Regulation Of Signal Transduction Research Articles

A major locus confers triclabendazole resistance in Fasciola hepatica and shows dominant inheritance

Fasciola hepatica infection is responsible for substantial economic losses in livestock worldwide and poses a threat to human health in endemic areas. The mainstay of control in livestock and the only drug licenced for use in humans is triclabendazole (TCBZ). TCBZ resistance has been reported on every continent and threatens effective control of fasciolosis in many parts of the world. To date, understanding the genetic mechanisms underlying TCBZ resistance has been limited to studies of candidate genes, based on assumptions of their role in drug action. Taking an alternative approach, we combined a genetic cross with whole-genome sequencing to localise a ~3.2Mbp locus within the 1.2Gbp F. hepatica genome that confers TCBZ resistance. We validated this locus independently using bulk segregant analysis of F. hepatica populations and showed that it is the target of drug selection in the field. We genotyped individual parasites and tracked segregation and reassortment of SNPs to show that TCBZ resistance exhibits Mendelian inheritance and is conferred by a dominant allele. We defined gene content within this locus to pinpoint genes involved in membrane transport, (e.g. ATP-binding cassette family B, ABCB1), transmembrane signalling and signal transduction (e.g. GTP-Ras-adenylyl cyclase and EGF-like protein), DNA/RNA binding and transcriptional regulation (e.g. SANT/Myb-like DNA-binding domain protein) and drug storage and sequestration (e.g. fatty acid binding protein, FABP) as prime candidates for conferring TCBZ resistance. This study constitutes the first experimental cross and genome-wide approach for any heritable trait in F. hepatica and is key to understanding the evolution of drug resistance in Fasciola spp. to inform deployment of efficacious anthelmintic treatments in the field.

Immune response gene 1 deficiency aggravates high fat diet-induced nonalcoholic fatty liver disease via promotion of redox-sensitive AKT suppression

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder worldwide. Immune response gene 1 (IRG1) catalyzes the production of bio-active itaconate, which is actively involved in the regulation of signal transduction. A recent study has found that the expression of IRG1 was significantly down-regulated in obesity-associated fatty liver, but the potential roles of IRG1 in the development NAFLD remain unclear. The present study found that genetic deletion of IRG1 aggravated high fat diet (HFD)-induced metabolic disturbance, including obesity, dyslipidemia and insulin resistance. In addition, HFD induced more severe liver steatosis and higher serum ALT and AST level in IRG1 KO mice, which were accompanied with altered expression of genes involved in lipid uptake, synthesis and catabolism. RNA-seq and immunoblot analysis indicated that deficiency of IRG1 is associated with suppressed activation of AKT, a master metabolic regulator. Mechanistically, IRG1/itaconate enhanced the antioxidative NRF2 pathway and prevented redox-sensitive suppression of AKT. Interestingly, supplementation with 4-octyl itaconate (4-OI), a cell-permeable derivate of itaconate, alleviated HFD-induced oxidative stress, AKT suppression and liver steatosis. Therefore, IRG1 probably functions as a protective regulator in the development of NAFLD and the cell-permeable 4-OI might have potential value for the pharmacological intervention of NAFLD.

MicroRNAs balance growth and salt stress responses in sweet sorghum.

Salt stress is one of the major causes of reduced crop production, limiting agricultural development globally. Plants have evolved with complex systems to maintain the balance between growth and stress responses, where signaling pathways such as hormone signaling play key roles. Recent studies revealed that hormones are modulated by microRNAs (miRNAs). Previously, two sweet sorghum (Sorghum bicolor) inbred lines with different salt tolerance were identified: the salt-tolerant M-81E and the salt-sensitive Roma. The levels of endogenous hormones in M-81E and Roma varied differently under salt stress, showing a different balance between growth and stress responses. miRNA and degradome sequencing showed that the expression of many upstream transcription factors regulating signal transduction and hormone-responsive genes was directly induced by differentially expressed miRNAs, whose levels were very different between the two sweet sorghum lines. Furthermore, the effects of representative miRNAs on salt tolerance in sorghum were verified through a transformation system mediated by Agrobacterium rhizogenes. Also, miR-6225-5p reduced the level of Ca2+ in the miR-6225-5p-overexpressing line by inhibiting the expression of the Ca2+ uptake gene SbGLR3.1 in the root epidermis and affected salt tolerance in sorghum. This study provides evidence for miRNA-mediated growth and stress responses in sweet sorghum.

