Contact inhibition (CI) represents a crucial tumor-suppressive mechanism responsible for controlling the unbridled growth of cells, thus preventing the formation of cancerous tissues. CI can be further categorized into two distinct yet interrelated components: CI of locomotion (CIL) and CI of proliferation (CIP). These two components of CI have historically been viewed as separate processes, but emerging research indicates that they share both distinctive and common pathways. Moreover, they exhibit intriguing intersections with mechanotransduction, a process that involves cells sensing and responding to mechanical forces. This review article describes the intricate interplay between mechanical forces and CI, shedding light on how these forces regulate CIL and CIP. Emphasis is placed on filamin A (FLNA)-mediated mechanotransduction, elucidating how FLNA senses mechanical forces and translates them into crucial biochemical signals that regulate cell locomotion and proliferation. In addition to FLNA, trans-acting factors (TAFs) emerge as sensitive players in both CI and the mechanotransduction process. This article presents methods for identifying these TAFs and profiling the associated changes in chromatin structure, offering valuable insights into CI and mechanotransduction regulation. Finally, it addresses unanswered research questions in these fields and delineates their possible future directions.

Based on screening in computational biology and biological in vitro assays, five natural products isolated from extracts of the herbal medicine toad skin, such as cinobufagin (CBFi), bufalin (BFi), arenobufagin (ABFi), telocinobufagin (TBFi), bufotalin (BFTi), were subjected to molecular docking calculations with the use of SARS-CoV-2 main protease (PDB 6LU7 and 7BTF) and top-scoring ligand-receptor complexes were obtained. The results showed that the binding energy of ABFi to the 3CL protein was -17.044kcal/mol, which was higher than CBFi and TBFi. However, the binding energy of ABFi to the RdRp protease was -23.250 kcal/mol, which was much lower than that of CBFi and TBFi, EVEN lower than that of ABFi to the 3CL protein. ABFi also has polar interactions with amino acids such as Glu811, Ser814, Ser681 and Thr680 of RdRp enzyme. The results revealed that ABFi had a moderate inhibitory effect on the cell proliferation of SARS-CoV-2 in vitro, with an inhibition rate of 61.12%, even weaker than Remdesivir. This new discovery provides us with new ideas for in-depth studies on the development of natural products with this class of structural generalizations as inhibitors of SARS-CoV-2, and provides an experimental basis for the next step of mechanistic studies.

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

Amitriptyline is a tricyclic antidepressant commonly used for depressive disorders and pre-scribed off-label for several neurological conditions like neuropathic pain, migraine and anxiety. Amitriptyline potentiates the monoaminergic transmission by blocking the reuptake of norepi-nephrine and serotonin. However, antidepressants also act on additional targets that contribute to either therapeutic or adverse effects and may suggest new indications for their repurposing. Furthermore, since depression is often a co-morbidity in patients with chronic conditions (i.e. cancer, neurodegenerative diseases) the use of antidepressants interfering with pathways in-volved in cell homeostasis may affect the progression and outcome of these pathologies. Here we investigate the effects of amitriptyline on proliferation and autophagy in human SH-SY5Y neuroblastoma cells. Dose and time-dependent upregulation of the autophagy markers LC3II and autophagy receptor p62, with accumulation of LAMP1 positive compartments, were observed in SH-SY5Y cells exposed to amitriptyline. Alteration of autophagy was accompanied by reduced cell viability and decreased clonogenic capacity, without a significant induction of apoptosis. Decrease viability and clonogenic activity were still observed in autophagy deficient Atg5 -/- MEF and following pre-treatment of SH-SY5Y culture with the autophagy inhibitor chloroquine suggesting that the amitriptyline’s effects on cell proliferation were not caused by the modulation of autophagy. Our findings demonstrate that amitriptyline acts on pathways that are crucial for cell and tissue homeostasis and pose the basis for further studies on the potential application of these effects and the consequences during long-term antidepressant treatment.

Purpose of research was to determine changes in optical quality for monthly disposable soft contact lenses (SCL) wearers with new and monthly worn SCL. Retinal straylight was assessed in SCL wearers using a C-Quant straylight meter. The study included 33 participants (age 22 ± 1.4 years) who wore monthly disposable silicone hydrogel contact lenses. Measurements were taken with month-old SCL that had been worn for no more than 4 hours. Participants then replaced the old lenses with new ones. After a 15-minute adaptation period, straylight measurements were taken with the new SCL. A questionnaire was administered to all participants, inquiring about vision complaints and the type of contact lens material used. The decimal logarithm of the stray-light parameter, log(s), was notably higher with month-old SCL (log(s) = 0.97±0.17) than with brand-new SCL (log(s) = 0.86±0.15), p < 0.001. The average increase in retinal straylight after a month of SCL use was log(s) = 0.11 ± 0.08. The questionnaire revealed that 35% of participants observed a reduction in visual quality after wearing the contact lenses for a month. Results showed that monthly disposable soft contact lenses could reduce visual quality when scheduled replacement time has been reached.

In this paper, we study the global existence and exponential decay for a dynamic contact problem between a Timoshenko beam with second sound and two rigid obstacles, of which the heat flux is given by Cattaneo's law instead of the usual Fourier's law. The main difficulties arise from the irregular boundary terms, from the low regularity of the weak solution and from the weaker dissipative effects of heat conduction induced by Cattaneo's law. By considering related penalized problems, proving some a priori estimates and passing to the limit, we prove the global existence of the solutions. By considering the approximate framework, constructing some new functionals and applying the perturbed energy method, we obtain the exponential decay result for the approximate solution, and then prove the exponential decay rate to the original problem by utilizing the weak lower semicontinuity arguments.

Electrical contacts are important circuit components with diverse industrial applications, and their failure can lead to multiple unwanted effects. Hence, the behavior of electrical contacts is a widely studied topic in scientific literature based on various approaches, tools, and techniques. The present study proposes a numerical modeling and simulation approach based on the Holm contact theory to study the dependence between the electric potential and the temperature within an electrical contact. Structured in 5 sections, the research was conducted using COMSOL Multiphysics software and its solid-state mechanics, electric current, and heat transfer modules in order to highlight contact behavior from mechanical, electrical and thermal points of view: the von Mises stress, contact force, the electric field amplitude, the variation of the electrical potential along the current path, the temperature gradient, and dependence of temperature along the contact elements edges were obtained by simulation and graphically represented. The results are in line with the expectations and with past research that was studied in the literature review.

In the present work, an innovative range of foams, based on flax gum-filled epoxy resin was developed, reinforced or not by flax fibers. Foams and composites with different gum and epoxy resin contents were produced and characterized for mechanical and thermal performances. To enhance the organic flax gum filler's cross-linking, we exploited the oxidized components' reactivity with the amine hardener (isophorone diamine). We compared the materials obtained with those derived from the native components. Flax gum and fibers were primarily characterized by chemical analysis, NMR, and FTIR to evaluate the mild oxidation of native materials. The formation of chemical bonds between oxidized polymer chains, epoxy resin, and hardener has been evidenced by FTIR, and the materials were then studied by SEM, X-ray computed micro-tomography (CT), and submitted to mechanical and thermal tests. The relevance of oxidation treatment was highlighted, through a significant increase in density and mechanical performances (+36% and +81%, respectively for the 100% flax gum material). The positive effect of flax fibers on homogeneity evidenced through micro-CT analysis was also clearly addressed. This set of promising results paves the way for future development of fully flax-based insulation composite materials.

The SARS-CoV-2 pandemic has resulted in the generation of evolutionary-related variants. The S-protein of the B.1.1.7 variant (deletion N-terminal domain (NTD) His69Val70Tyr144) may contribute to altered infectivity. These mutations may have been presaged by animal mutations in minks housed in mink farms that according to the present analysis by modelling of protein ligand docking altered a high affinity binding site in the S-protein NTD. These mutants likely occurred only sporadically in humans. Tissue-adaptations and the size of the mink relative to the infected human population size back then may have comparatively increased the relative mutation rate. Simple, multi-threaded automated docking that is widely available, assigns increased binding of the blood type II A antigen to the SARS-Cov-2 S-protein NTD of B.1.1.7 with an overall increased docking interaction of blood group A harbouring glycolipids relative to group B or H (H, p=0.04). The top scoring glycan is identified as a DSGG (also classified as sialosyl-MSGG or disialosyl-Gb5) that may compete with heparin, which is similar to heparan sulfate linked to proteinaceous receptors on the tissue surface. Other glycolipids are found to interact with lower affinity, except long ligands that have suitable ligand binding poses to match the curved binding pocket.

Increasing evidence points to the role of endogenous retroviruses (ERVs) in driving cancer cell proliferation. The purpose of this study was to explore the possibility of repurposing antiretroviral agents to inhibit ERVs as a new approach in cancer treatment. We found that an integrase strand-transfer inhibitor, dolutegravir (DTG), effectively inhibited the proliferation of multiple cancer cell lines and its antiproliferative potency was positively correlated with the expression levels of the human endogenous retrovirus type K (HERV-K). DTG inhibited the expression of HERV-K in multiple human cancer cell lines and the mouse mammary tumor virus (MMTV) in the murine 4T1 mammary cancer cell line. We chose the fast-growing BT-20 cell line as a model to study the in vitro antiproliferative mechanisms of DTG. BT-20 cells overexpressing both HERV-K env and pol genes became more resistant to DTG than cells transduced with vector alone. Knockdown of HERV-K also increased DTG resistance of BT-20 cells. The antiproliferative effect of DTG correlated with enhanced expression of E-cadherin and reduction in cell motility and invasiveness. Surprisingly, DTG stimulated expression of the env gene of MMTV in vivo and promoted metastasis of 4T1 tumor cells to the lungs. Taken together, our data support a role of ERVs in tumor development and encourage further search for antiretroviral agents to treat malignancies in which endogenous retroviruses are active.

Predation is a driving force of organismal ecology and evolution. Predator-prey interactions, constrained by other environmental factors and historical contingency, shape physical and behavioral phenotypes of organisms on both sides of the interaction arrow. Yet despite the universality of trophic interactions in biology, study of the ecology and evolution of anti-predator defense is challenging because these interactions tend to be brief and unpredictable, and thus gathering direct evidence requires patience and serendipity. The evolution of prey defenses can be studied by DNA sequencing followed by phylogenetic analysis, and the ecology can be studied by field observation and bringing tractable systems into the lab. However, animal models generally do not allow genetic manipulation, strict control of environmental variables, or detailed observation of evolution in real time, all of which are important for demonstrating evolutionary causes and consequences. Developing complementary microbial predator-prey systems can help overcome this hurdle. There is an extensive body of work on microbial experimental evolution, and many microbes come with well-characterized genomes and established methods for genetic manipulation. As understanding of microbial ecology and the mechanisms of their trophic interactions grows apace, these systems are poised to make valuable contributions to our understanding of how predator behaviors evolve, why certain anti-predator defenses evolve and not others, and how multiple defenses function together in a single defense portfolio. These systems will enable us to both test hypotheses formulated from the study of larger organisms and to propose new ones that can be tested in larger organisms with existing methods.

Pancreatic cancer is the fourth most common cause of cancer mortality worldwide. Furthermore, patients with pancreatic cancer experience limited benefit from current chemotherapeutic approaches because of drug resistance. Therefore, an effective therapeutic strategy for patients with pancreatic cancer is urgently required. Deguelin is a natural chemopreventive drug that exerts potent antiproliferative activity in solid tumors by inducing cell death. However, the molecular mechanisms underlying this activity have not been fully elucidated. Here we show that deguelin blocks autophagy and induces apoptosis in pancreatic cancer cells in vitro. Autophagy induced by doxorubicin plays a protective role in pancreatic cancer cells, and suppressing autophagy by chloroquine or silencing autophagy protein 5 enhanced doxorubicin-induced cell death. Similarly, inhibition of autophagy by deguelin also chemosensitized pancreatic cancer cell lines to doxorubicin. These findings suggest that deguelin has potent anticancer effects against pancreatic cancer and potentiates the anti-cancer effects of doxorubicin. These findings provide evidence that combined treatment with deguelin and doxorubicin represents an effective strategy for treating pancreatic cancer.

Our results demonstrated that SWT stimulates osteoblastogenesis and increase the cell number of osteoblasts, suggesting positive regulatory effects on osteoblast differentiation. However, the effect of SWT on bone formation need further examination, since the expression of alp gene is downregulated. On the other hand, SWT appears to negatively regulate osteoclast differentiation and bone resorption, as number of osteoclasts and the expression of critical bone resorptive genes are all downregulated. Collectively, SWT might change the equilibrium of bone remodeling and increase the bone mass. Our data provided supportive evidences that this medicine formulation can be applied to treat osteoporosis or bone destructive diseases.

A reliable and efficient rail track defect detection system is essential for maintaining rail track integrity and avoiding safety hazards and financial losses. Eddy current (EC) testing is a non-destructive technique that can be employed for this purpose. The trade-off between spatial resolution and lift-off should be carefully considered in practical applications to distinguish closely spaced cracks such as those caused by rolling contact fatigue (RCF). A multi-channel eddy current sensor array has been developed to detect defects on rails. Based on the sensor scanning data, defect reconstruction along the rails is achieved using an inverse algorithm that includes both direct and iterative approaches. In experimental evaluations, the EC system with the developed sensor is used to measure defects on a standard test piece of rail with a probe lift-off of 4-6 mm. The reconstruction results clearly reveal cracks at various depths and spacings on the test piece.

