Single-cell and transcriptomic analyses reveal the influence of diabetes on ovarian cancer.

BACKGROUND: There has been a significant surge in the global prevalence of diabetes mellitus (DM), which increases the susceptibility of individuals to ovarian cancer (OC). However, the relationship between DM and OC remains largely unexplored. The objective of this study is to provide preliminary insights into the shared molecular regulatory mechanisms and potential biomarkers between DM and OC. METHODS: Multiple datasets from the GEO database were utilized for bioinformatics analysis. Single cell datasets from the GEO database were analysed. Subsequently, immune cell infiltration analysis was performed on mRNA expression data. The intersection of these datasets yielded a set of common genes associated with both OC and DM. Using these overlapping genes and Cytoscape, a protein‒protein interaction (PPI) network was constructed, and 10 core targets were selected. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were then conducted on these core targets. Additionally, advanced bioinformatics analyses were conducted to construct a TF-mRNA-miRNA coregulatory network based on identified core targets. Furthermore, immunohistochemistry staining (IHC) and real-time quantitative PCR (RT-qPCR) were employed for the validation of the expression and biological functions of core proteins, including HSPAA1, HSPA8, SOD1, and transcription factors SREBF2 and GTAT2, in ovarian tumors. RESULTS: The immune cell infiltration analysis based on mRNA expression data for both DM and OC, as well as analysis using single-cell datasets, reveals significant differences in mononuclear cell levels. By intersecting the single-cell datasets, a total of 119 targets related to mononuclear cells in both OC and DM were identified. PPI network analysis further identified 10 hub genesincludingHSP90AA1, HSPA8, SNRPD2, UBA52, SOD1, RPL13A, RPSA, ITGAM, PPP1CC, and PSMA5, as potential targets of OC and DM. Enrichment analysis indicated that these genes are primarily associated with neutrophil degranulation, GDP-dissociation inhibitor activity, and the IL-17 signaling pathway, suggesting their involvement in the regulation of the tumor microenvironment. Furthermore, the TF-gene and miRNA-gene regulatory networks were validated using NetworkAnalyst. The identified TFs included SREBF2, GATA2, and SRF, while the miRNAs included miR-320a, miR-378a-3p, and miR-26a-5p. Simultaneously, IHC and RT-qPCR reveal differential expression of core targets in ovarian tumors after the onset of diabetes. RT-qPCR further revealed that SREBF2 and GATA2 may influence the expression of core proteins, including HSP90AA1, HSPA8, and SOD1. CONCLUSION: This study revealed the shared gene interaction network between OC and DM and predicted the TFs and miRNAs associated with core genes in monocytes. Our research findings contribute to identifying potential biological mechanisms underlying the relationship between OC and DM.

Diabetes and osteoporosis: a two-sample mendelian randomization study.

BACKGROUND: The effects on bone mineral density (BMD)/fracture between type 1 (T1D) and type 2 (T2D) diabetes are unknown. Therefore, we aimed to investigate the causal relationship between the two types of diabetes and BMD/fracture using a Mendelian randomization (MR) design. METHODS: A two-sample MR study was conducted to examine the causal relationship between diabetes and BMD/fracture, with three phenotypes (T1D, T2D, and glycosylated hemoglobin [HbA1c]) of diabetes as exposures and five phenotypes (femoral neck BMD [FN-BMD], lumbar spine BMD [LS-BMD], heel-BMD, total body BMD [TB-BMD], and fracture) as outcomes, combining MR-Egger, weighted median, simple mode, and inverse variance weighted (IVW) sensitivity assessments. Additionally, horizontal pleiotropy was evaluated and corrected using the residual sum and outlier approaches. RESULTS: The IVW method showed that genetically predicted T1D was negatively associated with TB-BMD (ß = -0.018, 95% CI: -0.030, -0.006), while T2D was positively associated with FN-BMD (ß = 0.033, 95% CI: 0.003, 0.062), heel-BMD (ß = 0.018, 95% CI: 0.006, 0.031), and TB-BMD (ß = 0.050, 95% CI: 0.022, 0.079). Further, HbA1c was not associated with the five outcomes (ß ranged from - 0.012 to 0.075). CONCLUSIONS: Our results showed that T1D and T2D have different effects on BMD at the genetic level. BMD decreased in patients with T1D and increased in those with T2D. These findings highlight the complex interplay between diabetes and bone health, suggesting potential age-specific effects and genetic influences. To better understand the mechanisms of bone metabolism in patients with diabetes, further longitudinal studies are required to explain BMD changes in different types of diabetes.