Role of nerve signal transduction and neuroimmune crosstalk in mediating the analgesic effects of acupuncture for neuropathic pain.

Neurogenic pain rises because of nervous system damage or dysfunction and is the most difficult to treat among other pathological pains. Acupuncture has been reported as a great treatment option for neurogenic pain owing to its unlimited advantages. However, previous studies on the analgesic effects of acupuncture for NP were scattered and did not form a whole. In this study, we first comprehensively review the relevant basic articles on acupuncture for NP published in the last 5 years and summarize the analgesic mechanisms of acupuncture in terms of nerve signaling, neuro-immune crosstalk, and metabolic and oxidative stress regulation. Acupuncture inhibits the upstream excitatory system and suppresses neuronal transmission efficiency by downregulating glutamate, NMDA receptors, P2XR, SP, CGRP, and other neurotransmitters and receptors in the spinal cord, as well as plasma channels such as TRPV1, HCN. It can also activate the downstream pain inhibitory pathway by upregulating opioid peptide (β-endorphin), MOR receptors, GABA and GABA receptors, bi-directional regulating 5-hydroxytryptamine (5-HT) and its receptors (upregulate 5-HT 1A and downregulate 5-HT7R) and stimulating hypothalamic appetite-modifying neurons. Moreover, neuroinflammation in pain can be inhibited by acupuncture through inhibiting JAK2/STAT3, PI3K/mTOR pathways, down regulating chemokine receptor CX3CR1 on microglia and up regulating adenosine receptor A1Rs on astrocytes, inhibiting the activation of glia and reducing TNF-α and other inflammatory substances. Acupuncture also inhibits neuronal glucose metabolism by downregulating mPFC's GLUT-3 and promotes metabolic alterations of the brain, thus exerting an analgesic effect. In conclusion, the regulation of nerve signal transduction and neuroimmune crosstalk at the peripheral and central levels mediates the analgesic effects of acupuncture for neuropathic pain in an integrated manner. These findings provide a reliable basis for better clinical application of acupuncture in the management of neuropathic pain.

Protein content of blood-derived extracellular vesicles: An approach to the pathophysiology of cerebral hemorrhage.

Introduction: Extracellular vesicles (EVs) participate in cell-to-cell paracrine signaling and can be biomarkers of the pathophysiological processes underlying disease. In intracerebral hemorrhage, the study of the number and molecular content of circulating EVs may help elucidate the biological mechanisms involved in damage and repair, contributing valuable information to the identification of new therapeutic targets. Methods: The objective of this study was to describe the number and protein content of blood-derived EVs following an intracerebral hemorrhage (ICH). For this purpose, an experimental ICH was induced in the striatum of Sprague-Dawley rats and EVs were isolated and characterized from blood at baseline, 24 h and 28 days. The protein content in the EVs was analyzed by mass spectrometric data-dependent acquisition; protein quantification was obtained by sequential window acquisition of all theoretical mass spectra data and compared at pre-defined time points. Results: Although no differences were found in the number of EVs, the proteomic study revealed that proteins related to the response to cellular damage such as deubiquitination, regulation of MAP kinase activity (UCHL1) and signal transduction (NDGR3), were up-expressed at 24 h compared to baseline; and that at 28 days, the protein expression profile was characterized by a higher content of the proteins involved in healing and repair processes such as cytoskeleton organization and response to growth factors (COR1B) and the regulation of autophagy (PI42B). Discussion: The protein content of circulating EVs at different time points following an ICH may reflect evolutionary changes in the pathophysiology of the disease.

The effects of ERN1 on gene expression during early rhizobial infection in Lotus japonicus.

