In the process of oil and gas development and production, when the flow rate in the wellbore is large, the materials underground will be eroded, causing the operation to be unable to proceed smoothly and reducing the efficiency of oil and gas production. Therefore, optimizing the anti-erosion coating under high-speed flow conditions in wellbore is a very interesting thing. It can greatly improve operational efficiency. In this paper, laser cladding was used to prepare the new coating used in the PDC drill bit. Then, the effects of tungsten carbide and multi-layer graphene on the microstructure and properties of the tungsten carbide coating were studied. The research results indicate that, for new coatings, 60% tungsten carbide and 0.3% graphene are the optimal ratios. After adding WC, the hardness has significantly improved. However, when the WC content further increases more than 30%, the increase in hardness is relatively small. In addition, when the content of graphene is more than 0.3%, the branched structure became thicker, and not only the segregation of Cr, Si and W became very obvious again, but also the segregation of Fe occurred at the Ni enrichment site. The research results contribute to improving oil and gas production and operational efficiency under high-speed fluid flow conditions in the wellbore.

In this paper, a new type of self-excited thermomechanical oscillator containing an oscillating shape memory alloy (SMA) filament with two symmetrically arranged spheres is investigated. The self-excitation of the oscillations is due to a heater of constant temperature, which causes periodic contractions of the filament when it approaches it. The contracted filament moves away from the heater a distance sufficient to cool it. Under the action of the weight of the spheres, the cooled filament re-approaches the heater, causing the above processes to repeat periodically. On the basis of experimental studies, approximating functions of the heater's heat field distribution are derived. A dynamic model of the oscillator has been created, in which the minor and major hysteresis in the SMA alloy and the distribution of the heat field around the heater have been taken into account. By numerical solutions of the differential equations, the laws of motion of the spheres are obtained. The displacements of the spheres in two perpendicular directions were measured using an experimental system. The obtained experimental results validate the proposed dynamic model and its assumptions with a high degree of confidence. Conclusions are drawn about the stochastic nature of the oscillations due to the hysteresis properties of the SMA and the temperature variation of the natural frequency of the oscillating system.

This project designed a set of network security mechanisms for cloud applications in VANETs. At present, cloud computing is one of the government’s development priorities in the industry. We divide cloud into public, private, and hybrid clouds in this project. Vehicles or passengers can access road conditions or public transport information through the public cloud; public transportation can access current driving records and users can access relevant enterprise information on the private cloud and hybrid cloud is a combination of public and private clouds. Both cloud computing or VANETs require network and information security. At present, many researches on VANETs security only focus on message communication, and neglect information storage. Researches on cloud computing security only focus on information protection, and neglect user privacy and anonymity. This project designed a set of network and information security mechanisms in line with the requirements of Confidentiality, Authentication, Non-repudiation, Conditional Anonymity, and Conditional Untraceability. This project primarily needs to achieve the following: 1.an authentication mechanism to verify the identity of each other between the passenger and the vehicle and to verify the identity with Single Sign-On; 2. vehicle or user privacy and anonymity, which need to be able to replace the anonymous ID and related parameters for the vehicle or the user; 3. a private communication mechanism, which enables any vehicle or user to communicate privately; and 4. an information security encryption method, which can encrypt the information on a cloud server to avoid unauthorized access by internal personnel or hackers.

Immune checkpoint inhibitors (ICI) are a promising form of immunotherapy that has significantly changed the therapeutic landscape for many advanced cancers. They have shown unique clinical benefit against a broad range of tumour types and a strong overall impact on survival in studied patient populations. However, there are still many limitations holding back this immunotherapy from reaching its full potential as a possible curative option for advanced cancer patients. A great deal of research is being undertaken in the hope of driving advancements in this area, building a better understanding of the mechanisms behind immune checkpoint inhibition and ultimately developing more effective, safer, and wider-reaching agents. Taking into account the current literature on this topic, this review aims to explore in depth the basis of the use of ICIs in the treatment of advanced cancers, evaluate its efficacy and safety, consider its current limitations, and finally reflect on what the future holds for this very promising form of cancer immunotherapy.

This review aims to explore the intricate relationship between epigenetic mechanisms, stress, and affective disorders, focusing on how early life experiences and coping mechanisms contribute to susceptibility to mood disorders. Epigenetic factors play a crucial role in regulating gene expression without altering the DNA (deoxyribonucleic acid) sequence, and recent research has revealed associations between epigenetic changes and maladaptive responses to stress or psychiatric disorders. A scoping review of 33 studies employing the PRISMA-S (Preferred Reporting Items for Systematic Reviews and Meta-Analyses – Statement) guidelines investigates the role of stress-induced epigenetic mechanisms and coping strategies in affective disorders' occurrence, development, and progression. The analysis encompasses various stress factors, including childhood trauma, work-related stress, and dietary deficiencies, alongside epigenetic changes such as DNA methylation and altered gene expression. Findings indicate that specific stress-related genes frequently exhibit epigenetic changes associated with affective disorders. Moreover, the review examines coping mechanisms in patients with bipolar disorder and major depressive disorder, revealing mixed associations between coping strategies and symptom severity. While active coping is correlated with better outcomes, emotion-focused coping may exacerbate depressive or manic episodes. Overall, this review underscores the complex interplay between genetic predisposition, environmental stressors, coping mechanisms, and affective disorders. Understanding these interactions is essential for developing targeted interventions and personalized treatment strategies for individuals with mood disorders. However, further research is needed to elucidate specific genomic loci involved in affective disorders and the clinical implications of coping strategies in therapeutic settings.

The regulation of cell death is a fundamental issue in cell biology and continues to be intensely investigated worldwide. The significance of research in this field persists because understanding the determinants of cell lifespan directly impacts the maintenance of multicellular organism homeostasis and, consequently, is crucial for addressing biomedical challenges associated with various diseases. It is recognized that the initiation of cell death can be prompted by both specific signals (such as cytokines or hormones) and nonspecific stimuli, including radiation, temperature increase, or oxidants. When these factors affect a cell, numerous signaling pathways are triggered in the cell, leading to neutralization of the effects of their negative effects or, in case of irreparable damage, to cell elimination. This removal of damaged cells occurs through apoptosis or programmed cell death, a highly regulated process. Numerous signaling molecules participate in orchestrating the apoptotic process, many of which also govern other essential functions within the organism. Physiological factors capable of triggering the apoptotic program in cells include nitric oxide (NO), which serves as one of the key signaling molecules regulating the functions of the cardiovascular, nervous, and immune systems of the organism. The unique chemical nature of NO, along with its numerous intracellular targets and physiologically active redox forms, raises questions about the specific mechanisms through which NO exerts its damaging effects on cells. Utilizing pharmacological preparations- such as sources (donors) of exogenous nitric oxide- represents an approach to investigating the initiation and execution of the apoptotic program in sensitive target cells. Furthermore, this approach holds promise as a direction for discovering new selective drugs.

Capacitive contact imaging has shown potential in measuring skin properties including hydration, micro relief analysis, as well as solvent penetration measurements. Through calibration we can also measure the absolute permittivity of the skin, and from absolute permittivity we then work out the absolute solvent content in skin. In this paper, we present our latest study of capacitive contact imaging for skin characterizations and vivo skin solvent penetration. We will show how to use capacitive occlusion measurements to characterize skin damages, and how to calculate the absolute water content and solvent content in skin.

Glycosphingolipids (GSLs), a subtype of glycolipids containing sphingosine, are critical components of vertebrate plasma membranes, playing a pivotal role in cellular signaling and interactions. In human articular cartilage in osteoarthritis (OA), GSL expression is known notably to decrease. This review focuses on the roles of gangliosides, a specific type of GSL, in cartilage degeneration and regeneration, emphasizing their regulatory function in signal transduction. The expression of gangliosides, whether endogenous or augmented exogenously, is regulated at the enzymatic level, targeting specific glycosyltransferases. This regulation has significant implications for the composition of cell surface gangliosides and their impact on signal transduction in chondrocytes and progenitor cells. Different levels of ganglioside expression can influence signaling pathways in various ways, potentially affecting cell properties, including malignancy. Moreover, gene manipulations against gangliosides have been shown to regulate cartilage metabolism and chondrocyte differentiation in vivo and in vitro. This review highlights the potential of targeting gangliosides in the development of therapeutic strategies for osteoarthritis and cartilage injury and addresses promising directions for future research and treatment.

Considering the worldwide impact of heart failure, it is crucial to develop approaches that can help us comprehend its root cause and make accurate predictions about its outcome. This is essential for lowering the suffering and death rates connected with this widespread illness. Cardiomyopathies frequently result from genetic factors, and the study of heart failure genetics is advancing quickly. Dilated cardiomyopathy (DCM) is the most prevalent kind of cardiomyopathy, encompassing both hereditary and nongenetic abnormalities. It is distinguished by the enlargement of the left ventricle or both ventricles, accompanied by reduced contractility. The discovery of the molecular origins and subsequent awareness of the molecular mechanism is broadening our knowledge of DCM development. Additionally, it emphasizes the complicated nature of DCM and the necessity to formulate several different strategies to address the diverse underlying factors contributing to this disease. Genetic variations that can be transmitted from one generation to another can be a significant contributor to causing family or isolated DCM. Genetic variation also plays a significant role in determining susceptibility for acquired triggers for DCM. The genetic causes of DCM can have a diverse range of phenotypic expressions. It is crucial to select the most probable patients to have advantages from genetic testing. The purpose of this research is to emphasize the significance of identifying genetic DCM, the crucial relationships between genotype and phenotype, and the usefulness of genetic testing in the therapeutic care of both those affected and their relatives. This approach is expected to gain importance once treatment is guided by genotype-specific advice and disease-modifying medications.

Background: in this paper, a new physical penetration technology for transdermal administration with traditional Chinese medicine (TCM) characteristics - Fu’s cupping therapy (FCT) - was established and studied by in-vitro and in-vivo experiments; the penetration effect and mechanism of FCT physical penetration technology (FCT-PPT) was preliminarily discussed. Method: Indomethacin (IM) as a model drug，by transdermal in vitro tests the establishment of the high，medium and low reference were finished as the chemical permeation system；chemical penetration enhancers and iontophoresis as a reference，the percutaneous penetration effect of FCT for IM patch was evaluated with 7 species diffusion kinetics model and in vitro drug distribution；naproxen as an internal standard，using UPLC-MS/MS technology，the IM quantitative analysis method in vivo was established，and pharmacokinetic parameters (AUC0-t，AUC0-∞，AUMC0-t，AUMC0-∞, Cmax and MRT) as indicators were used evaluate to FCT penetration role in vivo；in the same time，the group used 3K factorial design to study joint synergistic penetration effect on FCT and chemical penetration enhancers (CPEs)；by SEM and TEM，the skin micro and ultrastructural changes of the stratum corneum (SC) surface were observed, to explore pay tank penetration mechanism. Results: In vitro and in-vivo skin permeation experiments revealed that both the total cumulative percutaneous amount and in-vivo percutaneous absorption amount (AUC and AUMC) of indomethacin that permeated SD mouse skin using FCT techniques were greater than the amount observed using CPE and iontophoresis: Firstly, in contrast to the control group, the indomethacin percutaneous rate (PR) of the FCT lower group (FCTL) was 35.52%, and the enhancement ratio (ER) at 9h was 1.76X, which was roughly equivalent to the penetration enhancing effect of the CPEs and iontophoresis; secondly, the indomethacin PR of the FCT middle (FCTM) group and the FCT high intensity group (FCTH) were respectively 47.36% and 54.58%, ER at 9h were separately 3.58X and 8.39X; thirdly, pharmacokinetic studies showed that in-vivo indomethacin percutaneous absorption of the FCTs was higher than that of the control group, that of the FCTM group was slightly higher than that of the CPEs group, and that of the FCTM group was significantly higher than that of the others. Meanwhile, the variance analysis indicated that the combination of the FCT penetration enhancement method and the CPE method had beneficial effects in penetration enhancing of the skin: the significance level of the CPE method was 0.0004, which was apparently lower than the 0.001, meaning the difference was markedly significant; the significance level of the FCT was under 0.0001, its difference markedly significant; and the significance level of factor interaction A×B was lower than 0.0001, indicating that its difference of the synergism was markedly significant. Moreover, SEM and TEM images showed that the SC surfaces of SD rats treaded with FCT-PPT was damaged, and hard to observe the complete surface structure with its SC pores growing bigger and its special “brick structure” becoming looser, indicating that it broke the barrier function of skin, which revealed potentially a major route of skin penetration. Conclusion: FCT, as percutaneous penetration new technologies, has penetration effects significantly, with Chinese characteristics and highly clinical value, worth promoting development.

Visible light communication (VLC) has attracted much attention in recent years among industrial and academic researchers. The large scale use of energy efficient light emitting diodes (LEDs) in lighting applications offers a unique opportunity to use license free visible light as the carrier in wireless communications. It has many potentials to complement radio frequency (RF) based communication systems. Researchers working on VLC have mainly concentrated on improving the communication speeds to match with Wi-Fi though the latest generation Wi-Fi standards offer significantly higher capacity at longer communication distances. Thus, market penetration is challenging for VLC as Wi-Fi is already quite mature and ubiquitous. Commercialization of VLC can only be successful if VLC can offer applications where VLC is more advantageous over the existing RF-based solutions. Once VLC enters the market through specific applications and becomes more mature in the process, the ecosystem may gradually adopt VLC in broader applications. In this article, the state of the art of the three promising VLC applications, their issues, and possible solutions have been discussed.

