Acemetacin (ACM) is a new non-steroidal anti-inflammatory drug with anti-inflammatory, analgesic, and antipyretic effects. However, the poor water solubility and gastrointestinal side effects limit its use. Recently, the co-amorphous (CAM) strategy has attracted great interest to improve solubility for poorly water-soluble drugs, and basic amino acids have the potential to protect the gastrointestinal tract. In order to develop highly efficient and low toxic ACM formulation, we propose to prepare ACM CAM, with basic amino acids (lysine, arginine and histidine) as co-formers, using a cryo-milling method. The solid-state behaviors of the ACM CAMs were characterized by polarizing light microscopy, differential scanning calorimetry and powder X-ray diffraction. Fourier transform infrared spectroscopy and molecular docking were carried out to understand the formation mechanism. Moreover, the gastro-protective effects of ACM CAMs were evaluated in a rat gastric ulcer model. The results demonstrated CAMs improved the dissolution rates of ACM compared with the neat amorphous counterpart. Furthermore, ACM CAMs are significantly effective in mitigating the ACM-induced gastric ulcer in rats, and the ulcer inhibition rates were almost 90%. More importantly, this study provided a useful method for mitigating drug-induced gastrointestinal damage and broadened the applications of drug-amino acid CAMs.

Cancer cells require substantial amounts of energy and substrates for their metabolic hyperactivity, enabling the synthesis of new cells at the expense of healthy ones. Preliminary in vitro data suggest that a mix of free essential amino acids (EAA-mix) can promote cancer cell apoptosis by enhancing autophagy. This study aimed to confirm, both in vitro and in vivo, whether EAA intake could influence the development of colon cancer in mice. We investigated changes in cancer proliferation in CT26 cells treated with EAA-mix, and in mice fed with EAA rich modified diets (EAARD) as compared to those on a standard laboratory diet (StD). CT26 cells were injected subcutaneously (s.c.) or intraperitoneally (i.p.). After 21 days, tumors were removed and measured. In vitro data corroborated that EAA-mix impairs cancer growth by inducing autophagy and apoptosis. In vivo data revealed that mice on StD developed significantly larger (s.c.) and more numerous (i.p.) cancers than those on EAARD. EAA administration appears to influence cancer cell survival with notable anti-proliferative properties.

Cancer cells cannot proliferate and survive unless they obtain sufficient levels of the 20 proteinogenic amino acids (AAs). Unlike normal cells, cancer cells have genetic and metabolic alterations that may limit their capacity to obtain adequate levels of the 20 AAs under challenging metabolic environments. However, since normal diets provide all AAs at relatively constant levels and ratios, these potentially lethal genetic and metabolic defects are eventually harmless to cancer cells. If we temporarily replace the normal diet of cancer patients with artificial diets in which the levels of specific AAs are manipulated, cancer cells may be unable to proliferate and survive. This article reviews in vivo studies that have evaluated the antitumor activity of diets restricted or supplemented with the 20 proteinogenic AAs, individually and in combinations. It also reviews our recent studies that show that manipulating the levels of several AAs simultaneously can lead to marked survival improvements in mice with metastatic cancers.

Amino acid metabolism promotes cancer cell proliferation and survival by supporting building block synthesis, producing reducing agents to mitigate oxidative stress, and generating immunosuppressive metabolites for immune evasion. Malignant cells rewire amino acid metabolism to maximize their access to nutrients. Amino acid transporter expression is upregulated to acquire amino acids from the extracellular environment. Under nutrient depleted conditions, macropinocytosis can be activated where proteins from the extracellular environment are engulfed and degraded into the constituent amino acids. The demand for non-essential amino acids (NEAAs) can be met through de novo synthesis pathways. Cancer cells can alter various signaling pathways to boost amino acid usage for the generation of nucleotides, reactive oxygen species (ROS) scavenging molecules and oncometabolites. The importance of amino acid metabolism in cancer proliferation makes it a potential target for therapeutic intervention, including via small molecules and antibodies. In this review, we will delineate the targets related to amino acid metabolism and promising therapeutic approaches.

This paper describes the preparation and description of four new complexes [Bu₂Sn(AA)Cl] (AA = glycine, DL-valine and L-leucine) and [Bu₂SnPhen₂] (Phen = DL-phenylalanine) They were characterized by elemental analyses of carbon, hydrogen, nitrogen, chlorine and tin; and by infrared, ^119mSn-Mössbauer and ^119mSn-RMN spectroscopies, and by the applications of TG and DSC techniques in dynamic helium atmosphere. For the [Bu₂Sn(AA)Cl], trigonal bipyramidal tin species, AA were coordinated bidentatedly by the carboxylic oxygen and by the NH₂ group. The [Bu₂SnPhen₂)], with tin atoms in trans-octahedral sites, had the Phen-coordinated by both carboxylic oxygen atoms.

Carbonic Anhydrases (CAs) are a superfamily of metalloenzymes widespread in all life kingdoms, classified into seven genetically different families (α-θ). These enzymes catalyse the reversible hydration of carbonic anhydride (CO2), generating bicarbonate (HCO3-) and protons (H+). Fifteen isoforms of human CA (hCA I-XV) have been isolated, their presence being fundamental for the regulation of many physiological processes. In addition, overexpression of some isoforms has been associated with the outbreak or the progression of several diseases. For this reason, for a long time CA inhibitors (CAIs) are used in the control of glaucoma and as diuretics. Furthermore, the search for new potential CAIs for other pharmacological applications is a very active field. Amino acids constitute the smallest fundamental monomers of protein and, due to their useful bivalent chemical properties, are widely used in organic chemistry. Both proteinogenic and non-proteinogenic amino acids have been extensively used to synthesize CAIs. This article provides an overview of the different strategies that have been used to design new CAIs containing amino acids, and how these bivalent molecules influence the properties of the inhibitors.

Tree peony flowers are traditional ornamental and medicinal materials in China. In this study, 23 tree peony flowers at a broad color spectrum were analyzed. Gas chromatography-mass spectrometer (GC-MS) revealed that tree peony flowers are rich in sugars and organic acids. Up to 18 amino acids were identified by liquid chromatography-mass spectrometer (LC-MS), including all essential amino acids, except for methionine. The majority of amino acids were significant positively correlated with each other and were significant negatively correlated with glucose, fructose and galactose. A total of 11 polyphenols were identified in these tree fresh peony flowers by LC-MS. There was a high consistency in grouping peony flowers by using sugars and organic acids and amino acids, which differed from that based on color components and polyphenols. Tree peony flowers are also rich in K, Ca, Mg and Fe. In together, peony flowers can be a good resource of health-promoting compounds.

The world is now undergoing through a global emergency due to COVID-19 which needs immediate remedies in order to strengthen the healthcare facility to save the nations. Looking towards to the remedies, research on different aspects including the genomic and proteomic level characterizations of the SARS-CoV2 are necessarily important. In this present study, the spatial representation/composition of twenty amino acids across the primary protein sequences of SARS-CoV2 have been looked into through different parameters viz. Shannon entropy, Hurst exponent in order to fetch the autocorrelation and amount of information over the spatial representations. Also frequency distribution of each of the amino acids over the protein sequences have been chalked out.

The aim of this study was characterization of some dairy drinks based on Milk Serum regarding major whey proteins (WP) and free amino acids (FAAs) using reversed phase high performance liquid chromatographic (RP-HPLC) methods. The studied WP, -lactalbumin (-La), bovine serum albumin (BSA), -lactoglobulin A (-Lg A) and -lactoglobulin B (-Lg B) were separated on Aeris XB-C18 column at 214 nm detection. The RP-HPLC method was validated by selectivity, linearity (R2 ≥0.99), sensitivity (LOQ, 1.35–10.08 µg mL−1), accuracy (recovery 96.79-103.07%) and precision (% RSD ≤ 4.13%). The total studied WP in studied dairy drinks varied between 1.42 and 3.047 g·L-1. The chromatographic profile of FAAs (aspartic acid, glutamic acid, serine, histidine, arginine, glycine, threonine, alanine, tyrosine, cysteine, tryptophan, methionine, valine, phenylalanine, isoleucine, leucine and lysine) was determined in lyophilized concentrate of Milk Serum by RP-HPLC using pre-column derivatization reaction with orthophthalaldehyde (OPA). The total studied FAAs in studied samples varied between 1.103 and 1.119 mg·g-1. Moreover, the Milk Serum showed bacteriostatic activity against two bacterial strains Escherichia coli and Staphylococcus aureus. The obtained results confirm that dairy drinks based on the Milk Serum constitutes a valuable sources of bioactive components with benefits for human healthy nutrition.

We research the interaction between six representative carbon-based nanoparticles (CBNs) and 20 standard amino acids through all-atom molecular dynamics simulations. The six carbon-based nanoparticles are fullerene(C60), CNT55L3, CNT1010L3, CNT1515L3, CNT2020L3, and two-dimensional-graphene(Graphene33). Their curvatures decrease sequentially, and all of CNT are single-walled carbon nanotubes. We have observed that as the curvature of CBNs decreases, the adsorption effect of 20 amino acids with them has an increasing trend. In addition, we also used multi-dimensional clustering to analyze the adsorption effects of 20 amino acids on six carbon-based nanoparticles. We observed that the π-π interaction still plays an extremely important role in the adsorption of amino acids on carbon-based nanoparticles. Individual long-chain amino acids and “Benzene-like” Pro also have a strong adsorption effect with carbon-based nanoparticles.

Production of energy is a main task of cancer cells metabolism, since costs of duplicating are enormous. Although energy is derived in cells by dismantling carbon to carbon bonds of any macronutrient, cancer nutritional needs for energetic purposes have been studied primarily as dependent on glycolysis. Since the end of the last century, awareness of dependence of cancer metabolism on amino acids not only for protein syntheses but also for matching energy needs has grown. The roles of specific amino acids, like glutamine, glycine and serine have been explored in different experimental conditions and reviewed. Moreover, there are epidemiological evidences that some amino acids used as supplement for therapeutic reasons (the branched chain ones) may reduce incidence of liver cancer, and some molecular mechanism has been proposed as functional to their protective action. On the contrary, metabolic signature of some pathology connected with increased risk of cancer, like prolonged hyperinsulinemia in insulin resistant patients, is signed by plasma elevated levels of the same branched chain amino acids, posing puzzling questions to clinicians. Most recently, peculiar formulations of amino acids, deeply different if compared to amino acids compositions normally present in foods, have shown the power to master epigenetics slowing growth or driving cancer cells to apoptotic death, while being even beneficial for normal cells and for animals health and life span. In this review, we will analyze and try to disentangle some of the many knots dealing with complexities of amino acids biology and linked to cancer metabolism.

Abstract: Amino acids are widely present as intermediates in marine nitrogen cycle. However, the information of amino acid distribution in deep-sea seawater, especially in abyss and hadal zone, is very limited. In the present study, we determined the concentrations of dissolved free amino acids (DFAA), dissolved combined amino acids (DCAA) and total hydrolysable amino acids (THAA) in the seawater from sea surface to hadal zone of the Yap Trench. Their occurrence, vertical variations and degradation behavior in the Yap Trench were investigated. The results showed that concentrations of ΣDFAA, ΣDCAA and ΣTHAA ranged from 0.09 to 1.78, 0.99 to 17.69 and 1.18 to 18.01 μmol/L, respectively, in the study area. In the seawater samples from the trench, Glycine (Gly) was the predominant DFAA, while the DCAA and THAA was dominated by threonine (Thr). Concentration of chlorophyll a (chl a) was not significantly correlated with any amino acids (DFAA, DCAA and THAA) in the euphotic layer. Mean concentrations for DFAA, DCAA and THAA in different water layers were in the order of: mesopelagic > euphotic > abyssal > bathyal. The concentrations of DCAA and THAA in sediment-seawater interface were higher than those from the euphotic to abyssal layer. Stations near the Yap Islands have the older organic matter (OM), while the organic matter in stations near the Yap Trench axis was relatively fresh above 1000-m depth. Degradation behavior of OM in the mesopelagic and abyssal layer are affected by transport of dissolved organic matter with water current. The organic matter in the sediment-seawater interface are older, especially on the west side of the trench. This is a survey of amino acids (DFAA, DCAA and THAA) in the Yap Trench, which provides information on the vertical variations and degradation behavior of amino acids from sea surface to hadal environment, and will be helpful to understand marine organic nitrogen cycle.

We studied surface enhanced Raman spectra of amino acids D-alanine and DL-serine and their mixture on silver nanoisland films (SNF), immersed in phosphate buffer saline solution at millimolar amino acid concentrations. It is shown that the spectra from the amino acid solutions differ from the reference spectra for microcrystallites due to electrostatic orientation of amino acid zwitterions by the metal nanoisland film. Moreover, non-additive peaks are observed in the spectrum of the mixture of amino acids adsorbed on SNF, which means that intermolecular interactions between adsorbed amino acids are very significant. The results indicate the need for a thorough analysis of the Raman spectra from amino acid solutions in the presence of a nanostructured metal surface, and may also be of interest for studying molecular properties and intermolecular interactions.