Legumes develop root nodules in association with compatible rhizobia to overcome nitrogen deficiency. Rhizobia enter the host legume, mainly through infection threads, and induce nodule primordium formation in the root cortex. Multiple transcription factors have been identified to be involved in the regulation of the establishment of root nodule symbiosis, including ERF Required for Nodulation1 (ERN1). ERN1 is involved in a transcription network with CYCLOPS and NODULE INCEPTION (NIN). Mutation of ERN1 often results in misshapen root hair tips, deficient infection thread formation, and immature root nodules. ERN1 directly activates the expression of ENOD11 in Medicago truncatula to assist cell wall remodeling and Epr3 in Lotus japonicus to distinguish rhizobial exopolysaccharide signals. However, aside from these two genes, it remains unclear which genes are regulated by LjERN1 or what role LjERN1 plays during root nodule symbiosis. Thus, we conducted RNA sequencing to compare the gene expression profiles of wild-type L. japonicus and Ljern1-6 mutants. In total, 234 differentially expressed genes were identified as candidate LjERN1 target genes. These genes were found to be associated with cell wall remodeling, signal transduction, phytohormone metabolism, and transcription regulation, suggesting that LjERN1 is involved in multiple processes during the early stages of the establishment of root nodule symbiosis. Many of these candidate genes including RINRK1 showed decreased expression levels in Ljnin-2 mutants based on a search of a public database, suggesting that LjERN1 and LjNIN coordinately regulate gene expression. Our data extend the current understanding of the pleiotropic role of LjERN1 in root nodule symbiosis.

Identification, Classification and Characterization of bZIP Transcription Factor Family Members in Pinus massoniana Lamb.

Basic leucine zipper (bZIP) transcription factors (TFs) are ubiquitous in eukaryotes. Members of this family play significant roles in the regulation of plant growth, signal transduction, and various stresses. To date, bZIP TFs have been extensively studied in various plants, but there is little information about them in Pinus massoniana Lamb. In this study, 55 bZIP TFs were identified based on data from four different P. massoniana transcriptomes, and a systematic analysis was performed. According to the phylogenetic results, P. massoniana bZIP TFs were divided into 11 groups. Each bZIP protein contained a highly conserved bZIP domain, and the numbers and types of motifs were similar in the same group. The PmbZIPs were nuclear localization proteins. Based on the pine wood nematode inoculation transcriptome, the transcriptional profiles revealed that 25 PmbZIP genes could respond to pine wood nematodes at different levels. Genes PmbZIP3, PmbZIP4, PmbZIP8, PmbZIP20, and PmbZIP23 were selected to be upregulated in the process of inoculation with pine wood nematodes. These five genes had different expression levels in different tissues and were responsive to the related treatment conditions. Transcriptional activity analysis showed that PmbZIP3 and PmbZIP8 were transcriptional activators; PmbZIP4, PmbZIP20 and PmbZIP23 were transcriptional repressors. These findings provide preliminary information on PmbZIP TFs, which is helpful for further study of other physiological functions of bZIP TFs in P. massoniana.

Countercurrent chromatography as a frontier tool to discover new mechanical roles in liquid-liquid phase separation of cellular biomolecules.

The development of countercurrent chromatography (CCC) technology enabled us to achieve higher peak resolutions and more shortened separation times even for protein separation using aqueous two-phase solvent systems composed of polyethylene glycol and inorganic salts (or dextrans). By eliminating the solid support matrix, all analytes can be recovered from the coiled column after the separation is completed. Recently, it has been found that droplets of biomolecules formed by liquid-liquid phase separation in cells closely relate to the transcription, regulation of signal transduction, and formation of amyloids. Meanwhile, although CCC is a separation technique based on liquid-liquid partitioning of analytes between two immiscible phases, the mechanism of separation could suggest some idea concerning the formation of biomolecule droplets in cells. This article describes the recent advances in the CCC apparatus, the coiled separation column, the choice of a suitable two-phase solvent system, and the application to separation and purification of bioactive macromolecules such as proteins and enzymes, and also discusses the possibility of CCC as a tool to reveal new mechanical roles of biomolecule droplets in the cellular environments.

Utilizing In Silico Approaches to Investigate the Signaling Pathway's Crucial Function in Pennisetum glaucum Under Thermal Stress.