A Novel Platinum Resistance-Related Immune Gene Signature for Overall Survival Prediction in Patients with Ovarian Cancer.

Ovarian cancer (OV) is a highly heterogeneous gynecological tumor that makes the prognostic prediction challenging. Resistance to platinum-based chemotherapy is associated with a poor prognosis in OV. There seems to be an overlap between molecular mechanisms responsible for platinum resistance and immunogenicity in OV. However, the predictive role of platinum resistance-related immune genes for OV prognosis needs to be further explored. In our study, the mRNA expression data of OV patients with corresponding clinical information were collected from The Cancer Genome Atlas (TCGA) cohort and International Cancer Genome Consortium (ICGC) cohort. A multigene signature was constructed for OV patients in the TCGA cohort using the least absolute shrinkage and selection operator (LASSO) Cox regression model according to the optimal value of λ and was validated in the ICGC cohort. Furthermore, we performed functional analysis to explore the immune status between low- and high-risk groups based on the median value of the risk score for the multigene signature. Our data showed that there were 41.1% of the platinum resistance-related genes which differentially expressed between immune score low- and high-OV patients in the TCGA cohort. Univariate Cox regression analysis identified 30 differentially expressed genes (DEGs) associated with overall survival (OS) (P < 0.05). 14 genes were identified to construct a novel platinum resistance-related immune model for classifying OV patients into the low- and high- risk groups. Patients in the low-risk group showed significantly higher OS than those in the high-risk group (P < 0.0001 in the both TCGA and ICGC cohort), which was associated with different immune status for the two risk groups. A novel platinum resistance-related immune model can be used for prognostic prediction in OV. Targeting tumor immunity may be a therapeutic alternative for OV with platinum resistance.

Effects of mitochondrial dysfunction on bone metabolism and related diseases: a scientometric study from 2003 to 2022.

BACKGROUND: In recent years, mitochondrial dysfunction has been extensively studied and published, but research on the effects of mitochondrial dysfunction on bone metabolism and related diseases is only just beginning. Furthermore, no studies have been carried out to systematically illustrate this area from a scientometric point of view. The goal of this research is to review existing knowledge and identify new trends and possible hotspots in this area. METHODS: All publications related to the relationship between mitochondrial dysfunction and bone metabolism and related diseases from 2003 to 2022 were searched at the Web of Science Core Collection (WoSCC) on May 7, 2022. Four different analytical tools: VOSviewer 1.6.18, CiteSpace V 6.1, HistorCite (12.03.07), and Excel 2021 were used for the scientometric research. RESULTS: The final analysis included 555 valid records in total. Journal of Biological Chemistry (Co-citations = 916) is the most famous journal in this field. China (Percentage = 37%), the United States (Percentage = 24%), and Korea (Percentage = 12%) are the most productive countries. Blanco FJ and Choi EM are the main researchers with significant academic influence. Current research hotspots are basic research on mitochondrial dysfunction and the prevention or treatment of bone metabolism-related diseases. CONCLUSION: The study of the consequences of mitochondrial dysfunction on bone metabolism and associated diseases is advancing rapidly. Several prominent researchers have published extensive literature and are widely cited. Future research in this area will focus on oxidative stress, aging, gene expression, and the pathogenesis of bone metabolism-related diseases.

Udder health of dairy cows with an extended voluntary waiting period from calving until the first insemination.

