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Memory is composed of various phases including cellular consolidation, systems consolidation, reconsolidation, and extinction. In the last few years it has been shown that simple association memories can be encoded by a subset of the neuronal population called engram cells. Activity of these cells is necessary and sufficient for the recall of association memory. However, it is unclear which molecular mechanisms allow cellular engrams to encode the diverse phases of memory. Further research is needed to examine the possibility that it is the synapses between engram cells (the synaptic engram) that constitute the memory. In this review we summarize recent findings on cellular engrams with a focus on different phases of memory, and discuss the distinct molecular mechanism required for cellular and synaptic engrams.

Sleep requires that we disconnect from the environment, losing the ability to promptly respond to stimuli. There must be at least one essential function that justifies why we take this risk every day, and that function must depend on the brain being offline. We have proposed that this function is to renormalize synaptic weights after learning has led to a net increase in synaptic strength in many brain circuits. Without this renormalization, synaptic activity would become energetically too expensive and saturation would prevent new learning. There is converging evidence from molecular, electrophysiological, and ultrastructural experiments showing a net increase in synaptic strength after the major wake phase, and a net decline after sleep. The evidence also suggests that sleep-dependent renormalization is a smart process of synaptic down-selection, comprehensive and yet specific, which could explain the many beneficial effects of sleep on cognition. Recently, a key molecular mechanism that allows broad synaptic weakening during sleep was identified. Other mechanisms still being investigated should eventually explain how sleep can weaken most synapses but afford protection to some, including those directly activated by learning. That synaptic down-selection takes place during sleep is by now established; why it should take place during sleep has a plausible explanation; how it happens is still work in progress.

Circular RNAs (circRNAs) are covalently closed single-stranded RNAs. Four subclasses of circRNAs have been identified in animal cells, and they have unique features in their biogenesis, degradation, and transport. CircRNAs have diverse molecular functions in sponging miRNAs, regulating transcription, modulating RNA-binding proteins, and even encoding proteins. Some circRNAs are important regulators of various physiological processes to maintain homeostasis. Dysregulation of circRNAs is associated with human disorders, and individual circRNAs are crucial factors that contribute to major diseases including non-immunological diseases such as cancers, neurological disorders, cardiovascular disease, and metabolic disease. Debates on circRNAs have also been raised in recent years, and further studies would help to resolve these disputes and potentially lead to biomedical applications of circRNAs.

Mesenchymal stem cells (MSCs), multipotent stromal cells, have attracted extensive attention in the field of regenerative medicine and cell therapy due to the capacity of self-renewal, multilineage differentiation, and immune regulation. MSCs have different cellular effects in different diseases, and even have markedly different curative effects with different tissue sources, indicating the plasticity of MSCs. The phenotypes, secreted factors, and proliferative, migratory, differentiating, and immunomodulatory effects of MSCs depend on certain mediators present in their microenvironment. Understanding microenvironmental factors and their internal mechanisms in MSC responses may help in subsequent prediction and improvement of clinical benefits. This review highlighted the recent advances in MSC plasticity in the physiological and pathological microenvironment and multiple microenvironmental factors regulating MSC plasticity. It also highlighted some progress in the underlying molecular mechanisms of MSC remodeling in the microenvironment. It might provide references for the improvement in vitro culture of MSCs, clinical application, and in vivo induction.

Hepatocellular carcinoma (HCC) is among the most aggressive and lethal diseases with poor prognosis, worldwide. However, the mechanisms underlying HCC have not been comprehensively elucidated. With the recent application of high-throughput sequencing techniques, a diverse catalogue of differentially expressed long non-coding RNAs (lncRNA) in cancer have been shown to participate in HCC. Rather than being “transcriptional noise,” they are emerging as important regulators of many biological processes, including chromatin remodelling, transcription, alternative splicing, translational and post-translational modification. Moreover, lncRNAs have dual effects in the development and progression of HCC, including oncogenic and tumour-suppressive roles. Collectively, recently data point to lncRNAs as novel diagnostic and prognostic biomarkers with satisfactory sensitivity and specificity, as well as being therapeutic targets for HCC patients. In this review, we highlight recent progress of the molecular patterns of lncRNAs and discuss their potential clinical application in human HCC.

Graphical abstract, Highlights • The formation of single RNA polymerase–promoter open complexes probed in real-time. • Substantial heterogeneity was found along the promoter-opening pathway. • Branched steps include template strand loading into the active site. • Branched steps also include transcription bubble stabilisation. • RNA polymerase rudder loop stabilises open transcription bubble., The expression of most bacterial genes commences with the binding of RNA polymerase (RNAP)–σ70 holoenzyme to the promoter DNA. This initial RNAP–promoter closed complex undergoes a series of conformational changes, including the formation of a transcription bubble on the promoter and the loading of template DNA strand into the RNAP active site; these changes lead to the catalytically active open complex (RPO) state. Recent cryo-electron microscopy studies have provided detailed structural insight on the RPO and putative intermediates on its formation pathway. Here, we employ single-molecule fluorescence microscopy to interrogate the conformational dynamics and reaction kinetics during real-time RPO formation on a consensus lac promoter. We find that the promoter opening may proceed rapidly from the closed to open conformation in a single apparent step, or may instead involve a significant intermediate between these states. The formed RPO complexes are also different with respect to their transcription bubble stability. The RNAP cleft loops, and especially the β′ rudder, stabilise the transcription bubble. The RNAP interactions with the promoter upstream sequence (beyond −35) stimulate transcription bubble nucleation and tune the reaction path towards stable forms of the RPO.

