Molecular Perspective Research Articles

Nonspecific Orbital Inflammation (NSOI): Unraveling the Molecular Pathogenesis, Diagnostic Modalities, and Therapeutic Interventions.

Nonspecific orbital inflammation (NSOI), colloquially known as orbital pseudotumor, sometimes presents a diagnostic and therapeutic challenge in ophthalmology. This review aims to dissect NSOI through a molecular lens, offering a comprehensive overview of its pathogenesis, clinical presentation, diagnostic methods, and management strategies. The article delves into the underpinnings of NSOI, examining immunological and environmental factors alongside intricate molecular mechanisms involving signaling pathways, cytokines, and mediators. Special emphasis is placed on emerging molecular discoveries and approaches, highlighting the significance of understanding molecular mechanisms in NSOI for the development of novel diagnostic and therapeutic tools. Various diagnostic modalities are scrutinized for their utility and limitations. Therapeutic interventions encompass medical treatments with corticosteroids and immunomodulatory agents, all discussed in light of current molecular understanding. More importantly, this review offers a novel molecular perspective on NSOI, dissecting its pathogenesis and management with an emphasis on the latest molecular discoveries. It introduces an integrated approach combining advanced molecular diagnostics with current clinical assessments and explores emerging targeted therapies. By synthesizing these facets, the review aims to inform clinicians and researchers alike, paving the way for molecularly informed, precision-based strategies for managing NSOI.

Bile Acid Diarrhea: From Molecular Mechanisms to Clinical Diagnosis and Treatment in the Era of Precision Medicine.

Bile acid diarrhea (BAD) is a multifaceted intestinal disorder involving intricate molecular mechanisms, including farnesoid X receptor (FXR), fibroblast growth factor receptor 4 (FGFR4), and Takeda G protein-coupled receptor 5 (TGR5). Current diagnostic methods encompass bile acid sequestrants (BAS), 48-h fecal bile acid tests, serum 7α-hydroxy-4-cholesten-3-one (C4), fibroblast growth factor 19 (FGF19) testing, and 75Selenium HomotauroCholic acid test (75SeHCAT). Treatment primarily involves BAS and FXR agonists. However, due to the limited sensitivity and specificity of current diagnostic methods, as well as suboptimal treatment efficacy and the presence of side effects, there is an urgent need to establish new diagnostic and treatment methods. While prior literature has summarized various diagnostic and treatment methods and the pathogenesis of BAD, no previous work has linked the two. This review offers a molecular perspective on the clinical diagnosis and treatment of BAD, with a focus on FXR, FGFR4, and TGR5, emphasizing the potential for identifying additional molecular mechanisms as treatment targets and bridging the gap between diagnostic and treatment methods and molecular mechanisms for a novel approach to the clinical management of BAD.

Advances in the Involvement of Metals and Metalloids in Plant Defense Response to External Stress.

Plants, as sessile organisms, uptake nutrients from the soil. Throughout their whole life cycle, they confront various external biotic and abiotic threats, encompassing harmful element toxicity, pathogen infection, and herbivore attack, posing risks to plant growth and production. Plants have evolved multifaceted mechanisms to cope with exogenous stress. The element defense hypothesis (EDH) theory elucidates that plants employ elements within their tissues to withstand various natural enemies. Notably, essential and non-essential trace metals and metalloids have been identified as active participants in plant defense mechanisms, especially in nanoparticle form. In this review, we compiled and synthetized recent advancements and robust evidence regarding the involvement of trace metals and metalloids in plant element defense against external stresses that include biotic stressors (such as drought, salinity, and heavy metal toxicity) and abiotic environmental stressors (such as pathogen invasion and herbivore attack). We discuss the mechanisms underlying the metals and metalloids involved in plant defense enhancement from physiological, biochemical, and molecular perspectives. By consolidating this information, this review enhances our understanding of how metals and metalloids contribute to plant element defense. Drawing on the current advances in plant elemental defense, we propose an application prospect of metals and metalloids in agricultural products to solve current issues, including soil pollution and production, for the sustainable development of agriculture. Although the studies focused on plant elemental defense have advanced, the precise mechanism under the plant defense response still needs further investigation.