The rapid increase in metabolic diseases occurred in the last three decades in both industrialized and developing countries has been related to the rise in sugar-added foods and sweetened beverages consumption. An emerging topic in the pathogenesis of metabolic diseases related to modern nutrition is the role of Advanced Glycation Endproducts (AGEs). AGEs can be ingested with high temperature processed foods, but also endogenously formed as consequence of a high dietary sugars intake. Animal models of high sugars consumption, in particular fructose, have reported AGEs accumulation in different tissues in association with peripheral insulin resistance and lipid metabolism alterations. The in vitro observation that fructose is one of the most rapid and effective glycating agent when compared to other sugars has prompted the investigation of the in vivo fructose-induced glycation. In particular, the widespread employment of fructose as sweetener has been ascribed by many experimental and observational studies for the enhancement of lipogenesis and intracellular lipid deposition. Indeed, diet-derived AGEs have been demonstrated to interfere with many cell functions such as lipid synthesis, inflammation, antioxidant defences, and mitochondrial metabolism. Moreover, emerging evidences also in humans suggest that this impact of dietary AGEs on different signalling pathways can contribute to the onset of organ damage in liver, skeletal and cardiac muscle, and brain, affecting not only metabolic control, but global health. Indeed, the here reviewed most recent reports on the effects of high sugars consumption and diet-derived AGEs on human health suggest the need to limit the dietary sources of AGEs, including added sugars, to prevent the development of metabolic diseases and related comorbidities.

This work presents the possibility of using a synthetic membrane for pretracing mucosal penetration studies. The permeability of two types of membranes, porcine oral mucosa and a synthetic Nuclepore membrane, to water was compared. Moreover, the water permeability of membranes modified with waterproofing formulations was measured to study their ability to protect against the penetration of viruses, toxins, etc. A very good correlation was obtained between the transmucosal water loss (TMWL) values of the artificial membrane and the mucosa. These results support the possible use of this synthetic membrane in the screening of the water permeability of formulations. In addition, studies of the permeation of different actives, drugs and biocides through the two membranes were carried out, and these results were compared with their skin permeation data. The synthetic membrane does not seem to discern between compounds in terms of permeability, which could be due to the lack of lipids in the composition of this synthetic membrane. Therefore, Nuclepore alone cannot be used as a model for the release of actives. Additionally, the permeation of caffeine through intact or modified membranes incorporating waterproofing formulations was also studied. In this case, similar permeation profiles through the synthetic membrane and mucosa were found. The results from these assays should lend support to the use of this synthetic membrane when screening formulations to be applied in oral penetration studies.

Due to the high solar irradiance or energy price, certain regions in the U.S. may reach 100% PV penetration and experience degradation of frequency response greater than the interconnection as a whole. Therefore, in this section, the 100% PV penetration region in each interconnection is simulated to study the local high PV penetration effects. The study was performed by quantifying RoCoF, frequency nadir, and settling frequency at different regional PV penetration levels. The impact of high regional PV penetration on the compliance of grid code on frequency response is also studied.

Candidiasis is considered an emerging public health concern because of the occurrence of drug-resistant Candida strains and the lack of available structurally diverse antifungal drug armamentariums. The indole alkaloid globospiramine from the anticandidal Philippine medicinal plant Voacanga globosa exhibits a variety of biological activities; however, its antifungal properties remain to be explored. In this study, we report the in vitro antifungal activities of globospiramine against Candida albicans and Candida tropicalis and explore its possible target proteins using in silico methods. The colony-forming unit (CFU) viability assay revealed time- and concentration-dependent anticandidal effects of the alkaloid by decreasing almost 50% of the viable CFUs 60 min after treatment. Results of the MIC and MFC assays indicated inhibitory and fungicidal effects of globospiramine against C. albicans (MIC = 8 µg/mL; MFC = 4 µg/mL) and potential fungistatic effects against C. tropicalis at lower concentrations (MIC = 4 µg/mL; MFC > 64 µg/mL). The FAM-FLICA poly-caspase assay showed metacaspase activation in C. albicans cells at concentrations of 16 and 8 µg/mL, which agreed with the MIC and MFC values. Molecular docking and molecular dynamics simulation experiments indicated stable, strong binding of globospiramine with the target proteins 1,3-β-glucan synthase and Als3 adhesin enzymes, which are indirectly involved in apoptotic-driven candidal inhibition.

In response to the issue of vehicle escape guidance, this manuscript proposes a unified intelligent control strategy synthesizing optimal guidance and Meta Deep Reinforcement Learning (DRL). Optimal control with minor energy consumption is introduced to meet terminal latitude, longitude and altitude. Maneuvering escape is realized by adding longitudinal and lateral direction maneuver overloads. Maneuver command decision model is calculated based on Soft-Actor-Critic (SAC) networks. Meta learning is introduced to enhance autonomous escape capability, which improves generalization performance to time-varying scenarios not encountered in the training process. In order to obtain training samples at a faster speed, this manuscript uses the prediction method to solve reward values, which avoiding a large number of numerical integration. The simulation results manifest that the proposed intelligent strategy can achieve high precise guidance and effective escape.

Ground penetrating radar (georadar, GPR), widely used in geology, archeology and road construction, is an efficient tool for searching and studying subsurface objects and structures. When planning GPR missions, it is necessary to predict the resolution of the device and the achievable probing depth. The article discusses the methods and results of assessing these characteristics of the Loza-V and Loza-N radars obtained in the course of archaeological and geographical expedition works.

To advance probiotic research, a comprehensive understanding of bacterial interactions with human physiology at the molecular and cellular levels is fundamental. Lacticaseibacillus rhamnosus LGG® is a bacterial strain that has long been recognized for its beneficial effects on human health. Probiotic effector molecules derived from LGG®, including secreted proteins, surface-anchored proteins, polysaccharides, and lipoteichoic acids, that interact with host physiological processes have been identified. In vitro and animal studies have revealed that specific LGG® effector molecules stimulate epithelial cell survival, preserve intestinal barrier integrity, reduce oxidative stress, mitigate excessive mucosal inflammation, enhance IgA secretion, and provide long-term protection through epigenetic imprinting. Pili on the cell surface of LGG® promote adhesion to the intestinal mucosa and ensure close contact to host cells. Extracellular vesicles produced by LGG® recapitulate many of these effects through their cargo of effector molecules. Collectively, the effector molecules of LGG® exert a significant influence on both the gut mucosa and immune system, that promotes intestinal homeostasis and immune tolerance.

Lynch syndrome (LS) is one of the most common hereditary cancer syndrome in human populations, associated with germline variants in MLH1, MSH2/EPCAM, MSH6 and PMS2 genes. The advent of next generation sequencing has proven a significant impact in germline variant detection in the causative genes; however, a large proportion of patients with clinical criteria still receive uncertain or negative results. PMS2 is the least frequent reported gene, associated with up to 15% of LS cases with late-onset disease and low penetrance phenotype; however, the proportion of PMS2-LS cases is considered to be highly underestimated. In this context, we consulted public available databases (ClinVar, LOVD) for missense and intronic PMS2 variants and performed an in silico analysis of the genomic sequence. Splicing bioinformatics tools proven effective in other genes were used to assess both the wild-type DNA sequence and reported genetic variants. Splicing alterations were predicted in silico and using GTEx short-read RNA expression data. Out of the 2384 missense variants discovered, 90% were classified with uncertain significance (VUS). 4.9% of missense variants were shown to have a potential splicing consequence (DS > 0.2) using SpliceAI. As described in the original publication, SpliceAI-visual was proven effective in annotation of short intronic variants (< 50 bp). Four short intronic variants were identified using SpliceAI-visual as potentially splicing disturbing, in spite of using a lower threshold (DS > 0.1). Moreover, we observed that Splicing Regulatory Elements (SREs) may play a fundamental role in alternative splicing in PMS2 gene, ESE motifs being overrepresented in highly expressed exons 5, 11 and 14. Computational analysis performed in our study serves as a valuable filtering step for guiding further RNA sequencing experiments. Additional functional data is necessary to evaluate the significance of our findings.

The global trade and transportation sectors heavily rely on the maritime industry. Still, its dependence on fossil energy sources poses significant environmental challenges and leads to unstable fuel prices that affect the cost of goods transported by sea. This paper aims to evaluate the viability of seaports as energy-intensive entities and explore the feasibility of implementing a Nuclear-Renewable Hybrid Energy System (NRHES). The study presents a case study of the Tanjung Priok Port in Indonesia, focusing on estimating energy consumption, emissions, and the potential impact of carbon taxation on seaport operations. By quantifying these factors, the research provides insights into the energy requirements, environmental effects, and potential costs associated with seaport carbon taxation. A comprehensive analysis of the technical and economic feasibility of implementing an NRHES in the seaport case study is conducted, determining the optimal sizing and composition of components, considering the proportion of nuclear and renewable energy sources. Additionally, the economic analysis considers energy costs, net present cost, cash flow, return on investment, and internal rate of return. The findings aim to inform decision-makers about the benefits and challenges of adopting an NRHES, contributing to a cleaner and more sustainable future for the maritime industry.

In CNS drug discovery, estimation of brain exposure of lead compounds is critical for their optimization. Compounds need to cross the blood-brain barrier (BBB) to reach the pharmacological targets in the CNS. The BBB is a complex system involving passive and active mechanisms of transport and efflux transporters such as P-glycoproteins (P-gp) and breast cancer resistance protein (BCRP), which play an essential role in CNS penetration of small molecules. Several in vivo, in vitro and in silico methods are available to estimate human brain penetration. Preclinical species are used as in vivo models to understand the unbound brain exposure by deriving the Kp,uu parameter, the brain/plasma ratio of exposure corrected with the plasma and brain free fraction. MDCK-mdr1 (Madin Darby canine kidney cells transfected with the MDR1 gene encoding for the human P-gp) assay is the most commonly used in vitro assay to estimate compound permeability and human efflux. The in silico methods to predict brain exposure, such as CNS MPO, CNS BBB scores and various Machine Learning models, help save costs and speed up compound discovery and optimization at all stages. These methods enable the screening of virtual compounds and building of a CNS penetrable compounds library as well as optimization of lead molecules for CNS penetration. Therefore, it is crucial to understand these methods' reliability and ability to predict CNS penetration. We review the in silico, in vitro and in vivo data and their correlation with each other and assess published in silico approaches to predict the BBB penetrability of compounds.

The dynamic effects observed in collisions represent a specific area of high-energy interaction located at the boundary of mechanics, hydrodynamics, shock wave physics, and alternating high-pressure regions. The paper shows that in the volume of a solid metal body, as a result of dynamic alloying by a high-speed stream of powder particles in the super-deep penetration mode (SDP), fibre structures of altering material arise, forming the framework of the composite material. The stream of powder particles in the metal obstacle following the path of least resistance and the impact of shock waves on particles results in a volumetric framework from the products of interaction between the injected and matrix materials. When using SDP, defective structural elements (channelled) - germs of reinforcing fibres arise. At the subsequent heat treatment, there is an intensive diffusion. The growth process of reinforcing fibres shifts to higher temperatures (as compared to the standard mode), leading to an increase in the bending strength of the fibre material up to 13 times for high-speed tool W6Mo5Cr4V2 steel. As a result of the completion of the growth of reinforcing fibres in the volume of the W6Mo5Cr4V2 steel, the material's bending strength in 1.2 times is realised. Simultaneously, it provides an increase of wear resistance 1.7-1.8 times.

Biological gels (bio-gels) are hydrated polymer networks that serve diverse biological functions, which often lead to intentional or unintentional exposure to particulate matter. In this work, we derive a microscopically motivated framework that enables the investigation of penetration mechanisms into bio-gels. We distinguish between two types of mechanisms: spontaneous (unforced) penetration and forced penetration. Using experimental data available in literature, we exploit the proposed model to characterize and compare between the micro-structures of respiratory, intestinal, and cervicovaginal mucus and two types of biofilms. Next, we investigate the forced penetration process of spherical and ellipsoidal particles into a locally quadrilateral network. The proposed framework can be used to improve and complement the analysis of experimental findings in vitro, ex vivo, and in vivo. Additionally, the insights from this work pave the way towards enhanced designs of nano-medicines and allow to assess risk factors related to the nano-pollutants exposure.

Broad-spectrum antifungal drug deployed for topical therapy, specific for onychomycosis, Itraconazole was used as the active pharmaceutical ingredient in a nail lacquer formulation¹. The objective of the study was to optimize an antifungal nail lacquer, which when applied topically onto the dorsal surface of the nail plate would facilitate the transungual penetration of the drug. Itraconazole hydrochloride was synthesized to aid the formulation of the lacquers. The optimization involved comparing four different formulations of 1%w/w Itraconazole nail lacquers containing combinations of penetration enhancers (Papain, Salicylic acid, Urea) based on their ability to facilitate diffusion of the drug through the nail plate over five days. The drug uptake was quantified by extracting the drug from the nail clippings and analyzing it. The tests conducted to account for the quality of the optimized formulation were drug content, spread ability, check for precipitation, and accelerated stability. The results demonstrated that the optimized 1%w/w Itraconazole nail lacquer contained 5%w/w Papain, 5 %w/w Salicylic Acid, and 2.8% w/w Urea. The drug uptake from nail clippings was higher than the literature derived reference MIC90 value for T. Rubrum strain, and the quality of the optimized lacquer was not compromised throughout three weeks [2]. The hypothesis stated that the inclusion of Salicylic acid, Papain, and Urea in an Itraconazole (1%w/w) nail lacquer would have the highest transungual penetration on application to the nail plate. In conclusion, the hypothesis was accepted, and the optimized lacquer passed the drug uptake evaluation and all quality control tests.