Barnacles are notorious marine fouling creatures; their planktonic cyprid larvae attach to material substrates and metamorphose. Histamine has shown great importance in regulating cyprid settlement and metamorphosis. This study aimed to investigate the mechanisms of histamine-induced larval settlement. Cyprids were exposed to histamine or loratadine, an anti-histamine compound. The percent larval settlements of the histamine- and anti-histamine-treated cyprids were significantly higher and lower, respectively, than the control group. Transcriptomic analyses showed that histamine-treated cyprids had 18498 differentially expressed genes (DEGs, 14531 up-regulated, 3967 down-regulated) and the anti-histamine group had 18055 DEGs (17237 up-regulated, 818 down-regulated) in comparison to untreated controls. In both treatment groups, significant enrichment of DEGs involved in the mitogen-activated protein kinase signaling pathway was observed. Based on the results of larval settlement bioassays, we set 4 filter conditions to perform DEG analyses, and 19 DEGs were selected as functional genes related to cyprid settlement. The functional categories of these genes included structural proteins, spider silk proteins, energy metabolism proteins, cement proteins, glycosyl proteins, and multifunctional proteins. The energy metabolism protein AdipoR was significantly up-regulated in the histamine-treated cyprids but significantly down-regulated in the anti-histamine group. The activity of adenosine monophosphate-activated protein kinase, a downstream signaling protein of AdipoR, increased in the histamine-treated group and decreased in the anti-histamine-treated group. Our results provide new insights into the molecular mechanisms underlying the histamine-induced settlement of barnacle cyprids and identify AdipoR as an important gene that can affect the settlement of cyprids, likely through regulating cyprid energy metabolism.

Infections caused by virus are one of the foremost causes of morbidity and mortality in the world. Although a number of antiviral drugs are currently used for treatment of various kinds of viral infection diseases, there is still no available therapeutic agent for the most of virus in clinical practice. Coumarin is a chemical compound which is found naturally in a variety of plants, as well as it can be synthetically produced possessing diverse biological effects. More recently, reports have highlighted the potential role of coumarin derivatives as antiviral agents. This review outlines the advances in coumarin-based compounds against various viruses including human immunodeficiency virus, hepatitis virus, herpes simplex virus, Chikungunya virus and Enterovirus 71, the structure activity relationship and the possible mechanism of action of the most potent coumarin derivatives are also discussed.

To explore the mechanism of miR-29b in gestational diabetes mellitus (GDM) and its effect on the function of trophoblast cell (TBC), the placenta tissues of 55 normal term pregnancies and 55 GDM patients were selected and rolled into control group and observation group. In the early stage, microRNA (miRNA) chips were utilized to screen the differentially expressed miRNAs in the placenta of observation group and control group. According to the microarray results of miRNAs, three differentially expressed miRNAs, namely let-7b, miR-1202, and miR-29b were selected. Then, the differences in the miR-29b level in the four groups were analyzed, namely the microRNA-29b (miR-29b minic), mini-control (minic control), microRNA-29b inhibitor (miR-29b inhibitor), and inhibitor control (inhibitor control). The results showed that miR-29b level in the placenta of observation group was substantially inferior to that of controls, with remarkable differences (P < 0.05). miR-29b level in miR-29b minic and minic control had significant changes (P < 0.01). The TBC activity of minic control was greatly superior to that of minic control, and there was considerable difference between the two (P < 0.05). The difference between miR-29b inhibitor and inhibitor control in TBC was not obvious, without considerable differences (P > 0.05). The invasion ability of miR-29b inhibitor TBC was notably superior to inhibitor control, and there were substantial differences (P < 0.05). To sum up, miR-29b had a significant inhibitory effect on the proliferation and cell activity of TBC, and can promote the apoptosis and death of TBC. Moreover, its inhibitory effect on cell migration and invasion was also suggested.

Abstract: Garcinia pedunculata Roxb.(GP) belongs to the family of Clusiaceae and is an evergreen tree that grows in semi-wild conditions and is widely distributed throughout the Northeastern part of India. Traditionally, this plant is believed to be of immense medicinal importance and is used for the treatment of various ailments. In Assam, the acidic fruit of GP is effectively used in folklore medicine to treat gastrointestinal disorders and is an integral part of ethnic Assamese cuisine. The ripe fruit, seldom consumed fresh or raw, is cut into thin slices, sun-dried for preservation as it is believed that the medicinal property of the fruit increases as it ages. With much traditional claims and beliefs regarding the medicinal properties of this plant, many therapeutic potentials of GP have been explored through research till now, including its antioxidant, antibacterial, antifungal, anthelmintic, hypolipidemic, antidiabetic, hepatoprotective, neuroprotective, and nephroprotective properties. Moreover, the presence of polyphenols, flavonoids along with bioactive components like hydroxycitric acid, garcinol, and cambogin have also been reported from this plant, thereby increasing its research avenues. Even with the available knowledge, there is a huge lacking in the understanding of its underlying molecular mechanism responsible for the therapeutic properties, pharmacological mode of action, and its effect in different pathological conditions, along with detailed information about its chemical composition. This review mainly aims to summarise the potentially beneficial properties of GP that have already been reported, along with identifying the new avenues that still need to be addressed, thereby increasing the future prospect for in-depth research on this plant, along with its distribution and conservation status.