Background/Objectives: Dental implants have become a cornerstone of restorative dentistry, providing a long-lasting method for tooth replacement. The level of osseointegration has a big impact on the biomechanical stability at the bone-implant contact (BIC), which determines how long these implants will work. However, the exact consequences of changing osseointegration levels on different implant designs, especially in bones with variable densities, are not well known. Three short dental implants were tested in this study: BioMet 3iT3, Straumann® Standard Plus Short Regular Neck (SPS-RN), and Straumann® Standard Plus Short-Wide Neck (SPS-WN). 3D finite element analysis (FEA) was used to look at how well they worked biomechanically. This paper tests the implants at four stages of osseointegration: 25%, 50%, 75%, and 100% in both high-density (Bone Type III) and low-density (Bone Type IV) cancellous bone. It also created and examined realistic CAD models under static occlusal loading conditions to assess stress distribution and major strains at the bone-implant contact.; Results: The study discovered that as osteointegration increases, von Mises stress and principal strains go down significantly for all implant types. The SPS-WN implant had the lowest strain values, especially for bone with low density. These reductions demonstrate increased mechanical stability as the bone-implant inter-face becomes more capable of dispersing mechanical stresses, minimizing the potential for localized deformation and bone resorption.; Conclusions: The results highlight the importance of achieving optimum osseointegration to reduce mechanical stress and increase the lifespan of dental implants. The SPS-WN type implant performed better in biomechanical tests than the others, especially when bone conditions were not ideal. This makes it a great choice for clinical applications that need long-term implant success.

Predictive numerical models in the study of ground-borne vibrations generated by railway sys-tems have traditionally relied on the segmented approach of subsystems. In this approach, loads are individually applied, and the cumulative effect of rolling stock is obtained through superposi-tion. While this method serves to mitigate computational costs, it may not fully capture the com-plex interactions involved in ground-borne vibrations. Recent advancements in computational and software tools have enabled the development of more sophisticated vibrational pollution models. These advanced models encompass the entire dynamic system, from the rolling stock to the terrain, allowing for continuous simulations with a defined time step. Furthermore, the incorporation of computational contact tools between various ele-ments not only ensures temporal accuracy but also extends the analysis to the frequency domain. This paper explores the evolution of predictive numerical models in the context of ground-borne vibrations generated by trains on ballasted tracks. It highlights the shift from segmented models to continuous simulations, demonstrating the progressive advancement towards more comprehen-sive and accurate representations of railway-induced and generated vibrations in the track sur-roundings as an additional way of evaluate sustainability of infrastructures. In particular, this development of a numerical model from its inception aimed to expand upon ex-isting emission - prediction models by enriching the data with frequency-domain information. This approach has been driven by the aspiration to bridge the gap between numerical predictions and measured signals, striving for a higher level of accuracy in our obtained results. This model can predict the impact of a high-speed rail (HSR) vehicle passing on its own track. It possesses sufficient information in both the time and frequency domains to precisely characterize vibrations. This initiative marks a pivotal advancement, enabling us to more effectively capture the intricacies of ground-borne vibrations and their impact on the surrounding environment due to a deeper comprehension of the occurrences in the frequency domain, there's a heightened ca-pability to accurately characterize vibrations.

The targeted compounds in this research, resveratrol analogs 1–14 were synthesized as mixtures of isomers by the Wittig reaction using heterocyclic triphenylphosphonium salts and various benzaldehydes. The planned compounds were those possessing the trans-configuration as the biologically active trans-resveratrol. The pure isomers were obtained by repeated column chromatography in various isolated yields depending on the heteroaromatic ring. It was found that butyrylcholinesterase (BChE) was more sensitive to the heteroaromatic resveratrol analogs than acetylcholinesterase (AChE), except for 6, the methylated thiophene derivative with chlorine, which showed equal inhibition toward both enzymes. Compounds 5 and 8 achieved the highest BChE inhibition with IC50 values of 22.9 and 24.8 μM, respectively. The same as with AChE and BChE, methylated thiophene subunits of resveratrol analogs showed better enzyme inhibition than unmethylated ones. Two antioxidant spectrophotometric methods, DPPH and CUPRAC, were applied to determine the antioxidant potential of new heteroaromatic resveratrol analogs. Molecular docking of these compounds was conducted to visualize the ligand-active site complexes' structure and identify the non-covalent interactions responsible for the complex's stability, which influence the inhibitory potential. As ADME properties are crucial in developing drug product formulations, they have also been addressed in this work. The potential genotoxicity is evaluated by in silico studies for all compounds synthesized.

Emphasizing the importance of acoustic attenuation in maintaining compliance with stringent noise regulations and enhancing workplace safety, the analysis covers the theoretical and practical aspects of sound attenuation in a turboengine testing stand. This paper presents a preliminary analysis and also an evaluation of a procedure for projecting a noise attenuator for industrial application and especially for turboengine test stands. While primarily focusing on the static acoustic behavior of the attenuator, considerations were also made regarding flow dynamics, Mach number-dependent attenuation, pressure drop, and self-generated noise aspects to provide a comprehensive perspective in selecting the optimal design configuration. The study investigates different calculation methods for assessment of the noise reduction for linear and staggered baffles, applied on a scaled reduced model of attenuator. Thus, the critical parameters and projecting requirements necessary for effective noise reduction in high-performance turboengine testing environments will be evaluated in a down-scaled model. Key factors examined include the selection of design parameters and configurations from various options. Advanced computational methods, like analytic and finite element analysis (FEM) are utilized to predict the acoustic performance and identify potential design optimizations. Experimental validation is performed to corroborate the simulation results, ensuring the reliability and efficiency of the attenuator. The findings indicate that a well-designed sound attenuator module can significantly reduce noise levels without compromising the operational performance of the turboengine inside a test cell.

Atopic dermatitis (AD) is a chronic inflammatory disorder presenting a dysregulated immune response and derangement of the epidermal barrier lipids. The Th2-type cytokines interleukin IL-4 and IL-13 play a prominent role in AD by activating the Janus Kinase/Signal Transduction and Activator of Transcription (JAK/STAT) intracellular signal axis. This study aimed to investigate the role of JAK/STAT in the lipid perturbations induced by Th2 signaling in 3D-epidermal equivalents. We used tofacitinib, a low-molecular-mass JAK inhibitor, to screen for the JAK/STAT-mediated deregulation of lipid metabolism. Th2 cytokines decreased the expression of elongases 1, 3, and 4, and serine-palmitoyl-transferase and increased that of sphingolipid delta(4)-desaturase, and carbonic anhydrase 2. Th2 cytokines inhibited the synthesis of palmitate and caused a depletion of triglycerides. This depletion was associated with altered PC profiles and fatty acid (FA) metabolism. Overall, the ceramide profiles were minimally affected. Except for most sphingolipids and very long chain FAs, the effects of Th2 on lipid pathways were reversed by co-treatment with tofacitinib. An increase in the mRNA levels of CPT1A and ACAT1, reduced by tofacitinib, suggests that Th2 cytokines promote FA beta-oxidation. In conclusion, pharmacological inhibition of JAK/STAT activation prevents the lipid disruption caused by halted homeostasis of FA metabolism.

Cisplatin is a widely used anticancer drug for treating solid tumors, but it is associated with severe side effects, including nephrotoxicity. Various studies have suggested that the nephrotoxicity of cisplatin could be overcome; nonetheless, an effective adjuvant drug has not yet been established. Oleanolic acid acetate (OAA), a triterpenoid isolated from Vigna angularis, is commonly used to treat inflammatory and allergic diseases. This study aimed to investigate the protective effects of OAA against cisplatin-induced apoptosis and necroptosis using TCMK-1 cells and a mouse model. In cisplatin-treated TCMK-1 cells, OAA treatment significantly reduced Bax and cleaved-caspase3 expression, whereas increased Bcl-2 expression. Moreover, in cisplatin-induced kidney injury mouse model, OAA treatment alleviated weight loss in the body and major organs and also relieved cisplatin-induced nephrotoxicity symptoms. RNA sequencing analysis of kidney tissues identified lipocalin-2 as the most upregulated gene by cisplatin. Additionally, necroptosis-related genes such as receptor interacting protein kinase (RIPK) and mixed lineage kinase domain like (MLKL) were identified. In vitro study, the phosphorylation of RIPKs and MLKL was reduced by OAA pretreatment in both cisplatin-treated cells and cells boosted by co-treatment with z-VAD-FMK. In conclusion, OAA could protect the kidney from cisplatin-induced nephrotoxicity and may serve as an anticancer adjuvant.

Natural rivers in urban areas bear significant potential to provide ecosystem services for the surrounding inhabitants. However, surface sealing by houses and street networks, urban drainage, disposal of waste and wastewater resulting from advancing urbanization usually lead to the deterioration of urban rivers and their riparian areas. This ultimately damages their ability to provide ecosystem services. This paper presents an innovative methodology for a rapid and low-cost assessment of the ecological status of urban rivers and riparian areas in developing countries under data scarce conditions. The methodology uses a combination of field data and freely available high-resolution satellite images to assess three ecological status categories: river hydromorphology, water quality, and riparian land cover. The focus here is on the assessment of proxies for biophysical structures and processes representing ecological functioning that enable urban rivers and riparian areas to provide ecosystem services. These proxies represent a combination of remote sensing land cover- and field-based indicators. Finally, the three ecological status categories are combined to quantify the potential of different river sections to provide regulating ecosystem services. The development and application of the methodology is demonstrated and visualized for each 100 m section of the Pochote River in the City of León, Nicaragua. This spatially distributed information of the ecosystem service potential of individual sections of the urban river and riparian areas can serve as important information for decision making regarding the protection, future use, and city development of these areas, as well as the targeted and tailor-made development of nature-based solutions such as green infrastructure.

Licochalcone H (LCH), a regioisomer of licochalcone C derived from the root of Glycyrrhiza inflata. CRC treatment has always been challenged by the development of resistance. We investigated the antiproliferative activity of LCH in oxaliplatin (Ox)-sensitive and -resistant CRC cells. LCH significantly inhibited cell viability and colony growth in both Ox-sensitive and Ox-resistant CRC cells. We found that LCH decreased epidermal growth factor receptor (EGFR) and AKT kinase activities and related activating signaling proteins including phospho (p)-EGFR and pAKT. A computational docking model indicated that LCH may interact with EGFR, AKT1, and AKT2 at the ATP-binding sites. LCH induced ROS generation, as verified by N-acetyl-L-cysteine (NAC) treatment, and increased the expression of the ER stress markers. LCH treatment of CRC cells induced depolarization of MMP and increased. Multi-caspase activity was induced by LCH treatment and confirmed by Z-VAD-FMK treatment. LCH increased the number of subG1 cells and arrested the cell cycle at the G1 phase. LCH inhibits the growth of Ox-sensitive and Ox-resistant CRC cells by targeting EGFR and AKT, and inducing ROS generation and ER stress-mediated apoptosis. Therefore, LCH could be a potential therapeutic agent for improving not only Ox-sensitive but also Ox-resistant CRC treatment.

The novel coronavirus disease (COVID-19) pandemic has resulted in over 720 million confirmed cases and 7 million deaths worldwide, with insufficient treatment options. Innumerable efforts are being made around the world for faster identification of therapeutic agents to treat the deadly disease. Postacute sequelae of SARS-CoV-2 infection or COVID-19 (PASC), also called Long COVID, is still being understood and lacks treatment options as well. A growing list of drugs are being suggested by various in silico, in vitro and ex vivo models, however currently only two treatment options are widely used: the RNA-dependent RNA polymerase (RdRp) inhibitor remdesivir, and the main protease inhibitor nirmatrelvir in combination with ritonavir. Computational drug development tools and in silico studies involving molecular docking, molecular dynamics, entropy calculations and pharmacokinetics can be useful to identify new targets to treat COVID-19 and PASC, as shown in this work and our recent paper that identified alendronate as a promising candidate. We have now investigated all bisphosphonates which can bind competitively to nidovirus RdRp-associated nucleotidyl (NiRAN) transferase domain, and systematically down selected seven candidates (CHEMBL608526, CHEMBL196676, CHEMBL164344, CHEMBL4291724, CHEMBL4569308, CHEMBL387132, CHEMBL98211), two of which closely resemble the approved drugs minodronate and zoledronate. This work and our recent paper together provide an in silico mechanistic explanation for alendronate and zoledronate users having dramatically reduced odds of SARS-CoV-2 testing, COVID-19 diagnosis, and COVID-19-related hospitalizations, and indicate that similar observational studies with minodronate could be valuable.

Treatment of neurological disease is hampered by the lack of validated specific and sensitive biomarkers, resulting in delayed diagnosis and nonspecific disease modifying therapies. For example, in ALS the lack of a sensitive and specific biomarker impedes the ability to administer a treatment prior to or at the onset of motor neuron dysfunction. Although viral or other infectious etiologies have been proposed as a contributing factor to neurodegeneration, it can be argued that these are casual and not causal associations. In the case of ALS, evidence for direct causality would require in vivo validation of specific nucleotide sequences of microbial origin which are known to be neuroinvasive with tropism for motor neurons, such as polio and non-polio. Several viral enteropathogens recapitulate the pathological events in sporadic ALS, including the ability to cleave TDP-43 resulting in accumulation of misfolded proteins in the cytoplasm. This review provides supporting evidence that motor neuron disease is causally related to specific enteroviruses and argues that prospective validation is imperative for effective prevention and treatment.

Proteins have the ability to adsorb on the surface of materials, such as soft contact lenses (SCLs), and can affect the hydrophobicity, roughness and surface properties of the contact lenses (CLs), which, in turn, can influence the friction between the lenses and the ocular surface. Excessive friction between contact lenses and the ocular surface can lead to discomfort for the wearer and may cause irritation or inflammation of the cornea, better known as corneal ulcers (keratitis). Bovine serum albumin (BSA) is often used as a standard protein in biocompatibility testing of materials, including contact lenses. One standard commercial contact lenses was tested under lubricated conditions to access the coefficient of friction (CoF), being the contact lubricated with a tear like fluid (TLF) solution containing six different concentrations of BSA. In all cases, a good linearity of the results of the friction force was verified, so the first friction law can be applied to determine the value of the coefficient of friction. It was found that friction increases with increasing protein concentration.

