Combining TP53 mutation and isoform has the potential to improve clinical practice.

The clinical importance of assessing and combining data on TP53 mutations and isoforms is discussed in this article. It gives a succinct overview of the structural makeup and key biological roles of the isoforms. It then provides a comprehensive summary of the roles that p53 isoforms play in cancer development, therapy response and resistance. The review provides a summary of studies demonstrating the role of p53 isoforms as potential prognostic indicators. It further provides evidence on how the presence of TP53 mutations may affect one or more of these activities and the association of p53 isoforms with clinicopathological data in various tumour types. The review gives insight into the present diagnostic hurdles for identifying TP53 isoforms and makes recommendations to improve their evaluation. In conclusion, this review offers suggestions for enhancing the identification and integration of TP53 isoforms in conjunction with mutation data within the clinical context.

Air-Stable Perylene Diimide Trimer Material for N-Type Organic Electrochemical Transistors.

A new method is reported to make air-stable n-type organic mixed ionic-electronic conductor (OMIEC) films for organic electrochemical transistors (OECTs) using a solution-processable small molecule helical perylene diimide trimer, hPDI[3]-C11. Alkyl side chains are attached to the conjugated core for processability and film making, which are then cleaved via thermal annealing. After the sidechains are removed, the hPDI[3] film becomes less hydrophobic, more ordered, and has a deeper lowest unoccupied molecular orbital (LUMO). These features provide improved ionic transport, greater electronic mobility, and increased stability in air and in aqueous solution. Subsequently, hPDI[3]-H is used as the active material in OECTs and a device with a transconductance of 44 mS, volumetric capacitance of ≈250 F cm-3, µC* value of 1 F cm-1 V-1 s-1, and excellent stability (> 5 weeks) is demonstrated. As proof of their practical applications, a hPDI[3]-H-based OECTs as a glucose sensor and electrochemical inverter is utilized. The approach of side chain removal after film formation charts a path to a wide range of molecular semiconductors to be used as stable, mixed ionic-electronic conductors.

RBM3 Promotes Anti-inflammatory Responses in Microglia and Serves as a Neuroprotective Target of Ischemic Stroke.

Ischemic stroke is a major cause of death and disability in adults. Hypothermic treatment is successful in treating neonatal cerebral ischemia, but its application is restricted in adult patients due to complex management strategies and severe adverse effects. Two homologous RNA-binding proteins, RBM3 and CIRP, are the only known cold-inducible proteins in vertebrates, and their expression levels are robustly elevated by mild to moderate hypothermia. In previous studies, we and others have demonstrated that both RBM3 and CIRP mediate the neuroprotective and neurogenic effects of hypothermia in cell and animal models. However, CIRP can also be detrimental to neurons by triggering neuroinflammatory responses, complicating its post-stroke functions. In this study, we compared the properties of the two cold-inducible RNA-binding proteins after ischemic stroke. Our results indicated that RBM3 expression was stimulated in the ischemic brain of stroke patients, while CIRP expression was not. In an experimental model, RBM3 can ameliorate ischemic-like insult by promoting neuronal survival and eliciting anti-inflammatory responses in activated microglia, while the impact of CIRP was intriguing. Collectively, our data supported the notion that RBM3 may be a more promising therapeutic target than CIRP for treating ischemic stroke. We further demonstrated that zr17-2, a small molecule initially identified to target CIRP, can specifically target RBM3 but not CIRP in microglia. zr17-2 demonstrated anti-inflammatory and neuroprotective effects after ischemic stroke both in vitro and in vivo, suggesting its potential therapeutic value.

The Rapid Non-Destructive Differentiation of Different Varieties of Rice by Fluorescence Hyperspectral Technology Combined with Machine Learning.

A rice classification method for the fast and non-destructive differentiation of different varieties is significant in research at present. In this study, fluorescence hyperspectral technology combined with machine learning techniques was used to distinguish five rice varieties by analyzing the fluorescence hyperspectral features of Thai jasmine rice and four rice varieties with a similar appearance to Thai jasmine rice in the wavelength range of 475-1000 nm. The fluorescence hyperspectral data were preprocessed by a first-order derivative (FD) to reduce the background and baseline drift effects of the rice samples. Then, a principal component analysis (PCA) and t-distributed stochastic neighborhood embedding (t-SNE) were used for feature reduction and 3D visualization display. A partial least squares discriminant analysis (PLS-DA), BP neural network (BP), and random forest (RF) were used to build the rice classification models. The RF classification model parameters were optimized using the gray wolf algorithm (GWO). The results show that FD-t-SNE-GWO-RF is the best model for rice classification, with accuracy values of 99.8% and 95.3% for the training and test sets, respectively. The fluorescence hyperspectral technique combined with machine learning is feasible for classifying rice varieties.