Effect of phenyl functional groups on the adsorption behaviour of dodecyl anionic emulsifiers on oxides on the aggregate surface

ABSTRACT Emulsified asphalt finds extensive application in pavement repair, addressing issues like road ruts and cracks. While the adsorption behaviour of emulsifiers on oxide surfaces (CaCO3 and SiO2) of aggregates is influenced by the presence of phenyl functional groups, the precise mechanism of this influence remains insufficiently understood. This study employs molecular dynamics models and macroscopic experiments to investigate the mechanism involving emulsifiers, sodium ions, and water at aggregate interfaces, quantifying the role of phenyl functional groups from a molecular perspective. The results reveal the following: strong electrostatic attraction between alkaline aggregates and Na+, leading to substantial Na+ adsorption. The phenyl functional groups reduce diffusion coefficient, adsorption energy, and amounts in alkaline aggregates (−34.6%, −16%, −12.5%), while increasing them in acidic aggregates (+15.9%, + 14.7%, + 27.7%). The phenyl functional groups impact hydrogen bond acceptors, TPSA, and emulsifier complexity, altering adsorption. They enhance emulsifier electrostatic potential, affecting adsorption on different surfaces. In summary, this ongoing research framework aims to fine-tune emulsifiers through the use of phenyl functional groups, enhancing adsorption strength, adsorption amount, and diffusion between emulsifiers and aggregates. This work holds great significance for optimizing emulsifier molecular structures.

Characterizing the Molecular Mechanism of the Lethal C423D Mutation in FgMyoI: A Molecular Perspective.

The lethal mutation C423D in Fusarium graminearum myosin I (FgMyoI) occurs close to the binding pocket of the allosteric inhibitor phenamacril and causes severe inhibition on mycelial growth of F. graminearum strain PH-1. Here, based on extensive Gaussian accelerated molecular dynamics simulations and wet experiments, we elucidate the underlying molecular mechanism of the abnormal functioning of the FgMyoIC423D mutant at the atomistic level. Our results suggest that the damaging mutation C423D exhibits a synergistic allosteric inhibition mechanism similar to but more robust than that of phenamacril, including effects on the active site and actin binding. Unlike phenamacril-induced closure of Switch2, the mutation results in unfolding of the N-terminal relay helix with a partially opened Switch2 and blocks the structural rearrangement of the relay/SH1 helices, impairing the proper initiation of the recovery stroke. Due to the significant influence of C423D mutation on the function of FgMyoI, designing covalent inhibitors targeting this site holds tremendous potential.

Molecular Docking Perspectives on Phytochemicals: Optimizing Dairy Animal Health through Feed Additives

Molecular Docking Perspectives on Phytochemicals: Optimizing Dairy Animal Health through Feed Additives

Molecular study of the KCNJ11 gene and its correlation with Prakriti to preventing and managing type 2 diabetes

In Ayurveda, every individual is believed to possess a unique entity known as Prakriti, which distinguishes them from others physically, physiologically, and psychologically. This entity also determines an individual's response to a particular stimulus, and it is believed that such responses are not solely determined by genetics. The present research aims to validate the Ayurvedic concept of Prakriti from a modern molecular perspective to strengthen the personalized and precise treatment approach. A study was conducted to investigate the role of the KCNJ11gene in the susceptibility of individuals to type 2 diabetes mellitus (T2DM) with their metabolic status. The research involved allele mining on three major Prakriti groups - Vata, Pitta, and Kapha - in 112 patients with T2DM and 112 healthy individuals. The KCNJ11 gene, responsible for insulin secretion membrane pore formation, was analyzed to determine the susceptibility of different Prakriti types to T2DM. The MutPred tool predicted the molecular cause of disease-related amino acid substitution. According to the study, only Pitta and Kapha Prakriti were diagnosed with diabetes, while all three Prakriti types were present in the control group of healthy individuals. A protein model was prepared, and the changes resulting from mutations were observed for each group in their protein sequence, both as synonymous and non-synonymous mutations. Ultimately, these changes contributed to the manifestation of T2DM. Based on the findings, it appears that Prakriti groups may experience changes in protein function due to nonsynonymous mutations and differences in amino acids at the protein level.