This study aims to assess the action of miR-34a on MSCs homing onto OSCC. Sixty cases of tissue sample in OSCC was analyzed retrospectively and thirty of normal oral tissue was included as a control group. miR-34a expression in OSCC was detected by qRT-PCR. The relation of expression with OSCC was analyzed. The independent risk factor in the life time of OSCC was studied. pc-DNA-miR-34a and si-miR-34a was transfected into MSCs to analyze its action on MSCs homing onto OSCC by CCK-8 and clone formation assays as well as on cell apoptosis by flow cytometry. The level of miR-34a in patients with OSCC was significantly elevated and was associated with overall survival and prognosis. The FIGO staging and miR-34a expression was the independent risk factor of DFS and OS of patients with OSCC. The cell activity and homing capacity of MSCs was reduced significantly after knock-down of miR-34a expression along with increased apoptotic cell rate. In addition, the miR-34a could prompt the MSC homing onto OSCC. In conclusion, miR-34a level was up-regulated significantly in OSCC and associated with the prognosis, indicating that it might be a novel target for the treatment of OSCC.

One of the goals of precision medicine is to uncover selective vulnerabilities in various cancers. A notable success has been the development of PARP inhibitors for the treatment of breast and ovarian cancers with mutations in BRCA genes. Only two years ago, it was discovered that cancers with microsatellite instability (MSI) were selectively dependent on the RecQ DNA helicase WRN. Subsequently, the molecular mechanism underlying WRN dependency in MSI cancers was uncovered. Here, we review how these developments have led to a promising new drug target in MSI cancers.

Bushen Huoxue (BSHX) has been applied in clinical traditional Chinese medicine treatment, and has definitive clinical efficacy in the treatment of Premature Ovarian Insufficiency (POI) in China. However, little is known of the underlying mechanism of BSHX. The purpose of this paper is to study the pharmacological mechanisms of BSHX acting on POI based on a pharmacology and experimental validation. The pharmacological database of chinese medicine system and analysis platform (TCMSP) were used to search the effective active ingredients and potential action targets of BSHX. Drugbank, Online Mendelian Inheritance in Man (OMIM), Genecards, and Disgenet databases were used to obtain relevant targets of POI. Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and the visual network of protein-protein interaction network were constructed by FunRich3.1. Pymol software, and Auto Dock tools 1.5.6 were used for molecular docking. Murine model of POI was used to further investigate the mechanism of BSHX against on POI. Finally, 127 active compounds were collected from TCMSP database, and 215 active targets were identified. There were 1366 targets related to POI and 99 targets of BSHX for the treatment of POI. Quercetin, kaempferol, and stigmasterol were recognized as the most effective compounds corresponding to targets. The top three genes according to degree value are TP53, Akt1, and VEGFA. Further, the results of GO and KEGG enrichment analysis revealed that those core targets were mainly enriched on TRAIL and TGF-β receptor signaling. The results of molecular docking showed that stigmasterol had good binding ability to Akt1. Moreover, experimental validation suggests that BSHX significantly Increased the expression of TGF-β1 and Smad2/3, regulating the release of serum sex hormones, which include Follicular stimulating hormone (FSH), Estradiol (E2), and Antimullerin hormone (AMH)., HIGHLIGHTS BSHX treats POI by regulating TGF-β1 and Smad2/3 signaling pathways; Quercetin, kaempferol, and stigmasterol were the most effective compounds in BSHX.

Objective. Nephrotic syndrome (NS) is a common glomerular disease caused by a variety of causes and is the second most common kidney disease. Guizhi is the key drug of Wulingsan in the treatment of NS. However, the action mechanism remains unclear. In this study, network pharmacology and molecular docking were used to explore the underlying molecular mechanism of Guizhi in treating NS. Methods. The active components and targets of Guizhi were screened by the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), Hitpick, SEA, and Swiss Target Prediction database. The targets related to NS were obtained from the DisGeNET, GeneCards, and OMIM database, and the intersected targets were obtained by Venny2.1.0. Then, active component-target network was constructed using Cytoscape software. And the protein-protein interaction (PPI) network was drawn through the String database and Cytoscape software. Next, Gene Ontology (GO) and pathway enrichment analyses of Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed by DAVID database. And overall network was constructed through Cytoscape. Finally, molecular docking was conducted using Autodock Vina. Results. According to the screening criteria, a total of 8 active compounds and 317 potential targets of Guizhi were chosen. Through the online database, 2125 NS-related targets were identified, and 93 overlapping targets were obtained. In active component-target network, beta-sitosterol, sitosterol, cinnamaldehyde, and peroxyergosterol were the important active components. In PPI network, VEGFA, MAPK3, SRC, PTGS2, and MAPK8 were the core targets. GO and KEGG analyses showed that the main pathways of Guizhi in treating NS involved VEGF, Toll-like receptor, and MAPK signaling pathway. In molecular docking, the active compounds of Guizhi had good affinity with the core targets. Conclusions. In this study, we preliminarily predicted the main active components, targets, and signaling pathways of Guizhi to treat NS, which could provide new ideas for further research on the protective mechanism and clinical application of Guizhi against NS.

BACKGROUND Basic 7S globulins, a group of proteins commonly found in legumes, undergo the intriguing phenomenon of release from the seeds into hot water. γ-Conglutin is a representative of this group of proteins found in lupin seeds. The physiological significance and the molecular mechanism of the selective release of γ-conglutin from lupin seeds remain unknown. Therefore, the presented study aimed to determine changes in the functionality of this protein in response to the high temperature occurring during lupin seed incubation. RESULTS It was confirmed that the main protein fraction released from the seeds during high-temperature incubation was γ-conglutin. The incubation condition favours the occurrence of this protein in a monomeric form, and the temperature used corresponds to its midpoint unfolding temperature. Subsequent analysis carried out on the γ-conglutin monomer revealed changes in its functionality after heat shock. The thermally treated protein shows a considerable increase in its interaction strength with flavonoids. Moreover, the inhibitory activity against glycoside hydrolases was enhanced when γ-conglutin monomer was exposed to specific temperatures. CONCLUSION The results of the present study provide a potential explanation of the physiological relevance of γ-conglutin and shed new light on a possible mechanism of its activation upon specific heat treatment. This knowledge will help characterise homologous proteins, which are commonly found in other legumes and undergo a similar heat-induced secretion phenomenon. © 2021 Society of Chemical Industry.