There are important challenges for modeling large electrical distribution circuits, even more with the presence of distributed renewable generation. Constructing simulations for assessing the effect of the penetration of distributed generation on electrical distribution networks has become of great importance for Distribution Network Operators (DNOs). This paper proposes a simulation strategy based on open-source platforms and the integration of scripting tools for the rapid modeling of large-scale electrical distribution circuits with distributed renewable generation. The implementation is based on the adaptation of a tool called QGIS2OpenDSS, which creates OpenDSS distribution network models directly from an open-source geographic information system, QGIS. The plugin’s capabilities are demonstrated using a real distribution feeder with more than 60% penetration of renewable generation based on photovoltaic systems. These simulations are carried out using real data from a circuit provided by a DNO in the Dominican Republic, which is used to demonstrate how this approach provides a more accessible and flexible way to simulate and assess the effect of Distributed Energy Resources (DERs) in Medium Voltage (MV) and Low Voltage (LV) networks, enabling utilities to evaluate system performance and identify potential issues.

Borneol and menthol were two terpenes wildly used as penetrate enhancer in transdermal drug delivery. To explore their penetration enhancement effect towards hydrophilic drug, 5-FU was selected as model drug. A method combined vitro permeation studies and coarse grain molecular dynamics was used to investigate their penetration enhancement effect towards 5-FU. As a result, although both borneol and menthol showed a penetration enhancement effect towards 5-FU, they differed a lot in the penetration enhancement mechanism, which was also thought to account for their different penetration enhancement effect. As for menthol, SC bilayer disrupting effect seemed to be its main mechanism. While for borneol, its mechanism seemed to be more complicated. Except for disrupting the SC bilayer, it could also increase the permeation of 5-FU by enhancing the diffusion rate of 5-FU or inducing the formation of transient pore. All of this enable us a molecular understanding of borneol and menthol’s penetration enhancement effect towards hydrophilic drug, which might provide some guidance in the latter research and application.

L-ascorbic acid represents one of the most potent antioxidant, photoprotective, anti-aging and anti-pigmentary cosmeceutical agents, with a good safety profile. However, the challenge remained to design the stable topical formulation, with such a permeability of L-ascorbic acid as active that the optimal effects on skin could be achieved. The aim of our research was to evaluate the difference between the penetration ability of ascorbyl palmitate incorporated in the same percentage (2%) within the creams and emulgels as carriers, as well as to determine the impact of its incorporation into liposome on the kinetics of penetration. Tape stripping was applied for studying the penetration of the ascorbyl palmitate into the stratum corneum. In addition, the sensory and textural properties of examined formulations were determined. In both cases (liposomal and non-liposomal formulations), creams exhibited a better penetration profile of active substance compared to the use of emulgel. Encapsulation of ascorbyl palmitate into liposomes led to an increase in the adhesiveness and density of the prepared cream and emulgel samples. The best spreadability and absorption during application were detected in liposomal samples. The obtained results confirmed improved dermal penetration of ascorbyl palmitate, either cream or emulgel bases were employed, which further indicates the advantages of its liposomal encapsulation.

Dermal penetration is considered to mainly occur via passive diffusion. Therefore, a high concentration gradient of dissolved active ingredient between formulation and skin is needed to achieve an effective dermal penetration. The concentration gradient between formulation and skin can be changed by changing the amount of dissolved active ingredient in the formulation. In case of poorly soluble active ingredients this can be achieved by using nanosized drug material instead of larger sized material. The smaller size and the resulting larger surface increase the kinetic solubility and thus increase the concentration gradient of dissolved active ingredient between formulation and skin, which then results in an increased dermal penetration. In this study we demonstrated that the concentration gradient between formulation and skin can also be influenced by the number of particles being present in the formulation and by the dose (volume of formulation) applied to the skin. Particles of undissolved active ingredient are known to act as a reservoir by releasing dissolved molecules in the liquid phase of the formulation. It could now be demonstrated that the particles - once the liquid in which they are dispersed evaporates - can connect to the skin via an aqueous meniscus. The aqueous meniscus contains dissolved active ingredient and therefore creates a small local spot with a locally high concentration gradient and improved dermal penetration. Therefore, the dermal penetration can be increased with formulations that contain high amounts of particles. This can be achieved by applying formulations with high numbers of particles and/or by applying larger volumes of particle containing formulations to the skin.

Background: Hyaluronic acid (HA) is well known in the cosmetic industry for its hydrating properties linked to its interaction with keratin in the stratum corneum. Hair is also mainly composed of keratin, but no evidence of penetration and interaction of HA in hair had yet been established. Herein, we examined, with appropriate methods, this penetration and interaction. Methods: Confocal Raman Spectroscopy was used to track HA penetration in hair fibers. Human hair was UV-irradiated, or not, before washing with a number of different shampoo formulations. Low-molecular weight hyaluronic acid, high-molecular weight HA, and an optimized blend of low- and high-molecular weight HA, were used. The benefits of HA for cosmetic application were then evaluated at the ex vivo level. Results: Raman analysis of non-irradiated samples revealed that the HA blend penetrated the hair cortex 5.9 times more than the placebo and with irradiated samples, a 1.8-fold increase in penetration was observed. Whatever the irradiation status, penetration of this optimal HA blend was significantly greater than that of the other two active substances. Compared to the placebo, the HA blend significantly decreased spontaneous frizzing by 11%, repaired the hair by increasing the elastic modulus and the break force, and increased the water content in the hair shafts. Conclusion: Confocal Raman Spectroscopy can be considered as a powerful, non-invasive technique to investigate the penetration of active ingredients into the hair.

Microplastics (MPs) are a critical environmental issue, with impacts ranging from ecosystem contamination to health risks through bioaccumulation. This review addresses the inefficacy of traditional water treatments in removing MPs and proposes photodegradation, particularly via nanomaterial-enhanced photocatalysts, as a solution. Utilizing their unique properties like large surface area and tunable bandgap, nanomaterials significantly improve degradation efficiency. Different strategies for photocatalysts modification to improve photocatalytic performance are thoroughly summarized, with the particular emphasis on element doping and heterojunction construction. Furthermore, this review thoroughly summarizes the possible fundamental mechanisms driving photodegradation of microplastics facilitated by nanomaterials, with a focus on processes like free radical formation and singlet oxygen oxidation. By clearly elucidating these strategies and mechanisms, this review aims to provide valuable insights and inspire further progress in microplastic photodegradation.

Transportation systems through the ages have seen drastic evolutions in terms of transportation methods, speed of transport, infrastructure, technology, connectivity, influence on the environment, and accessibility. The massive transformation seen in the transportation sector has been fueled by the industrial revolutions which have continued expansion and progress into the fourth industrial revolution. However, the methodologies of data collection and processing used by the many drivers of this progress differ. The significance of standardized data and its mode of collection cannot be overstated as it has a major impact on the process outcomes. In order to achieve a better understanding of the impact of this, this study methodically reviewed the literature on the subject of the data collection and processing mechanism of 4IR technologies in the context of the transport industry with an emphasis on the areas of accomplishment of several studies and drawing attention to their limitations. Although the industry has advanced significantly as a result of the adoption and application of various research studies in this field, considerable focus needs to be placed in the areas of standardized data collection and computational approaches, which will ultimately assist in achieving various benefits in the transportation industry.

Metal creep has been a subject of extensive study for more than 110 years, because it affects the useful life of engineering components operating at high temperatures. It is even more so with ever-increasing operating temperatures of propulsion/power-generation systems by the environmental regulations to reduce greenhouse emissions. This review summaries the recent development in creep modeling with regards to creep strain evolution, creep rate, creep ductility, creep life and fracture mode, attempting to provide a comprehensive mechanism-based framework to address all the important creep phenomena and the long-standing issue of long-term creep life prediction with microstructural evolution and environmental effects.

Delivery of drugs through the nasal route provides an alternative, yet highly efficacious modality for administering both large and small pharmaceutic molecules. This method proves particularly advantageous for drugs that are unstable during oral administration, as they undergo significant degradation in the gastrointestinal tract or metabolization through the first-pass effect in the liver. Nasal administration stands as a viable alternative to parenteral therapy and is also suitable for long-term medical management. The nasal mucosa, characterized by high vascularity and permeability, facilitates rapid pharmaceutical absorption, ensuring a swift onset of therapeutic action. Despite its noninvasive nature, the nasal delivery technique finds broad applicability for both local treatment and systemic therapy, as the drug directly enters systemic circulation. This article explores the feasibility of a novel spray delivery mechanism for intranasal drug deposition. The study aims to determine whether users can correctly follow the state-of-the-art application instructions for a nasal spray with an optimal nozzle placement angle (namely, 12-15°) at the nostril while maintaining sufficient safety and efficacy, and without engaging in preventable usage errors that could harm the user. Additionally, the study evaluates the effectiveness of device labeling, instructions for use, and a short video in supporting the correct application of the nasal spray at the optimal angle (12-15°) and assesses whether users can differentiate the product from others with similar appearances. We have also performed physical spray tests to experimentally evaluate drug penetration to the nasopharynx (a key target site for viral infections) for two different nozzle placements – one for current package instructions coming with over-the-counter spray products and the other for the optimal spray usage procedure to enhance targeted drug delivery. Human Factors (HF) validation studies were also conducted, instructing users to follow the application instructions of the nasal spray bottle with the nozzle placed at the optimal angle to target the nasopharynx. The experimental tests consistently confirmed improved penetration with the 12-15° nozzle placement, with visual cues proving effective when used in tandem with written instructions for guiding the study participants to adhere to the recommended usage procedures.

Permeability has an important effect on drug absorption. In this study, the effect of different concentrations of sodium sulfobutyl ether-β-cyclodextrin (SBE-β-CD) on the absorption of ranitidine was investigated to examine the mechanism of permeability changes. The results of parallel artificial membrane permeability assay (PAMPA) showed that increasing the concentration of sodium sulfobutyl ether-β-cyclodextrin, 0, 0.12% (w/v), 0.36% (w/v) and 3.6% (w/v), respectively, the apparent permeability coefficient of ranitidine decreased to 4.62×10-5 , 4.5×10-5 , 3.61×10-5 and 1.08×10-5 in Caco-2 cells, respectively. The same results were obtained from oral pharmacokinetic study in rats; Further studies indicated that SBE-β-CD significantly increased the zeta potential of ranitidine. SBE-β-CD interacted with ranitidine charges to form a complex that reduced ranitidine permeability, and SBE-β-CD should be chosen with caution for drugs with poor permeability.

Psoriasis is considered an immune-mediated disease involving the innate and adaptative immune system triggered by environmental risk factors in genetically susceptible individuals. However, its physiopathology is not fully understood yet. Recent technological advances, specially genome and epigenome-wide studies, have allowed a more sensitive study of the genetic and epigenetic mechanisms, allowing an enhanced understanding of its physiopathology and facilitating the development of new drugs. In this review, we aim to summarize the current evidence on genetic and epigenetic mechanisms of psoriasis.

Modern electrical power systems integrate renewable generation, with solar generation being one of the pioneers worldwide. In Latin America, the greatest potential and development of solar generation is found in Chile through the National Electric System. However, its energy matrix faces a crisis of drought and reduction of emissions that limits hydroelectric generation and involves the definitive withdrawal of coal generation. The dispatch of these plants is carried out by the system operator, who uses a simplified mechanism, called “economic merit list” and which does not reflect the real costs of the plants to the damage of the operating and marginal cost of the system. This inefficient dispatch scheme fails to optimize the availability of stored gas and its use over time. Therefore, a real-time redispatch model is proposed that minimizes the operation cost function of the power plants, integrating the variable generation cost as a polynomial function of the net specific fuel consumption, adding gas volume stock restrictions and water reservoirs. In addition, the redispatch model uses an innovative "maximum dispatch power" restriction, which depends on the demand associated with the automatic load disconnection scheme due to low frequency. Finally, by testing real simulation cases, the redispatch model manages to optimize the operation and dispatch costs of power plants, allowing the technical barriers of the market to be broken down with the aim of integrating ancillary services in the short term, using the power reserves in primary (PFC), secondary (SCF), and tertiary (TCF) frequency control.

Electrical energy demand increase does evolve rapidly due to several socioeconomic factors such as industrialization, population growth, urbanization and of course the evolution of modern technologies in this 4th industrial revolution era. Such rapid increase in energy demand introduces a huge challenge in power system. Such has paved way for network operators to seek for alternative energy resources other than the conventional fossil fuel system. Hence, the penetration of renewable energy into the electricity supply mix has evolved rapidly in the past three decades. However, the grid system has to be well planned ahead to accommodate such increase in energy demand in the long run. Transmission Network Expansion Planning (TNEP) is a well ordered and profitable expansion of power facilities that meets the expected electric energy demand with an allowable degree of reliability. This paper proposes a TNEP model that minimises the network reinforcements, operational costs and costs of renewable energy penetrations, while satisfying the increase in demand. The problem is formulated as a mixed integer linear programming (MILP) problem. The developed model has been tested in several IEEE test systems in multi-period scenarios. The paper also carried out a detailed derivation of the new non-negative variables in terms of the power flow magnitudes, the bus voltage phase angles and the lines’ phase angles for proper mixed integer variables’ decomposition techniques. Moreover, this paper tends to provide additional recommendation in terms of which particular year (within 20 years of planning period) can the network operators install new line(s), new corridor(s) and/or additional generation capacity to the respective existing power networks. Such is achieved by running incremental periods simulations from base year through the planning horizon. The results show the efficacy of the developed model in solving the TNEP problem with a reduced and acceptable computation time even for large power grid system.

