unknown. The air-liquid interface of our lung on chip model was exposed to indoor dust collected from highly polluted houses in Delhi, India. The media were collected after 4 days and cytokine levels were measured. We found that the concentration of IFN, IFNγ, Interleukin-6 (IL-6), IL1b, TNFa, and Granulocyte monocyte colony stimulating factor (GM-CSF) were significantly increased after exposure to indoor dust. IFN type I pathways were a major response from dust exposure. Further investigation is needed to determine the mechanism of action and targets of dust in bronchial epithelial cells.

Cervical cancer is the fourth most common malignancy in women worldwide, although it is preventable with prophylactic HPV vaccination. HPV transmission-dynamic models can predict the potential for global elimination of cervical cancer. The random network model is a new approach that allows individuals to be followed, and to implement a given vaccination policy according to their clinical records. We developed an HPV transmission dynamics model on a lifetime sexual partners network based on individual contacts, also accounting for the sexual behavior of men who have sex with men (MSM). We analyzed the decline in the prevalence of HPV infection in a scenario of 75% and 90% coverage for both sexes. An important herd immunity effect for men and women was observed in the heterosexual network, even with 75% coverage. However, HPV in-fections are persistent in the MSM population, with sustained circulation of the virus among un-vaccinated individuals. Coverage around 75% of both sexes would be necessary to eradicate HPV-related conditions in women within five decades. Nevertheless, the variation in the decline in infection in the long term between vaccination coverage of 75% and 90% is relatively small, suggesting that reaching coverage of around 70-75% in the heterosexual network may be enough to confer high protection. Nevertheless, HPV eradication maybe achieved if men’s coverage is strictly controlled. This accurate representation of HPV transmission demonstrates the need to maintain high HPV vaccination coverage, especially in men, for whom the cost-effectiveness of vaccination is questioned.

According to Hofstede’s theory of cultural dimensions, cultures differ in cultural values and norms; values and norms that may influence differences in trendsetting, creative traits and behaviors, and pro-environmental behaviors. Further, because men and women have been socialized within particular cultures, gender differences may exist in trendsetting, creative traits and behaviors, and pro-environmental behaviors. Trendsetters have characteristics that are interrelated with creative traits and behaviors, perhaps inclining them to endorse pro-environmental behaviors. However, the interrelationships among these variables remain unexplored. Thus, the purpose of this study was to examine these three variables among college students in South Korea and the United States, specifically looking at cultural and gender differences. Participants were 225 Korean college students and 221 U.S. college students. Questionnaires included demographic items and scales measuring trendsetting, creative traits and behaviors, and pro-environmental behaviors. Data analyses included descriptive statistics, Cronbach’s alpha reliability, MANOVA, ANOVA and SNK posthoc test. Results show that U.S. (vs Korean) students indicated greater trendsetting and creative traits and behaviors but not greater pro-environmental behaviors. Fashion trendsetting groups in both Korea and the U.S. differed in creative traits and behaviors and pro-environmental behaviors. Among Korean trendsetting groups, reluctant adopters scored lowest on creative traits and behaviors and pro-environmental behaviors. Among U.S. trendsetting groups, trendsetters scored highest on creative traits and behaviors and pro-environmental behaviors; reluctant adopters scored lowest on pro-environmental behaviors. Theoretical and practical implications are provided for researchers and marketers.

The increased prevalence of obesity worldwide has been implicated for the alarming rise of the incidence of gestational diabetes and preeclampsia as well, both considered as threatening conditions for both mother and fetus. We studied gene polymorphisms of the proinflammatory cytokine Interleukin 6 (IL-6) and the gene expression levels of VEGF and VEGF-receptor all known to be involved in pregnancy complications aiming to identify possible predisposing risk factors in pregnancies with obesity. G allele of IL-6 was found to correspond with an increased risk for gestational diabetes and preeclampsia occurrence. Furthermore, in obese pregnant mothers with either gestational diabetes or pre-existing type 2 diabetes and to those developed preeclampsia it was confirmed that gene expression levels of VEGF were reduced while they were increased for VEGF receptor. We conclude that the genetic profile of the obese pregnant woman shares a common background with that of a pre-existing type 2 diabetes mellitus and therefore predisposes to complications in pregnancy.