P-Coumaric acid (p-CA) is a hydroxycinnamic acid, an organic compound that is a hydroxyl derivative of cinnamic acid. P-CA is the most abundant isomer in nature and can be found in a wide variety of edible plants such as fungi, peanuts, navy beans, tomatoes, carrots, basil, and garlic. Recently, the therapeutic properties of p-CA have received a great deal of attention from scientific society. Here, we described the medicinal effects of p-CA on various pathological conditions. This review was performed via evaluating PubMed reported studies from January 2010 to January 2020. Also, reference lists were checked to find additional studies. All intermediation or complementarity of animal models, case-control and cohort studies, in vitro studies, and controlled trials (CTs) on p-CA were acceptable. However plant extract studies without indication of main active substances were excluded due to the considerable diversities and heterogeneities. According to recent evidence regarding the beneficial effects of p-CA, numerous diseases such as nephropathies, cardiovascular diseases, neuroinflammatory diseases, liver diseases, cancers, and some metabolic disorders could potentially be controlled by this natural herb. Interestingly, autophagy is a novel molecular mechanism involved in the crosstalk between classic effects of p-CA and introduces alternative therapeutic pathways for this compound. Much work remains in clarifying the main therapeutic properties among the various p-CA effects; these will be the subject of forthcoming work, resulting in presenting further mechanism of action.

The favorable physicochemical properties are essential for the application of protein-based nanovehicles in the field of biomaterials. Herein, we found that the thermal stability of Marsupenaeus japonicus ferritin (MjFer) (Tm = 109.1 ± 0.4 °C) is markedly higher than human H-chain ferritin (HuHF) (Tm = 87.7 ± 0.3 °C), although they share a high structural similarity. Multiple results indicated that the promoted thermal stability of MjFer is mainly derived from the salt bridges located at the C3 interface. Consequently, MjFer exhibits strong protective effects on encapsulated curcumin upon exposure at high temperatures. In contrast, most of the curcumin loaded HuHF composites precipitated rapidly under the same conditions. These findings elucidated the molecular mechanism of the hyperthermostability of MjFer and illustrated that MjFer could act as a robust insulation nanocarrier for bioactive compounds against various thermal treatments.

As a crucial molecular mechanism, post-translational modifications (PTMs) play critical roles in a wide range of biological processes in plants. Recent advances in mass spectrometry-based proteomic technologies have greatly accelerated the profiling and quantification of plant PTM events. Although several databases have been constructed to store plant PTM data, a resource including more plant species and more PTM types with quantitative dynamics still remains to be developed. In this paper, we present an integrative database of quantitative PTMs in plants named qPTMplants (http://qptmplants.omicsbio.info), which hosts 1 242 365 experimentally identified PTM events for 429 821 nonredundant sites on 123 551 proteins under 583 conditions for 23 PTM types in 43 plant species from 293 published studies, with 620 509 quantification events for 136 700 PTM sites on 55 361 proteins under 354 conditions. Moreover, the experimental details, such as conditions, samples, instruments and methods, were manually curated, while a variety of annotations, including the sequence and structural characteristics, were integrated into qPTMplants. Then, various search and browse functions were implemented to access the qPTMplants data in a user-friendly manner. Overall, we anticipate that the qPTMplants database will be a valuable resource for further research on PTMs in plants.

In this study, we aim to identify the clinical significance of basonuclin 1 ( BNC1) expression in ovarian carcinoma (OV) and to explore its latent mechanisms. Via integrating in-house tissue microarrays, gene chips, and RNA-sequencing data, we explored the expression and clinical value of BNC1 in OV. Immunohistochemical staining was utilized to confirm the protein expression status of BNC1. A combined SMD of –2.339 (95% CI: –3.649 to –1.028, P < 0.001) identified that BNC1 was downregulated based on 1346 samples, and the sROC (AUC = 0.93) showed a favorable discriminatory ability of BNC1 in OV patients. We used univariate and multivariate Cox regulation to evaluate the prognostic role of BNC1 for OV patients, and a combined hazard ratio of 0.717 (95% CI: 0.445–0.989, P < 0.001) revealed that BNC1 was a protective factor for OV. Furthermore, the fraction of infiltrating naive B cells, memory B cells, and other immune cells showed statistical differences between the high- and low- BNC1 expression groups through cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) algorithm. Enrichment analysis showed that BNC1 may have a relationship with immune-related items in OV. By predicting the potential regulatory transcription factors (TFs) of BNC1, friend leukemia virus integration 1 ( FLI1) may be a potential upstream TF of BNC1. Corporately, a decreasing trend of BNC1 may serve as a tumor suppressor and prognostic biomarker in OV patients. Moreover, BNC1 may take part in immune-related pathways and influence the fraction of tumor-infiltrating immune cells.

