Background: Staphylococcus aureus (S. aureus) is an opportunistic pathogen and a predominant cause of life-threatening nosocomial infections. Drug resistance in S. aureus is attributed to production of biofilm, which is controlled largely by bacterial quorum sensing (QS) systems. Methodology: In vitro analysis of biofilm inhibition assay was performed using crystal violet staining assay, swarming motility, light microscopy and growth curve analyses. Identification of the major constituents of I. verum fruit extract was performed by GC-MS. Ligand-protein interaction was analyzed by molecular docking investigations. Results: The methanol extract of I. verum inhibited the growth of MRSA at the concentration of 4.8 mg/ml. At the sub-inhibitory concentration (2.4mg/ml), the extract showed significant reduction in biofilmogenesis. Light microscopy analysis confirmed the antibiofilm activity as well as the efficacy in disturbing biofilm architecture. A reduced swarming motility was observed at the lowest concentration of 2.4mg/ml. GC-MS analysis revealed anethol (AL) as the major constituent. The molecular docking analysis attributes the antibiofilm activity to an active ligand AL, which strongly interacted with the active site residues of AgrA and SarA proteins of S. aureus. Conclusion: We report the activities of I. verum to be immensely interfering with QS system and biofilm formation in MRSA.

Controversy exists on whether animal and plant proteins influence obesity differently. The purpose of this study was to evaluate the association between total, animal, and plant protein intake with the obesity index and renal function in Korean adults. Study participants included Korean adults aged 60 years or older from the Korean National Health and Nutrition Examination Survey in 2013-2014. Height, weight, and waist circumference (WC) were measured and the body mass index (BMI) was calculated. One-day 24-hour recall data were used to estimate the daily total, animal, and plant protein intake. Glomerular filtration rate (GFR) was calculated by using the Modification of Diet in Renal Disease (MDRD) equation. General linear modellings were used to assess the relationships between protein intake, BMI and WC. The mean age was 69.2 ± 0.2 years, 44.2% were male. The total daily protein intake was 1.1 ± 0.02 g/kg/d and 0.9 ± 0.02 g/kg/d for males and females, respectively. Only one third of protein intake was from animal sources. In males, BMI (p < 0.001, p = 0.016, p < 0.001 respectively) and WC (p < 0.001, p = 0.010, p < 0.001, respectively) decreased as daily intake of plant protein (g/kg/d), animal protein (g/kg/d) and total protein (g/kg/d) increased. Similar associations were shown in Korean female. GFR was not associated with protein intake regardless of protein source in both sexes. In Korean adults aged 60 years or older, the protein intake was associated with a favorable obesity index without decrease in renal function. The effect was similar in both male and females, with both animal and plant proteins.

Rationale: The 14-3-3 protein family is known to interact with many proteins in non-cardiac cell types to regulate multiple signaling pathways, particularly those relating to energy and protein homeostasis; and the 14-3-3 network is a therapeutic target of critical metabolic and proteostatic signaling in cancer and neurological diseases. Although the heart is critically sensitive to nutrient and energy alterations, and multiple signaling pathways coordinate to maintain the cardiac cell homeostasis, neither the structure of cardiac 14-3-3 protein interactome, nor potential functional roles of 14-3-3 protein-protein interactions (PPIs) in heart has been explored. Objective: To establish the comprehensive landscape and characterize the functional role of cardiac 14-3-3 PPIs. Methods and Results: We evaluated both RNA expression and protein abundance of 14-3-3 isoforms in mouse heart, followed by co-immunoprecipitation of 14-3-3 proteins and mass spectrometry in left ventricle. We identified 52 proteins comprising the cardiac 14-3-3 interactome. Multiple bioinformatic analyses indicated that more than half of the proteins bound to 14-3-3 are related to mitochondria; and the deduced functions of the mitochondrial 14-3-3 network are to regulate cardiac ATP production via interactions with mitochondrial inner membrane proteins, especially those in mitochondrial complex I. Binding to ribosomal proteins, 14-3-3 proteins likely coordinate protein synthesis and protein quality control. Localizations of 14-3-3 proteins to mitochondria and ribosome were validated via immunofluorescence assays. The deduced function of cardiac 14-3-3 PPIs is to regulate cardiac metabolic homeostasis and proteostasis. Conclusions: Thus, the cardiac 14-3-3 interactome may be a potential therapeutic target in cardiovascular metabolic and proteostatic disease states, as it already is in cancer therapy.

Protein Contact Network (PCN) is an emerging paradigm for modelling protein structure. A common approach to interpreting such data is through network-based analyses. It has been shown that clustering analysis may discover allostery in PCN. Nevertheless Network Embedding has shown good performances in discovering hidden communities and structures in network. In this work, we compare some approaches for graph embedding with respect to some classical clustering approaches for annotating protein structures.

Interactome depicts the arrangement of all atomic communications in cells, particularly with regards to protein-protein collaborations. We look at different strategies for foreseeing protein-protein collaborations utilizing grouping and structure data. A definitive objective of those methodologies is to introduce the total approach for the programmed choice of communication accomplices utilizing their amino corrosive arrangements as well as three dimensional structures, whenever known. The proposed approval of the hypothetical strategies utilizing test information would be a superior appraisal of their exactness.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a pleiotropic myelopoietic growth factor and proinflammatory cytokine, clinically used for multiple indications and serving as a promising target for treatment of many disorders, including cancer, multiple sclerosis, rheumatoid arthritis, psoriasis, asthma, COVID-19. We have previously shown that dimeric Ca2+-bound forms of S100A6 and S100P proteins, members of the multifunctional S100 protein family, are specific to GM-CSF. To probe selectivity of these interactions, the affinity of recombinant human GM-CSF to dimeric Ca2+-loaded forms of 18 recombinant human S100 proteins was studied by surface plasmon resonance spectroscopy. Of them, only S100A4 protein specifically binds to GM-CSF with equilibrium dissociation constant, Kd, values of 0.3-2 μM, as confirmed by intrinsic fluorescence and chemical crosslinking data. Calcium removal prevents S100A4 binding to GM-CSF, whereas monomerization of S100A4/A6/P proteins disrupts S100A4/A6 interaction with GM-CSF and induces a slight decrease in S100P affinity for GM-CSF. Structural modelling indicates the presence in the GM-CSF molecule of a conserved S100A4/A6/P-binding site, consisting of the residues from its termini, helices I and III, some of which are involved in the interaction with GM-CSF receptors. The predicted involvement of the ‘hinge’ region and F89 residue of S100P in GM-CSF recognition was confirmed by mutagenesis. Examination of S100A4/A6/P ability to affect GM-CSF signaling showed that S100A4/A6 inhibit GM-CSF/S100-induced suppression of viability of monocytic THP-1 cells. The ability of the S100 proteins to modulate GM-CSF activity is relevant to progression of various neoplasms and other diseases, according to bioinformatics analysis. The direct regulation of GM-CSF signaling by extracellular forms of the S100 proteins should be taken into account in the clinical use of GM-CSF and development of the therapeutic interventions targeting GM-CSF or its receptors.

The polymerase chain reaction (PCR) is a widely used technique in the biosciences and has become increasingly popular in recent years. One of the key elements of this technique is the use of a DNA polymerase that is heat-stable and retains fidelity during the process. To this end, archaeal Fam-ily-B DNA polymerases are preferred due to their high thermostability and fidelity. In particular, the DNA polymerase from Thermus aquaticus (Taq DNApol) is widely utilized in PCR procedures. In this work, a novel in-silico structure-based methodology was employed to examine the most heat-tolerant DNA polymerase available. In spite of this, Thermococcus kodakarensis and Geobacillus stearothermophilus DNApol are more stable and heat-tolerant DNApols due to their high number of intra-protein interactions. Variations in the content of polar amino acids also played a significant role in the increase in heat stability. A further factor contributing to the stability of proteins is the stabilization of helix in secondary structure through the use of charged amino acids. DNApol from these organisms has been shown to be suitable for use in PCR, as well as in other biological processes able to withstand high temperatures. In this study, it has been demonstrated that im-provements in PCR performance can be easily obtained by blending elements from closely related archaeal polymerases, a strategy that may, in the future, be extended to other archaeal polymer-ases. This approach allowed for a comprehensive analysis of the enzyme's thermal stability and fidelity, leading to an improved understanding of the polymerase's properties and potential ap-plications

Production of silkworm silk is the most economically important traits in the silk industry. Silk protein synthesis is regulated by juvenile hormone (JH) and 20-Hydroxyecdysone (20E). Therefore, it is important to understand the genetic regulation of silk production is thus a priority. JH binding protein (JHBP) transports JH from the hemolymph to target organs and cells and protects JH. In a previous study, we identified 41 genes containing a JHBP domain in the Bombyx mori genome. Only one JHBP gene, that is, BmJHBPd2, is highly expressed in the posterior silk gland (PSG) and its function remains unknown. In the present study, we investigated the expression levels of BmJHBPd2 and the major silk protein genes in the high silk-producing practical strain 872 (S872) and the low silk-producing local strain Dazao. Our results have shown that BmJHBPd2 was more highly expressed in S872, than in the Dazao strain, which is consistent with the expression pattern of fibroin genes. A subcellular localization assay indicated that BmJHBPd2 is located in the cytoplasm. In vitro hormone induction experiments showed that BmJHBPd2 was upregulated by treatment with juvenile hormone analogue (JHA). BmKr-h1 upregulation was significantly inhibited by overexpression of BmJHBPd2 at the cell level when induced by JHA. However, overexpression of BmJHBPd2 in the posterior silk gland by transgenic methods led to the inhibition of the expression of the silk fibroin gene, resulting in a reduction in silk yield. Further investigation has shown that in the BmJHBPd2OE individual, the key transcription factor Krüppel homolog 1 (Kr-h1) of the JH signaling pathway was inhibited, and 20E signaling pathway genes, such as broad complex (Brc), E74A, and ultraspiracle protein(USP), were upregulated. Our results have indicated that BmJHBPd2 plays an important role in the JH signaling pathway and was important for silk protein synthesis. Furthermore, our findings have helped to elucidate the mechanisms by which JH regulates silk protein synthesis.

This study used established biomarkers of death due to ischemic stroke (IS) and performed network, enrichment, and annotation analysis. Protein-protein interaction (PPI) network analysis revealed that the backbone of the highly connective network of IS death consisted of IL6, ALB, TNF, SERPINE1, VWF, VCAM1, TGFB1, and SELE. Cluster analysis revealed immune and hemostasis subnetworks, which were strongly interconnected through the major switches ALB and VWF. Enrichment analysis revealed that the PPI immune subnetwork of death due to IS was highly associated with TLR2/4, TNF, JAK-STAT, NOD, IL10, IL13, IL4, and TGF-β1/SMAD pathways. The top biological and molecular functions and pathways enriched in the hemostasis network of death due IS were platelet degranulation and activation, the intrinsic pathway of fibrin clot formation, the urokinase-type plasminogen activator pathway, post-translational protein phosphorylation, integrin cell surface interactions, and the proteoglycan-integrin-extra cellular matrix complex (ECM). Regulation Explorer analysis of transcriptional factors shows: a) that NFKB1, RELA and SP1 were the major regulating actors of the PPI network; and b) hsa-mir-26-5p and hsa-16-5p were the major regulating microRNA actors. In conclusion, prevention of death due to IS should consider that current IS treatments may be improved by targeting VWF, VEGFA, proteoglycan-integrin-ECM complex, NFKB/RELA and SP1.

Hepatitis C Virus (HCV) is the main causative factor for liver cirrhosis and the development of liver cancer, with a confirmed ~ 180 million infections worldwide. E2 is an HCV structural protein responsible for virus entry to the host cell. Heat Shock Protein A5 (HSPA5), also termed BiP and GRP78, is the master regulator of the unfolded protein response mechanism, where it mainly localizes in the lumen of the Endoplasmic Reticulum (ER) in normal conditions. Under the stress of HCV infection or carcinogenesis, HSPA5 is upregulated. Consequently, HSPA5 escapes the ER retention localization and translocates to the cytoplasm and plasma membrane. Pep42, a cyclic peptide that was reported to target explicitly cell-surface HSPA5 in vivo. Owing to the high sequence and structural conservation between the C554-C566 region of HCV E2 and the Pep42, then we propose that the HCV E2 C554-C566 region could be the recognition site. The motivation of this work is to predict the possible binding mode between HCV E2 and HSPA5 by implementing molecular docking to test such proposed binding. Docking results reveal the high potent binding of the HCV E2 C554-C566 region to HSPA5 substrate-binding domain β (SBDβ). Moreover, the full-length HCV E2 also exhibits high binding potency to HSPA5 SBDβ. Defining the binding mode between HCV E2 and HSPA5 is of significance, so one can interfere with such binding and reducing the viral infection.

Recent studies supported a clinical association between Parkinson’s Disease (PD) and periodontitis. Hence, investigating possible protein interactions between these two conditions is of interest. In this study, we conducted a protein-protein network interaction analysis with recognized genes encoding proteins for PD and periodontitis. Genes of interest were collected via GWAS database. Then, we conducted a protein interaction analysis using STRING database, with a highest confidence cut-off of 0.9. Our protein network casted a comprehensive analysis of potential protein-protein interactions between PD and periodontitis. This analysis may underpin valuable information for new candidate molecular mechanisms between PD and periodontitis and may serve new potential targets for research purposes. These results should be carefully interpreted giving the limitations of this approach.

