Signal Transduction Mechanisms Research Articles

Hedgehog Signaling in Cortical Development.

The Hedgehog (Hh) pathway plays a crucial role in embryonic development, acting both as a morphogenic signal that organizes tissue formation and a potent mitogenic signal driving cell proliferation. Dysregulated Hh signaling leads to various developmental defects in the brain. This article aims to review the roles of Hh signaling in the development of the neocortex in the mammalian brain, focusing on its regulation of neural progenitor proliferation and neuronal production. The review will summarize studies on genetic mouse models that have targeted different components of the Hh pathway, such as the ligand Shh, the receptor Ptch1, the GPCR-like transducer Smo, the intracellular transducer Sufu, and the three Gli transcription factors. As key insights into the Hh signaling transduction mechanism were obtained from mouse models displaying neural tube defects, this review will also cover some studies on Hh signaling in neural tube development. The results from these genetic mouse models suggest an intriguing hypothesis that elevated Hh signaling may play a role in the gyrification of the brain in certain species. Additionally, the distinctive production of GABAergic interneurons in the dorsal cortex in the human brain may also be linked to the extension of Hh signaling from the ventral to the dorsal brain region. Overall, these results suggest key roles of Hh signaling as both a morphogenic and mitogenic signal during the forebrain development and imply the potential involvement of Hh signaling in the evolutionary expansion of the neocortex.

The comparative transcriptome analysis of two green super rice genotypes with varying tolerance to salt stress.

Salinity is one of the main abiotic factors that restrict plant growth, physiology, and crop productivity is salt stress. About 33% of the total irrigated land suffers from severe salinity because of intensive underground water extraction and irrigation with brackish water. Thus, it is important to understand the genetic mechanism and identify the novel genes involved in salt tolerance for the development of climate-resilient rice cultivars. In this study, two rice genotypes with varying tolerance to salt stress were used to investigate the differential expressed genes and molecular pathways to adapt under saline soil by comparative RNA sequencing at 42 days of the seedling stage. Salt-susceptible (S3) and -tolerant (S13) genotypes revealed 3982 and 3463 differentially expressed genes in S3 and S13 genotypes. The up-regulated genes in both genotypes were substantially enriched in different metabolic processes and binding activities. Biosynthesis of secondary metabolites, phenylpropanoid biosynthesis, and plant signal transduction mechanisms were highly enriched. Salt-susceptible and -tolerant genotypes shared the same salt adaptability mechanism with no significant quantitative differences at the transcriptome level. Moreover, bHLH, ERF, NAC, WRKY, and MYB transcription factors were substantially up-regulated under salt stress. 391 out of 1806 identified novel genes involved in signal transduction mechanisms. Expression profiling of six novel genes further validated the findings from RNA-seq data. These findings suggest that the differentially expressed genes and molecular mechanisms involved in salt stress adaptation are conserved in both salt-susceptible and salt-tolerant rice genotypes. Further molecular characterization of novel genes will help to understand the genetic mechanism underlying salt tolerance in rice.

CRK and NCK adaptors may functionally overlap in zebrafish neurodevelopment, as indicated by common binding partners and overlapping expression patterns.

CRK adaptor proteins are important for signal transduction mechanisms driving cell proliferation and positioning during vertebrate central nervous system development. Zebrafish lacking both CRK family members exhibit small, disorganized retinas with 50% penetrance. The goal of this study was to determine whether another adaptor protein might functionally compensate for the loss of CRK adaptors. Expression patterns in developing zebrafish, and bioinformatic analyses of the motifs recognized by their SH2 and SH3 domains, suggest NCK adaptors are well-positioned to compensate for loss of CRK adaptors. In support of this hypothesis, proteomic analyses found CRK and NCK adaptors share overlapping interacting partners including known regulators of cell adhesion and migration, suggesting their functional intersection in neurodevelopment.