High temperature (HT) stress has become one of the most detrimental stresses in crop production among constantly changing environmental factors. Exploiting approaches to enhance crop thermotolerance would have great significance in assuaging adverse effects of HT stress on crop growth and development. As jasmonates (JAs) and brassinosteroids (BRs) are novel phytohormones and play important roles in responses to biotic and abiotic stresses and in a wide range of plant developmental processes, this paper reviewed the roles and mechanisms of JAs and BRs in mitigating HT stress, with focus on rice (Oryza sativa L.) subjected to HT stress during anthesis. It is demonstrated that JAs alleviate spikelet-opening impairment and BRs ameliorate pistil fertilization ability under HT stress during anthesis of rice, although there are controversial observations. Activating the defense system, enhancing osmotic regulation, protecting photosynthesis, and interacting with other phytohormones, especially with ethylene and abscisic acid, are main physiological mechanisms by which JAs or BRs attenuate HT stress to plants. Elevating levels of JAs or BRs in plants could be considered as an important approach to enhance crop thermotolerance through breeding new varieties. Using JAs or BRs as chemical regulators and adopting proper water and nitrogen management practices could reduce the harm of HT stress to rice. Further research is needed to elucidate the roles of JAs and BRs in different plant tissues in responses to HT stress under different genetic backgrounds and environments, reveal the molecular mechanism underlying JAs and BRs mediating HT stress, understand the cross-talk between phytohormones in modulating HT stress, and establish integrated crop management to minimize the hazard of HT stress in rice production.

The annual herb, Ageratum conyzoides L. (Asteraceae), is distributed throughout the world. Although invasive, it can be very useful as a source of essential oils, pharmaceuticals, biopesticides, and bioenergy. However, very limited information exists on the molecular basis of its different utility as previous investigations were mainly focused on phytochemical/biological activity profiling. Here we have explored various properties of A. conyzoides that may offer environmental, ecological, agricultural, and health benefits. As this aromatic plant harbors many important secondary metabolites that may have various implications, biotechnological interventions such as genomics, metabolomics and tissue-culture can be indispensable tools for their mass-production. Further, A. conyzoides acts as a natural reservoir of begomoviruses affecting a wide range of plant species. As the mechanisms of disease spreading and crop infection are not fully clear, whole-genome sequencing and various advanced molecular technologies including RNAi, CRISPER/Cas9, multi-omics approaches, etc., may aid to decipher the molecular mechanism of such disease development and thus, can be useful in crop protection. Overall, improved knowledge of A. conyzoides is not only essential for developing sustainable weed control strategy but can also offer potential ways for biomedicinal, environment, safe and clean agriculture applications. Supplementary Information The online version contains supplementary material available at 10.1007/s12033-021-00409-5.

Understanding paradoxical responses to anabolic stimulation and identifying the mechanisms for this inconsistency in mobility-limited older adults may provide new targets for the treatment of sarcopenia. Our laboratory has discovered that dysregulation in microRNA (miRNA) that target anabolic pathways is a potential mechanism resulting in age-associated decreases in skeletal muscle mass and function (sarcopenia). The objective of the current study was to assess circulating miRNA expression profiles in diametric response of leg lean mass in mobility-limited older individuals after a 6-mo progressive resistance exercise training intervention (PRET) and determine the influence of differentially expressing miRNA on regulation of skeletal muscle mass. Participants were dichotomized by gain (Gainers; mean +561.4 g, n = 33) or loss (Losers; mean −589.8 g, n = 40) of leg lean mass after PRET. Gainers significantly increased fat-free mass 2.4% vs. −0.4% for Losers. Six miRNA (miR-1-3p, miR-19b-3p, miR-92a, miR-126, miR-133a-3p, and miR-133b) were significantly identified to be differentially expressed between Gainers and Losers, with miR-19b-3p being the miRNA most highly associated with increases in fat-free mass. Using an aging mouse model, we then assessed if miR-19b-3p expression was different in young mice with larger muscle mass compared with older mice. Circulating and skeletal muscle miR-19b-3p expression was higher in young compared with old mice and was positively associated with muscle mass and grip strength. We then used a novel integrative approach to determine if differences in circulating miR-19b-3p potentially translate to augmented anabolic response in human skeletal muscle cells in vitro. Results from this analysis identified that overexpression of miR-19b-3p targeted and downregulated PTEN by 64% to facilitate significant ∼50% increase in muscle protein synthetic rate as measured with SUnSET. The combine results of these three models identify miR-19b-3p as a potent regulator of muscle anabolism that may contribute to an inter-individual response to PRET in mobility-limited older adults.

Yam (Dioscorea opposita) is a kind of vegetables with important nutritional, medicinal and economic value. To reveal the relationship between starch synthesis and gene expression in yam tubers at gene transcription level, transcriptome profiling was conducted by RNA-Seq in Bikeqi yam (Dioscorea opposita Thunb.) tubers at five key developmental stages (105, 120, 135, 150, and 165 days after sowing, DAS). Based on transcriptome sequencing data, a total of 45,867 unigenes were obtained. The results showed that 135 days after sowing are the key period of starch accumulation. During yam tuber development, 1,941 candidate differentially expressed genes (DEGs) were successfully classified into three GO categories, respectively, and there were 292, 267 and 478 unigenes in cellular component, molecular function and biological process. There were 767, 90 and 73 DEGs enriched in metabolic, plant hormone signal transduction and Plant-pathogen interaction pathway by Kyoto Encyclopedia of Genes and Genomes (KEGG), individually. Especially 72 DEGs were enriched in starch and sucrose metabolism pathway. In this pathway, the metabolic process was mainly positive regulated by genes encoding sucrose synthase, glucose-1-phosphate adenylyltransferase, alpha-trehalase, and so on. There was negative regulated by genes encoding beta-glucosidase. 10 DEGs involved in starch synthesis were selected to prove the accuracy of the RNA-Seq data by qPCR, 85% (34/40) of the results were consistent. The results lay a theoretical foundation be used for further understanding the starch synthesis mechanism of yam tubers development and accelerating breeding progress.