Cacalol (C), a sesquiterpene isolated from Psacalium decompositum, has demonstrated anti-inflammatory and antioxidant activities. Its cytotoxic, antiproliferative, and pro-apoptotic effects have been previously shown in an in vitro breast cancer model. A derivative, Cacalol Acetate (CA), shows potential in regulating these processes, which had not been previously reported. This study focused on an in vitro cervical cancer model, assessing CA's anti-proliferative, pro-apoptotic, cytostatic, and anti-migratory activities using the HeLa cell line. The natural anticancer agent I3C was used as a control for comparison. CA demonstrated significant antitumor activities, including inhibiting cell growth, inducing apoptosis, arresting cells in the G2 phase of the cell cycle, and inhibiting cell migration. These effects were notably greater compared to I3C. I3C, while following a similar trend, did not induce Cas-3 expression, suggesting a different apoptotic pathway. Neither CA nor I3C increased p62 and LC3B levels, indicating they do not stimulate autophagy marker expression. Both compounds inhibited HeLa cell migrate on and induced cell cycle arrest. Despite both holding promise as anticancer agents for cervical cancer, CA's lower cytotoxicity and stronger regulation of tumor phenotypes make it a more promising agent compared to I3C.

This article delves into the pro-cyclicality of Loan Loss Provisions (LLPs) and earnings management, along with equity management, in Portuguese banks against the backdrop of implementing the IFRS 9's Expected Credit Loss (ECL) model. It concentrates on how LLPs mirror economic cycles and financial management practices, providing valuable insights into the operational dynamics of the Portuguese banking sector, marked by distinct economic and regulatory challengesThe research examined a sample of five Portuguese commercial banks, chosen from a group of seventeen in the Portuguese Banking Association. Data spanning from 2013 to 2022 were manually gathered. A multiple linear regression model was employed to scrutinize the relationship between LLPs and variables indicative of economic cycles and the earnings and equity management. The methodology aligns with the approaches of Araújo et al. (2018), Beatty and Liao (2014), and Casta et al. (2019). The analysis indicates a pro-cyclicality in LLPs within the Portuguese context, with a positive response of LLPs to economic indicators like unemployment. Contrarily, the extent of earnings and equity management under the ECL model was less marked compared to the Incurred Credit Loss (ICL) model, suggesting the impact of more stringent regulatory measures. The research corroborates the pro-cyclicality of LLPs in Portuguese banks under the ECL framework, underscoring the necessity for ongoing monitoring and refinement of models for forecasting and recognizing credit losses. The findings point to an area for improvement in financial management practices, despite regulatory enhancements, to promote transparency and ensure financial stability.

The main objective of this paper is to assess pro-environmental behavior, climate change perception, anxiety, hope and despair in different political orientations. Specific aims included to validate all the instruments; to assess whether the factor structure of the scales were valid across political orientations; to evaluate their reliability; to assess differences concerning age, gender and political orientation; to know the variables that explain pro-environment behavior; and to evaluate the moderating role of climate change perception, despair and hope in the relationship between climate change anxiety and pro-environmental behavior. Confirmatory factor analysis (CFAs), multi-group CFAs (to measurement invariance), multiple linear regressions and moderations were performed. Results showed that pro-environment behavior and climate change hope achieved the four levels of invariance across different political orientations; climate change anxiety achieved the three first levels of invariance; climate change perception and climate change despair achieved configural invariance. Climate change anxiety personal experience, climate change perception total, reality and consequences present higher values in left political orientation that in right or center. Climate change anxiety variables contribute most to explaining pro-environmental behaviors. Hope, despair and climate change perception consequences moderate de relationship between climate change anxiety and pro-environment behavior. These results open up new avenues of investigation, namely, to understand why high levels of anxiety lead to more pro-environment al behaviors.