Green Infrastructures (GI) are considered key to reconcile ecological and social benefits by providing multiple functions. The concept is increasingly promoted and guidelines for its implementation have been developed in many countries and regions of the Western Hemisphere. However, for other parts of the world, especially for countries with less developed infrastructures, promotion, guidance for decision-making and manuals for GI are often lacking. But the state of infrastructure development and often unplanned character of settlements in the Global South differ and result in specific constraints as well as demands to GI that need to be addressed explicitly. This study presents a methodological approach to explicitly address the specific conditions and physical limitations to GI development in urban areas of the Global South. A four step methodology was developed to assess the implementation potential for retrofitted and multifunctional urban green infrastructure in public areas. An initial site analysis (1) and the definition of design criteria as well as general strategies (2) to achieve the different dimensions of multi-functionality are the basis to derive spatial typologies (3) for GI elements and finally the spatial suitability assessment for potential placements (4). An application of the methodology to a study area in the metropolitan region of San José, Costa Rica, shows exemplarily that the potential to improve the hydrological conditions (up to 34% of surface runoff reduction), ecological conditions (increase of green space by 2,2 %, creation of 1500 m length of roadside greenery and two new habitat types), and social conditions (2.200 m of road type upgrading) of multi-functionality of the site through Green Infrastructures. These assessment results of different multi-functionality dimension can serve as a guidance for GI promotion and implementation in urban areas of the Global South.

Twelve overnight fasted, healthy, male volunteers received on separate days a test breakfast consisting of (A) 100 g fresh white bread (providing 50 g starch) and 250 mL drinking water, (B) the same bread with a supplement of 10 g alpha-cyclodextrin dissolved in the drinking water (250 mL), and (C) 250 mL drinking water containing 25 g alpha-cyclodextrin. Capillary and venous blood samples were collected before breakfast and at regular intervals for a period of 3 hours thereafter. Plasma glucose was determined in capillary blood and plasma insulin in venous blood samples. Breakfast (A) let to the expected rise in blood glucose and insulin concentrations. Breakfast (C) did not produce a significant glycemic and insulinemic response, demonstrating that alpha-cyclodextrin is not hydrolyzed to glucose in the human digestive tract. Mild intestinal symptoms after the ingestion of alpha-cyclodextrin were reported by 4 subjects. The postprandial rises of plasma glucose and insulin were significantly smaller after breakfast (B) than (A). Under the conditions of this study, alpha-cyclodextrin reduced the glycemic and insulinemic index of white bread by 57 and 55 %, respectively. The postprandial time profile of plasma glucose and insulin suggests that, in an initial phase, the digestion of starch is inhibited by alpha-cyclodextrin almost completely. Yet, despite the delayed and reduced digestion of starch, the intake of breakfast (B) was not associated with flatulence or any other gastrointestinal symptoms.

Digital gait monitoring is increasingly used to assess locomotion and fall risk. The aim of this work is analyzing the changes in the foot-floor contact sequences of Parkinson’s Disease (PD) patients in the year following the implant for deep brain stimulation (DBS). During their best-ON condition, 30 PD patients underwent gait analysis at baseline (T0), at 3 months (T1), and 12 months (T2) after the DBS neurosurgery for bilateral high-frequency subthalamic nucleus stimulation. Thirty age-matched controls underwent gait analysis once. Each subject was equipped with bilateral foot-switches and a 5-minute walk was recorded, including both straight-line and turnings. The walking speed, turning time, stride time variability, percentage of atypical gait cycles, stance, swing, and double support duration were estimated. Overall, the gait performance of PD patients improved after DBS, as also confirmed by the decrease in the UPDRS-III score from 19.4±1.8 to 10.2±1.0 points (T0 vs. T2) (p < 0.001). In particular, the percentage change of atypical gait cycles of PD more affected side decreased at T1 (Straigh-line: -72%; Turnings: -43%) and at T2 (Straigh-line: -54%; Turnings: -20%). The percentage of atypical gait cycles proved an informative digital biomarker for quantifying PD gait changes after DBS, both in straight-line paths and turnings.

An optical fiber scale sensor based on the detection principle of surface plasmon resonance (SPR) was developed for the rapid, high-sensitivity real-time evaluation of scale precipitation from geothermal fluids. The optical fiber SPR scale sensor was fabricated by depositing a gold thin film on the surface of an optical fiber with an exposed core. The optimal gold film thickness of the sensor was determined to be 30 nm, which achieved a refractive index sensitivity of 2140 nm per refractive index unit. A field test was conducted using geothermal brine from the Obama Binary Geothermal Power Plant in Unzen, Nagasaki Prefecture. A conventional optical fiber scale sensor and the SPR sensor were simultaneously assessed using raw and pH-adjusted brines. For the SPR sensor, a peak shift of 0.27 nm/min was observed at a response time of 1 min, whereas no change in transmittance was observed for the conventional sensor until 180 min. After the experiments, scanning electron microscopy–energy-dispersive spectroscopy analysis was conducted on the sensors, and findings showed that the deposition of Mg–SiO2 scale did not significantly differ between the two sensors. The developed SPR sensor achieved faster scale precipitation detection (tens of minutes to hours) than the conventional sensor.

Acute Respiratory Distress Syndrome (ARDS) is a severe lung condition with a high mortality rate for which there are no effective therapeutics. The failure of the alveolar-capillary barrier, composed of lung endothelial (EC) and alveolar epithelial (AEC) cells, is a critical factor leading to excessive inflammation and edema characteristics of acute lung injury (ALI). Phosphodiesterases (PDE) are enzymes well-recognized for their roles in regulating endothelial permeability and inflammation. Although PDE inhibitors are used as therapeutics for inflammatory diseases like COPD (chronic obstructive pulmonary disease), their efficacy in treating ARDS has not yet been established. In this study, we investigate the effects of ensifentrine, an FDA-approved novel dual PDE 3/4 inhibitor, on lung endothelial and epithelial dysfunction caused by methicillin-resistant S. aureus (MRSA), a pathogen involved in bacterial ARDS. Human primary lung endothelial cells and alveolar epithelial cell lines (A549 and immortalized AEC) were treated with heat-killed MRSA, and their responses were assessed in the presence or absence of ensifentrine. Ensifentrine given either pre- or post exposure attenuated MRSA-induced increased lung endothelial permeability. VE-cadherin junctions, which serve to stabilize the EC barrier, were disrupted by MRSA; however, ensifentrine effectively prevented this disruption. Pre-treatment with ensifentrine protected against MRSA-induced EC pro-inflammatory signaling by inhibiting the expression of VCAM-1, ICAM-1, and by reducing the IL-6 release. In AEC, MRSA caused upregulation of ICAM-1, activation of NF-kB and production of IL-8, all of which were inhibited by ensifentrine. These results indicate that dual inhibition of phosphodiesterases 3 and 4 by ensifentrine is barrier protective and attenuates MRSA-induced inflammation in both lung endothelial and epithelial cells. The PDE3/4 inhibitor ensifentrine may represent a promising novel strategy for the treatment of ALI.

Clusterin (CLU) protein is involved in various pathophysiological processes including carcinogenesis and tumor progression. In recent years, the role of the secretory isoform has been demonstrated in tumor cells, where it inhibits apoptosis and favors the acquisition of resistance to conventional treatments used to treat cancer. To determine the possible therapeutic potential of inhibiting this protein, numerous studies have been carried out in this field. In this paper, we show the existing knowledge on the inhibition of this protein in different types of cancer and discuss the importance it could have in the development of new therapies directed against this pathology.

Limited understanding exists regarding the intricate dynamics between the levels of social inhi-bition exhibited by both wives and husbands concerning their perceived family support and de-pressive symptoms, particularly within couples who are parents of children diagnosed with au-tism spectrum disorder (ASD). This study used the actor-partner, interdependence mediation model to analyze data collected from 397 pairs of Chinese parents with children diagnosed with ASD. The findings of the study revealed significant indirect actor effects, indicating that the levels of social inhibition exhibited by both wives and husbands were associated with their own de-pressive symptoms through their respective perceptions of family support. In general, the study did not find significant partner effects, except for some indirect effect (IE) of wives on their hus-bands' depressive symptoms through the wives' perceived social support. This observation sug-gests that cultural norms and role expectations within the family context may influence these dy-namics. These results underscore the potential importance of interventions aimed at addressing social inhibition and enhancing perceived family support to alleviate depressive symptoms in this population. Additionally, interventions targeting fathers should emphasize the importance of their involvement in parenting and collaboration with their partners in caring for children with ASD. Such collaborative efforts may contribute to improved outcomes for both parents and chil-dren within families affected by ASD.

The chemical investigation of the anti-yeast methanol extract from the stem bark of Terminalia mantaly led to the isolation of seven compounds: 3-O-methyl-4-O-α-rhamnopyranoside ellagic acid (1), 3-O-mehylellagic acid (2), arjungenin or 2,3,19,23-tetrahydroxyolean-12-en-28-oïc acid (3), arjunglucoside or 2,3,19,23-tetrahydroxyolean-12-en-28-oïc acid glucopyranoside (4), 2α,3α,24-trihydroxyolean-11,13(18)-dien-28-oïc acid (5), stigmasterol (6), stigmasterol 3-O-β-D-glucopyranoside (7). Their structures were established by means of spectroscopic analysis and comparison with published data. Compounds 1-5 were tested in vitro for activity against three pathogenic yeast isolates, Candida albicans, Candida parapsilosis and Candida krusei. The activity of compounds 1, 2 and 4 were comparable to that of the reference compound fluconazole (MIC values below 32 µg/ml) against the three tested yeast isolates. They were also tested for inhibitory properties against four enzymes of metabolic significance: Glucose-6-Phosphate Deshydrogenase (G6PD), human erythrocyte Carbonic anhydrase I and II (hCA I and hCA II), Glutathione S-transferase (GST). Compound 4 showed highly potent inhibitory property against the four tested enzymes with overall IC₅₀ values below 4 µM and inhibitory constant (Ki) <3 µM.

Naturally fermented dairy products are an important component of the human diet. They are a valuable source of nutrients as well as vitamins and minerals. Their importance as a source of probiotic bacterial strains should not be overlooked. A number of studies highlights the positive effects of species of the Lactobacillacea on the intestinal microbiota, the overall homeostasis of the body, as well as a complementary treatment for some diseases. However, data on the effects on intestinal epithelial cells of postmetabolites released by bacteria are incomplete. This is likely due to the fact that these effects are species and strain specific. In the present study, we investigated the effects of postmetabolites produced by a pre-selected candidate probiotic strain Limosilactobacillus fermentum on HT-29 intestinal epithelial cells. Our data showed a pronounced proliferative effect, evaluated by flow cytometry, quantification of cell population, and determination of mitotic index. This was accompanied by stabilization of the cell monolayer, measured by increase of TEER (trans epithelial electric resistance) and reorganization of actin filaments. The data obtained are a clear indication of the positive effects, that the products secreted by L. fermentum strain 53 have on the intestinal epithelial cells.

We are presenting a new method for the treatment of large macular holes (MH) with the use of an inverted flap consisting of both internal limiting membrane (ILM) and epiretinal proliferation (EP). A prospective interventional case series was conducted from September 2021 to January 2023. MH patients with coexistent EP visualized preoperatively in macula optical coherence tomography and MH minimum linear diameter larger than 400 microns underwent standard pars plana vitrectomy with the creation of an inverted petaloid flap (consisting of both ILM and EP) and gas tamponade. 16 eyes were included in our study. MH closure was successful in all the eyes with a single procedure. Preoperative minimum linear diameter was 707.63(±164.02μm) and preoperative best corrected visual acuity was 1.11±0.52. Postoperative BCVA was 0.51±0.20 (p=0.01) at 6weeks postoperatively and final BCVA was 0.45±0.20 (p=0.008). EP can be safely combined with ILM for the creation of an inverted, petaloid flap to cover and facilitate the closure of large MH.

Africa's health landscape is rapidly changing, requiring new solutions such as a focus on health literacy. However, there is currently a limited overview of the development and application of health literacy in African countries and societies. To inform progress, a scoping review was conducted, including a systematic literature search of research approaches, historical developments, geographic origins, target populations and settings, and topical interests. 336 articles were retrieved from six databases following PRISMA guidelines. Sources identified included reports, policy briefs, book chapters, and research publications. The analysis provided the most comprehensive overview of the current scope and scale of health literacy in Africa to date. The publications represented 38 of the 54 African Union countries and dated back to 2001, although most were published in the last decade. The content analysis identified 13 broad themes, including mental health, communicable diseases, non-communicable diseases, maternal health, digital health, information and communication, health care, prevention and health promotion, conceptual perspectives, cultural perspectives, outcomes and measurement. The stakeholder analysis revealed a wide range of actors involved in different settings, mostly in health care or community settings. These comprehensive and novel findings can be used to prioritize future actions for public and professional capacity building, policy development and improved practice to improve health literacy for all in Africa.

Green Infrastructure promotes the use of natural functions and processes as potential solutions to reduce negative effects derived from anthropocentric interventions such as urbanization. In cities of Latin America, for example, the need for more nature-sound infrastructure is evident due to its degree of urbanization and degradation of ecosystems, as well as the alteration of the local water cycle. In this study, an experimental approach for implementation of a prototype is presented. The experiment took place in a highly urbanized watershed located in the Metropolitan Area of Costa Rica. Initially, understanding the characteristics of the study area at different scales was achieved by applying the Urban Water System Transition Framework to identify the existing level of development of the urban water infrastructure, and potential future stages. Subsequently, preferences related to spatial locations and technologies were identified from different local decision-makers. Those insights were adopted to identify a potential area for implementation of the prototype. The experiment consisted on an adaptation of the local sewer to act as a temporal reservoir to reduce the effects derived from rapid generation of stormwater runoff. Unexpected events, not considered initially in the design, are reported in this study as a means to identify necessary adaptations of the methodology. Our study shows from an experimental learning-experience that the relation between different actors advocating for such technologies influences the implementation and operation of non-conventional technologies. Furthermore, the perception of security associated to green spaces was found as a key driver to increase the willingness of residents to modify their urban environments. In consequence, those aspects should be carefully considered as factors of designs of engineering elements when they are related to complex socio-ecological urban systems.