Pearl millet (Pennisetum glaucum (L.)) is a remarkable cereal crop known for its ability to thrive in challenging environmental conditions. Despite its resilience, the intricate molecular mechanisms behind its toughness remain a mystery. To address this knowledge gap, we conducted advanced next-generation RNA sequencing. This approach allowed us to compare the gene expression profiles of pearl millet seedlings exposed to heat stress with those grown under standard conditions. Our main focus was on the shoots of 13-day-old pearl millet plants, which we subjected to a brief heat stress episode at 50°C for 60 seconds. Within the vast genomic landscape comprising 36 041 genes, we successfully identified a set of 10 genes that exhibited significant fold changes, ranging from 11 to 14-fold compared to the control conditions. These 10 genes were previously unknown to have such substantial changes in expression compared to the control. To uncover the functional significance hidden within these transcriptomic findings, we utilized computational tools such as MEME, String, and phylogenetic tree analysis. These efforts collectively revealed conserved domains within the transcriptomic landscape, hinting at potential functions associated with these genetic sequences. Of particular note, the distinct transcriptomic patterns specific to pearl millet leaves under thermal stress shed light on intricate connections to fundamental biological processes. These processes included the Ethylene-activated signaling pathway, Regulation of intracellular signal transduction, Negative regulation of signal transduction, Protein autophosphorylation, and Intracellular signal transduction. Together, these processes provide insight into the molecular strategies employed by pearl millet to overcome thermal stress challenges. By integrating cutting-edge RNA sequencing techniques and computational analyses, we have embarked on unraveling the genetic components and pathways that empower pearl millet's resilience in the face of adversity. This newfound understanding has the potential to not only advance our knowledge of plant stress responses but also contribute to enhancing crop resilience in challenging environmental conditions.

Recent Advancement and Novel Application of Natural Polyphenols for the Treatment of Allergy Asthma: From Phytochemistry to Biological Implications.

Allergic diseases, primarily IgE-mediated, exert a substantial global health burden. A pivotal role in allergic reactions is played by mast cells, with histamine serving as a central mediator. Within this context, plant-based polyphenols, abundantly present in vegetables and fruits, show promising potential for allergy prevention. These natural compounds, particularly flavonoids, possess anti-inflammatory and anti-allergic properties, influencing dendritic cells, modulating macrophages, and fostering the proliferation of B cells and T cells. The potent anti-allergic effects of flavonoids are attributed to their ability to reduce the production of signaling factors, suppress cytokine production, and regulate signal transduction and gene expression in mast cells, basophils, and T cells. Notably, their benefits extend beyond allergy prevention, as they hold promise in the prevention and treatment of autoimmune illnesses such as diabetes, rheumatoid arthritis, and multiple sclerosis. In the context of allergic reactions and autoimmune diseases, polyphenols exhibit immunomodulatory effects by inhibiting autoimmune T cell proliferation and downregulating pro-inflammatory cytokines. In recent times, flavonoids, being the most prevalent polyphenols in food, have garnered significant attention from researchers due to their potential health advantages. This review compiles the latest scientific research to highlight the impact of flavonoids on allergic illnesses and their potential as a beneficial dietary component.

A20 Restricts NOS2 Expression and Intestinal Tumorigenesis in a Mouse Model of Colitis-Associated Cancer.

Colon cancer can occur sporadically or in the setting of chronic inflammation, such as in patients with inflammatory bowel disease. We previously showed that A20, a critical negative regulator of tumor necrosis factor signal transduction, could regulate sporadic colon cancer development. In this report, we investigate whether A20 also acts as a tumor suppressor in a model of colitis-associated cancer. Colitis and colitis-associated tumors were induced in wild-type and A20 intestinal epithelial cell-specific knockout (A20dIEC) mice using dextran sodium sulfate and azoxymethane. Clinicopathologic markers of inflammation were assessed in conjunction with colonic tumor burden. Gene expression analyses and immunohistochemistry were performed on colonic tissue and intestinal enteroids. Nitric oxide (NO) production and activity were assessed in whole colonic lysates and mouse embryonic fibroblasts. A20dIEC mice develop larger tumors after treatment with dextran sodium sulfate and azoxymethane than wild-type mice. In addition to elevated markers of inflammation, A20dIEC mice have significantly enhanced expression of inducible nitric oxide synthase (iNOS), a well-known driver of neoplasia. Enhanced iNOS expression is associated with the formation of reactive nitrogen species and DNA damage. Loss of A20 also enhances NO-dependent cell death directly. Mechanistically, we propose that A20 normally restricts tumor necrosis factor-induced nuclear factor kappa B-dependent production of iNOS in intestinal epithelial cells, thereby protecting against colitis-associated tumorigenesis. We also propose that A20 plays a direct role in regulating NO-dependent cell death.

High Throughput Sequencing Analysis of Exosomal miRNA Expressions in Early-Onset Preeclampsia Patients.