Sanguinarine modulates microglial function via PPARγ activation and protects against CNS demyelination.

Microglia aggregate in regions of active inflammation and demyelination in the CNS of multiple sclerosis (MS) patients and are considered pivotal in the disease process. Targeting microglia is a promising therapeutic approach for myelin repair. Previously, we identified two candidates for microglial modulation and remyelination using a Connectivity Map (CMAP)-based screening strategy. Interestingly, with results that overlapped, sanguinarine (SAN) emerged as a potential drug candidate to modulate microglial polarization and promote remyelination. In the current study, we demonstrate the efficacy of SAN in mitigating the MS-like experimental autoimmune encephalomyelitis (EAE) in a dose-dependent manner. Meanwhile, prophylactic administration of a medium dose (2.5 mg/kg) significantly reduces disease incidence and ameliorates clinical signs in EAE mice. At the cellular level, SAN reduces the accumulation of microglia in the spinal cord. Morphological analyses and immunophenotyping reveal a less activated state of microglia following SAN administration, supported by decreased inflammatory cytokine production in the spinal cord. Mechanistically, SAN skews primary microglia towards an immunoregulatory state and mitigates proinflammatory response through PPARγ activation. This creates a favorable milieu for the differentiation of oligodendrocyte progenitor cells (OPCs) when OPCs are incubated with conditioned medium from SAN-treated microglia. We further extend our investigation into the cuprizone-induced demyelinating model, confirming that SAN treatment upregulates oligodendrocyte lineage genes and increases myelin content, further suggesting its pro-myelination effect. In conclusion, our data propose SAN as a promising candidate adding to the preclinical therapeutic arsenal for regulating microglial function and promoting myelin repair in CNS demyelinating diseases such as MS.

eNOS Regulates Lymphatic Valve Specification by Controlling ß-Catenin Signaling During Embryogenesis in Mice.

BACKGROUND: Lymphatic valves play a critical role in ensuring unidirectional lymph transport. Loss of lymphatic valves or dysfunctional valves are associated with several diseases including lymphedema, lymphatic malformations, obesity, and ileitis. Lymphatic valves first develop during embryogenesis in response to mechanotransduction signaling pathways triggered by oscillatory lymph flow. In blood vessels, eNOS (endothelial NO synthase; gene name: Nos3) is a well-characterized shear stress signaling effector, but its role in lymphatic valve development remains unexplored. METHODS: We used global Nos3-/- mice and cultured human dermal lymphatic endothelial cells to investigate the role of eNOS in lymphatic valve development, which requires oscillatory shear stress signaling. RESULTS: Our data reveal a 45% reduction in lymphatic valve specification cell clusters and that loss of eNOS protein inhibited activation of ß-catenin and its nuclear translocation. Genetic knockout or knockdown of eNOS led to downregulation of ß-catenin target proteins in vivo and in vitro. However, pharmacological inhibition of NO production did not reproduce these effects. Co-immunoprecipitation and proximity ligation assays reveal that eNOS directly binds to ß-catenin and their binding is enhanced by oscillatory shear stress. Finally, genetic ablation of the Foxo1 gene enhanced FOXC2 expression and partially rescued the loss of valve specification in the eNOS knockouts. CONCLUSIONS: In conclusion, we demonstrate a novel, NO-independent role for eNOS in regulating lymphatic valve specification and propose a mechanism by which eNOS directly binds ß-catenin to regulate its nuclear translocation and thereby transcriptional activity.

VEGFR3 is required for button junction formation in lymphatic vessels.

