BGWAS: Bayesian variable selection in linear mixed models with nonlocal priors for genome-wide association studies.

BACKGROUND: Genome-wide association studies (GWAS) seek to identify single nucleotide polymorphisms (SNPs) that cause observed phenotypes. However, with highly correlated SNPs, correlated observations, and the number of SNPs being two orders of magnitude larger than the number of observations, GWAS procedures often suffer from high false positive rates. RESULTS: We propose BGWAS, a novel Bayesian variable selection method based on nonlocal priors for linear mixed models specifically tailored for genome-wide association studies. Our proposed method BGWAS uses a novel nonlocal prior for linear mixed models (LMMs). BGWAS has two steps: screening and model selection. The screening step scans through all the SNPs fitting one LMM for each SNP and then uses Bayesian false discovery control to select a set of candidate SNPs. After that, a model selection step searches through the space of LMMs that may have any number of SNPs from the candidate set. A simulation study shows that, when compared to popular GWAS procedures, BGWAS greatly reduces false positives while maintaining the same ability to detect true positive SNPs. We show the utility and flexibility of BGWAS with two case studies: a case study on salt stress in plants, and a case study on alcohol use disorder. CONCLUSIONS: BGWAS maintains and in some cases increases the recall of true SNPs while drastically lowering the number of false positives compared to popular SMA procedures.

BG2: Bayesian variable selection in generalized linear mixed models with nonlocal priors for non-Gaussian GWAS data.

BACKGROUND: Genome-wide association studies (GWASes) aim to identify single nucleotide polymorphisms (SNPs) associated with a given phenotype. A common approach for the analysis of GWAS is single marker analysis (SMA) based on linear mixed models (LMMs). However, LMM-based SMA usually yields a large number of false discoveries and cannot be directly applied to non-Gaussian phenotypes such as count data. RESULTS: We present a novel Bayesian method to find SNPs associated with non-Gaussian phenotypes. To that end, we use generalized linear mixed models (GLMMs) and, thus, call our method Bayesian GLMMs for GWAS (BG2). To deal with the high dimensionality of GWAS analysis, we propose novel nonlocal priors specifically tailored for GLMMs. In addition, we develop related fast approximate Bayesian computations. BG2 uses a two-step procedure: first, BG2 screens for candidate SNPs; second, BG2 performs model selection that considers all screened candidate SNPs as possible regressors. A simulation study shows favorable performance of BG2 when compared to GLMM-based SMA. We illustrate the usefulness and flexibility of BG2 with three case studies on cocaine dependence (binary data), alcohol consumption (count data), and number of root-like structures in a model plant (count data).

Integrative proteomic and phosphoproteomic analysis in the female goat hypothalamus to study the onset of puberty.

BACKGROUND: Puberty marks the end of childhood and achieve sexual maturation and fertility. The role of hypothalamic proteins in regulating puberty onset is unclear. We performed a comprehensive differential proteomics and phosphoproteomics analysis in prepubertal and pubertal goats to determine the roles of hypothalamic proteins and phosphoproteins during the onset of puberty. RESULTS: We used peptide and posttranslational modifications peptide quantification and statistical analyses, and identified 69 differentially expressed proteins from 5,057 proteins and 576 differentially expressed phosphopeptides from 1574 phosphorylated proteins. Combined proteomic and phosphoproteomics, 759 correlated proteins were identified, of which 5 were differentially expressed only at the protein level, and 201 were only differentially expressed at the phosphoprotein level. Pathway enrichment analyses revealed that the majority of correlated proteins were associated with glycolysis/gluconeogenesis, Fc gamma R-mediated phagocytosis, focal adhesion, GABAergic synapse, and Rap1 signaling pathway. These pathways are related to cell proliferation, neurocyte migration, and promoting the release of gonadotropin-releasing hormone in the hypothalamus. CTNNB1 occupied important locations in the protein-protein interaction network and is involved in focal adhesion. CONCLUSION: The results demonstrate that the proteins differentially expression only at the protein level or only differentially expressed at the phosphoprotein level and their related signalling pathways are crucial in regulating puberty in goats. These differentially expressed proteins and phosphorylated proteins may constitute the proteomic backgrounds between the two different stages.