Hypoxia-Inducible Factor and Oxidative Stress in Tendon Degeneration: A Molecular Perspective.

Tendinopathy is a debilitating condition marked by degenerative changes in the tendons. Its complex pathophysiology involves intrinsic, extrinsic, and physiological factors. While its intrinsic and extrinsic factors have been extensively studied, the role of physiological factors, such as hypoxia and oxidative stress, remains largely unexplored. This review article delves into the contribution of hypoxia-associated genes and oxidative-stress-related factors to tendon degeneration, offering insights into potential therapeutic strategies. The unique aspect of this study lies in its pathway-based evidence, which sheds light on how these factors can be targeted to enhance overall tendon health.

The MSC-EV-microRNAome: A Perspective on Therapeutic Mechanisms of Action in Sepsis and ARDS.

Mesenchymal stromal cells (MSCs) and MSC-derived extracellular vesicles (EVs) have emerged as innovative therapeutic agents for the treatment of sepsis and acute respiratory distress syndrome (ARDS). Although their potential remains undisputed in pre-clinical models, this has yet to be translated to the clinic. In this review, we focused on the role of microRNAs contained in MSC-derived EVs, the EV microRNAome, and their potential contribution to therapeutic mechanisms of action. The evidence that miRNA transfer in MSC-derived EVs has a role in the overall therapeutic effects is compelling. However, several questions remain regarding how to reconcile the stochiometric issue of the low copy numbers of the miRNAs present in the EV particles, how different miRNAs delivered simultaneously interact with their targets within recipient cells, and the best miRNA or combination of miRNAs to use as therapy, potency markers, and biomarkers of efficacy in the clinic. Here, we offer a molecular genetics and systems biology perspective on the function of EV microRNAs, their contribution to mechanisms of action, and their therapeutic potential.

The unfolded protein response pathway as a possible link in the pathogenesis of COVID-19 and sepsis.

The global impact of the COVID-19 pandemic has been substantial. Emerging evidence underscores a strong clinical connection between COVID-19 and sepsis. Numerous studies have identified the unfolded protein response (UPR) pathway as a crucial pathogenic pathway for both COVID-19 and sepsis, but it remains to be investigated whether this signaling pathway operates as a common pathogenic mechanism for both COVID-19 and sepsis. In this study, single-cell RNA-seq data and transcriptome data for COVID-19 and sepsis cases were downloaded from GEO (Gene Expression Omnibus). By analyzing the single-cell transcriptome data, we identified B cells as the critical cell subset and the UPR pathway as the critical signaling pathway. Based on the transcriptome data, a machine learning diagnostic model was then constructed using the interleaved genes of B-cell-related and UPR-pathway-related genes. We validated the diagnostic model using both internal and external datasets and found the accuracy and stability of this model to be extremely strong. Even after integrating our algorithmic model with the patient's clinical status, it continued to yield identical results, further emphasizing the reliability of this model. This study provides a novel molecular perspective on the pathogenesis of sepsis and COVID-19 at the single-cell level and suggests that these two diseases may share a common mechanism.

Lysosomal Dysfunction: Connecting the Dots in the Landscape of Human Diseases.

Lysosomes are the main organelles responsible for the degradation of macromolecules in eukaryotic cells. Beyond their fundamental role in degradation, lysosomes are involved in different physiological processes such as autophagy, nutrient sensing, and intracellular signaling. In some circumstances, lysosomal abnormalities underlie several human pathologies with different etiologies known as known as lysosomal storage disorders (LSDs). These disorders can result from deficiencies in primary lysosomal enzymes, dysfunction of lysosomal enzyme activators, alterations in modifiers that impact lysosomal function, or changes in membrane-associated proteins, among other factors. The clinical phenotype observed in affected patients hinges on the type and location of the accumulating substrate, influenced by genetic mutations and residual enzyme activity. In this context, the scientific community is dedicated to exploring potential therapeutic approaches, striving not only to extend lifespan but also to enhance the overall quality of life for individuals afflicted with LSDs. This review provides insights into lysosomal dysfunction from a molecular perspective, particularly in the context of human diseases, and highlights recent advancements and breakthroughs in this field.