Candida albicans, a prominent constituent of the human microbiota, poses a significant health threat due to its opportunistic pathogenicity and adept biofilm-forming capabilities. This research delves into the antifungal attributes and biofilm inhibition potential of Tea Tree Oil (Melaleuca alternifolia) cultivated in Vietnam. Renowned for its bioactive compounds, including terpinen-4-ol, 1,8-cineole, and terpinolene, the essential oil of Melaleuca alternifolia, commonly referred to as tea tree oil (TTO), is scrutinized for its impact on Candida albicans. The study meticulously determines the Minimum Inhibitory Concentration (MIC) and Minimum Fungicidal Concentration (MFC) of TTO against Candida albicans in both planktonic and biofilm states. Additionally, it assesses the biofilm-forming capacity of Candida albicans and establishes the Minimum Biofilm Inhibitory Concentration (MBIC) and Minimum Biofilm Eradication Concentration (MBEC) of TTO. Employing a liquid culture dilution method within a defined concentration range of 0.1 μL/mL to 10 μL/mL, the experimental approach adheres to established protocols. The outcomes reveal a noteworthy MIC and MIC₈₀ of 0.1 μL/mL and 2 μL/mL, respectively, and an MFC of 10 μL/mL for TTO against Candida albicans. Furthermore, TTO exhibits an MBIC of 2 μL/mL, showcasing its efficacy in inhibiting biofilm formation. However, the MBEC of TTO remains uncertain, possibly due to insufficient concentration tested, which may not effectively disrupt over 50% of the pre-formed biofilm mass within 24 hours. These results underscore the promising potential of TTO as a potent antifungal agent and biofilm inhibitor against Candida albicans, offering valuable insights for the innovation of novel therapeutic strategies in the realm of fungal infections.

B-cell lymphoid malignancies is a heterogeneous group of hematologic cancers, where Bruton's tyrosine kinase (BTK) inhibitors have received FDA approval for several subtypes. The first-in-class covalent BTK inhibitor, ibrutinib, binds to the C481 amino acid residue to block the BTK enzyme and prevent the downstream signaling. Resistance to covalent BTK inhibitors can occur through mutations at the BTK binding site (C481S) but also other BTK sites and the phospholipase C gamma 2 (PLCγ2) resulting in downstream signaling. To bypass the C481S mutation, non-covalent BTK inhibitors, such as pirtobrutinib, were developed and are active against both wild-type and the C481S mutation. In this review, we discuss the molecular and genetic mechanisms which contribute to acquisition of resistance to covalent and non-covalent BTK inhibitors. In addition, we discuss the new emerging class of BTK degraders, which utilize the evolution of proteolysis-targeting chimeras (PROTACs) to degrade the BTK protein and constitute an important avenue of overcoming resistance. The moving landscape of resistance to BTK inhibitors and the development of new therapeutic strategies highlight the ongoing advances, that are being made towards the pursue of cure of B-cell lymphoid malignancies.

Human-robot collaboration is a new trend in modern manufacture. The safety or human protection is of great significance due to the share of the same workshop between humans and robots. To achieve effective protection, in this paper, a contact force sensor based on the 8-shaped wound polymer optical fiber is proposed. The 8-shaped wound structure can convert the normal contact force to the shrinkage of the 8-shaped optical fiber ring. The macro-bending loss of the optical fiber is used to detect the contact force. Compared with conventional sensors, the proposed scheme has the advantage of high flexibility, low cost, fast response, high repeatability, which shows the great promise on actively alarming collision and passively reducing the hurt.

This study presents the chemical synthesis, purification, and characterization of a novel non-natural synthetic amino acid. The compound was synthesized in solution, purified, and characterized using NMR spectroscopy, polarimetry, and melting point determination. Dynamic Light 22 Scattering (DLS) analysis demonstrated its ability to form aggregates with an average size of 391 nm, extending to low micrometric sizes. Furthermore, cellular biological assays revealed its ability to enhance fibroblast cell growth, highlighting its potential for tissue regenerative applications. Circular dichroism (CD) spectroscopy showed the ability of the synthetic amino acid to bind serum albumins (using bovine serum albumin (BSA) as a model), and CD deconvolution provided insights into the changes in secondary structures of BSA upon interaction with the amino acid ligand. Additionally, molecular docking using HDOCK software elucidated the most likely binding mode of the ligand inside the BSA structure. We also performed in silico oligomerization of the synthetic compound in order to obtain a model of aggregate to investigate computationally. More in detail, in the dimer formation achieved by molecular self-docking, two distinct poses were observed, corresponding to the lowest and comparable energies, with one pose exhibiting a quasi-coplanar arrangement characterized by a close alignment of two aromatic rings from the synthetic amino acids within the dimer, suggesting the presence of π-π stacking interactions. In contrast, the second pose displayed a non-coplanar configuration, with the aromatic rings oriented in a staggered arrangement, indicating distinct modes of interaction. Both poses were further utilized in the self-docking procedure. Notably, iterative molecular docking of amino acid structures resulted in the formation of higher-order aggregates, with a model of a 512-mer aggregate obtained through self-docking procedures. This model of aggregate presented a cavity capable of hosting therapeutic cargoes and biomolecules, rendering it a potential scaffold for cell adhesion and growth in tissue regenerative applications. Overall, our findings highlight the potential of this synthetic amino acid for tissue regenerative therapeutics and provide valuable insights into its molecular interactions and aggregation behavior.

Our decisions today are part of an economic thinking which aims to fix problems and increase the efficiency of capital markets. Our economy is still largely approached as a system which is unre-lated to our environment or social returns like community well-being, social cohesion, equitable distribution of resources, etc. To fully incorporate sustainability into cost-benefit analysis, busi-nesses need to change their financial approach, showcasing how long-term thinking impacts prof-its. Money's value is not static and evolves with time and technology. We propose to introduce a variation of cost/benefit and present value calculations. Precise calculations reveal the benefits of long-term strategies over short-term profit focus. As financial systems evolve and technology advances, the accurate calculation of money's time value will continue to play a crucial role in shaping economic landscapes and guiding financial choices. In this article, we demonstrate that updated calculations could be a key enabler to visualize the benefits of long-term thinking or “patient finance” as compared to a short-term focus on profit. We introduce the concept and calculation of a Present Future Value (PFV).

Graphene nanoplatelets (UGZ-1004) are advancing as a promising biomaterial for regenerative medicine. This study provides a detailed assessment of UGZ-1004, emphasizing its physical properties, cytotoxicity, intracellular interactions, and particularly its effects on mesenchymal stem cells (MSCs). UGZ-1004 was characterized to have lateral sizes and layer counts in line with ISO standards and exhibited high carbon purity (0.08%). Cytotoxicity evaluations demonstrated that UGZ-1004 is non-toxic to various cell lines, including fibroblast 3T3, epithelial kidney VERO, microglia BV-2, and MSCs, in accordance with ISO-10993-5/2020/2023 guidelines. The study focused on MSCs, revealing that UGZ-1004 supports their self-renewal and proliferation. MSCs exposed to UGZ-1004 maintained their characteristic surface markers and proliferation rates. Importantly, UGZ-1004 promoted significant upregulation of genes crucial for cell cycle regulation and DNA repair, such as CDK1, CDK2, and MDM2. This gene expression profile suggests that UGZ-1004 enhances MSC self-renewal capabilities, ensuring robust cellular function and longevity. Moreover, UGZ-1004 exposure led to the downregulation of genes associated with tumor development, including CCND1 and TFDP1, mitigating potential tumorigenic risks. These findings underscore the potential of UGZ-1004 to not only bolster MSC proliferation but also enhance their self-renewal processes, which are critical for effective regenerative therapies. The study highlights the need for continued research into the long-term impacts of graphene nanoplatelets and their application in MSC-based regenerative medicine.

Inositol is a natural carbocyclic sugar that plays an essential role in regulating the vital cellular functions of plants and animals. Current research has explored methyl derivatives of inositol, reporting on their various biological activities, including antitumor, anti-inflammatory, and anti-osteoporosis activities. Our previous study demonstrated that L-quebrachitol, a methyl derivative of inositol, enhances osteoblastogenesis and bone formation; however, its effect on osteoclastogenesis remains unclear. Consequently, we aimed to investigate the effect of L-quebrachitol on the receptor activator of nuclear factor-κB ligand-induced osteoclastogenesis in pre-osteoclastic RAW 264.7 cells. The results revealed that L-quebrachitol suppressed RANK-mediated signalling, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and Fos proto-oncogene (cFOS) pathways, at both gene and protein levels. Moreover, the critical transcription factor for osteoclastogenesis, nuclear factor of activated T cells c1 (NFATc1), was downregulated. Inhibition of osteoclast-associated marker genes encoding proteolytic enzymes, such as tartrate-resistant acid phosphatase (TRAP), matrix metallopeptidase 9 (MMP-9), and cathepsin K, led to reduced formation of TRAP-positive multinucleated cells and resorption pits. These findings demonstrate the dose-dependent inhibitory effect of L-quebrachitol on osteoclastogenesis through the modulation of receptor activator of nuclear factor κB (RANK)-mediated signalling pathways. However, further exploration of L-quebrachitol's potential as a therapeutic approach for osteoporosis is warranted.

Malignant Pleural Mesothelioma (MPM) is an aggressive cancer associated to asbestos exposure. MPM pathogenesis has been related both to oxidative stress, evoked by and in response to asbestos fibers exposure, and the Epithelial Mesenchymal Transition (EMT), an event induced by oxidative stress itself and related to cancer proliferation and metastasis. Asbestos related primary oxidative damage is counteracted in the lung by various redox-sensitive factors, often hyperactivated in some cancers. Among these redox-sensitive factors, Apurinic-apyrimidinic endonuclease 1 (APE-1)/Redox effector factor 1 (Ref-1) has been demonstrated to be overexpressed in MPM and lung cancer, but the molecular mechanism has not yet fully understood. Moreover, asbestos exposure has been associated to induced EMT event, via some EMT transcription factors, such as Twist, Zeb-1 and Snail-1, in a possible crosstalk with oxidative stress and inflammation events. To demonstrate this hypothesis, we inhibited/silenced Ref-1 in MPM cells: as a consequence, both EMT (Twist, Zeb-1 and Snail-1) markers and cellular migration/proliferation were significantly inhibited. Take as a whole, these results show, for the first time, a crosstalk between oxidative stress and EMT in MPM carcinogenesis and invasiveness, so improving the knowledge to better address a preventive and therapeutic approach against this aggressive cancer.

The corrosion inhibition behavior of cetyl pyridinium chloride (CPC) on mild steel (MS) in 0.5 M H₂SO₄ solution was examined using the weight loss method and potentiodynamic polarization method. The experimented MS surface was characterized by Fourier Transform Infrared Spectroscopy (FTIR), Field Emission Scanning Electron Microscopy (FESEM), and Atomic Force Microscopy (AFM). Corrosion rate and corrosion efficiency was calsulated via weight loss and potentiodynamic polarization methods where the corrosion rate in 0.5 M H₂SO₄ , 0.000192 M, and 0.0077 M of CPC solution was 12.09×10^-3, 8.23×10^-3, 6.63×10^-5 (mm/Year), respectively and the inhibition efficiency of 94.42% and 98.54%. FESEM studies demonstrated the corrosion attack on MS surface. Also, the EDX showed the presence of nitrogen of CPC. Thus, CPC acts as an important corrosion inhibitor.

The acoustic startle response (ASR) is an explosive motor response leaded by a sudden and intense acoustic stimulus. ASR has several clinically relevant forms of plasticity, including habituation and sensorimotor gating. Although ASR and its plasticity have been intensively studied in different animal models, including zebrafish (Danio rerio) larvae, information in adult zebrafish is still very scarce. In this manuscript we present Zebra_K, a new automated high-content kinematic analysis platform for assessing ASR, its habituation and prepulse inhibition (PPI), a quantitative measure of sensorimotor gating, in adult zebrafish. The analysis of the kinematic parameters in 1,875 ASR in adult zebrafish has shown a single response wave consistent with the short-latency C-bend described in zebrafish larvae. Moreover, protocols have been designed and validated in Zebra_K for the analysis of sensitivity, habituation and PPI of this response. Then, this platform has been used to determine the effect of pharmacological and physiological modulators of ASR plasticity. As described in other animal models, the NMDA-receptor antagonist ketamine increased the responsiveness to the acoustic stimuli, decreasing habituation and leading to complete abolition of PPI. Moreover, the effect of the gender on zebrafish ASR plasticity has been analyzed for the first time. Females exhibited higher responsiveness and a lower habituation and PPI than males, a result consistent with the gender effect described in other animal models and in humans. These results enhance the interest of using adult zebrafish to assess the potential effect of chemicals or genetic manipulations on ASR plasticity.

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.

Tuberculosis (TB) remains a significant public health challenge in Nigeria, with high rates of transmission and low case detection rates. This paper presents the challenges of TB screening and the existing gaps in Contact Investigation (CI). This descriptive qualitative study was conducted in 8 local government areas with high TB burdens in Oyo and Osun States, Nigeria. Twenty-four focus group discussions and 27 key informant interviews were conducted among TB patients, household TB contacts, and government TB staff, among others. Respondents' ages ranged from 17-85 years with a mean of 42.08±14.9 years, and (4.0%) had a postgraduate degree. The unwillingness of the majority of TB contacts who tested negative for TB to be placed on TB preventive therapy because of the belief that only a sick person should take drugs and hostility from the TB contacts to the contact tracers during the house-to-house screening of presumptive TB cases due to community stigma associated with TB were some of the existing gaps reported in TB contact investigations. The findings emphasize the importance of tailored approaches in TB prevention and control, addressing challenges in testing and contact investigations; this necessitates investments in community engagement strategies to enhance the cooperation of TB contacts.