In this study we used a recently developed ex vivo-in vitro model to assess the effect of feeding older adults a casein protein hydrolysate (CPH) compared with non-bioactive non-essential amino acid (NEAA) supplement on Muscle Protein Synthesis (MPS) and Breakdown (MPB). Serum from six healthy older males following overnight fast and 60 min postprandial ingestion of CPH or NEAA (0.33 g.kg^-1 body mass) was used to condition C2C12 myotube media. CPH-fed serum significantly increased MPS compared to fasted serum. In addition, CPH-fed serum induced myotube growth and markedly suppressed atrogin-1, but not MuRF1, expression. Comparatively, no change in MPS, myotube growth and gene expression was observed following NEAA-fed serum treatment. CPH-fed serum from older adults stimulated de novo MPS, suppressed markers of protein breakdown and resulted in myotube growth, indicating a potential role for CPH as a dietary protein source to prevent age-related sarcopenia.

A model to predict the relative levels of respiratory and fecal-oral transmission potentials of coronaviruses (CoVs) by measuring the percentage of protein intrinsic disorder (PID) of the M (Membrane) and N (nucleoprotein) proteins in their outer and inner shells, respectively, was built before the MERS-CoV outbreak. Application of this model to the 2003 SARS-CoV indicated that this virus with M_PID = 8.6% and N_PID = 50.2% falls into group B, which consists of CoVs with intermediate levels of both fecal-oral and respiratory transmission potentials. Further validation of the model came with MERS-CoV (M_PID = 9%, N_PID = 44%) and SARS-CoV-2 (M_PID = 5.5%, N_PID = 48%) falling into the groups C and B, respectively. Group C contains CoVs with higher fecal-oral but lower respiratory transmission potentials. Unlike SARS-CoV, SARS-CoV-2 with M_PID = 5.5% has one of the hardest outer shells among CoVs. This shell hardness is believed to be responsible for high viral loads in the mucus and saliva making it more contagious than SARS-CoV. The hard shell is able to resist the anti-microbial enzymes in body fluids. Further searches have found that high rigidity of outer shell is characteristic for the CoVs of burrowing animals, such as rabbits (M_PID = 5.6%) and pangolins (M_PID = 5-6%), which are in contact with the buried feces. A closer inspection of pangolin-CoVs from 2017-19 reveals that these animals provided a unique window of opportunity for the entry of an attenuated SARS-CoV-2 precursor into the human population in 2017 or earlier, with the subsequent slow and silent spread as a mild cold that followed by its mutations into the current more virulent form. Evidence of this lies in the similarity of shell disorder and genetic proximity of the pangolin-CoVs to SARS-CoV-2 (~90%). A 2017 pangolin-CoV strain shows evidence of higher levels of attenuation and higher fecal-oral transmission associated with lower human infectivity via having lower N_PID (44.8%). Our shell disorder analysis also revealed that lower inner shell disorder is associated with the lesser virulence in a variety of viruses.

A model that predicts levels of coronavirus (CoV) respiratory/fecal-oral transmission potentials based on the outer shell hardness has been built using neural network (artificial intelligence, AI) analysis of the percentage of disorder (PID) in the nucleocapsid, N, and membrane, M, proteins of the inner and outer viral shells, respectively. Based mainly on the PID of N, SARS-CoV-2 is categorized as having intermediate levels of both respiratory and fecal oral transmission potential. Related to this, other studies have found strong positive correlations between virulence and inner shell disorder among numerous viruses, including Nipah, Ebola, and Dengue viruses. There is some evidence that this is also true for SARS-CoV-2 and SARS-CoV, which have N PIDs of 48% and 50%, and are characterized by case-fatality rates of 7.1% and 10.9%, respectively. The link between levels of respiratory transmission and virulence lies in viral load of body fluids and organ respectively. A virus can be infectious via respiratory modes only if the viral loads in saliva and mucus exceed certain minima. Likewise, a person may die, if the viral load is too high especially in viral organs. Inner shell proteins of viruses play important roles in the replication of viruses, and structural disorder enhances these roles by providing greater efficiency in protein-protein/DNA/RNA/lipid binding. This paper outlines a novel strategy in attenuating viruses involving comparison of disorder patterns of inner shells of related viruses to identify residues and regions that could be ideal for mutation. The M protein of SARS-CoV-2 has one of the lowest M PID values (6%) in its family, and therefore this virus has one of the hardest outer shells, which makes it resistant to antimicrobial enzymes in body fluid. While this is likely responsible for its contagiousness, the risks of creating an attenuated virus with a more disordered M are discussed.

Quercetin is a flavonoid with a low molecular weight that belongs to the human diet's phenolic phytochemicals and non-energy constituents. Quercetin has a potent antioxidant capacity, being able to capture Reactive Oxygen Species (ROS), reactive nitro-gen species (RNS), and Reactive Chlorine Species (ROC), which act as reducing agents by chelating transition metal ions. Its structure has five functional hydroxyl groups, which work as electron donors and are responsible for capturing free radicals. In addition to its antioxidant capacity, it was described different pharmacological properties of Quercetin, such as carcinostatic properties, antiviral, antihypertensive, anti-inflammatory, protection of Low-Density Lipoprotein (LDL) oxidation, and inhibi-tion of angiogenesis are developed in this review.

Pancakes are fast food snacks that are generally made with the basic ingredients of wheat flour, which is an imported commodity and detrimental for people who are allergic to gluten. To reduce the use of wheat, alternative raw materials derived from local commodities are used, such as modified cassava flour (mocaf), arrowroot flour, and suweg flour. The experiment was carried out by mixing mocaf flour, arrowroot flour, and suweg flour to produce composite flour with a ratio of 70:15:15 (CF1), 70:20:10 (CF2), and 70:20:5 (CF3). The result showed that the ratio of mocaf flour, arrowroot flour, and suweg flour had a significant effect on pasting temperature, peak viscosity, hold viscosity, breakdown viscosity, setback, L*, a*, hue, whiteness, ∆E, as well as swelling volume and solubility on the characteristics of the composite flour It also had a significant effect on the texture characteristics of hardness, adhesiveness, chewiness, color characteristics L*, a*, whiteness, ∆E, and preference for the flavor of gluten-free pancake products. It is known that the best formulation for the resulting pancake product is P1, with the addition of a 70% ratio of mocaf flour, 15% ratio of arrowroot tuber flour, and 15% ratio of suweg flour.

Background: Free-living amoebas (FLA), also amebas, are eukaryotic and mitochondrial microorganisms that are capable of growing in any environment, aquatic or terrestrial. These free-living amoebas are mostly non-pathogenic to humans. However, there exist some highly pathogenic species, such as Acanthamoeba — mainly T-4 genotype —, Naegleria fowleri (known as brain-eating amoeba), and Balamuthia mandrillaris. They can be called "brain-eating amoebas” because of their ability to cause substantial destruction of brain tissue. There is no standard treatment; immunological processes which predispose humans to acquire and infection and, then, a disease are unknown. In addition, there are other species of free-living amoebas such as, Sappinea pedata, Vermamoeba vermiformes, Vanellas sp,Vahlkampfia sp., and, more recently, Paravahlkampfia francinae, which is less virulent and aggressive than the first three mentioned above. Methods: All CSF samples were evaluated in our laboratory under the microscope. Monoxenic and axenic cultures were negative as well as the presence of cysts or exponential growth. PCR was negative using the FLA primers. Results: Under close observation of sterile CSF, we can see mobile forms of non-human cells. None of the observed forms has the morphotype of Acanthamoeba, Naegleria sp. or Balamuthia mandrillaris. Conclusions: Due to these findings, we know these structures can be observed in the CSF and many of them do not form cysts as others do. In addition, these microorganisms are uncultivable in conventional medium culture to FLA and impossible to detect even when using molecular tools such as PCR, using the primers for EUK A/B or 18s RNAr gene as a target.

Consciousness is usually perceived as a state of being aware of one’s environment as well as self. Despite its omnipresence in our life, understanding this concept is challenging. This has given rise to several theories attempting to explain the nature of consciousness, as well as hard and soft problems of consciousness. In fact, the boundaries of consciousness defined by these theories are a topic of continued discussion, particularly in light of the recent advances in artificial intelligence (AI). Some of these theories consider consciousness as a simple integration of information while others purport the need for an agency in the process of integration for an entity to be considered conscious. Some theories consider consciousness as a graded entity and some equate consciousness with content of awareness. In this work, major theories of consciousness are reviewed and compared, focusing on awareness, attention, and sense of self. These findings are interpreted in relation to AI in order to ascertain what makes AI distinct from natural intelligence.

Consciousness is usually interpreted as a state of being aware of one’s environment as well as self, while awareness is understood as knowledge of something. Despite their semantic differences, in philosophy, these terms are often used interchangeably, as is the case of the hard problem of consciousness proposed by Chalmers, which in fact is the hard problem of awareness. Trilogy paradigm of consciousness (or simply “trilogy”) offers a new paradigm where consciousness is the result of a unique interaction between awareness and the decision-making process. By conferring the input of awareness to the decision-making process, a new mental function of awareness-based choice selection (ABCS) or true free will emerges. Likewise, application of the power of decision-making to the process of awareness gives rise to discretionary selection of information for awareness (DSIA) or intentional attention. The intertwined actions of ABCS and DSIA comprise “I” which is the faculty of our consciousness and is what sets natural intelligence (NI) apart from artificial intelligence (AI). Based on trilogy, mind is an unconscious compilation of all mental function excluding ABCS and DSIA that are the essence of consciousness. As humans, we are a union of “I,” our minds, and our bodies.

Endometriosis occurs when endometrial-like tissue grows outside the uterine cavity, leading to pelvic pain, infertility, and increased risk of ovarian cancer. The present study describes the optimization and characterization of cellular spheroids as building blocks for Kenzan scaffold-free method biofabrication and proof-of-concept models of endometriosis and the endometriotic microenvironment. The spheroid building blocks must be a specific diameter (~500 m), compact, round, and smooth to withstand Kenzan biofabrication. Under optimized spheroid conditions for biofabrication, the endometriotic epithelial-like cell line, 12Z, expressed high levels of estrogen-related genes and secreted high amounts of endometriotic inflammatory factors that were independent of TNF stimulation. Heterotypic spheroids, composed of 12Z and T-HESC, an immortalized endometrial stromal cell line, self-assembled into a biologically relevant pattern, consisting of epithelial cells on the outside of the spheroids and stromal cells in the core. 12Z spheroids were biofabricated into large three-dimensional constructs alone, with HEYA8 spheroids, or as heterotypic spheroids with T-HESC. These three-dimensional biofabricated constructs containing multiple monotypic or heterotypic spheroids represent the first scaffold-free biofabricated in vitro models of endometriosis and the endometriotic microenvironment. These efficient and innovative models will allow us to study the complex interactions of multiple cell types within a biologically relevant microenvironment.

Transition-metal-free synthesis of 4-pyrones via TfOH-promoted nucleophilic addition/cyclization of diynones and water has been developed. This transformation is simple, atom economical and environmentally benign, providing rapid and efficient access to substituted 4-pyrones.

Background: Gluten and casein-containing foods could aggravate the symptoms of children and adolescents with autism spectrum disorder (ASD), and subsequently impact their quality of life. However, there is a mixed opinion among researchers concerning the impact of alternative diet on reducing ASD symptoms. Objective: This scoping review aimed at examining the impact of the ‘’gluten-free, casein-free’’ (GFCF) diet on health outcomes and the quality of life among autistic children and adolescents. Methods: A scoping review of the literature was performed following the Joanna Briggs Institute (JBI) guidelines. Four databases including EbscoHost, Medline, CINAHL and ProQuest were used to obtain subject-specific studies relevant to the research question and published between July 2013 and March 2024. A comprehensive search using keywords such as “autism spectrum disorder”, “gluten-free diet”, and “casein-free diet” was conducted to obtain articles related to the research focus area. Only full-text, peer-reviewed, written in English articles were selected. Data extraction and data analysis were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses- extension to Scoping Review (PRISMA-ScR) protocol. Results: From the initial 586 studies a total of 27 articles were included in the final analysis of the review. The thematic analysis included ‘GFCF diet and improvement of the core autistic symptoms’’, “the gut-brain link’’, ‘’dietary interventions and autism’’, ‘’possible side effects due to the GCFC diet’’, and ‘’ inconclusive studies and mixed opinions’’. Majority of the studies showed positive effect of the GFCF diet on a variety of autistic symptoms including positive changes in cognitive skills, behaviour, and gastrointestinal symptoms while some showed conflicting evidence. Conclusion: The currently available evidence on the impact of ‘GFCF’’ diet on the quality of life of autistic children and adolescents may warrant potentially effective interventions for alleviating symptoms of autism spectrum disorders. However, this scoping review highlighted the need for more research to provide more reliable evidence on the health outcomes and quality of life of ASD sufferers to guide practice.