Our work uses Iterative Boltzmann Inversion (IBI) to study the coarse-grained interaction between 20 amino acids and the representative carbon nanotube CNT55L3. IBI is a multi-scale simulation method that has attracted the attention of many researchers in recent years. It can effectively modify the coarse-grained model derived from the Potential of Mean Force (PMF). IBI is based on the distribution result obtained by All-Atom molecular dynamics simulation, that is, the target distribution function, the PMF potential energy is extracted, and then the initial potential energy extracted by the PMF is used to perform simulation iterations using IBI. Our research results have gone through more than 100 iterations, and finally, the distribution obtained by coarse-grained molecular simulation (CGMD) can effectively overlap with the results of all-atom molecular dynamics simulation (AAMD). In addition, our work lays the foundation for the study of force fields for the simulation of the coarse-graining of super-large proteins and other important nanoparticles.

Highly pathogenic (HP) avian influenza viruses (AIVs) are naturally restricted to H5 and H7 subtypes with a polybasic cleavage site (CS) in the hemagglutinin (HA) and any AIV with an intravenous pathogenicity index (IVPI) ≥1.2. Only few non-H5/H7 viruses fulfill the criteria of HPAIVs; nevertheless, it remains unknown why these viruses did not spread in domestic birds. In 2012, a unique H4N2 virus with a polybasic CS 322PEKRRTR/G329 was isolated from quails in California which, however, was avirulent in chickens. This is the only known non-H5/H7 virus with four basic amino acids in the HACS. Here, we investigated the virulence of this virus in chickens after expansion of the polybasic CS by substitution of T327R (322PEKRRRR/G329) or T327K (322PEKRRKR/G329) with or without reassortment with HPAIVs H5N1 and H7N7. The impact of single mutations or reassortment on virus fitness in vitro and in vivo was studied. Efficient cell culture replication of T327R/K carrying H4N2 viruses increased by trypsin, particularly in MDCK cells, and reassortment with HPAIV H5N1. Likewise, replication, virus excretion and bird-to-bird transmission of H4N2 was remarkably compromised by the CS mutations, but restored after reassortment with HPAIV H5N1, although not with HPAIV H7N7. Viruses carrying the H4-HA with or without R327 or K327 mutations and the other gene segments from HPAIV H5N1 exhibited high virulence and efficient transmission in chickens. Together, increasing the number of basic amino acids in the H4N2 HACS was detrimental for viral fitness particularly in vivo but compensated by reassortment with HPAIV H5N1. This may explain the absence of non-H5/H7 HPAIVs in poultry.

The early diagnosis of mastitis represents an essential factor for a prompt detection of the animal for further actions. In fact, if not culled, infected cows must be segregated from the milking herd and milked last, or milked with separate milking units. Besides microbiological analysis, the somatic cell count (SCC) commonly used as predictor of intramammary infection, frequently lead to a misclassification of milk samples. To overcome these limitations, more specific biomarkers are continuously evaluated. Total amino acid content increases significantly in mastitic milk compared to normal one. Bovine mastitis can arise as a result of infection of the mammary gland by Staphylococcus aureus. Multiplication of this bacterium within the mammary gland is required for infection to persist. S. aureus requires branched-chain amino acids (BCAAs: isoleucine, leucine, valine) for protein synthesis, branched-chain fatty acids synthesis and environmental adaptation by responding to their availability via transcriptional regulators. The importance of BCAAs for S. aureus physiology necessitates that it either synthesize them or scavenge them from the environment. Increase of BCAAs in composite milk has been postulated to be linked to mammary infection by S. aureus. In the present work, we demonstrated, by a direct ion-pairing reversed-phase method based on the use of the evaporative light-scattering detector (IP-RP-HPLC-ELSD), applied to 65 composite cow milk samples, a correlation between the concentration of isoleucine and leucine and S. aureus load.

qNMR is a valuable technique for metrological studies due to the uniformity of its signal response for all chemical species of an isotope of interest, which enables compound-independent calibration. However, protein quantification remained challenging as large molecules produce wide, low-intensity signals that reduce the already low sensitivity. Combining qNMR with the hydrolysis of protein samples into amino acids circumvents many of these issues and facilitates the use of NMR spectroscopy for absolute protein and peptide quantification.In this work, different conditions have been tested for quantifying aromatic amino acids and proteins. First, we examined the pH-based signal shifts in the aromatic region. The preferable pH depends on the selection of the amino acids for quantification and which internal standard substance should be used to avoid peak overlap. Several aromatic compounds, such as terephthalic acid, sulfoisophthalic acid, and benzene tricarboxylic acid, have been applied as internal standards. The quantification of amino acids from an amino acid standard, as well as from a certified reference material (bovine serum albumin), was performed. Using the first two suggested internal standards, recovery was ~ 97 % for histidine, phenylalanine, and tyrosine at a concentration of approximately 1 mM in solution. Acidic hydrolysis of a certified reference material (CRM) of bovine serum albumin (BSA) and subsequent quantification of Phe and Tyr yielded recoveries of 98 ± 2 and 88 ± 4 %, respectively, at a protein concentration of 16 g/L or 250 µM.

Three different fields intersect in search of an understanding of the point-of-origin of modern-age diseases: 1) D-amino acids and their role under stress conditions; 2) evolutionary origin of the mitochondrion organelle in the eukaryotic cell; and 3) gut microbiota and human healthHere it is first suggested that D-amino acids function as universal signaling agents, after having evolved as prokaryotic communication, part of an organic communication process that governs the basic activities of all the cells and coordinates cell action.Mitochondria (symbiotic prokaryotic organelles), are creative source of D-amino acids as signaling agents in the central nervous system and in the neuroendocrine systems.Amino acids racemases catalyzes the conversion between the L-enantiomers ( protein building blocks) into D-enantiomers (signaling agents).It is suggested that hectic modern life may affect human health by causing stress to the gut microbiota. These affected, gut microbiota then secrete D-amino acids that enter the blood stream, as signaling agents, causing communication errors in the central nervous system, and in the neuroendocrine systems due to excessive quantity of D-amino acids.Treating gut microbiota with inhibitors of amino acids racemases or finding D-amino acid scavengers may be used in developing novel therapeutic strategies for diseases related to the central nervous system and neuroendocrine systems caused by stressed gut microbiota.

The global prevalence of insulin resistance (IR) is increasing continuously, influencing metabolic parameters and fertility as well. The metabolic changes due to IR can alter the molecular composition of plasma and other body fluids. Follicular fluid (FF) is derived mainly from plasma, and it is a critical microenvironment for the developing oocytes. It contains various metabolites and amino acids, and the quality of the oocytes is linked at least partially to amino acid metabolism. Our goal was to determine quantitatively the amino acid (AA) profile of FF in IVF patients and to compare IR and non-insulin resistance (NIR) groups to investigate the AA changes in their FF. By UHPLC-based method we quantified the main 20 amino acids from human FF samples in the IR and NIR groups. Several amino acids (aspartate, glycine, glutamate, and cysteine) differed significantly (p<0.05 or less) between the two groups. The most significant alterations between the IR and NIR groups were related to the glutathione metabolic pathway involving glycine, serine, and threonine. Since insulin resistance alters the amino acid composition of the FF, the oocytes may undergo metabolism-induced changes resulting in poor oocyte quality and less fertility in the insulin resistance groups.

Biotechnological potential of Thermoanaerobacter strain AK15 to produce ethanol and valuable alcohols from carbohydrates and amino acids were evaluated in present study. The strain is highly ethanologenic, producing a maximum of 1.57 mol ethanol per mol of glucose degraded at high liquid-gas phase ratios. The strain degrades most of the sugars tested as well as starch and pretreated hydrolysates of biopolymers (Whatman paper, newspaper, Timothy grass, Rhubarb leaves, and several macroalgae species) to ethanol mainly. The strains degraded serine and threonine when used as a single substrate, producing mainly acetate and ethanol as end products, and the branched-chain amino acids (leucine, isoleucine, valine) when cultivated in the presence of thiosulfate. The main end products from branched-chain amino acids were a mixture of their corresponding branched-chain fatty acids and alcohols. Finally, the strain was also shown to use butyrate as an electron sink during glucose degradation resulting in the reduced product butanol in addition to end products produced from glucose. Thus, strain AK15 is a promising candidate for ethanol and fine chemical production from a range of lignocellulosic and algal biomass.

Mitochondrial pyruvate dehydrogenase complex (PDHC) is essential for the brain glucose and neurotransmitter metabolism, dysregulated in many pathologies. Using specific inhibitors of PDHC in vivo, we determine biochemical and physiological responses to PDHC dysfunction. Dose dependence of the responses to membrane-permeable dimethyl acetylphosphonate (Ac-PMe2) is non-monotonous. Primary decreases in glutathione and its redox potential, methionine and ethanolamine are alleviated with increasing PDHC inhibition, the alleviation accompanied by physiological changes. Comparison of 39 brain biochemical parameters after administration of four phosphinate and phosphonate analogs of pyruvate at a fixed dose of 0.1 mmol/kg reveals no primary, but the secondary changes, such as activation of 2-oxoglutarate dehydrogenase complex (OGDHC) and decreased levels of glutamate, isoleucine and leucine. The accompanying decreases in RMSSD of ECG and freezing time are most pronounced after administration of me-thyl acetylphosphinate and dimethyl acetylphosphonate. The levels of PDHA1 expression and phosphorylation, sirtuin 3 and total protein acetylation are not significantly changed by the PDHC inhibitors that affect the brain protein succinylation and glutarylation. Thus, decreased production of the tricarboxylic acid cycle substrate acetyl-CoA by inhibited PDHC is compen-sated by increased degradation of amino acids through the cycle with activated OGDHC, increas-ing total protein succinylation and decreasing anxiety indicators.

Peach (L.) is a kind of fruit tree with considerable economic and nutritional significance. However, it shows a high sensitivity to drought stress, which has a profound impact on its growth. L-methionine (MET) and L-proline (PRO) are two amino acids synthesized by plants, which play an important role in abiotic stress response. However, their exact mechanism of action remains elusive. Through physiological analysis, MET (500ppm) and PRO (500ppm) treatments can effectively reduce the adverse effects of drought stress on the growth of peach seedlings. The results show that MET and PRO can effectively inhibit the stomatal opening of plant leaves under drought conditions and reduce the water evaporation of leaves under drought conditions. In addition, the application of MET or PRO promoted the accumulation of carbohydrates in the leaf tissues of peach seedlings under drought conditions, increased the intracellular relative water content (24%, 24%), decreased the leaf electrical conductivity (21%, 24%), and alleviated the membrane damage caused by drought. Experimental studies have confirmed that the alleviation of drought stress is due to the removal of reactive oxygen species (ROS) in vivo, that is, the downregulation of malondialdehyde (18%, 19%)，peroxidase (50%, 5%) and superoxide dismutase (12%, 14%) activities. In addition, the application of exogenous amino acids also improved the root morphological structure and root vitality of peach seedlings，which was conducive to absorbing external buffer substances and alleviating drought stress. In summary, the application of exogenous amino acids can effectively alleviate the effects of drought stress on plants and reduce the harm.

This research evaluates the inhibitory effect of L-amino acids (AAs) with different side chain lengths on Fe surface implementing Monte Carlo (MC) simulation. A quantitative and qualitative description of the adsorption behavior of AAs on the iron surface has been carried out. Calculations have shown that the absolute values of the adsorption energy of L-amino acids increase with side chain prolongation; they are also determined by the presence of heteroatoms. AAs from nonpolar and basic groups have the best adsorption ability to the iron surface, which indicates their highest inhibitory efficiency according to the results of MC simulation.

Primary ciliary dyskinesia (PCD) is an inherited disorder that impairs motile cilia, essential for respiratory health, with a reported prevalence of 1 in 16,309 within Hispanic populations. Despite having the RSPH4A [c.921+3_921+6del (intronic)] founder mutation in 70% of Puerto Rican patients, the characterization of the ciliary dysfunction remains unidentified due to the unavailability of advanced diagnostic modalities like High-Speed Video Microscopy Analysis (HSVA). Our study implemented HSVA for the first time on the island as a tool to better diagnose and characterize the RSPH4A [c.921+3_921+6del (intronic)] founder mutation in Puerto Rican patients. By applying HSVA, we analyzed the ciliary beat frequency (CBF) and pattern (CBP) in native Puerto Rican patients with PCD. Our results showed decreased CBF and a rotational CBP linked to the RSPH4A founder mutation in Puerto Ricans, presenting a novel diagnostic marker that could be implemented as an axillary test into the PCD diagnosis algorithm in Puerto Rico. The integration of HSVA technology in Puerto Rico substantially enhances the framework for PCD evaluation and diagnosis, facilitating prompt detection and early intervention for improved disease management. This initiative, demonstrating the potential of HSVA as an adjunctive test within the PCD diagnostic algorithm, could serve as a blueprint for analogous developments throughout Latin America.

Extracellular vesicles (EVs) hold enormous potential in the diagnosis and treatment of diseases, benefit from their roles in intercellular signaling, as well as their plentiful presence and stability in body fluids. However, conventional EV isolation methods are labor-intensive, and harvest EVs with low purity and compromised recovery. In addition, the drawbacks, such as limited sensitivity and specificity of traditional EV analysis methods hinder the application of EVs in clinical use. Therefore, it is urgent to develop effective and standardized methods for isolating and detecting EVs. Microfluidics technology is a powerful and rapidly developing technology that has been introduced as a potential solution for the above bottlenecks. It holds the advantages of high integration, short analysis time, low consumption of samples and reagents. In this review, we summarize the traditional techniques alongside microfluidic-based methodologies for the isolation and detection of EVs. We emphasize the separation advantages of microfluidic technology in enhancing EV capture efficiency and precise targeting, while summarizing its analytical role in targeted detection and discussing the significance of EV detection in the tumor microenvironment, providing a direction for achieving automated and high-throughput EV detection in clinical samples.