Background: Virtual Reality (VR) is an emerging tool in the management of anxiety, one of the most disturbing symptoms of Alcohol Use Disorder (AUD), which often leads to relapse. Still, patients with Alcohol Use Disorder frequently have a history of Acute Symptomatic Seizures, and they are subsequently excluded from studies using VR because of the hypothesized fear of inducing photosensitive seizures. The first part of this narrative review explores the pathophysiological mechanisms of seizures associated with AUD, specifically acute symptomatic seizures. In contrast, the second part explores virtual reality’s safe use in seizure-prone individuals, highlighting that the current state-of-the-art is based on a biased per-ception and old epidemiological data from studies conducted on photosensitive seizures in the late 90s. VR exposure has yet to be reported as triggering seizures within known pharmacovigilance databases. Significance: The implications weigh heavily on VR research currently associated with this significant adverse event. Further studies are necessary to address the risk of seizures triggered by VR in patients predisposed to developing seizures, like alcohol use disorder patients with a history of acute symptomatic seizures. Such research is essential to ensure that the potential benefits of Virtual Reality as a tool for managing anxiety in individuals with alcohol use disorder and acute symptomatic seizures are not unduly restricted. Furthermore, AUD can also serve as an intervention model feasible to de-bias attitudes toward the current lack of evidence base concerning the significant adverse events of VR-induced seizures, therefore facilitating the clinical implementation of this unharnessed digital treatment interface.

In Parkinson's disease, neuroinflammation is a complex defense mechanism. Activated microglia and Proteinase-activated receptor-2 (PAR2) are key points in the regulation of neuroinflammation. 1-Piperidin Propionic Acid (1-PPA) has been recently described as a novel inhibitor of PAR2. The aim of our study was to evaluate the effect of 1-PPA in neuroinflammation and microglial activation in Parkinson's disease. Protein aggregates and PAR2 expression were analyzed by thioflavin S assay and immunofluorescence in cultured human fibroblasts from Parkinson's patients, treated or not with 1-PPA. A significant decrease of amyloid aggregates and expression of PAR2 were observed after 1-PPA treatment in all patients. A parallel decrease of PAR2 expression, that was higher in sporadic Parkinson’s patients, was also observed both at transcriptional and protein level. In addition, in mouse LPS-activated microglia, the inflammatory profile was significantly downregulated after 1-PPA treatment, with a remarkable decrease of IL-1, IL-6 and TNF-togheter with PAR2 decreased expression.In conclusion, 1-PPA determines reduced neuroglia inflammation and amyloid aggregates formation, suggesting that pharmacological inhibition of PAR2 could be proposed as a novel strategy to control neuroinflammation.

Lipid droplet (LD) accumulation in hepatocytes is one of the major symptoms associated with fatty liver disease. Mitochondria play a key role in catabolizing fatty acids for energy production through β-oxidation. The interplay between mitochondria and LD assumes a crucial role in lipid metabolism, while it is obscure how mitochondrial morphology affects systemic lipid metabolism in the liver. We previously reported that cilnidipine, an already existing anti-hypertensive drug, has potency to prevent pathological mitochondrial fission by inhibiting protein-protein interaction between dynamin-related protein 1 (Drp1) and filamin, an actin-binding protein. Here, we found that cilnidipine and its new dihydropyridine (DHP) derivative, 1,4-DHP, which lacks Ca2+ channel blocking action of cilnidipine, prevent the palmitic ac-id-induced Drp1-filamin interaction, LD accumulation and cytotoxicity of human hepatic HepG2 cells. Cilnidipine and 1,4-DHP also suppressed the LD accumulation accompanied by reducing mitochondrial contact with LD in obese model and high fat diet-fed mouse livers. These results propose that targeting Drp1-filimin interaction becomes a new strategy for the prevention or treatment of fatty liver disease.

The shikimate pathway is crucial for the biosynthesis of aromatic amino acids in plants and represents a promising target for developing new herbicides. This work aimed to identify inhibitors of shikimate dehydrogenase (SDH), a key enzyme of the shikimate pathway that catalyzes the conversion of 3-dehydroshikimate to shikimate. Virtual screening and molecular docking were performed on the SDH active site of Arabidopsis thaliana (AtSDH), and 6-nitroquinazoline-2,4-diol (NQD) was identified as a potential inhibitor. In vitro assays showed that NQD decreased the activity of AtSDH by reducing Vmax while keeping KM unchanged, indicating noncompetitive inhibition. In vivo, hydroponic experiments revealed that NQD reduced the root length of soybean and maize. Additionally, NQD increased the total protein content and certain amino acids. Soybean roots uptake NQD more efficiently than maize roots. Furthermore, NQD reduced shikimate accumulation in glyphosate-treated soybean roots, suggesting its potential to restrict the flow of metabolites along the shikimate pathway in soybean. Simultaneous treatment of maize seedlings with glyphosate and NQD accumulated gallic acid in the roots, indicating that NQD inhibits SDH in vivo. Overall, the data indicate that NQD inhibits SDH both in vitro and in vivo, providing valuable insights into the potential development of herbicides targeting SDH.

The present study was aimed to evaluate the levels of oxidative stress markers in breast diseases by measuring the 8-hydoxy-2-deoxyguanosine (8-OHdG), vitamin A, vitamin C, vitamin E and total antioxidant status (TAS) alterations in relation to cell proliferation activity and disease progression. Significant increases in the level of oxidative damage marker 8-OHdG and cell proliferation activity were observed in breast carcinoma patients in comparison to benign and normal controls, which were accompanied by significant decrease in non enzymatic antioxidants and TAS concentrations. 8-OHdG and cell proliferation level were negatively correlated with non enzymatic antioxidants viz., Vitamin A, Vitamin C, vitamin E level and total antioxidant activity. Altered levels of biomarkers of oxidative stress and cell proliferation activity amongst the malignant, benign and controls suggest a correlation of increased oxidative stress and cell proliferation activity in the progression of disease in breast carcinoma patients. Among the oxidative stress markers and cell proliferation index, decreased level of vitamin A, vitamin C, vitamin E, TAS and increased level of 8-OHdG, cell proliferation index emerged as best predicted biomarkers for subjects with malignancy and benign breast disease.

Metalloproteinases are zinc-dependent endopeptidases that function as primary effectors of tissue remodelling, cell-signalling, and many other roles. Their regulation is ferociously complex, and is exquisitely sensitive to their molecular milieu, making in vivo studies challenging. Phenanthroline (PhN) is an inexpensive, broad-spectrum inhibitor of metalloproteinases that functions by chelating the catalytic zinc ion, however its use in vivo has been limited due to suspected off-target effects. PhN is very similar in structure to phenanthrene (Phe), a well-studied poly aromatic hydrocarbon (PAH) known to cause toxicity in aquatic animals by activating the aryl hydrocarbon receptor (AhR). We show that zebrafish are more sensitive to PhN than Phe, and that PhN causes a superset of the effects caused by Phe. Morpholino knock-down of the AhR rescues the effects of PhN that are shared with Phe, suggesting these are due to PAH toxicity. The effects of PhN that are not shared with Phe (specifically disruption of neural crest development and angiogenesis) involve processes known to depend on metalloproteinase activity. Furthermore these PhN-specific effects are not rescued by AhR knock-down, suggesting that these are bona fide effects of metalloproteinase inhibition, and that PhN can be used as a broad spectrum metalloproteinase inhibitor for studies with zebrafish in vivo.

Signaling modules that integrate the diverse extra- and intracellular inputs to control cell proliferation are essential during both development and adult stages to guarantee organism homeostasis. Mobs are small adaptor proteins that participate in several of these signalling pathways. Here we review recent advances unraveling Mob4 cellular functions, a highly conserved non-catalytic protein, that plays a diversity of roles in cell proliferation, sperm cell differentiation and simultaneously is involved in synapse formation and neural development. In addition, the gene is often overexpressed in a wide range of tumors and is linked to poor clinical outcomes. Nevertheless, Mob4 molecular functions remain poorly defined, although it integrates the core structure of STRIPAK, a kinase/phosphatase protein complex, that can act upstream of the Hippo pathway. In this review we focus on the recent findings of Mob4 functions, that have begun to clarify its critical role on cell proliferation and development of tissues and individuals.

The objective of the analysis carried out in this paper is to quantify the impact of subsidies on the activity of two vegetable farms, of different sizes in terms of agricultural area under cultivation, 600 ha and 3000 ha, which can constitute a model at macroeconomic level, indicating the ways in which these farms can ensure their income. For the analysis carried out, indicators were taken into account concerning production, net profit and subsidies received over a period of three years for the agricultural crops grown on these farms, identifying their contribution and effects on profitability. Descriptive statistics, visual inspections and basic comparison methods were also used, thus determining the patterns of the impact of subsidies and their variation for each of the existing crops in the vegetable farms studied. The data on which the statistical models are based are extracted from the financial statements of the farms analysed, giving the possibility of a predictive extension of the evolution of income and, very importantly, of their profitability. The conclusions revealed, for the 600 ha vegetable farm, that this farm maintained its area constant during the analysis period, benefiting from annual subsidies, and that the practice of crop diversification (rape, barley, winter wheat, oats, soybean, maize, lucerne), appropriate rotation, conservation farming and crop irrigation on 85.34% of the area, ensured average yields/ha that exceeded those recorded at national and regional level, except for 2020. The economic performance of this farm is oscillating in the period 2018-2021, with the ability to consistently generate profit, but in 2020 it is close to break-even, a year in which subsidy income tipped the balance towards positive but modest financial results. For this farm, the statistical model carried out was inconclusive because the farm optimises its cropping plan every year, depending on agrometeorological predictions, subsidy levels and market trends, changing crops, thus not being able to estimate the extent to which each crop contributes to maintaining the financial balance of the farm. Thus, although subsidies have impacted the level of net income, the extent to which they have done so is unclear. For the 3000 ha farm, the findings revealed that this farm also has a roughly constant area in use over the analysis period and for which it receives subsidies. This farm practices crop diversification (rape, barley, winter wheat, sunflower, soybean, grain maize, late potatoes, sweet potato, carrot and flowers) and adequate crop rotation. The data highlight that subsidies played a significant and sometimes overwhelming role in determining the gross output of each crop to achieve a positive value of this indicator. Modern conservation farming technologies and crop irrigation on 74.14% of the area justify the average yields/ha achieved, which again exceeded those recorded at national, regional and county level, with the exception of 2020. Maize and soybean crops consistently contributed to the farm's income, with a high gross product and net income, despite changes in the average yield per hectare achieved each year. Good and rising economic performance for this farm during the period under review, which justifies the profitability of the business from an economic, financial and commercial point of view. Although there have been fluctuations in the value of yields realized on different crops, net revenues continued to be high and even up significantly in 2021. Thus, the study highlighted and identified trends and patterns in agriculture, patterns that can serve as a source of information for relevant policy decisions, playing a key role in guiding future research and allocating resources efficiently in the agricultural sector.

DNA methylation is one of the epigenetic mechanisms which have been implicated in cellular differentiation, ageing and disease development. The effect of hypomethylating drug 5-aza-2´deoxycytidine (5-aza dC) on the biosynthetic profile of caudal region chondrocytes from chick sternum was studied in detail. The chondrocytes in culture were treated with varying doses of 5-aza dC for 48h and maintained subsequently without the treatment and harvested at selected time points for analysis of growth and differentiation status. 15µg/ml of 5-aza dC showed optimum Concentration at which there was a significant increase in DNA synthesis and RNA synthesis as per cell basis. There was also a significant increase in total protein synthesis and collagen synthesis as per cell basis at this concentration. This optimal concentration also showed to up regulate the gene expression of Type X collagen and alkaline phosphatase, which are the marker of hypertrophic chondrocyte expression. These results further support the notion that methylation is the major epigenetic factor controlling the differentiation and maturation of chondrocytes.

An outbreak caused by coronavirus disease 2019 (COVID-19) occurred in Wuhan City, Hubei Province, China, in December 2019. Up to March 2, 2020, at least 80180 cases have been reported. Most of the patients had a history of visiting Hubei Province or contacting with people who had ever stayed in or passed by Hubei Province, or exposed to symptoms. Some patients got infected only from asymptomatic contacts. This study aimed to report the epidemic features and lab identification of a patient confirmed with COVID-19 infection only from asymptomatic contact.

Monitoring is an important component of pest management, to prevent or mitigate outbreaks of native pests, and to check for quarantine organisms. Surveys often rely on trapping, especially when the target species respond to semiochemicals. Many traps are available for this purpose, but they are bulky in most cases, which raises transportation and deployment issues, and they are expensive, which limits the size and accuracy of any network. To overpass these difficulties, entomologists have used recycled material, such as modified plastic bottles, producing cheap and reliable traps but at the cost of recurrent handywork, not necessarily possible for all end-users (e.g., for national plant protection organizations). These bottle-traps have allowed very large surveys which would have been impossible with standard commercial traps, and we illustrate this approach with a few examples. Here we present, under a Creative Commons BY-SA License, the blueprint of a fan-trap, a foldable model, laser-cut from a sheet of polypropylene, that can rapidly be produced in large numbers, and could be transported and deployed in the field with very little efforts. Our first field comparisons show that fan-traps are as efficient as bottle-traps, and we describe two cases where they are being used for monitoring.

In cross-country skiing the time difference between a race winner and the person coming second is typically very small. Since much of the energy is spent on overcoming resistive forces, a relatively small reduction of these can have a significant impact on the results. The resistive forces come partly from the friction in the tribological interface, between the ski and the snow, and as with many tribological applications the characterisation of its origin, plays an important role in determining the frictional properties. Also in cross-country ski friction, there are several scales impacting the frictional performance, with the major contributors being the ski-camber profile and ski-base structure. Macro-scale measurements of the ski's camber profile under load, are often used to determine how adequate the ski is for a specific condition. The characteristic properties usually obtained are, the force required to collapse the ski to a certain camber height, the topography of the kick-wax zone, and by simple means a determined lengths of the frictional interface, i.e., the apparent contact length. To this date, there are some mathematical models, but there is no robust way of determining the macro-scale contact properties between a cross-country ski and a counter surface using simulations. In the present paper an Artificial neural networks (ANN) is trained to predict the ski-camber profile for various loads placed at different positions, and a well established deterministic approach is used to simulate the contact between the ANN-predicted ski-camber profile and a linearly elastic body with a flat surface, representing the snow. The results suggest that this method is feasible for the determination of the apparent contact characteristics of different skis. Moreover, we show that the apparent contact area does not linearly depend on the load, and that the elastic properties of the counter surface also has a large impact on the apparent contact area and the average apparent contact pressure.