Lymphatic capillaries develop discontinuous cell-cell junctions that permit the absorption of large macromolecules, chylomicrons, and fluid from the interstitium. While excessive vascular endothelial growth factor 2 (VEGFR2) signaling can remodel and seal these junctions, whether and how VEGFR3 can alter lymphatic junctions remains incompletely understood. Here, we use lymphatic-specific Flt4 knockout mice to investigate VEGFR3 signaling in lymphatic junctions. We show that loss of Flt4 prevents specialized button junction formation in multiple tissues and impairs interstitial absorption. Knockdown of FLT4 in human lymphatic endothelial cells results in impaired NOTCH1 expression and activation, and overexpression of the NOTCH1 intracellular domain in Flt4 knockout vessels rescues the formation of button junctions and absorption of interstitial molecules. Together, our data reveal a requirement for VEGFR3 and NOTCH1 signaling in the development of button junctions during postnatal development and may hold clinical relevance to lymphatic diseases with impaired VEGFR3 signaling.

Endothelial Nitric Oxide Synthase Regulates Lymphatic Valve Specification By Controlling ß - catenin Signaling During Embryogenesis.

Objective: Lymphatic valves play a critical role in ensuring unidirectional lymph transport. Loss of lymphatic valves or dysfunctional valves are associated with several diseases including lymphedema, lymphatic malformations, obesity, and ileitis. Lymphatic valves first develop during embryogenesis in response to mechanotransduction signaling pathways triggered by oscillatory lymph flow. In blood vessels, eNOS (gene name: Nos3 ) is a well characterized shear stress signaling effector, but its role in lymphatic valve development remains unexplored. Approach and Results: We used global Nos3 -/- mice and cultured hdLECs to investigate the role of eNOS in lymphatic valve development, which requires oscillatory shear stress signaling. Our data reveal a 45% reduction in lymphatic valve specification cell clusters and that loss of eNOS protein inhibited activation of ß-catenin and its nuclear translocation. Genetic knockout or knockdown of eNOS led to downregulation of ß-catenin target proteins in vivo and in vitro . However, pharmacological inhibition of NO production did not reproduce these effects. Coimmunoprecipitation experiments reveal that eNOS forms a complex with ß-catenin and their association is enhanced by oscillatory shear stress. Finally, genetic ablation of the Foxo1 gene enhanced FOXC2 expression and rescued the loss of valve specification in the eNOS knockouts. Conclusion: In conclusion, we demonstrate a novel, nitric oxide-independent role for eNOS in regulating lymphatic valve specification and propose a mechanism by which eNOS forms a complex with ß-catenin to regulate its nuclear translocation and thereby transcriptional activity.

Activated CD90/Thy-1 fibroblasts co-express the Δ133p53ß isoform and are associated with highly inflamed rheumatoid arthritis.

BACKGROUND: The p53 isoform Δ133p53ß is known to be associated with cancers driven by inflammation. Many of the features associated with the development of inflammation in rheumatoid arthritis (RA) parallel those evident in cancer progression. However, the role of this isoform in RA has not yet been explored. The aim of this study was to determine whether Δ133p53ß is driving aggressive disease in RA. METHODS: Using RA patient synovia, we carried out RT-qPCR and RNAScope-ISH to determine both protein and mRNA levels of Δ133p53 and p53. We also used IHC to determine the location and type of cells with elevated levels of Δ133p53ß. Plasma cytokines were also measured using a BioPlex cytokine panel and data analysed by the Milliplex Analyst software. RESULTS: Elevated levels of pro-inflammatory plasma cytokines were associated with synovia from RA patients displaying extensive tissue inflammation, increased immune cell infiltration and the highest levels of Δ133TP53 and TP53ß mRNA. Located in perivascular regions of synovial sub-lining and surrounding ectopic lymphoid structures (ELS) were a subset of cells with high levels of CD90, a marker of 'activated fibroblasts' together with elevated levels of Δ133p53ß. CONCLUSIONS: Induction of Δ133p53ß in CD90+ synovial fibroblasts leads to an increase in cytokine and chemokine expression and the recruitment of proinflammatory cells into the synovial joint, creating a persistently inflamed environment. Our results show that dysregulated expression of Δ133p53ß could represent one of the early triggers in the immunopathogenesis of RA and actively perpetuates chronic synovial inflammation. Therefore, Δ133p53ß could be used as a biomarker to identify RA patients more likely to develop aggressive disease who might benefit from targeted therapy to cytokines such as IL-6.

ALAS1 associated with goat kidding number trait was regulated by the transcription factor ASCL2 to affect granulosa cell proliferation.