Base-Assisted Polymerizations of Elemental Sulfur and Alkynones for Temperature-Controlled Synthesis of Polythiophenes or Poly(1,4-dithiin)s.

With the increasing demand for functional polythiophenes in extensive applications such as organic solar cells, electronic skins, thermoelectric materials, and field effect transistors, efficient and economic synthetic approaches for polythiophenes are urgently required. In this work, KOH-assisted polymerizations of elemental sulfur and alkynones were developed to directly afford polythiophenes with various backbones, regioselective structures, and high molecular weights (Mns up to 20700 g/mol) in high yields (up to 97%) at 80 °C in 30 min. When the same polymerization was conducted at room temperature, stable and unique poly(1,4-dithiin)s (Mns up to 21800 g/mol) could be rapidly obtained in high yields (up to 87%) in 10 min. The temperature-controlled KOH-assisted polymerizations of sulfur and alkynones possessed high efficiency, mild conditions, and simple operation, which had provided an economic, efficient, and convenient approach for the direct conversion from elemental sulfur to functional polythiophenes and poly(1,4-dithiin)s with the in situ constructed aromatic or nonaromatic heterocycles embedded in the polymer backbones, demonstrating great synthetic simplicity, high efficiency, good selectivity, and robustness. It is anticipated to accelerate the development of semiconducting polymer materials and their applications.

Bayesian model selection for generalized linear mixed models.

We propose a Bayesian model selection approach for generalized linear mixed models (GLMMs). We consider covariance structures for the random effects that are widely used in areas such as longitudinal studies, genome-wide association studies, and spatial statistics. Since the random effects cannot be integrated out of GLMMs analytically, we approximate the integrated likelihood function using a pseudo-likelihood approach. Our Bayesian approach assumes a flat prior for the fixed effects and includes both approximate reference prior and half-Cauchy prior choices for the variances of random effects. Since the flat prior on the fixed effects is improper, we develop a fractional Bayes factor approach to obtain posterior probabilities of the several competing models. Simulation studies with Poisson GLMMs with spatial random effects and overdispersion random effects show that our approach performs favorably when compared to widely used competing Bayesian methods including deviance information criterion and Watanabe-Akaike information criterion. We illustrate the usefulness and flexibility of our approach with three case studies including a Poisson longitudinal model, a Poisson spatial model, and a logistic mixed model. Our proposed approach is implemented in the R package GLMMselect that is available on CRAN.

Research on Mfn2 Gene Expression in Hepatocellular Carcinoma and its Antitumor Mechanism.

Objective: To detect the expression level of the Mfn2 gene in hepatocellular carcinoma (HCC) and adjacent normal liver tissues and further analyze its anticancer effects. Methods: The expression levels of Mfn2, GLS1 and the autophagy-related proteins lc3b and Beclin1 in liver cancer and adjacent tissues in patients with liver cancer were detected by real-time-quantitative polymerase chain reaction (RT-qPCR). The HepG2 human HCC cell line was cultured in vitro, and the Mfn2 protein was stably expressed through transfection of a high Mfn2 expression plasmid. The Cell-Counting Kit-8 (CCK-8) method was used to observe the effect of Mfn2 overexpression on the activity of HepG2 cells. Furthermore, RT-qPCR and Western blotting were performed to detect the effects of Mfn2 overexpression on the protein expression of GLS1, Beclin1 and lc3b. Results: Compared with tissues adjacent to cancer tissues, the mRNA levels of Mfn2, GLS1, Beclin1 and lc3b in liver cancer tissues were lower. Compared with normal hepatocytes, the expression of Mfn2, Beclin1 and lc3b in HCC cells was decreased, but the expression of GLS1 was increased. Compared with the control group (NC) transfected with empty plasmid, Mfn2 overexpression led to significant time-dependent inhibition of HepG2 cell activity and GLS1 protein expression (P < .05). In addition, Mfn2 overexpression induced autophagy by triggering the expression of autophagy-related proteins Beclin-1 and lc3b in HCC cells (all P < .05). The effect of transfection with a high-dose Mfn2 plasmid was more obvious than that of transfection with a low-dose Mfn2 plasmid (all P < .05). Conclusions: The expression of Mfn2, GLS1, Beclin1 and lc3b in HCC was lower than in normal liver tissue. The expression of Mfn2, Beclin1 and lc3b in HCC cells was decreased, but the expression of GLS1 was increased. Overexpression of Mfn2 inhibited GLS1 gene expression by inhibiting the activity of HCC cells and promoted the expression of Beclin1 and lc3b to induce autophagy, thereby exerting an anticancer effect. Further research is needed to clarify the mechanism of Mfn2 activity.

