The master molecular regulators and mechanisms determining longevity and health span include nitric oxide (NO) and superoxide anion radicals (SOR). L-arginine, the NO synthase (NOS) substrate, can restore a healthy ratio between the dangerous SOR and the protective NO radical to promote healthy aging. Antioxidant supplementation orchestrates protection against oxidative stress and damage—L-arginine and antioxidants such as vitamin C increase NO production and bioavailability. Uncoupling of NO generation with the appearance of SOR can be induced by asymmetric dimethylarginine (ADMA). L-arginine can displace ADMA from the site of NO formation if sufficient amounts of the amino acid are available. Antioxidants such as ascorbic acids can scavenge SOR and increase the bioavailability of NO. The topics of this review are the complex interactions of antioxidant agents with L-arginine, which determine NO bioactivity and protection against age-related degeneration.

The master molecular regulators and mechanisms determining longevity and health span include nitric oxide (NO) and superoxide anion radicals (SOR). L-arginine, the NO synthase (NOS) substrate, can restore a healthy ratio between the dangerous SOR and the protective NO radical to promote healthy aging. Antioxidant supplementation orchestrates protection against oxidative stress and damage—L-arginine and antioxidants such as vitamin C increase NO production and bioavailability. Uncoupling of NO generation with the appearance of SOR can be induced by asymmetric dimethylarginine (ADMA). L-arginine can displace ADMA from the site of NO formation if sufficient amounts of the amino acid are available. Antioxidants such as ascorbic acids can scavenge SOR and increase the bioavailability of NO. The topics of this review are the complex interactions of antioxidant agents with L-arginine, which determine NO bioactivity and protection against age-related degeneration.

Although working memory (WM) is crucial for intellectual abilities, not much is known about its brain underpinnings, especially the structural connectivity. We used diffusion tensor imaging (DTI) to look across the whole brain for the white matter integrity correlates of the individual differences in the reading span (verbal WM capacity during reading) in healthy adults. Right-handed healthy native Russian speakers (N = 67) underwent DTI on a 3T Philips Ingenia scanner. Verbal WM was assessed with the Daneman-Carpenter reading span test (Russian version). Fractional anisotropy maps from each participant were entered into the group tract-based spatial statistics analysis with the reading span as a covariate; the results were TFCE-corrected. After taking into account effects of age, sex, education and handedness, reading span positively correlated with the white matter integrity in multiple sites: the body, the genu and the splenium of corpus callosum; bilateral corona radiata (anterior, posterior, and superior); bilateral superior longitudinal fasciculus; several tracts in the right hemisphere only, including the internal and external capsule; bilateral superior parietal and frontal white matter. Although the left hemisphere is central for verbal processing, we revealed the important role of the right hemisphere white matter for the verbal WM capacity. Our finding indicates that larger verbal working memory span may originate from additional processing resources of the right hemisphere.

The purpose of the study was to provide support in the decision-making process for architects and engineers regarding large-spans structures for the presentation of archaeological sites in situ - construction of roofs, shelters, and bridges. We examined existing practice and analyzed their engineering classifications looking for a pattern in their application regarding sustainability and relation between type of cultural heritage site and type of applied large span structure. Contemporary engineering structures at built heritage sites create a sharp contrast between old and new. A presentation of cultural heritage in situ requires an understanding of heritage theory and internationally accepted doctrine which exceeds common engineering education. Nevertheless, application of large-span structures, which often take advantages of state-of-art construction-technologies nowadays, is also an aesthetical statement that affects the appearance of the site. Therefore, we gave an overview of the theoretical background of aesthetical issues and the overall ethics of the decision-making process in such sensitive cases. Within the framework of heritage-presentation, engineering and architectural issues, and selected case studies, we concluded in favor of the application of large-span structures under certain conditions.

Due to the extraordinary mechanical properties of ultra-high-performance concrete (UHPC), the shear stirrups in UHPC beams could potentially be removed. The aim of this study is to determine the effect of beam height and steel fiber volume content on the shear behavior of non-stirrup UHPC beams under a larger shear span-depth ratio (up to 2.8). Eight beams were designed and fabricated, including six non-stirrup UHPC beams and two comparing stirrup-reinforced normal concrete (NC) beams. The experimental results demonstrated that the volume content of steel fiber could be a crucial factor affecting the ductility, cracking strength, and shear strength of non-stirrup UHPC beams and altering their failure modes. Additionally, the height of the beam had a considerable effect on its shear resistance. This study revealed that the French standard formulae were more accurate for the UHPC beams with larger shear span-depth ratios and PCI-2021 formulae greatly overestimate the shear capacity of UHPC beams with larger shear span-depth ratios. Xu’s formulae were more accurate for the steel fiber-reinforced UHPC beams with larger shear span-depth ratios.

The recently defined and yet rather new topic of Healthy aging is gathering more attention on the global stage. With world’s population getting older - it is rapidly becoming very important to develop and maintain functional abilities in older age and develop mechanisms to protect senior population from chronic diseases. One of the most effective components, as well as, one may call - process involved in, and strongly associated with aging is recently discovered and Nobel prize awarded - nitric oxide as a signaling molecule, which followed by later discoveries showed to have a positive metabolic, immune and anti-inflammatory effects. One of the most debated topics of the last decade in the scientific community is nitrates, one of the pathways involved in nitric oxide production. Thus, the objective of this study was to evaluate effect of different potassium nitrate concentrate supplementation on Drosophila melanogaster longevity. 0,5-3% potassium nitrate medium was analyzed on the life span and motor function in different groups consisting of 100 females fruit flies each. In this assay, female fly species supplemented with potassium nitrate diet showed life span increase by 18.6% and 5.1% with 1% and 2% KNO3- respectively with a positive impact on locomotor function. In conclusion, we found that low concentration of potassium nitrate medium increased lifespan and locomotor function in Drosophila melanogaster.

Large-span post-tensioned (PT) beams play a crucial role in maximizing the benefits of post-tensioning techniques. Bonded and unbonded systems are prevalent, with the latter being more widespread in the United States. While bonded systems are advantageous for creating long spans when multiple tendons are grouped in ducts, limited literature exists on their demolition. In a case study, this paper addresses the unique challenge of demolishing large-span bonded post-tensioned beams due to a building's functional change. Emphasizing insights for engineers, it explores the use of cutting and dismantling methods, considering the presence of prestressed cables. The demolition process is distinctive due to the presence of numerous pre-stressed cables along the beams, necessitating a specialized and cautious cutting approach. This is accomplished through the use of a drilling technique that selectively distresses the tendons, ensuring they are not all affected simultaneously. An intriguing observation discussed in this paper pertains to the occurrence of horizontal cracks accompanied by loud sounds following the drilling process, offering insights from the design perspective of PT systems. The paper details an innovative method for safely demolishing large-span bonded PT beams, using ground-penetrating radar and computer models to navigate structural complexities and ensure nearby structures' safety.

The BP neural network and PSO algorithm are applied into analyzing the reliability of long-span Concrete Filled Steel Tubular (CFST) arch bridges. Firstly, using BP neural network to fit the structural performance function. And then the PSO method was used to calculate the reliability index. A long-span Concrete Filled Steel Tubular arch bridges reliability indices were calculated whether considering the geometric nonlinearity or not. The calculation and analysis results showed that the BP neural network and PSO algorithm compensated the deficiency of the traditional reliability analysis methods, improved the calculation accuracy, provided a new thought and means for the research on the reliability of long-span bridge structure, and well applied to the reliability analysis of long-span Concrete Filled Steel Tubular arch bridges. Additionally, the reliability analysis of long-span Concrete Filled Steel Tubular arch bridges on service limit state must consider the geometric nonlinearity effect, or the results will tend to be unsafe.

In view of the limitations of the existing optimization method of suspender cable force, in order to improve the stress of suspender under completion state and avoid frequent adjustment of cable force and grid beam elevation during construction, a new method of cable force optimization is proposed. The article takes the longest large span arch bridge in the world, Pingnan Third Bridge, a Concrete-filled steel tube (CFST) arch bridge with a span of 575m as the engineering background combined with the finite element analysis and multi-objective optimization method. One cable force optimization method that suspender “Real-time correction during construction, in the process variable optimal and results reliable” during panel girder lifting of long span CFST arch bridges is clarified. Taking the panel girder weight and displacement during the construction as parameter variables, the displacement and unevenness of the panel girder under completion state as constraint conditions, the displacement and cable force during the hoisting construction as the objective equation, through the optimization of the objective equation, the suspender cable force and dis-placement of each hoisting section are calculated. The results show that it is feasible to introduce the optimization theory into the cable force optimization when lifting the panel girder. the segment displacement variation is minimized to meet the destination. The cable force distributed evenly under completion state of the bridge that further making sure the completion state satisfies the requirements. No repeating iteration is needed, thus avoiding cumberso me calculation, getting cable force once. With higher optimization efficiency and better effects, the method provides high value for the cable force calculation of same type bridge suspender construction and for guiding construction.

Noise model selection criteria has a significant impact on identifying the stochastic noise proper-ties of any GNSS daily coordinate time series. The low-frequency random walk noise existing in these time series could lead to overestimation of the tectonic rate, so it is of great significance to accurately detect the random walk component. This study focuses on noise model estimation cri-terion (BIC_tp) derived from the AIC and the BIC by introducing 2π factors. It is more sensitive to abnormal steps (random jumps). Using observation data from 72 GNSS stations from 1992 to 2022 and simulated data, four combined noise models are used to explore the impacts of time se-ries lengths (ranging from2 to 24 years) and data loss (between 2% and 30%) on noise models and velocity estimation. The results show that as the time length increased, the selected optimal noise model, and the estimated uncertainty of the tectonic trend with different data gap, gradually con-verge. When the time length is short (less than 8 years), it could lead to the FNRWWN, FNWN, and PLWN models being mistakenly estimated as GGMWN models, thereby affecting the accura-cy of determining the station velocity parameters. When the time length is 12 years, the RW noise component is more probably detected, As the time length increases, the impact of RW on velocity uncertainty is weakened. Finally, we conclude that for a time series with a minimum time length of 12 years, both the selection of the optimal stochastic noise model and the estimation of the ve-locity parameters are reliable.

Improper lifting measures of long-span spatial steel structures during construction process may delay the construction period and even cause safety accidents. Few studies on long-span spatial steel structures considered time-varying mechanical characteristic during construction process. In order to achieve safe and efficient installation in a long-span spatial steel structure, this research presents a time-varying mechanical analysis of the synchronous and asynchronous integral lifting and a single and interlaced point’s asynchronous integral lifting analysis method of a long-span spatial steel structure. The results showed that in the case of asynchronous lifting of single point, the displacement influence on other members is related to the distance. The closer the distance from the lifting point, the greater the influence. In asynchronous integral lifting, the lifting point with large lifting force is first installed to the specified position, and the lifting point with small lifting force is installed to the specified position.

The determination of the non-loading condition of the rail cable shifting (RCS) system, which consists of main cables, hangers and rail cables, is the premise of the girder erection for the long-span suspension bridges. An analytical form-finding analysis model of shifting system is established according to the basic assumptions of flexible cable structures. Herein, the rail cable is discretized into segmental linear cable elements and the main cable is discretized into segmental catenary elements. Moreover, the calculation and analysis equation of each member and their iterative solutions are derived by taking the elastic elongation of the sling into account. In addition, by taking the girder construction of Aizhai suspension bridge as engineering background, a global scale model of the RCS system is designed and manufactured; also the test system and working conditions are established. The comparison between the test results and analytical results shows the presented analytical method is correct and effective. The process is simplified in the analytical method, and the computational results and precision can satisfy the practical engineering requirements. In addition, the proposed method is suitable to apply to the computation analysis of similar structures.

Long span cable-stayed bridge is the main bridge type with a span of more than 400 meters. It is generally designed as a double tower long-span structure with good spanning capacity and economic performance. Wind resistance safety performance is the main index to control the long-span cable-stayed bridge structure. During the operation of long-span cable-stayed bridge structure, because the service life of the cable is far less than the design life of the structure, the wind resistance performance of the structure will inevitably deteriorate significantly, which will seriously affect the structural service performance of symmetric cable-stayed bridge. Based on symmetric reliability theory, this paper takes flutter and static wind stability of long-span cable-stayed bridge structure as the main design control index, uses positive reliability theory to calculate the reliability index of symmetric cable-stayed bridge structure, uses inverse reliability theory to calculate the safety factor of symmetric cable-stayed bridge structure, and evaluates the wind resistant time-varying performance of long-span cable-stayed bridge structure by comprehensively considering the reliability index and safety factor. Taking a practical project of a long-span cable-stayed bridge as a specific case, the wind resistant time-varying reliability of the bridge during its operation for more than 30 years is analyzed, and the parameter sensitivity is analyzed. The results show that the wind resistance performance of the cable-stayed bridge structure is obviously affected by the cable, and the degradation of the cable performance will have an important impact on the wind resistance time-varying performance of the structure, especially the critical wind speed of the structure has obvious time-varying characteristics. The safety factor and reliability index can objectively evaluate the wind resistance time-varying performance of the long-span cable-stayed bridge structure.