Molecular modeling is widely utilized in subjects including but not limited to physics, chemistry, biology, materials science and engineering. Impressive progress has been made in development of theories, algorithms and software packages. To divide and conquer, and to cache intermediate results have been long standing principles in development of algorithms. Not surprisingly, Most of important methodological advancements in more than half century of molecule modeling are various implementations of these two fundamental principles. In the mainstream classical computational molecular science based on force fields parameterization by coarse graining, tremendous efforts have been invested on two lines of algorithm development. The first is coarse graining, which is to represent multiple basic particles in higher resolution modeling as a single larger and softer particle in lower resolution counterpart, with resulting force fields of partial transferability at the expense of some information loss. The second is enhanced sampling, which realizes "dividing and conquering" and/or "caching" in configurational space with focus either on reaction coordinates and collective variables as in metadynamics and related algorithms, or on the transition matrix and state discretization as in Markov state models. For this line of algorithms, spatial resolution is maintained but no transferability is available. Deep learning has been utilized to realize more efficient and accurate ways of "dividing and conquering" and "caching" along these two lines of algorithmic research. We proposed and demonstrated the local free energy landscape approach, a new framework for classical computational molecular science and a third class of algorithm that facilitates molecular modeling through partially transferable in resolution "caching" of distributions for local clusters of molecular degrees of freedom. Differences, connections and potential interactions among these three algorithmic directions are discussed, with the hope to stimulate development of more elegant, efficient and reliable formulations and algorithms for "dividing and conquering" and "caching" in complex molecular systems.

Structural information of biological macromolecules is crucial and necessary to deliver predictions about the effects of mutations—whether polymorphic or deleterious (i.e., disease causing), wherein, thermodynamic parameters, namely, folding and binding free energies potentially serve as effective biomarkers. It may be emphasized that the effect of a mutation depends on various factors, including the type of protein (globular, membrane or intrinsically disordered protein) and the structural context to which it occurs. Such information may positively aid drug-design. Furthermore, due to the intrinsic plasticity of proteins, even mutations involving radical change of the structural and physico-chemical properties of the amino acids (native vs. mutant) can still have minimal effects of protein thermodynamics. However, if a mutation causes significant perturbation of either folding or binding free energies, it is quite likely to be deleterious. Mitigating such effects is a promising alternative to the traditional approaches of designing inhibitors. This can be done by structure-based in silico screening of small molecules for which binding to the dysfunctional protein restores its wild type thermodynamics. In this review we emphasize on the effects of mutations on two important biophysical characteristics, stability and binding affinity, and how structures can be used for structure-based drug design to mitigate the effects of disease-causing variants on the above biophysical characteristics.

How Nature discovered genetic coding is a largely ignored question, yet the answer is key to explaining the transition from biochemical building blocks to life. Other, related puzzles also fall inside the aegis enclosing the codes themselves. The peptide bond is unstable with respect to hydrolysis. So, it requires some form of chemical free energy to drive it. Amino acid activation and acyl-transfer are also slow and call for catalysis. All living things must thus also convert free energy and synchronize cellular chemistry. Most importantly, functional proteins occupy only small, isolated regions of sequence space. Nature evolved heritable symbolic data processing to seek out and use those sequences. That system has three parts: a memory of how amino acids behave in solution and inside proteins, a set of code-keys to access that memory, and a scoring function. The code-keys themselves are the genes for cognate pairs of tRNA and aminoacyl-tRNA synthetases, AARS. I outline the surprising links between all these questions and the structural duality of the base-pairing that holds genes together and how those links arise from the experiments.

Arginine shows Jekyll and Hyde behavior in several respects. It participates in protein folding via ionic and H-bonds and cation-pi interactions; the charge and hydrophobicity of its side chain makes it a disorder-promoting amino acid. Its methylation in histones; RNA binding proteins; chaperones regulates several cellular processes. The arginine-centric modifications are important in oncogenesis and as biomarkers in several cardiovascular diseases. The cross-links involving arginine in collagen and cornea are involved in pathogenesis of tissues but have also been useful in tissue engineering and wound-dressing materials. Arginine is a part of active site of several enzymes such as GTPases, peroxidases, and sulfotransferases. Its metabolic importance is obvious as it is involved in production of urea, NO, ornithine and citrulline. It can form unusual functional structures such as molecular tweezers in vitro and sprockets which engage DNA chains as part of histones in vivo. It has been used in design of cell-penetrating peptides as drugs. Arginine has been used as an excipient in both solid and injectable drug formulations; its role in suppressing opalescence due to liquid-liquid phase separation is particularly very promising. It has been known as a suppressor of protein aggregation during protein refolding. It has proved its usefulness in protein bioseparation processes like ion-exchange, hydrophobic and affinity chromatographies. Arginine is an amino acid, whose importance in biological sciences and biotechnology continues to grow in diverse ways.

In this work, we explore the intrinsic disorder status of the three members of the synuclein family of proteins - α-, β-, and γ-synucleins. We also analyzed the peculiarities of the amino acid sequences and modeled 3D structures of the human synuclein family members to find potential effects of pathological mutations. Furthermore, we conducted a comparative sequence-based analysis of the synuclein proteins from various evolutionary distant species and evaluated their levels of intrinsic disorder using a set of commonly used bioinformatics tools. Next, we conducted a detailed functional disorder analysis of the proteins in the interactomes of the human synuclein family members using various web-based disorder analysis and prediction tools, such as RIDAO, D2P2 and FuzDrop. We identify that the interactome of human α-synuclein has relatively higher levels of intrinsic disorder, as compared to the interactomes of human β- and γ- synucleins. These observations highlight the critical importance of intrinsic disorder of human α-synuclein and its interactors in neuronal processes as compared to other proteins of the synuclein family.

Background: A significant proportion of SARS-CoV-2-infected patients develops respiratory failure. Thromboembolism is also prevalent in coronavirus disease 2019 (Covid-19). Vitamin K plays a role in coagulation and possibly also in lung diseases. We therefore hypothesized that vitamin K is implicated in Covid-19 pathogenesis. Methods: 134 Covid-19 patients and 184 controls were included. Inactive vitamin K-dependent matrix Gla protein (i.e.dp-ucMGP) and prothrombin (i.e. PIVKA-II) were measured, which are inversely related to respectively extrahepatic and hepatic vitamin K status. Desmosine was measured to quantify elastic fiber degradation. Lung involvement and arterial calcifications severity were assessed by computed tomography. Results Dp-ucMGP was elevated in Covid-19 patients compared to controls (P=0.001). Higher dp-ucMGP was found in Covid-19 patients with poor compared to better outcomes (P=0.002). PIVKA-II was normal in 81.8%, mildly elevated in 14.0% and moderately elevated in 4.1% of Covid-19 patients not using vitamin K antagonists. Dp-ucMGP in Covid-19 patients was correlated with desmosine (P<0.001), thoracic aortic calcification (P<0.001) but not with pneumonia severity. Conclusions: Extrahepatic vitamin K status was severely reduced in Covid-19 patients, as reflected by elevated inactive MGP, and related to poor outcome. Procoagulant prothrombin activity remained preserved in the majority of Covid-19 patients, which is compatible with the increased thrombogenicity that is frequently observed in severe Covid-19. Impaired MGP activation was linked to accelerated elastic fiber degradation and premorbid vascular calcifications. A trial should assess whether increasing MGP and protein S activity by vitamin K administration improves Covid-19 outcomes.

The dual leucine zipper kinase (DLK) alias mitogen-activated protein 3 kinase 12 (MAP3K12) has gained much attention in recent years. DLK belongs to the mixed lineage kinases, characterized by homology to serine/threonine and tyrosine kinase but exerts serine/threonine kinase activity. DLK has been implicated in many diseases including several neurodegenerative diseases, glaucoma, and diabetes mellitus. As a MAP3K, it is generally assumed that DLK becomes phosphorylated and activated by upstream signals and phosphorylates and activates itself, the downstream serine/threonine MAP2K, and ultimately MAPK. In addition, other mechanisms such as protein-protein interactions, proteasomal degradation, dephosphorylation by various phosphatases, palmitoylation, and subcellular localization have been shown to be involved in the regulation of DLK activity or its fine-tuning. In the present review, the diverse mechanisms regulating DLK activity will be summarized to provide a better insight into DLK action and possibly new targets to modulate DLK function.

The catalytically inactive caspase-8-homologous protein, c-FLIP, is a potent antiapoptotic protein highly expressed in various types of cancers. c-FLIP competes with caspase-8 for binding to the adaptor protein FADD (Fas-Associated Death Domain) following Death Receptors (DRs) activation by the ligands of the TNF-R family. As a consequence, the extrinsic apoptotic signaling pathway involving DRs is inhibited. Inhibition of c-FLIP activity in tumor cells might enhance DR-mediated apoptosis and overcome immune and anticancer drug resistance. Based on an in silico approach, the aim of this work was to identify, new small inhibitory molecules able to bind selectively to c-FLIP and block its anti-apoptotic activity. Using a homology 3D model of c-FLIP, an in silico screening of 1880 compounds from the NCI database (National Cancer Institute) was performed. Nine molecules were selected for in vitro assays, based on their binding affinity to c-FLIP and their high selectivity compared to caspase-8. These compounds selectively bind to the Death Effector Domain 2 (DED2) of c-FLIP. We have tested in vitro the inhibitory effect of these 9 molecules using the human lung cancer cell line H1703 overexpressing c-FLIP. Our results showed that 6 of these newly identified compounds efficiently prevent FADD/c-FLIP interactions in a molecular pull-down assay, as well as in a DISC Immunoprecipitation assay. Overexpression of c-FLIP in H1703 prevents TRAIL-mediated apoptosis, however, combination of TRAIL with these selected molecules signifi-cantly restored TRAIL-induced cell death by rescuing caspase cleavage and activation. Altogether, our findings indicate that new inhibitory chemical compounds efficiently prevent c-FLIP recruit-ment into the DISC complex, thus restoring caspase-8 dependent apoptotic cascade. These results pave the way to design new c-FLIP inhibitory compounds that may serve as anticancer agents in tumors overexpressing c-FLIP.

This paper describes new horizons in the diversity and taxonomy of negev-like viruses encoding the membrane-embedded SP24 protein. First, our data extend the known host range of SP24-encoding negev-like viruses to include brown algae, fungi, green plants, the phylum Entoprocta, the phylum Mollusca, and vertebrates. Second, our phylogenetic analysis suggests that the evolution of the SP24 gene family may have involved frequent events of inter-order virus genome shuffling. Third, the identification of 2-3 copies of SP24 protein genes in some virus RNAs shows that virus genomes may have acquired additional SP24 genes during the evolutionary process due to duplications or new acquisition steps. Forth, the broad host specificity of some SP24-encoded viruses may be related to an important adaptive role of SP24. Fifth, insect and nematode genomes may acquire viral SP24 genes by putative horizontal transfer from negev-like viruses known to infect species of both taxa.

The development of sarcopenia in the elderly is associated to many potential factors and/or processes, that impair the renovation and the maintenance of skeletal muscle mass and strength as ageing progresses. Among them, a defect by skeletal muscle to respond to anabolic stimuli is to be considered. Common anabolic stimuli/signals in skeletal muscle are hormones (insulin, growth hormones, IGF-1, androgens, β-agonists such epinephrine), substrates (amino acids as protein precursors on top, but also glucose and fat, as source of energy), metabolites (such as β-agonists and HMB), some cytokines, various biochemical/ intracellular mediators), physical exercise, neurogenic and immune-modulating factors, etc. Each of them may exhibit a reduced effect upon skeletal muscle as ageing progresses. In this review article, we will concisely overview the effects of anabolic signals on muscle metabolism, as well as currently available evidence of a resistance, at skeletal muscle level, to any of the above-mentioned anabolic factors, from both in vitro and in vivo studies.

Two related tumor suppressor genes, Brca1 and Brca2, attract a lot of attention from both fundamental and clinical points of view. Oncogenic hereditary mutations in these genes are firmly linked to the early onset of breast and ovarian cancers. However, the molecular mechanisms that drive extensive mutagenesis in these genes are not known. In this review we hypothesize that one of the potential mechanisms behind this phenomenon can be mediated by Alu mobile genomic elements. Linking mutations in the BRCA1 and BRCA2 genes to the general mechanism(s) of genome stability and DNA repair is critical to ensure the rationalized choice of anti-cancer therapy. Accordingly, we review the literature available on mechanisms of DNA damage repair where these proteins are involved in and how the inactivating mutations in these genes (BRCAness) can be exploited in anti-cancer therapy. We also propose a hypothesis that explains why breast and ovarian epithelial tissues are preferentially susceptible to mutations in BRCA genes. Finally, we discuss perspectives of novel therapeutic approaches for treating BRCAness cancers.