Structural insights into the heterodimeric complex of the nuclear receptors FXR and RXR.

Farnesoid X receptor (FXR) is a member of the family of ligand-activated nuclear receptors. FXR plays critical roles in maintaining many metabolic pathways, including bile acid regulation and glucose and lipid homeostasis, and forms a heterodimeric complex with the retinoid X receptor (RXR). Despite the important roles of the FXR/RXR heterodimerization in human physiology, the molecular basis underlying the FXR/RXR interaction is still uncertain in the absence of a complex structure. Here, we report the heterodimeric structure of FXR and RXR in the presence of an FXR agonist (WAY-362450), RXR agonist (9-cis-retinoic acid), and a peptide derived from a steroid receptor coactivator (SRC2), revealing both unique and conserved modes for FXR heterodimerization. We found that the dimerization with RXR induced allosteric conformational changes on the coactivator-binding site of FXR. These changes enhanced the transcriptional activity of FXR by promoting the coactivator binding, thus suggesting a structural basis for the functional permissiveness of the FXR/RXR heterodimer complex. Furthermore, sequence analyses together with functional mutagenesis studies indicated that the helix H10 largely responsible for the dimerization is highly conserved and also critical for the FXR transcriptional activity. Our findings highlight the important roles of RXR heterodimerization in the nuclear receptor signaling, providing a potential framework to develop pharmaceutical agents in treating FXR/RXR-related diseases.

Structural basis for the hepatoprotective effects of antihypertensive 1,4-dihydropyridine drugs.

BACKGROUND: The 1,4-dihydropyridines (DHPs) are one of the most frequently prescribed classes of antihypertensive monotherapeutic agents worldwide. In addition to treating hypertension, DHPs also exert other beneficial effects, including hepatoprotective effects. However, the mechanism underlying the hepatoprotection remains unclear. METHODS: Biochemical AlphaScreen and cell-based reporter assays were employed to detect the activities of DHPs towards FXR. A crystallographic analysis was adopted to study the binding modes of four DHPs in complex with FXR. Acetaminophen (APAP)-treated wild-type and FXR knockout mice were used to investigate the functional dependence of the effects of the selected DHPs on FXR. RESULTS: A series of DHPs were uncovered as FXR ligands with different activities for FXR, suggesting FXR might serve as an alternative drug target for DHPs. The structural analysis illustrated the specific three-blade propeller binding modes of four DHPs to FXR and explained the detailed mechanisms by which DHPs bind to and are recognized by FXR. The results in mice demonstrated that cilnidipine protected the liver from APAP-induced injury in an FXR-dependent manner. CONCLUSIONS: This study reports the crystal structures of FXR in complex with four DHPs, and confirms that DHPs exert hepatoprotection by targeting FXR. GENERAL SIGNIFICANCE: Our research not only reveals valuable insight for the design and development of next-generation Ca2+ blocker drugs to provide safer and more effective treatments for cardiovascular disorders but also provides a novel and safe structural template for the development of drugs targeting FXR. Moreover, DHPs might be potentially repurposed to treat FXR-mediated diseases other than hypertension.

Analysis of radiation measurement of FDG radiopharmaceuticals and the development of medical image processing techniques.

This paper based on the theory of radiopharmaceuticals and the theory of radiation risk prediction, the author mainly studies the dose distribution of F-FDG and its radiation risk. Through the assessment of the risk of radiation carcinogenesis, the effective dose range was 4.61mSv to 8.97mSv, and the range of radiation carcinogenic risk was 1.57 ×10-3-3.14×10-3. Also, we reviewed the development trend of medical image processing techniques, and the development of medical imaging processing in three-dimensional (3D) medical imaging visualization and PACS-based medical imaging compression is introduced.