The goal of this study was to screen for differentially expressed exosomal miRNAs in peripheral blood samples of early-onset preeclampsia and normal pregnant patients using high-throughput sequencing methods and explore their effects on the pathogenesis of preeclampsia. Peripheral blood samples from 5 patients with early-onset preeclampsia and 5 normal pregnant women (control group) were enrolled. Then, exosomes were extracted from each sample, and the procedure was replicated three times. An Illumina HiSeq4000 sequencing platform was used to analyze exosomal miRNAs in all samples before comparison. The target genes and signaling pathway predictions and the biological function enrichments of significant and differentially expressed miRNAs were assessed using Miranda and Starbase software, as well as GO and KEGG databases. Compared with the control, patients in the early-onset preeclampsia group had 65 significantly and differentially expressed exosomal miRNAs in their peripheral blood samples. The results have shown that of the 65 differentially expressed miRNAs, 17, including has-miR-6855, has-miR-7151, and has-miR-6777, were up-regulated, and 48, including has-miR-1247, has-miR-29B2, and has-miR-941, were down-regulated (p < 0.05). The Miranda and TargetScanS algorithms predicted a total of 2,231 target genes from the differentially expressed miRNAs. The Go and KEGG analyses showed that the principal biological function of these target genes was the regulation of Ras protein signal transduction, histone modification, GTPase-mediated signal transduction, and transforming growth factor (TGF)-β. Additionally, the results also showed that the major pathways involved in the regulation of these functions were the PI3K Akt, MAPK, tumor necrosis factor, and EGFR tyrosine kinase inhibition signaling pathways. There are significant differences in the expression profiles of exosomal miRNAs between early-onset preeclampsia patients and normal pregnant women. These differentially expressed miRNAs may not only play an important regulatory role in the occurrence of early-onset preeclampsia but also participate in its pathophysiological process through genetic regulation of a variety of biological functions and signal pathways.

Genome-wide identification and expression analysis of SlRR genes in response to abiotic stress in tomato.

The cytokinin two-component signal transduction system (TCS) is involved in many biological processes, including hormone signal transduction and plant growth regulation. Although cytokinin TCS has been well characterized in Arabidopsis thaliana, its role in tomato remains elusive. In this study, we characterized the diversity and function of response regulator (RR) genes, a critical component of TCS, in tomato. In total, we identified 31 RR genes in the tomato genome. These SlRR genes were classified into three subgroups (type-A, type-B and type-C). Various stress-responsive cis-elements were present in the tomato RR gene promoters. Their expression responses under pesticide treatment were evaluated by transcriptome analysis. Their expression under heat, cold, ABA, salinity and NaHCO3 treatments was further investigated by qRT-PCR and complemented with the available transcription data under these treatments. Specifically, SlRR13 expression was significantly upregulated under salinity, drought, cold and pesticide stress and was downregulated under ABA treatment. SlRR23 expression was induced under salt treatment, while the transcription level of SlRR1 was increased under cold and decreased under salt stress. We also found that GATA transcription factors played a significant role in the regulation of SlRR genes. Based on our results, tomato SlRR genes are involved in responses to abiotic stress in tomato and could be implemented in molecular breeding approaches to increase resistance of tomato to environmental stresses.

Genome–Wide Investigation of the CBL–CIPK Gene Family in Oil Persimmon: Evolution, Function and Expression Analysis during Development and Stress

Ca2+-sensors, calcineurin B-like proteins (CBLs), and calcineurin B-like protein-interacting protein kinases (CIPKs) form a CBL–CIPK complex to regulate signal transduction. This study aimed to reveal the characteristics of the CBL–CIPK gene family in oil persimmon (Diospyros oleifera). Ten DoCBL and 23 DoCIPK genes were identified, and gene duplication among them was mainly attributed to segmental duplication. According to phylogenetic and structural analysis, DoCBLs were clustered into four groups with distinct motifs, namely myristoylation and palmytoylation sites in their N-terminus, and DoCIPKs containing a NAF/FISL domain were clustered into intron-rich and intron-less groups. The expression patterns of DoCBLs and DoCIPKs were tissue- and time-specific in different tissues and at different stages of fruit development. Most CBL–CIPK genes were upregulated under NaCl, drought, and Ca(NO3)2 stress using qRT-PCR analysis. DoCBL5 and DoCIPK05 were both located in the plasma membrane of cells using green fusion proteins (GFP) in tobacco leaves. DoCBL5 and DoCIPK05 might interact with AKT1, PP2C, and SNF to regulate the Ca2+ signals, K+, and ABA homeostasis in cells. In conclusion, these results suggested that the CBL–CIPK family genes might play important roles in oil persimmon growth and stress responses.