Functional profiling of the G protein-coupled receptor C3aR1 reveals ligand-mediated biased agonism

G protein-coupled receptors (GPCRs) are leading druggable targets for several medicines, but many GPCRs are still untapped for their therapeutic potential due to poor understanding of specific signaling properties. The complement C3a receptor 1 (C3aR1) has been extensively studied for its physiological role in C3a-mediated anaphylaxis/inflammation, and in TLQP-21-mediated lipolysis, but direct evidence for the functional relevance of the C3a and TLQP-21 ligands and signal transduction mechanisms are still limited. In addition, C3aR1 G protein coupling specificity is still unclear, and whether endogenous ligands, or drug-like compounds, show ligand-mediated biased agonism is unknown. Here, we demonstrate that C3aR1 couples preferentially to Gi/o/z proteins and can recruit β-arrestins to cause internalization. Furthermore, we showed that in comparison to C3a63-77, TLQP-21 exhibits a preference toward Gi/o-mediated signaling compared to β-arrestin recruitment and internalization. We also show that the purported antagonist SB290157 is a very potent C3aR1 agonist, where antagonism of ligand-stimulated C3aR1 calcium flux is caused by potent β-arrestin-mediated internalization. Finally, ligand-mediated signaling bias impacted cell function as demonstrated by the regulation of calcium influx, lipolysis in adipocytes, phagocytosis in microglia, and degranulation in mast cells. Overall, we characterize C3aR1 as a Gi/o/z-coupled receptor, and demonstrate functional relevance of ligand-mediated signaling bias in key cellular models. Due to C3aR1 and its endogenous ligands being implicated in inflammatory and metabolic diseases, these results are of relevance toward future C3aR1 drug discovery.

Involvement of protein kinases associated signal transduction mechanisms in cardiac diseases

Protein kinases, a family of enzymes responsible for regulating various cellular processes, have been implicated in the development and progression of various heart diseases, making them attractive therapeutic targets. This review focuses on the role of protein kinases induced phosphorylation and protein phosphatase-induced dephosphorylation in cardiovascular disorders, including heart failure, ischemic heart disease, arrhythmias, hypertension, and diabetic cardiomyopathy. This paper explores the potential of novel kinase-targeted therapies and emerging technologies for the prevention and treatment of these conditions. It also discusses the involvement of protein kinase A (PKA), protein kinase C (PKC), phosphoinositide 3-kinases (PI3Ks), mitogen-activated protein kinases (MAPKs), and Ca2+/calmodulin-dependent protein kinase II (CaMKII) in heart dysfunction and alterations in their function that contribute to their respective cardiac disorders. Furthermore, this article presents a comprehensive overview of protein kinases in cardiac disorders and the potential of innovative kinase-targeted therapies, advanced technologies, and multidisciplinary approaches for the effective prevention and treatment of cardiovascular diseases, ultimately aiming to improve patient outcomes and quality of life.

Modification of Peripheral Blood Flow and Angiogenesis by CO2 Water-Bath Therapy in Diabetic Skeletal Muscle with or without Ischemia.

Previously, it was shown that both blood flow and angiogenesis in the ischemic hind limb of diabetic rats were increased upon CO2 treatment for 4 weeks. In the present study, we have compared the effects of 6 weeks CO2 therapy in diabetic rats with or without peripheral ischemia. Diabetes was induced in rats by a tail vein injection of streptozotocin (65 mg/kg body weight), whereas peripheral ischemia was produced by occluding the femoral artery at 2 weeks of inducing diabetes. Both diabetic and diabetic-ischemic animals were treated with or without CO2 water-bath at 37 °C for 6 weeks (30 min/day; 5 days/week) starting at 2 weeks, after the induction of ischemia. CO2 treatment did not affect heart rate and R-R interval as well as plasma levels of creatine kinase, glucose, cholesterol, triglycerides and high density lipoproteins. Unlike the levels of plasma Ox-LDL, MDA and TNF-α, the levels of NO in diabetic group were increased by CO2 water-bath treatment. On the other hand, the levels of plasma Ox-LDL and MDA were decreased whereas that of NO was increased without any changes in TNF-α level in diabetic-ischemic animals upon CO2 therapy. Treatment of diabetic animals with CO2 increased peak, mean and minimal blood flow by 20, 49 and 43% whereas these values were increased by 53, 26 and 80% in the diabetic-ischemic group by CO2 therapy, respectively. Blood vessel count in diabetic and diabetic-ischemic skeletal muscles was increased by 73 and 136% by CO2 therapy, respectively. These data indicate that peripheral ischemia augmented the increase in blood flow and development of angiogenesis in diabetic skeletal muscle upon CO2 therapy. It is suggested that greater beneficial effects of CO2 therapy in diabetic-ischemic animals in comparison to diabetic group may be a consequence of difference of changes in the redox-sensitive signal transduction mechanisms.

