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Alcohol abuse, a global health problem, is closely associated with many pathological processes, such as dyslipidemia and cardiovascular disease. In particular, excessive alcohol consumption promotes dyslipidemia and liver damage, such as hepatic steatosis, fibrosis, and cirrhosis. Beeswax alcohol (BWA) is a natural product used for its antioxidant properties that has not been evaluated for its efficacy in alcohol-induced liver injury. In the present study, zebrafish were exposed to 1% ethanol with supplementation of 10% fermented black rice bran (BRB-F), 10% BWA, or 10% mixtures of BWA+BRB-F (MIX). The BRB-F, BWA, and MIX supplementation increased the survival rate dramatically without affecting the body weight changes. In histology of hepatic tissue, alcoholic foamy degeneration was ameliorated by the BWA or MIX supplements. Moreover, dihydroethidium (DHE) and immunohistochemistry staining suggested that the MIX supplement decreased the hepatic ROS production and interleukin-6 expression significantly owing to the enhanced antioxidant properties, such as paraoxonase. Furthermore, the MIX supplement improved alcohol-induced dyslipidemia and oxidative stress. The BWA and MIX groups showed lower blood total cholesterol (TC) and triglyceride (TG) levels with higher high-density lipoprotein-cholesterol (HDL-C) than the alcohol-alone group. The MIX group showed the highest HDL-C/TC ratio and HDL-C/TG ratio with the lowest low-density lipoprotein (LDL)-C/HDL-C ratio. In conclusion, BWA and BRB-F showed efficacy to treat alcohol-related metabolic disorders, but the MIX supplement was more effective in ameliorating the liver damage and dyslipidemia, which agrees with an enhanced antioxidant and anti-inflammatory activity exhibited by BWA/BRB-F in a synergistic manner.

Glutamate is the major excitatory neurotransmitter in the central nervous system, and there is evidence that Group-I metabotropic glutamate receptors (mGlu1 and mGlu5) have established roles in excitatory neurotransmission and synaptic plasticity. While glutamate is abundantly present in the gut, it plays a smaller role in neurotransmission in the enteric nervous system. In this study, we examined the roles of Group-I mGlu receptors in gastrointestinal function. We investigated the expression of Grm1 (mGlu1) and Grm5 (mGlu5) in the mouse myenteric plexus using RNAscope in situ hybridization. Live calcium imaging and motility analysis were performed on ex vivo preparations of the mouse colon. mGlu5 was found to play a role in excitatory enteric neurotransmission, as electrically-evoked calcium transients were sensitive to the mGlu5 antagonist MPEP. However, inhibition of mGlu5 activity did not affect colonic motor complexes (CMCs). Instead, inhibition of mGlu1 using BAY 36-7620 reduced CMC frequency but did not affect enteric neurotransmission. These data highlight complex roles for Group-I mGlu receptors in myenteric neuron activity and colonic function.

Gum arabic (GA) is a natural product commonly used as a household remedy for treating various diseases in the Sub-Saharan Africa region. Despite its claimed benefits, there has been a lack of research on the findings of current clinical trials (CTs) that investigated its efficacy in the treatment of various medical diseases. The aim of this systematic review was to study CTs which focused on GA and its possible use in the management of various medical diseases. A search of the extant literature was performed in the PubMed, Scopus, and Cochrane databases to retrieve CTs focusing on evidence-based clinical indications. The databases were searched using the keywords ("Gum Arabic" OR "Acacia senegal" OR "Acacia seyal" OR "Gum Acacia" OR "Acacia Arabica") AND ("Clinical Trial" OR "Randomized Controlled Trial" OR "Randomized Clinical Trial"). While performing the systematic review, data were obtained on the following parameters: title, authors, date of publication, study design, study aim, sample size, type of intervention used, targeted medical diseases, and main findings. Twenty-nine papers were included in this systematic review. The results showed that ingestion of GA altered lipid profiles, renal profiles, plaque, gingival scores, biochemical parameters, blood pressure, inflammatory markers, and adiposity. GA exhibited anti-inflammatory, prebiotic, and antibacterial properties. GA has been successfully used to treat sickle cell anemia, rheumatoid arthritis, metabolic disorders, periodontitis, gastrointestinal conditions, and kidney diseases. Herein, we discuss GA with respect to the underlying mechanisms involved in each medical disease, thereby justifying GA's future role as a therapeutic agent.