The emergence of non-canonical amino acids (ncAAs) has enriched the functional pool inherent in canonical amino acids (cAAs). ncAAs are important building blocks in the production of various pharmaceuticals. The biosynthesis of ncAAs has emerged as an alternative to traditional chemical synthesis because of its environmental friendliness and high efficiency. The breakthrough genetic code expansion (GCE) technique developed in recent years has allowed for the incorporation of ncAAs into target proteins, giving them special functions and biological activities. Biosynthesis of ncAAs and their incorporation into target proteins within a single microbe has become an enticing application of such molecules. Based on that, in this study we first review the biosynthesis methods for ncAAs and analyze the difficulties in biosynthesis. We then summarize the GCE methods and analyze their advantages and disadvantages. Further, we review the application progress of ncAAs and anticipate the challenges and future development directions of ncAAs.

Unmetamorphosed carbonaceous chondrites provide important information concerning the formation and evolution of organic matter, such as amino acids. However, terrestrial contamination remains a valid concern when investigating the organic inventory of meteorites that have fallen to Earth. Accordingly, JAXA’s Hayabusa2 and NASA’s OSIRIS-REx have been launched with the task of returning uncontaminated C-type asteroid material to Earth. The successful Hayabusa2 mission has a very limited sample size (5.4 g). Therefore, many conventional compound specific techniques will struggle to detect amino acids above detection limit with available sample amounts (~several mg to 10’s of mg) being much smaller than those typically used. Here a novel method utilizing ultrahigh performance liquid chromatography-Orbitrap-mass spectrometry is validated and applied to very small meteorite samples, thus providing an approach that can overcome the small sample size constraints of sample return missions. The method is highly sensitive, enabling the detection of amino acids in the carbonaceous chondrites Murchison (2.28 mg) and Orgueil (2.30 mg). Furthermore, quantitation was possible for many of the detected amino acids in Murchison and Orgueil. Using the data presented here, both the amino acid reservoirs of Murchison and Orgueil and the potential application of this method to sample return samples are discussed.

Altered amino acid levels have been found in nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). However, it is not clear whether this alteration is due to altered hepatic metabolism or insulin resistance. The aim of this study was to clarify the association among amino acid levels, fatty liver, and liver fibrosis while eliminating the influence of insulin resistance. NAFLD and liver fibrosis were diagnosed using transient elastography and subjects were divided in three groups: normal, NAFLD, and liver fibrosis. To exclude the influence of insulin resistance, the subjects were matched using the homeostasis model assessment of insulin resistance (HOMA-IR). The amino acid serum levels were compared among the groups. Of 731 enrolled subjects, 251 and 33 were diagnosed with NAFLD and liver fibrosis. Although significant differences were observed among the groups in the serum levels of most amino acids, all but those of glutamate and glycine disappeared after matching for HOMA-IR. The multivariate logistic regression revealed that glutamate, glycine, and HOMA-IR were independent risk factors for liver fibrosis. The altered serum levels of most amino acids were associated with insulin resistance, while the increase in glutamate and the decrease in glycine levels were strongly associated not only with insulin resistance, but also with altered liver metabolism in patients with liver fibrosis.

In this work we demonstrate the proof-of-concept of real-time discrimination between patches of serine or isoleucine monomers in the primary structure of custom-engineered, macro-dipole-like peptides, at uni-molecular level. We employed single-molecule recordings to examine the ionic current through the α-hemolysin (α-HL) nanopore, when hydrophilic serine or hydrophobic isoleucine residues, flanked by segments of oppositely charged arginine and glutamic amino acids functioning as a voltage-dependent ‘molecular brake’ on the peptide, were driven at controllable rates across the nanopore. The observed differences in the ionic currents blockades through the nanopore, visible at time resolutions corresponding to peptide threading through the α-HL’s constriction region, was explained by a simple model of the volumes of electrolyte excluded by either amino acid species, as groups of three serine or isoleucine monomers transiently occupy the α-HL. To provide insights into the conditions ensuring optimal throughput of peptide readout through the nanopore, we probed the sidedness-dependence of peptide association to and dissociation from the electrically and geometrically asymmetric α-HL.

Astrocytes are considered to possess a noticeable role in brain metabolism and as a partners in neuron-glia cooperation contribute to synthesis, bioconversions and regulation of the flux of substrates for neuronal metabolism. With the aim to investigate to which extend are human astrocytes metabolizing amino acids and by which compounds are they enriching their surrounding we employed the metabolomics analysis of their culture media by 1H-NMR. In addition, we compered the composition of media with either 5 mM or 25 mM glucose. The quantitative analysis of culture media by 1H-NMR revealed that astrocytes readely dispose from their milieu glutamine, branched-chain amino acids, and pyruvate with significantly high rate, while they enrich the culture media with lactate, branched-chain keto acids, citrate, acetate, ketone bodies, and alanine. The hyperglycemia suppressed the capacity of astrocytes to release branched-chain amino acids while stimulating the generation of ketone bodies. Our results highlight the active involvement of astrocytes in metabolism of several amino acids, and the regulation of key metabolic intermediates. The observed metabolic activities of astrocytes provide valuable insights into their roles in supporting neuronal function, brain metabolism, and intercellular metabolic interactions within the brain. Understanding the complex metabolic interactions between astrocytes and neurons is essential for elucidating brain homeostasis and the pathophysiology of neurological disorders.

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) have been linked to changes in amino acid (ΑΑ) levels. The current observational study sought to investigate the relationship between plasma AA concentrations in a NAFLD population and MRI parameters reflecting inflammation and fibrosis, inflammatory and oxidative stress markers, and disease-related anthropometric and biochemical indicators. Approach & Results: Plasma AA levels were quantified with liquid chromatography in 97 NAFLD patients from the MAST4HEALTH study. Medical, anthropometric and lifestyle characteristics were collected and biochemical parameters, as well as inflammatory and oxidative stress biomarkers were measured. In total, males and subjects with higher MRI-proton density fat fraction (MRI-PDFF) exhibited higher plasma AA levels compared to females and subjects with lower PDFF respectively. Several associations of AAs with disease related markers were revealed, with the more prominent ones being those of aromatic amino acids with log-PDFF (beta: 1.190E-02, p-Value: 0.001) and log-ALT (beta: 7.55E-03, p-Value: 0.001), of branched amino acids with log-insulin (beta: 1.97E-03, p-Value: 1.16E-04) and of ethanolamine (beta: 0.036, p-Value: 3.65E-04) and L-ornithine (beta: 5.4E-04, p-Value: 0.021) with log-total antioxidant status (TAS). Conclusions: Plasma AA levels varied according to sex, BMI, and several MRI clinical factors. Furthermore, significant relationships were demonstrated between AA and several disease indicators, such as MRI parameters, biochemical and oxidative stress indices, showing the potential utility of AAs as diagnostic dis-ease-related indicators activity.

The BET family of proteins is characterized by the presence of two tandem bromodomains and an extra-terminal domain. The mammalian BET family of proteins comprises Brd2, Brd3, Brd4, and Brdt, which are encoded by paralogous genes that may have been generated by repeated duplication of an ancestral gene during evolution. Bromodomains that can specifically bind acetylated lysine residues in histones serve as chromatin-targeting modules that decipher the histone acetylation code. BET proteins play a crucial role in regulating gene transcription through epigenetic interactions between bromodomains and acetylated histones during cellular proliferation and differentiation processes. On the other hand, BET proteins have been reported to mediate latent viral infection in host cells and be involved in oncogenesis. Human BRD4 is involved in multiple processes of the DNA virus life cycle, including viral replication, genome maintenance, and gene transcription through interaction with viral proteins. Aberrant BRD4 expression contributes to carcinogenesis by mediating hyperacetylation of the chromatin containing the cell proliferation-promoting genes. BET bromodomain blockade using small-molecule inhibitors gives rise to selective repression of the transcriptional network driven by c-Myc. These inhibitors are expected to be potential therapeutic drugs for a wide range of cancers. This review presents an overview of the basic roles of BET proteins and highlights the pathological functions of BET and the recent developments in cancer therapy targeting BET proteins in animal models.

In this study, we once again use a set of Fibonacci-like sequences to examine the symmetries within the genetic code. This time, our focus is on the physiological state of the amino acids, considering them as charged, in contrast to our previous work where they were seen as neutral. In a pH environment around 7.4, there are four charged amino acids. We utilize the properties of our sequences to accurately describe the symmetries in the genetic code table. These include Rumer’s symmetry, the third-base symmetry and the "ideal" symmetry, along with the "supersymmetry" classification schemes. We also explore the special chemical structure of the amino acid proline, presenting two perspectives—shCherbak’s view and the Downes-Richardson view, which perspectives are included in the description of the above-mentioned symmetries. Our investigation employs also elementary modular arithmetic to precisely describe the chemical structure of proline, connecting the two views seamlessly. Finally, our Fibonacci-like sequences prove instrumental in quickly establishing the multiplet structure of non-standard versions of the genetic code. We illustrate this with an example, showcasing the efficiency of our method in unraveling the complex relationships within the genetic code.

The development of effective vaccines against SARS-CoV-2 remains a critical challenge amidst the ongoing global pandemic. This study introduces a novel approach to enhance mRNA vaccine efficacy by leveraging the untranslated region (UTR) of TMSB10, a gene identified for its significant mRNA abundance in antigen-presenting cells. Utilizing the GEO database, we identified TMSB10 among nine genes with the highest mRNA abundance in dendritic cell subtypes. Subsequent experiments revealed that TMSB10's UTR significantly enhances the expression of a reporter gene in both antigen-presenting and 293T cells, surpassing other candidates and a previously optimized natural UTR. Comparative analysis demonstrated that TMSB10 UTR not only facilitated higher reporter gene expression in vitro but also showed marked superiority in vivo, leading to enhanced specific humoral and cellular immune responses against the SARS-CoV-2 Delta variant RBD antigen. Specifically, vaccines incorporating TMSB10 UTR induced significantly higher levels of specific IgG antibodies and promoted a robust T-cell immune response, characterized by increased secretion of IFN-γ and IL-4 and the proliferation of CD4+ and CD8+ T cells. These findings underscore the potential of TMSB10 UTR as a strategic component in mRNA vaccine design, offering a promising avenue to bolster vaccine-induced immunity against SARS-CoV-2 and potentially other pathogens.

Purpose. This paper aims to present a unique perspective that emphasizes the intricate interplay between energy, dietary proteins, and amino acid composition, underscoring their mutual dependence for health-related considerations. Energy and protein synthesis are fundamental to biological processes, crucial for the sustenance of life and growth of organisms. Methods and Results. We explore the intricate relationship between energy metabolism, protein synthesis, regulatory mechanisms, protein sources, amino acid availability, and autophagy, in order to elucidate how these elements collectively maintain cellular homeostasis. We underscore the vital role this dynamic interplay has in preserving cell life. Conclusion. A deeper understanding of the link between energy and protein synthesis is essential to comprehend fundamental cellular processes. This insight could have wide-ranging impact in several medical fields, such as nutrition, metabolism, and disease management.

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

Microbial competition within plant tissues affects invading pathogens' fitness. Metabolomics is a great tool for studying their biochemical interactions by identifying accumulated metabolites. Xylella fastidiosa, a Gram-negative bacterium causing Pierce's disease (PD) in grapevines, secretes various virulence factors including cell wall degrading enzymes, adhesion proteins, and quorum sensing molecules. These factors, along with outer membrane vesicles, contribute to its pathogenicity. Previous studies demonstrated that co-inoculating X. fastidiosa with Paraburkholderia phytofirmans strain PsJN suppressed PD symptoms. Here, we further investigated the interaction between the phytopathogen and the endophyte by analyzing the exometabolome of wild-type X. fastidiosa and a diffusible signaling factor (DSF) mutant lacking quorum sensing, cultivated with 20% P. phytofirmans spent media. LC-MS and MAGI were used to detect and map metabolites to genomes revealing a total of 121 metabolites, of which 25 were further investigated. These metabolites potentially relate to host adaptation, virulence, and pathogenicity. Notably, this study presents the first comprehensive profile of X. fastidiosa in the presence of P. phytofirmans spent media. The results highlight that P. phytofirmans and the absence of a functional quorum sensing affect the ratios of glutamine to glutamate (Gln:Glu) in X. fastidiosa. Additionally, two compounds with plant metabolism and growth properties, 2-Aminoisobutyric acid and Gibberellic Acid, were downregulated when X. fastidiosa interacted with P. phytofirmans. These findings suggest that P. phytofirmans-mediated disease suppression involves modulation of the exometabolome of X. fastidiosa, impacting plant immunity.