Cannabinoid receptor 2 as a regulator of inflammation induced oleoylethanolamide in eosinophilic asthma

BackgroundOleoylethanolamide (OEA), an endogenously generated cannabinoid-like compound, has been reported to be increased in patients with severe asthma and aspirin-exacerbated respiratory disease. Recruitment of activated eosinophils in the airways is a hallmark of bronchial asthma. ObjectiveTo explore the direct contribution of cannabinoid receptor 2 (CB2), a cognate receptor of OEA, which induces of eosinophil activation in vitro and in vivo. MethodsWe investigated OEA signaling in the eosinophilic cell line dEol-1, in peripheral blood eosinophils from asthmatics. In order to confirm whether eosinophil activation by OEA is CB2 dependent or not, CB2 siRNA and the CB2 antagonist SR144528 were used. The numbers of airway inflammatory cells and the levels of cytokines were measured in bronchoalveolar lavage fluid, and airway hyper-responsiveness were examined in the BALB/c mice. ResultsCB2 expression was increased after OEA treatment in both peripheral blood eosinophils and dEol-1 cells. It was also elevated after OEA-induced recruitment of eosinophils to the lungs in vivo. However, SR144528 treatment reduced the activation of peripheral blood eosinophils from asthmatic patients. Furthermore, CB2 knockdown decreased the activation of dEol-1 cells and the levels of inflammatory and T2 cytokines. SR144528 treatment alleviated airway hyper-responsiveness and eosinophil recruitment to the lungs in vivo. ConclusionThese results suggest that CB2 may contribute to the pathogenesis of eosinophilic asthma. Our results provide a new insight into the molecular mechanism of signal transduction by OEA in eosinophilic asthma.

Progress in the regulation of nitrate uptake by plants by Auxin response factors

Nitrogen is indispensable for plant growth, as plants can take up external nitrates to promote the development of the organism. However, improving effective nitrate uptake by plants is a problem that needs to be solved worldwide. Growth hormone plays an essential role in regulating nitrogen utilization in plants, and most of the processes are regulated by ARF family genes. In this paper, the signal transduction mechanism, spatial and temporal expression patterns of ARF family genes and the biological functions of ARF in regulating nitrogen utilization were introduced according to the latest research in China and abroad. Finally, the shortcomings of plant ARF research are analyzed, and the future research direction is prospected.

Regulation of the cell division hydrolase RipC by the FtsEX system in Mycobacterium tuberculosis

The FtsEX complex regulates, directly or via a protein mediator depending on bacterial genera, peptidoglycan degradation for cell division. In mycobacteria and Gram-positive bacteria, the FtsEX system directly activates peptidoglycan-hydrolases by a mechanism that remains unclear. Here we report our investigation of Mycobacterium tuberculosis FtsEX as a non-canonical regulator with high basal ATPase activity. The cryo-EM structures of the FtsEX system alone and in complex with RipC, as well as the ATP-activated state, unveil detailed information on the signal transduction mechanism, leading to the activation of RipC. Our findings indicate that RipC is recognized through a “Match and Fit” mechanism, resulting in an asymmetric rearrangement of the extracellular domains of FtsX and a unique inclined binding mode of RipC. This study provides insights into the molecular mechanisms of FtsEX and RipC regulation in the context of a critical human pathogen, guiding the design of drugs targeting peptidoglycan remodeling.

Angiotensin-(1-7) Improves Islet β-cell Dedifferentiation by Activating PI3K/Akt/FoxO1 Pathway.