ALAS1 is a member of the α-oxoamine synthase family, which is the first rate-limiting enzyme for heme synthesis and is important for maintaining intracellular heme levels. In the ovary, ALAS1 is associated with the regulation of ovulation-related mitochondrial P450 cytochromes, steroid metabolism, and steroid hormone production. However, there are few studies on the relationship between ALAS1 and reproductive traits in goats. In this study, a mutation located in the promoter region of ALAS1 (g.48791372C>A) was found to be significantly (p < 0.05) associated with the kidding number of Yunshang black goats. Specifically, the mean kidding number in the first three litters and the kidding numbers of all three litters were significantly (p < 0.05) higher in individuals with the CA genotype or AA genotype than in those with the CC genotype. To further investigate the regulatory mechanism of ALAS1, the expression of ALAS1 in goat ovarian tissues with different genotypes was verified by real-time quantitative PCR. The results showed that the expression of ALAS1 was significantly higher in the ovaries of individuals with AA genotype than those with AC and CC genotypes (p < 0.01), and the expression trend of transcription factor ASCL2 was consistent with ALAS1. Additionally, the ALAS1 g.48791372C>A mutation created a new binding site for the transcription factor ASCL2. The luciferase activity assay indicated that the mutation increased the promoter activity of ALAS1. Overexpression of the transcription factor ASCL2 induced increased expression of ALAS1 in goat granulosa cells (p < 0.05). The opposite trend was shown for the inhibition of ASCL2 expression. The results of real-time quantitative PCR, EdU and Cell Counting Kit-8 assays indicated that the transcription factor ASCL2 increased the proliferation of goat granulosa cells by mediating the expression of ALAS1. In conclusion, the transcription factor ASCL2 positively regulated the transcriptional activity and expression levels of ALAS1, altering granulosa cell proliferation and the kidding number in goats.

Dynamic changes of urotensin II and its receptor during ovarian development of olive flounder Paralichthys olivaceus.

Urotensin II (UII) is a kind of fish somatostatins cyclic peptide, which was originally extracted from the caudal neurosecretory system (CNSS). The system of UII and UII receptor (UIIR) has been reported to have multiple physiological regulatory functions, such as cardiovascular control, osmoregulation, and lipid metabolism. However, the effect of UII and UIIR on the ovarian development has not been covered. This study investigated the expression pattern of UII and UIIR in the ovarian follicles and explored their impact on ovarian development in olive flounder Paralichthys olivaceus. The results showed that the highest UII and UIIR mRNA levels were observed at stage II and stage III follicles during ovarian development, respectively. In situ hybridization revealed that a strong signal of UII was expressed in the oocyte nuclei of stage II follicles, however, UIIR was found in the follicle cells and oocyte cytoplasm of stage II and stage III follicles. Similarly, immunohistochemistry found positive signal of UII was detected in the oocyte nuclei of stage II follicles. The results from in vitro culture of olive flounder follicles suggested the expression of UII and UIIR mRNA levels significantly increased by 10 IU/ml human chorionic gonadotropin (hCG) for 9 h. Furthermore, the transcriptional expression of UII and UIIR was not statistically significantly changed by 17α, 20ß-dihydroxy-4-pregnen-3-one (DHP). These results firstly suggested that UII and UII receptor may play vital roles in regulating ovarian growth in olive flounder.

Targeting Plk1 Sensitizes Pancreatic Cancer to Immune Checkpoint Therapy.

Polo-like kinase 1 (Plk1) plays an important role in cell-cycle regulation. Recent work has suggested that Plk1 could be a biomarker of gemcitabine response in pancreatic ductal adenocarcinoma (PDAC). Although targeting Plk1 to treat PDAC has been attempted in clinical trials, the results were not promising, and the mechanisms of resistance to Plk1 inhibition is poorly understood. In addition, the role of Plk1 in PDAC progression requires further elucidation. Here, we showed that Plk1 was associated with poor outcomes in patients with PDAC. In an inducible transgenic mouse line with specific expression of Plk1 in the pancreas, Plk1 overexpression significantly inhibited caerulein-induced acute pancreatitis and delayed development of acinar-to-ductal metaplasia and pancreatic intraepithelial neoplasia. Bioinformatics analyses identified the regulatory networks in which Plk1 is involved in PDAC disease progression, including multiple inflammation-related pathways. Unexpectedly, inhibition or depletion of Plk1 resulted in upregulation of PD-L1 via activation of the NF-κB pathway. Mechanistically, Plk1-mediated phosphorylation of RB at S758 inhibited the translocation of NF-κB to nucleus, inactivating the pathway. Inhibition of Plk1 sensitized PDAC to immune checkpoint blockade therapy through activation of an antitumor immune response. Together, Plk1 suppresses PDAC progression and inhibits NF-κB activity, and targeting Plk1 can potentiate the efficacy of immunotherapy in PDAC. SIGNIFICANCE: Inhibition of Plk1 induces upregulation of PD-L1 expression in pancreatic ductal adenocarcinoma, stimulating antitumor immunity and sensitizing tumors to immunotherapy.