Over the last decades, the energy market around the world has reshaped due to accommodating the high penetration of renewable energy resources. Although renewable energy sources have brought various benefits, including low operation cost of wind and solar PV power plants, and reducing the environmental risks associated with the conventional power resources, they have imposed a wide range of difficulties in power system planning and operation. Naturally, classical optimal power flow (OPF) is a nonlinear problem. Integrating renewable energy resources with conventional thermal power generators escalates the difficulty of the OPF problem due to the uncertain and intermittent nature of these resources. To address the complexity associated with the process of the integration of renewable energy resources into the classical electric power systems, two probability distribution functions (Weibull and lognormal) are used to forecast the voltaic power output of wind and solar photovoltaic, respectively. Optimal power flow, including renewable energy, is formulated as a single-objective and multi-objective problem in which many objective functions are considered, such as minimizing the fuel cost, emission, real power loss, and voltage deviation. Real power generation, bus voltage, load tap changers ratios, and shunt compensators values are optimized under various power systems’ constraints. This paper aims to solve the OPF problem and examines the effect of renewable energy resources on the above-mentioned objective functions. A combined model of wind integrated IEEE 30-bus system, solar PV integrated IEEE 30-bus system, and hybrid wind and solar PV integrated IEEE 30-bus system are performed using the equilibrium optimizer technique (EO) and other five heuristic search methods. A comparison of simulation and statistical results of EO with other optimization techniques showed that EO is more effective and superior.

Over the last decades, the energy market around the world has reshaped due to accommodating the high penetration of renewable energy resources. Although renewable energy sources have brought various benefits, including low operation cost of wind and solar PV power plants, and reducing the environmental risks associated with the conventional power resources, they have imposed a wide range of difficulties in power system planning and operation. Naturally, classical optimal power flow (OPF) is a nonlinear problem. Integrating renewable energy resources with conventional thermal power generators escalates the difficulty of the OPF problem due to the uncertain and intermittent nature of these resources. To address the complexity associated with the process of the integration of renewable energy resources into the classical electric power systems, two probability distribution functions (Weibull and lognormal) are used to forecast the voltaic power output of wind and solar photovoltaic, respectively. Optimal power flow, including renewable energy, is formulated as a single-objective and multi-objective problem in which many objective functions are considered, such as minimizing the fuel cost, emission, real power loss, and voltage deviation. Real power generation, bus 13 voltage, load tap changers ratios, and shunt compensators values are optimized under various power systems’ 14 constraints. This paper aims to solve the OPF problem and examines the effect of renewable energy resources 15 on the above-mentioned objective functions. A combined model of wind integrated IEEE 30-bus system, solar 16 PV integrated IEEE 30-bus system, and hybrid wind and solar PV integrated IEEE 30-bus system are performed 17 using the equilibrium optimizer technique (EO) and other five heuristic search methods. A comparison of 18 simulation and statistical results of EO with other optimization techniques showed that EO is more effective 19 and superior.

Superantigens are unconventional antigens which recognise immune receptors outside the usual binding sites e.g. complementary determining regions (CDRs), to elicit a response within the target cell. T-cell superantigens crosslink T-cell receptors and MHC Class II molecules on antigen-presenting cells, leading to lymphocyte recruitment, induction of cytokine storms and T-cell anergy or apoptosis among many other effects. B-cell superantigens, on the other hand, bind immunoglobulin receptors on B-cells affecting opsonisation, IgG-mediated phagocytosis, and drive B-cells into apoptosis. Here, through a review of the structural basis for recognition of immune receptors by superantigens, we show that their binding interfaces share specific physicochemical characteristics when compared with other protein-protein interaction complexes. Given that antibody-binding superantigens have been exploited extensively in industrial antibody purification, these observations could facilitate further protein engineering to optimize the use of superantigens in this and other areas of biotechnology.

Metformin use in pregnancy is increasing worldwide as randomised controlled trial (RCT) evidence is emerging demonstrating its safety and efficacy. The Metformin in Gestational Diabetes (MiG) RCT changed practice in many countries demonstrating that metformin had similar pregnancy outcomes to insulin therapy with less maternal weight gain and a high degree of patient acceptability. A multicentre RCT is currently assessing the addition of metformin to insulin in pregnant women with type 2 diabetes. RCT evidence is also available for the use of metformin for women with Polycystic Ovarian Syndrome and for non-diabetic women with obesity. No evidence of an increase in congenital malformations or miscarriages has been observed even when metformin is started before pregnancy and continued to term. Body composition and metabolic outcomes at two, seven and nine years have now been reported for the offspring of mothers treated in the MiG study. In this review, we will briefly discuss the action of metformin and then consider the evidence from the key clinical trials.

Overweight and Obesity are global health and economic concerns. According to the World Health Organization, the number of individuals with obesity has nearly tripled since 1975. This health issue is currently considered an epidemic, affecting over 1.9 billion adults and 340 million children and adolescents. It contributes to more than 5 million deaths each year and has a global economic burden that will reach $4.32 trillion annually by 2035, according to the World Obesity Federation. This disease can affect every system of the human body and can lead to complications such as metabolic syndrome, diabetes, cancer, dyslipidemia, cardiovascular diseases, and hypertension, among others. Treatment may sometimes include diet, exercise, drugs, and bariatric surgery. Nonetheless, not all people have access to these treatments, and public health strategies consider prevention the most important factor. In this regard, recent investigations are aiming to find alternatives and adjuvants for the treatment of obesity, its prevention, and the reversion of some of its complications, using natural sources of anti-obesogenic compounds like polyphenols, terpenes, alkaloids, saponins, among others. In this review, we gather the most current information using PubMed, Google Scholar, Scopus, Cochrane, and Web of Science. We present and discuss the current information about natural products that have shown anti-obesogenic effects at a molecular level. We also consider the impact of dietary habits and lifestyle in preventing overweight and obesity due to the evidence of the benefits of certain foods and compounds consumed regularly. We discuss mechanisms, pathways, and receptors involved in the modulation of obesity, especially those related to inflammation and oxidative stress linked to this disease, due to the relevance of these two aspects in developing complications.

The introduction on Zinc oxide nanoparticles (ZnOn) in sunscreens solved the issue of poor spreadability of these formulations, which often left a white film on the skin. However, safety concerns have arisen regarding the topical application of ZnOn. Some studies employed commercial sunscreens to address the safety issues of the topical application of ZnOn; however, commercial formulations are often complex and contain a wide range of ingredients that could attenuate the potential damage caused by the ZnOn. Therefore, in this study we aimed to develop a simple stable formulation containing 20% of coated and uncoated ZnOn, characterize the formulations and the nanoparticles, and assess the skin penetration in Franz diffusion cell. The Feret's diameter for the uncoated and coated ZnOn was 137 nm and 134 nm, respectively. For the uncoated ZnOn the hydrodynamic size in water was 368 nm and for the coated ZnOn, the average hydrodynamic size in ethyl acetate was 135 nm. The incorporation of ZnOn led to formulations more consistent and easier to spread, as suggested by the lower work of shear and higher values of firmness, cohesiveness, consistency and index of viscosity compared with the vehicle. The stability assessment at 45ºC suggested that the formulations containing the ZnOn were stable for 30 days and the vehicle was stable for 90 days. The assessment off the skin penetration by reflectance confocal laser microscopy indicated that the formulations did not permeate into the deepest layers of the skin, but accumulated on the skin furrows, hair and hair follicle.

With the global increase of photovoltaic (PV) modules deployment in recent years, the need to explore and realize their reported failure mechanisms has become crucial. Despite PV modules being considered reliable devices, failures and extreme degradations often occur. Some degradations and failures can be minor and cause no critical harm if within the expected range. Others, may start mildly and then deteriorate faster to become catastrophic, especially in harsh environments. This paper conducts a state-of-the-art literature review to scan PV failures, types, and their root cause based on PV’s constructed components (from protective glass to junction-box). It outlines the hazardous consequences beyond PV module failures, describing what harm they can bring to the PV system. As we delve into the literature, it becomes clear that every component is vulnerable to certain types of failures; some can deteriorate within themselves, and others infect further PV components resulting in emerging more severe failures. In the end, the review briefly summarises PV failure detection techniques, emphasising electrical characterization techniques, and disclosing the need to engage more electrical parameters. Most importantly, this review can prepare the stage for the PV research community to identify the most prevalent degradation processes. This, in turn, encourages researchers to investigate them throughout modelling and experimental studies to forecast them at the early onset in order to protect the PV systems from hazardous malfunctions.

Influenza viruses cause acute respiratory infections responsible for significant mortality and morbidity around the world. Various factors, such as antigenic drift, allow influenza strains to avoid being fully suppressed by seasonal vaccines. This has led to the increased scrutiny of antivirals as treatment and prophylaxis options for seasonal outbreaks and potential pandemics. Unfortunately, many influenza antivirals suffer from a lack of adequate clinical trials, as well as a lack of toxicity data. This is especially true of umifenovir (arbidol), a drug popularly used for the prevention and treatment of influenza strains in China and Russia. Neuraminidase inhibitors, though widely prescribed, display a potential for future resistance. Adamantanes, while proven to be effective in treating influenza A, are already encountering rapid and widespread cross-resistance and are effectively obsolete. Baloxavir marboxil, a newer antiviral, shows promise in treating acute uncomplicated influenza and may avoid the development of resistance when co-administered with other antiviral drugs. Indeed, the low genetic barrier to resistance associated with influenza antivirals could potentially be overcome by co-administration with other antivirals. This review explores the most widely prescribed antivirals for influenza treatment, their mechanisms of action, and the data currently available about their susceptibility to resistance and efficacy.

The human body is inhabited by unique microbial communities that protect and regulate the host against pathogens and inflammation. To address issues related to disrupted microbial composition, microbial transfer therapy (MTT) has emerged as a potential treatment option. The most popular form of MTT is fecal microbiota transplantation (FMT), which has been successful in treating various diseases. Another emerging form of MTT is vaginal microbiota transplantation (VMT), transferring of the vaginal microbiota from a healthy female donor to a diseased patient's vaginal cavity, which aims to restore normal vaginal microbial composition. However, VMT is vastly unexplored due to safety concerns and lack of research. This paper explores the mechanisms involved in VMT's therapeutic effect and discusses future perspectives. Further research is needed to advance VMT's clinical applications and techniques.

Though early-stage colorectal cancer has a high 5-year survival rate of 65-92% depending on the specific stage, this probability drops to 13% after the cancer metastasizes. Frontline treatments for colorectal cancer such as chemotherapy and radiation often produce dose-limiting toxicities in patients and acquired resistance in cancer cells. Additional targeted treatments are needed to improve patient outcomes and quality of life. Immunotherapy involves treatment with peptides, cells, antibodies, viruses, or small molecules to engage or train the immune system to kill cancer cells. Preclinical and clinical investigations of immunotherapy for treatment of colorectal cancer including immune checkpoint blockade, adoptive cell therapy, monoclonal antibodies, oncolytic viruses, anti-cancer vaccines, and immune system modulators have been promising, but demonstrate limitations for patients with proficient mismatch repair enzymes. In this review, we discuss preclinical and clinical studies investigating immunotherapy for treatment of colorectal cancer and predictive biomarkers for response to these treatments. We also consider open questions including optimal combination treatments to maximize efficacy, minimize toxicity, and prevent acquired resistance and approaches to sensitize mismatch repair proficient patients to immunotherapy.

The intestinal microbiota and its functions are regarded as critical for host health and disease. Probiotics can influence the gut microbiome and its interactions with the host, and are currently defined as “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host”. Probiotics have become common components of strategies to promote livestock health, welfare and productivity, not least due to restrictions on the use of antimicrobial drugs. Common probiotic organisms are considered commensals and are ‘generally recognized as safe’ (GRAS) via oral administration. This review outlines potential probiotic mechanisms, including recent findings. These mechanisms include those interactions primarily occurring between the supplemented probiotic microorganisms and the indigenous intestinal microbiota, perhaps within the gut lumen, as well as more direct interactions with the host via mucosal receptors or more distally following absorption of microbial components. There is good evidence that the gut microbiome is relatively stable in ‘healthy’ individuals and resistant to ‘colonisation’ by exogenous microbes, which helps exclude pathogens, but has implications for the establishment of probiotics, and could increase the importance of microbe-microbe interactions. However, such microbiomes may be receptive to complementary microbes or functions, while supplemented probiotics may dominate luminal populations, particularly in less populated regions of the intestine. Moreover, host-adapted microbes or microbiomes may elicit different host responses and/or be more effective. Some considerations for the interpretation of study results, including extrapolation from different models or microbial strains, are also included. In addition, notable mechanistic and/or pathogen challenge studies from pigs and poultry are highlighted to underline the recognised potential of probiotics in these species, particularly as the appropriate selection of microorganisms and their application continues to be better understood and improve.