Screening of antitumor polypeptide drug and enhanced CT imaging based on drug target analysis.

Molecular targeted antitumor drugs is a major progress in recent years, these drugs usually target specific molecules to tumor cell signaling pathways, reduce toxicity, and can achieve individualized treatment. In this study, we screened three polypeptide proteins by yeast two hybrid systems, which could inhibit tumor growth obviously. The results of this study are expected to further develop new antitumor drugs. Moreover, by using contrast-enhanced computed tomography (CECT) imaging, this study proposes an algorithm for the computer-aided diagnosis (CAD) and classification of adrenal tumors. The experimental results demonstrate an excellent classification performance of this algorithm. Therefore, the method proposed in this paper may accurately locate and qualitatively diagnose the adrenal tumor in an effective manner, thereby providing important references for treatment.

Spinal Heme Oxygenase-1 (HO-1) Exerts Antinociceptive Effects Against Neuropathic Pain in a Mouse Model of L5 Spinal Nerve Ligation.

OBJECTIVE: Heme oxygenase-1 (HO-1) exerts protective effects against ischemia and inflammation in the central nervous system. However, its role in neuropathic pain is still unclear. This study was undertaken to explore the distribution and possible mechanism of HO-1 in a mouse model of peripheral nerve injury. DESIGN AND METHODS: The experiment was conducted using a mouse model of L5 spinal nerve ligation (SNL). Mice received repeated intraperitoneal injection of Carbon monoxide-releasing molecule-2 (CO-RM-2), HO-1 inducer cobalt protoporphyrin IX (CoPP) or single intraspinal injection of lentivirus (LV) over-expressing HO-1. The behavior analyses were conducted. The distribution and expression of HO-1 in the spinal cord were analyzed. RESULTS: HO-1 but not HO-2 was upregulated in spinal cord microglia cells after nerve injury, and the repeated intraperitoneal administration of CORM-2 (10 mg/kg/d) or CoPP (5 mg/kg/d) both significantly reduced the mechanical allodynia and thermal hyperalgesia induced by SNL (P < 0.01). Intraspinal injection of LV-HO-1 persistently suppresses SNL-induced neuropathic pain (P < 0.01 or P < 0.05), significantly induced the spinal HO-1 protein content (P < 0.01) and inhibited the microglia activation (P < 0.01) 7 days after SNL. CONCLUSION: HO-1 upregulation could elicit potent analgesic effects against neuropathic pain, which might partly be attributed to inhibition of spinal microglia activation. HO-1 signaling pathway may present a novel strategy for the treatment of neuropathic pain.

Determination of fatty acids in soil samples by gas chromatography with mass spectrometry coupled with headspace solid-phase microextraction using a homemade sol-gel fiber.

Through the use of a homemade sol-gel-derived fiber, a headspace solid-phase microextraction technique coupled to gas chromatography with mass spectrometry was developed for the determination of fatty acids with long, even-numbered carbon chains (C12 -C24 ) in soil samples. The experimental parameters such as reaction time, temperature, and ionic strength that might affect derivatization, extraction, and desorption were investigated. Under the optimized conditions, the linearity of the method ranged from 0.1 to 100 mg/L with a correlation coefficient >0.997. The limit of detection values based on a signal-to-noise ratio of 3:1 were determined with the concentration from 0.39 to 39.4 µg/L. The recoveries of the method for the soil samples were from 91.15 to 108.1%. This developed method using a homemade fiber showed a higher sensitivity than that using a commercial polydimethylsiloxane fiber and was also for the analysis of real soil samples from the Paomaling geological park of China.

Wu Wei in Mindfulness: A Systematic Perspective.