VMP1 Regulated by chi-miR-124a Effects Goat Myoblast Proliferation, Autophagy, and Apoptosis through the PI3K/ULK1/mTOR Signaling Pathway.

The production of goat meat is determined by the growth speed of muscle fibers, and the autophagy and apoptosis of myoblast cells is a crucial process in the growth of muscle fibers. The rapid growth of muscle fibers occurs from one month old to nine months old in goats; however, the mechanisms of myoblast cells' autophagy and apoptosis in this process are still unknown. To identify candidate genes and signaling pathway mechanisms involved in myoblast apoptosis and autophagy, we compared the expression characteristics of longissimus dorsi tissues from Wu'an goats-a native goat breed of China-at 1 month old (mon1 group) and 9 months old (mon9 group). Herein, a total of 182 differentially expressed mRNAs (DEGs) in the mon1 vs. mon9 comparison, along with the KEGG enrichments, showed that the PI3K-Akt pathway associated with autophagy and apoptosis was significantly enriched. Among these DEGs, expression of vacuole membrane protein 1 (VMP1)-a key gene for the PI3K-Akt pathway-was significantly upregulated in the older goats relative to the 1-month-old goats. We demonstrated that VMP1 promotes the proliferation and autophagy of myoblasts, and inhibits their apoptosis. The integration analysis of miRNA-mRNA showed that miR-124a was a regulator of VMP1 in muscle tissue, and overexpression and inhibition of miR-124a suppressed the proliferation and autophagy of myoblasts. The PI3K/Akt/mTOR pathway was an important pathway for cell autophagy. Additionally, the activator of the PI3K/Akt/mTOR pathway, the expression of VMP1, and ULK1 were higher than the negative control, and the expression of mTOR was depressed. The expression of VMP1, ULK1, and mTOR was the opposite when the inhibitor was added to the myoblasts. These results show that the PI3K/Akt/mTOR pathway promoted the expression of VMP1 and ULK1. By using adenovirus-mediated apoptosis and proliferation assays, we found that that miR-124a inhibits myoblast proliferation and autophagy, and promotes their apoptosis by targeting VMP1. In conclusion, our results indicated that VMP1 was highly expressed in the LD muscle tissues of nine-month-old goats, and that it was regulated by miR-124a to inhibit myoblast cells' apoptosis through the PI3K/Akt/mTOR pathway, and to promote proliferation and autophagy. These findings contribute to the understanding of the molecular mechanisms involved in myoblast proliferation, autophagy, and apoptosis.

Transcriptome Analysis Reveals Key miRNA-mRNA Pathways in Ovarian Tissues of Yunshang Black Goats With Different Kidding Numbers.