Islet β-cell dedifferentiation may be the main cause of reduced insulin secretion. Angiotensin-(1-7) [Ang-(1-7)] can attenuate high glucose-induced apoptosis and dedifferentiation of pancreatic β-cell, but the specific signal transduction pathway and mechanism are not yet clear. This study aimed to investigate the effects of Ang-(1-7) on high glucose-induced islet β-cell dedifferentiation by activating the phosphatidylinositol-3-kinase/Protein kinase B/ Forkhead box transcription factor O1 (PI3K/Akt/FoxO1) signaling pathway. The mouse islet β-cell line MIN6 cells were passaged and cultured and randomly divided into five groups: control (Con) group, high glucose (HG) group, HG with Ang-(1-7) group, HG with Ang-(1-7) and specific MasR antagonist A-779 group, and HG with Ang-(1-7) and PI3K inhibitor LY294002 group. After 48 hours, glucose-stimulated insulin secretion (GSIS) was detected by Enzyme-Linked Immunosorbent Assay (ELISA). The mRNA and protein expression levels of β-cell-specific factors (Pancreatic duodenal homeobox-1 (Pdx1), v-maf musculoaponeurotic fibrosarcoma oncogene homolog A(MafA)) and endocrine progenitor cell-specific factors (Octamer binding transcription factor 4(Oct4), Nanog) were measured by Real Time-PCR and Western blot. The factors of protein expression levels of PI3K/Akt/FoxO1 signaling pathway (Akt, p-Akt, Fox- O1, p-FoxO1) were determined by Western blot. We observed for the first time that high glucotoxicity can induce dedifferentiation of pancreatic islet β-cell, causing a decrease in insulin secretion levels and expression of Pdx1, MafA, p-- FoxO1, and p-Akt and an increase in expression of Oct4 and Nanog. After Ang-(1-7) intervention, insulin secretion levels and expression of Pdx1, MafA, p-FoxO1 and p-Akt were increased, and the levels of Oct4 and Nanog were reduced. However, A-779 and LY294002 could reverse this effect. During these processes, the total Akt and total FoxO1 expression did not change significantly. Ang-(1-7) may prevent high glucose-induced pathological dedifferentiation of pancreatic β-cell by activating the PI3K/Akt/FoxO1 signaling pathway.

Methylene Blue-Stained Single-Stranded DNA Aptamers as a Highly Efficient Electronic Switch for Quasi-Reagentless Exosomes Detection: An Old Dog with New Tricks.

Improving the convenience, sensitivity, and cost-effectiveness of electrochemical biosensors is crucial for advancing their clinical diagnostic applications. Herein, we presented an elegant approach to construct electrochemical aptasensors for tumor-derived exosome detection by harnessing the alterable interaction between methylene blue (MB) and DNA aptamer. In detail, the anti-EpCAM aptamer, named SYL3C, was found to exhibit a strong affinity toward MB due to the specific interaction between MB and unbound guanine bases. Thereby, SYL3C could be stained with MB to arouse a strong electrochemical signal on a gold electrode (AuE). Upon binding to EpCAM-positive exosomes, SYL3C underwent a conformational transformation. The resulting conformation, or exosomes-SYL3C complex, not only reduced the accumulation of MB on SYL3C by obstructing the accessibility of guanines to MB but also impeded the transfer of electrons from the bound MB to AuE, leading to a notable decrease in the electrochemical signal. Using MB-stained SYL3C as an electronic switch, an electrochemical aptasensor was readily established for the detection of EpCAM-positive exosome detection. Without the need for signal amplification strategies, expensive auxiliary reagents, and complex operation, this unique signal transduction mechanism alone could endow the aptasensor with ultrahigh sensitivity. A limit of detection (LOD) of 234 particles mL-1 was achieved, surpassing the performance of most reported methods. As a proof of concept, the aptasensor was applied to analyze clinical serum samples and effectively distinguish non-small-cell lung cancer (NSCLC) patients from healthy individuals. As EpCAM exhibits broad expression in exosomes derived from different tumor sources, the developed aptasensor holds promise for diagnosing other tumor types.