Electron can tunnel between cofactor molecules positioned along biological electron transport chains up to the distance of ≃20 Å on the millisecond time scale of enzymatic turnover. This tunneling range mostly determines the design of biological energy chains facilitating cross-membrane transport of electrons. Tunneling distance and cofactors’ redox potentials become main physical parameters of this design. The protein identity, flexibility, or dynamics are missing from this picture assigning universal charge-transport properties to all proteins. This paradigm is challenged by dynamical models of electron transfer showing that the hopping rate is constant within the crossover distance R*≃12 Å, followed with an exponential tunneling falloff at longer distances. In this view, energy chains for electron transport are best designed by placing redox cofactors near the crossover distance R*. Protein flexibility and dynamics affect the magnitude of the maximum hopping rate within the crossover radius. Protein charge transport is not driven by universal parameters anymore and protein identity matters.

Modularity and organizational hierarchy are important concepts in understanding the structure and evolution of interactions in complex biological systems. In this work, we introduce and use a spectral characterization measure (Spectral Entropy) to quantify modularity in protein-to-protein interaction (PPI) networks in species across the tree of life. We evaluated the relation between the size of a PPI network and its (Spectral Entropy-based) modularity, and found a sigmoidal response between the two. We also found significant differences in the distribution of Spectral Entropy values among the three domains of life (Bacteria, Archaea, Eukaryotes). To explore further correlations with biological traits, we focused solely on bacterial PPI networks, which are the most numerous among the three domains and had associated trait metadata, and investigated how modularity impacts or is impacted by growth, aerobicity, selection and location on the tree of life. We found no relation between maximal growth rate and Spectral Entropy, but a strong dependence between G-C content (a proxy for selection) and Spectral Entropy. We also discovered that Spectral Entropy is negatively affected by phylogenetic placement (evolutionary distance from the last universal common ancestor). The general nature of the Spectral Entropy measure of hierarchical modularity in networks suggests that it will be useful in other settings where structural properties of real-world networks are being compared.

Human cytomegalovirus (HCMV) is a leading cause of severe diseases in immunocompromised individuals, including AIDS and transplanted patients, and in congenitally infected newborns. The utility of available drugs is limited by poor bioavailability, toxicity, and emergence of resistant strains. Therefore, it is crucial to identify new targets of therapeutic intervention. Among the latter, viral protein-protein interactions are becoming increasingly attractive. Since dimerization of HCMV DNA polymerase processivity factor ppUL44 plays an essential role in the viral life cycle being required for oriLyt-dependent DNA replication, we performed an in silico screening and selected 18 small molecules (SMs) potentially interfering with ppUL44 homodimerization. Antiviral assays using recombinant HCMV TB40-UL83-YFP in the presence of the selected SMs led to the identification of four active compounds. The most active one, B3, also efficiently inhibited AD169 in plaque reduction assays and impaired replication of an AD169-GFP reporter virus and its ganciclovir-resistant counterpart to a similar extent. As assessed by Western blotting experiments, treatment of infected cells with B3 specifically reduced viral gene expression starting from 48 h post infection, consistent with activity on viral DNA synthesis. Therefore, inhibition of ppUL44 dimerization could represent a new class of HCMV inhibitors, complementary to those targeting the DNA polymerase catalytic subunit or the viral terminase complex.

The outbreak of COVID-19, the disease caused by SARS-CoV-2, continues to affect millions of people around the world. The absence of a globally distributed effective treatment makes the exploration of new mechanisms of action a key step to address this situation. Stabilization of non-native Protein-Protein Interactions (PPIs) of the nucleocapsid protein of MERS-CoV has been reported as a valid strategy to inhibit viral replication. In this study, the applicability of this unexplored mechanism of action against SARS-CoV-2 is analyzed. During our research, we were able to find three inducible interfaces of SARS-CoV-2 N protein NTD, compare them to the previously reported MERS-CoV stabilized dimers, and identify those residues that are responsible for their formation. A drug discovery protocol implemented consisting of docking, molecular dynamics and MM-GBSA enabled us to find several compounds that might be able to exploit this mechanism of action. In addition, a common catechin skeleton was found among many of these molecules, which might be useful for further drug design. We consider that our findings could motivate future research in the fields of drug discovery and design towards the exploitation of this previously unexplored mechanism of action against COVID-19.

Objective: The aim of study is to find key genes and enriched pathways associated with lung cancer. Participants and Methods: Differentially expressed genes (DEGs) data of 54674 genes based on stage, tumor and status of lung cancer was taken from 66 patients of African American (AAs) origin. 2392 DEGs were found based on stage, 13502 DEGs were found based on tumor, 2927 DEGs were found based on status having p value (p<0.05). Results: Total 33 common DEGs were found from stage, tumor and status of lung cancer. Gene ontology (GO) and KEGG pathway enrichment analysis was performed and 49 significant pathways were obtained, out of which 10 pathways were found to be exclusively involved in lung cancer development. Protein-protein interaction (PPI) network analysis found 69 nodes and 324 edges and identified 10 hub genes based on their highest degrees. Module analysis of PPI found that ‘Viral carcinogenesis’, ‘pathways in cancer’, ‘notch signaling pathway’, ‘AMPK signaling pathways’ had a close association with lung cancer. Conclusion: These identified DEGs regulate other genes which play important role in growth of lung cancer. The key genes and enriched pathways identified can thus help in better identification and prediction of lung cancer.

Effective sports training should be attuned to the athlete's specific conditionings and characteristics. In motor learning research, two often neglected factors that influence this resonance are the learner's athletic background and the structural diversity of exercises (e.g., relative similarity). This study examines the effects of three learning approaches (i.e., contextual interference (CI), differential learning (DL), and free-play control condition (CO)) on the parallel learning of Handball (HB), Volleyball (VB), and Basketball (BB) skills, considering participants' prior sport backgrounds. Forty-five males (15 HB, 15 VB, and 15 BB players) with a mean age of 22±1.4 years and at least 6 years of experience in the mastered discipline voluntarily participated in this study. A pre-post-retention test design including a 6-week-intervention program was employed. In terms of short-term (pre-post) gain, only the DL- group significantly improved their performance in both non-mastered disciplines (p=0.03 for the BB free-throw and p=0.05 for the HB shooting tests), with a trend (ES=0.53) towards an improvement in the performance of the mastered VB underarm-pass skill. In terms of relatively permanent gains, the CI group significantly improved their performances from pre- to retention-test only in the non-mastered BB free-throw skill (p=0.018). In contrast, the DL group significantly improved their performance at retention compared to the pre-test in both non-mastered BB (p=0.004) and HB (p=0.003) skills, with a trend (ES=0.4) towards improvement in the mastered VB test. In both short, and relatively permanent terms, higher composite score gains were observed in DL compared to CI (p=0.001 and 0.002) and CO (p=0.001 and <0.0001). In conclusion, the present findings provide additional support for the potential advantages of the DL model over those of CI. These findings can serve as the basis for tailored training and intervention strategies and provide a new perspective for addressing various issues related to individual and situational learning.

Abstract: Power generation using dielectric elastomer (DE) artificial muscle is attracting attention because of its light weight, low cost, and high efficiency. Since this method is a system that produces electricity without emitting carbon dioxide nor using rare earths, it would contribute to the goal of environmental sustainability. In this paper, the background of DEs, the associated high-efficient wave energy generation (WEG) systems that we developed using DEs, as well as the latest development of its material are summarized. By covering the challenges we face and the achievements that we’ve reached, we can discuss the opportunities to build the foundation of a recycled energy society through the usage of these WEGs. On the other hand, to make these possibilities commercially successful, the advantages of DEs need to be integrated with traditional technologies. To achieve this, we also consider the method of using DEs alone and a system used in combination with an oscillating water column. Finally, the current status and future of DEGs are discussed.

In this work we have critically reviewed the processes in high-temperature sublimation growth of graphene in Ar atmosphere using enclosed graphite crucible. Special focus is put on buffer layer formation and free charge carrier properties of monolayer graphene and quasi-freestanding monolayer garphene on 4H-SiC. We show that by introducing Ar at different temperatures, TAr one can shift to higher temperatures the formation of the buffer layer for both n-type and semi-insulating substrates. A scenario explaining the observed suppresed formation of buffer layer at higher TAr is proposed and discussed. Increased TAr is also shown to reduce the sp3 hybridization content and defect densities in the buffer layer on n-type conductive substrates. Growth on semi-insulating substrates results in ordered buffer layer with significantly improved structural properties, for which TAr plays only a minor role. The free charge density and mobility parameters of monolayer graphene and quasi-freestanding monolayer graphene with different TAr and different environmental treatment conditions are determined by contactless terahertz optical Hall effect. An efficient annealing of donors on and near the SiC surface takes place in intrinsic monolayer graphene grown at 2000∘C, and which is found to be independent of TAr. Higher TAr leads to higher free charge carrier mobility parameters in both intrinsically n-type and ambient p-type doped monolayer graphene. TAr is also found to have a profound effect on the free hole parameters of quasi-freestanding monolayer graphene. These findings are discussed in view of interface and buffer layer properties in order to construct a comprehensive picture of high-temperature sublimation growth and provide guidance for growth parameters optimization depending on the targeted graphene application.

Complementary and alternative treatment approaches are becoming more common among children with chronic conditions. The pravelance of CAM use among US adults was estimated to be around 42% in 2015, and around 44% to 50% among adults with neurologic disorders. Studies report children with chronic illnesses such as cancer, asthma, attention-deficit/hyperactivity disorder (ADHD), genetic disorders, and other neurodevelopmental disorders are treated with complementary and alternative treatments at higher rates. Dietary therapies are gaining increasing popularity in the mainstream population, due to the heavy media involvement. Although, majority of “fad” diets do not have enough supporting evidence, some dietary therapies have been utilized for decades and have numerous published studies. The objective of this review is to describe the dietary interventions used in children with the specific chronic conditions, to evaluate their efficacy based on published data, and to encourage pharmacist involvement in the management and care of such patients.

Urolithiasis is an increasingly common clinical problem worldwide. The formation of stones is a combination of metabolic status, environmental factors, family history and many other aspects. It’s important to find new ways to quickly detect and assess urolithiasis because it causes sudden, severe pain and often comes back. One way to do this is by exploring new biomarkers. Current advances in proteomic studies provide a great opportunity for breakthroughs in this field. The study focuses on protein biomarkers and their connection to kidney damage and inflammation during urolithiasis.

Industrialization, intensive farming, rapid population growth and urbanization are the source of a large number of pollutants entering the environment. The current concentration of xenobiotics released into the environment exceeds its natural ability to decompose them. Enzymatic degradation of pollutants seems to be an environmentally friendly process. Due to the wide spectrum of substrate specificity, from inorganic compounds to high molecular weight organic compounds such as PAH or dyes, as well as favorable biochemical properties, laccase has been used in the biological removal of xenobiotics from the environment. It is important to understand the degradation mechanisms of pollutants and to evaluate the final products in terms of their toxicity. The laccase oxidizes the substrates with the simultaneous reduction of molecular oxygen to water, which is the purest reaction co-substrate. That is why it is called a green biocatalyst. The trend is an increase in the production of enzymes related to the intensive development of industry, bioremediation or synthetic chemistry. This leads to the search for laccases with greater activity and stability under extreme conditions. The potential of laccases to degrade xenobiotics can be promoted by improving enzymatic catalytic characterization using protein engineering and other genetic engineering methods.

In 1984, Susumu Ohno hypothesized that the nylon-degrading enzyme NylB arose de novo via a frameshift mutation within a hypothetical precursor protein (PR.C). However, Ohno never tested his hypothesis or provided supporting biological evidence. For decades, Ohno’s famous frame-shift hypothesis has been uncritically accepted as the correct explanation for the origin of NylB and has been used to illustrate how simple it is for a totally new enzyme to arise spontaneously. In this paper we test Ohno’s hypothesis in light of data not available in 1984. We searched multiple protein databases and found that the NylB protein is widely occurring, has thousands of homologs, and is found in diverse organisms and diverse habitats. Conserved domain searches showed that the NylB sequence is homologous to beta lactamases - a family of highly conserved enzymes. However, our searches showed that there is no evidence for the existence of Ohno’s hypothetical PR.C protein, nor any credible homolog. Our results effectively falsify Ohno's frameshift hypothesis. We extended this analysis to other nylonases and found all the nylonases we examined had large numbers of homologs throughout the biosphere. This falsifies the long-held assumption that all nylonases evolved after the invention of nylon in 1935.

regulating translational speed and accuracy. Threonylcarbamoyl adenosine (t6A37) and 5-methoxycarbonylmethyl-thiouridine (mcm5s2U34) are critical ASL modifications that have been linked to several human diseases. The model yeast Saccharomyces cerevisiae is viable despite the absence of both modifications, growth is however greatly impaired. The major observed consequence is a subsequent increase in protein aggregates and aberrant morphology. Proteomic analysis of the t6A-deficient strain revealed a global mistranslation leading to protein aggregation without regard to physicochemical properties or t6A-dependent or biased codon usage in parent genes. However, loss of sua5 led to increased expression of soluble proteins for mitochondrial function, protein quality processing/trafficking, oxidative stress response, and energy homeostasis. These results point to a global function for t6A in protein homeostasis very similar to mcm5/s2U modifications.