Mitochondria function to generate ATP and also play important roles in cellular homeostasis, signaling, apoptosis, autophagy, and metabolism. The loss of mitochondrial function results in cell death and various types of diseases. Therefore, quality control of mitochondria via intra- and intercellular pathways is crucial. Intracellular quality control consists of biogenesis, fusion and fission, and degradation of mitochondria in the cell, whereas intercellular quality control involves tunneling nanotubes and extracellular vesicles. In this review, we outline the current knowledge on the intra- and intercellular quality control mechanisms of mitochondria.

The present work analyzes the behavior in terms of corrosion resistance of three reinforced concrete formulations over a period of 1 year. The samples were accompanied by creating a monitoring methodology using the Electrochemical Impedance Spectroscopy (EIE) technique, working only with the real component over time. Three mixtures were used, one conventional without pozzolanic addition (REF) and two others with pozzolanic additions, rice husk ash (RCA) and metakaolin (MK). Prototypes were created and exposed to the action of a 165g/l NaCl sodium chloride solution. The characterization of the materials was carried out by determining the chloride diffusion profile (ASTM 1556), analyzing images using tomography and with the support of analytical techniques such as x-ray fluorescence and x-ray diffraction. The monitoring methodology using the EIE demonstrated the positive effect of the insertion of pozzolans, rice husk ash (RCA) and metakaolin (MK), by delaying the process of chloride diffusion in the concrete, resulting in greater resistance to corrosion. The EIE also showed that the active mineral addition in concrete, of aluminum-silicic composition (MK), had a predominant protective effect on the steel//concrete interface against the attack of chloride ions.

In 2011, it was reviewed that there is a strong co-occurrence between major depression and chronic fatigue syndrome (CFS), with fatigue and physio-somatic symptoms being key symptoms of depression, and depressive symptoms appearing during the course of CFS. Moreover, the comorbidity between both conditions may in part be explained by activated immune-inflammatory pathways, including increased translocation of Gram-negative bacteria and increased levels of pro-inflammatory cytokines, such as interleukin (IL)-1. Nevertheless, the possible involvement of activated microglia in this comorbidity has remained unclear. This paper aims to review microglial disturbances in major depression, CFS and their comorbidity. A comprehensive literature search was conducted using the PubMed / MEDLINE database to identify studies that are relevant to this current review. Depressed patients present neuroinflammatory alterations, probably related to microglial activation, while animal models show that a microglial response to immune challenges including lipopolysaccharides is accompanied by depressive-like behaviors. Recent evidence from preclinical studies indicate that activated microglia have a key role in the onset of fatigue. In chronic inflammatory conditions, such as infections and senescence, microglia orchestrate an inflammatory microenvironment thereby causing fatigue. In conclusion, based on our review we may posit that shared immune-inflammatory pathways and activated microglia underpin comorbid depression and CFS and that activated microglia are the main orchestrators of this comorbidity. As such, microglial activation and neuro-inflammation may be promising targets to treat the overlapping manifestations of both depression and CFS.

Social biases may concentrate attention of researchers on a small number of well-known molecules/mechanisms leaving others underexplored. In accordance with this view, central to mechanistic toxicology is a narrow range of molecular pathways that are assumed to be involved in significant part of responses to toxicity. It is unclear, however, if there are other molecular mechanisms which play important role in toxicity events but are overlooked by toxicology. To identify overlooked genes sensitive to chemical exposures we used publicly available databases. First, we used data on published chemical-gene interactions for 17,338 genes to estimate their sensitivity to chemical exposures. Next, we extracted data on publication numbers per gene for 19,243 human genes from Find My Understudied Genes database. Threshold were applied to both datasets using our algorithm to identify chemically sensitive and chemically insensitive genes and well-studied and underexplored genes. 1,110 underexplored genes highly sensitive to chemical exposures were used in GSEA and Shiny GO analyses to identify enriched biological categories. Metabolism of fatty acids, amino acids, and glucose were identified as underexplored molecular mechanisms sensitive to chemical exposures. These findings suggest that future effort is needed to uncover the role of xenobiotics in the current epidemics of metabolic diseases.

PIEZO channels PIEZO1 and PIEZO2 are the newly identified mechanosensitive, non-selective cation channels permeable to Ca2+. In higher vertebrates, PIEZO1 expresses ubiquitously in most of the tissues and cells while PIEZO2 expresses more specifically in the peripheral sensory neurons. PIEZO channels contribute to a wide range of biological behaviors and developmental processes, therefore driving a significant attention in the effort to understand their molecular properties. One prominent property of PIEZO channels is their rapid inactivation, which manifests itself as a decrease of channel open probability in the presence of a sustained mechanical stimulus. Lack of the PIEZO channel inactivation is linked to various mechanopathologies emphasizing the significance of studying this PIEZO channel property and the factors affecting it. In the present review, we discuss the mechanisms underlying the PIEZO channel inactivation, its modulation by interaction of the channels with lipids and/or proteins, and how the changes of PIEZO inactivation by the channel mutations can cause a variety of diseases in animals and humans.

Biochemical signaling is the key mechanism to coordinate a living organism in all aspects of its life. It is still enigmatic how exactly cells and organisms deal with environmental signals and irritations precisely because of the limited number of signaling proteins and a multitude of transitions inside and outside the cell. Many components of signaling pathways are functionally pleiotropic, which means they have several functions. A single stimulus often activates multiple effectors, a distinct effector can be activated by numerous stimuli and signals triggered by different stimuli are often transduced via shared network components. This very compact and concise review sheds light on the most important molecular mechanisms of cellular signaling in fungi.

Gap junctions (GJ) and connexins play integral roles in cellular physiology and have been found to be involved in multiple pathophysiological states from cancer to cardiovascular disease. Studies over the last 60 years have demonstrated the utility of altering GJ signaling pathways in experimental models, which has led to them being attractive targets for therapeutic intervention. A number of different mechanisms have been proposed to regulate GJ signaling, including channel blocking, enhancing channel open state, and disrupting protein-protein interactions. The primary mechanism for this has been through the design of numerous peptides as therapeutics, that are either currently in early development or are in various stages of clinical trials. Despite over 25 years of research into connexin targeting peptides, the overall mechanisms of action are still poorly understood. In this overview, we discuss published connexin targeting peptides, their reported mechanisms of action and the potential for these molecules in the treatment of disease.

In this review, we provide an overview of the current knowledge on the different sexual systems and sex determining mechanisms in bivalves, with a focus on the various epigenetic and genetic factors that may be involved. The final section of the review provides recent discoveries on sex-specific mitochondrial genes in bivalves possessing the unconventional system of doubly uniparental inheritance of mitochondria (which is found in several members of the orders Mytiloida, Unionoida, Veneroida and Nuculanoida). The genes involved in this developmental pathway could represent the first sex determination system in animals in which mitochondrially-encoded genes are directly involved.

Micro/Nano Robot is an intelligent and efficient microrobot that can perform specific tasks under the influence of external stimuli. Depending on the application scenarios, the microrobot can adaptively transform into appropriate functional forms under different external stimuli, thus perfectly matching the needs. To date, microbots have been widely used in targeted therapy, drug delivery, tissue engineering, environmental remediation, and other fields. Although the applications of microrobots are promising, there are only a few reviews that can focus on the preparation methods and driving mechanisms. Therefore, it is necessary to outline the current status of the development of these microrobots in order to provide some new insights for the further development of the field. Therefore, this paper reviews the research progress of microrobots in terms of preparation methods, stimulus response mechanisms and applications, and highlights the applicability of different preparation methods and stimulus types. Finally, the current challenges faced by microrobots are highlighted and possible solutions are proposed to facilitate the practical application of microrobots.

The basis for computation in the brain is the quantum threshold of the ‘soliton’ accompanying the ion changes of the action potential and the refractory membrane at convergences. We provide a logical explanation from the action potential to a neuronal model of the coding and computation of the retina and have explained how the visual cortex operates by quantum phase processing. In the small world network parallel frequencies collide into definable patterns of distinct objects. Elsewhere we have shown how many sensory cells are mean sampled to a single neuron and that convergences of neurons are common. We have also demonstrated, using the threshold and refractory period of a quantum phase pulse, that action potentials diffract across a neural network due to the annulment of parallel collisions in phase ternary computation (PTC). Thus, PTC applied to neuron convergences results in collective mean sampled frequency and is the only mathematical solution within the constraints of brain neural networks (BNN). In the retina and other sensory areas, we discuss how this information is coded and then understood in terms of network abstracts within the lateral geniculate nucleus (LGN) and visual cortex. First by defined neural patterning within a neural network, and then in terms of contextual networks, we demonstrate that the output of frequencies from the visual cortex contain information amounting to abstract representations of objects in increasing detail. We show that nerve tracts from the LGN provide time synchronisation to the neocortex (defined as the location of the combination of connections of the visual cortex, motor cortex, auditory cortex, etc). The full image is therefore combined in the neocortex with other sensory modalities so that it receives information about the object from the eye, and all abstracts that make up the object. Spatial patterns in the visual cortex are formed from individual patterns illuminating the retina and memory is encoded by reverberatory loops of computational actions potentials (CAPs). We demonstrate that a similar process of PTC may take place in the cochlea and associated ganglia, as well as ascending information from the spinal cord, and that this function should be considered universal where convergences of neurons occur.

Many of the potential immune therapeutic targets are similarly affected in adult-onset neurodegenerative diseases such as Alzheimer’s (AD) disease, Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD), but also in a seemingly distinct Niemann-Pick type C disease with primarily juvenile-onset. This strongly argues for an overlap in pathogenic mechanisms. The commonly researched immune targets include various immune cell subsets such as microglia, peripheral macrophages, or regulatory T cells (Tregs), the complement system, and other soluble factors. In this review, we will compare these neurodegenerative diseases from a clinical point of view and point out the common pathways and mechanisms of protein aggregation, neurodegeneration and/or neuroinflammation that could potentially lead to shared treatment strategies. We also describe the common therapeutic approaches in treating the immune dysfunctions in these disorders, moving from immunization to microbiome regulation and stem cell treatment.

Endothelial cells are the crucial inner lining of blood vessels, pivotal in vascular homeostasis and integrity. However, these cells are perpetually subjected to a myriad of mechanical, chemical, and biological stresses that can compromise their plasma membranes. A sophisticated repair system involving key molecules, such as calcium, annexins, dysferlin, and MG53, is essential for maintaining endothelial viability. These components orchestrate complex mechanisms, including exocytosis and endocytosis, to repair membrane disruptions. Dysfunctions in this repair machinery, often exacerbated by aging, are linked to endothelial cell death, subsequently contributing to the onset of atherosclerosis and the progression of cardiovascular diseases (CVD) and stroke, major causes of mortality in the United States. Thus, identifying the core machinery for endothelial cell membrane repair is critically important for understanding the pathogenesis of CVD and stroke and developing novel therapeutic strategies for combating CVD and stroke. This review summarizes the recent advances in understanding the mechanisms of endothelial cell membrane repair. The future directions of this research area are also highlighted.

The metabolism of lipoproteins, which regulates the transit of the lipid to and from tissues, is crucial to maintaining cholesterol homeostasis. Cardiac remodeling is referred to as a set of molecular, cellular, and interstitial changes that, following injury, affect the size, shape, function, mass, and geometry of the heart. Acetyl coenzyme A (acetyl CoA), which can be made from glucose, amino acids, or fatty acids, is the precursor for the synthesis of cholesterol. In this article, authors explain concepts behind cardiac remodeling, its clinical ramifications, and the pathophysiological roles played by numerous various components, such as cell death, neurohormonal activation, oxidative stress, contractile proteins, energy metabolism, collagen, calcium transport, inflammation, and geometry. The levels of cholesterol are traditionally regulated by two biological mechanisms at the transcriptional stage. First, the SREBP transcription factor family regulates the transcription of crucial rate-limiting cholesterogenic and lipogenic proteins, which in turn limits cholesterol production. Immune cells become activated, differentiated, and divided, during an immune response with the objective of eradicating the danger signal. In addition to creating ATP, which is used as energy, this process relies on metabolic reprogramming of both catabolic and anabolic pathways to create metabolites that play a crucial role in regulating the response. Because of changes in signal transduction, malfunction of the sarcoplasmic reticulum and sarcolemma, impairment of calcium handling, increases in cardiac fibrosis, and progressive loss of cardiomyocytes, oxidative stress appears to be the primary mechanism that causes the transition from cardiac hypertrophy to heart failure. De novo cholesterol production, intestinal cholesterol absorption, and biliary cholesterol output are consequently crucial processes in cholesterol homeostasis. In the article's final section, the pharmacological management of cardiac remodeling is explored. The route of treatment is explained into different steps: including, promising, and potential strategies. This chapter offers a brief overview of the history of the study of cholesterol absorption as well as the different potential therapeutic targets.