As Chronic Non-Communicable Diseases (CNCD) increase, preventive approaches become more crucial. In this review, Calorie Restriction (CR) effects on human beings were evaluated, comparing benefits and risks of different CR diets: classic CR vs ketosis-inducing diets, including Intermittent Fasting (IF), Classic Ketogenic Diet (CKD), Fasting Mimicking Diet (FMD), Very-Low-Calorie Ketogenic Diet (VLCKD) and Spanish Ketogenic Mediterranean Diet (SKMD). Special emphasis on Insulin Resistance (IR) was placed, as it mediates Metabolic Syndrome (MS), a risk factor for CNCD, and predicts MS diagnosis. CR is the most robust intervention known to increase lifespan and health span, with high evidence and known biochemical mechanisms. CR improves cardiometabolic risk parameters, boosts exercise insulin sensitivity response, and there may be benefits of implementing moderate CR on healthy young and middle-aged individuals. However, there is insufficient evidence to support long-term CR. CKD is effective for weight and MS management, and may have additional benefits such as prevention of muscle loss and appetite control. SKMD has extreme significance benefits for all the metabolic parameters studied. Studies show inconsistent benefits of IF compared to classic CR. More studies are required to study biochemical parameters, reinforce evidence, identify risks, and seek effective and safe nutritional CR approaches.

One of the non-linear phenomena that affect high bandwidth and long reach communication systems is the non-linear phenomenon called four-wave mixing (FWM). Unfortunately, the simulation of such systems aiming to obtain their design parameter limitations require more time as the number of channels increases. In this paper, we propose a new high-performance computational model to obtain optimal design parameters in a multi san Dense Wavelength Division Multiplexing (DWDM) system, limited by FWM and the intrinsic Amplified Spontaneous Emission (ASE) noise of optical amplifiers employed in each segment. The simulation in this work provides a complete optical design characterization and compares the efficiency and speed improvement of the proposed parallelization model versus a previous sequential model. Additionally, an analysis of the computational complexity of parallel model is presented, where two parallel implementations are used. First, Open Multi−Processing (OpenMP), based on the use of a central, multi-core processing unit is used and secondly the Compute Unified Device Arquitecture (CUDA), which is based on the use of graphics processing unit. Results show that parallelism improves to up to 40 times the performance of the simulation when nested parallelization with CUDA is used, over de sequential method and up to 6 times compared with the implementation with OpenMP using 12 processors. Within our parallel implementation, it is possible to simulate with an increased number of channels, that was unpractical in the sequential simulation.

Epoxy asphalt (EA) concrete is widely used in constructing long-span steel bridge pavements (SBDPs). This study aims to derive a fatigue damage evolution law, conducting an experimental investigation of SBDP. First, a general theoretical form of the fatigue damage evolution law of materials is established based on the thermal motion of atoms. Then, fatigue experiments demonstrate that this evolution law well represents the known damage–life relationships of SBDP. Taking into account the experimental relationships between damage and fatigue life under symmetrical cyclic loadings with different overload amplitudes and temperature variations, a detailed damage evolution law is deduced. Finally, the role of damage accumulation is discussed on the basis of the proposed damage evolution law for the extreme situation of heavy overload and severe environments. The results show that both heavy loading and falling temperatures increase the fatigue damage of SBDP considerably; therefore, SBDP should avoid heavy loading combined with winter temperatures. EA shows a fatigue life two to three times longer than that of modified matrix asphalt (SMA) or guss asphalt (GA). For the same thickness, EA pavement is demonstrated to be more suitable for an anti-fatigue design of large-span SBDP under high traffic flows and low temperatures.

Bridge load testing is crucial in evaluating bridge load-carrying capacity and construction quality. However, conventional techniques have many limitations such as the need for direct contact and low acquisition frequency. This study provides a comprehensive examination of the static and dynamic load tests of a multi-span cable-stayed bridge utilizing a ground-based radar inter-ferometer (GB-radar). The case study was conducted at the Fifth Nanjing Yangtze River Bridge (FNYRB), which is recognized as the world's first lightweight steel-concrete composite cable-stayed bridge, with two spans measuring 600 m. To enhance measurement accuracy, a method was proposed to detect and recover radar phase jumps caused by vehicle motion. Furthermore, precise geometry projection was employed to acquire vertical displacements from GB-radar which were taken along the line-of-sight (LOS) direction. Moreover, during the static load test, a continuous deformation was observed with a maximum pace of 0.31 mm/min, indicating a post-construction settlement caused by soft soil consolidation. This case study highlights the high sampling frequency, high measurement accuracy, and exceptional weatherproof ability of GB-radar, thereby demonstrating its potential to be an alternative to the structural health monitoring (SHM) system.

Rheumatoid arthritis (RA) is a chronic inflammatory disease. Despite new methods of diagnostics and treatment as well as extensive biological and immunosuppressive treatment, the etiology of RA is not fully understood. Moreover, the problem of diagnosis and treatment of RA patients is still current and affects a large group of patients. It is suggested that these ER-related features may impair adaptation to chronic stress, inferring the risk of rheumatoid arthritis. The main goal in this study was evaluation of changes in mRNA translation to determine chronic ER stress conditions in rheumatoid arthritis patients. The study group consist of 86 individuals including total 56 rheumatoid arthritis patients and 30 healthy controls. The expression level of mRNA form blood samples of RA patients as well as controls of the PERK-UPR associated genes: p-eIF2, BCL-2, PERK, ATF4, BAX were investigated by Real-Time qPCR. GAPDH expression was used as a standard control. Considering the median, the expression of PERK, BCL-2, p-eIF2, ATF4, BAX was found to be significantly increased in the blood of RA patients compared with the control group. The p-value for the PERK gene was 0.0000000036, the p-value for the BCL-2 gene was 0.000000014, the p-value for the p-eIF2 gene was 0.006948, the p-value for the ATF4 gene was 0.0000056 and the p-value for the BAX gene was 0.00019, respectively. Thus, it can be concluded that targeting of the components of the PERK-dependent UPR signaling pathway via small-molecule PERK inhibitors, may contribute to the development of novel, innovative treatment strategies against rheumatoid arthritis.

This theoretical article reviews the model describing processes in social systems based on the analysis of their resource base. Application of the system theory can help to explain why some systems are aimed at prevention of type I errors, while other seek to decrease quantity of type II errors. Such differences are manifested in investment of resources either into deep interaction or into wide coverage. Some examples of such strategies in economic, market and production systems are provided in the article. The article introduces some provisions of the system theory in the context of the resource flows. The main indicators that are considered in this article are the characteristics of the sources of the exchanging flows of resources. Their relative frequency and quality are investigated, on the basis of which the most effective strategy of the system is derived, as a mechanism for redistributing resources. The rigor of the system's strategy depends on the magnitude of the difference in characteristics. It is explained how exactly it influences the exchange processes, that in reality systems do not interact simultaneously, and one of the opposite resource flows is always delayed. It is shown how the system strategy depends on the risks linked with interactions. Also, there are grounds for the need to accumulate resources, including in the situation of their surplus. The model helps also explain shift of economic centers throughout history. Additionally, there is an analogy between systems strategies and the competitive strategies described by M. Porter, and outsourcing versus integration.

This article presents description of social structures such as, for example, states, in the context of their consideration as systems. Moreover, it seeks to develop K. Marx’s model in terms of systematic approach, as well as to justify the application of the Fibonacci sequence to systems in general and, in particular, to social systems. The description covers a wide range of issues, ranging from the assertion of the basic principle of living systems as patterns in resources flows to description of functions of various aspects of states and their economics in terms of objective needs of such structures. In addition, this article justifies synergetic effect based on proposed model, and the way this effect is applied to state systems. Moreover, it includes the description of main changes of socio-economic formations throughout the history as a natural development of social systems, including possible modern stages. The fundamental tool of this description is description of essence of the mechanism of property rights and its formation options. The differences of two extreme directions of such development are also described on the basis of the objective factor of resource provision. Special attention is given to the concept of surplus value as a feature of social production systems.

This theoretical article provides a brief description of the model of living systems' functioning by defining them as resource flows patterns. It reviews the living systems growth limitation between their development cycles by the Fibonacci sequence. Besides, there are presented systems resource base criteria, necessary for accumulating the resources and their investment. The article also considers the conditions for the formation of various systems strategies. Then we reviewed the principles of elemental analysis of information by a person as a living system according to the considered model. The study also shows the possibility of forming priorities in analyzing information for 16 combinations as maximum. At that, it remains crucial to divide a human's information analysis between the two hemispheres of the brain. The described combinations of priorities in a person's information analysis are compared with the existing differential personality models, such as the big five personality traits, the Myers-Briggs type indicator, temperaments model and Honey and Mumford Learning styles.

This article presents the results of the consideration of the Bertrand paradox in terms of geometric probability theory. Although the method and conclusions of this article are straightforward, no equivalent studies were found when reviewing the relevant literature. This could be conditioned by the fact that the hypotheses presented in this research have low intuitive obviousness and, in contrast, could be due to the historically established agreement regarding the issue. This article shows that out of three classical solutions to the problem described by Bertrand, two methods are inconsistent with the claimed relative objectivity. Although the remaining solution (1/4) seems to be the most correct, we cannot claim that we have exhaustively ruled out all aspects that could reduce its adequacy to solve the problem.

Background: The control of energy metabolism is fundamental for cell growth and function, and anomalies are implicated in complex diseases and ageing. It is important for cells to carefully tune metabolic pathways to optimize their function in response to different nutrient or physiological conditions. Metabolism in yeast cells can be easily manipulated by supplying different carbon sources: on glucose yeast rapidly proliferates by fermentation, analogous to tumour cells growing by aerobic glycolysis, whereas on non-fermentable carbon sources metabolism shifts towards respiration. Results: We screened deletion libraries of fission yeast to identify over 200 genes required for respiratory growth. The growth medium and auxotrophic mutants strongly influenced respiratory metabolism. Most genes uncovered in the mutant screens have not been implicated in respiration in budding yeast. We applied gene expression profiling approaches to compare steady-state fermentative and respiratory growth and to analyse the dynamic adaptation to respiratory growth. The transcript levels of most genes functioning in key energy metabolism pathways were coherently tuned, reflecting anticipated differences in metabolic flows between fermenting and respiring cells. We show that the acetyl-CoA synthase, rather than the citrate lyase, is essential for acetyl-CoA synthesis in fission yeast. We also investigated the transcriptional response to mitochondrial damage by genetic or chemical perturbations, defining a retrograde response that involves the concerted regulation of distinct groups of nuclear genes that may avert harm from mitochondrial malfunction. Conclusions: These systematic and targeted analyses provide a rich framework of the genetic and regulatory basis of fundamental metabolic states to guide future studies on energy metabolism in fission yeast and beyond. Our study pinpoints weaknesses of commonly used auxotroph mutants for investigating energy metabolism. As a model for cellular energy regulation, fission yeast provides an attractive and complementary system to budding yeast.

Proteomics research has become one of the most important topics in the fields of life science and natural science. At present, research on protein–protein interaction networks (PPINs) mainly focuses on detecting protein complexes or function modules. However, existing approaches are either ineffective or incomplete. In this paper, we investigate function module detection mechanisms in PPIN, including open databases, existing detection algorithms and recent solutions. After that, we describe the proposed solution based on simplified swarm optimization (SSO) algorithm and gene ontology knowledge. The proposed solution implements SSO algorithm for clustering proteins with similar function, and imports biological gene ontology knowledge for further identifying function complexes and improving detection accuracy. Furthermore, we use four different categories of species dataset for experiment: Fruitfly, Mouse, Scere, and Human. The testing and analysis result show that the proposed solution is feasible, efficient and could achieve a higher accuracy of prediction than existing approaches.

Human milk composition is dynamic and substitute formulae are intended to mimic its protein content. The purpose of this study was to investigate the potentiality of matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS) followed by multivariate data analyses as a tool to analyze peptide profiling of mammalian, human and formula milks. Breast milk samples from women at different lactation stages (2 (n = 5), 30 (n = 6), 60 (n = 5), and 90 (n = 4) days postpartum), and milk from donkeys (n = 4), cows (n = 4), buffaloes (n = 7), goats (n = 4), ewes (n = 5), and camels (n = 2) were collected. Different brands (n = 4) of infant formulae were also analyzed. Protein content (<30 kDa) was analyzed by MS and data were exported for statistical elaborations. Mass spectra for each milk closely clustered together, whereas different milk samples resulted well separated. Human samples formed a cluster in which colostrum constituted a well-defined subcluster. None of the milk formulae correlated with animal or human milk, although specifically characterized and well correlated each other. These findings propose MALDI-TOF MS milk profiling as an analytical tool to discriminate, in a blinded way, different milk types. As each formula has a distinct specificity, shifting a baby from one to another formula implies a specific proteomic exposure. These profiles may assist in milk proteomics for easiness of use and low cost consuming, suggesting that the MALDI-TOF MS pipelines may result useful for milk adulteration assessment but also for the characterization of banked milk specimens in paediatric clinical settings.