The TRPV3 calcium ion channel is vital for maintaining skin health and has been associated with various skin-related disorders. Since TRPV3 is involved in the development of skin inflammation, inhibiting TRPV3 could be a potential treatment strategy. Alpha-mangostin isolated from Garcinia mangostana L. extract exhibits diverse positive effects on skin health; however, the underlying mechanisms remain obscure. This study investigated the TRPV3-inhibitory properties of alpha-mangostin on TRPV3 hyperactive mutants associated with Olmsted syndrome and its impact on TRPV3-induced cytokine secretion and cell death. Our findings demonstrate that alpha-mangostin effectively inhibits TRPV3, with an IC50 of 0.077 ± 0.013 μM, showing inhibitory effects on both wild-type and mutant TRPV3. TRPV3 inhibition with alpha-mangostin decreased calcium influx and cytokine release, protecting cells from TRPV3-induced death. These results indicate that alpha-mangostin reduced inflammation in TRPV3-activated skin keratinocytes, suggesting that alpha-mangostin could be potentially used for improving inflammatory skin conditions such as dermatitis.

Work on callings has burgeoned in the past 20 years, yet recent reviews exposed a lack of conceptual clarity and disagreements around its definition, components and measures. One lingering point of contention revolves around the element of prosociality: Is a calling orientation primarily motivated by self-interest, prosocially orientated, or a mix of both? This conceptual paper reviews and examines the pro-self and prosocial component of a calling outlook, by examining and comparing the ways in which they feature in different calling subtypes: Classic, neoclassic, and modern callings. Our analysis suggests that these subtypes vary in where they are located on a pro-self – prosocial continuum: Classic callings are located on the prosocial side of the axis, modern callings are located on pro-self side of the axis, and neoclassic callings can be situated in the middle of the con-tinuum, integrating self-orientated and other-orientated motivations. Our analysis further suggests that these calling subtypes draw on divergent value systems: Classic callings are propelled by self-transcendent values, modern callings are driven by self-actualization motivations, and neoclassic callings integrate both value systems. We therefore argue that the subjective experiences of pursuing a calling within each subtype pathway differ, alt-hough they may culminate in similar outcomes. The paper offers a novel framework for analyzing people’s calling that draws on their values.

Methane (CH4) has attracted attention as not only synthetic natural gas, but also one of the hy-drogen carriers in terms of energy density. On the other hand, there exist bacterial ecosystems in nature that can decompose organic compounds to produce CH4 and CO2. In this study, Clostridi-um cellulovorans was first cultivated with pig manure (PM) as an unused biomass. Regarding the measurement of organic acids by high-performance liquid chromatography (HPLC), acetate and butyrate were increased in the C. cellulovorans medium containing 0.5% PM, while formate and lactate were decreased in it. Next, in comparison with carbon sources such as glucose, cellobiose, and acetate, cocultivation of C. cellulovorans and Methanosarcina mazei or microbial flora of me-thane production (MFMP) was performed in the C. cellulovorans medium. These results revealed that 0.5% acetate as the sole carbon source produced CH4 only by cocultivating C. cellulovorans and MFMP. Furthermore, MFMP was only cultivated with 1% acetate or 1% methane as a carbon source after precultivated with 0.5% glucose medium for 12 h. As a result, methane productivity of MFMP with 1% methanol medium was approximately eight times higher than that with 1% acetate medium. Finally, next-generation sequencing (NGS) analysis of MFMP after cultivation with 1% acetate or 1% methane was carried out. Interestingly, Methanofollis (0.211%) belonging to H2/CO2 -using methanogens (CO2 reduction pathway) was dominant in the 1% acetate medium for 72 h cultivation, whereas Methanosarcina siciliae (1.178%), M. barkeri (0.571%), and Methano-follis (0.490%) were major species in 1% methanol medium for 72 h cultivation. Since Methano-sarcina spp. are belonging to acetoclasts (acetoclastic pathway), methanol could promote to grow Methanosarcina spp. rather than acetate. Therefore, it seemed Methanosarcina spp. may play a key methanogenesis in MFMP. Thus, these results will provide important information for low cost biomethane production.