This study aimed to evaluate the effect of an extended voluntary waiting period (VWP) on SCC, SCC elevations and clinical mastitis incidence during the complete lactation and the first 6 weeks of the next lactation. Holstein-Friesian dairy cows (N = 154) were blocked for parity, expected milk yield, calving season and breeding value for persistency and were randomly distributed across 3 VWP (50, 125, or 200 d: VWP-50, VWP-125, VWP-200). Cows were monitored from calving until 6 weeks into the next lactation, or until culling. An elevation of SCC in milk was defined as SCC in milk ≥200 000 cells/ml after two previous weeks with SCC < 200 000 cells/ml. Over the complete lactation, extending the VWP did not affect SCC elevations and the occurrence of clinical mastitis per lactation or per cow per year. There was no clear effect of VWP length on SCC in the complete lactation, except that multiparous cows in VWP-125 had a higher SCC compared with multiparous cows in VWP-50. Dry-off antibiotic usage per cow per year was lower in VWP-200 compared with VWP-50 for multiparous cows. In the first 6 weeks of the next lactation, cows in VWP-200 had a higher SCC compared with cows in VWP-50, with no effect of VWP on the number of elevations of SCC or the occurrence of clinical mastitis. Extending the VWP may therefore be used to reduce the frequency of transition periods and the associated use of dry-cow antibiotics, with limited impact on udder health, and a similar occurrence of SCC elevations and clinical mastitis per year.

Chronic maternal hepatitis B virus infection and pregnancy outcome- a single center study in Kunming, China.

BACKGROUND: Chinese population has a high prevalence of chronic hepatitis B virus (HBV) infection, the impact of which on pregnancy outcome remains controversial. A single-center retrospective cohort study was performed in Kunming, a multi-ethnic city in south-western China to examine this issue. METHODS: The singleton pregnancies delivering at ≥28 weeks gestation under our care in 2005-2017 constituted the study cohort. Maternal characteristics and pregnancy outcome were compared between mothers with and without seropositivity for hepatitis B surface antigen (HBsAg) determined at routine antenatal screening. RESULTS: Among the 49,479 gravidae in the cohort, the 1624 (3.3%) HBsAg seropositive gravidae had a lower incidence of nulliparity (RR 0.963, 95% CI 0.935-0.992) and having received tertiary education (RR 0.829, 95% CI 0.784-0.827). There was no significant difference in the medical history, pregnancy complications, or labor or perinatal outcome, except that HBV carriers had significantly lower incidence of labor induction (RR 0.827, 95% CI 0.714-0.958) and of small-for-gestational age (SGA) infants (RR 0.854, 95% CI 0.734-0.994). On regression analysis, maternal HBV carriage was independently associated with spontaneous labor (aRR 1.231, 95% CI 1.044-1.451) and reduced SGA infants (aRR 0.842, 95% CI 0.712-0.997). CONCLUSIONS: Our 3.3% prevalence of maternal HBV infection was around the lower range determined in the Chinese population. The association with spontaneous labor and reduced SGA infants could have helped to promote the perpetuation of the infection through enhanced survival of the offspring infected at birth, thus explaining the high prevalence in the Chinese population.

Impact of childbirth policy changes on obstetric workload over a 13-year period in a regional referral center in China - implications on service provision planning.