NMR Structural Study of Syndecan-4 Transmembrane Domain with Cytoplasmic Region

Syndecan-4 (SDC4) consists of transmembrane heparan sulfate proteoglycan (HSPG) belonging to the syndecan family. It is present in most cell types of Mammalia. Its structure contains a heparan-sulfate-modified extracellular domain, a single transmembrane domain, and a short C-terminal cytoplasmic domain. Regarding the overall cellular function of SDC4, other cells or ligands can bind to its ecto-domain. In addition, 4,5-bisphosphate phosphatidylinositol (PIP2) or protein kinase Cα can bind to its cyto-domain to activate downstream signaling pathways. To understand the signal transduction mechanism of syndecan, it is important to know the interactions between their actual structure and function in vivo. Therefore, it is important to identify the structure of SDC4 to understand the ligand binding behavior of SDC4. In this study, expression and purification were performed to reveal structures of the short ecto-domain, the transmembrane domain, and the cytoplasmic domain of Syd4-eTC (SDC4). Solution-state NMR spectroscopy and solid-state NMR spectroscopy were used to study the structure of Syd4-eTC in membrane environments and to demonstrate the interaction between Syd4-eTC and PIP2.

Modular Aptamer Switches for the Continuous Optical Detection of Small-Molecule Analytes in Complex Media.

Aptamers are a promising class of affinity reagents because signal transduction mechanisms canbe built into the reagent, so that they can directly produce a physically measurable output signal upon target binding. However, endowing the signal transduction functionality into an aptamer remains a trial-and-error process that can compromise its affinity or specificity and typically requires knowledge of the ligand binding domain or its structure. In this work, a design architecture that can convert an existing aptamer into a "reversible aptamer switch" whose kinetic and thermodynamic properties can be tuned without a priori knowledge of the ligand binding domain or its structure is described. Finally, by combining these aptamer switches with evanescent-field-based optical detection hardware that minimizes sample autofluorescence, this study demonstrates the first optical biosensor system that can continuously measure multiple biomarkers (dopamine and cortisol) in complex samples (artificial cerebrospinal fluid and undiluted plasma) with second and subsecond-scale time responses at physiologically relevant concentration ranges.

A molluscan IRF interacts with IKKα/β family protein and modulates NF-κB and MAPK activity

Interferon regulatory factor (IRF) family proteins are key transcription factors involved in vital physiological processes such as immune defense. However, the function of IRF in invertebrates, especially in marine shellfish is not clear. In this study, a new IRF gene (CfIRF2) was identified in the Zhikong scallop, Chlamys farreri, and its immune function was analyzed. CfIRF2 has an open reading frame of 1107 bp encoding 368 amino acids. The N-terminus of CfIRF2 consists of a typical IRF domain, with conserved amino acid sequences. Phylogenetic analysis suggested close evolutionary relationship with shellfish IRF1 subfamily proteins. Expression pattern analysis showed that CfIRF2 mRNA was expressed in all tissues, with the highest expression in the hepatopancreas and gills. CfIRF2 gene expression was substantially enhanced by a pathogenic virus (such as acute viral necrosis virus) and poly(I:C) challenge. Co-immunoprecipitation assay identified CfIRF2 interaction with the IKKα/β family protein CfIKK1 of C. farreri, demonstrating a unique signal transduction mechanism in marine mollusks. Moreover, CfIRF2 interacted with itself to form homologous dimers. Overexpression of CfIRF2 in HEK293T cells activated reporter genes containing interferon stimulated response elements and NF-κB genes in a dose-dependent manner and promoted the phosphorylation of protein kinases (JNK, Erk1/2, and P38). Our results provide insights into the functions of IRF in mollusks innate immunity and also provide valuable information for enriching comparative immunological theory for the prevention of diseases in scallop farming.

Bibliometric and visual analyses of trends in the field of T cell exhaustion research: Findings from 2000 to 2022.