Rett syndrome (RTT), a neurodevelopmental disorder, is mainly caused by mutations in methyl CpG-binding protein 2 (MECP2), which alter the functions of domains to either bind to methylated DNA or interact with a transcriptional co-repressor complex. It has been established that alterations in cyclin-dependent kinase-like 5 (CDKL5) or forkhead box protein G1 (FOXG1) correspond to distinct neurodevelopmental disorders, given that a series of studies have indicated that RTT is also caused by alterations in either one of these genes. We tried to elucidate RTT through evolution and structure assessment of MeCP2, CDKL5, and FOXG1, by focusing on their binding partners and disordered structures. Here, we provide insight into the similarities of the FOXG1 and MECP2 binding partners evolution and function. On the other hand, we suggest that CDKL5 could be a potential candidate for a classical RTT treatment, particularly based on its disordered structure that spans after the catalytic domain to the C-terminus, which shows abundant linear motifs that can bind to molecules with divergent structures of similar affinity. Additionally, we provide insight into the relationship between disordered structure and disease.

Multidrug resistance protein 4 (MRP4) is an energy-dependent membrane transporter that is responsible for cellular efflux of a broad range of xenobiotics and physiological substrates. In this trial, we aimed to investigate the co-effects of aging and MRP4 deficiency using gene expression microarray and morphological and electrophysiological analyses of the mouse retina. Mrp4-knockout (null) mice and wild-type (WT) mice were reared in the same condition to 8–12 wk (young) or 45–55 wk (aged). Microarray analysis identified 186 differently expressed genes from the retinas of aged Mrp4-null mice as compared to that from aged WT mice, and subsequence gene ontology and KEGG pathway analyses showed that differently expressed genes were related to lens, eye development, vision, and transcellular barrier function that are involved in metabolic pathways or viral infection pathways. No significant change in thickness was observed for each retinal layer among young/aged WT mice and young/aged Mrp4-null mice. Moreover, immunohistochemical analyses of retinal cell type did not exhibit an overt change in the cellular morphology or distribution among the 4 age/genotype groups, and the electroretinogram responses showed no significant differences in the amplitude or the latency between aged WT mice and aged Mrp4-null mice. Aging would be an insufficient stress to cause some damage to the retina in the presence of MRP4 deficiency.

Few studies have examined the dietary protein intake and sources in combination with the longitudinal changes in brain structure markers. Our study aimed to examine the association between dietary protein intake and different sources of dietary protein with the longitudinal rate of change in brain structural markers. A total of 2723 and 2679 participants from the UK Biobank were included in the analysis. The relative and absolute amounts of dietary protein intake were calculated through a 24-hour dietary recall questionnaire. The longitudinal change rates of brain structural biomarkers were computed using two waves of brain imaging data. We utilized multiple linear regression to examine the association between dietary protein and different sources and the longitudinal changes in brain structural biomarkers. Restrictive cubic splines were used to explore nonlinear relationships, and stratified and sensitivity analyses were conducted. Increasing the proportion of animal protein in dietary protein intake is associated with a slower reduction in the total hippocampus volume (THV, β: -0.02524, P&lt;0.05), left hippocampus volume (LHV, β: -0.02435, P&lt;0.01) and right hippocampus volume (RHV, β: -0.02544, P&lt;0.05).Higher intake of animal protein relative to plant protein is linked to a lower atrophy rate in THV (β: -0.01249, P&lt;0.05) and LHV (β: -0.01173, P&lt;0.05) and RHV (β: -0.01193, P&lt;0.05). Individuals with higher intake of seafood exhibit lower longitudinal rate of change in HV compared to those with no consume (THV, β: -0.004514; P&lt;0.05; RHV, β: -0.005527, P&lt;0.05). In subgroup and sensitivity analyses, there was not a significantly alteration. A moderate increase in the intake and proportion of animal protein in the diet, especially from seafood, is associated with a lower longitudinal change rate in hippocampus volume.

Identifying anti-spike antibodies that exhibit strong neutralizing activity against current dominant circulating variants and antibodies that are escaped by these variants have important implications in the development of therapeutic and diagnostic solutions as well as in improving understanding of the humoral response to SARS-CoV-2 infection. We characterized seven anti-RBD monoclonal antibodies for their binding activity, pairing capability and neutralization activity to SARS-CoV-2 and three variant RBDs (UK, SA and BR P.1) via lateral flow immunoassays. The results allowed us to group these antibodies into three distinct epitope bins. Our studies showed that two antibodies had broadly potent neutralizing activity against SARS-CoV-2 and these variant RBDs and that one antibody did not neutralize the SA and BR P.1 RBDs. The antibody escaped by the SA and BR P.1 RBDs retained binding activity to SA and BR P.1 RBDs but was unable to induce neutralization. Further, we demonstrated that the lateral flow immunoassay can be a rapid and effective tool for antibody characterization, including epitope classification and antibody neutralization kinetics. From these studies, the potential contributions of the mutations (N501Y, E484K and K417N/T) contained in these variants’ RBDs on antibody pairing capability, neutralization activity and therapeutic antibody targeting strategy are discussed.

Land use and cover change (LUCC) is an important method to investigate the causes of global environment change. We utilized the emergy ecological footprint (EEF) model to construct a land-use change model to be used as a systematic measuring tool for monitoring sustainable development trends. In particular, we estimated the eco-security of the Cing-jing region as a case study so that responsible agencies can use it to maintain a balance between ecological preservation and tourism development. The results indicated the following: First, the ecological environment of the Cing-jing region satisfied the safety standard in 2008–2014; however, the related indices increased considerably. Second, the grey model predicted a decrease in 2015–2024 ecological carrying capacities of Cing-jing and a large increase in capita EFs, resulting in a larger ecological deficit and higher EFI. The eco-security from 2015–2024 was higher compared to 7 years ago and is predicted to reach the Grade 2 intermediate level in 2022; thus the Cing-jing region is gradually becoming ecologically unsustainable. Strengths of our study included the use of EEF theory in a quantitative analysis of slope lands for the effective evaluation of ecological security. Finally, we expanded our research to include ecological security issues.

Electron beam treatment of ZnS:Cu,Br (Cu activator content 0…0.6%wt.) radioluminescent phosphors as well as charge mixture with the electron energy 900 keV and absorbed dose of 600 kGy resulted in a enhancement of brightness up to 80%. The increased brightness is due to increase of content of wurtzite phase relative to sphalerite one with formation of wurtzite/sphalerite nanocomposite structure. Transformation of crystal structure is accompanied with corresponding change in content of active surface centers characteristic for sphalerite and wurtzite phases. A model describing surface centers of ZnS:Cu,Br radioluminescent phosphor is suggested.

G protein-coupled receptors (GPCRs) are expressed essentially on all cells, facilitating cellular responses to external stimuli, and are involved in nearly every biological process. Several members of this family play significant roles in the regulation of adipogenesis and adipose me-tabolism. However, the expression and functional significance of a vast number of GPCRs in adipose tissue are unknown. We used a high-throughput RT-PCR panel to determine the expres-sion of the entire repertoire of non-sensory GPCRs in mouse white, and brown adipose tissue and assess changes in their expression during adipogenic differentiation of murine adipocyte cell line, 3T3-L1. In addition, the expression of GPCRs in subcutaneous adipose tissues from lean, obese, and diabetic human subjects was evaluated by re-analyzing RNA-sequencing data. We detected a total of 292 and 271 GPCRs in mouse white and brown adipose tissue, respectively. There is a significant overlap in the expression of GPCRs between the two adipose tissue depots but several GPCRs are specifically expressed in one of the two tissue types. Adipogenic differ-entiation of 3T3-L1 cells had a profound impact on the expression of several GPCRs. RNA se-quencing of subcutaneous adipose from healthy human subjects detected 255 GPCRs and obesity significantly changed the expression of several GPCRs in adipose tissue. Finally, we report sev-eral highly expressed GPCRs with no known role in adipose biology whose expression was sig-nificantly altered during adipogenic differentiation and/or in the diseased human subjects. These GPCRs could play an important role in adipose metabolism and serve as a valuable translational resource for obesity and metabolic research.

The rise of digital technology and artificial intelligence has led to a significant change in the way financial services are delivered. One such development is the emergence of robo-advising, which is an automated investment advisory service that utilizes algorithms to provide investment advice and portfolio management to investors. Robo-Advisors collect information about their clients’ preferences, financial situation and future goals through questionnaires, then recommend ETF based portfolios supposed to fit investor’s risk profile. However, questionnaires seem to be vague, and robos do not reveal the methods used for investor profiling or asset allocation. This study aims at contributing by proposing an investor profiling method, based only on the level of relative risk aversion (RRA) of investors. We show how to determine RRA optimal portfolios and compare the performance of our portfolios with portfolios proposed by the Riskalyze platform.

Lung cancer is the leading cause of cancer related mortality worldwide. In order to improve its overall survival, early diagnosis is required. Since current screening methods still face some pitfalls, such as high false positive rates for low-dose computed tomography, researchers are still looking for early biomarkers to complement existing screening techniques in order to provide a safe, faster and more accurate diagnosis. Biomarkers are biological molecules found in body fluids, such as plasma, that can be used to diagnose a condition or disease. Metabolomics has already shown to be a powerful tool in the search for cancer biomarkers since cancer cells are characterised by impaired metabolism, resulting in an adapted plasma metabolite profile. The metabolite profile can be determined using nuclear magnetic resonance, or NMR. Although metabolomics and NMR metabolite profiling of blood plasma are still under investigation, there is already evidence for its potential for early-stage lung cancer diagnosis, therapy response, and follow-up monitoring. This review highlights some key breakthroughs in this research field, where the most significant biomarkers will be discussed in relation with their metabolic pathways and in light of the altered cancer metabolism.

Pardosa pseudoannulata is one of the most common wandering spiders in agricultural fields and a potentially good bioindicator for heavy metal contamination. However, little is known about the mechanism by which spiders respond to heavy metals at the molecular level. In this study, high-throughput transcriptome sequencing was employed to characterize the de novo transcriptome of the spiders and to identify differentially expressed genes (DEGs) after cadmium exposure. We obtained 60,489 assembled unigenes, 18,773 of which were annotated in the public databases. Ultimately, 3450 cDNA simple sequence repeats were identified and validated as potential molecular markers in the unigenes. A total of 2939, 2491 and 3759 DEGs were detected among the three libraries of two Cd-treated groups and the control. Functional enrichment analysis revealed that metabolism processes and digestive system function were predominately enriched in response to Cd stress. At the cellular and molecular levels, significantly enriched pathways in lysosomes and phagosomes as well as replication, recombination and repair demonstrated that oxidative damage resulted from Cd exposure. Based on the selected DEGs, certain critical genes involved in defence and detoxification were analysed. These results may elucidate the molecular mechanism underlying spiders' responses to heavy metal stress.

Silencing of the fragile X mental retardation 1 (FMR1) gene and consequently lack of synthesis of FMR protein (FMRP) are associated with fragile X syndrome, which is one of the most prevalent inherited intellectual disabilities. FMRP is a multifunctional protein involved in many cellular functions in nearly all subcellular compartments under normal conditions and under conditions of cellular stress in both neuronal and non-neuronal cell types. This is achieved through its trafficking signals, nuclear localization signal (NLS), nuclear export signal (NES), and nucleolar localization signal (NoLS), as well as its RNA and protein binding domains, and is modulated by various post-translational modifications such as phosphorylation, ubiquitination, sumoylation, and methylation. This review summarizes recent advances in understanding the interaction networks of FMRP with a special focus on FMRP stress-related functions, including stress granule formation, mitochondrion and endoplasmic reticulum plasticity, ribosome biogenesis, cell cycle control, and DNA damage response.

Insulin-like growth factor binding proteins (IGFBPs) are critical modulators of the metabolism. In adults, IGFBPs are associated with obesity and insulin resistance but the association of IGFBPs with metabolic homeostasis in children and adolescents is not fully characterized. In this study we investigated the association of plasma IGFBPs (IGFBP-1, 3 and 7) with weight status, central adiposity and cardiovascular disease markers Hs-CRP and Ox-LDL. A total of 420 adolescents (age 11-14 years) were randomly recruited from public middle schools in Kuwait. IGFBPs were measured using bead-based multiplexing while Hs-CRP and Ox-LDL were measured using ELISA. IGFBP-1 levels were significantly lower in obese and overweight participants compared to normal weight children. Only IGFBP-1 was negatively associated with waist circumference to height (WC/Ht) ratio. IGFBP-1 was negatively correlated with Hs-CRP while IGFBP-3 and IGFBP-7 were negatively correlated with Ox-LDL. These data demonstrate a robust negative association of IGFBP-1, but not IGFBP-3 or -7, with overweight and obesity, and the inflammation marker Hs-CRP. Central adiposity (WC/Ht ratio) was a stronger predictor of IGFBP-1 than BMI-for-age z-score. IGFBP-1 could thus be used as a sensitive predictive diagnostic tool for obesity and its subsequent effects in screening and monitoring of obesity-related metabolic complications in adolescents.