BACKGROUND: We aimed to appraise the impact of the changing national childbirth policy since 2002, currently allowing two children per family, on obstetric workload in a regional referral center in China. METHODS: In a retrospective cohort study, temporal changes were examined in relation with maternal demographics, incidence of women with high risk pregnancies and resource statistics in our hospital in managing singleton viable pregnancies (birth from 28 weeks gestational age onwards) for the period 2005-2017. RESULTS: During this 13-year period, the number of singleton livebirths from 28 weeks gestational age onwards was 49,479. Annual numbers of births increased from 1,941 to 2005 to 5,777 in 2017. There were concomitant and significant increases in the incidence of multiparous women (10.6-50.8 %), of age ≥35 years (6.5-24.3 %), with prior caesarean Sec. (2.6-23.6 %), with ≥3 previous pregnancy terminations (1.0-4.9 %), with pre-gestational diabetes (0.2-0.9 %), and with chronic hypertension (0.2-1.2 %). There were associated increases in beds and staff complement and reduced average hospital stay. Nevertheless, while the workload of medical staff remained stable with increasing staff complement, that of midwives increased significantly as reflected by the total births: midwife ratio which increased from 194.1:1 to 320.9:1 (p < 0.001). CONCLUSIONS: In our hospital, progressively increasing numbers of annual births in combination with an increased incidence of women with high risk pregnancies took place following the revised national childbirth policy. Only the increase in medical and nursing, but not midwifery, staff was commensurate with workload. Remedial measures are urgently required before the anticipated progressive increase in care demand would overwhelm maternity care with potentially disastrous consequences.

[Rehmanniae Radix and Rehmanniae Radix Praeparata improve diabetes induced by high-fat diet coupled with streptozotocin in mice through AMPK-mediated NF-κB/NLRP3 signaling pathway].

This study investigated the differential mechanisms of Rehmanniae Radix and Rehmanniae Radix Praeparata in improving diabetes in mice through AMPK-mediated NF-κB/NLRP3 signaling pathway. The diabetic mouse model was established with high-fat diet coupled with streptozotocin(STZ, intraperitoneal injection, 100 mg·kg~(-1), once a day for three consecutive days), after which the mice were randomly divided into model group, low-dose(5 g·kg~(-1)) and high-dose(15 g·kg~(-1)) Rehmanniae Radix groups, low-dose(5 g·kg~(-1)) and high-dose(15 g·kg~(-1)) Rehmanniae Radix Praeparata groups, catalpol group(250 mg·kg~(-1)), 5-hydroxymethylfurfural(5-HMF) group(250 mg·kg~(-1)), metformin group(250 mg·kg~(-1)), with the normal group also set. The organ indexes of heart,liver, spleen, lung, kidney and pancreas were calculated after four weeks of administration. The pathological changes and fibrosis of pancreas, kidney and liver in mice were observed by hematoxylin-eosin(HE) staining and Masson staining. Western blot was used to determine the expression levels of Toll-like receptor-4(TLR4), nuclear factor-κB(NF-κB), Nod-like receptor protein 3(NLRP3),interleukin-1ß(IL-1ß), adenosine monophosphate-activated protein kinase(AMPK), phosphorylated AMPK(p-AMPK) in the pancreas, kidney and liver of mice. Compared with the model group, the administration groups witnessed significant decrease in the liver,spleen, kidney, pancreas and fat indexes of diabetic mice, and there was no significant difference in heart and lung indexes. The pathological states and fibrosis of pancreatic, kidney and liver tissues were significantly improved after administration. Additionally, the expression levels of TLR4, NF-κB and NLRP3 in pancreas, kidney and liver of diabetic mice were significantly lowered. The expression levels of p-AMPK/AMPK were enhanced significantly in kidney and liver of mice in Rehmanniae Radix group while in pancreas, kidney and liver in Rehmanniae Radix Praeparata group. This suggests that Rehmanniae Radix and Rehmanniae Radix Praeparata differ in the mechanism of regulating energy metabolism of multiple organs and thereby exerting anti-inflammatory effects to alleviate symptoms of diabetic mice.

Risk for Cesarean section in women of advanced maternal age under the changed reproductive policy in China: A cohort study in a tertiary hospital in southwestern China.