The granulosa cell (GC) is the basic functional unit of follicles, and it is important for promoting follicle growth and sex hormones, as well as growth factor secretion in the process of reproduction. A variety of factors influence granulocyte proliferation, yet there are still many gaps to be filled in target and non-coding RNA regulation. In our study, the differentially expressed (DE) mRNAs and miRNAs were detected by using RNA-seq, and we constructed a mRNA-miRNA network related to goat prolificacy. Then, the goat primary GCs were isolated from the follicle for the function validation of candidate genes and their regulator miRNAs. A total of 2,968 DE mRNAs and 99 DE miRNAs were identified in the high- and low-prolificacy goat by RNA-seq, of which there were 1,553 upregulated and 1,415 downregulated mRNAs, and 80 upregulated and 19 downregulated miRNAs, respectively. JAK3 was identified as highly expressed in the low-prolificacy goats (3 times higher than high-prolificacy goats), and the integrated analysis showed that chi-miR-493-3p was a potential regulator of JAK3. The analysis of Kyoto Encyclopedia of Genes and Genomes (KEGG) showed that JAK3 was involved in the PI3K-Akt signaling pathway, the Jak-STAT signaling pathway, and signaling pathways regulating pluripotency of stem cells. In particular, the PI3K-Akt signaling pathway was a typical pathway for cell proliferation, differentiation, apoptosis, and migration. We found that the chi-miR-493-3p targets JAK3 directly via RT-qPCR, dual fluorescence assays, and Western blot. Furthermore, the expression of JAK3 was significantly decreased by the chi-miR-493-3p mimic and increased by the chi-miR-493-3p inhibitor. The CCK-8 assay showed that overexpression of JAK3 promoted cell proliferation, while inhibiting JAK3 had the opposite effect. The expression of cell proliferation markers CDK4 and cyclin D2 also showed the same results. Moreover, the enzyme-linked immunosorbent assay showed that steroid hormones E2 and PROG were increased by overexpressing JAK3 and decreased by inhibiting JAK3. Therefore, our results identified a chi-miR-439-3p-JAK3 regulatory pathway, which provided a new insight into the GC proliferation and prolificacy of goat.

A Novel SNP in the Promoter Region of IGF1 Associated With Yunshang Black Goat Kidding Number via Promoting Transcription Activity by SP1.

IGF1, a member of the insulin-like growth factor (IGF) superfamily, is also known as the growth-promoting factor (somatomedin C). IGF1 is involved in vertebrate growth and development, immunity, cell metabolism, reproduction, and breeding. However, there are relatively few studies on the relationship between IGF1 and goat reproduction. In this study, a new transcription factor SP1 bound to the IGF1 g. 64943050T>C promoted granulosa cell (GC) proliferation. A mutation g.64943050T>C located in the promoter region of IGF1 was identified. Association analysis revealed that the kidding number in the first and second litters and the average number of first three litters of the CC genotype (2.206 ± 0.044, 2.254 ± 0.056, and 2.251 ± 0.031) were significantly higher than those in the TC genotype (1.832 ± 0.049, 1.982 ± 0.06, and 1.921 ± 0.034) and TT genotype (1.860 ± 0.090, 1.968 ± 0.117, and 1.924 ± 0.062) (p < 0.05). The kidding number in the third litter of the CC genotype (2.355 ± 0.057) was significantly higher than that in the TT genotype (2.000 ± 0.107) (p < 0.05). Then, the function of this mutation was validated by the dual-luciferase reporter assay and EMSA. The results showed that the luciferase activity of IGF1-mutant-C was significantly higher than that of IGF1-Wild-T (p < 0.05). The EMSA also showed that the binding ability of IGF1-mutant-C was higher than that of IGF1-Wild-T (p < 0.05). Subsequently, the transcription factor SP1 was predicted to bind to the mutation of IGF1 (g.64943050T>C). Overexpression of SP1 promotes the expression of IGF1 in the primary granulosa cells (GCs). The results of the CCK-8 assay and the expression of GC proliferation factors (CDK4, cyclin D1, and cyclin D2) demonstrated that SP1 promoted GC proliferation by regulating IGF1 expression. Our results suggested that the IGF1 g.64943050T>C was significantly associated with the kidding number of Yunshang black goats, and SP1 as a transcription factor of IGF1 binding to the mutation T>C regulated the expression of IGF1. Furthermore, SP1 promoted goat GC proliferation by regulating the expression of IGF1, which provides a new insight for the goat fertility trait.

Importance of crosstalk between the microbiota and the neuroimmune system for tissue homeostasis.

The principal function of inflammation is cellular defence against 'danger signals' such as tissue injury and pathogen infection to maintain the homeostasis of the organism. The initiation and progression of inflammation are not autonomous as there is substantial evidence that inflammation is known to be strongly influenced by 'neuroimmune crosstalk', involving the production and expression of soluble signalling molecules that interact with cell surface receptors. In addition, microbiota have been found to be involved in the development and function of the nervous and immune systems and play an important role in health and disease. Herein, we provide an outline of the mechanisms of neuroimmune communication in the regulation of inflammation and immune response and then provide evidence for the involvement of microbiota in the development and functions of the host nervous and immune systems. It appears that the nervous and immune systems in multicellular organisms have co-evolved with the microbiota, such that all components are in communication to maximise the ability of the organism to adapt to a wide range of environmental stresses to maintain or restore tissue homeostasis.