Sialylated milk oligosaccharides (SMOs) is the most important oligosaccharides in human milk oligosaccharides (HMOs), and have a multifunctional health benefit, and the most abundant SMOs are sialyllactose (SLs). The previous studies indicate that the growth of tumor cells, and angiogenesis on tumor tissues with Lewis lung carcinoma, melanoma, and colon carcinoma cells could be prevented by SL. Thus, it has been proposed that SL might be an ideal candidate for the development of anti-angiogenic drugs without any side effects. It has been proposed that the Sialic acid (Sia) can be produced through SL’s hydrolysis, and the dietary Sia is further transported to the brain and other tissues though blood for formation of CMP-Sia, the activated precursor of Sia, and then is catalyzed by polysialyltransferases (polySTs) for synthesis of polysialic acid (polySia) or polysialylation of neural cell adhesion molecule (NCAM). Thus, it’s necessary to study and develop new inhibitors, which not only modulate a proper balance between the gut health and neuros system development, but also inhibit the overexpression of polySia, and thus block the tumor cell migration. In this study, we proposed that 3’-SL and 6’-SL may be more ideal inhibitors comparing with two previous inhibitors, the low molecular weight heparin (LMWH) and cytidine monophosphate (CMP) in the previous studies.

The MAPK signaling pathway with BRAF mutations has been shown to drive the pathogenesis of 40-60% of melanomas. Inhibitors of this pathway's BRAF and MEK components are currently used to treat these malignancies. However, responses to these treatments are not always successful. Therefore, identifying noninvasive biomarkers to predict treatment responses is essential for personalized medicine of melanoma patients. Using noninvasive 1H magnetic resonance spectroscopy (1H MRS), we previously showed that BRAF inhibition reduces lactate and alanine tumor levels at early stages of effective therapy and could be construed as metabolic imaging biomarkers for drug response. The present work aimed to demonstrate if these metabolic changes and those assessed by 31P MRS are also found in preclinical human melanoma models treated with MEK inhibitors. Apart from 1H and 31P MRS, additional supporting in vitro biochemical analyses are described. Our results indicate significant early metabolic correlations with response levels to MEK inhibition in the melanoma models and are consistent with our previous study of BRAF inhibition. Given these results, our study supports the potential clinical utility of noninvasive MRS to objectively image metabolic biomarkers for early predicting melanoma response to MEK inhibition.

Epidemiologic studies have shown an association between tuberculosis and lung cancer. The al-tered tumor microenvironment after tuberculosis infection appears to contribute to cancer pro-gression. Pleural effusions are enriched in exosomes, which act as mediators of intercellular communication. We hypothesized that tuberculous pleural effusion (TPE)-derived exosomes mediate intercellular communication. Then we examined the interaction between TPE-derived exosomes and cancer cells. Exosomal miRNA profiling of TPE was performed using a microRNA array. An in vitro lung cancer cell experiment and an in vivo mouse xenograft tumor model were used to evaluate the effects of select exosomal microRNAs. TPE-derived exosome treatment en-hanced the growth of A549 cells both in vitro and in a nude mouse xenograft model. Neighboring cancer cells were observed to take up TPE-derived exosomes, which promoted cancer cell inva-sion. Exosome-mediated transfer of select microRNAs, including miR-130b-3p and miR-423-5p, to A549 lung cancer cells activated cyclin D1 signaling and increased the expression of phos-phorylated p65, a cyclin D1 transcription factor. Inhibitors of miR-130b and miR-423-5p sup-pressed the promotion of lung cancer by TPE derived exosomes and reduced the expression of p65 and cyclin D1. These results suggest that TBE-derived exosomal miRNAs can serve as a novel therapeutic target in tuberculous fibrosis-induced lung cancer.

Almost contact complex Riemannian manifolds, known also as almost contact B-metric manifolds, are equipped with a pair of pseudo-Riemannian metrics that are mutually associated with each other using the tensor structure. Here we consider a special class of these manifolds, those of the Sasaki-like type. They have an interesting geometric interpretation: the complex cone of such a manifold is a holomorphic complex Riemannian manifold (also called a Kähler–Norden manifold). The basic metric on the considered manifold is specialized here as a soliton, i.e. has an additional curvature property such that the metric is a self-similar solution of an intrinsic geometric flow. Almost solitons are more general objects than solitons because they use functions rather than constants as coefficients in the defining condition. A β -Ricci-Bourguignon-like almost soliton ( β is a real constant) is defined using the pair of metrics. The introduced soliton is a generalization of some well-known (almost) solitons (such as those of Ricci, Schouten, Einstein), which in principle arise from a single metric rather than a pair of metrics. The soliton potential is chosen to be pointwise collinear to the Reeb vector field, or the Lie derivative of any B-metric along the potential to be the same metric multiplied by a function. The resulting manifolds equipped with the introduced almost solitons are characterized geometrically. Appropriate examples for two types of almost solitons are constructed and the properties obtained in the theoretical part are confirmed.

Analytics have become increasingly popular among sports in recent years, providing valuable information regarding physical and mental health. Many athletes have found that analytics during training can help to improve their performance, reduce the risk of injury, and enhance their overall well-being. This paper aims to improve the results of handball players by applying a method for measuring the influence of different trials on aggregate performance calculated per each athlete in order to qualify for the Olympic Games. By separating the isolated action of each trial, the result is an additional influence caused by the interaction of factors or the simultaneous action. That might explain why the neuromuscular feedback loop is utterly necessary to perform handball motor actions. Further on, the ML analysis can help identify areas for improvement, optimize training programs, and enhance overall team performance.

This paper delves into the transformative impact of artificial intelligence (AI) in the forklift industry, particularly focusing on logistics and procurement within small and medium-sized enterprises (SMEs) in the field of industrial machinery. The study highlights the growing influence of AI in automating and improving the forklift industry. Using the environmental, social, and corporate governance (ESG) balanced scorecard (BSC), benchmarking, and activity-based management (ABM) models, the paper analyses the risks and the implications of AI integration in the industry in the actual turbulent context. The research highlights the significant shifts in logistics and procurement processes due to AI, projecting a future where forklift operations are deep automatized, leading to a possible loss of forklift operator jobs. A case study of the most relevant Romanian SME in the forklift industry is also presented, examining the company's financial strategies using McKinsey’s 7S framework. The paper concludes with a perspective that, in the future, machines will predominantly operate in roles currently held by humans, significantly altering the industry landscape.

Should our planet be visited by an extraterrestrial civilization, the prevailing assumption would undoubtedly be that the extraterrestrial civilization is Type I i.e. its capacity for interstellar travel results from its technological development. This assumption is dangerous for it unnecessarily leads to the Extraterrestrial Tandem Hypothesis (ETH): the belief than an extraterrestrial civilization technologically capable of interstellar travel must also be technologically compatible with the inexorably rapid annihilation of life on Earth. Such a state of things would compromise the planet’s capacity to stage a confident defense should the extraterrestrials prove belligerent. The presumption of Type I extraterrestrials (on the premise of the capacity for interstellar travel alone) is unfounded as extraterrestrials may be Type II i.e. capable of interstellar travel by virtue of natural intrinsic or extrinsic factors. This paper advances, most importantly, that the fundamental policy of first contact should be the employment of various strategies toward the evaluation of the technological capacity of visiting extraterrestrials. This evaluation must be particularly devoted to the detection of Type II extraterrestrials masquerading as Type I (using concealment and Wizard of Oz strategies). Integral to this detection are the concepts of the precedence relation and The Extraterrestrial Exclusion Principle (EEP). A precedence relation is a qualitative relation expressing the relative difficulty of producing a technological action. The Extraterrestrial Exclusion Principle states that a Type I extraterrestrial life form is excluded from certain actions. Such actions are lower in precedence than interstellar travel and may be described as in violation of the EEP or EEP forbidden. EEP actions reveal extraterrestrials to be Type II. As an example, the value of the Hawking Warning is subjected to EEP analysis. Furthermore, a hypothetical conundrum in linguistics termed the Kryptonian Linguistic Paradox (KLP) is discussed as a case of an EEP forbidden act. Finally, the paper explores the limitations of the stated fundamental policy of first contact.

Inflammation is a vital aspect of the body's immune response, appearing either as an acute reaction that swiftly develops (e.g., after injury or during an infection) or as a chronic condition that persists over a prolonged period, often linked with autoimmune disorders or cancer. This study introduces potential TNF-alpha inhibitors investigated by Molecular Docking investigation. They are Dactolisib with a binding energy of -10.1 kcal/mol, Nilotinib with -9.6 kcal/mol, Eltrombopag with -9.7 kcal/mol, Radotinib with -9.6 kcal/mol, and Nilotinib again with -9.7 kcal/mol. Additionally, Hypericin exhibited a notable binding energy of -9.9 kcal/mol, suggesting its potential as a natural TNF-alpha inhibitor. While these computational results are preliminary, they provide a foundation for further biological studies to confirm their efficacy. The significance of these findings extends to the scientific community, offering potential applications in the field of inflammatory diseases.

Polar auxin transport (PAT) and auxin efflux carriers are known components controlling leaf complexity and venation patterns in some model plant species. Evidence indicates that PAT generates auxin converge points (CPs) that in turn lead to local leaf formation and internally into major vein formation. However, the role of PAT in more diverse leaf arrangements and vein patterns is largely unknown. We used pharmacological inhibition of PAT in developing pinnate tomato, trifoliate clover, palmate lupin, and bipinnate carrot leaves and observed dosage-dependent reduction to simple leaves in these eudicots. Leaf venation patterns changed from craspedodromous (clover, carrot), semi-craspedodromous (tomato) and brochidodromous (lupin) to more parallel patterning with PAT inhibition. The visualization of auxin responses in transgenic tomato plants showed that discrete and separate CPs in control plants were replaced by diffuse convergence areas near the margin. These effects indicate that PAT plays a universal role in the formation of different leaf and vein patterns in eudicot species via a mechanism that depends on the generation as well as separation of auxin CPs. Computer simulations indicate that variations in PAT can alter the number of CPs, corresponding leaf lobe formation and position of major leaf veins along the leaf margin in support of experimental results.

This study investigated the inhibitory effect of Siegesbeckia orientalis ethanolic extract (SOE) on growth and metastasis of hepatic tumors in C57BL/6JNarl mice, which is the model of tumor-igenesis induced by subcutaneous injection of Hepa1-6 murine hepatoma cells on the back of mice. Feeding 25 mg SOE/kg BW daily for 14 days effectively reduced the hepatoma weight in tu-mor-bearing mice by 59.7%. SOE intervention reduced the expression of anti-apoptotic Bcl-2 gene in tumor tissue by 48.5% and down-regulated the antioxidant system, by reducing the gene ex-pression of catalase (48.0%), glutathione peroxidase (46.3%), and superoxide dismutase (32.0%). In addition, SOE intervention increased the production of ROS by 21.4%, and the gene expression of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 by 135.3%, 179.3% and 91.7%, respectively, indicating that SOE intervention promoted the acute inflammatory response. Results of H&E staining analysis showed that SOE had the ability to inhibit angiogenesis in tumor tissue. Fur-thermore, SOE treatment inhibited the expression of migration-related genes, such as MMP-2, MMP-7, MMP-9 and β-catenin, and the inhibition rates were 24.8%, 27.4%, 10.4% and 21.9%, respectively. These results imply that SOE had the ability to suppress tumor metastasis. On the other hand, SOE intervention decreased the serum contents of inflammatory cytokines, such as TNF-α, IL-1β and IL-6 by 27.4%, 30.4%, and 30.7%, respectively, indicating that SOE intervention has an anti-inflammatory effect on normal tissues of mice. Since SOE intervention had no signif-icant effect on liver and kidney weights, and no mice died throughout the experiment, it shows that it is safe to feed SOE under this experimental condition. Based on the above results, SOE has a great potential to be used in the treatment of hepatoma.

Colorectal cancer is one of the most common causes of cancer mortality worldwide, and innovative drugs for the treatment of colorectal cancer are continually being revealed. 5-Fluorouracil (5-FU) is a common clinical chemotherapeutic drug. Acquired resistance to 5-FU is a clinical challenge in colorectal cancer. Parecoxib is a selective COX-2-specific inhibitor, which has been demonstrated to inhibit metastasis in colorectal cancers in our previous study. This study aimed to investigate the synergistic antimetastatic activities of parecoxib to 5-FU in human colorectal cancer cells and determine the underlying mechanism. parecoxib and 5-FU synergistically suppressed metastasis in colorectal cancer cells. Treatment with the parecoxib /5-FU combination induced an increase in E-cadherin and decrease in β-catenin. The parecoxib/5-FU combination could inhibit MMP-9 and MMP-2 expression and MMP-9 activity, and the NF-κB pathway might be suppressed as well. Mechanistic analysis denoted that the parecoxib/5-FU combination hindered the essential molecules of the PI3K/Akt route to obstruct metastatic colorectal cancer. Furthermore, the parecoxib/5-FU combination could inhibit reactive oxygen species. Our work showed the antimetastatic capacity of the parecoxib/5-FU combination for colorectal cancers via targeting the PI3K/Akt /NF-κB pathway.