The aim of this study was to examine the oxidation of human serum albumin (HSA) caused by oxidative stress after an exhaustive exercise such as ultra-marathon race. Thus, blood samples from 12 adult runners who underwent a 103 km mountain ultra-marathon race were collected pre- and 24, 48 and 72 h post race. HSA was partially purified using affinity chromatography and then was subjected to Western blot analysis for disulfide dimers determination, indicating oxidation. The results were correlated with those from a previous study in which the same samples were analyzed using different oxidative stress markers and a good correlation with protein carbonyls (PC) at all time points was observed. Moreover there was a significant correlation with static oxidation-reduction potential (sORP) at 24 h, and a negative correlation with capacity oxidation-reduction potential (cORP) at 24 and 48 h. In addition, an individual analysis of albumin dimers exhibited great inter-individual differences. This inter-individual variability in the oxidation of HSA may suggest different interventions (e.g. through diet) in order to confront the effects on athletes’ organism after a strenuous exercise. In conclusion, this study supported the importance of the assessment of albumin dimers as a predictive marker for exercise-induced oxidative stress.

Sea cucumber peptides are small molecular peptides with biological function obtained from fresh sea cucumber as feedstock, which were hydrolyzed by protease, separated ,and purified. As the main product of sea cucumber refinement, it more accurately expresses the nutritional effect of sea cucumber and has a wide range of potential applications. It has been demonstrated that sea cucumber has a certain value-added effect on bone mineral density regulation, but the differences in bone mineral density regulation of extracts from different parts of sea cucumber and the techniques contributing to the efficient isolation of bone sea cucumber peptides have not been reported. Firstly, the aim of this study was to reveal the differences in osteogenic activities of enzymatic peptides from three major parts of sea cucumber: the body wall, the egg protein, and the intestinal protein. Then, the bone-enhancing sea cucumber peptides were isolated based on the characteristics of the dif-ferences in molecular weight distribution, hydrophilicity, and ionisation degree of sea cucumber, and to explore the possible mechanisms of their action. The findings indicated that sea cucumber peptides extracted from three distinct sites exhibited a dose-dependent enhancement of osteoblast proliferation and differentiation. Upon evaluating the three methods of sea cucumber peptide separation based on molecular weight distribution, hydrophilicity, and ionization, it was observed that the fraction isolated by hydrophobicity and

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

The sexual reproduction of ascomycetes is controlled by the mating-type(MAT) locus. (Pseudo)homothallic reproduction has been hypothesized based on genetic data from Hirsutella sinensis (Genotype #1 of Ophiocordyceps sinensis). In this study, the differential occurrence of the mating-type genes in the MAT1-1 and MAT1-2 idiomorphs, which constitute the genetic control of O. sinensis reproduction, was analyzed in 237 strains and 5 genomes of H. sinensis. The mating-type genes were differentially transcribed in H. sinensis Strain L0106, and the MAT1-2-1 transcript in H. sinensis Strain 1229 was alternatively spliced, with an unspliced intron I containing stop codons; these findings constitute O. sinensis reproduction controls at the transcriptional and coupled transcriptional-translational levels. The occurrence of the mating-type genes and a-/α-pheromone receptor genes differed among the 5 H. sinensis genomes. The differential occurrence and transcription of these genes are inconsistent with self-fertilization under (pseudo)homothallism but suggest self-sterility of H. sinensis, which therefore needs a mating partner to achieve sexual outcrossing under heterothallism or hybridization. Consistent occurrence and transcription of the mating-type genes of both the MAT1-1 and MAT1-2 idiomorphs have been reported in natural and cultivated Cordyceps sinensis, but these findings are insufficient to determine the reproduction mode(s) because of the co-occurrence of >90 fungal species and multiple genomically independent genotypes of O. sinensis. The mutant MAT1-1-1 and α-pheromone receptor transcripts in natural C. sinensis result in the N-terminus or middle-truncated proteins, with changes in hydrophobicity and secondary structures of the proteins, suggesting heterogeneous fungal source(s) of the proteins and hybridization reproduction.

Burkholderia andropogonis is a severe plant pathogen that can infect more than 50 plant species. Although its genome has been sequenced and annotated, various mechanisms underlying its physiology and pathogenicity remain unknown. Some of these mechanisms can be uncovered through understanding its proteome. In this study, sodium dodecyl polyacrylamide gel electrophoresis (SDS-PAGE) and mass spectrometry analysis were used to profile the proteome of B. andropogonis. Exactly 538 proteins, which belong to 190 protein families performing 88 different functions were identified. The resulting STRING network analysis identified 28 proteins having highly connected interactions with adenosine triphosphate (ATP)-binding-cassette and (ABC) transport system. To the knowledge of the authors, this is the first comprehensive proteomic study on B. andropogonis.

Tuberculosis (TB) remains a global health threat, necessitating innovative strategies for control and prevention. This comprehensive review explores the Mycobacterium tuberculosis Lysine Exporter (LysE) gene, unveiling its multifaceted roles and potential uses in controlling and preventing tuberculosis (TB). As a pivotal player in eliminating excess L-lysine and L-arginine, LysE contributes to the survival and virulence of M. tuberculosis. This review synthesizes findings from different electronic databases and includes 13 studies focused on the LysE of M. tuberculosis. The research unveils that LysE can be a potential drug target, a diagnostic marker for TB, and a promising candidate for vaccine development. The absence of LysE in the widely used BCG vaccine underscores its uniqueness and positions it as a novel area for TB prevention. In conclusion, this review underscores the significance of LysE in TB pathogenesis and its potential as a drug target, diagnostic marker, and vaccine candidate. The multifaceted nature of LysE positions it at the forefront of innovative approaches to combat TB, calling for sustained research efforts to harness its full potential in the global fight against this infectious disease.

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

The plant Allium hookeri, belonging to the Allium genus, has a history of being used both as a common food ingredient and in herbal medicine. It has recently been reported to have anti-oxidant and anti-inflammatory effects. A. hookeri has been also shown to exhibit neuroprotective and anti-neuroinflammatory activities, but the active compounds responsible for these effects have not been identified in previous studies. This study aimed to perform a metabolite profiling using an HRESI-qTOF MS/MS-based molecular networking approach and identify the active compounds from A. hookeri that target senescent cell-associated secretory phenotype (SASP) inhibitory effects, which contribute to neuroprotective activities. As a result, ten compounds, including one new flavonoid (2) and nine known compounds (1 and 3–10), were identified, and their biological activity was tested. The most potent compound was N-trans-feruloyltyramine (7), which inhibited SASP markers and contributed to the senomorphic activities of A. hookeri. These findings suggest that the phenolamides from A. hookeri could be a promising source of bioactive compounds for preventing senescence-associated diseases.

Gymnema sylvestre is a pharmacological plant which has a rich source of bioactive compounds specifically gymnemic acid (GA) and phenolic compounds (PC) that used for pharmaceutical industries. Sources for naturally occurring bioactive compounds are limited, due to geographical and seasonal variations; on the other hand, it is commercially in demand. Biosynthesis of G. sylvestre phytochemicals through in vitro culture often enhanced by elicitation. The use of cell suspension cultures (CSC) has interested serious attention on the production of essential phytochemicals. The current study is aimed at improving the contents of GA and PC in G. sylvestre CSC using the copper oxide nanoparticles (CuO NPs). Callus was obtained on MS medium with 2.0 mg/L 2,4-dichlorophenoxyacetic acid (2,4-D), 0.1 mg/L kinetin (KIN), phytoagar (8.0 g/L), and sucrose (30 g/L). The above medium devoid of agar was used for the initiation of CSC. The CSC was treated with three levels of CuO NPs (1, 3 or 5 mg/L) to enhance the production of GA and PC. The greatest amount of GA (89.25 mg/g dry cell mass, DCM), total phenolic (245.10 mg/g), and flavonoid (4.57 mg/g) in CSC were achieved when G. sylvestre cells were treated for 48 h with 3 mg/L CuO NPs. Also, the biomedical potential (antioxidant, antidiabetic, anti-inflammatory, antibacterial, antifungal and anticancer activities) were also high in the CuO NPs (3 mg/L) treated CSC extracts of G. sylvestre. CuO NPs elicitation of CSC significantly increased production of GA (9-fold), and PC than non-elicited CSC in G. sylvestre.

Background and Objectives: High job strain is worsening the outcome in coronary artery disease, CAD. Severe dissatisfaction on workplace, imbalance between high demands , and low rewards, are affecting the quality of life, and diminishing the duration of life, especially in CAD patients. Our study included two samples : CAD patients (experimental group), and without CAD patients, but with traditional risk factors (control group). The main objective of the study was the role played by high sensitivity C reactive protein, hs CRP, and microalbuminuria, as mediators of job strain and CAD relationship. Secondary objectives were the following: identification of the most vulnerable patients( with significant job strain) and intervention towards this category, for cardiovascular events prevention (primary or secondary). Materials and Methods: The utilized methods were the following : clinical exam; electrocardiogram; echocardiogram; non contrast enhanced computed chest tomography; laboratory findings ( lipid profile, glycemia, hs CRP, microalbuminuria); type D scale, DS 14; depression questionnaire, PHQ-9; and satisfaction with work scale, SWWS. Results: The highest values for hs CRP and microalbuminuria were noticed in patients with the lowest Likert score, for both samples CAD, and without CAD patients. The highest job strain was noticed in females. More than half of CAD patients ,with low Likert scores, revealed myocardial infarction. Conclusions: Microalbuminuria and hs CRP were statistical significant in the study as intercessors, in job strain and CAD relationship. The most vulnerable patients for vascular events were females, in both groups : CAD and “CAD waiting desk”. In CAD sample, the vascular vulnerability was also increased by high job strain.

The COVID-19 pandemic over the past years has shown a great need for rapid, low-cost and on-site detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this paper, an aptamer-based colloidal gold nanoparticle lateral flow test strip was well developed to realize the visual detection of wild type SARS-CoV-2 spike protein (SP) and multiple variants. Under the optimal reaction conditions, a low detection limit of SARS-CoV-2 S protein of 0.68 nM was acquired, and the actual detection recovery was 83.3% to 108.8% for real world samples. This suggests a potential tool for the prompt detection of SARS-CoV-2 with good sensitivity and accuracy, and a new method for the development of alternative antibody test strips for the detection of other viral targets.

The snATAC + snRNA platform allows epigenomic profiling of open chromatin and gene expression with single-cell resolution. The most critical assay step is to isolate high-quality nuclei to proceed with droplet-base single nuclei isolation and barcoding. With the increasing popularity of multiomic profiling in various fields, there is a need for optimized and reliable nuclei isolation methods, mainly for human tissue samples. Herein we compared different nuclei isolation methods for cell suspensions, such as peripheral blood mononuclear cells (PBMC, n=18) and a solid tumor type, ovarian cancer (OC) (n=18), derived from debulking surgery. Nuclei morphology and sequencing output parameters were used to evaluate the quality of preparation. Our results show that NP-40 detergent-based nuclei isolation yields better sequencing results than collagenase tissue dissociation for OC, significantly impacting cell identification and analysis. Given the utility of applying such techniques to frozen samples, we also tested frozen preparation and digestion (n=6). A paired comparison between frozen and fresh samples validated the quality of both specimens. Finally, we demonstrate the reproducibility of scRNA and snATAC + snRNA platform, by comparing the gene expression profiling of PBMC. Our results highlight how the choice of nuclei isolation methods is critical for obtaining quality data in multiomic assays. It also shows that the measurement of expression between scRNA and snRNA is comparable and effective for cell type identification.

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that has been shown to be an essential regulator of a broad spectrum of biological activities required for maintaining the body's vital functions. AhR also plays a critical role in tumorigenesis. Its role in cancer is complex, encompassing both pro- and anti-tumorigenic activities. Its level of expression and activity are specific to each tumor and patient, increasing the difficulty of understanding the activating or inhibiting roles of AhR ligands. We explored the role of AhR in tumor cell lines and patients using genomic data sets and discuss the extent to which AhR can be considered as a therapeutic target.

Anti-interferon (IFN)-γ autoantibodies are linked to varicella-zoster virus (VZV) infection. Given the elevated risks of herpes zoster (HZ) in rheumatoid arthritis (RA) patients treated with Janus kinase inhibitors (JAKi), we aimed to examine the relationship between anti-IFN-γ autoantibodies with HZ development in JAKi-treated patients. In twenty-four RA patients with new-onset HZ and forty-two without HZ, serum titers of anti-IFN-γ autoantibodies, plasma levels of IFN-γ, monocyte chemoattractant protein-1 (MCP-1), and IFN-γ inducible protein-10 (IP-10) were measured by ELISA. Significantly lower MCP-1 levels were observed in patients with HZ compared to those without (median, 98.21pg/ml, interquartile range (IQR) 77.63-150.30pg/ml versus 142.3pg/ml, IQR 106.7-175.6pg/ml, p&lt;0.05). There was no significant difference in anti-IFN-γ titers, IFN-γ levels, or IP-10 levels between patients with and without HZ. Three of 24 patients with HZ had severe HZ with multi-dermatomal involvement. Anti-IFN-γ titers were significantly higher in patients with severe HZ than in those with non-severe HZ (median 24.8ng/ml, IQR 21.0-38.2ng/ml versus 10.5ng/ml, IQR 9.9-15.0ng/ml, p&lt;0.005). In conclusion, patients with HZ had significantly lower MCP-1 levels than those without HZ, and patients with severe HZ had significantly higher titers of anti-IFN-γ than those with non-severe HZ. Given small sample size, our results need further validation in future studies.