The features of a class of cubic curves with a shape factor are analyzed by means of the theory of envelope and topological mapping. The effects of the shape factor on the cubic curves are made clear. Necessary and sufficient conditions are derived for the curve to have one or two inflection points, a loop or a cusp, or to be locally or globally convex. Those conditions are completely characterized by the relative position of the edge vectors of the control polygon and the shape factor. The results are summarized in a shape diagram, which is useful when the cubic parametric curves are used for geometric modeling. Furthermore we discussed the influences of the shape factor on the shape diagram and the ability for adjusting the shape of the curve.

Many ethical issues arise when robots are introduced into elder-care settings. When ethically charged situations occur, robots ought to be able to handle them appropriately. Some experimental approaches use (top-down) moral generalist approaches, like Deontology and Utilitarianism, to implement ethical decision-making. Others have advocated the use of bottom-up approaches, such as learning algorithms, to learn ethical patterns from human behaviour. Both approaches have their shortcomings when it comes to real-world implementations. Human beings have been observed to use a hybrid form of ethical reasoning called Pro-Social Rule Bending, where top-down rules and constraints broadly apply, but in particular situations, certain rules are temporarily bent. This paper reports on implementing such a hybrid ethical reasoning approach in elder-care robots. We show through simulation studies that it leads to better upholding of human values such as autonomy, whilst not sacrificing beneficence.

Beta-glucan-stimulated mammalian macrophages show an increased responsiveness to secondary stimulation in a nonspecific manner. This phenomenon is known as trained innate immunity. Our study aimed to explore training of primary chicken monocytes. We hypothesized that primary chicken monocytes, similar to their mammalian counterparts, can be trained with β-glucan resulting in increased responses of these cells to a secondary stimulus. Primary blood monocytes of white leghorn chickens were primary stimulated with β-glucan microparticulates (M-βG), LPS, recombinant chicken interleukin-4 (IL-4) or combinations of these components for 48 h. On day 6, the primary stimulated cells were secondary stimulated with LPS. Nitric oxide (NO) production levels were measured as an indicator of pro-inflammatory activity. In addition, the cells were analysed by flow cytometry to characterize the population of trained cells and to investigate the expression of surface markers associated with activation. After the secondary LPS stimulation, surface expression of CSF1R and the activation markers CD40 and MHC-II was higher on macrophages that were trained with a combination of M-βG and IL-4 compared to unstimulated cells. This increased expression was paralleled by enhanced NO production. In conclusion, this study showed that trained innate immunity can be induced in primary chicken monocytes with β-glucan, which is in line with previous experiments in mammalian species. Innate immune training may have potential to improve health and vaccination strategies within the poultry sector.

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.

Pro-regenerative lipid mediator 1 (PreM1) is a specialized pro-resolving lipid mediator capable of promoting wound healing and regenerative functions of mesenchymal stem cells (MSCs), en-dothelial cells, and macrophages. The third-degree (3o) burn healing and regenerative functions of MSCs are also enhanced by ACgel1, an arginine and chitosan-based protein-mimic hybrid hy-drogel. Adipose-tissue derived microvascular fragments (MVFs) are native vascularization units and a rich source of MSCs, endothelial cells, and perivascular cells for tissue regeneration. Here we describe an innovative PreM1-MVFs-ACgel1 construct that incorporates PreM1 and MVFs into ACgel1 via optimal design and fabrication is capable of delivering PreM1 to 3o burn wounds at least up to 7 days post-burn (dpb), and of scaffolding and delivering MVFs, which promoted 3o burn the healing in mice, including vascularization and collagen formation. The re-epithelization and closure of 3o burn wounds were promoted by ACgel1, MVFs, PreM1, MVFs-ACgel1, PreM1-ACgel1, or PreM1-MVFs-ACgel1 at certain time-point(s) while PreM1-MVFs-ACgel1 was most effective. The PreM1-ACgel1 and MVFs-ACgel1 also promoted blood vessel regeneration of the 3o burns. These PreM1- and/or MVFs- functionalized ACgel1 have nonexistent or minimal graft-donor requirements and are promising adjuvant therapies for overcoming the drawbacks of current skin grafting or substituting for treating severe deep burns.