Physical frailty and sarcopenia (PF&S) are hallmarks of aging that share a common pathogenic background. Perturbations in protein/amino acid metabolism may play a role in the development of PF&S. In this preliminary study, 68 community-dwellers aged 70 years and older, 38 with PF&S and 30 non-sarcopenic, non-frail controls (nonPF&S), were enrolled. A panel of 37 serum amino acids and derivatives was assayed by UPLC-MS. Partial Least Squares Discriminant Analysis (PLS-DA) was used to characterize the amino acid profile of PF&S. The optimal complexity of the PLS-DA model was found to be three latent variables. The proportion of correct classification was 76.6 ± 3.9% (75.1 ± 4.6% for enrollees with PF&S; 78.5 ± 6.0% for controls). Older adults with PF&S were characterized by higher levels of asparagine, aspartic acid, citrulline, ethanolamine, glutamic acid, sarcosine, and taurine. The profile of nonPF&S individuals was defined by higher levels of α-aminobutyric acid and methionine. Distinct profiles of circulating amino acids and derivatives characterize older individuals with PF&S. The dissection of these patterns may provide novel insights into the role played by protein/amino acid perturbations in the disabling cascade and possible new targets for interventions.

Inadequate protein intake can impair protein balance and lead to skeletal muscle atrophy, impaired body growth, and functional decline. Foods provide both non-essential (NEAAs) and essential amino acids (EAAs) that may convey different metabolic stimuli to specific organs and tissues. In this study, we sought to evaluate the impact of six diets with various EAA/NEAA blends on body composition and the risk of developing tissue wasting in late middle-aged male mice. Mice consuming NEAA-based diets, although showing increased food and calorie intake, suffered the most severe weight loss. Interestingly, even moderate NEAAs prevalence was able to induce inflammatory catabolic stimuli, generalized body wasting and systemic metabolic alterations. Complete depletion of retroperitoneal white adipose tissue and a severe loss (>75%) of brown adipose tissue were observed together with muscle wasting. Conversely, EAA-based diets induced significant decreases in weight by reducing primarily fat reserves, but improved clinical parameters. Tissue wasting was caused by altered AA quality, independent of reduced nitrogen or caloric intake. Our results indicate that an optimized balance of AA composition is necessary for preserving overall bodily energy status. These findings are particularly relevant in the context of aging and may be exploited for contrasting its negative correlates including body wasting.

The influence of humic aggregates in water solution upon the chemical stability under basic conditions of different substrates has been reviewed. The kinetic behavior of each substrate has been modelized in terms of micellar pseudophase model.

Wheat and corn silages are widely used as ruminant feed in Israel due to their availability and cost-effectiveness. To ensure long-term preservation without compromising nutritional quality, effective methods must be employed. Inclusion of additives during harvest and ensiling can enhance efficiency and address preservation challenges. In the current study, the effects of microbial inoculum (MI) and urea on the chemical composition, amino acid profiles, aerobic stability, and in vitro digestibility of wheat and corn silages were investigated. Samples of wheat and corn were subjected to four treatments: control, MI, Urea, and a combination of MI+Urea. The treatments were ensiled in anaerobic conditions and opened after 1, 7, 14, or 28 days. Results showed that additives improved the quality parameters of wheat and corn silages. The inclusion of MI produced the most aerobically stable silages. The inclusion of urea in silages deteriorated aerobic stability. Additives improved in vitro cell wall carbohydrates digestibility in both silages and was the best when MI was combined with urea. These results imply additives could be incorporated in silages to enhance their nutritional value, aerobic stability and digestibility. Nonetheless, increased CP content with additives was not accompanied with parallel increase in amino acids content in corn silage.

Preventive Maintenance (PM) is a periodic maintenance strategy, which has great results for devices in extending their life, increasing productivity, and most importantly, help avoid unexpected breakdowns and their costly consequence. A preventive maintenance scheduling (PMS) is determining the time for carrying out PM, and it represents a sensitive issue in terms of impact on production if the time for the PM process is not optimally distributed. In this study, hybrid heuristic methods were used to solve the PMS problem, as genetic algorithm and Tabu research were adopted. The optimal solution was reached in a short time compared to previous studies in which optimal methods were used, integer programming and nonlinear integer programming. Also, sensitivity analysis was applied to measure the robustness and strength of the method used, where an optimal solution was obtained for all experiments and in record time. This method can be used for power plants in privet or public sectors, to generate an optimal PMS, to save money, and to avoid water or electricity cuts.

The eutrophication of open water bodies, especially in coastal water area, has received intensive public focuses in recent years. Biological treatment of organic pollutants in industrial and domestic wastewater requires microbial flora to participate. The environmental impact of these microbes, particularly in regard to the spread of antibiotic resistance genes and pathogenicity in coastal water, remains largely unknown. We initiate studies to examine antibiotic resistance genes (ARGs) in microbial flora and study the mode of antibiotic spread in the coastal waters of Bohai Bay, North China by using high performance liquid chromatography-mass spectrum analysis and quantitative polymerase chain reaction. The metabolic features of bacteria related to the presence of ARGs in the coastal area showed the enrichment of Pseudomonadale species with triple resistance properties (ampicillin, kanamycin and gentamycin) at the estuary site locating adjacent to a coastal sewage treatment plant where both type I and type II polyketide synthase genes and b-lactam type antibiotics are detected. Pseudomonadale order is phylogenetically belonged to Proteobacteria Phylum, Gamma-proteobacteria Class and contains Pseudomonadaceae family and Pseudomonas genus. QPCR analysis suggests that the percent occupation of Pseudomonadale species to total Proteobacteria in the examined stations is close to several sampling stations close to sewage treatment plants, where consistent release of organic wastes occurred.

The sulfur-containing amino acids methionine (Met), cysteine (Cys) and taurine (Tau) are common dietary constituents with important cellular roles. Met restriction is already known to exert in vivo anticancer activity. However, since Met is a precursor of Cys, and Cys produces Tau, the role of Cys and Tau in the anticancer activity of Met-restricted diets is poorly understood. In this work, we screened the in vivo anticancer activity of several Met-deficient artificial diets supplemented with Cys, Tau or both. Diet B1 (6% casein, 2.5% leucine, 0.2% Cys and 1% lipids) and diet B2B (6% casein, 5% glutamine, 2.5% leucine, 0.2% Tau and 1% lipids) showed the highest activity and were selected for further studies. Both diets induced a marked anticancer activity in two animal models of metastatic colon cancer, which were established by injecting CT26.WT murine colon cancer cells in the tail vein or peritoneum of immunocompetent BALB/cAnNRj mice. Diets B1 and B2B also increased the survival of mice with disseminated ovarian cancer (intraperitoneal ID8 Tp53 -/- cells in C57BL/6JRj mice) and renal cell carcinoma (intraperitoneal Renca cells in BALB/cAnNRj mice). The high activity of diet B1 in mice with metastatic colon cancer may be useful in colon cancer therapy.

The gastrointestinal tract is colonized by trillions of different microorganisms, named the gut microbiota, which is key to degrade undigested food such as dietary fibers. The fermentation of these food components leads to the production of short-chain fatty acids (SCFA) acetate, propionate, and butyrate, which exploit several beneficial roles for the host’s health. Their production and absorption happen in different ways in the human intestine and depend on the type of dietary fiber reaching the gut and the microorganisms involved in the fermentation. The supplementation of SCFAs, mostly butyrate, in treating gastrointestinal, metabolic, cardiovascular, and gut-brain-related diseases has been reported in the medical literature. This review aims to give an overview of the production and absorption dynamics of acetate, propionate, and butyrate in the human gut, with a final focus on the role played by these SCFAs on gastrointestinal and metabolic health and the present therapeutic implications.

Nowadays, there is extensive production and use of plastic materials for different industrial activities. These plastics, either from their primary production sources or through degradation processes of the plastics themselves, can contaminate the ecosystem with micro and nanoplastics. Once in the aquatic environment, these microplastics can be the basis for the adsorption of chemical pollutants, favoring that these chemical pollutants disperse more quickly in the environment and can affect living beings. Due to the lack of information on adsorption, three machine learning models (random forest, support vector machine, and artificial neural network) to predict different microplastic/water partition coefficients (log Kd) were developed using two different approximations (based on the number of input variables). The best-selected machine learning models present, in general, correlation coefficients upper than 0.92 in the query phase, which indicate that these type of models could be used for a rapid estimation of the absorption of organic contaminants on microplastics.

Patients with metastatic triple negative breast cancer (TNBC) need new therapies to improve the low survival rates achieved with standard treatments. In this work, we show that the survival of mice with metastatic TNBC can be markedly increased by replacing their normal diet with artificial diets in which the levels of amino acids (AAs) and lipids are strongly manipulated. After observing selective anticancer activity in vitro, we prepared five artificial diets and evaluated their anticancer activity in a challenging model of metastatic TNBC. The model was established by injecting 4T1 murine TNBC cells into the tail vein of immunocompetent BALB/cAnNRj mice. First-line drugs doxorubicin and capecitabine were used as positive controls. AA manipulation led to modest improvements in mice survival when the levels or lipids were normal. Reducing lipid levels to 1% markedly improved the activity of several diets with different AA content. Mice fed the artificial diets as monotherapy lived longer than mice treated with doxorubicin and capecitabine. An artificial diet without 10 non-essential AAs, with reduced levels of essential AAs, and with 1% lipids improved the survival not only of mice with TNBC but also of mice with other types of metastatic cancers.

Dengue virus (DENV), the causative agent of dengue fever (DF), is one of the most important mosquito-borne viruses that can infect humans. Although much effort has been made on prevention and control of dengue, there are currently no anti-viral drugs or worldwide approved vaccines yet. In this study, we immunized six-week-old Balb/c mice with DNA vaccine candidates E and NS1-2a of DENV serotype 2 or the combination of them (E+NS1-2a) via an electroporation (EP)-assisted intramuscular gene delivery system and evaluated the immune response and protection. The highest specific antibody titres and cytokine levels secreted by splenocytes as well as the highest survival rate were observed in the E+NS1-2a group, followed by E group and NS1-2a group. Our data suggested that the combination of E and NS1-2a delivered by EP may be a superior preventive strategy against DENV.

Background: A comparison of the amino acid (AA) plasma profile and markers of intestinal absorption-inflammation between healthy subjects aged 65-70 years and age-matched patients affected by stage 3b-4 chronic kidney disease (CKD3b-4) was performed. Methods: eleven healthy volunteers were compared with 12 CKD3b-4 patients at their first outpatient control (T0) and after 12-months (T12). Adherence to a low protein diet (LPD, 0.6±0.1 g/kg/day) was assessed by Urea Nitrogen Appearance. The following parameters were assessed: renal function, nutritional parameters, bioelectrical impedance analysis, plasma levels of 20 total aminoacids (TAAs), both essential (EAAs) including branched-chain amino acids (BCAAs) and non-essential (NEAAs). Zonulin and faecal Calprotectin markers were used to evaluate intestinal permeability/inflammation. Results: Four patients dropped out of the study; in the remaining 8 residual kidney function (RKF) remained stable, their LPD adherence had risen to 0.89g/kg/day, anaemia had worsened and extracellular body fluid had increased. In comparison to healthy subjects, TAA levels of histidine, arginine, asparagine, threonine, glycine, and glutamine had all increased. No variation in BCAAs was observed. A significant increase was detected in faecal calprotectin and zonulin levels in CKD patients as the disease progressed. Conclusions: This study confirms the finding in aged patients of an alteration in levels of several AAs secondary to uraemia. Intestinal markers provide confirmation of a relevant alteration to the intestinal function in CKD patients.

Ajuga arabica is an essential medicinal plant found naturally in Saudi Arabia, recognized for its therapeutic characteristics. Nevertheless, research on the genetic diversity and population arrangement of this species in Saudi Arabia is deficient. In this study, we conducted a comparative examination of DNA and gene sequences to evaluate the genetic diversity and population configuration of Ajuga arabica in Saudi Arabia. Our findings demonstrate that there are high levels of genetic diversity within populations, but low levels of genetic differentiation among populations. Moreover, we discovered proof of gene flow among populations, suggesting that there are no significant genetic barriers to gene flow. Our results offer valuable insights into the genetic diversity and population structure of Ajuga arabica in Saudi Arabia, which can support conservation efforts and promote the sustainable use of this valuable medicinal plant.

DNA barcoding has emerged as a powerful tool in the field of taxonomy, transforming the way we identify and classify species. This review article aims to provide an up-to-date overview of the advancements in DNA barcoding techniques, their applications, and their impact on taxonomy and biodiversity studies. We will explore the evolution of DNA barcoding, the development of standardized barcode regions, and the challenges and limitations associated with this methodology. Additionally, we will delve into the diverse range of taxonomic groups for which DNA barcoding has been applied, highlighting key case studies and their contributions to our understanding of biodiversity. Furthermore, we will discuss the integration of DNA barcoding with other molecular and bioinformatic approaches, such as metabarcoding and machine learning, to enhance species identification and biodiversity assessment. This review aims to provide a comprehensive perspective on how DNA barcoding is reshaping the field of taxonomy and its implications for conservation, ecology, and evolutionary biology.