Resuming the theoretical and historical conceptualization of mindfulness research is of utmost importance if we want to transcend the positivistic and instrumental trend in the present field and to understand better what mindfulness is and how mindfulness works. Based on von Fircks (2023)'s introduction of Daosim's wu wei into Meadian Social Psychology, this commentary continues dialoguing the two different traditions for understanding mindfulness's functioning by exploring the systematic principle underlying wu wei. From the systematic perspective, we can distinguish: 1) two focus of meaning in wu wei: (a) not forcing/interfering and (b) the existence of a spontaneously evolving system; 2) two positions a person can take faced with the spontaneous system: (a) as stepping back and not interfering; (b) as actively connecting and cultivating new relations into systems. Based on the two positions, the dynamic emergence of altered I from mindfulness is also approached in two different ways.

Mesenchymal stem cells and their extracellular vesicles in bone and joint diseases: targeting the NLRP3 inflammasome.

The nucleotide-binding oligomerization domain-like-receptor family pyrin domain-containing 3 (NLRP3) inflammasome is a cytosolic multi-subunit protein complex, and recent studies have demonstrated the vital role of the NLRP3 inflammasome in the pathological and physiological conditions, which cleaves gasdermin D to induce inflammatory cell death called pyroptosis and mediates the release of interleukin-1 beta and interleukin-18 in response to microbial infection or cellular injury. Over-activation of the NLRP3 inflammasome is associated with the pathogenesis of many disorders affecting bone and joints, including gouty arthritis, osteoarthritis, rheumatoid arthritis, osteoporosis, and periodontitis. Moreover, mesenchymal stem cells (MSCs) have been discovered to facilitate the inhibition of NLRP3 and maybe ideal for treating bone and joint diseases. In this review, we implicate the structure and activation of the NLRP3 inflammasome along with the detail on the involvement of NLRP3 inflammasome in bone and joint diseases pathology. In addition, we focused on MSCs and MSC-extracellular vesicles targeting NLRP3 inflammasomes in bone and joint diseases. Finally, the existing problems and future direction are also discussed.

The application of mesenchymal stem cells in the treatment of traumatic brain injury: Mechanisms, results, and problems.

Mesenchymal stem cells (MSCs) are multipotent stromal cells that can be derived from a wide variety of human tissues and organs. They can differentiate into a variety of cell types, including osteoblasts, adipocytes, and chondrocytes, and thus show great potential in regenerative medicine. Traumatic brain injury (TBI) is an organic injury to brain tissue with a high rate of disability and death caused by an external impact or concussive force acting directly or indirectly on the head. The current treatment of TBI mainly includes symptomatic, pharmacological, and rehabilitation treatment. Although some efficacy has been achieved, the definitive recovery effect on neural tissue is still limited. Recent studies have shown that MSC therapies are more effective than traditional treatment strategies due to their strong multi-directional differentiation potential, self-renewal capacity, and low immunogenicity and homing properties, thus MSCs are considered to play an important role and are an ideal cell for the treatment of injurious diseases, including TBI. In this paper, we systematically reviewed the role and mechanisms of MSCs and MSC-derived exosomes in the treatment of TBI, thereby providing new insights into the clinical applications of MSCs and MSC-derived exosomes in the treatment of central nervous system disorders.

Evolutionary trend analysis of the pharmaceutical management research field from the perspective of mapping the knowledge domain.

Background: Pharmaceutical management is a new frontier subject between pharmacy, law and management, and related research involves the whole process of drug development, production, circulation and use. With the development of medical systems and the diversification of patients' drug needs, research in the field of pharmaceutical management is becoming increasingly abundant. To clarify the development status of this field, this study conducted a bibliometric analysis of relevant literature in the field based on the knowledge graph method for the first time and explored the evolutionary trends of research hotspots and frontiers. Methods: Literature was obtained from the Web of Science Core Collection database. CiteSpace 6.2.R4 (Advanced), VOSViewer, Scimago Graphica, Pajek and the R programming language were used to visualize the data. Results: A total of 12,771 publications were included in the study. The publications in the field of pharmaceutical management show an overall increasing trend. In terms of discipline evolution, early research topics tended to involve the positioning of pharmacists and pharmaceutical care and the establishment of a management system. From 2000 to 2005, this period tended to focus on clinical pharmacy and institutional norms. With the development of globalization and the market economy, research from 2005 to 2010 began to trend to the fields of drug markets and economics. From 2010 to 2015, research was gradually integrated into health systems and medical services. With the development of information technology, after 2015, research in the field of pharmaceutical management also began to develop in the direction of digitalization and intelligence. In light of the global pandemic of COVID-19, research topics such as drug supply management, pharmaceutical care and telemedicine services under major public health events have shown increased interest since 2020. Conclusion: Based on the knowledge mapping approach, this study provides a knowledge landscape in the field of pharmaceutical management research. The results showed that the reform of pharmacy education, the challenge of drug management under the COVID-19 pandemic, digital transformation and the rise of telemedicine services were the hot topics in this field. In addition, the research frontier also shows the broad prospects of the integration of information technology and pharmaceutical management, the practical value of precision pharmaceutical services, the urgent need of global drug governance, and the ethical and legal issues involved in the application of artificial intelligence technology in drug design, which points out the direction for the future development of pharmaceutical practice.