This study aimed to investigate the appearance and frequencies of the booroola polymorphism of the bone morphogenetic protein receptor 1b (BMPR1B) gene (FecB) and the embrapa polymorphism of the growth differentiation factor 9 (GDF9) gene (FecGE) in sheep in Thailand. A total of 454 cross-bred sheep blood samples were collected from four provinces in Thailand during August 2022 to July 2023. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used to identify the FecB and FecGE genotype. The history of ewe birth types was collected from the owners to analyze the association between Fecundity (Fec) genotypes and the history of birth types. The genotypic frequencies of FecB for homozygous genotype (B/B), heterozygous genotype (+/B) and wild-type (+/+) were 0.22%, 1.54%, and 98.24%, respectively. Meanwhile, the genotypic frequencies of FecGE for homozygous genotype (E/E), heterozygous genotype (+/E), and wildtype (+/+) were 0.00%, 2.42%, and 97.58%, respectively. Furthermore, three ewes exhibited both FecB and FecGE genotypes. Fisher’s exact test revealed that the possessor of FecB genotype was associated with multiple births (p&lt;0.01). Both FecB and FecGE mutations were identified in crossbred sheep in Thailand. Sheep containing FecB allele is a better candidate to be selected to improve the prolificacy of crossbred sheep in Thailand.

Xaa-Pro dipeptidase (XPD, EC 3.4.13.9; also known as prolidase) catalyzes the hydrolysis of iminopeptide bond in the trans Xaa-Pro dipeptides (Xaa represents any amino acid except proline), which makes it find wide applications in food, medical and environmental protection fields. In the present study, a novel Xaa-Pro dipeptidase from Aspergillus phoenicis ATCC 14332 (ApXPD) was molecularly and biochemically characterized. Reclassification based on phylogenetic analysis and version 12.5 MEROPS database showed that this enzyme was the only fungal XPD in the unassigned subfamily which shared the highest sequence similarity with Xanthomonas campestris prolidase but not with that from the more related fungal species A. niudulans. As compared with other prolidases, ApXPD also contained an N-terminal tail (residues 81-89) and an additional region (PAPARLREKL), and used a different arginine residue for dipeptide selectivity. After heterologous expression and partial purification, recombinant ApXPD was highly active and stable over the alkaline range from 8.5 to 10.0, with a maximum activity at pH 9.0 and more than 80% activity retained after 1-h incubation at pHs of 8.5-10.0 (55oC). It also had an apparent optimum temperature of 55oC and remained stable at 20-30oC. Moreover, this enzyme was a cobalt dependent prolidase that only cleaved dipeptides Lys-Pro, Gly-Pro and Ala-Pro rather than other dipeptides, tripeptides and tetrapeptides. All these distinct features make A. phoenicis ATCC 14332 XPD unique among currently known prolidases, thus defining a novel Xaa-Pro dipeptidase subfamily.

Drought events are evident effects of climate change around the globe and yield several socio-economic impacts. Such effects are even more relevant for South America (SA) since different activities essential for the continent, like agriculture and energy generation, depend highly on water resources. Thus, this study aimed to evaluate future changes in precipitation and hydro-logical droughts occurrence in SA through climate projections from eight global climate models (GCMs) of CMIP6. To this end, statistical downscaling was applied to the projections with the Quantile Delta Mapping technique, and the method proved to be efficient in reducing systematic biases and preserving GCMs’ trends. For the following decades, the results show considerable and statistically significant reductions in precipitation over most of SA, especially during the austral spring, with the most intense signal under the SSP5-8.5 forcing scenario. Furthermore, GCMs showed mixed signals about projections of the frequency and intensity of drought events. Still, they indicated agreement regarding the increase in duration and severity of events over all of SA and a substantial proportion of moderate and severe events over most of Brazil during the 21st century. These results can be helpful for better management of water resources by deci-sion-makers and energy planners.