This comprehensive review traces the transformative journey of genomic mapping, ushering in the era of "Genomic Atlas 2.0," characterized by advanced strategies and cutting-edge technologies. Beginning with a historical overview, it highlights the evolution from early linkage analysis to the current landscape shaped by high-throughput sequencing. Key breakthroughs are emphasized, showcasing the pivotal role of platforms such as Illumina and Oxford Nanopore in accelerating the identification of genetic variations. Long-read sequencing technologies, including PacBio and Oxford Nanopore, are explored as transformative elements overcoming limitations associated with short-read sequencing. The review delves into spatial genomics and chromatin conformation capture techniques, revealing the three-dimensional intricacies of the genome, with a particular focus on the revolutionary impact of Hi-C in understanding chromatin interactions. CRISPR technologies emerge as indispensable tools in Genomic Atlas 2.0, enabling targeted genome editing and the generation of precise genetic models. Functional genomics screens, utilizing RNA interference and CRISPR-based techniques, are discussed for their scalable precision in deciphering genome functions. Navigating challenges, the review addresses complexities in data integration and ethical considerations, offering strategies to ensure the robustness and ethical conduct of genetic mapping. Looking optimistically towards the future, it explores opportunities such as improved sequencing accuracy and novel applications of CRISPR technologies. Envisioning the expansion of genomics into personalized medicine, agriculture, and conservation biology, the review serves as a guiding resource for researchers, scientists, and students navigating the intricate terrain of Genomic Atlas 2.0.

Blockchain technology has emerged as a necessity for the decentralization of payment methods and transactions, but it has brought with it many properties of distributed systems that have made it a crucial technology for overcoming some of society's challenges, especially in the context of decentralizing services, transparency of information, availability, and security. Its architecture and communication methods, although possessing some complex nuances to understand, particularly for the lay audience in the field of distributed systems, protocols, and computer networks. In this article, we will explore some topics of distributed systems related to blockchain technology.

Cancer diagnosis stands at the cusp of a profound transformation, driven by the burgeoning capabilities of Artificial Intelligence (AI) and Machine Learning (ML). This comprehensive review illuminates the extraordinary impact of AI and ML in the field, unraveling their multifaceted roles in the realm of oncology. In the arena of cancer diagnosis, AI and ML serve as invaluable allies, empowering healthcare professionals with unparalleled tools for precision and efficiency. Notably, AI's prowess in analyzing medical images, including radiological scans and pathology slides, elevates the early detection of malignancies to new heights. Coupled with its ability to dissect genomic data, AI tailors therapeutic strategies to the individual, promising optimized treatment outcomes. However, the incorporation of AI and ML into clinical practice necessitates a careful navigation of ethical considerations, data privacy, and regulatory landscapes. Safeguarding patient data, ensuring transparency, and addressing algorithmic biases emerge as pivotal challenges that require vigilant attention. Yet, the future of AI and ML in cancer diagnosis is brimming with promise. The integration of multi-modal data, real-time monitoring, and Explainable AI (XAI) methods holds the potential to enrich diagnostic capabilities and engender patient trust. Global collaboration and data sharing initiatives are fostering the development of robust AI models. Furthermore, AI's role in cancer prevention, identifying high-risk individuals and enabling targeted preventive strategies, is poised to revolutionize healthcare. AI and ML are forging a path toward an era of unparalleled accuracy, efficiency, and personalization in cancer diagnosis. Challenges notwithstanding, these technologies bear the promise of fundamentally reshaping patient care, elevating outcomes, and advancing the fight against cancer. The ongoing exploration and responsible implementation of AI and ML in oncology will be pivotal in harnessing their full potential and paving the way for a brighter future for cancer patients.

Advancements in genomics and molecular biology have propelled our understanding of genetic information far beyond the iconic double helix structure of DNA. This comprehensive review delves into the intricate world of DNA and RNA networks, exploring the complexities that extend beyond the classical model. We investigate the dynamic interactions, regulatory mechanisms, and functional implications of the broader genetic landscape, encompassing both coding and non-coding elements. From chromatin architecture to the diverse array of non-coding RNAs, this exploration seeks to provide a holistic perspective on the multifaceted roles played by DNA and RNA in cellular processes. The three-dimensional organization of genetic material within the cell has emerged as a crucial determinant of cellular function. Chromatin architecture, comprising DNA, histones, and other associated proteins, plays a dynamic role in regulating gene expression. We delve into the intricate choreography of chromatin remodeling, deciphering the interplay between transcription factors, epigenetic modifications, and higher-order structures that modulate gene activity. The exploration of chromatin dynamics unveils a nuanced understanding of how the genome responds to environmental cues, cellular signals, and developmental processes. Moreover, the once-dismissed non-coding portion of the genome has emerged as a key regulator of cellular function. Various classes of non-coding RNAs, such as microRNAs, long non-coding RNAs, and circular RNAs, have been implicated in diverse cellular processes, ranging from fine-tuning gene expression to modulating chromatin structure. The review critically examines the functional roles of these non-coding RNAs, shedding light on their involvement in cellular homeostasis, development, and disease. As I traverse this landscape beyond the double helix, our review synthesizes current knowledge on the intricacies of DNA and RNA networks. By exploring the regulatory mechanisms, functional implications, and emerging paradigms, we aim to inspire a deeper appreciation for the molecular choreography that underlies the cellular symphony of life. Furthermore, we discuss the implications of these findings in the context of disease, highlighting potential diagnostic and therapeutic avenues that arise from a comprehensive understanding of DNA and RNA networks. In doing so, this exploration not only broadens our theoretical understanding but also opens new frontiers for translational research in genetics and molecular medicine.

Recent advancements in molecular diagnostics have highlighted the potential of circulating cell-free DNA (ccfDNA) as a biomarker in various diseases. This study aims to explore the role of ccfDNA in the early diagnosis, prognosis, and therapeutic monitoring of diseases, with a focus on oncology. We conducted a comprehensive review and analysis of current literature, combined with experimental approaches involving advanced genomic sequencing and bioinformatics techniques. Our research systematically characterizes the molecular composition of ccfDNA, including its origins, size distribution, and methylation patterns, across different disease states. Furthermore, we investigate the dynamics of ccfDNA release and clearance in the bloodstream, elucidating mechanisms that could influence its diagnostic accuracy. In the context of cancer, we analyze the correlation between tumor-derived ccfDNA and disease progression, response to therapy, and overall survival. Our findings indicate that ccfDNA holds promise as a non-invasive biomarker for early disease detection, real-time monitoring of treatment efficacy, and potentially, predicting relapse. This study contributes to the growing field of liquid biopsies and opens new avenues for personalized medicine, emphasizing the need for standardized protocols in ccfDNA analysis to maximize its clinical utility. The implications of our findings extend beyond oncology, suggesting potential applications of ccfDNA in other pathological conditions.

DNA barcoding has emerged as a transformative tool in the realm of biodiversity assessment, facilitating rapid and precise species identification. This review article delves into the evolving landscape of DNA barcoding, with a particular focus on the emergence of mini-barcodes and alternative genes as innovative approaches. Traditional DNA barcoding, anchored in the COI gene, has significantly advanced our understanding of species diversity; however, inherent challenges persist, especially when dealing with degraded samples or taxonomic groups where COI falls short. The introduction of mini-barcodes, characterized by their reduced sequence length, has revolutionized DNA barcoding by expanding its applicability. We explore the utility of mini-barcodes in various scenarios, ranging from DNA extraction from ancient or fragmented specimens to in-field identification using portable sequencing technologies. Case studies and practical insights into their effectiveness are presented, emphasizing their role in overcoming traditional limitations. Alternative genes, a complementary facet of DNA barcoding, offer a novel avenue for enhancing taxonomic resolution and accuracy. This review showcases instances where researchers have harnessed alternative genes to overcome COI's constraints, particularly in diverse taxonomic groups, such as fungi, plants, and microorganisms. The selection of these genes is discussed, along with their potential to uncover hidden biodiversity and improve species delimitation. Examining the broader implications of mini-barcodes and alternative genes, we unveil their pivotal roles in advancing conservation efforts, forensic science, and citizen science initiatives. The adaptable nature of these approaches empowers a diverse range of stakeholders, from scientists conducting critical research to concerned citizens contributing to our collective understanding of the natural world. Looking ahead, we envision an exciting future for DNA barcoding, as these innovations continue to evolve. Integration with cutting-edge sequencing technologies, data analysis methods, and the harnessing of big data hold immense potential. Nonetheless, challenges related to standardization, scalability, and data sharing persist.

The exploration of three-dimensional (3D) DNA structures marks a pivotal shift in genomics, offering unprecedented insights into the intricacies of cellular regulation, disease genesis, and the potential for novel diagnostic and therapeutic strategies. This study delves into the dynamic nature of 3D genome organization, investigating how these structures influence cellular functions in response to environmental changes and over time. Through a combination of real-time imaging and advanced computational models, we aim to unravel the complex interplay between 3D DNA structures, non-coding RNAs, and chromatin organization, and their collective impact on gene expression and cellular differentiation. A significant focus is placed on understanding the role of 3D DNA structures in the development and progression of genetic disorders. By employing comprehensive genomic and epigenomic profiling, this research seeks to identify structural aberrations linked to diseases, paving the way for the development of targeted diagnostics and therapies. Additionally, the study explores the potential of genome editing technologies, such as CRISPR-Cas systems, in correcting these structural abnormalities, while also addressing the ethical, legal, and social implications (ELSI) of such interventions. Integrating data from various genomic analyses, we propose the development of advanced computational models to predict the effects of 3D DNA structures on gene expression and cellular function. This integrative approach not only promises to enhance our understanding of genomic regulation but also sets the stage for groundbreaking advances in genomics-based diagnostics and therapeutics. The findings of this study have the potential to revolutionize our approach to treating genetic disorders, offering a new frontier in personalized medicine.

The study titled "Molecular Choreography of DNA: Insights and Innovations" explores the intricate dance of DNA, shedding light on its structure, function, and regulation. This comprehensive review delves into the historical significance of DNA research, from Watson and Crick's double helix discovery to recent innovations in genomics and molecular biology. The review highlights DNA's roles in replication, repair, gene regulation, and chromatin dynamics, emphasizing the precision and complexity of its molecular choreography. Innovations like CRISPR-Cas9 gene editing and advanced sequencing technologies have revolutionized our understanding of DNA, opening new avenues for scientific exploration. This study aims to provide readers with a deeper appreciation of DNA's central role in life's choreographed processes.

This review article offers an in-depth look at DNA, its discovery, structure, functions, and the significant role it plays in modern biomedical research. It begins by revisiting the landmark discovery of the DNA double helix by scientists Watson and Crick, a structure resembling a twisted ladder that forms the blueprint of life. The review explains the basic processes of DNA replication (copying DNA), transcription (converting DNA to RNA), and translation (turning RNA into proteins), which are fundamental to understanding how genetic information is passed on and used by living organisms. The article then explores gene regulation and epigenetics, which involve how genes are turned on or off and how environmental factors can affect gene expression without changing the DNA sequence itself. It examines how DNA interacts with various proteins and modifiers, which play crucial roles in these processes. A major focus is on the advancements in DNA sequencing technologies. From the initial Sanger sequencing method, which was labor-intensive and time-consuming, to the highly efficient next-generation sequencing (NGS) and the latest single-molecule sequencing techniques, the review covers how these technologies have revolutionized genomics and personalized medicine. It also highlights the importance of computational genomics and bioinformatics, fields that deal with analyzing and interpreting the vast amounts of data generated by DNA sequencing. The review discusses DNA's crucial role in understanding human diseases. It covers DNA-based research in cancer, rare genetic disorders, infectious diseases, and pharmacogenomics (how genes affect a person's response to drugs). It emphasizes studies that have led to new ways of diagnosing and treating diseases. The article looks at the future of DNA research. It talks about emerging technologies like CRISPR-Cas9, a revolutionary gene-editing tool that allows scientists to modify DNA with high precision. Synthetic biology, an interdisciplinary field that combines biology and engineering for designing and constructing new biological parts and systems, is also discussed. Furthermore, DNA nanotechnology, which involves designing DNA molecules for technological uses, is explored. Finally, the review addresses ethical issues in DNA research, such as privacy concerns and debates over genome editing.

Pairs of pyrrolysyl-tRNA synthetase (PylRS) and tRNAPyl from Methanosarcina mazei and Methanosarcina barkeri are widely used for site-specific incorporations of non-canonical amino acids into proteins (genetic code expansion). Previously, we achieved full productivity of cell-free protein synthesis for bulky non-canonical amino acids, including Ne-((((E)-cyclooct-2-en-1-yl)oxy)carbonyl)-L-lysine (TCO*Lys), by using Methanomethylophilus alvus PylRS with structure-based mutations in and around the amino acid binding pocket (first-layer and second-layer mutations, respectively). Recently, the PylRS•tRNAPyl pair from a methanogenic archaeon ISO4-G1 was used for genetic code expansion. In the present study, we determined the crystal structure of the methanogenic archaeon ISO4-G1 PylRS (ISO4-G1 PylRS) and compared it with those of structure-known PylRSs. Based on the ISO4-G1 PylRS structure, we attempted the site-specific incorporation of Ne-(p-ethynylbenzyloxycarbonyl)-L-lysine (pEtZLys) into proteins, but it was much less efficient than that of TCO*Lys with M. alvus PylRS mutants. Thus, the first-layer mutations (Y125A and M128L) of ISO4-G1 PylRS, with no additional second-layer mutations, increased the protein productivity with pEtZLys up to 578% of that with TCO*Lys, at high enzyme concentrations in the cell-free protein synthesis.