Multidimensional decipherment of interactions in invert sugar–amino acid co-degradation colorants (IACDCs) capture by polyamine co-modified shaddock peel cellulose/graphene oxide aerogel

The development of an environmentally friendly scavenger with an outstanding ability to eliminate IACDCs from molasses-based distillery wastewater is essential for the safety of aquatic ecosystems and organisms. By combining polyamine co-modified shaddock peel cellulose (SPC) and graphene oxide (GO), a multistage porous aerogel (i.e., CP-GO/SPA) was constructed for the highly effective capture of IACDCs. CP-GO/SPA exhibited a surprisingly high IACDC adsorption capacity (1157 mg/g, which was 1.5–100 times that of previously reported ones). It also had an ultrafast adsorption mass transfer (AMT) rate. Advanced AMT-resistance models reveal that the capture on active site is the main AMT resistance, whereas liquid-film and pore diffusion are quite fast. CP-GO/SPA exhibited excellent reusability (>90% IACDC removal efficiency after six cycles) and considerable potential for industrial applications (i.e., treatment of actual wastewater by fixed-bed adsorption). The polyamine co-modified SPC and GO endowed CP-GO/SPA with substantial amine groups and high affinity for water, as validated by advanced molecular dynamics simulations. These features are extremely conducive for capturing electronegative and water-soluble IACDCs. A series of characterizations and multiple quantum chemical theory calculations (including ETP, ALIE, FMOs, IGM, and HIS analyses) further revealed the adsorption mechanisms from a molecular perspective. The IACDC capture by CP-GO/SPA resulted from charge, electron sharing, and van der Waals interactions. However, charge interactions played a dominant role. The optimal capture configurations were visualized at the molecular level, and the H-bond donor–acceptor relationship was determined. The IACDCs act as H-bond acceptors in a diverse range of capture configurations.

Electrostatic Potential of Functional Cations as a Predictor of Hydroxide Diffusion Pathways in Nanoconfined Environments of Anion Exchange Membranes.

Nanoconfined anion exchange membranes (AEMs) play a vital role in emerging electrochemical technologies. The ability to control dominant hydroxide diffusion pathways is an important goal in the design of nanoconfined AEMs. Such control can shorten hydroxide transport pathways between electrodes, reduce transport resistance, and enhance device performance. In this work, we propose an electrostatic potential (ESP) approach to explore the effect of the polymer electrolyte cation spacing on hydroxide diffusion pathways from a molecular perspective. By exploring cation ESP energy surfaces and validating outcomes through prior ab initio molecular dynamics simulations of nanoconfined AEMs, we find that we can achieve control over preferred hydroxide diffusion pathways by adjusting the cation spacing. The results presented in this work provide a unique and straightforward approach to predict preferential hydroxide diffusion pathways, enabling efficient design of highly conductive nanoconfined AEM materials for electrochemical technologies.

Nano-hydroxyapatite promotes cell apoptosis by co-activating endoplasmic reticulum stress and mitochondria damage to inhibit glioma growth.