A global existential and interlocking environmental, climate and cooperation/equity polycrisis is being faced, which increasingly impacts and is impacted by water and land systems. As a result, transformations in response are gaining increasing traction. Advances in approaches to visualising and communicating how innovations and changes in landscape features enable shifts, transformations and transitions are more crucial than ever before. Visions help focus actions, collaboration and alignment of multiple actors in working towards a common purpose, whilst also entering people’s consciousness at the deep level of values, transforming beliefs and consequently, thinking and action. They give direction on effort and pull on transformational innovation. The evidence-based ‘Water Visions Visualisation Platform’ presents an innovative and accessible way to illustrate, communicate and support future water visioning and strategizing at the landscape scale based on composite paradigms, scenarios, horizons and concepts. Plausible visions of the future are envisioned, illustrated, narratively described and qualitatively assessed, as well as connected with real-world examples and resources through the interactive Platform. This paper outlines the co-creation methodology, the architecture and the co-development of the Platform, as well as a preliminary evaluation through literature-based criteria and the sharing of the Platform with a number of audiences.

Contact tracing has become a vital tool for public health officials to effectively combat the spread of new diseases, such asthe novel coronavirus disease COVID-19. Contact tracing is not new to epidemiologist rather, it used manual or semi-manualapproaches that are incredibly time-consuming, costly and inefficient. It mostly relies on human memory while scalabilityis a significant challenge in tackling pandemics. The unprecedented health and socio-economic impacts led researchersand practitioners around the world to search for technology-based approaches for providing scalable and timely answers.Smartphones and associated digital technologies have the potential to provide a better approach due to their high level ofpenetration, coupled with mobility. While data-driven solutions are extremely powerful, the fear among citizens is thatinformation like location or proximity associated with other personal data and can be weaponised by the states to enforcesurveillance. Low adoption rate of such apps due to the lack of trust questioned the efficacy and demanded researchers tofind innovative solution for building digital-trust, and appropriately balancing privacy and accuracy of data. In this paper,we have critically reviewed such protocols and apps to identify the strength and weakness of each approach. Finally, wehave penned down our recommendations to make the future contact tracing mechanisms more universally inter-operable andprivacy-preserving.

This paper presents the formative assessment to implement mobile portable chest X-ray (PDX) machines for Tuberculosis (TB) contact tracing in Oyo and Osun States, Nigeria. This descriptive qualitative study was carried out in 8 Local Government Areas, and 24 FGDs and 33 KIIs were conducted using a 4-stage sampling technique to select participants. Validated transcribed notes were entered and analysed using Nvivo. The respondents' ages ranged from 17-85 years, with a mean age of 42.08±14.9 years, and 4.0% had a postgraduate degree. The majority of the government officials stated that deploying the PDX machine intervention at the community level is the best means as it offers a level of convenience to the community members in the sense that there will be limited disruption to their daily activities as well as zero concerns about the cost of transportation to the health facility. The portable X-ray machine intervention should be implemented at the community level for contact tracing to allow more TB contacts living with the index patient to be screened. However, the PDX machine can also be set up in a special location, and the TB contacts can be invited for the screening.

Resistance to hormone therapy and disease progression is the major challenge in clinical management of prostate cancer (PC). Drugs currently used in PC therapy initially show a potent antitumor effect. Nevertheless, PC gradually develops resistance, relapses and spreads. Most patients develop, indeed, castrate-resistant PC (CRPC), which is almost incurable. The nerve growth factor (NGF) acts on a variety of non-neuronal cells by activating the NGF tyrosine-kinase receptor, TrkA. NGF signaling is deregulated in PC. In androgen-dependent PC cells, TrkA mediates the proliferative action of NGF through its cross talk with the androgen receptor (AR). Epithelial PC cells, however, acquire the ability to express NGF and TrkA, as the disease progresses, indicating a role for NGF/TrkA axis in PC progression and androgen-resistance. We here report that once activated by NGF, TrkA mediates proliferation, invasiveness and epithelial-mesenchyme transition (EMT) in various CRPC cells. NGF promotes organoid growth in 3D models of CRPC cells, and specific inhibition of TrkA impairs all these responses. Thus TrkA represents a new biomarker to target in CRPC.

The interpretation of the local microenvironment of extracellular matrix for malignant tumor cells is in intimate relation with metastatic spread of cancer cells involving the associated issues of cellular proliferation and drug responsiveness. This study was aimed to assess the combination of both surface topographies (fiber alignments) and different stiffness of the polymeric substrates (PLLA and PCL) and collagen substrates (coat and gel) to elucidate the effect of the cellular morphology on cellular proliferation and drug sensitivities of two different types of breast cancer cells (MDA-MB-231 and MCF-7). The morphological spreading parameter of (Nuclear/Cytoplasm) induced by the anthropogenic substrates has correlated intimately with the cellular proliferation and the drug sensitivity (IC₅₀) of cancer cells. This study demonstrated the promising results of the parameter for the evaluation of cancer cell malignancy.

Medulloblastoma (MB) is one of the most common malignant pediatric brain tumors. Current therapy results in poor prognosis for high-risk SHH/p53-mutated MB, emphasizing the importance of more effective therapeutic strategies. Here, we investigated potential radiosensitizing effects of checkpoint kinase inhibitors (Chk-i) prexasertib (Chk1/2) and SAR-020106 (Chk1) in human SHH/p53-mutated MB in vitro and in vivo. UW228 and DAOY cells were treated with Chk-i and irradiation (RT). Metabolic activity, proliferation, and apoptosis was determined at d3, long-term clonogenicity at d14. DNA damage was assessed after 1, 24, and 72 h. Patient-derived SHH/p53-mutated, luciferase-transfected MB cells were implanted orthotopically into NSG mice (d0). Fractionated therapy (daily, d7-11) was applied. Body weight (BW) was documented daily, tumor growth weekly, and proliferation at d42. In vitro, Chk-i exhibited dose-dependent reduction of metabolic activity, proliferation, and clonogenicity, and enhancement of apoptosis. Combination with RT showed additive antitumor effects and enhanced residual DNA damage. In vivo, tumor growth was delayed by Chk-i alone. Low-dose prexasertib enhanced RT-induced tumor growth inhibition (37-fold) and reduced proliferating cells, high-dose prexasertib and SAR-020106 showed opposite effects (n=3, n.s.). BW assessments revealed that the treatment was well tolerated. Our data indicate a benefit of Chk-i in combination with RT in SHH/p53-mutated MB. However, high-dose Chk-i may compromise the RT effect, possibly by its anti-proliferative activity. Furthermore, we demonstrate for the first time the antitumor activity of the Chk1-specific inhibitor SAR-020106 in the murine brain.

Cancer therapy resistance is a persistent clinical challenge. Recently, inhibition of the mutagenic translesion synthesis (TLS) protein REV1 was shown to enhance tumor cell response to chemotherapy by triggering senescence hallmarks. These observations suggest REV1’s important role in determining cancer cell response to chemotherapy. Whether REV1 inhibition would similarly sensitize cancer cells to radiation treatment is unknown. This study reports a lack of radiosensitization in response to REV1 inhibition by small molecule inhibitors in ionizing radiation-exposed cancer cells. Instead, REV1 inhibition unexpectedly triggers autophagy, which is a known biomarker of radioresistance. Collectively, we report a possible role of REV1 TLS protein in determining cancer treatment outcomes depending upon the type of DNA damage inflicted. Furthermore, we discover REV1 inhibition directly triggers autophagy, an uncharacterized REV1 phenotype, with significant bearing on cancer treatment regimens.

Akt1 is a proto-oncogene that is over active in most cancers. Akt1 activation requires phosphorylation at Thr308; phosphorylation at Ser473 further enhances catalytic activity. Akt1 activity is also regulated via interactions between the kinase domain and the N-terminal auto-inhibitory pleckstrin homology (PH) domain. As it was previously difficult to produce Akt1 in site-specifically phosphorylated forms, the contribution of each activating phosphorylation site to auto-inhibition was unknown. Using a combination of genetic code expansion and in vivo enzymatic phosphorylation, we produced Akt1 variants containing programmed phosphorylation to probe the interplay between Akt1 phosphorylation status and the auto-inhibitory function of the PH domain. Deletion of the PH domain increased the enzyme activity for all three phosphorylated Akt1 variants. For the doubly phosphorylated enzyme, deletion of the PH domain relieved auto-inhibition by 295-fold. We next found that phosphorylation at Ser473 provided resistance to chemical inhibition by Akti-1/2 inhibitor VIII. The Akti-1/2 inhibitor was most effective against pAkt1T308 and showed 4-fold decreased potency with Akt1 variants phosphorylated at Ser473. The data highlight the need to design more potent Akt1 inhibitors that are effective against the doubly phosphorylated and most pathogenic form of Akt1.

In the text, the synthesis and characteristics of the novel ONS-type vanadium(V) complexes with thioanilide derivatives of amino acids are described. They have shown inhibition of human protein tyrosine phosphatases (PTP1B, LAR, SHP1 and SHP2) in the submicromolar range, as well as inhibition of non-tyrosine phosphatases (CDC25A and PPA2) similar to bis(maltolato)oxovanadium(IV)(BMOV). The ONS complexes increased [14C]-deoxy-D-glucose transport into C2C12 myocytes, and one of them, VC070, also enhanced this transport in 3T3-L1 adipocytes. These complexes inhibited gluconeogenesis in hepatocytes HepG2, but none of them decreased lipid accumulation in the non-alcoholic fatty liver disease model using the same cells. Compared to the tested ONO-type vanadium complexes with 5-bromosalicylaldehyde and substituted benzhydrazides as Schiff base ligand components, the ONS complexes revealed stronger inhibition of protein tyrosine phosphatases, but the ONO complexes showed greater activity in the cell models in general. Moreover, the majority of the active complexes from both groups showed better effects than VOSO4 and BMOV. Complexes from both groups activated AKT and ERK signaling pathways in hepatocytes to a comparable extent. One of the ONO complexes, VC068, showed activity in all of the above models, also including glucose utilization in the myocytes and glucose transport in insulin-resistant hepatocytes. The discussion section explicates the results within the wider scope of the knowledge about vanadium complexes.

Cervical cancer remains a significant global health challenge, ranking as the fourth most common cancer among women. The primary causative agents, Human papillomavirus (HPV) strains 16 and 18, are well-known for their role in cervical carcinogenesis, primarily through the actions of the E6 and E7 oncoproteins. This study aimed to identify a natural compound capable of inhibiting both E6 and E7 oncoprotein activities, thereby offering a potential therapeutic approach using a single agent. This study also comprises an extensive in silico analysis with molecular docking studies by AutoDock Vina and Schrodinger Maestro to analyse the binding affinity, hydrogen bonds interactions of selected compounds against HPV 16 E6 &E7 proteins. GROMACS package and iMODS server was used to perform molecular dynamics simulations of protein-ligand complexes to elucidate stability of the ligands around the receptor at different time points. SwissADME was utilized for the prediction of pharmacokinetic properties while PROTOX-II helped in predicting toxicological data Capsaicin emerged as the most promising candidate, exhibiting binding energies of -7.3 kcal/mol and -5.6 kcal/mol against the HPV 16 E6 and E7 proteins, respectively. Notably, Capsaicin formed a single hydrogen bond with each oncoprotein, indicating a strong and specific interaction. The compound also demonstrated a favourable pharmacokinetic profile, with no violations of drug-likeness rules, and was classified as Toxicity Class 4, suggesting a moderate safety profile. These results, thus branding Capsaicin as a promising lead compound for further investigations in cervical cancer therapy that deserves documentation through well-equipped wet lab experiments followed by clinical studies.

The modeling of tilting-pad journal and thrust bearings presents a level of complexity beyond that of bearings of fixed-arc geometry, particularly with regard to dynamic influences. With tilting-pad bearings, the theory surrounding the fluid film must be complemented with representative modeling of the pad dynamics. What has been recognized in recent decades has been the significance of the pad support, in particular the flexibility of the pivot region of the pad. The typical model for including the stiffness of the pivot has been based on Hertzian contact theory. Some researchers have been noting that the Hertzian theory does not permit sufficient flexibility in the pivot region. It is suggested that the contact mechanics at the pivot would be better represented as a pairing of rough surfaces. The modeling used here is based on a statistical asperity micro-contact theory for rough-surface line contact that has been extended to include contact stiffness. This model has been applied to the determination of the effective dynamic properties of tilting-pad bearings. The results show that pivot stiffness can be as low as one-third the stiffness determined by Hertzian theory. Comparison to published experimental results confirms the significance of the rough-surface modeling, particularly for the line contacts associated with rocker-back tilting pads.

This paper proposes a contact force controller for a constrained flexible manipulator in three-dimensional motion. This controller used the conversion formula obtained empirically and experimental results showed the effectiveness of the proposed contact force controller. First, the manipulator was operated with the tip of the second link restrained, then, time response of the root strain, joint angles and contact force were used to derive the relational between the three quantities. The effectiveness of the relational expression was verified by conducting a target contact force tracking experiment by inputting the angle from the relational expression. The contact force control using the strain feedback method was proposed with the strain amount estimated from the target contact force as the target value, and its effectiveness was verified by experiments. From the results obtained, controller using the strain feedback method was designed for the purpose of controlling the contact force at the tip of a flexible manipulator with two links and three degrees of freedom that performs three-dimensional spatial motion, and its effectiveness was shown by comparison with the contact force feedback method.