Expression Profile Analysis to Identify Circular RNA Expression Signatures in Muscle Development of Wu'an Goat Longissimus Dorsi Tissues.

The growth and development of skeletal muscle is a physiological process regulated by a variety of genes and signaling pathways. As a posttranscriptional regulatory factor, circRNA plays a certain regulatory role in the development of animal skeletal muscle in the form of a miRNA sponge. However, the role of circRNAs in muscle development and growth in goats is still unclear. In our study, apparent differences in muscle fibers in Wu'an goats of different ages was firstly detected by hematoxylin-eosin (HE) staining, the circRNA expression profiles of longissimus dorsi muscles from 1-month-old (mon1) and 9-month-old (mon9) goats were screened by RNA-seq and verified by RT-qPCR. The host genes of differentially expressed (DE) circRNAs were predicted, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes analyses (KEGG) of host genes with DE circRNAs were performed to explore the functions of circRNAs. The circRNA-miRNA-mRNA networks were then constructed using Cytoscape software. Ten significantly differentially expressed circRNAs were also verified in the mon1 and mon9 groups by RT-qPCR. Luciferase Reporter Assay was used to verify the binding site between circRNA and its targeted miRNA. The results showed that a total of 686 DE circRNAs were identified between the mon9 and mon1 groups, of which 357 were upregulated and 329 were downregulated. Subsequently, the 467 host genes of DE circRNAs were predicted using Find_circ and CIRI software. The circRNA-miRNA-mRNA network contained 201 circRNAs, 85 miRNAs, and 581 mRNAs; the host mRNAs were associated with "muscle fiber development" and "AMPK signaling pathway" and were enriched in the FoxO signaling pathway. Competing endogenous RNA (ceRNA) network analysis showed that novel_circ_0005314, novel_circ_0005319, novel_circ_0009256, novel_circ_0009845, novel_circ_0005934 and novel_circ_0000134 may play important roles in skeletal muscle growth and development between the mon9 and mon1 groups. Luciferase Reporter Assay confirmed the combination between novel_circ_0005319 and chi-miR-199a-5p, novel_circ_0005934 and chi-miR-450-3p and novel_circ_0000134 and chi-miR-655. Our results provide specific information related to goat muscle development and a reference for the goat circRNA profile.

Adaptive homeostasis and the p53 isoform network.

All living organisms have developed processes to sense and address environmental changes to maintain a stable internal state (homeostasis). When activated, the p53 tumour suppressor maintains cell and organ integrity and functions in response to homeostasis disruptors (stresses) such as infection, metabolic alterations and cellular damage. Thus, p53 plays a fundamental physiological role in maintaining organismal homeostasis. The TP53 gene encodes a network of proteins (p53 isoforms) with similar and distinct biochemical functions. The p53 network carries out multiple biological activities enabling cooperation between individual cells required for long-term survival of multicellular organisms (animals) in response to an ever-changing environment caused by mutation, infection, metabolic alteration or damage. In this review, we suggest that the p53 network has evolved as an adaptive response to pathogen infections and other environmental selection pressures.

Co-Targeting Plk1 and DNMT3a in Advanced Prostate Cancer.

Because there is no effective treatment for late-stage prostate cancer (PCa) at this moment, identifying novel targets for therapy of advanced PCa is urgently needed. A new network-based systems biology approach, XDeath, is developed to detect crosstalk of signaling pathways associated with PCa progression. This unique integrated network merges gene causal regulation networks and protein-protein interactions to identify novel co-targets for PCa treatment. The results show that polo-like kinase 1 (Plk1) and DNA methyltransferase 3A (DNMT3a)-related signaling pathways are robustly enhanced during PCa progression and together they regulate autophagy as a common death mode. Mechanistically, it is shown that Plk1 phosphorylation of DNMT3a leads to its degradation in mitosis and that DNMT3a represses Plk1 transcription to inhibit autophagy in interphase, suggesting a negative feedback loop between these two proteins. Finally, a combination of the DNMT inhibitor 5-Aza-2'-deoxycytidine (5-Aza) with inhibition of Plk1 suppresses PCa synergistically.