Despite a growing body of studies demonstrating the specific anti-tumor effect of nano-hydroxyapatite (n-HA), the underlying mechanism remained unclear. Endoplasmic reticulum (ER) and mitochondria are two key players in intracellular Ca2+ homeostasis and both require Ca2+ to participate. Moreover, the ER-mitochondria interplay coordinates the maintenance of cellular Ca2+ homeostasis to prevent any negative consequences from excess of Ca2+, hence there needs in-depth study of n-HA effect on them. In this study, we fabricated needle-like n-HA to investigate the anti-tumor effectiveness as well as the underlying mechanisms from cellular and molecular perspectives. Data from in vitro experiments indicated that the growth and invasion of glioma cells were obviously reduced with the aid of n-HA. It is interesting to note that the expression of ER stress biomarkers (GRP78, p-IRE1, p-PERK, PERK, and ATF6) were all upregulated after n-HA treatment, along with the activation of the pro-apoptotic transcription factor CHOP, showing that ER stress produced by n-HA triggered cell apoptosis. Moreover, the increased expression level of intracellular reactive oxygen species and the mitochondrial membrane depolarization, as well as the downstream cell apoptotic signaling activation, further demonstrated the pro-apoptotic roles of n-HA induced Ca2+ overload through inducing mitochondria damage. The in vivo data provided additional evidence that n-HA caused ER stress and mitochondria damage in cells and effectively restrain the growth of glioma tumors. Collectively, the work showed that n-HA co-activated intracellular ER stress and mitochondria damage are critical triggers for cancer cells apoptosis, offering fresh perspectives on ER-mitochondria targeted anti-tumor therapy.

The role of telomeres in the pathogenesis of cardiovascular diseases – a molecular perspective

The role of telomeres in the pathogenesis of cardiovascular diseases – a molecular perspective

Emerging investigator series: impacts of land use on dissolved organic matter quality in agricultural watersheds: a molecular perspective.

In aquatic systems, dissolved organic matter (DOM) has important ecological and biogeochemical functions, where the molecular composition of DOM has larger-scale implications for climate change and global carbon cycles. However, there is limited information about the relationships between landscape characteristics and human disturbance that influence the molecular composition of DOM changes in watersheds. In this study, we collected water samples from 22 sites across a gradient of topographically characterized agricultural land coverage and community infrastructure development in the Kawartha region in Ontario, Canada. We employed a combination of Fourier Transform Ion-Cyclotron Resonance Mass Spectrometry (FT-ICR-MS) and absorbance spectroscopy to investigate changes in the molecular composition of DOM with increasing agricultural and community development disturbance on the optical and molecular characteristics of DOM. We found that dissolved organic carbon (DOC) concentrations in disturbed (>75%) watersheds ranged from 3.67-32.8 mg L-1 and were significantly higher than in watersheds with more abundant forest coverage (3.78-9.13 mg L-1). In addition, watersheds with higher phosphorus concentrations had more negative nominal oxygenation state of carbon (NOSC) values, suggesting biologically processed DOM correlating with increased phosphorus levels in aquatic systems. To relate the molecular properties of DOM to landscape metrics, we used Spearman's correlation analysis to reveal that agriculturally impacted and community developments enhanced the molecular signature of unsaturated hydrocarbon. In addition, we identified 65 dissolved organic phosphorus (DOP) molecules that significantly increased in abundance with disturbance, likely due to microbial mineralization of existing DOM with the addition of phosphorus to form larger, biologically inaccessible molecules. The overall recalcitrance of the identified molecules can serve as molecular signatures when evaluating the level of disturbance of a watershed.

Computational analysis of peripheral blood RNA sequencing data unravels disrupted immune patterns in Alzheimer's disease.

The central nervous system (CNS) and the immune system collectively coordinate cellular functionalities, sharing common developmental mechanisms. Immunity-related molecules exert an influence on brain development, challenging the conventional view of the brain as immune-privileged. Chronic inflammation emerges as a key player in the pathophysiology of Alzheimer's disease (AD), with increased stress contributing to the disease progression and potentially exacerbating existing symptoms. In this study, the most significant gene signatures from selected RNA-sequencing (RNA-seq) data from AD patients and healthy individuals were obtained and a functional analysis and biological interpretation was conducted, including network and pathway enrichment analysis. Important evidence was reported, such as enrichment in immune system responses and antigen processes, as well as positive regulation of T-cell mediated cytotoxicity and endogenous and exogenous peptide antigen, thus indicating neuroinflammation and immune response participation in disease progression. These findings suggest a disturbance in the immune infiltration of the peripheral immune environment, providing new challenges to explore key biological processes from a molecular perspective that strongly participate in AD development.

Mitochondria in COVID-19: from cellular and molecular perspective.