Total hip arthroplasty is a complex procedure. The achievements of implantology enabled the development of a faithful representation of hip joint physiology as well as the production of materials that can successfully replace damaged natural tissues. A very important issue is the correct selection of the geometry of the endoprosthesis adequate to the load of the joint. Materials used for endoprosthesis are a metal head and a polymer cup (e.g. PE-UHMW). The main interactions in the endoprosthesis are friction and surface pressure, which must be limited, exceeding them causes the destruction of the biomechanical system - plastic deformation of the polymer and the formation of too large and unacceptable radial clearances. Based on the author's developed calculation method of hip joint endoprosthesis contact parameters, the impact on maximum contact pressure and the angle of contact of the joint load was estimated depending on the diameter of the endoprosthesis and radial clearance. The correctness of changing the values of maximum contact pressure from the mentioned parameters was determined. Correspondingly: an increase in joint load causes a linear increase in the maximum contact pressure; increasing the diameter of the endoprosthesis head - their non-linear decrease, and increasing radial clearance - their increase

The need for continuous research to refine the models used in accident reconstruction appears with the development of new car models that satisfy consumer complaints. The paper analyzed a sub-sequence of car and pedestrian accidents, from the perspective of the distance traveled by them in the contact phase, with the aim of improving the information regarding the reconstruction of road accidents. The research included the analysis of some accidents with pedestrian dummies, as well as the simulation of the impact between different classes of vehicles and pedestrians in two different walking positions. Specialized software was used with complex multibody models of pedestrians, modifying the speed and deceleration parameters at the time of the collision. The research results highlight the differences between bilinear models used in accident reconstruction and the proposed study. They can also be used to determine the distance traveled by the vehicle in the first phase of the collision with pedestrians.

Contact tracing is one of the oldest social network health interventions used to reduce the diffusion of various infectious diseases. However, some infectious diseases like COVID-19 amass at such a great scope that traditional methods of conducting contact tracing (e.g., face-to-face interviews) remain difficult to implement, pointing the need to develop reliable and valid survey approaches. The purpose of this research is to test the effectiveness of three different egocentric survey methods for extracting contact tracing data: (1) a baseline approach, (2) a retrieval cue approach, and (3) a context-based approach. A sample of 397 college students were randomized into one of each condition and were prompted to anonymously provide contacts and populated places visited from the past four days. After controlling for various demographic, social identity, psychological, and physiological variables, participants in the context-based condition were significantly more likely recall more contacts (medium effect size) and places (large effect size) than the other two conditions. Theoretically, the research supports suggestions by field theory that assume network recall can be significantly improved by activating relevant activity foci. Practically, the research contributes to developing innovative social network data collection methods for contract tracing survey instruments.

Togo is one of the countries characterized by the highest deforestation rate in the world, caused mainly by the overexploitation of domestic biomass energy. Uapaca togoensis being one of the species appreciated for its strong calorific power, is increasingly overexploited, and its rarefaction in the Togolese forest landscapes becomes worrying hence the need to conduct this study to evaluate the possibilities of its vegetative reproduction. This study contributes to the sustainable development of natural resources by determining the optimal conditions for assisted regeneration of Uapaca togoensis. The approach consisted in conducting a series of nursery trials to determine the impact of the substrate, size of cuttings, sunlight, and apical tip coverage of the plastic film on its germination and budburst capacity. The lower calorific value is determined from samples in dry wood slices of 350g to 500g in five diameter classes. After 33 days, only one unscarred seed germinated in the compost. Substrate type, diameter of cuttings, sunlight, and plastic film significantly influenced the budburst rate and delay. More than 70% of the medium-diameter segments budded compared to 60% and 50% for small and large-diameter segments. More than 80% of the segments exposed to sunlight budded compared to 60% for the shaded segments. The average lower calorific value of dry wood of Uapaca togoensis varies between 7.35 Mj/Kg and 12.12 Mj/Kg depending on the humidity rate and the diameter.

An investigation was made to determine the effects of tungsten surface coating on the coefficient of friction of sliding contact between lubricated steel surfaces. The four-ball test was modified, using a tungsten carbide ball bearing in the spindle to cause sliding contact onto three hard steel ball bearings coated with tungsten disulfide lamellar dry lubricant coating, with a coating of grease lubrication applied to the ball bearings. The coatings, loads, speed, and grease level was varied to best understand the impact of different conditions to the friction coefficient.

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

(1) Background: Little research has been done on professionals' perceptions of institutions and governments during epidemics. We aim to create a profile of physicians who feel they can raise public health issues with relevant institutions during a pandemic. (2) Methods: A total of 1285 Romanian physicians completed an online survey as part of a larger study. We used binary logistic regression to profile physicians who felt able to raise public health issues with relevant institutions; (3) Results: Five predictors could differentiate between respondents who tended to agree with the trust statement and those who tended to disagree: feeling safe at work during the pandemic, considering the financial incentive worth the risk, receiving training on the use of protective equipment, having the same values as colleagues, and enjoying work as much as before the pandemic; (4) Conclusions: Physicians who trust the system to raise public health issues with the appropriate institutions feel they share the same values as their colleagues, say they were trained in the use of protective equipment used during the pandemic, felt they were safe at work during the pandemic, enjoyed their work as much as before the pandemic, and felt the financial bonus justified the risk.

Histone deacetylase 6 (HDAC6) regulates many physiological processes that are involved in cancer development and progression such as cell proliferation, apoptosis, motility, epithelial to mesenchymal transition, by deacetylation of multiple substrates and association with interacting proteins. Due to its the ability to remove misfolded proteins, induce autophagy, and regulate unfolded protein response, HDAC6 plays a protective role in responses to stress and enables tumor cells survival. HDAC6 is often overexpressed in tumors, including colorectal cancer (CRC) and is correlated with poor disease prognosis. However, it has been shown in animal models that HDAC6 is not essential for normal mammalian development. Therefore, it represents a good target for the development of novel cancer therapeutics. Selective inhibition of HDAC6 impairs growth and progression of many tumors without inducing major adverse events in experimental animals. In CRC, HDAC6 inhibitors have shown potential to reduce tumor progression and to enhance the therapeutic effect of other drugs. As HDAC6 is involved in regulation of immune responses, HDAC6 inhibitors have shown potential to improve antitumor immunity by increasing immunogenicity of tumor cells, augmenting immune cell activity and alleviating immunosuppression in tumor microenvironment. Therefore, HDAC6 inhibitors may represent promising candidates to improve the effect and to overcome resistance to immunotherapy.

Anterior-tooth (ANT) contacts induce short latency reflex inhibition of human jaw-closing muscles. The jaw is a rigid class 1 lever for pinpoint-targeting muscle force into a single bite-point, the pivoting food particle. See-saw reflex movements around the food particle fulcrum multiply the food-crushing force. Unpredictable jolts of reaction force caused by food-crushing are subjected to the rostral ANT and caudally to the two articulate ends of the jaw triangle. Compression/distraction strains of food-crushing must be monitored and inhibited by withdrawal reflexes. The mesencephalic ganglion (Vmes), neural myelin sheath, and muscle stretch receptors evolved subsequently to the advent of jaws to improve the velocity of proprioceptive and withdrawal reflexes. In mammalians, the spindles of the taut motor units, stretched by the food-fulcrum send excitatory monosynaptic feedback for the efferent neurons of the respective ipsilateral muscle units, via Vmes. In the Vmes, the spindle-input-mediating afferent neurons are coupled with another source of afferent feedback, which is also excitatory, from the back-tooth (BAT) mechanoreceptors. The two sources of excitatory pulses are summated and targeted for the efferent neurons to boost the stretched and taut motor units. Likewise, the afferent feedback from ANT mechanoreceptors is also coupled in the Vmes with concomitant feedback from spindles. The ANT output, however, is inhibitory to negate the excitatory feedback from the stretched jaw-muscle units. The inhibitory feed from ANT temporarily blocks the excitatory potential of masticatory motor efferent neurons to protect the ANT and jaw-joints from inadvertent strains. The inhibitory inputs from ANT alternate with the excitatory inputs from BAT to determine which jaw-closing muscle units are activated or inhibited at any given instant of food-crushing. The Vmes exists in all jawed vertebrates, and its’ evolution was probably motivated by demands for the control of bite force. The monosynaptic unilateral food-crushing excitatory and inhibitory reflexes (UFCR) override the coexisting bilaterally executed feed for jaw muscles from the central nervous system. Hypothesis: The Vmes-mediated UFCR combine neural inputs from tooth contacts with concomitant feedback from muscle stretch receptors for the control of mammalian food-crushing bite force.

In this work, the surface of poly(ethylene terephthalate) track-etched membranes (PET TeMs) with pore sizes of 670-1310 nm was hydrophobized with 2,2,3,3,4,4,5,5,6,6,7,7-dodecafluoroheptyl acrylate (DFHA) by photoinitiated graft polymerization. Attenuated total reflection FTIR spec-troscopy (ATR-FTIR), scanning electron microscopy (SEM) coupled to an energy-dispersive X-ray spectrometer (EDX), and contact angle measurement were used to identify and characterize the TeMs. The optimal parameters for graft polymerization were determined as follows: polymeriza-tion time 60 min, monomer concentration of 30% and distance from the UV-source 7 cm. The wa-ter contact angle of the modified membranes reached 97° which is 51o for pristine membranes. The modified membranes were tested for water desalination using direct contact membrane distillation (DCMD) method. The effect of membrane pore size, the degree of grafting and salt concentration on the performance of membrane distillation process was investigated. According to the results obtained, it has been concluded that large pore size hydrophobic TeMs modified by using DFHA could be used for desalinating water.

Techniques for the controlled seeding and growth of cracks are urgently required for non-destructive testing technique evaluation, particularly for additive manufactured (AM) samples. This paper describes a method which uses a combination of tensile load and resonance excitation of notched AM samples, with in-situ monitoring of the resonance frequency serving to track crack dimensions. Mechanical low-cycle fatigue cracks, ranging in length from ~0.3 mm to ~5 mm, are successfully created in five AM samples using this technique. The samples are non-destructively characterized using optical microscopy and Nonlinear Resonance (NLR) testing. The exploitation of resonance enables the concentration of a significant number of stress cycles on the samples in much shorter timespans than conventional fatigue testing, enabling high throughput, while utilising compact components. Furthermore, the tracking of resonance frequency shift throughout the process enables non-invasive and non-contact real-time condition monitoring.

In this paper, we present a method to map information regarding service activity provision residing in governmental portals across European Commission. In order to perform this, we used as a basis the enriched Greek e-GIF ontology, modeling concepts, and relations in one of the two data portals (i.e., Points of Single Contacts) examined, since relevant information on the second was not provided. Mapping consisted in transforming information appearing in governmental portals in RDF format (i.e., as Linked data), in order to be easily exchangeable. Mapping proved a tedious task, since description on how information is modeled in the second Point of Single Contact is not provided and must be extracted in a manual manner.

Epigenetic modifications, mainly aberrant DNA methylation, have been shown to silence the ex-pression of genes involved in epigenetic diseases, including cancer suppression genes. Almost all conventional cancer therapeutic agents, such as the DNA hypomethylation drug, 5-aza-2-deoxycytidine, have insurmountable side effects. To investigate the role of ectoine in skin cell DNA methylation and cancer cell proliferation, comprehensive methylome sequence analysis, 5-methyl cytosine (5mC) analysis, proliferation and tumorigenicity assays, and DNA methyla-tion-related gene and marker analysis were performed. The results showed that ectoine hypo-methylation in skin cells, especially in the CpG island (CGIs) element and 5mC, was significantly reduced. Moreover, ectoine mildly inhibited skin cell proliferation, but did not induce tumorigenicity in HaCaT cells injected into athymic nude mice. HaCaT cells treated with ectoine for 24 weeks modulated the mRNA expression levels of Dnmt1, Dnmt3a, Dnmt3b, Dnmt3i, Hdac1, Hdac2, Kdm3a, Mettl3, Mettl14, Igf2, Snrpn, and Mest. Overall, ectoine, an excellent DNA protectant, mildly de-methylates DNA in skin cells, modulates the expression of methylation-related genes, and reduces cell proliferation. This evidence suggests that ectoine is a potential anti-aging agent that prevents DNA hypermethylation and subsequently activates cancer-suppressing genes.

Despite the existence of pasteurization and its advocacy worldwide, most marketed milk in a developing country like Nigeria are sold raw by the locals. It costs hundreds of millions of Naira to set up a conventional pasteurizing plant in Nigeria. Boiled milk ends up curdling which results in to a loss of nutrients, so it is not beneficial to treat milk by this method. This paper hence presents the re-designing and fabrication of the contact area of a solar milk pasteurizer

Berberine (BBR) is an isoquinoline that inhibits the proliferation of transformed cells in vitro, but due to its poor solubility and bioavailability, it has only moderate therapeutic potential in vivo. Increasing evidence indicates that BBR specifically targets several metabolic, signaling and gene transcription events in transformed cells, altering their progression through the cell cycle and decreasing their metabolic rate and proliferation. In order to further develop BBR as a therapeutic, its mode of cellular internalization and localization within the cell needs to be further examined. BBR’s molecular targets and interactions with kinases, transcription factors and some enzymes are discussed in an attempt to better understand BBR’s role in these important pathways and how they may lead to changes in metabolism. Lastly, this review examines some of the benefits and challenges of using BBR as an inhibitor in cancer cell proliferation in breast cancer and glioblastoma, as two examples. BBR is a potent drug with multiple targets and it is this multiplicity of function that makes BBR such a promising drug for targeting cell metabolism and proliferation.

The proliferation and differentiation of mammalian skeletal muscle satellite cells (MuSCs) are highly complicated. Apart from the regulatory signaling cascade driven by the protein-coding genes, non-coding RNAs like microRNAs (miRNA) and circular RNAs (circRNAs) play essential roles in this biological process. However, circRNA functions in MuSCs proliferation and differentiation remain largely to be elucidated. Here, we screened for an exonic circTCF4 based on our previous RNA-Seq data, specifically expressed during the development of the longest dorsal muscle in goats. Subsequently, the circular structure and whole sequence of circTCF4 were verified using Sanger sequencing. Besides, circTCF4 was spatiotemporally expressed in multiple tissues from goats but strikingly enriched in muscles. Furthermore, circTCF4 suppressed MuSCs proliferation and differentiation, independent of AGO2 binding. Finally, we conducted Poly(A) RNA-Seq using cells treated with small interfering RNA targeting circTCF4 and found that circTCF4 would affect multiple signaling pathways, including insulin signaling pathway and AMPK signaling pathway related to muscle differentiation. Our results provide additional solid evidence for circRNA regulating skeletal muscle formation.