Campylobacter jejuni is likely the most common bacterial cause of gastroenteritis worldwide, responsible for millions of cases of inflammatory diarrhea characterized by severe abdominal cramps and blood in the stool. Further, C. jejuni infections are associated with post-infection sequelae in developed countries and malnutrition and growth-stunting in low- and middle-income countries. Despite the increasing prevalence of the disease, campylobacteriosis, and the recognition that this pathogen is a serious health threat, our understanding of C. jejuni pathogenesis remains incomplete. In this review, we focus on the Campylobacter secretion systems proposed to contribute to host-cell interactions and survival in the host. Moreover, we have applied a genomics approach to defining the structural and mechanistic features of C. jejuni type III, IV, and VI secretion systems. Special attention is focused on the flagellar type III secretion system and the prediction of putative effectors, given that the proteins exported via this system are essential for host cell invasion and the inflammatory response. We conclude that C. jejuni does not possess a type IV secretion system and relies on the type III and type VI secretion systems to establish a niche and potentiate disease.

Elucidating protein-ligand interaction is crucial for studying the function of proteins and compounds in an organism and critical for drug discovery and design. The problem of protein-ligand interaction is traditionally tackled by molecular docking and simulation, which is based on physical forces and statistical potentials and cannot effectively leverage cryo-EM data and existing protein structural information in the protein-ligand modeling process. In this work, we developed a deep learning bioinformatics pipeline (DeepProLigand) to predict protein-ligand interactions from cryo-EM density maps of proteins and ligands. DeepProLigand first uses a deep learning method to predict the structure of proteins from cryo-EM maps, which is averaged with a reference (template) structure of the proteins to produce a combined structure to add ligands. The ligands are then identified and added into the structure to generate a protein-ligand complex structure, which is further refined. The method based on the deep learning prediction and template-based modeling was blindly tested in the 2021 EMDataResource Ligand Challenge and was ranked first in fitting ligands to cryo-EM density maps. These results demonstrate that the deep learning bioinformatics approach is a promising direction for modeling protein-ligand interactions on cryo-EM data using prior structural information.

Several studies have identified rare and common genetic variants associated with severe COVID-19, but no study has reported genetic determinants as predisposition factors for neurological complications. In this report, we identified rare/unique structural variants (SVs) implicated in neurological functions in two individuals with neurological manifestations of COVID-19. This report highlights the possible genetic link to the neurological symptoms with COVID-19 and calls for a collective effort to study these cohorts for a possible genetic linkage.

Poly(3-hydroxybutyrate) (PHB) is a versatile thermoplastic with superior biodegradability and biocompatibility that is intracellularly accumulated by numerous bacterial and archaeal species. Priestia sp. strain JY310 that was able to efficiently biotransform reducing sugars in d-xylose-rich rice husk hydrolysate (reducing sugarRHH) to PHB was isolated from the soil of a rice paddy. Reducing sugarRHH including 12.5% d-glucose, 75.3% d-xylose, and 12.2% d-arabinose was simply prepared using thermochemical hydrolysis of 3% H2SO4-treated rice husk for 15 min at 121 °C. When cultured with 20 g/L reducing sugarRHH under optimized culture conditions in a batch bioreactor, Priestia sp. strain JY310 could produce PHB homopolymer up to 50.4% of cell dry weight (6.2 g/L). The melting temperature, heat of fusion, and thermal decomposition temperature of PHB were determined to be 167.9 °C, 92.1 J/g, and 268.1 °C, respectively. The number average and weight average molecular weights of PHB with a broad polydispersity index value (4.73) were estimated to be approximately 16.2 and 76.8 kg/mol, respectively. The findings of the present study suggest that Priestia sp. strain JY310 can be exploited as a good candidate for the low-cost production of low molecular weight PHB with improved biodegradability and reduced brittleness from inexpensive agricultural waste hydrolysates.

Structure-function relationships in proteins have been one of the crucial scientific topics in recent research. Heme proteins have diverse and pivotal biological functions. Therefore, clarifying their structure-function correlation is significant to understand their functional mechanism and is informative for various fields of science. In this study, we constructed convolutional neural network models for predicting protein functions from the tertiary structures of heme-binding sites (active sites) of heme proteins to examine the structure-function correlation. As a result, we succeeded in the classification of oxygen-binding protein (OB), oxidoreductase (OR), proteins with both functions (OB-OR), and electron transport protein (ET) with high accuracy. Although the misclassification rate for OR and ET was high, the rates between OB and ET and between OB and OR were almost zero, indicating that the prediction model works well between protein groups with quite different functions. However, predicting the function of proteins modified with amino acid mutation(s) remains a challenge. Our findings indicate a structure-function correlation in the active site of heme proteins. This study is expected to be applied to the prediction of more detailed protein functions such as catalytic reactions.