The rapid development of the COVID-19 pandemic resulted in a closer analysis of cell functioning during β-coronavirus infection. This review will describe evidence for COVID-19 as a syndrome with a strong, albeit still underestimated, mitochondrial component. Due to the sensitivity of host mitochondria to coronavirus infection, SARS-CoV-2 affects mitochondrial signaling, modulates the immune response, modifies cellular energy metabolism, induces apoptosis and ageing, worsening COVID-19 symptoms which can sometimes be fatal. Various aberrations across human systems and tissues and their relationships with mitochondria were reported. In this review, particular attention is given to characterization of multiple alterations in gene expression pattern and mitochondrial metabolism in COVID-19; the complexity of interactions between SARS-CoV-2 and mitochondrial proteins is presented. The participation of mitogenome fragments in cell signaling and the occurrence of SARS-CoV-2 subgenomic RNA within membranous compartments, including mitochondria is widely discussed. As SARS-CoV-2 severely affects the quality system of mitochondria, the cellular background for aberrations in mitochondrial dynamics in COVID-19 is additionally characterized. Finally, perspectives on the mitigation of COVID-19 symptoms by affecting mitochondrial biogenesis by numerous compounds and therapeutic treatments are briefly outlined.

Mechanism of long-range hydrophobic force based on cavitation of metastable liquid film

Hydrophobic force, a key driving force in colloid physicochemical system and biological macromolecular system, exhibits a distinct multi-scale effect. The prevailing scholarly consensus attributes long-range hydrophobic force to bubble bridging, facilitated by unstable liquid film cavitation, while short-range force is thought to arise from the reorganization of water molecules at the solid-liquid interface. However, a comprehensive theoretical study remains elusive. To further elucidate the mechanism of the long-range hydrophobic force based on unstable liquid film cavitation, we carry out systematic research on the long-range hydrophobic force between perfluorooctyl trichlorosilane hydrophobic particles and the surface, by utilizing atomic force microscopy (AFM) and molecular dynamics simulations. According to AFM force tests, the long-range hydrophobic force escalates incrementally with subsequent close contacts before reaching a plateau. On the tenth contact, the penetration curve exhibits a sudden jump to an adhesion distance of 502.01 nm. A distinct step in the retraction curve suggests the rupture of the cavitation bubble capillary bridge. Importantly, the classical capillary force mathematical model provides an effective fit for the penetration curve. Our calculations estimate the volume of the capillary bridge at 0.30 μm³, offering direct theoretical evidence of the unstable liquid film cavitation bubble capillary bridge. Further insights are gained from large-scale tensile molecular dynamics simulations by using GROningen MAchine for Chemical Simulations (GROMACS). The inherent correlation mechanism of the formation, evolution, and mechanical behavior of the cavitation bubble capillary bridge in the separation process of hydrophobic particles are further explored from a molecular perspective. The results demonstrate that the local pressure drop occurring at the moment of “jump-out” separation of the hydrophobic particles attracts nitrogen molecules to diffuse into the liquid film, thereby forming a cavitation bubble capillary bridge. Simultaneously, a jumping behavior is observed in the calculated spring potential curve at the moment of capillary bridge rupture. Finally, the influence of solution gas content on long-range hydrophobic force is investigated. There is a positive correlation between gas molecule content and both the growth rate of cavitation bubble capillary bridge volume and the length of capillary bridge stretch-rupture, further demonstrating the gas concentration dependence of long-range hydrophobic forces. In a word, revealing the long-range hydrophobic force mechanism based on the cavitation of unstable liquid film can enhance our understanding of the interaction between colloid physical chemistry and biological macromolecules. Meanwhile, hydrophobic force is the fundamental driving force of particle-bubble adhesion in mineral flotation system, and the revelation of its action mechanism has important guiding significance for regulating the actual mineral flotation process.

Molecular perspective and engineering of thermal transport and thermoelectricity in polymers

This review highlights molecular and nanoscale engineering of electrically insulating and semiconducting polymers for improved heat transport and thermoelectricity.