Flap surgery is a common method used to cover defects following tumor ablation, trauma, or infection. However, insufficient vascularity in the transferred flap can lead to flap necrosis and failure. Proper postoperative monitoring is essential to prevent these complications. Recently, research has explored the use of infrared thermal imaging in plastic surgery, leading to its clinical application. This study investigates the use of a forward-looking infrared (FLIR) camera to monitor blood flow in flaps. In the study, 28 rats underwent reverse McFarlane flap surgery, and their flaps were analyzed using a FLIR thermal imaging camera seven days post-surgery. Additionally, thermal images of flaps were taken on postoperative days 0, 1, 2, 3, and 7 in 22 patients. The study focused on temperature differences between normal skin and the perforator compared to the average flap temperature. Results showed that the temperature difference was higher in the necrosis group and increased over time in cases of total necrosis. A lower perforator temperature compared to the flap's average indicated vascular compromise, potentially leading to flap failure. The FLIR camera, being contact-free and convenient, shows promise for understanding and inferring the clinical progression of flaps in postoperative monitoring.

This paper summarizes some works exploiting the ate-type addition of electron-withdrawing monomers to hydrogenosiloxane groups so as to generate new silicone materials. Two types of monomers were oligomerized onto silicone backbones, namely unsaturated phosphonate and sulfone monomers. Phosphonated silicones are thermally more resistant than conventional silicones and can be transformed into amphiphilic polymers after selective ester hydrolysis. Sulfoned silicones generate solid supramolecular elastomers thanks to the strong pseudo-ionic interactions in play between sulfone groups. Rheology and modulated DSC show a solid/viscoelastic transition around 175°C, which allows using these thermoplastic materials on a larger scale than conventional silicone urea copolymers. These results open new avenues in the generation of silicone block- and grafted-copolymers with unique functionality and properties.

Studies involving vortex in hybrid superconducting devices and their interaction with different components inside the sample are an important issue to reach higher values of their critical parameters in superconducting materials. The vortex distribution on each side of sample with different fundamental parameters, such as temperature T, penetration depth λ, coherence length ξ, electron mass m and the order parameter Ψ, may help to improve the superconducting properties. Thus, in this work, we used the modified Ginzburg-Landau theory to investigate hybrid superconductor (HS), but also to provide a highly tunable and adjustable theoretical tool to theoretically explain the experimental results involving HS, in order to study the vortex behaviour in superconductors of mesoscopic dimensions with extremely differences among their fundamentals parameters. Therefore, we evaluated the influence of HS on vortex configuration and their effects in the field-dependent magnetization. The results show that the during the increment of applied magnetic field H the diamagnetic response of HS, Meissner effect, include additional jumps of magnetization while diamagnetism continues its increase in the sample. In addition, the differences among parameters, create an interface between both components, two different magnitudes of supercurrent and vortex sizes producing a lower degradation of local superconductivity, which increase the upper critical field. On the other hand, this type HS with differences of parameters on both sides can be used to control the vortex movement in the selected superconducting region sample with more accuracy.

Aryl chlorides and bromides in the presence of NHC palladium hydroxo dimers of the type [{Pd(µ-OH)Cl(NHC)}2] (where NHC = IPr, SIPr, IMes, SIMes) undergo an efficient and selective Sonogashira cross-coupling with terminal acetylenes. For the coupling of 4-chlorotoluene with phenylacetylene TON = 560000 was observed. The procedure enables high-throughput and selective synthesis of a broad spectrum of unsymmetrically substituted 1,2-diarylacetylenes. Nearly a quantitative amount of HCl was detected within cross-coupling products. Water plays the role of the base and is regenerated in the process so that it does not have to be used in stoichiometric amounts (relative to the limiting reactant). Generation of the active Pd(0) complex proceeds via ethanol oxidation.

The notion of quantum-mechanics-free subsystem (QMFS) was introduced by Tsang and Caves in 2012. They showed that it is possible to design the dynamics of coupled quantum systems in such a way that one can construct a subsystem in which a given classical dynamics is realized, thus avoiding the measurement back-action of quantum mechanics. Although they mention that the Heisenberg picture equations of motion for QMFS was first proposed by Koopman in 1931 as a formulation of classical Hamiltonian dynamics in Hilbert space, in fact the connection between QMFS and Koopmann-von Neumann mechanics is deeper. Namely, quantum-mechanics-free subsystem is nothing but the realization of Sudarshan's perspective on the Koopman-von Neumann mechanics.

Background: Cell-free plasma DNA (cfDNA) is composed of circulating extracellular DNA originating from apoptosis or cell necrosis. It is generally present in healthy individuals, but its levels increase in different clinical conditions, such as kidney disease, sepsis, myocardial infarction, trauma and cancer. Caspase-3 plays a central role in apoptosis, a mechanism of programmed cell death involved in the pathogenesis of chronic kidney disease (CKD). Methods: We compared cfDNA and caspase-3 levels in 25 CKD patients and in 10 healthy subjects, evaluating the modification of their concentrations according to CKD stage. We also analyzed the correlation between cfDNA and caspase-3 levels in CKD patients and the correlation between cfDNA and caspase-3 levels and creatinine and urea. Results: CfDNA and caspase-3 levels were higher in CKD patients compared to healthy subjects, in particular in patients with advanced renal disease. A positive correlation between cfDNA and caspase-3 levels and between cfDNA and caspase-3 and creatinine and urea was also observed. Conclusion: Patients with chronic kidney disease present higher levels of cfDNA and caspase-3 levels compared with healthy subjects. The worsening of renal damage and the increase in uremic toxin concentration are associated to higher levels of cfDNA and caspase-3 levels, thus reflecting a central role of apoptosis in the pathogenesis of CKD.

Nonequilibrium work switching simulations and Jarzynski’s equation are a reliable method to compute free energy differences, ΔAlow→high, between two levels of theory, such as a pure molecular mechanical (MM) and a quantum mechanical/molecular mechanical (QM/MM) description of a system of interest. Despite the inherent parallelism, the computational cost of this approach can quickly get very high. This is particularly true for systems where the core region, the part of the system to be described at different levels of theory, is embedded in an environment, such as explicit solvent water. We find that even for relatively simple solute–water systems, switching lengths of at least 5 ps are necessary to compute ΔAlow→high reliably. In this study, we investigate two approaches towards an affordable protocol, with emphasis on keeping the switching length well below 5 ps. Inserting a hybrid charge intermediate state with modified partial charges which resembles the charge distribution of the desired high level makes it possible to obtain reliable calculations with 2 ps switches. Attempts using step-wise linear switching paths, on the other hand, did not lead to improvement, i.e., faster convergence for all systems. To understand these findings, we analyzed the solutes’ properties as a function of partial charges used, the number of waters in direct contact with the solute, and studied the time needed for water molecules to reorient themselves upon a change in the solute’s charge distribution.

There is evidence that behavioral risk factors such as western type diet, and life style can predispose to oxidative stress, deficiency in antioxidant status, hyperglycemia, dyslipidemia and increase in inflammation in tissues of various organs: beta cells of the pancreas, LDL receptors in the hepatocytes, endothelium, neurons, osteocytes and gut. Further studies indicate that diets rich in antioxidant flavonoids, omega-3 fatty acids and fiber in foods were inversely associated whereas western-type foods were positively associated with risk of mortality due to cardiovascular diseases (CVDs). One important cause for beneficial effects of diet may be certain foods and nutrients such as vegetables, fruits and whole grains that are rich in fiber and flavonoids, known to produce liters og molecular hydrogen in the gut. It seems that, high-fiber diets, prebiotic and probiotics can produce greater hydrogen, which acts as an antioxidant and may inhibit free radical generation. Recent studies indicate that molecular hydrogen can inhibit hydroxyl and nitrosyl radicals and can directly act as antioxidant in the cells and tissues, which can cause marked decline in oxidative stress and inflammation leading to significant decline in CVDs and metabolic diseases. Clinical and experimental studies indicate that hydrogen therapy such as hydrogen rich water can provide benefits in the management of CVDs and metabolic diseases. Larger studies are necessary to verify the role of hydrogen administration in CVDs.

Explaining the emergence of behavior and understanding on the basis of neuronal mechanisms is still elusive. One renowned proposal is the Free Energy Principle (FEP), which uses an information-theoretic framework derived from thermodynamic considerations to describe how behavior and understanding would emerge. FEP starts from a whole organism approach, based on mental states and phenomena, mapping them into the neuronal substrate. An alternative approach, the Energy Homeostasis Principle (EHP), initiates a similar explanatory effort, but starting from single neuron phenomena and building up to the whole organism’s behavior and understanding. In this work, we develop the EHP as an alternative but complementary vision to FEP and try to explain how behavior and understanding would emerge from the local requirements of the neurons. Based on EHP and a strict naturalist approach that sees living beings as physical and deterministic systems, we explain scenarios where learning would emerge without the need for volition or goals. Given these starting points, we state several considerations of how we see the nervous system, particularly the role of function, purpose, and the conception of goal-oriented behaviors. We problematize these conceptions, giving an alternative teleology-free framework in which behavior and, ultimately, understanding would still emerge. We reinterpret neural processing explaining basic learning situations up to simple anticipatory behavior. Finally, we end the work with an evolutionary perspective of how this non-goal-oriented behavior appears. We acknowledge that in the current form of our proposal, we are still far from explaining the emergence of understanding. Still, we set the ground for an alternative neuron-based framework to ultimately explain understanding.

Considering that the electric refrigeration temperature range of 0.94BNT-0.06BT ceramic materials is 100~140˚C, the electric refrigeration performance of the 0.94BNT-0.06BT ceramic material system was modified by LiNbO3 doping to reduce the cooling temperature. As a result, the refrigeration temperature range of the 0.94BNT-0.06BT ceramic material system was lowered to 25~80 ˚C, achieving its cooling effect near room temperature, and in this temperature range, the adiabatic temperature changes ∆T&gt;0.6K.

With the current rapid spread of COVID-19, global health systems are increasingly overburdened by the sheer number of people that need diagnosis, isolation and treatment. Shortcomings are evident across the board, from staffing, facilities for rapid and reliable testing to availability of hospital beds and key medical-grade equipment. The scale and breadth of the problem calls for an equally substantive response not only from frontline workers such as medical staff and scientists, but from skilled members of the public who have the time, facilities and knowledge to meaningfully contribute to a consolidated global response. Here, we summarise community-driven approaches based on Free and Open Source scientific and medical Hardware (FOSH) currently being developed and deployed to bolster access to personal protective equipment (PPE), patient treatment and diagnostics.

Graphene oxide was synthesized by a one-step environmentally friendly mechanochemistry process directly from graphite and characterized by Raman, FT-IR and UV/vis spectroscopies, Atomic Force Microscopy, X-ray Diffraction, Scanning Electron Microscopy, Energy-Dispersive X-ray Spectroscopy and Thermogravimetric Analysis. Spectroscopic analysis shows that the functional groups and oxygen content of the synthesized material are comparable with those of graphene oxide synthesized by other previously reported methods (Hummers). Thermogravimetric analysis reveals thermal stability up to 400 °C.

Ten-eleven translocation (TET) enzymes are implicated in DNA demethylation through dioxygenase activity, which converts 5-methylcytosine to 5-hydroxymethylcytosine (5-hmC). However, the specific roles of TET enzymes and 5-hmC levels in head and neck squamous cell carcinoma (HNSCC) have not yet been evaluated. In this study, we analyzed 5-hmC levels and TET mRNA expression in a well-characterized dataset of 117 matched pairs of HNSCC tissues and normal tissues. 5-hmC levels and TET mRNA expression were examined via enzyme-linked immunosorbent assay and quantitative real-time PCR, respectively. 5-hmC levels were evaluated according to various clinical characteristics and prognostic implications. Notably, we found that 5-hmC levels were significantly correlated with tumor stage (P = 0.032) and recurrence (P = 0.018). Univariate analysis revealed that low levels of 5-hmC were correlated with poor disease-free survival (DFS; log-rank test, P = 0.038). The expression of TET family genes was not associated with outcomes. In multivariate analysis, low levels of 5-hmC were evaluated as a significant independent prognostic factor of DFS (hazard ratio: 2.352, 95% confidence interval: 1.136–4.896; P = 0.021). Taken together, our findings showed that reduction of TET family gene expression and subsequent low levels of 5-hmC may affect the development of HNSCC.

Background User fee exemption for maternal and child health care service policy was introduced with a focus on providing free caesarean sections (CS) in Nigeria from 2011 to 2015. This policy had a positive impact on access to facility-based delivery, but its effect on socioeconomic and geographical inequality remains unclear. This study’s main objective is to examine access to birth by CS in the context of free maternal health care. Specifically, the study examines socio-demographic and geographical inequality in access to birth by CS among women who gave birth between 2011 and 2015 under the free maternal health care policy using a population-based survey data obtained from two of the six main regions of the country. Methods Data were obtained from 1227 women who gave birth during the period the policy was in operation selected using cluster random sampling between May and August 2016. Adjusted and unadjusted binary logistic regression models were used to examine whether there is socio-demographic and geographical inequality in access to birth by caesarean section. Results The overall caesarean section rate of 6.1% was found but varies by income (14.1% in monthly income of over $150 versus 4.9% in income of $150 and below), education (11.8% in women with higher education versus 3.9% among women with secondary education and less) and place of residence (7.8% in urban areas versus 3.6% in rural areas). Women who earn a monthly income of $150 or less were 48% less likely to have a birth by CS compared to those who earn more. Compared to women who were educated to tertiary level, women who had secondary education or less were 54% less likely to have birth by caesarean section. Conclusion This study shows that inequality in access to CS persists despite the implementation of free maternal health care services. Given the poor access to facilities with capabilities to offer CS in most rural areas, free maternal healthcare policy is not enough to make birth by CS universally accessible to all pregnant women in Nigeria.