AIM: To describe changed epidemiological features of advanced maternal age (AMA) and to examine the effect of AMA on the risk for Cesarean section (CS) in a Chinese pregnant population. METHODS: This retrospective single-center cohort study investigated the changes of epidemiological features of AMA parturients with respect to the revised reproductive policy in China in 43 702 singleton deliveries with live birth at ≥28 weeks managed from January 2005 to December 2016. We also evaluated the pregnancy outcomes in different age groups and risk factors of CS with multivariate analysis. RESULTS: In this 12-year study period, the average maternal age increased from 28.5 to 30.2 years, and the proportion of AMA raised from 6.5% to 17.2%. AMA was significantly associated with increased risk of adverse pregnancy outcomes, and after adjustment for confounding factors, AMA remained a significant independent risk factor for CS. Furthermore, the effect of AMA in nulliparous women on the risk of CS was more significant than in multiparous women, while the history of previous CS (adjusted odds ratio 39.85) and interdelivery interval ≥10 years (adjusted odds ratio 1.52) also increased the risk of CS in multiparous women. CONCLUSION: AMA increased the risk of a number of adverse pregnancy outcomes, and was independently associated with increased risk for CS. The increasing number of AMA parturients with risk factors is likely to increase CS rate in China in the near future, thus it is imperative to reduce the rate of primary CS as a matter of policy.

Effects of Rhizome Extract of Dioscorea batatas and Its Active Compound, Allantoin, on the Regulation of Myoblast Differentiation and Mitochondrial Biogenesis in C2C12 Myotubes.

With the aging process, a loss of skeletal muscle mass and dysfunction related to metabolic syndrome is observed in older people. Yams are commonly use in functional foods and medications with various effects. The present study was conducted to investigate the effects of rhizome extract of Dioscorea batatas (Dioscoreae Rhizoma, Chinese yam) and its bioactive compound, allantoin, on myoblast differentiation and mitochondrial biogenesis in skeletal muscle cells. Yams were extracted in water and allantoin was analyzed by high performance liquid chromatography (HPLC). The expression of myosin heavy chain (MyHC) and mitochondrial biogenesis-regulating factors, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), sirtuin-1 (Sirt-1), nuclear respiratory factor-1 (NRF-1) and transcription factor A, mitochondrial (TFAM), and the phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) were determined in C2C12 myotubes by reverse transcriptase (RT)-polymerase chain reaction (RT-PCR) or western blot. The glucose levels and total ATP contents were measured by glucose consumption, glucose uptake and ATP assays, respectively. Treatment with yam extract (1 mg/mL) and allantoin (0.2 and 0.5 mM) significantly increased MyHC expression compared with non-treated myotubes. Yam extract and allantoin significantly increased the expression of PGC-1α, Sirt-1, NRF-1 and TFAM, as well as the phosphorylation of AMPK and ACC in C2C12 myotubes. Furthermore, yam extract and allantoin significantly increased glucose uptake levels and ATP contents. Finally, HPLC analysis revealed that the yam water extract contained 1.53% of allantoin. Yam extract and allantoin stimulated myoblast differentiation into myotubes and increased energy production through the upregulation of mitochondrial biogenesis regulators. These findings indicate that yam extract and allantoin can help to prevent skeletal muscle dysfunction through the stimulation of the energy metabolism.

[Effect of Esculentoside A on Expression of AQP2 and AQP4 Protein of Kidney in Water-Loaded Rats].

OBJECTIVE: To observe the regulatory effect of Esculentoside A (EsA) on urination and the expression of AQP2 and AQP4 protein of kidney in water-loaded rats, and to discuss its mechanism of diuresis. METHODS: 50 male SD rats were randomly divided into five groups, including blank control group, hydrochlorothiazide group (0.4 mg/kg) and EsA high, middle and low dose groups (5.2, 2.6 and 1.3 mg/kg, respectively). After intraperitoneally injecting of different concentrations of EsA, urinary amount of model rats in continuous six hours was measured. Then the expression of AQP2 and AQP4 protein and mRNA of kidney were detected by immunohistochemistry method and Real-Time quantitative PCR. RESULTS: Compared with blank control group, the expression of AQP2 and AQP4 protein and mRNA of kidney were significantly reduced as well as the urinary amount was significantly increased in EsA high dose group (P < 0.05), while the expression of AQP2, AQP4 protein and mRNA of kidney as well as urinary amount had no obvious difference in EsA middle and low dose groups. CONCLUSION: 5.2 mg/kg of EsA can reduce the expression of AQP2 and AQP4 protein and mRNA of kidney and the reabsorption of water, which results in diuresis.