Tubulin superfamily (TSF) proteins are widespread, and are known for their multifaceted roles as cytoskeletal proteins underpinning many basic cellular functions, including morphogenesis, division, and motility. In eukaryotes, tubulin assembles into microtubules, a major component of the dynamic cytoskeletal network of fibres, whereas the bacterial homolog FtsZ assembles the division ring at midcell. The functions of the lesser-known archaeal TSF proteins are beginning to be identified and show surprising diversity, including homologs of tubulin and FtsZ as well as a third archaea-specific family, CetZ, implicated in the regulation of cell shape and possibly other unknown functions. In this study, we define sequence and structural characteristics of the CetZ family and CetZ1 and CetZ2 subfamilies, identify CetZ groups and diversity amongst archaea, and identify potential functional relationships through analysis of the genomic neighbourhoods of cetZ genes. We identified at least three subfamilies of orthologous CetZ proteins in the archaeal class Halobacteria, including CetZ1 and CetZ2 as well as a novel uncharacterized subfamily. CetZ1 and CetZ2 were correlated to one another as well as to cell shape and motility phenotypes across diverse Halobacteria. Among other known CetZ clusters in orders Archaeoglobales, Methanomicrobiales, Methanosarcinales, and Thermococcales, an additional uncharacterized group from Archaeoglobales and Methanomicrobiales is affiliated strongly with Halobacteria CetZs, suggesting that they originated via horizontal transfer. Subgroups of Halobacteria CetZ2 and Thermococcales CetZ genes were found adjacent to different type IV pili regulons, suggesting potential utilization of CetZs by type IV systems. More broadly conserved cetZ gene neighbourhoods include nucleotide and cofactor biosynthesis (e.g., F420) and predicted cell surface sugar epimerase genes. These findings imply that CetZ subfamilies are involved in multiple functions linked to the cell surface, biosynthesis, and motility.

The membrane of the human red cell consists of a lipid bilayer and a so-called membrane skeleton attached on the cytoplasmic side of the bilayer. Upon the deformation of red cells, energy is dissipated in their cytoplasm and their membrane. As to the membrane, three contributions can be distinguished: (i) A two-dimensional shear deformation with the membrane viscosity as the frictional parameter; (ii) A motion of the membrane skeleton relative to the bilayer; (iii) A relative motion of the two monolayers of the bilayer. The frictional parameter in contributions (ii) and (iii) is a frictional coefficient specific for the respective contribution. This perspective describes the history up to recent advances in the knowledge of these contributions. It reviews the mechanisms of energy dissipation on a molecular scale and suggests new ones, particularly for the first contribution. It proposes a parametric fitting expected to shed light on the discrepant values found for the membrane viscosity by different experimental approaches. It proposes strategies that could allow the determination of the frictional coefficients pertaining to the second and the third contribution. It highlights the consequences characteristic times have on the state of the red cell membrane in circulation as well as on the adaptation of computer models to the red cell history in an in vitro experiment.

DNA is an attractive material for a range of applications in nanoscience and nanotechnology, and it has recently been demonstrated that the electronic properties of DNA are uniquely sensitive to its sequence and structure, opening new opportunities for the development of electronic DNA biosensors. In this report, we examine the origin of multiple conductance peaks that can occur during single-molecule break-junction (SMBJ)-based conductance measurements on DNA. We demonstrate that these peaks originate from the presence of multiple DNA conformations within the solutions, in particular, double-stranded B-form DNA (dsDNA) and G-quadruplex structures. Using a combination of circular dichroism (CD) spectroscopy, computational approaches, sequence and environmental controls, and single-molecule conductance measurements, we disentangle the conductance information and demonstrate that specific conductance values come from specific conformations of the DNA and that the occurrence of these peaks can be controlled by controlling the local environment. In addition, we demonstrate that conductance measurements are uniquely sensitive to identifying these conformations in solutions and that multiple configurations can be detected in solutions over an extremely large concentration range, opening new possibilities for examining low-probability DNA conformations in solutions.

Osteoarthritis (OA) is the one of most common joint diseases worldwide. Cuproptosis, which had been discovered lately, is a novel form of cell death induced by copper. Our purpose is to study the relationship between cuproptosis-related genes (CRGs) and inflammatory microenvironments in patients with OA and identify characteristic cuproptosis-related biomarkers. First, the combinatory analysis of OA transcriptome data from five datasets identified differentially expressed CRGs associated with OA. Then, we applied single-sample gene set enrichment analysis (ssGSEA) to evaluate immune-cell infiltration and immune-function levels in OA patients and normal controls, respectively. Hub CRGs for OA were mined based on the random forest (RF) model, and a nomogram prediction model was constructed based on them. In total, four differentially expressed CRGs were identified through bioinformatics analysis and confirmed by RT-qPCR. FDX1 and LIPT1 were expressed at a high level in OA, while DBT and DLST were expressed higher in the normal group. In total, 10 CRGs were found to be significantly correlated with immune landscape. Four hub CRGs were subsequently obtained by the RF analysis as potential biomarkers for OA. We constructed an OA predictive model based on these four CRGs (DBT, DLST, FDX1, and LIPT1).