Customs law and procedures are important part of the trade system in Jordan. They regulate the flow of goods across the borders. The purpose of this paper is to examine Jordan's import regime by analyzing customs law, rules of origin, free trade zones, and tariffs reform.

The primary and proven therapy, in cases of celiac disease (CD), is a rigorous gluten-free diet. However, there are reports of its negative effects in the form of nutritional deficiencies, obesity and adverse changes in body composition. The aim of the study was to assess the impact of a gluten free diet (GFD) on the body composition of children with CD. In a case-controlled study (n = 41; mean age 10.81 y; SD = 3.96) children with CD, in various stages of treatment, underwent medical assessment. The control group consisted of healthy children and adolescents, strictly matched for gender and age in a 1:1 case-control manner. More than half of the examined children (n = 26) followed a GFD. CD children had significantly higher mean values of the fat free mass (FFM% = 80.68 vs. 76.66, p = 0.015), and total body water (TBW% = 65.22 vs. 60.47, p = 0.012), and lower mean values of the fat mass (FM% = 19.32 vs. 23.34, p = 0.015). Children who were on a GFD presented slightly higher, but not statistically significant, mean values of FM and FFM, than children who did not follow dietary recommendations (FM [kg] = 7.48 vs. 5.24, p = 0.064; FM% = 20.81 vs. 16.73, p = 0.087; FFM [kg] = 28.19 vs. 22.62, p = 0.110). After minimum one year of a GFD, CD children showed significantly higher values of FFM [kg] (p = 0.001), MM [kg] (p < 0.001), TBW [L] (p < 0.001) and BCM [kg] (p < 0.001). Furthermore, CD children who were on a GFD presented significantly higher weight (p = 0.034) and body mass index (BMI) (p = 0.021) increase. The children adhering to a GFD demonstrate a tendency towards higher indices of selected body composition components.

A new label-free molecular probe for luminescent nucleotide detection in neutral aqueous solution is presented. Phosphate-containing molecules such as nucleotides possess vital role in cell metabolism, energy economy, and signaling. Thus the monitoring of nucleotide concentration and nucleotide related enzymatic reactions is of high importance. Two component lanthanide complex formed from Tb(III) ion carrier and light harvesting antenna, readily distinguishes nucleotides containing different number of phosphates and enable direct detection of enzymatic reactions converting nucleotide triphosphate (NTP) to nucleotide di/monophosphate or the opposite. Developed sensor enables the detection of enzymatic activity with a low nanomolar sensitivity, as highlighted with K-Ras and apyrase enzymes in there hydrolysis assays performed in high throughput screening compatible 384-well plate format.

A novel method proposed in the production of Calophyllum inophyllum biodiesel has been investigated experimentally. In this study, we report the results of biodiesel processing with electromagnetic induction technology. The method used is to compare the results of Calophyllum inophyllum biodiesel processing between conventional, microwave and electromagnetic induction. The degumming, transesterification, and esterification process of the 3 methods are measured by stopwatch to obtain time comparison data. Characteristics of viscosity, density, and Fatty Acid Metil Ester (FAME) were obtained from testing of a Gas Chromatography-mass Spectrometry (GCMS) at the Polytechnic Chemistry Laboratory of the State of Malang. The results show that the biodiesel produced by this method satisfies the biodiesel standards and their characteristics are better than the biodiesel produced by conventional and microwave methods. The electromagnetic induction method also offers a fast and easy route to produce biodiesel with the advantage of increasing the reaction rate and improving the separation process compared to other methods. This advanced technology has the potential to significantly increase biodiesel production with considerable potential to reduce production time and costs.

Selective hydrogenation of nitrobenzene was carried out under solvent-free conditions using supported AuPd nanoparticles catalyst, prepared by modified impregnation method (MIm), as efficient catalyst. >99% yield of aniline (AN) was obtained after 15 hours at 90 °C, 3 bar H2 that can be used without any further purification or separation, therefore reducing cost and energy input. Supported AuPd nanoparticles catalyst, prepared by MIm, was found to be active and stable even after 4 recycle experiments whereas the same catalyst prepared by SIm deactivated during the recycle experiments. The most effective catalyst was tested for the chemoselective hydrogenation of 4-chloronitrobenzene (CNB) to 4-chloroaniline (CAN). The activation energy of CNB to CAN was found to be 25 kJ mol-1, while that of CNB to AN was found to be 31 kJ mol-1. Based on this, the yield of CAN was maximized (92%) by lowering the reaction temperature to 25 °C.

Label-free confocal photothermal (CPT) microscopy was utilized for the first time to investigate malignancy in mouse skin cells. A laser diode (LD) with 405nm or 488nm was used as a pump and 638nm LD as a probe for the CPT microscope. The Grey Level Cooccurrence Matrix (GLCM) for texture analysis was applied to the CPT images. Nine parameters of GLCM were calculated for the intracellular super-resolved CPT images, and the parameters Entropy and Prominence were found to be most suited among the nine parameters to discriminate between healthy cells and MM cells in case pump wavelength of 488nm is used.

The aim of this study (first analytical approach) was to obtain data on the fatty acid composition of gluten-free foods (bakery products) for celiac people. The study included 35 different products (snacks, biscuits, bakery products, pasta, flours, etc.) from several manufacturers. After extraction and esterification, the fatty acid content was determined by GC-MS. The monounsaturated fatty acids (MUFAs) are the major constitutes (57%) of the fatty acids pool followed by saturated fatty acids (SFAs) (30%) and polyunsaturated fatty acid (13%). Only fifteen, of the thirty-five gluten free samples analyzed, provide adequate energy intake, while in eleven samples, saturated fatty acids take more energy than that recommended by EFSA. It has emerged that local producers generally use the finest raw materials (olive oil, etc.) compared to the industries which, as has been pointed out, in many cases use palm and palm kernel oils although gluten free commercial products are high added value foods, expensive and intended for a particularly sensitive public.

The objective of this study is to investigate the performance of incorporating petroleum sludge waste as raw materials into the cement clinker production. The burnability and the structural analysis of the produced clinker were studied. The results showed that the addition of petroleum sludge into the clinker matrices improved the burnability of the clinker by lowering the free lime content. Moreover, 2.5% and 5% of this waste was effective and did not affect the quality of the cement clinker negatively. This study, which is the first to investigate the incorporation of petroleum sludge into cement production, provides also a complete elimination of this waste from the environment.

This study was conducted to evaluate the yield and quality parameters of milk from 60 indigenous South African goats of different genotypes namely Nguni, Boer and Non- descript reared under a free ranging system. Milk yield and quality parameters (milk fat, protein, lactose, solid non-fat and minerals) from Nguni (10), Boer (10) and Non-descript (10) goats was measured and analysed per week at each stage of lactation. Result showed that, Nguni goats produced (1.2±0.09, 1.3±0.11 and 1.2±0.07 litres per day) more milk (P ˂ 0.05) at early, mid and late stages of lactation than Boer (0.6±0.10, 1.0±0.17 and 0.6±0.09 litres per day) and Non-descript (0.3±0.10, 0.3±0.12 and 0.3±0.09 litres per day) goats, respectively. The mean value of milk fat, protein and lactose content from Nguni goat was (3.98, 3.54 and 5.31); Boer goat (2.9, 3.59 and 5.04) and Non-descript goat (4.05, 3.39 and 5.02), respectively. There was significant effect (P ˂ 0.05) of genotypes on milk fat, milk magnesium and sodium contents of Nguni, Boer and Non-descript goats. It could be concluded that, Nguni goat produced more milk than Boer and Non-descript goats, but the Non-descript goat had higher mean percentage of milk fat compared to Nguni and Boer goats.

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.

The conventional phytopathogen Pseudomonas syringae has been identified several significant virulence determinants against Caenorhabditis elegans, but their mechanisms of action remain elusive. Here, we report the nematicidal activity and action receptor of a methyl-accepting chemotaxis protein (MCP03) of a wild-type P. syringae MB03 against C. elegans. Purified MCP03 exhibited significant nematicidal toxicity against C. elegans, with a half-lethal concentration of 124.4 μg mL1, and detrimental effects on the growth and brood size of C. elegans. Additionally, MCP03-treated worms showed severe pathological destruction of the intestine and ovary, and depressed wrinkles of the cuticle. Through yeast two-hybrid assays, we identified a subunit of a COP9 signalosome, namely CSN-5, functionated as an action receptor of MCP03. In vitro pull-down and in vivo co-localization assays verified the binding interaction between MCP03 and CSN-5. RNA interference assays confirmed that MCP03 acts on CSN-5 to adversely affect the brood size, growth, and cuticle integrity of C. elegans. Following MCP03 infection, the expression of several genes relative to reproduction, growth, and cuticle formation, such as kgb-1, unc-98, and col-117, were significantly downregulated, which implicated the pathological changes of MCP03-treated nematodes. Thus, this study demonstrates that MCP03 acted on the receptor protein CSN-5 causing lethality and detrimental effects on the fertility, growth, and morphogenesis of C. elegans, which will provide new insights into the signaling pathways and mechanism underlying the nematicidal action of MCP03 towards C. elegans.

In the chloroplast, Calvin-Benson-Bassham enzymes are active in the reducing environment imposed in the light via the electrons from the photosystems. In the dark these enzymes are inhibited, and this regulation is mainly mediated via oxidation of key regulatory cysteine residues. CP12 is a small protein that plays a role in this regulation with four cysteine residues that undergo a redox transition. Using amide-proton exchange with solvent measured by nuclear magnetic resonance (NMR) and mass-spectrometry, we confirmed that reduced CP12 is intrinsically disordered. Using real-time NMR, we showed that the oxidation of the two disulfide bridges are simultaneous. In oxidized CP12, the C23-C31 pair is in a region that undergoes a conformational exchange in the NMR-intermediate timescale. The C66-C75 pair is in the C-terminus that folds into a stable helical turn. We confirmed that these structural states exist in a physiologically relevant environment that is, in cell extract from Chlamydomonas reinhardtii. Consistent with these structural equilibria, the reduction is slower for the C66-C75 pair compared to the C23-C31 pair. Finally, the redox mid-potentials for the two cysteine pairs differ and are similar to those found for phosphoribulokinase and glyceraldehyde 3-phosphate dehydrogenase, that we relate to the regulatory role of CP12.

Mitochondria are constantly subjected to stressful conditions due to their unique physiology and organization. The resulting damage leads to mitochondrial dysfunction, which underlies many pathophysiological conditions. Hence, constant surveillance is required to closely monitor mitochondrial health for sound maintenance of cellular metabolism and thus, for viability. In addition to internal mitochondrial chaperones and proteases, mitochondrial health is also governed by host cell protein quality control systems. The Ubiquitin-Proteasome System (UPS) and autophagy constitute the main pathways for removal of damaged or superfluous proteins in the cytosol, nucleus, and from certain organelles such as the ER and mitochondria. Although stress-induced ubiquitin-dependent degradation of mitochondrial outer membrane proteins has been widely studied, mechanisms of intramitochondrial protein ubiquitination have remained largely elusive due to the predominantly cytosolic nature of UPS components, separated from internal mitochondrial proteins by a double membrane. However, recent research has illuminated examples of intramitochondrial protein ubiquitination pathways and highlighted their importance under basal and stressful conditions. Owing to the dependence of mitochondria on the error-prone process of protein import from the cytosol, it is imperative that the cell eliminate any accumulated proteins in the event of mitochondrial import deficiency. Apparently, a significant portion of this activity involves ubiquitination in one way or another. In the present review article, following a brief introduction to mitochondrial protein quality control mechanisms, we discuss our recent understanding of intramitochondrial protein ubiquitination, its importance for the basal function of mitochondria, metabolic implications, and possible therapeutic applications.

As of today, there is not any direct report yet of the degree to which missing residues exist for experimentally determined membrane protein (MP) structures, which constitute more than half of current drug targets. With a chain- and position-specific visualisation and a statistical analysis of all MP structures inside PDB (as of September 25, 2019), this article argues that the experimentally uncharted territories (EUTs, i.e., consisting of missing residues) within PDB are pluggable and should be plugged with an experimental data-driven hybrid approach, and calls for continued development of MP structural determination with less and less EUTs, in light of MPs' crucial role in biological and biomedical research, both fundamental and pharmaceutical.