A thorough analysis and comparison of the fatty acid profiles of stipe and blade from Laminaria hyperborea, a kelp species found in the northern Atlantic, is presented. Lipids were extracted and fractionated into neutral lipids, free fatty acids and polar lipids, then derivatized to fatty acid methyl esters prior to GC-MS analysis. A total of 42 fatty acids were identified and quantified, including the n-3 fatty acids α-linolenic acid, stearidonic acid and eicosapentaenoic acid. An n-6/n-3 ratio of 0.8:1 was found in blade and 3.5:1 in stipe, respectively. The ratios vary between the lipid fractions within stipe and blade, with the lowest ratio in the polar lipid fraction of blade. The fatty acid amounts are higher in blade than in stipe, and the highest amounts of n-3 fatty acids are found within the neutral lipid fractions. The amounts of polyunsaturated fatty acids are 3.4 times higher in blade than stipe. This study highlights the compositional differences between the lipid fractions of stipe and blade from L. hyperborea. The amount of polyunsaturated fatty acids, compared to saturated- and monounsaturated fatty acids, as well as the n-6/n-3-ratio, is known to influence human health. In the pharmaceutical, food, and feed industries this can be of importance for production and sale of different health products. Additionally, lipids are today among the unused by products of alginate production, exploiting this material for commercial interest should give both economical and environmental benefits.

From a strategic and an economic point of view, patent prior art searches are very useful for several reasons such as avoiding the infringement of third parties’ rights, reinventing something already new in the state of the art, speeding up the prosecution of a patent application, and getting a patent granted with a lower associated cost. A prior art search is carried out in patent databases (free of charge or fee-based) through keywords or classification symbols, indexing codes (IPC – International Patent Classification or CPC – Cooperative Patent Classification), or a combination of these, using Boolean or proximity operators. The classification codes are independent of the language used and can increase the number of relevant documents retrieved. Patent databases are all incomplete and therefore a search in multiple sources is suggested.

Isothermal Nucleic Acid Amplification based-Lateral Flow Testing (INAA-LFT) has emerged as a robust technique for on-site pathogen detection, providing a visible indication of pathogen nucleic acid amplification that rivals or even surpasses the sensitivity of real-time quantitative PCR. The isothermal nature of INAA-LFT ensures consistent conditions for nucleic acid amplification, establishing it as a crucial technology for rapid on-site pathogen detection. However, despite its considerable promise, the widespread application of isothermal INAA amplification-based lateral flow testing faces several challenges. This review provides an overview of the INAA-LFT procedure, highlighting its advancements in detecting plant viruses. Moreover, the review underscores the imperative to address existing limitations and emphasizes ongoing research efforts dedicated to enhancing the applicability and performance of this technology in the realm of rapid on-site testing.

With the aging of China's population, the problem of pension security has become more and more prominent, and whether delayed retirement can effectively alleviate the pension fund gap and ensure the sustainability of the pension fund has become the focus of social concern. This study predicts the income and expenditure of urban workers' basic pension insurance fund from 2021 to 2050 by constructing an actuarial model of pension insurance fund income and expenditure, and simulates the effect of delayed retirement policy. The prediction results show that under the existing system, the basic pension insurance fund for urban workers will have a shortfall for the first time in 2027, and the shortfall will expand year by year. Compared with the non-implementation of delayed retirement policy, the simulation of the implementation of delayed retirementt program delayed the emergence of the fund gap until 2029, and the forecast period of the pension fund gap significantly narrowed, indicating that delayed retirement policy has a certain positive impact on alleviating the pressure of pension payments, but delayed retirementt can not completely eliminate the pension fund gap. In view of this, this paper suggests that a progressive and flexible delayed retirement policy should be introduced as soon as possible to better adapt to the needs of different groups. At the same time, differentiated policies should be formulated for different groups of people and a pension incentive mechanism for delayed retirement should be set up to improve public acceptance of delayed retirement policy. In addition, delayed retirement policy should be combined with other measures, such as lowering the corporate contribution rate and enhancing the value-added capacity of the pension fund, so as to ensure the sustainability of the pension fund.

This paper presents the results of investigations into the pyrolysis of waste polypropylene in a laboratory fixed-bed batch reactor. The experiments were designed and verified in such a way as to allow the application of the Response Surface Methodology (RSM) in the development of an empirical mathematical model that quantifies the impacts mentioned above. The influence of the mass of the raw material (50, 100 and 150 g), together with the reactor temperature (450, 475 and 500 °C) and the reaction time (45, 50 and 75 min) was examined. It has been shown that the mass of the raw material, i.e. the filling volume of the reactor, has a significant influence on the pyrolysis oil yield. This influence exceeds the influence of reactor temperature and reaction time. This was explained by observing the temperature change inside the reactor at three different spots at the bottom, middle and top of the reactor. Recorded temperature diagrams show that with greater masses of feedstock, local overheating occurs in the middle part of the reactor, which leads to overcracking of vapor products, and from there to an increased formation of non-condensable gases, i.e. reduced yield of pyrolytic oil.

Bicyclic peptides have attracted the interest of pharmaceutical companies because of their remarkable properties putting them on a new path in medicine. Their conformational rigidity that improves proteolytic stability, leads to rapid penetration into tissues via any possible route of administration and elimination, occurring by renal metabolism, is of great importance for people with a history of liver diseases. In addition, each ring can function independently, making them extremely versatile molecules for further optimization. In this paper we compared the potentiometric and spectroscopic properties studied by UV-Vis, MCD, and EPR, of four synthetic analogues of the bi-cyclic peptide c(PKKHP-c(CFWKTC)-PKKH). In particular we correlated the structural and spectral properties of complexes with coordinating abilities toward Cu(II) ions of MCL (Ac-PKKHPc(CFWKTC)PKKH-NH2) that contains the unbinding cycle and N- and C-terminal linear parts, with two histidine residues, one per part; two monocyclic ligands containing one histidine residue, both in the N-terminal position i.e., MCL2 (Ac-PKKHPc(CFWKTC)PKKS-NH2) and in the C-terminal position i.e., MCL3 (Ac-PKKSPc(CFWKTC)PKKH-NH2), respectively, and the linear structure LNL (Ac-PKKHPSFWKTSPKKH-NH2).

This study presents review of 7580 papers in 13 academic journals, published from January 2015 to January 2020. After a detailed analysis of all papers, 46 papers were further selected showing research on a student population aged between 6 and 15 years old. In order for the paper to be included in the research, the condition was that the paper deals with teaching at least one of the following content areas: programming languages, game design, computer thinking (CT), algorithmic thinking and robotics programming. This study shows the representation of the listed content area in reviewed papers for the specified time period as well as a detailed analysis of the selected papers. Available data about study, participants and education level, country (first author), learning domain, teaching tools, research questions, hypothesis, pre/post-test results, interviews, control groups, course duration, research design, previous experience, project or grant and re-search purpose in detected papers were analysed. In addition, impact of studying some of the listed content areas on student learning performance, motivation, attitude and perception were investigated.

It has been known that dimensional constants such as ℏ, c, G, e, and k are merely human constructs whose values and units vary depending on the chosen system of measurement. Therefore, the time variation of dimensional constants lacks operational significance due to their dependence on them. It is well-structured and represents a valid discussion. However, this fact only becomes a meaningful debate within the context of a static or present universe. As well-established theoretically and observationally, the current universe is undergoing accelerated expansion, wherein dimensional quantities, like the wavelength of light, also experience redshift phenomena elongating over cosmic time. In other words, in an expanding universe, dimensional quantities of physical parameters vary with cosmic time. From this perspective, there exists the possibility that dimensional constants, such as the speed of light, could vary with the expansion of the universe. In this review paper, we contemplate under what circumstances the speed of light may change or remain constant over cosmic time, and discuss the potential for distinguishing these cases observationally.

Cosmography, as an integral branch of cosmology, strives to characterize the Universe without relying on pre-determined cosmological models. This model-independent approach utilizes Taylor series expansions around the current epoch, providing a direct correlation with cosmological observations and the potential to constrain theoretical models. Various observable quantities in cosmology can be described as different combinations of cosmographic parameters. Furthermore, one can apply cosmography to models with a varying speed of light. In this case, the Hubble parameter can be expressed by the same combination of cosmographic parameters for both the standard model and varying speed of light models. However, for the luminosity distance, the two models are represented by different combinations of cosmographic parameters. Hence, luminosity distance might provide a method to constrain the parameters in varying speed-of-light models.

The epigenetic mechanism of DNA methylation is essential for regulating gene expression and adaptation in plants, especially when exposed to various environmental stressors such as drought, heat, and nutrient availability. The impact of these stressors can lead to alterations in DNA methylation patterns and gene expression, which this study aims to investigate. Specifically, we are interested in understanding how DNA methylation plays a role in controlling the expression of stress-response genes, as well as genes involved in plant growth and development. To accomplish this, we are analyzing the changes in DNA methylation patterns and gene expression in response to different stressors like drought and heat. Our research findings suggest that DNA methylation is a vital regulator of plant adaptation to environmental stress, and we hope to gain further insight into these mechanisms by identifying genes that exhibit differential expression in response to stress and analyzing their DNA methylation status. This study offers valuable insights into the development of crops that can thrive under changing climate conditions.

Gastric inflammation-related disorders are commonly observed digestive system illnesses char-acterized by the activation of proinflammatory cytokines, particularly tumor necrosis factor-α (TNF-α). This results in the induction of cyclooxygenase-2 (COX-2)/prostaglandin E2 (PEG2) and matrix metallopeptidase-9 (MMP-9). These factors contribute to the pathogenesis of gastric in-flammation disorders. We examined the preventive effects of Lonicera japonica Thunb. ethanol ex-tract (Lj-EtOH) on gastric inflammation induced by TNF-α in normal GES-1 cells. The GES-1 cell line was used to establish a model that simulated the overexpression of COX-2/PGE2 and MMP-9 proteins induced by TNF-α, to examine the anti-inflammatory properties of Lj extracts. The re-sults indicated that Lj-EtOH exhibits significant inhibitory effects on COX-2/PEG2 and MMP-9 ac-tivity, attenuates cell migration, and provides protection against TNF-α-induced gastric inflam-mation. The protective effects of Lj-EtOH are associated with the modulation of COX-2/PEG2 and MMP-9 through activation of TNFR–ERK 1/2 signaling pathways as well as the involvement of c-Fos and nuclear factor kappa B (NF-κB) signaling pathways. Based on our findings, Lj-EtOH ex-hibits a preventive effect on human gastric epithelial cells. Consequently, it may represent a novel treatment for the management of gastric inflammation.

We study various properties of the polygonal numbers; such as their recurrence relations; fundamental identities; weighted binomial and ordinary sums; partial sums and generating functions of their powers; and a continued fraction representation for them. A feature of our results is that they are presented naturally in terms of the polygonal numbers themselves and not in terms of arbitrary integers; unlike what obtains in most literature.

We present a brief history of the construction of models of the universe, followed by calculations of quantitative characteristics of basic geometric and kinematic properties of the Standard Cosmological Model ($\Lambda$CDM). Using the Friedmann equations of uniform space, we derive equations characterizing a $\Lambda$CDM model that describes a universe corresponding to current observational data. The equations take into account the effects of radiation and ultra-relativistic neutrinos. It is shown that the universe at very early and late stages can be described to sufficient accuracy by simple formulas. Certain important moments of cosmic evolution are determined: the times when densities of the gravitational components of the universe become equal, when they contribute equally to the gravitational force, when the accelerating expansion of space begins, and several others. The dependences of different distances on redshift and the scale factor of space are derived. The distance to the sphere that expands with the speed of light (the Hubble distance), and its current and future acceleration, are found. Concepts of a horizon, second inflation, and second horizon are discussed. We consider the remote future of the universe and the opportunity, in principle, of connection with extraterrestrial civilizations.

An out-of-hospital cardiac arrest (OHCA) is one of the leading causes of death in the world. The survival rate can be influenced by the Chain of Survival. The school is the institution that has the opportunity to promote the education of citizens in Basic Life Support (BLS), increasing the number of trained bystanders. This study aimed to identify the theoretical and practical knowledge and self-reported skills in BLS, in order to characterise the motivation to intervene in an emergency situation. A quantitative, descriptive, cross-sectional, and analytical study of the survey type was developed with a sample of 1215 students enrolled in 10th grade of secondary education in 2019-2020 in Portugal. The results point to a fragile appropriation of theoretical and practical knowledge in the field of BLS. Self-declared competences tend to rank below the theoretical knowledge manifested. Motivation to intervene is high: students are sensitive to the topic, willing to learn and highlight the importance and social relevance of the topic. We conclude that students do not feel nor are able to intervene in an OHCA episode. It seems necessary to develop didactic proposals that align the teaching of BLS with the Essential Learning at the end of compulsory education in Portugal.