T cell exhaustion refers to a state wherein T cells become less functional as a result of their prolonged exposure to cognate antigens. A wealth of T cell exhaustion-focused research has been conducted in recent decades, transforming the current understanding of this biologically relevant process. However, there have not been any comprehensive bibliometric analyses to date focused on clarifying the T cell exhaustion-related research landscape. Here, a bibliometric analysis was thus conducted with the goal of better elucidating the current state of knowledge and emerging research hotspots in this field. The Web of Science Core Collection was searched for articles and reviews related to T cell exhaustion, with the CiteSpace and VOSviewer programs then being employed to analyze the countries, institutions, authors, references, and keywords associated with studies in this research space. In total, 2676 studies were incorporated in this analysis, highlighting progressive annual increases in the number of T cell exhaustion-focused publications over the study period. These publications were affiliated with 3117 institutions in 85 countries, with the USA and China being the largest contributors to the field. Of the 18,032 authors associated with these publications, E. John Wherry exhibited the highest publication count and the greatest citation frequency. Keyword analyses indicated that immunotherapy, T cell exhaustion, and PD-1 are the dominant foci for T cell exhaustion-related research. These findings highlight the importance of collaborations among institutions and nations in order to further propel novel studies of T cell exhaustion. Efforts to unravel the signal transduction and transcriptional mechanisms underlying the onset of T cell exhaustion were also identified as an emerging hotspot in this field. Ultimately, these results support the pivotal status of T cell exhaustion research as a key direction for immunotherapeutic research and development efforts in the coming years.

Electrochemical Visualization of Single-Molecule Thiol Substitution with Nanopore Measurement.

Reactions involving sulfhydryl groups play a critical role in maintaining the structure and function of proteins. However, traditional mechanistic studies have mainly focused on reaction rates and the efficiency in bulk solutions. Herein, we have designed a cysteine-mutated nanopore as a biological protein nanoreactor for electrochemical visualization of the thiol substitute reaction. Statistical analysis of characteristic current signals shows that the apparent reaction rate at the single-molecule level in this confined nanoreactor reached 1400 times higher than that observed in bulk solution. This substantial acceleration of thiol substitution reactions within the nanopore offers promising opportunities for advancing the design and optimization of micro/nanoreactors. Moreover, our results could shed light on the understanding of sulfhydryl reactions and the thiol-involved signal transduction mechanisms in biological systems.

Phosphoproteomics changes due to allograft-induced stress responses of Pinctada fucata martensii

Protein phosphorylation modifications are post-translational modifications (PTMs) that play important roles in signal transduction and immune regulation. Implanting a spherical nucleus into a recipient shellfish is critical in marine pearl aquaculture. Protein phosphorylation may be important in the immune responses of Pinctada fucata martensii after nucleus implantation, but their involvement in regulation remains unclear. Here, phosphoproteomics of P. f. martensii gill tissues was conducted 12 h after nuclear implantation using label-free data-independent acquisition (DIA) with LC-MS/MS. Among the 4024 phosphorylated peptides with quantitative information, 181 were up-regulated and 148 were down-regulated. Functional enrichment analysis of these differentially expressed phosphorylated proteins (DEPPs) revealed significant enrichment in functions related to membrane trafficking, exosomes, cytoskeleton, and signal transduction mechanisms. Further, 16 conserved motifs were identified among the DEPPs, including the RSphP, SphP, RSphA, RSphE, PTphP, and ATphP motifs that were significantly conserved, and which may be related to specific kinase recognition. Parallel response monitoring (PRM) analysis validated the abundances of 12 DEPPs from the proteomics, indicating that the phosphoproteomics analyses were robust. 12 DEPPs were selected from the proteomics results through Quantitative real-time PCR (qPCR) technology, and verification analysis was conducted at the gene level. The study suggests that kinases such as MAPKs, Akt, and CK2 may regulate the phosphorylation of related proteins following nuclear implantation. Furthermore, the important signaling pathways of Rap 1, IL-17A, and NF-κB, which are influenced by phosphorylated or dephosphorylated proteins, are found to be involved in this response. Overall, this study revealed the protein phosphorylation responses after nucleus implantation in P. f. martensii, helping to elucidate the characteristics and mechanisms of immune regulation responses in P. f. martensii, in addition to promoting a further understanding of protein phosphorylation modification functions in P. f. martensii.