Matrix Metaloproteinase-2 (MMP-2) is an extracellular Zn²⁺ protease specific to type I and IV collagens. Its expression is associated with several inflammatory, degenerative, and malignant diseases. Conformational properties, domain movements, and interactions between MMP-2 and its associated metal ions were characterized using a 1.0 µs molecular dynamics simulation. Dihedral principle component analysis revealed 10 families of conformations with the greatest degree of variability occurring in the link region connecting the catalytic and hemopexin domains. Dynamics cross correlation analysis indicated domain movements corresponding to opening and closing of the hemopexin domain in relation to the fibronectin and catalytic domains facilitated by the link region. Interaction energies were calculated using the MMPBSA-interaction entropy analysis method and revealed strong binding energies for the catalytic Zn²⁺ ion 1, Ca²⁺ ion 1, and Ca²⁺ ion 3 with significant conformational stability at the binding sites of Zn²⁺ ion 1 and Ca²⁺ ion 1. Ca²⁺ ion 2 diffuses freely away from its crystallographically defined binding site. Zn²⁺ ion 2 plays a minor role in conformational stability of the catalytic domain while Ca²⁺ ion 3 is strongly attracted to the highly electronegative sidechains of the Asp residues around the central β-sheet core of the hemopexin domain.

The exploration and identification of targets and pathways for Atopic dermatitis (AD) treatment and diagnosis are critical for AD control. The conventional target exploration approach such as the literature review is not satisfying in terms of efficiency and accuracy. Recently, the bioinformatic approach is drawing attention for its unique advantage of high-volume data analysis for target and pathway exploration; Open Targets Platform is the targets source for this study to extract top 200 high-rank proteins from 3122 AD associated proteins. STRING, Cytoscape, CytoHubba, ClueGo, and CluePedia function had been applied for data analysis. The KEGG Mapper search & colour pathway was the pathway map resource for identified pathways; 23 key hub genes (VDR, KIT, BCL2L11, NFKBIA, KRAS, IL13, JAK2, STAT3, IL21, IL4R, REL, PDGFRB, FOXP3, RARA, RELB, EGFR, IL21R, MYC, CREBBP, NR3C1, IL2, JAK1, and KITLG). Additionally, 8 correlated pathways and the biological process had been identified; Through this study, a viable approach for target and pathway exploration had been presented. The identified AD targets and pathways will be tested for upcoming research for traditional Chinese medicinal herb interactions

In this work, we have studied the propagation of ultrasonic waves of lysozyme solutions characterized by different degrees of aggregation and networking. The experimental investigation has been performed by means of the Transient Grating (TG) spectroscopy as a function of temperature; this technique enables to measure the ultrasonic acoustic proprieties over a wide time window, ranging from nanoseconds to milliseconds. The fitting of the measured TG signal allows the extraction of several dynamic properties, here we focused on the speed and the damping rate of sound. The temperature variation induces in the lysozyme solutions a series of processes: protein folding-unfolding, aggregation and sol-gel transition. Our TG investigation shows how these self-assembling phenomena modulate the sound propagation, affecting both the velocity and the damping rate of the ultrasonic waves. In particular, the damping of ultrasonic acoustic waves proves to be a dynamic property very sensitive to the protein conformational rearrangements and aggregation processes.

Protein-DNA interactions are critical for the successful functioning of all natural systems. The key role in these interactions is played by processes of protein search for specific sites on DNA. Although it has been studied for many years, only recently microscopic aspects of these processes became more clear. In this work, we present a review on current theoretical understanding of the molecular mechanisms of the protein target search. A comprehensive discrete-state stochastic method to explain the dynamics of the protein search phenomena is introduced and explained. Our theoretical approach utilizes a first-passage analysis and it takes into account the most relevant physical-chemical processes. It is able to describe many fascinating features of the protein search, including unusually high effective association rates, high selectivity and specificity, and the robustness in the presence of crowders and sequence heterogeneity.

Inflammatory bowel disease (IBD), including Crohn’s Disease (CD) and Ulcerative Colitis (UC) are chronic multifactorial disorders which affect the gastrointestinal tract with variable extent. Despite extensive research, their etiology and exact pathogenesis are still unknown. Cell-free DNAs (cfDNAs) are defined as any DNA fragments which are free from origin cell and able to circulate into bloodstream with or without microvescicles. CfDNAs are now being increasingly studied in different human diseases, like cancer or inflammatory diseases. However, to date it is unclear how IBD etiology is linked to cfDNAs in plasma. Extrachromosomal circular DNA (eccDNA) are non-plasmidic, nuclear, circular and closed DNA molecules found in all eukaryotes tested. CfDNAs appear to play an important role in autoimmune diseases, inflammatory processes, and cancer; recently, interest has also grown in IBD, and their role in the pathogenesis of IBD has been suggested. We now suggest that eccDNAs also plays a role in IBD. In this review we have comprehensively collected available knowledge in literature regarding cfDNA, eccDNA, and structures involving them such as neutrophil extracellular traps and exosomes, and their role in IBD. Finally, we focused on old and novel potential molecular therapies and drug delivery systems, such as nanoparticles, for IBD treatment.

Dear Ladies and Gentlemen, I thank you for suggesting to submit the manuscript with the title “Insulin resistance develops due to an imbalance in the synthesis of cyclic AMP and the natural cyclic AMP antagonist prostaglandylinositol cyclic phosphate (cyclic PIP)” to the Editorial Board of the MDPI journal Stresses, and I ask for consideration to publish it in the journal Stresses. It was previously submitted to the MDPI journal Int. J. Mol. Sci. (IJMS-195 6513), but it was found that 1) it would not fit within the scope of this special edition and 2) it would primarily deal with cyclic PIP and would have not enough literature citation on the topic insulin resistance. The present version of the manuscript is improved, but the content is the same. The goal of this review is not to write again a summary on nearly all reports on insulin resistance as this was done by Dr. Petersen and Dr. Shulman, whose review has 961 literature citations. The present manuscript compiles what is known on cyclic PIP in relation to insulin resistance and the reason of writing this manuscript was that the discovered facts on cyclic PIP synthesis allow to suggest how insulin resistance most likely starts. Hitherto, reports on insulin resistance did not come close to this question. I am convinced that the manuscript makes an essential contribution to the question what causes the development of insulin resistance, and I have to say that stress overload is one of the reasons. Unfortunately, I have to mention a topic, about which I do not like to talk. Years ago, research groups postulated with rigor that the mediator of insulin action would be a peptide and then they suggested various, extracellularly synthesized glycans as mediators. They caused confusions and a high degree of disbelief in the matter of mediators of insulin action. In my review on cyclic PIP in IUBMB Life from 2020, I wrote in the introduction that cyclic PIP should not be confused with these mediators. But I cannot write this in the introduction of every report. I am keeping fingers crossed so that the editor in charge will find fair and openminded reviewers. Last not least I confirm that neither the manuscript nor any part of its content is currently under consideration or published in another journal. Kind regards, Henrich Wasner, PhD, BioReg Biopharm, TiLab; University of Illinois at Chicago; 2242 West Harrison St., Ste. 201, Chicago, Il 60612; USA

Peptides of hydrolysates of food proteins are an easily digestible source of amino acids necessary for the body to adapt to physical stress. Commercially significant hydrolysates include whey protein, casein, and other animal proteins. Hydrolysates of plant proteins are gaining popularity, but they are less common, then animal ones. Soy protein isolate is promising for obtaining the hydrolysates due to its affordable price and balanced amino acid profile. However, there are no direct studies showing an improvement in the result of physical activity when eating soy protein isolate hydrolysate (SPIH). In this work, for the first time, the study was conducted on the safety and efficacy of SPIH during physical load on model animals (rats). It was shown that the hydrolysate did not lead to pathological changes in the viscera, food intake, and weight of animals did not differ from the control group (animals consumed whey protein). Under physical load rats enteral fed SPIH showed a tendency to adapt more quickly to physical stress than the control group and the group of animals that was fed by free amino acids. The metabolites of animal blood serum were studied by NMR spectroscopy. It was shown that by the 95th minute after feeding in the group of rats receiving SPIH, the difference of proteinogenic amino acids concentrations in blood between individuals was significantly less than in the groups receiving whey protein or a mixture of amino acids. In other words, individual biochemical and physiological characteristics of individuals did not affect the assimilation of amino acids of hydrolysate.

The less virulent human (h) coronaviruses (CoVs) 229E, NL63, OC43, and HKU1 cause mild, self-limiting respiratory tract infections, while the more virulent SARS-CoV-1, MERS-CoV, and SARS-CoV-2 have caused severe outbreaks. The CoV envelope (E) protein, an important contributor to the pathogenesis of severe hCoVs infections, may provide insight into this disparate severity of the disease. We, therefore, generated full-length E protein models for SARS-CoV-1, -2, MERS-CoV, HCoV-229E, and HCoV-NL63 and docked C-terminal peptides of each model to the PDZ domain of the human PALS1 protein. The PDZ-binding motif (PBM) of the SARS-CoV-1, -2, and MERS-CoV models adopted a more flexible, extended coil while the HCoV-229E and HCoV-NL63 models adopted a less flexible alpha helix. All the E peptides docked to PALS1 occupied the same binding site and the more virulent hCoV E peptides generally interacted more stably with PALS1 than the less virulent ones. We propose that the increased flexibility of the PBM in more virulent hCoVs may permit more stable binding to various host proteins, thereby possibly contributing to more severe disease. This is the first paper to model full-length 3D structures for both more virulent and less virulent hCoVs E proteins, providing novel insights for possible drug and/or vaccine development.

Intrinsically disordered proteins mediate crucial biological functions through their interactions with other proteins. Mutual synergistic folding (MSF) occurs when all interacting proteins are disordered, folding into a stable structure in the course of the complex formation. In these cases, the folding and binding processes occur in parallel, lending the resulting structures uniquely heterogeneous features. Currently there are no dedicated classification approaches that would take into account the particular biological and biophysical properties of MSF complexes. Here we present a scalable clustering-based classification scheme, built on redundancy-filtered features that describe the sequence and structure properties of the complexes, and the role of the interaction, which is directly responsible for structure formation. Using this approach, we define six major types of MSF complexes, corresponding to biologically meaningful groups. Hence, the presented method also shows that differences in binding strength, subcellular localization, and regulation are encoded in the sequence and structural properties of proteins. While current structure classification methods can also handle complex structures, we show that the developed scheme is fundamentally different, and since it takes into account defining features of MSF complexes, it serves as a better representation of structures arising through this specific interaction mode.

In this study, we utilized the UniProt database to extract breast cancer genes Total 2658 genes in Homo sapiens are obtain. Then 166 genes are taken and after delating duplicates 158 genes were remains. These genes were then analyzed for their biological pathways using Gene Ontology enrichment analysis through the Genecodis platform, resulting in the identification of 12 unique genes involved in disease pathways. Protein-protein interaction (PPI) network analysis was conducted using the STRING database and Cytoscape software, identifying ANLN,TREM1,LZTFL1,OXSM,PLA2G3,TAS2R13,ABCB10,ECT2,TRPC,BCAS3,PLA2G3,ZDHHC7 and ERBB2 as potential gene targets for breast cancer.

Proteomic analysis of purified rabies virus (RABV) revealed 47 entrapped host proteins within viral particles. Out of these, 11 proteins were highly disordered. Our study was particularly focused on five of the RABV-entrapped mouse proteins with the highest levels of disorder, Neuromodulin, Chmp4b, DnaJB6, Vps37B, and Wasl. We extensively utilized bioinformatics tools, such as FuzDrop, D2P2, UniProt, RIDAO, STRING, AlphaFold, and ELM for comprehensive analysis of the intrinsic disorder propensity of these proteins. Our analysis suggested that these disordered host proteins might play a significant role in facilitating the rabies virus pathogenicity, immune system evasion, and the development of the antiviral drug resistance. Our study highlighted the complex interaction of the virus with its host, with the focus on how the intrinsic disorder can play a crucial role in virus pathogenic processes and suggested that these intrinsically disordered proteins (IDPs) and disorder-related host interactions can also be a potential target for the therapeutic strategies.

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.

Inflammatory bowel disease (IBD) comprises systemic inflammatory conditions primarily affecting the gastrointestinal tract, including Crohn's disease and ulcerative colitis. This research aims to analyze the clinical symptoms and pathogenesis of Dextran sodium sulfate (DSS)-induced canine IBD model, and evaluate the restorative effect of ginsenoside from a pathogenesis perspective. We established the DSS-induced canine IBD model and studied the pathological mechanisms. Additionally, we examined the therapeutic effect of ginsenosides by assessing the Canine Inflammatory Bowel Disease Activity Index (CIBDAI), C-reactive protein (CRP) levels, colonic tissue morphology, protein expression, and mucosal bacterial community analysis. Our findings revealed a total ginsenoside content of 22.7% in the ginsenoside extract. Animal experiments demonstrated that dogs with IBD exhibited decreased mental state, significantly increased CIBDAI and CRP levels, disrupted colonic epithelial tissue structure, decreased expression of mucin, tight junctions, and adherens junctions, as well as reduced diversity of the colonic mucosal bacterial community. Furthermore, correlation analysis highlighted a total of 38 bacterial strains correlated with physiological indices. Significantly, ginsenoside treatment could improve these symptoms and reverse the relative abundance of some bacterial communities. In conclusion, Alterations in the properties of the colonic mucus layer or the reduction of MUC2, its core component, in dogs with IBD can lead to bacterial penetration of the mucus layer and subsequent contact with intestinal epithelial cells, resulting in inflammation. Remarkably, ginsenoside intervention showcased the capacity to positively influence the relative abundance of bacteria and impact the colonic mucus layer properties, thereby offering promising prospects for IBD management and recovery.