Bioactive plant compounds, also known as phytochemicals, are essential for plant resistance, growth, and development. These chemicals often possess therapeutic properties that have been used in traditional medicine for centuries as herbal remedies for a variety of diseases. As a member of the Lamiaceae family, Rydingia (Syn: Otostegia) is found in Asia and northeastern Africa. R. michauxii, is a unique shrub that grows in the Southern region of Iran, Fars province. Rydingia species have been used as traditional herbal medicine in Iran for many years. It seems that R. michauxii offers great potential for in-depth research on its diverse biological properties, especially its antioxidant and lipid-lowering effects. Nevertheless, no clinical investigation has been carried out on the phytochemical characteristics of this plant to date. Therefore, this study aims to contribute to the scientific knowledge on the pharmacological properties of R. michauxii and its phytochemical compounds and encourage researchers to evaluate its biological properties in animal models. In this study, all available scientific literature was compiled and all phytochemical and pharmacological properties of the R. michauxii plant were investigated, including antibacterial, antifungal, antiviral, antioxidant, antimalarial, cytotoxic, and lipid-lowering effects, which may prove useful in developing novel formulations with greater therapeutic benefits in clinical applications.

Prunus dulcis is one of the most widely cultivated species in the world. Its fruit (almond) is rich in various nutritious and bioactive compounds that exert several beneficial effects. The aim of this study was to determine the chemical profile and evaluate the biological potential in vitro of almond shell extracts. The chemical analysis of shell extracts led to the identification of 15 com-pounds by HPLC-DAD of which 11 were first detected in the almond plant. Twenty-six volatile compounds were identified by the GC-MS technique, among them; seven were firstly detected in the studied plant. For the biological activities, the extracts demonstrated moderate inhibition potential against the antioxidant, antidiabetic, and cytotoxic activities. The methanol extract at 50 µg/mL showed the highest antioxidant (45%) and antidiabetic activities (45% against alpha-glucosidase and 31% against alpha-amylase extracts), while the cyclohexane and dichloromethane at 50 µg/mL showed the highest cytotoxic activity towards Hela (32.2% with cyclohexane), and RAW 264-7 (45% with dichloromethane). Overall, these findings demonstrate the potential of almond shell extracts as a source of bioactive compounds that could be applied in the pharmaceutical and medical fields.

A growing body of evidences is showing that dysbiotic gut microbiota may correlate with a wide range of disorders; hence, the clinical use of microbiota maps and fecal microbiota transplantation (FMT) can be exploited in the clinic of some infectious diseases. Through direct or indirect ecological and functional competition, FMT may stimulate decolonization of pathogens or opportunistic pathogens, modulating immune response and colonic inflammation, and restoring intestinal homeostasis, with reduction of host damage. Herein, we discuss how diagnostic parasitology may contribute to design clinical metagenomics pipelines and FMT programs, especially in pediatric subjects. The consequences of a more specialized diagnostics in the context of gut microbiota communities may improve the clinical parasitology and extend its applications to the prevention and treatment of several communicable and even noncommunicable disorders.

Epithelial-mesenchymal transition (EMT) plays an important role in the acquisition of cancer stem cell (CSC) feature and drug resistance, which are the main hallmarks of cancer malignancy. Although previous findings have shown that several signaling pathways are activated in cancer progression, the precise mechanism of signaling pathways in EMT and CSCs are not fully understood. In this study, we focused on the intestinal and diffuse-type gastric cancer (GC), and analyzed the gene expression of public RNAseq data to understand the molecular pathway regulation in different subtypes of gastric cancer. Network pathway analysis was performed by Ingenuity Pathway Analysis (IPA). Total 2815 probe set IDs were significantly different between intestinal- and diffuse-type GC data in cBioPortal Cancer Genomics. The 10 genes including male-specific lethal 3 homolog (Drosophila) pseudogene 1 (MSL3P1), CDC28 protein kinase regulatory subunit 1B (CKS1B), DEAD-box helicase 27 (DDX27), golgi to ER traffic protein 4 (GET4), chromosome segregation 1 like (CSE1L), translocase of outer mitochondrial membrane 34 (TOMM34), YTH N6-methyladenosine RNA binding protein 1 (YTHDF1), ribonucleic acid export 1 (RAE1), par-6 family cell polarity regulator beta (PARD6B), and MRG domain binding protein (MRGBP) were found to have difference in gene expression in intestinal- and diffuse-type GC. Total 463 direct relationships with 3 molecules (MYC, NTRK1, UBE2M) were found in the biomarker-filtered network generated by network pathway analysis. The networks and features in intestinal- and diffuse-type GC have been investigated and profiled in bioinformatics. Our results revealed the signaling pathways networks in intestinal- and diffuse-type GC, bringing new light for the elucidation of drug resistance mechanisms in CSCs.

Although the phenomenon of serial killers has received great attention from media, governments, and public, very little information is known about them and very few theories are presented by researchers specifically their definition and motives for killing. Through cross tabulation analysis of top ninety-eight serial killers, this present study poses six questions that investigate the correlations between, offender's gender, offender's level of education, time span of killing, killing severity, number of victims, killer's type of abuse, motives for killing, and victim's profile. Findings show that males kill more than females and for longer time, less educated serial killers kill more horribly, female serial killers consider their family members easy target, and finally males kill most for enjoyment and sex and females kill for financial gains.

With the rapid evolution of SARS-CoV-2, the emergence of new strains is an intriguing question. This paper presents an evolutionary theory to analyze the mutations of the virus and identify the conditions that lead to the generation of new strains. We represent the virus variants using a 4-letter sequence based on amino acid mutations on the spike protein and employ an n-distance algorithm to derive a variant phylogenetic tree. We show that the theoretically-derived tree aligns with experimental data on virus evolution. Additionally, we propose an A-X model, utilizing the set of existing mutation sites (A) and a set of randomly generated sites (X), to calculate the emergence of new strains. Our findings demonstrate that a sufficient number of random iterations can predict the generation of new macro-lineages when the number of sites in X is large enough. These results provide a crucial theoretical basis for understanding the evolution of SARS-CoV-2.

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

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

Genetic enhancement of grain production and quality is a priority in wheat breeding projects. In this study, we assessed two key agronomic traits - grain protein content (GPC) and thousand kernel weight (TKW) - across 179 Bulgarian contemporary and historic varieties, and landraces in three growing seasons. Significant phenotypic variation existed for both traits among genotypes and seasons, and no discernible difference was evident between the old and modern accessions. To understand the genetic basis of the traits, we conducted a genome-wide association study with MLM using phenotypic data from the crop seasons, best linear unbiased estimators, genotypic data from the 25K Infinium iSelect array, and a Bonferroni-adjusted p-value. As a result, 776 significant quantitative trait nucleotides (QTNs) organized into quantitative trait loci were discovered, including 25 loci associated with GPC, and 35 loci linked to TKW. Additionally, 14 environmentally stable QTNs were identified for TKW. Certain loci on chromosomes 2A, 3A, and 6B favorably in-fluenced GPC, while the locus on chromosome 6D impacted TKW positively. These loci may reflect novel associations to the two traits. Annotations for proteins involved in the remobilization of carbon and nitrogen from vegetative tissues to developing grain during senescence, as well as in the following buildup of resources required for seed germination, have been found for selected pu-tative candidate genes. These include genes coding for 11S globulin seed storage protein, glutamine synthetase, metalloendopeptidase, components of the ubiquitin/proteasome system, sucrose transporter, alpha-amylase, NAC and bZIP transcription factors. Our findings highlight promising genomic regions for targeted breeding programs aimed at improving grain yield and protein content.

Glioblastoma multiforme (GBM) is the most frequent and aggressive primary brain tumor. GBM is formed by a very heterogeneous astrocyte population, neurons, neovascularization and infiltrating myeloid cells (microglia and monocyte derived macrophages). The IQGAP1 scaffold protein interacts with components of the cytoskeleton, cell adhesion molecules, and several signaling molecules to regulate cell morphology and motility, cell cycle and other cellular functions. IQGAP1 overexpression and delocalization has been observed in several tumors, suggesting a role for this protein in cell proliferation, transformation and invasion. IQGAP1 has been identified as a marker of amplifying cancer cells in GBMs. To determine the involvement of IQGAP1 in the onco-biology of GBM, we performed immunohistochemical confocal microscopic analysis of the IQGAP1 protein in human GBM tissue samples using cell type-specific markers. IQGAP1 immunostaining and subcellular localization was heterogeneous; the protein was located in the plasma membrane and, at variable levels, in nucleus and/or cytosol. Moreover, IQGAP1 positive staining was found in podosome/invadopodia-like structures. IQGAP1⁺ staining was observed in neurons (Map2⁺ cells), in cancer stem cells (CSC; nestin⁺) and in several macrophages (CD31⁺ or Iba1⁺). Our results indicate that the IQGAP1 protein is involved in normal cell physiology as well as oncologic processes.

Obesity entails metabolic alterations across multiple organs, highlighting the role of inter-organ communication in its pathogenesis. Extracellular vesicles (EVs) are communication agents in physiological and pathological conditions and although they have been associated with obesi-ty-comorbidities, their protein cargo in this context remain largely unknown. To decipher the messages encapsulated in EVs, we isolated plasma derived EVs from diet induced obese murine models. Obese plasma EVs exhibited a decline in protein diversity while control EVs revealed significant enrichment in protein folding functions, highlighting the importance of proper folder in maintaining metabolic homeostasis. Previously, we revealed that gut derived EVs proteome holds particular significance in obesity. Here, we compared plasma and gut EVs and identified four proteins exclusively present in the control state of both EVs, revealing the potential for a non-invasive assessment of gut health by analyzing blood derived EVs. Given the relevance of post-translational modifications (PTMs), we observed a shift in chromatin-related proteins from glycation to acetylation in obese gut EVs, suggesting a regulatory mechanism targeting DNA transcription during obesity. This study provides valuable insights into novel roles of EVs and protein post-translational modifications in the intricate mechanisms underlying obesity, shed-ding light on potential biomarkers and pathways for future research.

The commercial cultivation of microalgae began in the 1960s and Chlorella was one of the first target organisms. The species has long been considered a potential source of renewable energy, an alternative for phytoremediation, and more recently, as a growth and immune stimulant. However, Chlorella vulgaris, which is one of the most studied microalga, has never been comprehensively profiled chemically. In the present study, comprehensive profiling of the Chlorella vulgaris metabolome grown under normal culture conditions was carried out, employing tandem LC-MS/MS to profile the ethanolic extract and GC-MS for fatty acid analysis. The fatty acid profile of C. vulgaris was shown to be rich in omega-6, -7, -9, and -13 fatty acids, with omega-6 being the highest, representing more than sixty percent (>60%) of the total fatty acids. This is a clear indication that this species of Chlorella could serve as a good source of nutrition when incorporated in diets. The profile also showed that the main fatty acid composition was that of C₁₆-C₁₈ (>92%), suggesting that it might be a potential candidate for biodiesel production. LC-MS/MS analysis revealed carotenoid constituents comprising violaxanthin, neoxanthin, lutein, β-carotene, vulgaxanthin I, astaxanthin, and antheraxanthin, along with other pigments such as the chlorophylls. In addition to these, amino acids, vitamins, and simple sugars were also profiled, and through mass spectrometry-based molecular networking, 48 phospholipids were putatively identified.

Elevated carbon dioxide (eCO₂) stimulates wheat grain yield, but simultaneously reduces protein (N) concentration. Also other essential nutrients are subject to change. This study is a comprehensive synthesis of wheat experiments with eCO₂, estimating effects on N, minerals (B, Ca, Cd, Fe, K, Mg, Mn, Na, P, S, Zn), and starch. Analysis was made by i) deriving response functions for the relative effect on element concentration in relation to CO₂ concentration, ii) meta-analysis to test the magnitude and significance of observed effects, and iii) relating CO₂ effects on minerals to effects on N and grain yield. Responses range from zero to strong negative effects of eCO₂ on mineral concentration, with largest reductions for the nutritionally important elements N, Fe, S, Zn and Mg. Together with the positive but small and non-significant effect on starch concentration, the large variation in effects suggests that CO₂-induced responses cannot be explained by a simple dilution model. To explain the observed pattern, uptake and transport mechanisms may have to be considered, along with the link of different elements to N uptake. Our study shows that eCO₂ has a significant effect on wheat grain stoichiometry, with implications for human nutrition in a world of rising CO₂.

In this study, the olive pomace was considered because of its importance in the environment. So, this study carried out to estimate the total nitrogen content and the fatty acids profile of olive pomace. The olive pomace samples were collected from Irbid, Jarash, Ajloun and Mafraq during the harvesting season 2014 to study the biochemical characteristics of fatty acid composition and the total nitrogen (TN) content. The total nitrogen content was determined by standard Kjeldahl method and the fatty acid profile was detected by gas chromatography (GC). The results show that the total nitrogen content ranged from (0.39 ± 0.0) to (0.62 ± 0.02) with statistically significant difference suggesting that the composition of matrices and their percentage may be responsible for composition of amendments. The calculated total protein percentage ranged between (2.43 ± 0.00) to (3.87 ± 0.17). Also, 13 different fatty acids were quantitatively profiled and quantitated. Oleic acid (C 18:1) was found to be the highest percentage of all other fatty acids and ranged between (59.03%) and (63.81%), moreover the C 18:1/C 18:2 (oil quality) was calculated and C.V% showed variation meaning that nutritional implication could affect the oxidative stability of oils. In conclusion, OP by-product could give a sustainable and alternative-cheap source for fertilizers, pharmaceutical industries, cosmetics and other industries.