Regulation of mesenchymal stem cell differentiation by autophagy.

Autophagy, a process that isolates intracellular components and fuses them with lysosomes for degradation, plays an important cytoprotective role by eliminating harmful intracellular substances and maintaining cellular homeostasis. Mesenchymal stem cells (MSCs) are multipotent progenitor cells with the capacity for self-renewal that can give rise to a subset of tissues and therefore have potential in regenerative medicine. However, a variety of variables influence the biological activity of MSCs following their proliferation and transplantation in vitro. The regulation of autophagy in MSCs represents a possible mechanism that influences MSC differentiation properties under the right microenvironment, affecting their regenerative and therapeutic potential. However, a deeper understanding of exactly how autophagy is mobilized to function as well as clarifying the mechanisms by which autophagy promotes MSCs differentiation is still needed. Here, we review the current literature on the complex link between MSCs differentiation and autophagy induced by various extracellular or intracellular stimuli and the molecular targets that influence MSCs lineage determination, which may highlight the potential regulation of autophagy on MSCs' therapeutic capacity, and provide a broader perspective on the clinical application of MSCs in the treatment of a wide range of diseases.

Relationship between dynamic changes of microorganisms in Qupi and the quality formation of Fengxiangxing Huairang Daqu.

Introduction: Fengxiangxing Huairang Daqu (FHD) is one of the major types of Daqu in China. However, the relationship between the microbial community structure at different stages, the changes in the sensory characteristics, fermentation characteristics, volatiles, the most critical process point, and the quality formation of FHD is not clear. Methods: Based on microscopic characterization, PacBio SMRT sequencing, and HS-SPME-GC-MS volatile metabolite analysis revealed the relationship between FHD quality formation and the dynamics of Qupi. Results: The results showed that the 12th day of the culture was the most critical process point, highlighting the most significant differences in microbial community structure, sensory characteristics, fermentation characteristics, and flavor substances. Bacillus licheniformis (43.25%), Saccharopolyspora rectivirgula (35.05%), Thermoascus aurantiacus (76.51%), Aspergillus amstelodami (10.81%), and Saccharomycopsis fibuligera (8.88%) were the dominant species in FHD. S. fibuligera, A. amstelodami, and T. aurantiacus were associated with the snow-white color of the FHD epidermis, the yellow color of the interior, and the gray-white color, respectively. The abundance of T. aurantiacus, A. amstelodami, B. licheniformis, and S. rectivirgula was positively associated with the esterifying power and liquefying power of FHD. The abundance of T. aurantiacus and A. amstelodami was positively correlated with the saccharifying power of FHD. The abundance of S. fibuligera was positively related to the fermenting power of FHD. A total of 248 volatiles were detected in Qupi, mainly including alcohols, esters, aldehydes, and ketones. Of them, eleven volatiles had a significant effect on the flavor of Qupi, such as 1-butanol-3-methyl-, hydrazinecarboxamide, ethanol, phenylethyl alcohol, ethyl acetate, 2-octanone, 1-octen-3-ol, formic acid-hexyl ester, (E)-2-octen-1-ol, ethyl hexanoate, and 2(3H)-furanone-dihydro-5-pentyl-. The abundance of B. licheniformis, S. rectivirgula, T. aurantiacus, and S. fibuligera was positively correlated with the alcohols, aromatic compounds, and phenols in FHD. The abundance of S. fibuligera was positively correlated with the acids, esters, and hydrocarbons in FHD. Discussion: These results indicate important theoretical basis and technical support for controllable adjustment of FHD microbial community structure, stable control of FHD quality, and precise, effective, and large-scale guidance of FHD production.