Transcriptome and targeted hormone metabolome reveal the molecular mechanisms of flower abscission in camellia.

Camellia is among the most ornamentally valuable flowers and plants worldwide. Flower abscission typically causes significant financial losses by the horticultural landscape. Previous research has revealed that phytohormones, transcription factors, and other genes involved in floral development regulate the maintenance and mortality of flowers. In this study, for the first time, the transcriptomes and targeted hormone metabolomics of three developmental stages of the receptacles of two distinct camellia strains (CF: abscission strain, CHF: nonabscission strain) were analyzed to determine their roles in regulating blossom abscission in camellia. ABA content was shown to be considerably upregulated throughout all phases of CF development, as were the genes implicated in the ABA production pathway and their downstream counterparts. Highly expressed genes in CF were involved in galactose metabolism, phenylpropanoid biosynthesis, amino and nucleotide sugar metabolism, pentose and glucuronate interconversions, and MAPK. Among others, highly expressed genes in CHF are associated with fructose and mannose metabolism, alpha-linolenic acid metabolism, biosynthesis of secondary metabolites, starch and sucrose metabolism, and cutin, suberin, and wax biosynthesis. A vast variety of stress response-related pathways and redox-related activities were also shown to be active in CHF. In contrast, CF dramatically activated pathways associated with lignin production, keratinogenesis, cell wall biogenesis, and ABA response. A comparative transcriptomic study of the CF and CHF pathways revealed that the downstream response pathways of hormones, including CTK, BR, IAA, ethylene, and GA, were very active in CF, indicating a significant amount of signal transduction and transcriptional regulation by CF. In addition, members of the transcription factor family, such as MYB, bHLH, MADS, and WD40, may regulate flower abscission. A comparative transcriptome analysis of two distinct strains of camellia receptacles elucidates the molecular processes and regulatory characteristics of flower abscission and provides direction for the targeted improvement and breeding of camellia.

Immunomodulatory role of metalloproteases in cancers: Current progress and future trends.

Metalloproteinases (MPs) is a large family of proteinases with metal ions in their active centers. According to the different domains metalloproteinases can be divided into a variety of subtypes mainly including Matrix Metalloproteinases (MMPs), A Disintegrin and Metalloproteases (ADAMs) and ADAMs with Thrombospondin Motifs (ADAMTS). They have various functions such as protein hydrolysis, cell adhesion and remodeling of extracellular matrix. Metalloproteinases expressed in multiple types of cancers and participate in many pathological processes involving tumor genesis and development, invasion and metastasis by regulating signal transduction and tumor microenvironment. In this review, based on the current research progress, we summarized the structure of MPs, their expression and especially immunomodulatory role and mechanisms in cancers. Additionally, a relevant and timely update of recent advances and future directions were provided for the diagnosis and immunotherapy targeting MPs in cancers.

Rat and fish peripheral blood leukocytes respond distinctively to Anisakis pegreffii (Nematoda, Anisakidae) crude extract.

Infective third-stage larvae (L3) of the marine nematode Anisakis pegreffii cause inflammation and clinical symptoms in humans, their accidental host, that subside and self-resolve in a couple of weeks after L3 die. To characterise the differences in an early immune response of a marine vs. terrestrial host, we stimulated peripheral blood leukocytes (PBLs) of fish (paratenic host) and rat (accidental, human-model host) with A. pegreffii crude extract and analysed PBL transcriptomes 1 and 12h post-stimulation. Fish and rat PBLs differentially expressed 712 and 493 transcripts, respectively, between 1 and 12h post-stimulation (false discovery rate, FDR <0.001, logFC >2). While there was a difference in the highest upregulated transcripts between two time-points, the same Gene Ontologies, biological processes (intracellular signal transduction, DNA-dependent transcription, and DNA-regulated regulation of transcription), and molecular functions (ATP and metal ion binding) were enriched in the two hosts, showing an incrementing dynamic between 1 and 12h. This suggests that the two distinct hosts employ qualitatively different transcript cascades only to achieve the same effect, at least during an early innate immunity response. Activation of later immunity elements and/or a combination of other host's intrinsic conditions may contribute to the death of L3 in the terrestrial host.