Aberrant glycosylation affects cancer progression and immune evasion. Approximately 15% of colorectal cancers (CRCs) demonstrate microsatellite instability (MSI) and display major differences in outcomes and therapeutic responses as compared to corresponding microsatellite stable (MSS) tumors. We compared the N-glycan profiles of stage II and IV MSI CRC tumors, further subdivided into BRAFV600E wild-type and mutated subgroups (n=10 in each subgroup), with each other and with those of paired non-neoplastic mucosal samples using mass spectrometry. Further, the N-glycans of BRAFV600E wild-type stage II MSI tumors were compared to corresponding MSS tumors (n=9). Multiple differences in N-glycan profiles were identified between MSI CRCs and control tissues, as well as between stage II MSI and MSS samples. MSI CRC tumors showed a lower relative abundance of high-mannose N-glycans than the control tissues or the MSS CRCs. Among MSI CRC subgroups, acidic N-glycans showed tumor stage and BRAF mutation status dependent variation. Especially large, sulfated/phosphorylated, and putative terminal N-acetylhexosamine containing acidic N-glycans differed between the MSI CRC subgroups, showing opposite changes in stage II and IV, when comparing BRAF mutated and wild-type tumors. Our results show that molecular subgroups of CRC have characteristic glycan profiles that may explain certain carcinogenic properties of MSI tumors.

Mitochondria are semiautonomous organelles, which are pivotal for the energy metabolism of eukaryotic cells. These organelles contain their own genetic system (mtDNA, mitogenome) that encodes to some structural RNAs and organellar proteins. The biogenesis and function of mitochondria is tightly regulated by nuclear-encoded protein cofactors. The mtDNAs of land plants are characteristically large, with a complex mode of gene organization and expression, in particularly at the post-transcriptional level. To become functional, the primary organellar transcripts undergo extensive maturation steps, which include endo- and exo-nucleolytic cleavage, RNA-base editing, and both ‘cis’- and ‘trans’-splicing events. These essential processing steps rely on the activities of a large set of nuclear-encoded factors. Among these, the RNA helicases serve as key players in organellar (mt-)RNA metabolism. This review summarizes the important roles played by these factors in regulating the highly dynamic processes of transcription, RNA processing, and translation within the mitochondria of land plants. We further discuss recent advancements in understanding how dysregulation of mitochondrial RNA helicases affects the organellar gene expression, respiratory functions, and hence the growth, development and physiology of land plants.

Lactoperoxidase (LP), which is a high-value minor whey protein, has recently drawn extensive attention from research scientists and industry due to its multi-function and potential therapeutic applications. In this study, the separation and optimization of two similar-sized proteins, LP and lactoferrin (LF) were investigated using strong cation exchange column chromatography. Optimization was started with central composite design based experiments to characterize the importance of different decision variables. The three variables used in the optimization were flow rate, length of gradient and final salt concentration in the linear elution gradient step. The obtained empiric functional model represented the effect of the significant factors on the yield as the objective function. Afterwards, the calibrated mechanistic model was employed to predict accurate optimal set of variables. The optimal operating points were found and the results were compared with validation experiments. Predictions respecting yield confirmed a very good agreement with experimental results while keeping purity, a product quality characteristic, equal or above to a predefined value.

The objective of this work was to evaluate the roast time, weight loss and quality of coffee grain at four different roasting degrees, aiming to recognize and develop sustainable patterns to industrialize specialty coffees. Coffee (Coffea arabica L.), from eight producers, with scores between 80 and 83 from SCA classification, were used. Samples of 300 g were roasted in a cylindric rotative roaster, until the grains reached four different roasting profiles (Agtron scale 22.36, #33.64, #40.05, #59.92). Afterwards, analysis of roasting time, gas pressure, weight loss, and sensorial grades were accomplished. It was observed that samples roasted at #22.36 led to significant differences, regarding roasting time and weight loss. Furthermore, there is a significant difference at the sensorial grades of the coffee beverage. Comparing the roast degree #40.05 (standard used for specialty coffee) with the roast degree #22.36 (most used for commodities coffee), the first one has a gas consumption of 0.34 kg per coffee kg, whilst the second presented a gas consumption of 0.41 kg per coffee kg. Thus, from gas consumption, roast degree # 40.05 is the more sustainable option, along with the remaining parameters analyzed.

Verticillium wilt is a soil borne disease caused by distinct vegetative compatibility groups (VCG) of the fungus Verticillium dahliae. Two V. dahliae isolates were recovered from symptomatic cot-ton plants in Australian cotton fields and were assigned to two distinct vegetative compatibility groups (VCGs). One corresponding to the defoliating (VCG 1A) and the other non-defoliating (VCG 2A) pathotypes of Verticillium, have been transformed with Red and Green Fluorescent protein genes, respectively. The transformants maintained their ability to infect cotton and both strains were observed to colonise the xylem vessels of cotton plants. Moreover, we observed that the cotton V. dahliae strains could also infect some sampled non-Gossypium species found in the Australian landscape. The fluorescently labelled strains of V. dahliae will allow us to gain a thorough understanding of the infection processes of this important pathogen.

Microalgae have emerged as potential feed stock for third generation biofuel and other bioactive compounds. In the present investigation we have evaluated the two native strains of Oscillatoria (O. subbrevis MTC-20702 and O. sancta MTC-20703) isolated from two different fresh water biotopes of Meerut, U.P., India and were subjected for the characterization of generation time, biomass, bio-molecules including Chlorophyll-a, carotenoids, carbohydrate, lipids, phycobilins and proteins. Both strains of Oscillatoria were grown in batch culture till the initiation of declining phase and were harvested on every 10th day of incubation till the starting of declining phase. Result of the present investigation revealed that O. subbrevis MTC-20702 can be potentially exploited for the production of high algal biomass, feed stock for biofuel, Chl-a, carotenoids, c-Allophycocyanin and maximum yield of these bioactive compounds can be achieved on 20th day. However, O. santa could be very good source for c-Phyocyanin, c-Phycoerythrin, carbohydrate and protein and these also can be achieved highest on 20th day of incubation. In addition, as these two strains were isolated from water reservoirs and they can be cultivated in large scale for the production of desired bio-molecules.

Ribonucleoproteins (RNP) condensates often contain intrinsically disordered proteins (IDPs) able to confer an exceptional multifunctionality necessary for gene expression, a process that defines cell types and enables cellular adaptation in metazoans. Centosomes, the microtubule-organizing centers of animal cells, are particularly enriched in disordered proteins but the role of RNPs surrounding the centrosome and the ciliary basal body remains largely unknown. By refining and integrating the existing protein-protein interaction network, spatial proteomics and transcriptomic data, we here report the subcellular and genomic proximity between the spliceosome, a huge nuclear RNP complex that removes introns from a transcribed pre-mRNA, and centrosome/cilia components. We present a comprehensive map of pre-RNA processing factors and other RNA-binding proteins playing a role in the regulation of splicing but localized to the centrosome and cilia. Protein-protein interactions studies reveal that a large number of spliceosome components interact with both centrosome linker and centriolar satellites elements, necessary for cellular division and ciliogenesis. RNAseq data from mouse Embryonic Stem Cells (mESC) and human tissues revealed a co-transcriptional coordination program of splicing and centrosome-related genes with relevance to tissue-specific neurosensory disorders and cancer types. Additionally, we found that centrosome and spliceosome genes form linearly and spatially colocalized genomic loci (CEP250, RBBM39, DHX35, and CTNNBL1) conserved in human and mouse genome, then explaining similarities in co-modification and subcellular distribution. Our results suggest that centrosome and cilia constitute cytoplasmic sites for the exchange of molecular machinery with nucleus, storage of RNA splicing and spliceosome condensates previously unrecognized. These complexes in response to external signals, could play an integral part in ciliogenesis and nuclear division to establish and maintain cellular identity in metazoans.

Increased sugar intake is implicated in Type-2 diabetes and fatty liver disease. Mechanisms by which glucose and fructose components promote these conditions are unclear. We hypothesize that alterations in intestinal metabolite and microbiota profiles specific to each monosaccharide are involved. Two groups of six adult C57BL/6 mice were fed for 10-weeks with a diet where either glucose or fructose was the sole carbohydrate component (G and F, respectively). A third group was fed with normal chow (N). Fecal metabolites were profiled every 2-weeks by ¹H NMR and microbial composition was analysed by real-time PCR (qPCR). Glucose tolerance was also periodically assessed. N, G and F mice had similar weight gains and glucose tolerance. Multivariate analysis of NMR profiles indicated that F mice were separated from both N and G, with decreased butyrate and glutamate and increased fructose, succinate, taurine, tyrosine and xylose. Compared to N and G, F mice showed a shift in microbe populations from gram-positive Lactobacillus spp. to gram-negative Enterobacteria species. Substitution of normal chow carbohydrate mixture by either pure glucose or fructose for 10 weeks did not alter adiposity or glucose tolerance. However, F G and N mice generated distinctive fecal metabolite signatures with incomplete fructose absorption as a dominant feature of F mice.

Transition between the unfolded and native states of the ordered globular proteins is accompanied by accumulation of several intermediates, such as pre-molten globule, wet molten globule, and dry molten globule. Structurally equivalent conformations can serve as native functional states of intrinsically disordered proteins. This overview captures the characteristics and importance of these molten globules in both structured and intrinsically disordered proteins. It also discusses examples of engineered molten globules. The formation of these intermediates under the conditions of macromolecular crowding and their interactions with nanomaterials are also reviewed.

Reducing meat consumption is better for the environment. Unfortunately, commercial plant-based meat substitutes are often more expensive than meat and thus have not seen widespread adoption. This paper analyzes commercially-available spirulina, soy, pea, and brown rice protein isolates characteristics to provide data for non-meat protein cost reductions. Thermal and rheological properties, viscosity, density, and particle size distribution are analyzed for further study on alternative protein-based food processing. Differential scanning calorimetry analysis produced dry amorphous-shaped curves and paste curves with a more distinct endothermic peak. Extracted linear temperature ranges for processing in food production for spirulina was 70-90ºC; soy protein was 87-116ºC; pea protein was 67-77ºC; and brown rice protein was 87-97ºC. Viscosity analysis determined each protein material was shear-thinning and that viscosity increased with decreased water concentration, with rice being an exception to the latter trend. The obtained viscosity range for spirulina was 15,100-78,000cP; soy protein was 3,200-80,000cP; pea protein was 1,400-32,700cP; and brown rice protein was 600-3,500cP. The results indicate that extrusion is a viable method for further processing of the protein isolates as this technique has a large temperature operating range and variable screw speed. Data provided here can be used to make single or multi-component protein substitutes.

Enveloped viruses represent a significant category of pathogens that cause serious diseases in animals. These viruses express envelope glycoproteins that are singularly important during infection of host cells by mediating fusion between the viral envelope and host cell membranes. Despite low homology at protein levels, three classes of viral fusion proteins have, as of yet, been identified based on structural similarities. Their incorporation into viral particles is dependent upon their proper sub-cellular localization after being expressed and folded properly in the endoplasmic reticulum (ER). However, viral protein expression can cause stress in the ER, and host cells respond to alleviate the ER stress in the form of the unfolded protein response (UPR); the effects of which have been observed potentiating or inhibiting viral infection. One important arm of UPR is to elevate the capacity of the ER-associated protein degradation (ERAD) pathway, which is comprised of host quality control machinery that ensures proper protein folding. In this review, we provide relevant details regarding viral envelope glycoproteins, UPR, ERAD, and their interactions in host cells.