Active immunization with recombinant GnRH6-CRM197 inhibits reproductive function of male rats.

Gonadotropin-releasing hormone (GnRH) vaccines have been successfully used for the inhibition of gonadal development and function, but current GnRH-based vaccines often present variability in the response. Cross-reactive material 197 (CRM197) has been used as carrier molecules to enhance an immune response to associated antigens. So, the synthetic mammalian tandem-repeated GnRH hexamer (GnRH6) gene was integrated into the expression plasmid pET-21a. Recombinant GnRH6-CRM197 protein was subsequently overexpressed in Escherichia coli strain BL21 and purified through Nickel column affinity chromatography and the antigenicity and biological effects of GnRH6-CRM197 were evaluated in rats. Sixteen 4-month-old adult male rats were randomly divided into two groups: the GnRH6-CRM197 group (n = 8) and the control group (n = 8). The GnRH6-CRM197 group rats were subcutaneously immunized with 100 µg of GnRH6-CRM197, administered thrice at 2-week intervals with GnRH6-CRM197.The control group received only a white oil adjuvant. Following the initial immunization, the weights of animals were recorded, and blood samples were collected from the orbital sinus at 4, 4.5, 5, 5.5, 6, 6.5, and 7 months. Serum antibody titers and testosterone concentrations were quantified using ELISA and CLIA, respectively. Additionally, testicular tissues were collected for morphological examination. The results revealed a significant increase in serum GnRH antibody titers (p < 0.05), but a significant decrease in serum testosterone concentrations (p < 0.05), and the weight, length, width, and girth of the testis, and the number of spermatogonia cells, spermatocytes, and sperm cells in the immunized rats. Furthermore, seminiferous tubules revealed significant atrophy and no sperm were observed in the immunized animals. Thus, GnRH6-CRM197 may be an effective antigen and a potential immunocastration vaccine.

Integrative proteomic and transcriptomic analysis in the female goat ovary to explore the onset of puberty.

Puberty is considered a prerequisite for affecting reproductive performance and productivity. Little was known about molecular changes in pubertal goat ovaries. Therefore, we measured and performed a correlation analysis of the mRNA and proteins changes in the pre-pubertal and pubertal goat ovaries. The results showed that only six differentially expressed genes and differentially abundant proteins out of 18,139 genes and 7550 proteins quantified had significant correlations. CNTN2 and THBS1, discovered in the mRNA-mRNA interaction network, probably participated in pubertal and reproductive regulation by influencing GnRH receptor signals, follicular development, and ovulation. The predicted core transcription factors may either promote or inhibit the expression of reproductive genes and act synergistically to maintain normal reproductive function in animals. The interaction between PKM and TIMP3 with other proteins may impact animal puberty through energy metabolism and ovarian hormone secretion. Pathway enrichment analyses revealed that the co-associated key pathways between ovarian genes and proteins at puberty included calcium signalling pathway and olfactory transduction. These pathways were associated with gonadotropin-releasing hormone synthesis and secretion, signal transmission, and cell proliferation. In summary, these results enriched the potential molecules and signalling pathways that affect puberty and provided new insights for regulating and promoting the onset of puberty. SIGNIFICANCE: This study conducted the first transcriptomic and proteomic correlation analysis of pre-pubertal and pubertal goat ovaries and identified six significantly correlated molecules at both the gene and protein levels. Meanwhile, we were drawn to several molecules and signalling pathways that may play a regulatory role in the onset of puberty and reproduction by influencing reproductive-related gene expression, GnRH receptor signals, energy metabolism, ovarian hormone secretion, follicular development, and ovulation. This information contributed to identify potential biomarkers in pubertal goat ovaries, which was vital for predicting the onset of puberty and improving livestock performance.