The members within the genus Thermoanerobacter have been much less investigated for protein and amino acid metabolism as compared with carbohydrates. The present study investigates the biotechnological potential of Thermoanaerobacter mathranii (DSM 11426) concerning its ability to produce high energy alcohols from amino and fatty acids. End-product formation was analyzed from glucose in the presence and absence of butyric acid as well as from selected proteins, and all amino acids. T. mathranii did not degrade any of the proteins tested to a large extent but de-grade several amino acids, namely serine and the branched-chain amino acids (leucine, isoleu-cine, valine) when cultivated in the presence of thiosulfate. The main end products from the branched-chain amino acids were a mixture of their corresponding branched-chain fatty acids and alcohols. 13C2-labeled leucine revealed that the strains degraded the amino acid in the pres-ence of thiosulfate, producing 3-methyl-1-butyrate, which was then used as an electron acceptor which led to the accumulation of 3-methyl-1-butanol. The strain is highly ethanologenic, pro-ducing more than 1.2 mol ethanol per mol of glucose degraded. The strain was able to reduce volatile fatty acids during glucose fermentation to their corresponding alcohol, further suggest-ing this strain may be of greater biotechnological value beyond bioethanol production.

Insufficient mixing in large-scale bioreactors, provokes gradient zones of substrate, dissolved oxygen, pH and other parameters. E. coli responds to a high glucose, low oxygen feeding zone with the accumulation of mixed acid fermentation products, especially formate, but also with the synthesis of non-canonical amino acids, such as norvaline, norleucine and -methyl-norleucine. These amino acids can be mis-incorporated into recombinant products, which causes a problem for pharmaceutical production whose solution is not trivial. While these effects can also be observed in scale down bioreactor systems, these are challenging to operate. Especially the high-throughput screening of clone libraries is not easy, as fed-batch cultivations would need to be controlled via repeated glucose pulses with simultaneous oxygen limitation, as has been demonstrated in well controlled robotic systems. Here we show that not only glucose pulses in combination with oxygen limitation can provoke the synthesis of these non-canonical branched-chain amino acids, but also that pyruvate pulses produce the same effect. Therefore we combined the enzyme based glucose delivery method Enbase® in a PALL24 mini-bioreactor system and combined repeated pyruvate pulses with simultaneous reduction of the aeration rate. These cultivation conditions, produced an increase in the non-canonical branched chain amino acids norvaline and norleucine in both the intracellular soluble protein and inclusion body fractions with mini-proinsulin as an example product, and this effect was verified in a 15 L stirred tank bioreactor. To our opinion this cultivation strategy is easy to apply for the screening of strain libraries under standard laboratory conditions if no complex robotic and well controlled parallel cultivation devices are available.

Oligonucleotides are key compounds widely used for research, diagnostics, and therapeutics. The rapid increase in oligonucleotide-based applications, together with the progress in nucleic acids research, led to the design of nucleotide analogs that when being part of these oligomers enhance their efficiency, bioavailability, or stability. One of the most useful nucleotide analogs are the first-generation bridge nucleic acids (BNA), also known as locked nucleic acids (LNA), which were used in combination with ribonucleotides, deoxyribonucleotides, or other analogs to construct oligomers with diverse applications. However, there is still room to improve their efficiency, bioavailability, stability, and, importantly, toxicity. A second generation BNA, BNANC (2'-O,4'-aminoethylene bridged nucleic acid), has been recently made available. Oligomers containing these analogs not only showed less toxicity when compared to LNA-containing compounds but in some cases also exhibited higher specificity. Although there are still few applications where BNANC-containing compounds were researched, the results are very promising warranting more efforts in incorporating these analogs for other applications. Furthermore, newer BNA compounds will be introduced in the near future offering great hope to oligonucleotide-based fields of research and applications.

Smoking is a pervasive global health concern associated with a myriad of diseases, but its impact on cellular aging, particularly in relation to telomeres, is increasingly recognized. Telomeres, protective caps at the ends of chromosomes, play a crucial role in maintaining genomic integrity. This review critically examines the existing evidence on the association between smoking and telomere atrophy, exploring the molecular mechanisms involved and the implications for accelerated aging and heightened disease risk. The comprehensive analysis encompasses both cross-sectional and longitudinal studies, elucidating potential gender and age disparities. Insights into the molecular pathways linking smoking to telomere shortening are discussed, along with the broader implications for public health. The review concludes by outlining potential interventions and suggesting future research directions in this critical area.

This review study, delves into the groundbreaking potential of quantum dots in revolutionizing the field of stem cell tracking for regenerative medicine. Beginning with an introduction that underscores the pivotal role of stem cell tracking in regenerative medicine, this review introduces quantum dots as promising tools for this purpose. It proceeds to explore the fundamental properties of quantum dots, including the quantum confinement effect, size-dependent emission, and exceptional brightness, which render them ideal candidates for stem cell tracking. The historical evolution and recent advancements of quantum dot technology in biomedicine are discussed, emphasizing their growing importance in terms of biocompatibility and safety. Furthermore, various labeling strategies for stem cells using quantum dots are detailed, encompassing surface modification and internalization techniques, with a comparison of their respective advantages and drawbacks. A comprehensive exploration of the wide range of imaging modalities that synergize with quantum dots for stem cell tracking is presented, accompanied by an evaluation of their strengths and limitations. Real-world applications of quantum dot-based stem cell tracking in regenerative medicine, spanning tissue regeneration to disease modeling, are showcased, with illuminating case studies. Current challenges and limitations in quantum dot-based stem cell tracking, including long-term stability and regulatory considerations, are addressed, and innovative directions and emerging trends in quantum dot technology are proposed. Safety considerations and strategies to enhance quantum dot biocompatibility within biological systems are discussed, while ethical and regulatory implications related to their use in stem cell tracking are explored, promoting responsible research and development practices. Finally, the review concludes by summarizing key insights and takeaways, reaffirming the transformative potential of quantum dots in advancing stem cell tracking and the field of regenerative medicine.

This review article delves into the pivotal role of DNA in advancing criminal investigations, presenting a comprehensive analysis of its impact on modern justice systems. DNA, as the genetic blueprint of individuals, has revolutionized forensic science, augmenting the accuracy and reliability of criminal investigations. This study explores the historical evolution of DNA analysis, from its initial discovery to the development of sophisticated techniques like polymerase chain reaction (PCR), short tandem repeat (STR) profiling, and next-generation sequencing (NGS). The article elucidates the intricate process of DNA collection, preservation, and analysis, highlighting its significance in establishing identity, proving guilt or innocence, and resolving cold cases. The utilization of DNA databases and international cooperation in cross-border investigations are also examined, emphasizing their contributions to solving complex criminal cases. Moreover, the ethical, legal, and privacy considerations surrounding DNA usage in criminal justice are critically evaluated. Through a comprehensive literature review, this article synthesizes empirical evidence showcasing how DNA evidence has exonerated wrongfully convicted individuals and provided closure to victims' families. It further elucidates how technological advancements have extended DNA analysis to trace evidence, touch DNA, and forensic genealogy, thereby broadening its application in criminal investigations.

Barcoding of DNA is a species identification technique that utilizes a small DNA fragment from a specific gene or genes known as "sequencing." The idea behind DNA barcoding is that a single sequence can be used to specifically identify an organism to species by comparison with a reference library of these DNA sections. Herbal adulteration can be monitored using DNA barcodes that utilize medicinal plants such as Atropa belladonna. Because it is challenging to distinguish between species solely based on morphology, other plants belonging to the same genus are replacing it in trade. Such replacement with plants not utilized for medical purposes could have negative side effects. Also, Atropa belladonna's positive effects can be completely lost. Taxonomists also have trouble distinguishing the genuine Atropa belladonna plant from cultivated items. As a result, DNA barcoding can now be used to overcome this challenge. The development of DNA barcodes may help with trade control, which protects and conserves endangered species from export outside of the country due to their economic and biological significance. In this review, we discuss the DNA barcoding of Atropa belladonna plant in the medicinal plants field.

Cyberspace map, as one of the important tools to describe cyberspace, gives an image to the unpredictable and illusory cyberspace, and has become a research hotspot in the fields of cartography, cyberspace security. Clarifying the concept of cyberspace map and constructing the conceptual model of cyberspace map can promote people's unified cognition of cyberspace. Based on the view of cartography, this paper compares and analyzes some related concepts of cyberspace map, discusses the characteristics of cyberspace map，and gives its concept. After that, it analyzes people's cognition of cyberspace composition. On this basis, it caters to this cognition mode and proposes the conceptual model of cyberspace map. Then, the connotation of the model is elaborated from three aspects: element-space association dimension, element mapping dimension and the map representation dimension. Finally, the specific composition and symbolization of various elements are analyzed. The model provides the top-level framework and theoretical guidance for the research of cyberspace map. This paper aims to adapt to the development trend of Cartography in ternary space, clarify the basic concept of cyberspace map, promote the development of cyberspace mapping theory, and lay the foundation for subsequent research.

The symptoms most commonly reported by patients affected by coronavirus disease 2019 (COVID-19) include cough, fever, and shortness of breath. However, other major events usually observed in COVID-19 patients (e.g. high blood pressure, thrombosis, pulmonary embolism) seem to suggest that the virus is targeting the endothelium, one of the largest organs in the human body. Herein, we report both clinical and preclinical evidence supporting the hypothesis that the endothelium is a key target organ of COVID-19.

To assess if SARS-CoV-2 infection induces changes in the urinary volatilomic fingerprint able to be used in the non-invasive COVID-19 diagnosis and management, urine samples of SARS-CoV-2 infected patients (62), recovered COVID-19 patients (30), and non-infected individuals (41) were analysed using solid-phase microextraction technique in headspace mode, combined with gas chromatography hyphenated with mass spectrometry (HS-SPME/GC-MS). In total, 101 volatile organic metabolites (VOMs) from 13 chemical families were identified, being terpenes, phenolic compounds, norisoprenoids, and ketones the most represented groups. Overall, a decrease in the levels of terpenes and phenolic compounds was observed in the control group, whereas norisoprenoids and ketones showed a significant increase. In turn, a remarkable increase was noticed in norisoprenoids and ketones and a milder increase in alcohols, furanic, and sulfur compounds in the recovery group than in the COVID-19 group. Multivariate statistical analysis identified sets of VOMs with the potential to constitute volatile signatures for COVID-19 development and progression. These signatures are composed of D-carvone, 3-methoxy-5-(trifluoromethyl)aniline (MTA), 1,1,6-trimethyl-dihydronaphthalene (TDN), 2-heptanone, and 2,5,5,8a-tetramethyl-1,2,3,5,6,7,8,8-octahydro-1-naphthalenyl ester acetate (TONEA) for COVID-19 infection and nonanoic acid, α-terpinene, β-damascenone, α-isophorone, and trans-furan linalool for patients recovering from the disease. This study provides evidence that changes in the urinary volatilomic profile triggered by SARS-CoV-2 infection constitute a promising and valuable screening and/or diagnostic and management tool for COVID-19 in clinical environment.

Sterepinic acids A–C (1–3), new carboxylic acids with two primary alcohols, have been isolated from a fungal strain of Stereum sp. OUPS-124D-1 attached to the marine alga Undaria pinnatifida. Dihydro-1,5-secovibralactone (4), a new vibralactone derivative, was isolated from the same fungal metabolites together with known vibralactone A (5), and 1,5-secovibralactone (6). The planar structures of these compounds have been elucidated by spectroscopic analyses using IR, HRFABMS, and NMR spectra. To determine the absolute configuration of the compounds, we used the phenylglycine methyl ester (PGME) method. These compounds exhibited less activity in the cytotoxicity assay against cancer cell lines.

Cancer is a disease that encompasses multiple and different malignant conditions and is among the leading causes of death in the world. Therefore, the search for new pharmacotherapeutic options and potential candidates that can be used as treatments or adjuvants to control this disease is urgent. Natural products, especially those obtained from plants, have played an important role as a source of specialized metabolites with recognized pharmacological properties against cancer, therefore, they are an excellent alternative to be used. The objective of this research was to evaluate the action of the monoterpene isoespintanol (ISO) against the human tumor cell lines MDA-MB-231, A549, DU145, A2780, A2780-cis and the non-tumor line MRC-5. Experiments with MTT and fluorescence with propidium iodide (PI), DAPI and green plasma revealed the cytotoxicity of ISO against these cells; furthermore, morphological and chromogenic studies revealed the action of ISO on cell morphology and the inhibitory capacity on reproductive viability to form colonies in MDA-MB-231 cells. Likewise, 3D experiments validated the damage in these cells caused by this monoterpene. These results serve as a basis for progress in studies of the mechanisms of action of these compounds and the development of derivatives or synthetic analogues with a better antitumor profile.

Enterococcus faecalis is a growing cause of nosocomial and antibiotic-resistant infections. Treating drug-resistant E. faecalis requires novel approaches. The use of bacteriophages (phages) against multidrug-resistant (MDR) bacteria has recently garnered global attention. Biofilms play a vital role in E. faecalis pathogenesis as they enhance antibiotic resistance. Phages eliminate biofilms by producing lytic enzymes, including depolymerases. In this study, Enterococcus phage vB_Efs8_KEN04 (ФKEN04), isolated from a sewage treatment plant in Nairobi, Kenya, was tested against clinical strains of MDR Enterococcus faecalis. This phage had a broad host range against 100% (26/26) of MDR E. faecalis clinical isolates and cross-species activity against Enterococcus faecium. It was able to withstand acidic and alkaline conditions, from pH 3 to 11, as well as temperatures between -80ᵒC and 37ᵒC. It could inhibit and disrupt the biofilms of MDR E. faecalis. Its linear double-stranded DNA genome of 142,402 bp contains 238 coding sequences with a G+C content and coding gene density of 36.01% and 91.46%, respectively. Genomic analyses showed that ФKEN04 belongs to the genus Kochikohdavirus in the family Herelleviridae. It lacked antimicrobial resistance, virulence, and lysogeny genes, and its stability, broad host range, and cross-species lysis indicate strong potential for the treatment of Enterococcus infections.