Mitochondrial diabetes (MD) is generally classified as a genetic defect of β-cells. The main pathophysiology is insulin secretion failure in pancreatic β-cells due to impaired mitochondrial ATP production. However, several reports have mentioned the presence of insulin resistance (IR) as a clinical feature of MD. As mitochondrial dysfunction is one of the important factors causing IR, we need to focus on IR as another pathophysiology of MD. In this special issue, we first briefly summarized the insulin signaling and molecular mechanisms of IR. Second, we overviewed currently confirmed pathogenic mitochondrial DNA (mtDNA) mutations from the MITOMAP database. The variants causing diabetes were mostly point mutations in the transfer RNA (tRNA) of the mitochondrial genome. Third, we focused on these variants leading to the recently described "tRNA modopathies" and reviewed the clinical features of patients with diabetes. Finally, we discussed the pathophysiology of MD caused by mtDNA mutations and explored the possible mechanism underlying the development of IR. This review should be beneficial to all clinicians involved in diagnostics and therapeutics related to diabetes and mitochondrial diseases.

Replication stress has been suggested to be an ultimate trigger of carcinogenesis. Oncogenic signal, such as overexpression of CyclinE, has been shown to induce replication stress. Here, we show that various biological stresses, including heat, oxidative stress, osmotic stress, LPS, hypoxia, and arsenate induce activation of Chk1, a key effector kinase for replication checkpoint. Some of these stresses indeed reduce the fork rate, inhibiting DNA replication. Analyses of Chk1 activation in the cell population with Western analyses showed that Chk1 activation by these stresses is largely dependent on Claspin. On the other hand, single cell analyses with Fucci cells indicated that while Chk1 activation during S phase is dependent on Claspin, that in G1 is mostly independent of Claspin. We propose that various biological stresses activate Chk1 either directly by stalling DNA replication fork or by some other mechanism that does not involve replication inhibition. The former pathway predominantly occurs in S phase and depends on Claspin, while the latter pathway, which may occur throughout the cell cycle, is largely independent of Claspin. Our findings provide evidence for novel links between replication stress checkpoint and other biological stresses and point to the presence of replication-independent mechanisms of Chk1 activation in mammalian cells.

The binding interactions of six ligands, neutral and monocationic asymmetric monomethine cyanine dyes comprising benzoselenazolyl moiety with duplex DNA and RNA and G-quadruplex structures were evaluated using fluorescence, UV/Vis (thermal melting) and circular dichroism (CD) spectroscopy. The main objective was to assess the impact of different substituents (methyl vs. sulfopropyl vs. thiopropyl/thioethyl) on the nitrogen atom of the benzothiazolyl chromophore on various nucleic acid structures. The monomethine cyanine dyes with methyl substituents showed a 100-fold selectivity for G-quadruplex versus duplex DNA. Study results indicate that cyanines bind with G-quadruplex via end π-π stacking interactions and possible additional interactions with nucleobases/phosphate backbone of grooves or loop bases. Cyanine with thioethyl substituent distinguishes duplex DNA and RNA and G-quadruplex structures by distinctly varying ICD signals. Furthermore, cell viability assay reveals the submicromolar activity of cyanines with methyl substituents against all tested human cancer cell lines. Confocal microscopy analysis shows preferential accumulation of cyanines with sulfopropyl and thioethyl substituents in mitochondria and indicates localization of cyanines with methyl in nucleus, particularly nucleolus. This confirms the potential of examined cyanines as theranostic agents, possessing both fluorescent properties and cell viability inhibitory effect.

Intense study of intrinsically disordered proteins (IDPs) did not begin in earnest until the late 1990s when a few groups, working independently, convinced the community that these 'weird' proteins could have important functions. Over the past two decades, it has become clear that IDPs play critical roles in a multitude of biological phenomena with prominent examples including coordination in signaling hubs, enabling gene regulation, and regulating ion channels, just to name a few. One contributing factor that delayed appreciation of IDP functional significance is the experimental difficulty in characterizing their dynamic conformations. The combined application of multiple methods, termed integrative structural biology, has emerged as an essential approach to understanding IDP phenomena. Here, we review some of the recent applications of the integrative structural biology philosophy to study IDPs.