Mechanism exploration and biomarker identification of glycemic deterioration in patients with diseases of the exocrine pancreas.

The damage to the endocrine pancreas among patients with diseases of the exocrine pancreas (DP) leads to reduced glycemic deterioration, ultimately resulting in diabetes of the exocrine pancreas (DEP). The present research aims to investigate the mechanism responsible for glycemic deterioration in DP patients, and to identify useful biomarkers, with the ultimate goal of enhancing clinical practice awareness. Gene expression profiles of patients with DP in this study were acquired from the Gene Expression Omnibus database. The original study defines DP patients to belong in one of three categories: non-diabetic (ND), impaired glucose tolerance (IGT) and DEP, which correspond to normoglycemia, early and late glycemic deterioration, respectively. After ensuring quality control, the discovery cohort included 8 ND, 20 IGT, and 12 DEP, while the validation cohort included 27 ND, 15 IGT, and 20 DEP. Gene set enrichment analysis (GSEA) employed differentially expressed genes (DEGs), while immunocyte infiltration was determined using single sample gene set enrichment analysis (ssGSEA). Additionally, correlation analysis was conducted to establish the link between clinical characteristics and immunocyte infiltration. The least absolute shrinkage and selection operator regression and random forest combined to identify biomarkers indicating glycemic deterioration in DP patients. These biomarkers were further validated through independent cohorts and animal experiments. With glycemic deterioration, biological processes in the pancreatic islets such as nutrient metabolism and complex immune responses are disrupted in DP patients. The expression of ACOT4, B2M, and ACKR2 was upregulated, whereas the expression of CACNA1F was downregulated. Immunocyte infiltration in the islet microenvironment showed a significant positive correlation with the age, body mass index (BMI), HbA1c and glycemia at the 2-h of patients. It was a crucial factor in glycemic deterioration. Additionally, B2M demonstrated a significant positive correlation with immunocyte infiltration and clinical features. Quantitative real-time PCR (qRT-PCR) and western blotting confirmed the upregulation in B2M. Immunofluorescent staining suggested the alteration of B2M was mainly in the alpha cells and beta cells. Overall, the study showed that gradually increased immunocyte infiltration was a significant contributor to glycemic deterioration in patients with DP, and it also highlighted B2M as a biomarker.

[Study on thermoanalysis-based calamina processing].

Thermogravimetry (TG), TG-MS, Fourier transform infrared spectroscopy (FTIR), scanning electron microscope (SEM)-energy dispersive spectrometer(EDS) were adopted to investigate the pyrolysis characteristics of calamina. According to the findings of the qualitative and quantitative studies on the changes in the content of relevant elements, the whole shape, the functional groups, and the volatile components of calamina before and after being pyrolyzed, the 200-360, 580-750 degrees C were two sensitive temperature ranges related to the changes in effective component during calamina processing. Thermal weight loss was observed for ZnCO3, Zn(OH)2 and ZnCO3-2Zn(OH)2-H2O under 200-360 degrees C and for CaCO3 under 580-750 degrees C. The results of studies on chemical reaction kinetics showed good linear relations. This experiment integrated relevant methods and theories of physical chemistry and science of traditional Chinese medicine processing, and interpretes calamina processing techniques and mechanism, in order to provide a good example for modem studies on other traditional Chinese medicine processing.

Bibliometric and visualized analysis of drug resistance in ovarian cancer from 2013 to 2022.