Noncoding RNA regions have emerged as pivotal players in the regulation of various cellular processes, and their involvement in HIV/AIDS pathogenesis is an evolving field of research. This review article delves into the intricate interplay between noncoding RNA regions and AIDS, shedding light on the diverse mechanisms by which these RNA molecules influence viral replication, immune responses, and disease progression. The review highlights recent discoveries, potential therapeutic applications, and the challenges ahead, illustrating the promising prospects of noncoding RNA research in the context of HIV/AIDS.

Non-coding RNA regions have long been considered the "dark matter" of the genome, with their significance in gene regulation remaining enigmatic. However, recent advances in genomics and molecular biology have illuminated the pivotal role that non-coding RNA regions play in the fine-tuned orchestration of hemoglobin expression. Hemoglobin, the oxygen-carrying protein vital for life, is tightly regulated, and any disruption in its production can lead to severe medical conditions, such as hemoglobinopathies. This review delves into the intricate world of non-coding RNA regions, exploring how they act as master conductors in controlling hemoglobin gene expression. We will discuss various classes of non-coding RNAs, including long non-coding RNAs, microRNAs, and circular RNAs, and their specific mechanisms in fine-tuning hemoglobin levels. Additionally, we will highlight emerging therapeutic approaches that target non-coding RNA regions to ameliorate hemoglobin-related disorders. Understanding the critical role of non-coding RNA regions in hemoglobin regulation opens new avenues for precision medicine and gene therapies, offering hope for those affected by hemoglobinopathies and related conditions. This comprehensive review sheds light on the significance of these non-coding RNA regions, demonstrating that the "silent" players in the genome are, in fact, the conductors of harmony in the symphony of hemoglobin regulation.

The aim of this publication is to analyze the topic of high-frequency jet ventilation (HFJV), namely the catheter HFJV (C-HFJV) from a mathematical-physical as well as a clinical point of view. There are known issues with applying anesthesia and artificial lung ventilation (ALV) during surgical procedures in the upper airways, e.g. during bronchoscopy or tracheostomy. The principles, advantages, and disadvantages of HFJV are discussed in context with basic physical principles to clarify the proper use of this method. The basic technical principles of catheter construction, as well as its functional properties from a biophysical point of view, are introduced. Also, the placement of the catheter in the airways, the set-up of the HFJV ventilator, and the indications as well as the risks and contraindications of the use of C-HFJV are analyzed. This leads to the explanation of potentially optimal techniques for C-HFJV applications. In this article, we present the positive effects of C-HFJV even with complications such as bacterial or viral pneumonia, including COVID-19. In conclusion, we offer recommendations for clinical practice obtained from a literature review as well as from our own rich clinical experience.

The study shows that the volumes and surfaces of the $n$-simplices, $n$-orthoplices, $n$-cubes, and $n$-balls are holomorphic functions of $n$, which makes those objects omnidimensional. Furthermore, the volume of an $n$-simplex is shown to be a bivalued function of $n$, and thus the surfaces of $n$-simplices and $n$-orthoplices are also bivalued functions of $n$. Applications of these formulas to the omnidimensional polytopes inscribed in and circumscribed about $n$-balls reveal previously unknown properties of these geometric objects in negative dimensions. In particular, for $0 < n < 1$, the volumes of the omnidimensional polytopes are larger than those of circumscribing $n$-balls, while their volumes and surfaces are smaller than the volumes of inscribed $n$-balls. Reflection relations around $n = 0$ for volumes and surfaces of these polytopes inscribed in and circumscribed about $n$-balls are disclosed. Specific products and quotients of volumes and surfaces of the omnidimensional polytopes and $n$-balls are shown to be independent of the gamma function.

The current work is dedicated to the search for new high-energy materials (HEMs) with improved characteristics which are gained through agglomeration with salts. The research was performed by Becke’s three-parameter hybrid functional approach with non-local correlation provided by Lee, Yang, and Parr and cc-pVTZ basis set. The geometry, total energy, and heat of formation of the most stable compounds forming due to 3-amino-5-[(2, 4, 6-trinitrophenyl) amino]-1H-1, 2, 4-triazole (APATO) within salts selected were obtained to foresee its influence on resistance to shock stimuli, detonation pressure, and velocity of the materials under study. Results obtained allow us to foresee that only agglomeration with precise salts could lead to significant improvement in the stability of the specific high-energy materials and the resistance to shock stimuli. We also show that the agglomeration leads to better energetic properties of the above compound, although the improvement could be insignificant in some cases.

The burden of chronic liver disease is globally increasing at an alarming rate. Chronic liver injury leads to liver inflammation and fibrosis (LF) as critical determinants of long-term outcomes such as cirrhosis, liver cancer and mortality. LF is a wound-healing process characterized by excessive deposition of extracellular matrix (ECM) proteins due to the activation of hepatic stellate cells (HSCs). In the healthy liver, quiescent HSCs metabolize and store retinoids. Upon fibrogenic activation, quiescent HSCs transdifferentiate into myofibroblasts, lose their vitamin A, upregulate -smooth muscle actin, and produce pro-inflammatory soluble mediators, collagens, and inhibitors of ECM degradation. Activated HSCs are the main effector cells during hepatic fibrogenesis. In addition, the accumulation and activation of profibrogenic macrophages in response to hepatocyte death play a critical role in the initiation of HSC activation and survival. The main source of myofibroblasts is resident HSCs. Activated HSCs migrate to the site of active fibrogenesis to initiate the formation of a fibrous scar. Single-cell technologies revealed that quiescent HSCs are highly homogenous, while activated HSCs/myofibroblasts are much more heterogeneous. The complex process of inflammation results from the response of various hepatic cells to hepatocellular death and inflammatory signals related to intrahepatic injury pathways or extrahepatic mediators. Inflammatory processes modulate fibrogenesis by activating HSCs and, in turn, drive immune mechanisms via cytokines and chemokines. Increasing evidence also suggests that cellular stress responses contribute to fibrogenesis. Recent data demonstrated that LF can revert even at advanced stages of cirrhosis if the underlying cause is eliminated, which inhibits the inflammatory and profibrogenic cells. However, despite numerous clinical studies on plausible drug candidates, an approved antifibrotic therapy still remains elusive. This state-of-the-art review presents cellular and molecular mechanisms involved in hepatic fibrogenesis and its resolution, as well as comprehensively discusses the drivers linking liver injury to chronic liver inflammation and LF.

In the case of solid slabs made of reinforced concrete that are usually subjected to bending, large areas of the structure are stressed well below their load-bearing capacity or remain stress-free. Contrary to this are shell structures, which can bridge large spans with little material if designed well. To improve the efficiency of ceiling slabs, we want to utilize the shell load-bearing behaviour on a smaller scale by dissolving the solid interior accordingly. In order to be able to study a wide range of such constructions virtually, a parametric multiobjective simulation environment is to be developed in an ongoing research project, basic analysis approaches of which are presented in this paper. In addition to the basic workflow and the programs used, the material models used, and their calibration are described on the basis of tests on textile reinforced concrete (TRC) samples. Initial tests on two individual TRC served to verify the model.

The adaptive immune system in vertebrates comes in two flavors. Historically, adaptive immunity focused on the study of immunoglobulins (also referred to as Ig-based antibodies herein); more recently, jawless vertebrates were found to use an entirely different class of proteins for their adaptive immunesystem. Specifically, these organisms express variable lymphocyte receptors (so called VLR antibodies) that create diversity based on the rearrangement of leucine-rich repeats. Meanwhile, various, naturally occurring repeat motifs have been used as building blocks for the design of artificial binding scaffolds which, among others, include designed ankyrin repeat proteins (DARPins). Such binding scaffolds are also referred to as non-Ig-based antibodies or non-Ig scaffolds herein). DARPins display several benefits such as a low molecular weight (~15 kDa), high thermal stability, high specificity and affinity, versatility (e.g., in terms of valency and multi-specificity), speedy preclinical development, low production costs and, thus, bear the potential to not only complement existing therapeutic Ig-based antibodies but also open up novel therapeutic strategies. The first generation DARPin therapeutic abicipar pegol has completed two Phase III studies in 2020 while several other DARPin drug candidates are currently undergoing clinical validation. Most recently, the rapid development of tri-specific SARSCoV-2 DARPin therapeutics showcases the immense potential of recombinant repeat proteins in adopting quickly e.g., new forms of target neutralization that a single Ig-based antibody cannot afford. Here, we highlight the design principles of repeat proteins in general and summarize in detail the continuous advancements of the DARPin scaffold that made it one of the most promising antibody mimetics to date. This review provides an overview of current and emerging applications of DARPins as both a research tool and therapeutic drug that can match or even surpass Ig-based antibody applications.

Coccomyxa subellipsoidea KJ (C-KJ) is a green alga with unique immunoregulatory characteristics. Here, we investigated the mechanism underlying the modification of T cell function by C-KJ components. The water-soluble extract of C-KJ was fractionated into protein (P) and sugar (S) fractions [acidic (AS), basic (BS), and neutral (NS)]. These fractions were used for the treatment of peripheral blood mononuclear cells stimulated with toxic shock syndrome toxin-1. Transcriptome analysis revealed that both P and AS enhanced the expression of the genes encoding metallothionein (MT) family proteins, inflammatory factors, and T helper (Th) 17 cytokine and suppressed that of those encoding Th2 cytokines in stimulated T cells. The kinetics of MT1 and MT2A gene expression showed a transient increase in MT1 and maintenance of MT2A mRNA after T cell stimulation in the presence of AS. The kinetics of Th17-related cytokine secretion in the early period were comparable to those of MT2A mRNA. Furthermore, our findings revealed that static, a STAT-3 inhibitor, significantly suppressed MT2A gene expression. These findings suggest that the expression of MTs is involved in the immune regulatory function of C-KJ components, which is partially regulated by Th17 responses, and may help develop innovative immunoregulatory drugs or functional foods.

The development of new and effective antimicrobial compounds is an urgent need with the emergence of resistant bacteria. Natural plant flavonoids are known to be effective molecules but their activity and selectivity have to be increased. Based on previous aurone potency, we designed new aurone derivatives bearing acetamido and amino groups at the position 5 of the A ring and managing various monosubstitutions at the B ring. A series of 31 new aurone derivatives were first evaluated for their antimicrobial activity with five derivatives being the most active (compounds 10, 12, 15, 16, and 20). The evaluation of their cytotoxicity on human cells and of their therapeutic index (TI) showed that compounds 10 and 20 have the highest TI. Finally, screening against a large panel of pathogens confirmed that compounds 10 and 20 possess a large spectrum antimicrobial activity, including on bioweapon BSL3 strains, with MIC values as low as 0.78 µM. These results demonstrate that 5-acetamidoaurones are far more active and safest compared with 5-aminoaurones, and that benzyloxy and isopropyl substitutions at the B ring are the most promising strategy in the exploration of new antimicrobial aurones.

Our health requires continual protein synthesis for maintaining and repairing tissues. For protein synthesis to function, all the essential (indispensable) amino acids (IAA) that must be available in the diet, along with those AAs that the cells can synthesize, the dispensable amino acids. Here we review studies that have shown the location of the detector for IAA deficiency in the brain, specifically for recognition of IAA deficient diets (IAAD diets) in the anterior piriform cortex (APC), with subsequent responses in downstream brain areas. The APC is highly excitable, uniquely suited to serve as an alarm for reductions in IAAs. With a balanced diet, these neurons are kept from over-excitation by GABAergic inhibitory neurons. Because several transporters and receptors on the GABAergic neurons have rapid turnover times, they rely on intact protein synthesis to function. When an IAA is missing, its unique tRNA cannot be charged. This activates the enzyme General Control Nonderepressible 2 (GCN2) that is important in the initiation phase of protein synthesis. Without the inhibitory control supplied by GABAergic neurons, excitation in the circuitry is free to signal an urgent alarm. Studies in rodents have shown rapid recognition of IAA deficiency by quick rejection of the IAAD diet.

Ursolic and oleanolic acids are secondary plant metabolites that are known to be involved in the plant defence system against water loss and pathogens. Nowadays these triterpenoids are also regarded as potential pharmaceutical compounds and there is mounting experimental data that either purified compounds or triterpenoid-enriched plant extracts exert various beneficial effects, including anti-oxidative, anti-inflammatory and anticancer, on model systems of both human or animal origin. Some of those effects have been linked to the ability of ursolic and oleanolic acids to modulate intracellular antioxidant systems and also inflammation- and cell death-related pathways. Therefore, our aim was to review the current knowledge about the distribution of ursolic and oleanolic acids in plants, bioavailability and pharmacokinetic properties of these triterpenoids and their derivatives, and to discuss their neuromodulatory effects in vitro and in vivo.