The achievement of reproductive competence in male mammals is dependent on the testis. Goat testis’ development and spermatogenesis involve physiological events with high complexity. In the current work, 6 testes were respectively collected from immature, sexually mature and physically mature Qianbei Ma goats (1, 6 and 12 months old, respectively). RNA-Seq was carried out to reveal changes in testis mRNA expression levels in Qianbei Ma goats at various developmental stages, and gene expression profiling at different ages was established. Totally 18 libraries were established for screening genes and pathways associated with testis development and spermatogenic processes. Totally 9,724 upregulated and 4,153 downregulated genes were identified between immature (I) and sexually mature (S) testes; 7 upregulated and 3 downregulated genes were detected between sexually mature (S) and physically mature (P) testes, and approximately 4% of genes were alternately spliced between the I and S groups. Selected genes were verified by qRT-PCR, in agreement with sequencing data indicating their reliability. Those genes have critical functions in various developmental stages of goat testicular development and spermatogenesis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were carried out to evaluate differentially expressed genes (DEGs). GO analysis suggested DEGs were involved in “reproduction process”, “channel activity” and “cell periphery part” between I and S, and in “ion transport process”, “channel activity” and “transporter complex part” between S and P. KEGG analysis indicated that pathways such as “glycerolipid metabolism”, “steroid hormone biosynthesis” and “MAPK signaling pathway” may be involved in testis development and spermatogenesis. Genes including IGF1, TGFB1, TGFBR1 and EGFR may regulate the development of the testis from immature to sexually mature, which may be key candidate genes for the development of goat testis. These findings provide novel insights into goat testicular development and spermatogenesis.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a characteristic dysregulated metabolism. Abnormal clinicopathological features linked to defective metabolic and inflammatory response pathways can induce PDAC development and progression. In this study, we investigated the metabolites and lipoproteins profiles of PDAC patients of African ancestry. Nuclear Magnetic Resonance (NMR) spectroscopy was conducted on serum obtained from consenting individuals (34 PDAC, 6 Chronic Pancreatitis, and 6 healthy participants). Seventy-five signals were quantified from each NMR spectrum. The Liposcale test was used for lipoprotein characterization. Spearman’s correlation and Kapan Meier tests were conducted for correlation and survival analyses respectively. In our patient cohort, the results demonstrated that levels of metabolites involved in the glycolytic pathway increased with the tumour stage. Raised ethanol and 3-hydroxybutyrate were independently correlated with a shorter patient survival time, irrespective of tumour stage. Furthermore, increased levels of bilirubin resulted in an abnormal lipoprotein profile in PDAC patients. Additionally, we observed that the levels of a panel of metabolites (such as glucose, lactate) and lipoproteins correlated with those of inflammatory markers. Taken together, the metabolic phenotype can help distinguish PDAC severity and be used in predicting patient survival and in informing treatment intervention.

Smart grids require flexible data driven forecasting methods. We propose clustering tools for bottom-up short-term load forecasting. We focus on individual consumption data analysis which plays a major role for energy management and electricity load forecasting. The two first sections are dedicated to the industrial context and a review of individual electrical data analysis. We are interested in hierarchical time-series for bottom-up forecasting. The idea is to disaggregate the signal in such a way that the sum of disaggregated forecasts improves the direct prediction. The 3-steps strategy defines numerous super-consumers by curve clustering, builds a hierarchy of partitions and selects the best one minimizing a forecast criterion. Using a nonparametric model to handle forecasting, and wavelets to define various notions of similarity between load curves, this disaggregation strategy applied to French individual consumers leads to a gain of 16\% in forecast accuracy. We then explore the upscaling capacity of this strategy facing massive data and implement proposals using R, the free software environment for statistical computing. The proposed solutions to make the algorithm scalable combines data storage, parallel computing and double clustering step to define the super-consumers.

The evolution of human societal dynamics over the course of decades and centuries has led to an ever-increasingly complex digital modern life, one of the hallmark of which is the need for multi-tasking, inclusive of that with media. Is there an empirical mapping between this macroscopic (digital) evolution of the human societal dynamics (in terms of multi-tasking) and the microscopic evolution of the functional molecular units within cells (i.e., proteins) and their manifold cross-talks? Multi-tasking requires a certain degree of intrinsic or adapted flexibility which is as true at the bio-molecular level. Evolutionary diversification of structure-function relationship in proteins emphasizes the functional importance of intrinsically disordered entities (IDPs/IDRs) which are highly dynamic biological soft matters. Multi-functionality is favorably supported by their fluid-like shapes and other new malleable members of the protein family. The new wealth of knowledge coming from recent research on protein intrinsic disorder, fold-switching, moonlighting, hub proteins etc. has given us new insights into protein structure – functional relationship. This has led to a paradigm shift in protein science, clearly diverging from the traditional 'one structure – one function' model applicable to enzyme classes to a more complex understanding of protein functionality. This paradigm shift has caused scientists to delve deeper into the subject, exploring various evolutionary toys and tools to fit the cumulative multi-functional demands in higher organisms. This commentary covers the different evolutionary arsenals to achieve the growing multi-functionality and argues in favor of protein intrinsic disorder as probably the sharpest weapon of all.

Dysregulation of the Cyclin-dependent kinase 8 (CDK8) activity has been associated to many diseases including the colorectal and breast cancer. As usual in the CDK family, the activity of CDK8 is controlled by a regulatory protein called cyclin C (CycC). But while human CDK family members are generally activated in two steps that is, the binding of the cyclin to CDK and the phosphorylation of a residue in the CDK activation loop, CDK8 does not require the phosphorylation step to be active. Another peculiarity of CDK8 is its ability to be associated to CycC while adopted an inactive form. These specificities raise the question of the role of CycC in the complex CDK8-CycC, which appears to be more complex than for the other members of CDK family. Through MD simulations and binding free energy calculations, we investigated the effect of CycC on the structure and dynamics of CDK8 on the one hand, and the structural molecular basis of the protein-protein interaction between the two partners on the other hand. We found that CycC has a stabilizing effect on CDK8 and identified specific interaction hotspots within its interaction surface compared to other human CDK/Cyc pairs. Targeting these specific interaction hotspots could be a promising approach in terms of specificity, to effectively disrupt the interaction between CDK8. The simulation of the conformational transition from the inactive to the active form of CDK8 suggests that the residue Glu99 of the CycC may assume the role of the missing phosphorylation step in the activation mechanism of CDK8. In a more general view, these results point the importance of keeping the CycC in computational studies when studying the human CDK8 protein in both the active and the inactive form.

Hepatitis B virus (HBV) is the dominant risk factor for hepatocellular carcinoma (HCC). HBV X protein (HBx) plays crucial roles in HCC carcinogenesis. HBx interferes with several signaling pathways including Notch1 pathway in HCC. In our study, we found that Notch1 was highly expressed in HCC especially in large HCC. Notch1 and HBx co-localized in HCC and their levels were positively correlated with each other. Notch1 expression was more elevated in HepG2.2.15 than that in HepG2. HBx activated Notch1 pathway in HepG2.2.15. Repression of HBx and Notch1 pathway attenuated the growth of HepG2.2.15. Notch1, ERK and AKT pathways were inhibited after a γ-secretase inhibitor treatment. Dual-specificity phosphatase 1 (DUSP1) and phosphatase and tensin homolog (PTEN) were up-regulated after the γ-secretase inhibitor treatment and Hes1 inhibition. Luciferase reporter assays showed that Hes1 repressed the promoters of DUSP1 and PTEN and this was reverted by γ-secretase inhibitor treatment. Western blotting demonstrated that DUSP1 dephosphorylated pERK and PTEN dephosphorylated pAKT. Collectively, we reported a link among HBx, Notch1 pathway, DUSP1/PTEN, and ERK/AKT pathways, which influenced HCC cell survival and could be a therapeutic target for HCC.

Myelin ensheathes selected axonal segments within the nervous system, resulting primarily in nerve impulse acceleration, as well as mechanical and trophic support for neurons. In the central and peripheral nervous systems, various proteins that contribute to the formation and stability of myelin are present, which also harbour pathophysiological roles in myelin disease. Many myelin proteins share common attributes, including small size, high hydrophobicity, multifunctionality, longevity, and intrinsic disorder. With recent advances in protein biophysical characterization and bioinformatics, it has become evident that intrinsically disordered proteins (IDPs) are abundant in myelin, and their flexible nature enables multifunctionality. Here, we review known myelin IDPs, their conservation, molecular characteristics and functions, and their disease relevance, along with open questions and speculations. We place emphasis on classifying the molecular details of IDPs in myelin and correlate these with their various functions, including susceptibility to post-translational modifications, function in protein-protein and protein-membrane interactions, as well as their role as extended entropic chains. We discuss how myelin pathology can relate to IDPs and which molecular factors are potentially involved.

Metabolomics analysis generates vast arrays of data, necessitating comprehensive workflows involving expertise in analytics, biochemistry and bioinformatics, in order to provide coherent and high-quality data that enables discovery of robust and biologically significant metabolic findings. In this protocol article, we introduce NoTaMe, an analytical workflow for non-targeted metabolic profiling approaches utilizing liquid chromatography–mass spectrometry analysis. We provide an overview of lab protocols and statistical methods that we commonly practice for the analysis of nutritional metabolomics data. The paper is divided into three main sections: the first and second sections introducing the background and the study designs available for metabolomics research, and the third section describing in detail the steps of the main methods and protocols used to produce, preprocess and statistically analyze metabolomics data, and finally to identify and interpret the compounds that have emerged as interesting.

High-density olive groves, despite their interesting production potential, have several limitations, also due to the high fruit load and the irrigation requirements.The study aimed to evaluate the effects of fruit load and deficit irrigation on oil yield and fruit quality, and on olive chemical composition in a high-density olive grove (cv Sikitita). Our main hypothesis was that the primary metabolism, as influenced by crop load and stress, could modify the accumulation of different phenolic classes.Different fruit loads were generated through flower thinning (66%, 50%, 33%, 0%) and two deficit irrigation treatments (-60%, -75%) were compared to the well-watered control (920 m3/ha).Thinning treatments had a limited effect on oil yield, on the other hand, deficit irrigation caused considerably less oil accumulation in the fruit on all sampling dates.Thinning 66% and deficit irrigation 75% were considered with the control for untargeted metabolomic analysis, considering three sampling dates. 233 different phenolic compounds were annotated. Multivariate HCA results indicated the impact of harvest time on the phenolic profile of olive fruits, yielding two separate clusters grouping t1 and t2 together and apart from t3. Regarding agronomic techniques, they played a differential role in the phenolic profile (supervised OPLS – DA). Fruit load mostly affected flavonoid glycosides. In contrast, the phenolic response to deficit irrigation is more heterogeneous, with phenolic acids (35%), flavonoids (25%), LMW, and other phenols (25%).

Alternative splicing can produce transcripts that affect cancer development and shows potential for cancer diagnosis and treatment. However, intron retention (IR), a type of alternative splicing, has been less systematically studied in cancer biology research. Here, we generated a pan-cancer IR landscape for more than 10,000 samples across 33 cancer types from The Cancer Genome Atlas (TCGA). We characterized differentially retained introns between tumor and normal samples and identified retained introns associated with survival. We discovered 988 differentially retained introns in 14 cancers, some of which demonstrated diagnostic potential in multiple cancer types. We also inferred a large number of prognosis-related introns in 33 cancer types, and the associated genes included well-known cancer hallmarks such as angiogenesis, metastasis, and DNA mutations. Notably, we discovered a novel intron retention event inside 5′UTR of STN1 that is associated with the survival of lung cancer patients. The retained intron reduces translation efficiency by producing upstream open reading frames (uORFs) and thereby inhibits colony formation and cell migration of lung cancer cells. Besides, the IR-based prognostic model achieved good stratification on certain cancers, as illustrated in acute myeloid leukemia. Taken together, we performed a comprehensive IR survey at a pan-cancer level, and the results implied that IR has the potential to be diagnostic and prognostic cancer biomarkers, as well as new drug targets.

Proposed fundamental laws of biology and a model of health and disease underscore the importance of the lymphatic system. The lymphatics are responsible for two of the laws of biology and the fulcrum of health and disease balancing proliferation with regeneration through the immune system. It is responsible for protection from the environment and repair of senile and damaged tissue. Life is constantly bombarded by forces that increase entropy. Lymphatics provide negative entropy to maintain health. Lymphatics help maintain cellular homeostasis removing products of metabolism. Using these principles, the role of lymphatics is investigated in salt sensitivity hypertension, cardiorenal system, the new pillar of heart failure and kidney disease - Sodium-Glucose Transport Protein 2 (SGLT2) Inhibitors, and brain diseases. The realization of organ lymphatics in maintenance of health and disease opens the avenue to new therapeutics. This is the unrealized potential of lymphatic study.

The study of rare diseases is important not only for the individuals affected but also for the advancement of medical knowledge and a deeper understanding of human biology and genetics. The wide repertoire of structural information now available from reliable and accurate prediction methods provides the opportunity to investigate the molecular origins of most of the rare diseases reviewed in the Orpha.net database. Thus, it has been possible to analyze the topology of the missense mutations found in the 2,535 proteins involved in Mendelian rare diseases (MRD), which form the database for our structural bioinformatics study. The amino acid substitutions responsible for MRD show different mutation site distributions at different three-dimensional protein depths. We then predicted the depth-dependent effects of mutations for the 20,248 pathogenic variants that are present in our database. The results of this structural bioinformatics investigation are relevant, as they provide additional clues to mitigate the damage caused by MRD.

Abstract: Background: Hemopexin (Hx) is a plasma glycoprotein that scavenges heme (Fe(III) protoporphyrin IX), Hx have important implication in hemolytic disorders and hemorrhagic condition because the release of hemoglobin increase labile heme, which is potentially toxic producing oxidative stress. Hx has been considered for therapeutic use and diagnostics. In this work, we analyzed and mapped interaction sequences of Hx with hemin and hemoglobin (2) Methods: Spot-synthesis technique was used to map human hemopexin (P02790) binding to hemin and human hemoglobin, a library of 15 amino acid peptides with a 10-amino acid overlap was designed to represent the entire coding region (aa 1-462) of hemopexin and synthesized onto cellulose membranes. In silico approach was performed to analyze amino acid frequency in identified interaction regions, and molecular docking was applied for protein-protein interaction (3) Results: Seven linear peptide sequences in Hx were identified to bind hemin (H1-H7), and five were described for Hb (Hb1-Hb5) interaction, with just two sequences shared between hemin and Hb. Amino acid composition of identified sequences demonstrated that Histidine residues are relevant for heme binding, H105, H293, H373, H400, H429, and H462 was distributed in H1-H7 peptide sequences, but other residues may also play an important role. Molecular docking analysis demonstrated Hx association with the β-chain of Hb, with several hot spot amino acids that coordinated interaction. (4) Conclusions: This study highlights new insights on Hx-hemin binding motifs and protein-protein interactions with Hb. Binding sequences and identified specific peptides can be used for therapeutic purposes and diagnostics, as hemopexin is under investigation to treat different diseases, and there is an urgent need for diagnostics of labile heme for monitoring hemolysis.