Organ transplantation remains the only treatment option for patients with end-stage organ dysfunction. However, there are numerous limitations that challenge its clinical application, including the shortage of organ donations, the quality of donated organs, injury during organ preservation and reperfusion, primary and chronic graft dysfunction, acute and chronic rejection, infection, and carcinogenesis in post-transplantation patients. Acute and chronic inflammation and cell death are two major underlying mechanisms for graft injury. Necroptosis is a type of programmed cell death involved in many diseases and has been studied in the setting of all major solid organ transplants, including the kidney, heart, liver, and lung. It is determined by the underlying donor organ conditions (e.g., age, alcohol consumption, fatty liver, hemorrhage shock, donation after circulatory death, etc.), preservation conditions and reperfusion, as well as allograft rejection. Specific molecular mechanisms of necroptosis have been uncovered in the organ transplantation setting, and potential targeting drugs have been identified. We hope this review article will promote more clinical research to determine the role of necroptosis and other types of programmed cell death in solid organ transplantation to alleviate the clinical burden of ischemia-reperfusion injury and graft rejection.

The climate and its changes are major risk factors for agricultural activities because agricultural systems are highly affected by climatic factors such as temperature, rain, humidity, wind, and solar radiation. While some agricultural areas of the world are irrigated, the vast majority rely on natural rainfall patterns. Farmers will consume more water as a result of climate change and experience less water availability, resulting in a decrease in production capacity. As one of the most important natural phenomena affecting agricultural productivity, drought is a limiting environment for plant growth. The response of plants to water stress is complex and involves coordination between gene expression and its integration with hormones. It has been shown that bacteria have mechanisms to reduce water stress in these plant species and promote greater growth. The underlined mechanism involves root-to-shoot phenotypic changes in growth rate, architecture, hydraulic conductivity, water conservation, plant cell protection, and damage restoration through integrating phytohormones modulation, stress-induced enzymatic apparatus, and metabolites. This review demonstrates how plant growth-promoting bacteria can mitigate negative effects associated with water stress in plants and provide examples of technology conversion in agroecosystems.

Equine fecal microbiota transplantation (FMT) is an emerging therapy for restoring gut microbiome balance in horses. An imbalance in the gut microorganisms, known as dysbiosis, can cause inflammation and metabolic disruptions. FMT, which involves transferring gut bacteria from a healthy donor to a diseased recipient, has shown positive results in treating gastrointestinal diseases in horses, but is still largely limited to research purposes due to safety concerns and lack of understanding of its mechanisms. This paper aims to shed light on the possible mechanisms of FMT in horses and discuss future perspectives for its clinical application. Further research is needed to develop more effective and safer FMT techniques for horses.

In sub-Saharan Africa, malaria is a leading cause of mortality and morbidity. As a result of the interplay between many factors, the control of this disease can be challenging. However, few studies have demonstrated malaria's complexity, control, and modeling although this perspective could lead to effective policy recommendations. This paper aims to be a didactic material providing the reader with an overview of malaria. More importantly, using a system approach lens, we intend to highlight the debated topics and the multifaceted thematic aspects of malaria transmission mechanisms, while showing the control approaches used as well as the model supporting the dynamics of malaria. As there is a large amount of information on each subject, we have attempted to provide a basic understanding of malaria that needs to be further developed. Nevertheless, this study illustrates the importance of using a multidisciplinary approach to designing next-generation malaria control policies.

Fecal microbiota transplantation (FMT) is an emerging therapeutic option for a variety of diseases, which is characterized as transferring fecal microorganisms from a healthy donor into the intestinal tract of a diseased receipt. In human clinics, FMT has been used for treating diseases for decades with promising results. In recent years, veterinary specialists adapted FMT in canine patients, however, compared to humans, canine FMT is more inclined to research purposes than practical applications in most cases due to safety concerns. Therefore, in order to facilitate the application of fecal transplant therapy in dogs, in this paper, we aimed to review recent application of FMT in canine clinical treatments as well as possible mechanisms that are involved in the process of therapeutic effect of FMT.

Candida glabrata is a yeast of increasing medical relevance, particularly in critically ill patients. It is the second most isolated Candida species associated with invasive candidiasis (IC) behind C. albicans. The attributed higher incidence is primarily due to an increase in the acquired immunodeficiency syndrome (AIDS) population, cancer, and diabetes patients. The elderly population and the frequent use of indwelling medical devices are also predisposing factors. The work aimed to review various virulence factors that facilitate the survival of pathogenic C. glabrata in IC. The available published research articles related to the pathogenicity of C. glabrata were retrieved and reviewed from four credible databases, mainly Google Scholar, ScienceDirect, PubMed, and Scopus. The articles highlighted many virulence factors associated with pathogenicity in C. glabrata, including adherence to a susceptible host surface, evading host defences, and producing hydrolytic enzymes (e.g., phospholipases, proteases, and haemolysins). The factors facilitate infection initiation. Other virulent factors include iron regulation and genetic mutations. Accordingly, biofilm production, tolerance to high-stress environments, and development of resistance to the antifungal drug, notably to fluconazole and other azole derivatives, were reported. The review provided evident pathogenic mechanisms and antifungal resistance associated with C. glabrata in ensuring its sustenance and survival.

There are presently more than 18 known aflatoxins (>18) most of which have been insufficiently studied for their incidence, health-risk, and mechanisms of toxicity to allow effective intervention and control means that would significantly and sustainably reduce their incidence and adverse effects on health and economy. Among these, aflatoxin B1 (AFB1) has by far been the most studied; and yet, many aspects of the range and mechanisms of the diseases it causes remain to be elucidated. Its mutagenicity, tumorigenicity, and carcinogenicity, which are the best known still suffer from many limitations regarding the relative contribution of the oxidative stress and the reactive epoxide derivative (Aflatoxin-exo 8,9-epoxide) in the induction of the diseases, as well as its metabolic and synthesis pathways. Additionally, despite the well-established additive effects for carcinogenicity between AFB1 and other risk factors, e.g., hepatitis viruses B and C, and the algal hepatotoxic microcystins, the mechanisms of this synergy remain unclear. This study reviews the most recent advances in the mechanisms of toxicity of aflatoxins and the adverse health effects that they cause in humans and animals.

Mitochondrial functions are essential for life, critical for development, maintenance of stem cells, adaptation to physiological changes, responses to stress and aging. The complexity of mitochondrial biogenesis requires coordinated nuclear and mitochondrial gene expression, owing to the need of stoichiometrically assemble the OXPHOS system for ATP production. It requires, in addition, the import of thousands of proteins from the cytosol to keep optimal mitochondrial function and metabolism. Moreover, mitochondria require lipid supply for membrane biogenesis, while it is itself essential for the synthesis of membrane lipids. To achieve mitochondrial homeostasis, multiple mechanisms of quality control have evolved to ensure that mitochondrial function meets cell, tissue and organismal demands. Herein, we give an overview of mitochondrial mechanisms that are activated in response to stress, including mitochondrial dynamics, mitophagy and the mitochondrial unfolded protein response (UPR^mt). We then discuss the role of these stress responses in aging, with particular focus on Caenorhabditis elegans. Finally, we review observations that point to the mitochondrial PHB (prohibitin) complex as a key player in mitochondrial homeostasis, being essential for mitochondrial biogenesis and degradation, and responding to mitochondrial stress. Understanding how mitochondria responds to stress and how such responses are regulated is pivotal to combat aging and disease.

Amyloids result from the aggregation of several unrelated proteins, due to either specific mutations or promoting intra- or extra-cellular conditions. Structurally, they are rich in intermolecular β-sheets and are the causative agents of several diseases, both neurodegenerative and systemic. It is believed that the most toxic species are small aggregates, referred to as oligomers, rather than the final fibrillar assemblies. Their mechanisms of toxicity are mostly mediated by aberrant interactions with the cell membranes, with resulting derangement of membrane-related functions. Much effort is being put in the search for natural antiamyloid agents, and/or in the development of synthetic molecules. Actually, it is well documented that the prevention of amyloid aggregation results in several cytoprotective effects. Here, we portray the state of the art in the field. Several natural compounds are effective antiamyloid agents, notably tetracyclines and polyphenols. They are generally non-specific, as documented by their partially overlapping mechanisms, and the capability to interfere with the aggregation of several unrelated proteins. Among rationally designed molecules, we mention the prominent examples of β-breakers peptides, whole antibodies and fragments thereof, and the special case of drugs contrasting transthyretin aggregation. In this framework, we stress the pivotal role of the computational approaches. When combined with biophysical methods, in several cases they have helped clarify in detail the protein/drug modes of interaction, which make it plausible that more effective drugs will be developed in the future.

Hypoxia, or reduced oxygen availability, has been studied extensively for its ability to activate specific genes. Hypoxia induced gene expression is mediated by the HIF transcription factors, although not exclusively so. Despite the great knowledge on the mechanisms by which hypoxia activates genes, much less is known about how hypoxia promotes gene repression. In this review, we discuss the potential mechanisms underlying hypoxia-induced transcriptional repression responses. We highlight HIF-dependent and independent mechanisms, but also the potential roles of dioxygenases with functions at the nucleosome and DNA level. Finally, we discuss recent evidence regarding the involvement of transcriptional repressor complexes in hypoxia.

Many neurodegenerative diseases are characterised by impairment of protein quality control mechanisms in neuronal cells. Ineffective clearance of misfolded proteins by the proteasome, autophagy pathways and exocytosis leads to accumulation of toxic protein oligomers and aggregates in neurons. Toxic protein species affect various cellular functions resulting in the development of a spectrum of different neurodegenerative proteinopathies, including Huntington’s disease (HD). Playing an integral role in proteostasis, dysfunction of the ubiquitylation system in HD is progressive and multi-faceted with numerous biochemical pathways affected, in particular the ubiquitin proteasome system and autophagy routes for protein aggregate degradation. Unravelling the molecular mechanisms involved in HD pathogenesis of proteostasis provides insight in disease progression in HD as well as possible therapeutic avenues. Recent developments of potential therapeutics are discussed in this review.

The complexity of modern power grids, exacerbated by integrating diverse energy sources, espe-cially inverter-based resources (IBRs), presents a significant challenge to grid operation and plan-ning since linear models fail to capture the intricate IBR dynamics. This study employs the Sparse Identification of Nonlinear Dynamics (SINDy) method to bridge the gap between theoretical un-derstanding and practical implementation in power system analysis. It introduces the novel Volterra-based Nonlinearity Index (VNI) to examine system-level nonlinearity comprehensively. The distinction of dynamics into first-order linearizable terms, second-order nonlinear dynamics, and third-order noise elucidates the intricacy of power systems. The findings demonstrate a fundamental shift in system dynamics as power sources transit to IBRs, revealing system-level nonlinearity compared to module-level nonlinearity in conventional syn-chronous generators. The VNI quantifies nonlinear-to-linear relationships, enriching our comprehension of power system behavior and offering a versatile tool for distinguishing between different nonlinearities and visualizing their distinct patterns through the proposed VIN profile.

Heavy and light quarks produced in high-pT partonic collisions radiate differently. Heavy quarks regenerate their color field, stripped-off in the hard reaction, much faster than the light ones and radiate a significantly smaller fraction of the initial quark energy. This peculiar feature of heavy-quark jets leads to a specific shape of the fragmentation functions observed in e+e− annihilation. Differently from light flavors, the heavy quark fragmentation function strongly peaks at large fractional momentum z, i.e. the produced heavy-light mesons, B or D, carry the main fraction of the jet momentum. This is a clear evidence of the dead-cone effect, and of a short production time of a heavy-light mesons. Contrary to propagation of a small qq¯ dipole, which survives in the medium due to color transparency, a heavy-light Qq¯ dipole promptly expands to a large size. Such a big dipole has no chance to remain intact in a dense medium produced in relativistic heavy ion collisions. On the other hand, a breakup of such a dipole does not affect much the production rate of Qq¯ mesons, differently from the case of light qq¯ meson production.

Hydrogenases are iron-sulfur enzymes that catalyze proton reduction and H₂ oxidation with outstanding efficiency. They are considered blueprints for the design of transition metal complexes, e.g. as heterogenous catalysts in the context of H₂ production from water. Moreover, hydrogenases are biological model systems for metal hydride chemistry and proton-coupled electron transfer. Depending on the composition of the active site cofactor, [NiFe]-hydrogenases are distinguished from [FeFe]-hydrogenases. The former binds a hetero bimetallic nickel/iron site, embedded in the protein by four cysteine ligands. The later, by contrast, carries a homo bimetallic iron/iron site attached to the protein by only a single cysteine. Carbon monoxide and cyanide ligands (CO/CN) at the active site facilitated detailed investigations of hydrogenase catalysis by infrared spectroscopy, owing to strong signals and redox-dependent frequency shifts. However, the details of proton transfer have not been addressed experimentally.We found that specific redox state transitions in [NiFe]- and [FeFe]-hydrogenase can be triggered by visible light to record extremely sensitive ‘light-minus-dark’ infrared difference spectra monitoring key amino acid residues as shown in the ToC figure. As these transitions are coupled to protonation changes, our data allowed investigating dynamic hydrogen-bonding changes that go well beyond the resolution of protein crystallography. In [NiFe]-hydrogenase, photolysis of the bridging hydride ligand in the ‘Ni-C’ state was followed by rapid accumulation of the ‘Ni-SI_a’ state and/or ‘Ni-L’ state. Infrared difference spectra in various isotopic media clearly indicated the formation of a protonated cysteine residue as well as hydrogen-bonding changes involving the COOH group of a glutamic acid residue and a ‘dangling water’ molecule. These findings are in excellent agreement with crystallographic analyses of [NiFe]-hydrogenase in the Ni-R state and allowed devising a molecular precise model of catalytic proton transfer. In [FeFe]-hydrogenase, an external redox dye was used to accumulate the ‘Hred’ state over the oxidized resting state ‘Hox’. Infrared difference spectra of wild-type enzyme and numerous amino acid variants indicated hydrogen-bonding changes involving the COOH groups of two glutamic acid residues. Moreover, we noted the deprotonation of an arginine residue. Crystallographic analyses of [FeFe]-hydrogenase in the Hox state failed to explain the rapid proton transfer due to a ‘breach’ in the succession of residues. To this end, our findings facilitated a molecular precise model of ‘discontinued’ proton transfer.The comparison of catalytic proton transfer in bimetallic hydrogenases emphasizes the role of the outer coordination sphere. We suggest that the stable protonation of a nickel-ligating cysteine in [NiFe]-hydrogenase has a crucial influence on the preferred direction of proton flow and catalysis (i.e., H₂ oxidation). On the contrary, proton transfer in [FeFe]-hydrogenase involves an adjacent cysteine as a relay group that promotes both proton release and proton uptake. We presume that this causes the notable bidirectionality of [FeFe]-hydrogenase. These observations must guide the design of biomimetic compounds for the production or consumption of H₂.