The abnormal expression of transgelin-2 (TAGLN2) is related to tumor occurrence and progression. However, the underlying molecular mechanism of TAGLN2 in human colorectal cancer (CRC) is still poorly understood. Compared with adjacent tissues, TAGLN2 is overexpressed in CRC tissues. Its expression level is negatively correlated with the overall survival rate of patients with CRC. In addition, knockdown of TAGLN2 inhibited the proliferation and invasion of CRC cells. We also showed that TAGLN2 could interact with CD44 to regulate the Notch-1 signaling pathway. Our findings indicate there is increased TAGLN2 expression in CRC and that it may serve as a promising potential therapeutic target for CRC.

Summary Yield in rice is determined mainly by panicle architecture. Using map‐based cloning, we identified an R2R3 MYB transcription factor REGULATOR OF GRAIN NUMBER1 (RGN1) affecting grain number and panicle architecture. Mutation of RGN1 caused an absence of lateral grains on secondary branches. We demonstrated that RGN1 controls lateral grain formation by regulation of LONELY GUY (LOG) expression, thus controlling grain number and shaping panicle architecture. A novel favourable allele, RGN1 C, derived from the Or‐I group in wild rice affected panicle architecture by means longer panicles. Identification of RGN1 provides a theoretical basis for understanding the molecular mechanism of lateral grain formation in rice; RGN1 will be an important gene resource for molecular breeding for higher yield.

Trichomes are specialized glandular or non-glandular structures that provide physical or chemical protection against insect and pathogen attack. Trichomes in Arabidopsis have been extensively studied as typical non-glandular structures. By contrast, the molecular mechanism underlying glandular trichome formation and elongation remains largely unknown. We previously demonstrated that Hair is essential for the formation of type I and type VI trichomes. Here, we found that overexpression of Hair increased the density and length of tomato trichomes. Biochemical assays revealed that Hair physically interacts with its close homolog SlZFP8-like (SlZFP8L), and SlZFP8L also directly interacts with Woolly. SlZFP8L-overexpressing plants showed increased trichome density and length. We further found that the expression of SlZFP6, which encodes a C2H2 zinc finger protein, is positively regulated by Hair. Using chromatin immunoprecipitation, yeast one-hybrid, and dual-luciferase assays we identified that SlZFP6 is a direct target of Hair. Similar to Hair and SlZFP8L, the overexpression of SlZFP6 also increased the density and length of tomato trichomes. Taken together, our results suggest that Hair interacts with SlZFP8-like to regulate the initiation and elongation of trichomes by modulating SlZFP6 expression in tomato.

Oncolytic therapy is a treatment method used to directly combat tumor cells by modifying the genes of naturally occurring low pathogenic viruses to form "rhizobia" virus. By taking the advantage of abnormal signal pathways in cancer cells, it selectively replicates in tumor cells leading to tumor cell lysis and death. At present, clinical studies widely employ biomolecular technology to transform oncolytic viruses to exert stronger oncolytic effects and reduce their adverse reactions. This review summarizes the current progresses and the molecular mechanism of oncolytic viruses towards tumor treatment and management.

The goal of this study is to reveal the hub genes and molecular mechanisms of the coronavirus disease 2019 (COVID‐19) acute respiratory distress syndrome (ARDS) based on the genome‐wide RNA sequencing dataset. The RNA sequencing dataset of COVID‐19 ARDS was obtained from GSE163426. A total of 270 differentially expressed genes (DEGs) were identified between COVID‐19 ARDS and control group patients. Functional enrichment analysis of DEGs suggests that these DEGs may be involved in the following biological processes: response to cytokine, G‐protein coupled receptor activity, ionotropic glutamate receptor signalling pathway and G‐protein coupled receptor signalling pathway. By using the weighted correlation network analysis approach to analyse these DEGs, 10 hub DEGs that may play an important role in COVID‐19 ARDS were identified. A total of 67 potential COVID‐19 ARDS targetted drugs were identified by a complement map analysis. Immune cell infiltration analysis revealed that the levels of T cells CD4 naive, T cells follicular helper, macrophages M1 and eosinophils in COVID‐19 ARDS patients were significantly different from those in control group patients. In conclusion, this study identified 10 COVID‐19 ARDS‐related hub DEGs and numerous potential molecular mechanisms through a comprehensive analysis of the RNA sequencing dataset and also revealed the difference in immune cell infiltration of COVID‐19 ARDS.

Graphical abstract Baicalin is one of the bioactive flavonoid glycosides isolated from the dried root of Scutellaria baicalensis Georgi, Lamiaceae, with antiviral properties. In recent years, the antiviral activity of baicalin has been widely investigated to explore its molecular mechanism of action. In this mini-review, the molecular mechanisms of action of baicalin as an antiviral agent are evaluated, which included three categories: the inhibition or stimulation of JAK/STAT, TLRs, and NF-κB pathways; up or down modulation of the expression levels of IFN, IL, SOCS1/3, PKR protein, Mx1 protein, and AP-1 protein; and inhibition of cell apoptosis caused by virus infection. In addition, clinical studies of baicalin are also discussed. This literature search suggested that baicalin can serve as a potential candidate for the development of a novel broad-spectrum antiviral drug. Supplementary Information The online version contains supplementary material available at 10.1007/s43450-021-00182-1.

Typical traditional probiotics lactobacilli and bifidobacteria are gaining great interest to be developed as living diagnostics and therapeutics for improving human health. However, the mechanistic basis underlying their inherent health beneficial property remain incompletely understood which can slow down the translational pipeline in the functional food and pharmaceutical field. Efficient genome editing will advance the understanding of the molecular mechanism of the probiotics' physiological properties and their interaction with the host and the host microbiota, thereby further promote the development of next-generation designer probiotics with improved robustness and tailored functionalities. With the expansion of genome editing strategies such as CRISPR-Cas-based tools and IPSD assisted genome engineering as well as other synthetic biology technologies, the research and application of these health-promoting bacteria for the food and pharmaceutical industry will be further enhanced.