Human NAD(P)H:quinone oxidoreductase 1 (NQO1) is a multi-functional protein whose alteration is associated with cancer, Parkinson´s and Alzheimer´s diseases. NQO1 displays a remarkable functional chemistry, capable of binding different functional ligands that modulate its activity, stability and interaction with proteins and nucleic acids. Our understanding on this functional chemistry is limited by the difficulty of obtaining structural and dynamic information on many of these states. Herein, we have used hydrogen/deuterium exchange monitored by mass-spectrometry (HDXMS) to investigate the structural dynamics of NQO1 in three ligation states: without ligands (NQO1apo), with FAD (NQO1holo) and with FAD and the inhibitor dicoumarol (NQO1dic). We show that NQO1apo has a minimally stable folded core holding the protein dimer and with FAD and dicoumarol ligand binding sites populating binding non-competent conformations. Binding of FAD significantly decreases protein dynamics and stabilizes the FAD and dicoumarol binding sites as well as the monomer:monomer interface. Dicoumarol binding further stabilizes all three functional sites, a result not previously anticipated by available crystallographic models. Our work provides an experimental perspective into the communication of stability effects through the NQO1 dimer, valuable to understand at the molecular level the effects of disease-associated variants, post-translation modifications and ligand binding cooperativity in NQO1.

Sarcomas are a heterogenous group of tumours that commonly carry poor prognosis with limited therapeutic options. Adolescents and young adults (AYA) with sarcoma are a unique and under-studied patient population that have only achieved modest survival gains compared to other groups. We present our institutional experience of AYA with sarcoma who underwent comprehensive molecular profiling (CMP) using either large-panel targeted DNA sequencing or whole genome and transcriptome sequencing and evaluated the feasibility and clinical impact of this approach. Genomic variants detected were determined to be clinically relevant and actionable following the Molecular Tumour Board evaluation. Clinicians provided feedback regarding the utility of testing three months after reporting. Twenty-five patients who were recruited for CMP are included in this analysis. The median time from consent to final molecular report was 45 days (interquartile range 37-57). Potentially actionable variants were detected for 14 patients (56%) and new treatment recommendations were identified for 12 patients (48%). Pathogenic germline variants were identified in three patients (12%), and one patient had a change of diagnosis. Implementation for CMP for AYA with sarcoma is clinically valuable, feasible and should be increasingly integrated into routine clinical practice as technologies and turnaround times continue to improve.

There is a pressing need for more precise biomarkers of chronic kidney disease (CKD). Plasma samples from 820 subjects [231 with CKD, 325 with end-stage kidney disease (ESKD) and 264 controls] were analyzed by LC-MS/MS to determine a metabolic profile of 28 aminoacids (AA) and biogenic amines to test their value as markers of CKD risk and progression. The Kynurenine/Tryptophan ratio showed the strongest correlation with estimated glomerular filtration rate values (coefficient=-0.731, P&lt;0.0001). Models created with Orthogonal Partial Least Squares-Discriminant Analysis (OPLS-DA) containing the metabolic signature showed high goodness of fit and predictability for controls/CKD (R2X:0.73;R2Y:0.92;Q2:0.92) and lower for CDK/ESKD (R2X:0.56;R2Y:0.59;Q2:0.55). Based on generated VIP scores, the most relevant markers for segregating samples into control/CKD or CKD/ESKD groups were citrulline (1.67) and tryptophan (1.59), respectively. ROC analysis showed that the addition of the metabolic profile to a model including CKD classic risk factors improved AUC from 86.7% (83.6-89.9) to 100% (100-100) for CKD risk (P&lt;0.0001), and from 63.0% (58.2-67.8) to 96.5% (95.3-97.8) for the risk of progression from CKD to ESKD (P&lt;0.0001). Plasma concentrations of AA and related amines may be useful as diagnostic biomarkers of kidney disease, both for CKD risk and for progression of CKD patients to ESKD.

Remdesivir (RDV) has garnered much hope for its moderate anti-COVID-19 effects, but its limited amelioration of survival in hospitalized patient causes a huge controversy over the applicability of RDV to COVID-19 treatment. Developing strategies to improve its antivirus efficacy is urgently required. As anticipated, RDV exhibits similar behavior with other nucleotide analogs to disrupt the metabolism of natural endogenous ribonucleotides (RNs) and deoxyribonucleotides (dRNs). Alterations in endogenous RNs and dRNs play a critical role in virus replication as well as other key cellular functions. Thus elucidation of the disturbances of RDV on RNs and dRNs could help to understand its exact mechanism of action. Here, the metabolic profiling determined by liquid chromatography–mass spectrometry method showed a general increase in the abundance of nucleotides and a more than 2-fold increase for specific nucleotides. However, the variation of pyrimidine ribonucleotides was relative slight or even contrary, resulting in obvious imbalance between purine and pyrimidine ribonucleotides, which implied the obstacle of RDV to pyrimidine synthesis and could further block the transcription and replication of viral RNA. Additionally, the extreme disequilibrium between cytidine triphosphate (CTP) and cytidine monophosphate might result from the inhibition of CTP synthase and provide a metabolic target for the treatment of COVID-19 infection. Since nucleotides metabolism pathways are vulnerable to nucleotide analogues and are liable to be the regulation targets, it is promising to enhance the efficacy of RDV through co-administration with CTP synthase inhibitors or de novo pyrimidine synthesis inhibitors to exacerbate the imbalance of nucleotide pools.

Here we describe ARSA-16S, a tool and accompanying reference database for the analysis of bacterial 16S amplicons. Among other features, ARSA-16S is based on a new model, approach, and algorithm for sequence-level assignment of reads understood as probability distributions, assigns reads individually, and is designed with non-overlapping amplicons covering two non-contiguous regions. A new set of primers for the amplification and sequencing of the V4 and V6 regions is also provided.

Tamarix nilotica (Ehrenb.) Bunge (Tamaricaceae), an indigenous plant to the Middle East region, is well-known as a medicinal plant for treating many human ailments. The current study aimed at exploring the polyphenols profile of T.nilotica alcohol soluble fraction of aqueous extract, assessing its in-vivo antifibrotic activity and the possible underlying mechanism, to unravel the impact of quantitative difference of sulphated polyphenols content on the antifibrotic activity of T.nilotca grown in two different habitats. Polyphenols profiling of T. nilotica extracts was performed using HPLC-HRESI-QTOF-MS-MS. The major polyphenol components included sulphated flavonoids, phenolic acids and free aglycones. The antifibrotic activity was evaluated through carbon tetrachloride-induced liver fibrosis in rats. Biochemical evaluations revealed that both fractions ameliorated the increased levels of hepatic aminotransferases, lipid peroxidation, hydroxyproline, α-smooth muscle actin (α-SMA), tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2) and nuclear factor kappa B (NF-κB). Moreover, both fractions reduced catalase activity (CAT) and enhanced hepatic glutathione (GSH) content. Histopathological imaging undoubtedly confirmed such results. In conclusion, T. nilotica polyphenols rich fraction exhibited potential antifibrotic activity in rats. Significant alterations in GSH levels were recorded based on sulphated polyphenol metabolites content.

The PII protein is an evolutionary highly conserved regulatory protein from bacteria to higher plants. In bacteria it modulates the activity of several enzymes, transporters and regulatory factors by interacting with them and thereby regulating important metabolic hubs like carbon/nitrogen homeostasis. More than two decades ago the PII protein was characterized for the first time in plants, but its physiological role is still not sufficiently resolved. To gain more insights into the function of this protein, we investigated the interaction behaviour of AtPII with candidate proteins by BiFC and FRET/FLIM in planta and with GFP/RFP traps in vitro. In the course of these studies we found that AtPII interacts in chloroplasts with itself as well as with known interactors like NAGK in dot-like aggregates, which we named PII foci. In these novel protein aggregates AtPII interacts also with yet unknown partners, which are known to be involved in plastidic protein degradation. Further studies revealed that the C-terminal part of AtPII is crucial for the formation of PII foci. Altogether, the presented results indicate a novel mode of interaction for PII proteins with other proteins in plants, which may be a new starting point for the elucidation of physiological functions of PII proteins in plants.

The cucumber mosaic virus (CMV) 2b protein is a suppressor of plant defenses and a pathogenicity determinant. Amongst the 2b protein’s host targets is the RNA silencing factor Argonaute 1 (AGO1), which it binds to and inhibits. In Arabidopsis thaliana, if 2b-induced inhibition of AGO1 is too efficient it induces reinforcement of antiviral silencing by AGO2, and triggers increased resistance against aphids, CMV’s insect vectors. These effects would be deleterious to CMV replication and transmission, respectively, but are moderated by the CMV 1a protein by sequestering sufficient 2b protein molecules into P-bodies to prevent excessive inhibition of AGO1. Mutant 2b protein variants were generated and red and green fluorescent protein fusions used to investigate subcellular colocalization with AGO1 and the 1a protein, and the effects of mutations on complex formation with the 1a protein and AGO1 were investigated using bimolecular fluorescence complementation and co-immunoprecipitation assays. Although we found that residues 56-60 influenced the 2b protein’s interactions with the 1a protein and AGO1, it appears unlikely that any single residue or sequence domain is solely responsible. In silico predictions of intrinsic disorder within the 2b protein secondary structure were supported by circular dichroism (CD) but not by nuclear magnetic resonance (NMR) spectroscopy. Intrinsic disorder provides a plausible model to explain the 2b protein’s ability to interact with AGO1, the 1a protein and other factors. However, the reasons for the conflicting conclusions provided by CD and NMR must first be resolved.

French Guiana mosquito fauna diversity encompasses 242 species, of which nearly half of them belong to Culex (Diptera: Culicidae) genus. Whereas several species from Culex genus are important vectors of arbovirus, scarce studies focus on Culex genus, notably due to the inaccurate morphological identification of field-caught females gender. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) has been reported as a promising method for the identification of mosquitoes. Culex females from French Guiana field were dissected based on morphological classification. Abdomens were used for molecular identification using COI (cytochrome oxydase 1) gene. Legs and thorax of 169 specimens belonging to 13 Culex species,( i.e. Cx. declarator, Cx. nigripalpus, Cx. quinquefasciatus, Cx. usquatus, Cx. adamesi, Cx. dunni, Cx. eastor, Cx. idottus, Cx. pedroi, Cx. phlogistus, Cx. portesi, Cx. rabanicolus and Cx. spissipes) were then submitted to MALDI-TOF MS analysis. A high intra-species reproducibility and inter-species specificity of MS spectra for each mosquito body part tested were noticed. A corroboration of the specimen identification was revealed between MALDI-TOF MS, morphological and molecular results. MALDI-TOF MS protein profiling proves to be a suitable tool for identification of neotropical Culex species and will permit to enhance knowledge on this highly diverse Culex mosquitoes genus.

The outbreak of the 2019 Novel Coronavirus (2019-nCoV) has rapidly spread from Wuhan, China to multiple countries, causing staggering number of infections and deaths. A systematic profiling of the immune vulnerability landscape of 2019-nCoV is lacking, which can bring critical insights into the immune clearance mechanism, peptide vaccine development, and antiviral antibody development. In this study, we predicted the potential of all the 2019-nCoV viral proteins to induce class I and II MHC presentation and form linear antibody epitopes. We showed that the enrichment for T cell and B cell epitopes is not uniform on the viral genome, with several focused regions that generate abundant epitopes and may be more targetable. We showed that genetic variations in 2019-nCoV, though fewer for the moment, already follow the pattern of mutations in related coronaviruses, and could alter the immune vulnerability landscape of this virus, which should be considered in the development of therapies. We create an online database to broadly share our research outcome. Overall, we present an immunological resource for 2019-nCoV that could significantly promote both therapeutic development and mechanistic research.

Leadership performance by village leaders is essential to promote sustainable life among rural communities, especially fisheries community who living along coastal villages. Otherwise, previous studies found that performance issues among village’s leaders remain as serious problems, and need to find the best solution. This study was conducted to profile the job performance among village leaders based on demographic factors such as educational level, age and experiences as village leader. The data of this cross-sectional survey were collected by questionnaires on 300 respondents consist of members of village organization through stratified sampling’s technique, while the data was analysed by SPSS using items of mean, standard deviation, independent-sample t-test and anova. The finding shown that there were differences in job performance among village leaders on educational level, age and experiences. Interestingly, the finding told the best on job performance among village leaders are (i) the age between 41 to 50 years old; (iii) the experience between 11 to 20 years; and (iii) the higher educational level the higher job performance among them. This result can be using by government or any responsible parties to improve job performance among village leaders, especially for recruitment selection and for in-service training.