Animal trypanosomiasis (AT) is a complex of veterinary diseases known under various names such as nagana, surra, dourine and mal de caderas, depending on the country, the infecting trypanosome species and the host. AT is caused by parasites of the genus Trypanosoma, and the main species infecting domesticated animals are T. brucei brucei, T. b. rhodesiense, T. congolense, T. vivax, T. evansi and T. equiperdum. AT transmission, again depending on species, is through tsetse flies or common Stomoxys and tabanid flies or through copulation. Therefore, the geographical spread of all forms of AT together is not restricted to the habitat of a single vector like the tsetse fly and currently includes almost all of Africa, and most of South America and Asia. The disease is a threat to millions of companion and farm animals in these regions, creating a financial burden in the billions of dollars to developing economies as well as serious impacts on livestock rearing and food production. Despite the scale of these impacts, control of AT is neglected and under-resourced, with diagnosis and treatments being woefully inadequate and not improving for decades. As a result, neither the incidence of the disease, nor the effectiveness of treatment is documented in most endemic countries, although it is clear that there are serious issues of resistance to the few old drugs that are available. In this review we particularly look at the drugs, their application to the various forms of AT, and their mechanisms of action and resistance. We also discuss the spread of veterinary trypanocide resistance and its drivers, and highlight current and future strategies to combat it.

Aquaculture is a fast-emerging food-producing sector in which fishery production plays an im-perative socio-economic role, providing ample resources and tremendous potential worldwide. However, aquatic animals are exposed to the deterioration of the ecological environment and in-fection outbreaks, which represent significant issues nowadays. One of the reasons for these threats is the excessive use of antibiotics and synthetic drugs that have harmful impacts on the aquatic atmosphere. It is not surprising that functional biotic feeds such as probiotics, prebiotics, postbiotics, and synbiotics have been developed as natural alternatives to sustain a healthy microbial envi-ronment in aquaculture. These functional feed additives possess several beneficial characteristics, including gut microbiota modulation, immune response reinforcement, resistance to pathogenic organisms, improved growth performance, and enhanced feed utilization in aquatic animals. Nevertheless, their mechanisms in modulating the immune system and gut microbiota in aquatic animals are largely unclear. This review discusses current research advancements to fill research gaps and promote effective and healthy aquaculture production.

Glycans play important roles as recognition molecules on cell surfaces in living organisms due to their remarkable structural diversity. Carbohydrates exist in numerous isomeric forms and can adopt diverse structures through various branching patterns. Despite their relatively small molecular weights, they exhibit extensive structural diversity. On the other hand, lectins, also known as carbohydrate-binding proteins, not only recognize and bind to the diverse structures of glycans but also induce various biological reactions based on structural differences. Initially discovered as hemagglutinins in plant seeds, lectins have been found to play significant roles in cell recognition processes in higher vertebrates. However, our understanding of lectins in marine animals, particularly marine invertebrates, remains limited. Recent studies have revealed that marine animals possess novel lectins with unique structures and glycan recognition mechanisms not observed in known lectins. Of particular interest is their role as pattern recognition receptors in the innate immune system, where they recognize glycan structures of pathogens. Furthermore, lectins serve as toxins for self-defense against foreign enemies. Recent discoveries have identified various pore-forming proteins containing lectin domains in fish venoms and skins. These proteins utilize lectin domains to bind target cells, triggering oligomerization and pore formation in the cell membrane. These findings have spurred research into the new functions of lectins and lectin domains. In this review, we present recent findings on the diverse structures and functions of lectins in marine animals.

Microbial communities inhabiting the human body play a crucial role in protecting the host against pathogens and inflammation. Disruptions to the microbial composition can lead to various health issues. Microbial transfer therapy (MTT) has emerged as a potential treatment option to address such issues. Fecal microbiota transplantation (FMT) is the most widely used form of MTT and has been successful in treating several diseases. Another form of MTT is vaginal microbiota transplantation (VMT), which involves transferring vaginal microbiota from a healthy female donor to a diseased patient's vaginal cavity with the goal of restoring normal vaginal microbial composition. However, VMT has not been extensively studied due to safety concerns and a lack of research. This paper explores the therapeutic mechanisms of VMT and discusses future perspectives. Further research is necessary to advance the clinical applications and techniques of VMT.

Airborne virus, such as COVID-19, caused pandemics all over the world. Virus-containing particles produced by infected individuals are suspended in the air for extended periods of time, actually results in viral aerosols and the spread of infectious diseases. Aerosol collection and detection devices are essential for limiting the spread of airborne virus diseases. This review provides an overview of the primary mechanisms and enhancement techniques for collecting and detecting airborne viruses. Indoor virus detection strategies for scenarios with varying ventilations are also summarized based on the excellent performance of existing advanced comprehensive devices. This review provides guidance for the development of future aerosol detection devices and aids in the control of airborne transmission diseases, such as COVID-19, monkeypox, and other airborne transmission viruses.

As a conceptual model of disease mechanisms, a disease map integrates available knowledge and is applied for data interpretation, predictions and hypothesis generation. It is possible to model disease mechanisms on different levels of granularity and adjust the approach to the goals of a particular project. This rich environment together with requirements for high-quality network reconstruction makes it challenging for new curators and groups to be quickly introduced to the development methods. In this review, we offer a step-by-step guide for developing a disease map within its mainstream pipeline that involves using the CellDesigner tool for creating and editing diagrams and the MINERVA Platform for online visualisation and exploration. We also describe how the Neo4j graph database environment can be used for managing and querying efficiently such a resource. For assessing the interoperability and reproducibility we apply FAIR principles.

This review aimed at synthesizing the mechanisms and outcomes of metabolic surgery on hormones, adipokines, metabolomics, and at the molecular level. We reviewed the endocrine, microRNA, and metabolomics changes in human and animal models following metabolic surgery for the treatment of obesity and diabetes. PubMed, Science Direct, Scopus, and Google Scholar databases were searched up to February 2022. The most relevant studies in the area over the past 17 years have been considered for this review. In most cases, metabolic procedures especially those that include intestinal bypass components, showed remission of type 2 diabetes. This involves a variety of weight-independent mechanisms to improve glucose homeostasis, improving insulin sensitivity, and secretion. The miRNAs’ dysregulated expressions have essential roles in metabolic processes. Metabolic surgery is a potentially sustainable treatment that can modify a patient’s physiology and glucose regulation mechanism. The feasibility and role of miRNA are important for potential targeted genetic pathways in future obesity with type 2 diabetes management.

Kynurenic acid (KYNA) is an endogenous tryptophan (Trp) metabolite known to possess neuroprotective property. KYNA plays critical roles in nociception, neurodegeneration, and neuroinflammation. A lower level of KYNA is observed in patients with neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases or psychiatric disorders such as depression and autism spectrum disorders, whereas a higher level of KYNA is associated with the pathogenesis of schizophrenia. Little is known about the optimal concentration for neuroprotection and the threshold for neurotoxicity. In this study the effects of KYNA on memory functions were investigated by passive avoidance test in mice. Six different doses of KYNA were administered intracerebroventricularly to previously trained CFLP mice and they were observed following 24 hours. High doses of KYNA (i.e., 20-40 μg/2 μl) significantly decreased the avoidance latency, whereas a low dose of KYNA (0.5 μg/2 μl) significantly elevated it compared with controls, suggesting that the low dose of KYNA enhanced memory function. Furthermore, six different receptor blockers were applied to reveal the mechanisms underlying the memory enhancement induced by KYNA. The series of tests revealed the possible involvement of the serotonergic, dopaminergic, α and β adrenergic, and opiate systems in the nootropic effect. The study confirmed that a low dose of KYNA improved a memory component of cognitive domain, which was mediated by, at least in part, four systems of neurotransmission in an animal model of learning and memory.

The mechanisms of natural oscillations and resonance are described, considering the peculiarities of the transformation of elastic and kinetic energy in the implementation of the law of conservation of energy in local and integral volumes of the body, using the concept of mechanics based on the concepts of space, time and energy. When describing the motion in the Lagrange form, the elastic deformation energy of the particles is determined by the quadratic invariant of the tensor, whose components are the partial derivatives of Euler variables with respect to Lagrange variables. The increment of the invariant due to elastic deformation is represented as the sum of two scalars, one of which depends on the average value of the relative lengths of the edges of the particles in the form of an infinitesimal parallelepiped, the second is equal to the standard deviation of these lengths from the average value. It is shown that each of the scalars can be represented in the form of two dimensionless kinematic parameters of elastic energy, which participate in different ways in the implementation of the law of conservation of energy. One part of the elastic energy passes into kinetic energy and participates in the implementation of the law of conservation of energy for the body as a whole, considering external forces. The second part is not converted into kinetic energy but changes the deformed state of the particles in accordance with the equations of motion while maintaining the same level of the part of the elastic energy of the particles used for this. The kinematic parameters differ from the volume density of the corresponding types of energy by a factor equal to the elastic modulus, which is directly proportional to the density and heat capacity of the material and inversely proportional to the volume compression coefficient. Transverse, torsional, and longitudinal vibrations are considered free and under resonance conditions. The mechanisms of transformation of forced vibrations into their own after the termination of external influences and resonance at the superposition of free and forced vibrations with the same or similar frequency are considered. The formation of a new free wave at each cycle with an increase in the amplitude, which occurs mainly due to internal energy sources, and not external forces, is justified.

RNA-guided genomic transcriptional regulation tools, namely Clustered Regularly Interspaced Short Palindromic Repeats interference (CRISPRi) and CRISPR-mediated gene activation (CRISPRa), are a powerful technology for the field of functional genomics. Deriving from the CRISPR/Cas9 system, both systems comprise a catalytically dead Cas9 (dCas9) and a single guide RNA (sgRNA). This type of dCas9 is incapable of cleaving DNA but retains its ability to specifically bind to DNA. The binding of the dCas9/sgRNA complex to a target gene results in transcriptional interference. The CRISPR/dCas9 system has been explored as a tool for transcriptional modulation and genome imaging. Despite its potential applications and benefits, the challenges and limitations faced by the CRISPR/dCas9 system include the off-target effects, PAM sequence requirement, efficient delivery methods, and the CRISPR/dCas9-interfered crops being labeled as genetically modified organisms in several countries. This review highlights the progression of CRISPR/dCas9 technology as well as its applications and potential challenges in crop improvement.

Ras is the most frequently mutated oncogene and recent drug development efforts have spurred significant new research interest. Here we will review progress toward understanding how Ras functions in nanoscale, proteo-lipid signaling complexes on the plasma membrane, called nanocluster. We will discuss how G-domain reorientation is plausibly linked to Ras-nanoclustering and -dimerization. We will then look at how these mechanistic features could cooperate in the engagement and activation of RAF by Ras. Moreover, we will show how this structural information can be integrated with microscopy data that provide nanoscale resolution in cell biological experiments. Synthesizing the available data, we propose to distinguish between two types of Ras nanoclusters, an active, immobile RAF-dependent type and an inactive/ neutral membrane anchor-dependent. We conclude that it is possible that Ras reorientation enables dynamic Ras dimerization, while the whole Ras/ RAF complex transits into an active state. These transient di/oligomer interfaces of Ras may be amenable to pharmacological intervention. We close by highlighting a number of open questions including, whether all effectors form active nanoclusters and whether there is an isoform specific composition of Ras nanocluster.

Phosphorus (P) is the second-most important element after nitrogen that is required for plant growth. Although this element is abundant in most soils, it is rarely available in plant-accessible forms since most of it normally exists in soil in insoluble forms such as phosphates. In conventional agriculture, P is normally supplied as chemical fertilizer to satisfy plant P requirements. This, to a large extent, boosts plant production. However, chemical fertilizers are costly, have a huge carbon footprint, and are environmentally-unsustainable owing to the high energy requirements during their synthesis. Besides, P-containing agricultural run-offs contribute hugely to the eutrophication of water bodies and environmental degradation. Moreover, plants can consume only a small amount of chemically-supplied P since between 75 and 90% of this form of P normally get precipitated into complexes and rapidly become fixed in soil. These issues and concerns necessitate research into alternative and viable ways of supplying P to plants. Rhizobacteria have for decades been investigated in vivo and in planta as suitable tools in sustainable agriculture due to the plant-growth-promoting activities such as nutrients’ solubilization, nitrogen fixation, and production of phytohormones. Although a lot of research has been done on different nutrients-solubilizing rhizobacteria and their potential in sustainable agriculture, their mechanisms of action and prospects in sustainable agriculture remain to be fully understood. This review particularly focuses on the P solubilizing rhizobacteria and evaluates their diversity, mechanisms of action, and prospects in sustainable agriculture based on the present and future scenario of their application. Such information is useful in determining their potential and evaluating their prospects in promoting sustainable agricultural systems.