The leucine zipper domain of the transcriptional repressor Opi1 underlies a signal transduction mechanism regulating lipid synthesis

In Saccharomyces cerevisiae, the transcriptional repressor Opi1 regulates the expression of genes involved in phospholipid synthesis responding to the abundance of the phospholipid precursor phosphatidic acid at the endoplasmic reticulum. We report here the identification of the conserved leucine zipper (LZ) domain of Opi1 as a hot spot for gain of function mutations and the characterization of the strongest variant identified, Opi1N150D. LZ modeling posits asparagine 150 embedded on the hydrophobic surface of the zipper and specifying dynamic parallel homodimerization by allowing electrostatic bonding across the hydrophobic dimerization interface. Opi1 variants carrying any of the other three ionic residues at amino acid 150 were also repressing. Genetic analyses showed that Opi1N150D variant is dominant, and its phenotype is attenuated when loss of function mutations identified in the other two conserved domains are present in cis. We build on the notion that membrane binding facilitates LZ dimerization to antagonize an intramolecular interaction of the zipper necessary for repression. Dissecting Opi1 protein in three polypeptides containing each conserved region, we performed invitro analyses to explore interdomain interactions. An Opi11-190 probe interacted with Opi1291-404, the C terminus that bears the activator interacting domain (AID). LZ or AID loss of function mutations attenuated the interaction of the probes but was unaffected by the N150D mutation. We propose a model for Opi1 signal transduction whereby synergy between membrane-binding events and LZ dimerization antagonizes intramolecular LZ-AID interaction and transcriptional repression.

Exploring molecular interactions of potential inhibitors against the spleen tyrosine kinase implicated in autoimmune disorders via virtual screening and molecular dynamics simulations

ABSTRACT The spleen tyrosine kinase (Syk) plays a pivotal role in immune cells’ signal transduction mechanism. While fostamatinib, an FDA-approved Syk inhibitor, is currently used to treat immune thrombocytopenia, the search for improved Syk-targeted medications to treat autoimmune diseases is still underway. Herein, we screened 38,493 compounds against Syk and selected eight leads based on the docking score and ADMET properties, and performed 3200 ns long molecular dynamics simulations of the apo and Syk-ligand complexes. We considered R406, the active component of fostamatinib, as a control. The molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) calculations demonstrated the lead1 ( = -30.35 kcal/mol) exhibited a similar binding free energy as the control (= −29.82 kcal/mol). The Syk stabilizing effect of lead1 was also indicated in its network features, sampling space, and residual correlation motion analysis. We further generated 100 structural analogues of lead1 using deep learning, and one of the analogues displayed a better binding free energy (= −47.58 kcal/mol) compared to the control or lead1, facilitated by more favourable van der Waals interactions and lesser binding-opposing net polar forces. This analogue may be further exploited to develop effective therapeutics against Syk-associated diseases after validation in vitro and in vivo.

Recent advances in DNA nanomaterials for cancer diagnosis and treatment

Abstract The elucidation of the structural characteristics of deoxyribonucleic acid (DNA) by Watson and Crick, the advent of polymerase chain reaction technology, and the development of primer-synthesis methods, enable DNA to be replicated and transformed in an increasingly easy manner, such that it is among the most directed and evolving nanomaterials in molecular biology. Traditional cancer diagnosis methods are somewhat limited and are unable to meet existing needs; consequently, DNA nanostructures with wide ranging properties are receiving increasingly more attention because a number of DNA materials have been shown to exhibit diagnostic properties. Some DNA materials can functionally alter the biological behavior of cells, such as cell migration, cell proliferation, cell differentiation, autophagy, and anti-inflammatory effects. Some single-stranded DNA or ribonucleic acid with secondary structure through self-pairing, called aptamer, systematic evolution of ligands by exponential enrichment (SELEX), have targeting capabilities and can be applied to tumor targeted diagnosis and therapy. Several DNA nanomaterials with three-dimensional nanostructures and stable structures are being investigated as drug carrier systems to act on a variety of antitumor drugs or gene therapy agents. This article reviews the use of functionalized DNA nanostructures in cancer diagnosis and treatment applications. Various biosensors and carriers based on DNA nanostructures are introduced and chemical reactions related to the preparation of the carrier and the signal transduction mechanism of the sensor are discussed. Efficient carrier/biosensor platforms based on various structural developments and current DNA nanomaterial developments are also presented.