Mass cells (MCs) are tissue cells that are derived from bone marrow stem cells that contribute to allergic reactions, inflammatory diseases, innate and adaptive immunity, autoimmunity, and mental disorders. MCs located near the meninges communicate with microglia through the production of mediators such as histamine and tryptase, but also through the secretion of IL-1, IL-6 and TNF, which can create pathological effects in the brain. Preformed chemical mediators of inflammation and tumor necrosis factor (TNF) are rapidly released from the granules of MCs, the only immune cells capable of storing the cytokine TNF, although it can also be produced later through mRNA. The role of MCs in nervous system diseases has been extensively studied and reported in scientific literature and is of great clinical interest. However, many of the published articles concern studies on animals (mainly rats or mice) and not on humans. MCs are known to interact with neuropeptides that mediate endothelial cell activation, resulting in central nervous system (CNS) inflammatory disorders. In the brain, MCs interact with neurons causing neuronal excitation with the production of neuropeptides and the release of inflammatory mediators such as cytokines and chemokines. This article explores the current understanding of MC activation by neuropeptides and the role of pro-inflammatory cytokines, suggesting a therapeutic effect of the anti-inflammatory cytokines IL-37 and IL-38.

Identifying the determinants of human behavior is useful to adjust interventions and lead the civil society towards a stronger commitment with climate change mitigation and adaptation objectives, achieving greater support for successfully implementing environmental policies. Existing research has largely focused on case studies of pro-environmental behaviors (PEBs) in developed economies but there is yet very little evidence for developing countries. This study provides estimations of the effect of internal factors, such as sociodemographic variables, and four psychological dimensions (climate change knowledge, environmental attitudes, self-efficacy, trust in sources of environmental information) on PEBs. Data was obtained through a survey applied with future decision makers - university students - from Colombia (n = 4769) and Nicaragua (n = 2354). Indices were generated for PEBs and the psychological dimensions using z-scores and Principal Component Analysis. Partial correlations were evaluated through the Ordinary Least Squares method. Our results suggest that, in order to reach the planned emission reduction targets, policy approaches should more strongly focus on educating and motivating citizens and prepare them for contributing to the environmental cause, as well as provide individual solutions to combat climate change, rather than providing only information on its causes and consequences.

In this study, bioactive compounds present in chestnut shells (CS) - derived from the industrial peeling processing - were extracted through different procedures. The aqueous extracts were characterized and the highest extraction yield and total phenolic content was obtained by Conventional Liquid Extraction (CLE). Gallic and protocatechuic acids were the main simple phenols in the extract with 86.97 and 11.20 mg/g chestnut shells dry extract (CSDE), respectively. Six tumor cell lines (DU 145, PC-3, LNCaP, MDA-MB-231, MCF-7 and Hep G2) and one normal prostate epithelial cell line (PNT2) were exposed to increasing concentration of CSDE (1-100 µg/mL) for 24 h and cell viability was evaluated using MTT assay. A reduced rate in cell viability was observed in DU 145, PC-3, LNCaP and MCF-7 cells while viability of MDA-MB-231 and Hep G2 cells was not affected except for PNT2 cells at a concentration of 100 µg/mL. Furthermore, CSDE-at concentrations of 55.5 and 100 µg/mL- lead to a significant increase of apoptotic cells in DU 145 cells of 28.2% and 61%, respectively. In conclusion, our findings showed that CS might be used for the extraction of several polyphenols that may represent good candidates for alternative therapies or in combination with current chemotherapeutics.