Objective: As one of the cancers that seriously threatens women's health, ovarian cancer has a high morbidity and mortality rate. Surgery and chemotherapy are the basic treatment strategies for ovarian cancer, and chemotherapy resistance is a significant factor in affecting the prognosis, survival cycle, and recurrence of ovarian cancer. This article aims to analyze articles about ovarian cancer and drug resistance via bibliometric software, offering new ideas and directions for researchers in this field. Methods: Both Citespace and Vosviewer are bibliometric software on the Java platform. Articles were collected on ovarian cancer and drug resistance in the Web of Science Core Collection database from 2013 to 2022. The countries, institutions, journals, authors, keywords, and references were analyzed, and the development status of this field was indicated from multiple perspectives. Results: Studies on ovarian cancer and drug resistance generally showed an increasing trend from 2013 to 2022. The People's Republic of China and Chinese institutions contributed more to this field. Gynecologic Oncology published the most articles, and the journal with the most citations was Cancer Research. Li Li was the author with the most publications, and Siegel RL was the author with the most citations. Through burst detection, it can be found that the research hotspots in this field mainly focused on the in-depth exploration of the drug resistance mechanism of ovarian cancer and the progress of PARP inhibitors and bevacizumab in the treatment of ovarian cancer. Conclusions: Many studies on the mechanism of drug resistance in ovarian cancer have been discovered; however, the deeper mechanism remains to be explored. Compared with traditional chemotherapy drugs, PARP inhibitors and bevacizumab have shown better efficacy, but PARP inhibitors have initially shown drug resistance. The future direction of this field should be to overcome the resistance of existing drugs and actively develop new ones.

Corrigendum: Bibliometric and visualized analysis of drug resistance in ovarian cancer from 2013 to 2022.

[This corrects the article DOI: 10.3389/fonc.2023.1173863.].

Experimental Study of Energy Evolution at a Discontinuity in Rock under Cyclic Loading and Unloading.

Energy is often dissipated and released in the process of rock deformation and failure. To study the energy evolution of rock discontinuities under cyclic loading and unloading, cement mortar was used as rock material and a CSS-1950 rock biaxial rheological testing machine was used to conduct graded cyclic loading and unloading tests on Barton's standard profile line discontinuities with different joint roughness coefficients (JRCs). According to the deformation characteristics of the rock discontinuity sample, the change of internal energy is calculated and analyzed. The experimental results show that under the same cyclic stress, the samples harden with the increase in the number of cycles. With the increase of cyclic stress, the dissipated energy density of each stage gradually exceeds the elastic energy density and occupies a dominant position and increases rapidly as failure becomes imminent. In the process of increasing the shear stress step-by-step, the elastic energy ratio shows a downward trend, but the dissipated energy is contrary to it. The energy dissipation ratio can be used to characterize the internal damage of the sample under load. In the initial stage of fractional loading, the sample is in the extrusion compaction stage, and the energy dissipation ratio remains quasi-constant; then the fracture develops steadily, the damage inside the sample intensifies, and the energy dissipation ratio increases linearly (albeit at a low rate). When the energy storage limit is reached, the growth rate of energy dissipation ratio increases and changes when the stress level reaches a certain threshold. The increase of the roughness of rock discontinuity samples will improve their energy storage capacity to a certain extent.

Extending lactation length: consequences for cow, calf, and farmer.

Traditionally, a 1-yr calving interval is advised to farmers from an economical point of view, to realize a yearly peak in milk yield. A 1-yr calving interval, however, implies a yearly event of drying-off, calving and start of lactation, which are all associated with an increased risk for diseases and disorders. Deliberately extending the lactation length by extending the voluntary waiting period (VWP) for first insemination reduces the frequency of these challenging events. This reduction in frequency of calvings can be beneficial for cow health and fertility, but also can be of interest to reduce the number of surplus calves and labor associated with drying off, calving, and disease treatments. Current concerns with respect to an extended lactation are that milk yield is too low in late lactation, which might be associated with an increased risk of fattening of cows in late lactation, and compromised economic returns at herd level. In addition, limited knowledge is available with respect to consequences for cow performance in the subsequent lactation and for calves born to cows with an extended lactation. Moreover, response of dairy cows to an extended VWP depends on individual cow characteristics like parity, milk yield level or body condition. A customized strategy based on individual cow characteristics can be a future approach to select high-producing cows with persistent lactation curves for an extended lactation to limit the risk for fattening and milk yield reduction at the end of the lactation while benefitting from a reduction in challenging events around calving.