Purpose Despite a few recent reports of patients harboring truncating variants in NSD2, a gene considered critical for the Wolf–Hirschhorn syndrome (WHS) phenotype, the clinical spectrum associated with NSD2 pathogenic variants remains poorly understood. Methods We collected a comprehensive series of 18 unpublished patients carrying heterozygous missense, elongating, or truncating NSD2 variants; compared their clinical data to the typical WHS phenotype after pooling them with ten previously described patients; and assessed the underlying molecular mechanism by structural modeling and measuring methylation activity in vitro. Results The core NSD2-associated phenotype includes mostly mild developmental delay, prenatal-onset growth retardation, low body mass index, and characteristic facial features distinct from WHS. Patients carrying missense variants were significantly taller and had more frequent behavioral/psychological issues compared with those harboring truncating variants. Structural in silico modeling suggested interference with NSD2’s folding and function for all missense variants in known structures. In vitro testing showed reduced methylation activity and failure to reconstitute H3K36me2 in NSD2 knockout cells for most missense variants. Conclusion NSD2 loss-of-function variants lead to a distinct, rather mild phenotype partially overlapping with WHS. To avoid confusion for patients, NSD2 deficiency may be named Rauch–Steindl syndrome after the delineators of this phenotype., Genetics in Medicine, 23 (8)

Background Hepatocellular carcinoma (HCC) remains one of the most common malignant neoplasms. Lysophosphatidylcholine acyltransferase 1 (LPCAT1) plays a key role in the lipid remodelling and is correlated with various neoplasms. Nonetheless, the biological functions and molecular mechanisms of LPCAT1 underlying HCC remain obscure. Methods In the present study, we investigated the role of LPCAT1 in the progression of HCC. In-house RT-qPCR, tissue microarrays, and immunohistochemistry were performed to detect the expression levels and the clinical value of LPCAT1 in HCC. External datasets were downloaded to confirm the results. Proliferation, migration, invasiveness, cell cycle, and apoptosis assays were conducted to reveal the biological effects LPCAT1 has on SMMC-7721 and Huh7 cells. HCC differentially expressed genes and LPCAT1 co-expressed genes were identified to explore the molecular mechanisms underlying HCC progression. Results LPCAT1 showed upregulated expression in 3715 HCC specimens as opposed to 3105 non-tumour specimens. Additionally, LPCAT1 might be an independent prognostic factor for HCC. LPCAT1-knockout hampered cellular proliferation, migration, and metastasis in SMMC-7721 and Huh7 cells. More importantly, the cell cycle and chemical carcinogenesis were the two most enriched signalling pathways. Conclusions The present study demonstrated that increased LPCAT1 correlated with poor prognosis in HCC patients and fuelled HCC progression by promoting cellular growth, migration, and metastasis.

5-methylcytosine (m(5)C) is identified as an abundant and conserved modification in various RNAs, including tRNAs, mRNAs, rRNAs, and other non-coding RNAs. The application of high-throughput sequencing and mass spectrometry allowed for the detection of m(5)C at a single-nucleotide resolution and at a global abundance separately; this contributes to a better understanding of m(5)C modification and its biological functions. m(5)C modification plays critical roles in diverse aspects of RNA processing, including tRNA stability, rRNA assembly, and mRNA translation. Notably, altered m(5)C modifications and mutated RNA m(5)C methyltransferases are associated with diverse pathological processes, such as nervous system disorders and cancers. This review may provide new sights of molecular mechanism and functional importance of m(5)C modification.

Long non-coding RNAs (lncRNAs) play a vital regulatory role in many human cancers. However, their underlying effect and molecular mechanism in chemoresistance need to be fully researched. This stud...

Purpose: To determine the molecular mechanism involved in the anti-migraine effect of Asari Radix et Rhizoma (ARR) using network pharmacology. Methods: The compounds present in ARR were identified through information retrieval from literature and public databases, and were screened based on absorption, distribution, metabolism, excretion and toxicity. Target genes related to the selected compounds and migraine were identified or predicted from public databases. Hub genes in ARR against migraine were identified through analysis of interactions in overlapping genes between compounds and migraine target genes, based on STRING database. Gene enrichment analysis of overlapping genes was performed using Database for Annotation, Visualization and Integrated Discovery. Results: A total of 138 compounds were selected as potential bioactive compounds in ARR. Target genes related to the selected compounds (611 genes) and migraine (278 genes) were obtained, including 71 overlapping genes. The hub genes in the anti-migraine effect of ARR were BDNF, IL6, COMT, APP and TNF. Gene enrichment analysis showed the top 10 biological processes or pathways involved in the mechanism of anti-migraine action of ARR. The tissue source of the overlapping genes was not limited to the brain. The results from gene enrichment analysis revealed that the effect of ARR on migraine was holistic, which is characteristic of traditional Chinese medicines. Conclusion: Network pharmacology has been used to decipher the molecular mechanism involved in the action of ARR against migraine. The results provide a scientific basis for the clinical effect of ARR on migraine.