Understanding the binding behavior and conformational dynamics of intrinsically disordered proteins (IDPs) is crucial for unraveling their regulatory roles in biological processes. However, their lack of stable 3D structures poses challenges for analysis. To address this, we propose an algorithm that explores IDP binding behavior with protein complexes by extracting topological and geometric features from the protein surface model. Our algorithm identifies a geometrically favorable binding pose for the IDP and plans a feasible trajectory to evaluate its transition to the docking position. We focus on IDPs from Homo sapiens and Mus-musculus, investigating their interaction with the Plasmodium Falciparum (PF) pathogen associated with malaria-related deaths. We compare our algorithm with HawkDock and HDOCK docking tools for quantitative (computation time) and qualitative (binding affinity) measures. Our results indicate that our method outperforms the compared methods in computation performance and binding affinity of experimental conformations.

Dual localization or dual targeting refers to the phenomenon by which identical, or almost identical, proteins are localized to two (or more) separate compartments of the cell. From previous work in the field, we had estimated that a third of the mitochondrial proteome is dual targeted to extra-mitochondrial locations and suggested that this abundant dual targeting presents an evolutionary advantage. Here we set out to study how many additional proteins whose main activity is outside mitochondria are also localized, albeit at low levels, to mitochondria (eclipsed). To do this we employed two complementary approaches utilizing the α-complementation assay in yeast to uncover the extent of such eclipsed distribution: one systematic and unbiased and the other based on Mitochondrial Targeting Signal (MTS) predictions. Using these approaches, we suggest 280 new eclipsed distributed protein candidates. Interestingly, these proteins are enriched for distinctive properties compared to their exclusively mitochondrial-targeted counterparts. We focus on one unexpected eclipsed protein-family of the Triose-phosphate DeHydrogenases (TDH), and prove that indeed their eclipsed distribution in mitochondria is important for mitochondrial activity. Our work provides a paradigm of deliberate eclipsed mitochondrial localization, targeting and function, and should expand our understanding of mitochondrial function in health and disease.

Specialized classes of proteins, working together in a tightly orchestrated manner, induce and maintain highly curved cellular and organelles membrane morphology. Due to the various ex- perimental constraints, including the resolution limits of imaging techniques, it is non-trivial to accurately elucidate interactions among the various components involved in membrane deformation. The spatial and temporal scales of the systems also make it formidable to investigate them using simulations with molecular details. Interestingly, mechanics-based mesoscopic models have been used with great success in recapitulating the membrane defor- mations observed in experiments. In this review, we collate together and discuss the various mechanics based mesoscopic models for protein-mediated membrane deformation studies. In particular, we provide an elaborate description of a mesoscopic model where the membrane is modeled as a triangulated sheet and proteins are represented as either nematics or fila- ments. This representation allows us to explore the various aspects of protein-protein and protein-membrane interactions as well as examine the underlying mechanistic pathways for emergent behavior such as curvature-mediated protein localization and membrane deforma- tion. We also put forward current efforts in the field towards back-mapping these mesoscopic models to finer-grained particle based models - a framework that could be used to explore how molecular interactions propagate to physical scales and vice-versa. We end the review with an integrative-modeling based road map where experimental imaging micrograph and biochemical data are combined with mesoscopic and molecular simulations methods in a theoretically consistent manner to faithfully recapitulate the multiple length and time scales in the membrane remodeling processes.

Herein, we are proposing two chalcone molecules, (E)-1-(4-methoxyphenyl)-3-(p-tolyl) prop-2-en-1-one and (E)-3-(4-hydroxyphenyl)-1-(2,4,6-trihydroxyphenyl) prop-2-en-1-one, based on the anticancer bioactive molecule Xanthohumol, which are suitable for further in vitro and in vivo studies. Their ability to create stable complexes with the antiapoptotic X-linked IAP (XIAP) protein makes them promising anticancer agents. The calculations were based on ligand-based and structure-based virtual screening combined for the pharmacophore built. Additionally, the structures passed Lipinski's rule for drug use, and their reactivity was confirmed using density functional theory studies. The candidates were chosen between 10639400 compounds, and the docking protocols were evaluated using molecular dynamics simulations.

The interaction of human immunodeficiency virus with human cells is responsible for all stages of the viral life cycle, from the infection of CD4+ cells to reverse transcription, integration, and the assembly of new viral particles. To date, a large amount of OMICs data as well as information from functional genomics screenings regarding the HIV-1-host interaction has been accumulated in the literature and in public databases. We processed databases containing HIV-host interactions and found 2910 HIV-1-human protein-protein interactions, mostly related to viral group M subtype B, 137 interactions between human and HIV-1 coding and non-coding RNAs, essential for viral lifecycle and cell defense mechanisms, 232 transcriptomics, 27 proteomics, and 34 epigenomics HIV-related experiments. Numerous studies regarding network-based analysis of corresponding OMICs data have been published in recent years. We overview various types of molecular networks, which can be created using OMICs data, including HIV-human protein-protein interaction networks, co-expression networks, gene regulatory and signaling networks, and approaches for the analysis of their topology and dynamics. The network-based analysis can be used to determine the critical pathways and key proteins involved in the HIV life cycle, cellular and immune responses to infection, viral escape from host defense mechanisms, and mechanisms mediating different susceptibility of humans to infection. The proteins and pathways identified in these studies may represent a basis for developing new anti-HIV therapeutic strategies such as new small-molecule drugs preventing infection of CD4+ cells and viral replication, effective vaccines, "shock and kill" and "block and lock" approaches to cure latent infection.

The description of protein disordered states is important for understanding protein folding mechanisms and their functions. In this short review, we briefly describe a simulation approach to modeling disordered protein interactions and unfolded states of globular proteins. It is based on the CABS coarse-grained protein model that uses a Monte Carlo (MC) sampling scheme and a knowledge-based statistical force field. We review several case studies showing that description of protein disordered states resulting from CABS simulations is consistent with experimental data. The case studies comprise investigations of protein-peptide binding and protein folding processes. The CABS model has been recently made available as the simulation engine of multiscale modeling tools enabling studies of protein-peptide docking and protein flexibility. Those tools offer customization of the modeling process, driving the conformational search using distance restraints, reconstruction of selected models to all-atom resolution and studies of large protein systems in a reasonable computational time. Therefore, CABS can be combined in integrative modeling pipelines incorporating experimental data and other modeling tools of various resolution.

This study throws more light on the new Co-free and Ni-rich LiNi0.8Mn0.1Fe0.1O2 cathode material for lithium-ion batteries. This cobalt-free cathode material is prepared using a two-step process: the formation of an oxalate precursor by co-precipitation followed by a solid-state reaction with lithium hydroxide and iron citrate. The physico-chemical properties of LiNi0.8Mn0.1Fe0.1O2 are characterized using X-ray diffraction, Raman spectroscopy, scanning electron microscopy, thermal gravimetric analysis, and energy dispersive X-ray spectroscopy, respectively. The LiNi0.8Mn0.1Fe0.1O2 electrode tested at at C/2 rate within voltage window of 3.0-4.4 V vs. Li+/Li delivers a specific capacity of ~80 mAh g-1 and retain about 45% of its initial capacity after 100 cycles.

This work focuses on the well-known issue of mass conservation in the context of the finite element technique for computational fluid dynamic simulations. Specifically, non-conventional finite element families for solving Navier-Stokes equations are investigated to address the mathematical constraint of incompressible flows. Raviart-Thomas finite elements are employed for the achievement of a discrete free-divergence velocity. In particular, the proposed algorithm projects the velocity field into the discrete free-divergence space by using the lowest-order Raviart-Thomas element. This decomposition is applied in the context of the projection method, a numerical algorithm employed for solving Navier-Stokes equations. Numerical examples validate the approach’s effectiveness, considering different types of computational grids. Additionally, the presented paper considers an interface advection problem using marker approximation, in the context of multiphase flow simulations. Numerical tests, equipped with an analytical velocity field for the surface advection, are presented to compare exact and non-exact divergence-free velocity interpolation.

Background/Objectives: An age-associated increase in serum levels of sex hormone binding globulin (SHBG) is considered to be one of the factors leading to the development of male hy-pogonadism. Aim of the study: to study the relationship between the concentration of sex hor-mone-binding globulin in the blood serum and the age of the man, the level of total and free testosterone. A single-center retrospective cross-sectional study was conducted. The results of laboratory tests of 162 male patients aged from 18 to 56 years (median - 34 years) were analyzed. Methods: The level of total testosterone and sex hormone binding globulin (SHBG) was deter-mined by chemiluminescent immunoassay. The level of free testosterone was determined by the calculation method according to Vermeullen. Statistical analysis was performed using SPSS Sta-tistics v23. Results: Correlation analysis did not reveal a significant relationship between age and SHBG levels, as well as between age and total testosterone levels. Serum SHBG concentration showed a significant (p

In this paper we define families of open sets as sums of idempotent ideals and sums of square-free ideals in a ring. We investigate some topological properties of such topologies. We define the square-free spectrum of a ring as the set of all square-free ideals and examine what topological properties it has for a given monoid.

The stability issues in the widely known organic inorganic halide perovskite, CH3NH3PbI3, lead to the development of alternative halide double perovskite materials which get great attention in recent times. Although the stability issue seems promising, both materials and device performance of these photovoltaic materials remain inferior and challenging for improvements. Furthermore, the power conversion efficiency of single junction organic inorganic halide perovskite is now 24.2% and 29.15% for textured monolithic perovskite/silicon tandem solar cell, but for all-inorganic halide perovskite solar cell is 7.11% and halide double perovskite solar cells based on Cs2AgBiBr6 and Cs2TiBr6 is 2.8% and 3.3%, respectively, which is far less than 24.2% and 29.15%, respectively. This creates big question and concern that can both all-inorganic halide perovskite solar cell and halide double perovskites solar cells really be an acceptable alternatives to replace organic inorganic halide perovskite solar cells or lead based perovskite solar cells in the market in order to realize the practical applications? Not only this concern, but also there are many other big challenges facing by halide double perovskite solar cells. Such big challenges include: a) geometric constraints and limited integration with interfacial materials, b) dynamic disorder and a wide bandgap and localized conduction band caused by cubic unit cell which restrains the interactions of orbitals, c) high processing temperature which may limit on the diverse applications, d) low electronic dimensionality making them less appropriate for single junction solar cell purpose and etc. Moreover, origin of electronic and optical properties such as the polarizability, the presence of molecular dipoles and their influence on the dynamics of the photo-excitations in the halide double perovskites remains unlock concern that need to be elucidated. Now, another big question is how to develop overcoming mechanisms for such challenges. Can we really overcome these current limitations faced by halide double perovskites so that we use them for commercialization? This research roadmap for performance improvement is suggested focusing on: materials surface and bulk engineering, bandgap engineering, interfacial engineering, composition engineering, doping engineering, device architectural engineering, polar and domain order engineering. This was the reason that this review was developed in order to forward great contributions to the readers and commercial ventures.

Colorectal cancer is the third most diagnosed cancer in males and in females, representing 8% of estimated new cases and the third cause of cancer-related death in both sexes, accounting for 9% of cancer deaths in men and 8% in women. About 20% of patients diagnosed with CRC present metastatic disease. Although lung metachronous or synchronous metastatic spread without other involved sites has been reported in only a small proportion of patients, considering that this tumor is frequently diagnosed, the clinical approach to CRC pulmonary metastases represents a major issue for thoracic surgeons and CRC oncologists. Among patients diagnosed with pulmonary metastases from CRC, about 9 – 12% are eligible for local treatments with radical intent, including surgical resection, SBRT and ablation therapy. Due to the lack of randomized controlled trials among different local strategies, there is no definitive evidence about the optimal approach, although surgical resection is considered the most effective therapeutic option in this clinical scenario. Oncological achievement of primary radical resection, the biology of primary tumor and metastatic sites, disease free interval and or progression free survival are independent prognostic factors which make it possible to define a cohort of patients which might significantly benefit from pulmonary metastasectomy.

Nucleosomes are non-uniformly distributed across eukarytic genomes, with stretches of ‘open’ chromatin strongly associated with transcriptionally active promoters and enhancers. Understanding chromatin accessibility patterns in normal tissue and how they are altered in pathologies can provide critical insights to development and disease. With the advent of high-throughput sequencing, a variety of strategies have been devised to identify open regions across the genome, including DNase-seq, MNase-seq, FAIRE-seq, ATAC-seq, and NicE-seq. However, the broad application of such methods to FFPE (formalin-fixed paraffin embedded) tissues has been curtailed by the major technical challenges imposed by highly fixed and damaged genomic material. Here we review the most common approaches for mapping open chromatin regions, recent optimizations to overcome the challenges of working with FFPE tissue, and a brief overview of a typical data pipeline with analysis considerations.