Increased motivation towards alcohol use and suboptimal behavioural control are suggested to predispose adolescents to Alcohol Use Disorders (AUDs). Paradoxically however, most adolescent AUDs resolve over time without any formal intervention, suggesting adolescent resilience to AUDs. Importantly, studies directly comparing adolescent and adult alcohol use are largely missing. We therefore aimed to unravel the moderating role of age in the relation between alcohol use and motivational and control-related cognitive processes in 45 adolescent drinkers compared to 45 adults. The results showed that enhancement drinking motives and impulsivity related positively to alcohol use. Although enhancement drinking motives and impulsivity were higher in adolescents, the strength of the relation between these measures and alcohol use did not differ between age groups. None of the alcohol use-related motivational measures (i.e., craving, attentional bias, approach bias) and behavioral control measures (i.e., interference control, risky decision making, working-memory) were associated with alcohol use or differed between age groups. These findings support the role of impulsivity and affective sensitivity in adolescent drinking, but question the moderating role of age therein. The current study contributes towards understanding the role of age in the relation between alcohol use and cognition.

Cardiovascular disease is the most common cause of death. Oxidative stress and inflammation are pathophysiological processes involved in the development of cardiovascular diseases, so anti-inflammatory and antioxidant agents that modulate redox balance have become the targets of research to evaluate their molecular mechanisms and therapeutic properties. Astaxanthin, a carotenoid of the xanthophyll group, has potent antioxidant effects due to its molecular structure and its arrangement in the plasma membrane, factors that favor the neutralization of reactive oxygen and nitrogen species. This carotenoid also stands out for its anti-inflammatory activity, possibly interrelated with its antioxidant effect, as well as for its modulation of lipid and glucose metabolism. Considering the potential positive effects of astaxanthin on cardiovascular health evidenced by preclinical and clinical studies, this paper describes the molecular and cellular mechanisms related to the antioxidant and anti-inflammatory properties of this carotenoid in cardiovascular diseases, especially atherosclerosis.

Membrane remodeling and phospholipid biosynthesis are normally tightly regulated to maintain the shape and function of cells. Indeed, different physiological mechanisms ensure a precise coordination between de novo phospholipid biosynthesis and modulation of membrane morphology. Interestingly, the overproduction of certain membrane proteins hijack these regulation networks, leading to the formation of impressive intracellular membrane structures in both prokaryotic and eukaryotic cells. The proteins triggering an abnormal accumulation of membrane structures inside the cells (or membrane proliferation) share two major common features: 1) they promote the formation of highly curved membrane domains and 2) they lead to an enrichment in anionic, cone-shaped phospholipids (cardiolipin or phosphatidic acid) in the newly formed membranes. Taking into account the available examples of membrane proliferation upon protein overproduction, together with the latest biochemical, biophysical and structural data, we explore the relationship between protein synthesis and membrane biogenesis. We propose a mechanism for the formation of these non-physiological intracellular membranes that shares similarities with natural inner membrane structures found in α-proteobacteria, mitochondria and some viruses-infected cells, pointing towards a conserved feature through evolution. We hope that the information discussed in this review will give a better grasp of the biophysical mechanisms behind physiological and induced intracellular membrane proliferation, and inspire new applications, either for academia (high-yield membrane protein production and nanovesicle production) or industry (biofuel production and vaccine preparation).

Modern life implies a constant exposure of living organisms to electromagnetic fields generated by human made technology. The question of whether or not electromagnetic fields in the non-ionizing frequency range can affect cellular functions, increasing the risk of cancer or another pathologies is currently a subject of interest for scientific community of several disciplines of physics, biology, chemistry and medicine. The first part of this short review presents briefly the possible mechanism of interaction of electromagnetic fields in cellular level based in theoretical models and experimental results. The second part refers to experimental observations published by several authors about the potential cytotoxic and genotoxic effects of electromagnetic fields. Results of researches are no yet conclusive enough to accept or reject the genotoxic, carcinogenic or cytotoxic potential of these fields. Up to date the International Agency for Research on Cancer (IARC) has classified the X, gamma and ultraviolet radiation as carcinogenic and the fields generated by radio frequencies as possibly carcinogenic.

This research aims to delve into the intricacies of combustion processes, specifically focusing on heating oil and a blend of heating oil with TPO (Tire Pirolysis Oil) in a self-developed evaporative combustion chamber featuring steam injection. The primary objective is to scrutinize the impact of steam injection on the combustion dynamics. Conducting a series of tests, the investigation involved the meticulous manipulation of stoichiometric ratios while introducing ambient air through gravity fuel flow. Subsequent iterations of these tests incorporated the introduction of steam into the ambient air stream. The examination encompassed the combustion of both heating oil and the TPO blend within the combustion chamber. The evaluation criteria comprised an in-depth analysis of flame characteristics, temperature distribution within the combustion chamber, and the quantification of emissions such as particulate matter (PM), nitrogen oxides (NOx), carbon dioxide (CO2), carbon monoxide (CO), and water vapor (H2O). Throughout the experimentation phase, commercially available diesel fuel served as the primary fuel source. To facilitate the tests, the combustion chamber under scrutiny was seamlessly integrated into an AVL engine test bench system. Essential parameters, including fuel consumption, were meticulously gauged using an AVL 735 fuel flow meter, while fuel temperature was monitored using the AVL 745 fuel temperature conditioning system. The intake air, a crucial element in the combustion process, was quantified with precision using an AVL Flowsonix sensor. Emission measurements were conducted meticulously using state-of-the-art equipment, with gaseous emissions analyzed using an AVL FTIR AMA i60 exhaust gas analyzer. Simultaneously, soot emissions were quantified through employment of an AVL Micro Soot sensor. This comprehensive approach not only delves into the fundamental aspects of combustion but also extends its reach to the exploration of innovative techniques, such as steam injection, to enhance combustion efficiency and reduce emissions. The integration of advanced measurement tools ensures a robust and thorough analysis of the combustion process and its environmental implications.

T cells follow a triphasic distinct pathway of activation, proliferation and differentiation before becoming functionally and phenotypically ‘exhausted’ in settings of chronic infection, autoimmunity and in cancer. Exhausted T cells progressively lose canonical effector functions, exhibit altered transcriptional networks and epigenetic signatures and gain constitutive expression of a broad coinhibitory receptor suite. This review outlines recent advances in our understanding of exhausted T cell biology and examines cellular and molecular mechanisms by which a state of dysfunction or exhaustion is established, and mechanisms by which exhausted T cells may still contribute to pathogen or tumour control. Further, this review describes our understanding of exhausted T cell heterogeneity and outlines the mechanisms by which checkpoint blockade differentially engages exhausted T cell subsets to overcome exhaustion and recover T cell function.

Inflammation plays a key role in the development and progression of type-2 diabetes (T2D), a disease characterised by peripheral insulin resistance and systemic glucolipotoxicity. Visceral adipose tissue (AT) is the main source of inflammation early in disease course. Macrophages are innate immune cells that populate all peripheral tissues, including AT. Dysregulated AT macrophage (ATM) responses to microenvironmental changes are at the root of aberrant inflammation and development of insulin resistance, locally and systemically. The inflammatory activation of macrophages is regulated at multiple levels: cell surface receptor stimulation, intracellular signalling, transcriptionally and metabolically. This review will cover the main mechanisms involved in AT inflammation and insulin resistance in T2D. First, we will describe the physiological and pathological changes in AT that lead to inflammation and insu- lin resistance. We will next focus on the transcriptional and metabolic mechanisms described that lead to the activation of ATMs. We will discuss more novel metabolic mechanisms that influence macrophage polarisation in other disease or tissues contexts that may be relevant to future work in insulin resistance and T2D.

How to achieve sustainable development and protection of historical district is a worthwhile research topic. As a vital way to update urban space, tourism development in historical district is an effective solution to redistribute urban functions and increase urban vitality. This paper takes the Insadong in South Korea as a case to carry out the evaluation of tourist satisfaction in historical districts. The research finds that: 1) The tourist satisfaction evaluation of Insadong includes 6 dimensions in total, namely “Embodiment of historical elements”, “The blend of tradition and modernity”, Industry distribution and type", "Consumer demand", "Street layout and function", "Landscaping". The most satisfying for tourists is "Landscaping", and the most dissatisfying is "Street layout and function". 2) “The blend of tradition and modernity” has the highest weight while “Industry distribution and type” has the lowest one in the analysis of influencing factors on overall satisfaction. 3) The analysis of the common factor weight and the common factor satisfaction shows that “The blend of tradition and modernity” and “Street layout and function” are the parts that need to be improved. “Consumer demand” also has a lot of room for promotion. The research results will benefit to enhance the tourist experiences of historical district and provide theoretical basis and practical experience reference for effective protection and sustainable development of historical district.

Friction and wear take place on two solid surfaces in sliding contact as a result of the mechanical, thermal and chemical interactions with the participation of environmental species. Electron microscopy and the associated spectroscopic analyses are powerful in probing these mechanisms in spatial resolutions from micro to atomic scale. This article provides a review of the author’s work in the wear and friction mechanisms of PVD hard coatings in which various SEM- and TEM-based microscopic and spectroscopic techniques were employed. Understanding on the failure mechanisms and the origin of self-adaptive friction has been improved to nano-scale. Other related issues are also discussed, such as sample preparation techniques for cross-sectional electron microscopy, energy dispersive X-ray spectroscopy and electron energy loss spectroscopy.

Osteoporosis is a bone condition where bones become weaker, leading to fractures, especially in older adults and postmenopausal women. Bioceramics for bone regeneration have indeed emerged as a promising solution for conditions like osteoporosis. Choosing the right bioceramic depends on how quickly it dissolves, how strong it is, and whether the body will react to it. Studies show that bioceramics can help bones grow back by activating (bone morphogenetic protein) BMP, (mitogen-activated protein kinase) MAPK, and Wingless/integrated (Wnt)/β-catenin pathways in the body when combined with stem cells, drugs, and supports. However, bioceramics have some problems like not being flexible enough and being prone to breaking, as well as difficulties in growing stem cells and finding the right supports for different bone types. While there has been progress in improving bioceramics for bone healing, we need to keep looking for new ideas from other areas of medicine to keep improving them. This review aims to add to the expanding field of scientific research by offering a detailed look at how bioceramics and growth factors contribute to bone regeneration. Ultimately, this knowledge will help in creating new types of bioceramics that can improve bone regrowth, providing new treatment options for people with bone diseases.

Metformin, a widely used anti-diabetic drug, has garnered attention for its potential in cancer management, particularly in breast and colorectal cancer. It is established that metformin reduces mitochondrial respiration, but its specific molecular targets within mitochondria vary. Proposed mechanisms include inhibiting mitochondrial respiratory chain Complex I and/or Complex IV, and mitochondrial glycerophosphate dehydrogenase, among others. These actions lead to cellular energy deficits, redox state changes, and several molecular changes that reduce hyperglycemia in type 2 diabetic patients. Clinical evidence supports metformin’s role in cancer prevention in type 2 diabetes mellitus patients. Moreover, in these patients with breast and colorectal cancer, metformin consumption leads to an improvement of survival outcomes and prognosis. The synergistic effects of metformin with chemotherapy and immunotherapy highlights its potential as an adjunctive therapy for breast and colorectal cancer. However, nuanced findings underscore the need for further research and stratification by molecular subtype, particularly for breast cancer. This comprehensive review integrates metformin-related findings from epidemiological, clinical, and preclinical studies in breast and colorectal cancer. Here, we discuss current research addressed to define metformin's bioavailability and efficacy, exploring novel metformin-based compounds and drug delivery systems, including derivatives targeting mitochondria, combination therapies, and novel nanoformulations, showing enhanced anticancer effects.

Probiotics, living microorganisms with demonstrated health benefits when administered in sufficient quantities, have a rich history as dietary supplements to benefit human health. Recently, understanding of their mechanisms in the gastrointestinal tract has prompted exploration of probiotics in treating human diseases. However, the effective and precise delivery of probiotics remains a significant challenge in therapeutic applications. Here, we review the mechanisms of action of probiotics in human health and the most advanced strategies for efficient probiotic delivery. We also discuss the potential applications of engineered probiotics in disease treatment. This review contributes insights into the evolving landscape of probiotic research for therapeutic applications.

This review focuses on the role of small extracellular vesicles in the pathophysiological mechanisms of retinal degenerative diseases. Many of these mechanisms are related or modulated by the oxidative burden of the retinal cells. It has been recently demonstrated that cellular communication in the retina involves extracellular vesicles and that their rate of release and cargo features might be affected by the cellular environment and in some instances also mediated by autophagy. The fate of these vesicles is diverse, and could end up in the circulation and be used as markers, or target neighbour cells modulating gene and protein expression and eventually also angiogenesis. Neovascularization in the retina promotes vision loss in diseases such as diabetic retinopathy and age-related macular degeneration. The importance of micro RNAs, either as small extracellular vesicles’ cargo or free circulating, on the regulation of retinal angiogenesis is also discussed.