This study was performed to investigate the difference in developmental competence of oocytes derived from ovum pick-up (OPU) and slaughterhouse ovaries (SLH), and its underlying mechanisms. The OPU and SLH oocytes were in-vitro maturated and fertilized to produce blastocysts, and these blastoycsts were collected to explore the expression of key genes for developmental potential and telomere (Oct-4, Sox2, Nanog, Cdx2, Gata3, E-cadherin, β-catenin, TERT, TERF1 and TERF2). The results showed that both the cleavage and blastocyst rates were significantly higher for the OPU group (68.31%, 39.48%, respectively) than SLH group (57.59%, 26.50%, respectively) (P 0.01). The relative mRNA abundances of Sox2, Oct-4, Nanog and E-cadherin were significantly higher in the OPU blastocysts than the SLH ones (P 0.01). Protein expression analysis by Western blot and immunofluorescence also revealed that the expression of E-cadherin and Sox2 was significantly higher in OPU blastocysts than SLH ones. However, there was no significant differences between the two groups in the expression of Cdx2, β-catenin, Gata3, TERT, TERF1, TERF2. These results imply oocyte sources modify the expression of development and adhesion related genes in blastocysts, which may elucidate a possible reasoning for the low development competence of buffalo SLH embryos.

Degrader technologies, which enable the chemical knockdown of disease-causing proteins, are promising for drug discovery. After two decades of research, degraders using the ubiquitin-proteasome system (UPS) are currently in clinical trials. However, the UPS substrates are mainly limited to soluble proteins. Autophagy-targeting chimeras and autophagosome-tethering compounds are degraders that use autophagy, which has functions complementary to the UPS. They can degrade organelles and aggregate-prone proteins, making them promising treatments against age-related conditions such as mitochondrial dysfunction and neurodegenerative diseases. The molecular mechanism of selective autophagy is an ongoing research topic, which explains why autophagy-based degraders were not available until recently. In this review, we introduce four classifications of selective autophagy mechanisms to facilitate the understanding of the degrader design.

Background Browning spot (BS) disorders seriously affect the appearance quality of ‘Huangguan’ pear and cause economic losses. Many studies on BS have mainly focused on physiological and biochemical aspects, and the molecular mechanism remains unclear. Results In the present study, the structural characteristics of ‘Huangguan’ pear with BS were observed via scanning electron microscopy (SEM), the water loss and brown spots were evaluated, and transcriptomic and metabolomics analyses were conducted to reveal the molecular mechanism underlying ‘Huangguan’ pear skin browning disorder. The results showed that the occurrence of BS was accompanied by a decrease in the wax layer and an increase in lignified cells. Genes related to wax biosynthesis were downregulated in BS, resulting in a decrease in the wax layer in BS. Genes related to lignin were upregulated at the transcriptional level, resulting in upregulation of metabolites related to phenylpropanoid biosynthesis. Expression of calcium-related genes were upregulated in BS. Cold-induced genes may represent the key genes that induce the formation of BS. In addition, the results demonstrated that exogenous NaH2PO4·2H2O and ABA treatment could inhibit the incidence of BS during harvest and storage time by increasing wax-related genes and calcium-related genes expression and increasing plant resistance, whereas the transcriptomics results indicated that GA3 may accelerate the incidence and index of BS. Conclusions The results of this study indicate a molecular mechanism that could explain BS formation and elucidate the effects of different treatments on the incidence and molecular regulation of BS.

O-glycosylation is a post-translational protein modification essential to life. One of the enzymes involved in this process is protein O-fucosyltransferase 1 (POFUT1), which fucosylates threonine or serine residues within a specific sequence context of epidermal growth factor-like domains (EGF-LD). Unlike most inverting glycosyltransferases, POFUT1 lacks a basic residue in the active site that could act as a catalytic base to deprotonate the Thr/Ser residue of the EGF-LD acceptor during the chemical reaction. Using quantum mechanics/molecular mechanics (QM/MM) methods on recent crystal structures, as well as mutagenesis experiments, we uncover the enzyme catalytic mechanism, revealing that it involves proton shuttling through an active site asparagine, conserved among species, which undergoes tautomerization. This mechanism is consistent with experimental kinetic analysis of Caenorhabditis elegans POFUT1 Asn43 mutants, which ablate enzyme activity even if mutated to Asp, the canonical catalytic base in inverting glycosyltransferases. These results will aid inhibitor development for Notch-associated O-glycosylation disorders.

DNA damage can be introduced by intrinsic or extrinsic stimuli and threaten the transmission of genetic information and ultimately, survival. Eukaryotes have evolved a sophisticated mechanism, DNA damage response (DDR), to counteract this threat posed by DNA damage. The DDR requires a series of proteins involved in multiple DNA repair pathways, of which ATM, ATR and DNA–PK serve as the three most critical kinases. The signaling mechanisms underlying these pathways have been extensively studied and these three master kinases structures determined by cryo-electron microscopy (cryo-EM) have led to tremendous progress in understanding the molecular mechanism of the DDR. In this review, we discuss the recent advances made in understanding the structures of ATM, ATR, and DNA–PK. We highlight the implications of these structures in terms of their function and regulation, and speculate on the critical role of PIKK regulatory domain (PRD) in their activation.

The orderly organelle interaction network is prerequisite for normal life activity of cell, ensuring a balance between communication and uniqueness of organelles. Disorder organelle interaction is implicated in the occurrence and development of many diseases. An in-depth understanding of mechanisms of orderly organelle interaction helps to reveal the pathogenesis of related diseases. Chemical and genetic tools have identified the roles of specific proteins in orderly organelle interaction; however, little is known about the modes, functions and mechanisms of orderly interaction between organelles. With rapid development of imaging tools, deep-going insights into the structure feature of cell membranes have substantially improved our understanding of the mechanisms of ordered organelle interactions. This review summarizes the conventional molecular mechanism of orderly organelle interactions, and highlights the new progress regarding membrane structure and the novel structural mechanism of orderly organelle transport.