Molecular Insights into the Calcium Binding in Troponin C through a Molecular Dynamics Study

Calcium-binding proteins play critical roles in various biological processes such as signal transduction, cell growth, and transcription factor regulation. Ion binding and target binding of Ca2+-binding proteins are highly related. Therefore, understanding the ion binding mechanism will benefit the relevant inhibitor design toward the Ca2+-binding proteins. The EF-hand is the typical ion binding motif in Ca2+-binding proteins. Previous studies indicate that the ion binding affinity of the EF-hand increases with the peptide length, but this mechanism has not been fully understood. Herein, using molecular dynamics simulations, thermodynamic integration calculations, and molecular mechanics Poisson-Boltzmann surface area analysis, we systematically investigated four Ca2+-binding peptides containing the EF-hand loop in site III of rabbit skeletal troponin C. These four peptides have 13, 21, 26, and 34 residues. Our simulations reproduced the observed trend that the ion binding affinity increases with the peptide length. Our results implied that the E-helix motif preceding the EF-hand loop, likely the Phe99 residue in particular, plays a significant role in this regulation. The E-helix has a significant impact on the backbone and side-chain conformations of the Asp103 residue, rigidifying important hydrogen bonds in the EF-hand and decreasing the solvent exposure of the Ca2+ ion, hence leading to more favorable Ca2+ binding in longer peptides. The present study provides molecular insights into the ion binding in the EF-hand and establishes an important step toward elucidating the responses of Ca2+-binding proteins toward the ion and target availability.

Divergent Carry-Over Effects of Hypoxia during the Early Development of Abalone

After being exposed to environmental stimuli during early developmental stages, some organisms may gain or weaken physiological regulating abilities, which would have long-lasting effects on their performance. Environmental hypoxia events can have significant effects on marine organisms, but for breeding programs and other practical applications, it is important to further explore the long-term physiological effects of early hypoxia exposure in economically significant species. In this study, the Pacific abalone Haliotis discus hannai was exposed to moderate hypoxia (∼4 mg/L) from zygote to trochophora, and the assessments of hypoxia tolerance were conducted on the grow-out stage. The results revealed that juvenile abalones exposed to hypoxia at the early development stages were more hypoxia-tolerant but with slower weight growth, a phenomenon called the trade-off between growth and survival. These phenotypic effects driven by the hypoxia exposure were explained by strong selection of genes involved in signal transduction, autophagy, apoptosis, and hormone regulation. Moreover, long non-coding RNA regulation plays an important role modulating carry-over effects by controlling DNA replication and repair, signal transduction, myocardial activity, and hormone regulation. This study revealed that the ability to create favorable phenotypic differentiation through genetic selection and/or epigenetic regulation is important for the survival and development of aquatic animals in the face of rapidly changing environmental conditions.

Inhibition of FAAH suppresses RANKL-induced osteoclastogenesis and attenuates ovariectomy-induced bone loss partially through repressing the IL17 pathway.

Fatty amide hydrolase (FAAH) is a key degradation enzyme of the endocannabinoid system, mainly responsible for the hydrolysis of arachidonic acid ethanolamine (AEA). Previous investigations have shown that FAAH is involved in a series of biological processes, such as inflammation, immune regulation, and transmembrane signal transduction of neurons. Endogenous cannabinoids and cannabinoid receptors have been reported to participate in the regulation of bone homeostasis by regulating the differentiation of osteoblasts and osteoclasts. We hypothesized that FAAH may play an important role in osteoclastogenesis based on the above evidence. The present study found that the FAAH expression was increased at both mRNA and protein levels during RANKL-induced osteoclastogenesis. Pharmacological and genetic inhibition of FAAH in bone marrow-derived macrophages (BMMs) inhibited osteoclastogenesis, F-actin ring formation, bone resorption, and osteoclast-specific gene expression in vitro. Moreover, intragastric administration of the FAAH inhibitor PF-04457845(PF) ameliorated ovariectomy (OVX)-induced bone loss in mice. Further investigation revealed that nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways were inhibited by PF treatment and FAAH knockdown. RNAseq indicated that the IL17 pathway was blocked by PF, and administration of recombinant murine IL17 protein could partially restore osteoclastogenesis and activate NF-κB and MAPK pathways. To sum up, our findings demonstrate that targeting FAAH could be a promising candidate strategy for treating osteoclast-related diseases, especially osteoporosis.