Traditionally, a 1-yr calving interval is advised to dairy farmers to realize a yearly peak in milk yield. A 1-yr calving interval, however, implies a yearly event of drying-off, calving, and start of lactation, which are all associated with an increased risk for diseases and disorders. Deliberately extending the lactation length reduces the frequency of these challenging events both for individual cows and at herd level. This reduction in frequency of calvings can be beneficial for cow health and fertility, but also can be of interest to reduce the number of surplus calves and labor associated with drying off, calving, and disease treatments. Current concerns with respect to an extended lactation are that milk yield is too low and cows can get fat in late lactation. Moreover, limited knowledge is available with respect to consequences for cows in the subsequent lactation and for calves born to cows with an extended lactation. Moreover, response of dairy cows to an extended voluntary waiting period depended on individual cow characteristics such as parity, milk yield level, or body condition. A customized strategy based on individual cow characteristics can be a future approach to select suitable cows for an extended lactation.

Effects of Jowiseungki-tang on high fat diet-induced obesity in mice and functional analysis on network pharmacology and metabolomics analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: In traditional Chinese and Korean medicine, Jowiseungki-tang (JST) is a prescription for diabetes mellitus (DM) treatment. However, little scientific evidence is known of its effect in diabetic condition. AIMS: We assessed the effects of JST on high-fat diet (HFD)-induced obesity with inflammatory condition in mice and to analyze the therapeutic function of JST on network pharmacology as well as targeted metabolomics. MATERIALS AND METHODS: JST administration at 100 mg/kg and 500 mg/kg for a period of 4 weeks in HFD-induced obese mice, body weight gain, energy utility, calorie intake, and levels of glucose, insulin, total cholesterol, triglyceride, LDL-cholesterol as well as interleukin-6 were measured. Measurements of HDL-cholesterol (HDL-C) were performed and compared to those of the control group. Moreover, the therapeutic function of JST on obesity was analyzed furtherly based on network pharmacology and targeted metabolomics methods. RESULTS: Administration of JST at 100 mg/kg and 500 mg/kg for a period of 4 weeks in HFD-induced obesity mice significantly decreased the body weight gain, energy utility, calorie intake, and levels of insulin, total cholesterol, LDL-cholesterol, triglyceride, and interleukin-6. However, HDL-cholesterol (HDL-C) levels showed marked elevation relative to control groups. JST administration strongly inhibited expressions of inducible nitric oxide synthase, inflammatory proteins, and cyclooxygenase-2 in the pancreas, stomach, and liver tissues, and reduced hepatic steatosis and pancreatic hyperplasia. In network pharmacological analysis, the putative functional targets of JST are underlie on modulation of cofactor-, coenzyme-, and fatty acid-bonding, insulin resistance, and inflammatory response, fine-tuned the phosphatase binding and signal pathway activation, such as mitogen activated protein kinases, phosphatidylinositol 3-kinases/protein kinase B, protein kinase C, and receptor of glycation end products as well-advanced glycation end products. According to the metabolomics analysis, the contents and energy metabolites, and medium and long chain fatty acids was significantly changed in mice pancreases. CONCLUSIONS: JST is a valuable prescription for treatment of patients with DM in traditional clinics through inhibition of obesity, inflammatory condition and metabolism.

Consequences of extending the voluntary waiting period for insemination on reproductive performance in dairy cows.

The aim of the study was to evaluate the effect of extended voluntary waiting period (VWP) on ovarian cyclicity and reproductive performance of dairy cows. Holstein-Friesian dairy cows (N = 154) were blocked and randomly assigned to one of 3 groups with different VWP (50, 125 or 200 d: VWP-50, VWP-125 or VWP-200). Milk samples were collected 3 times a week and analysed for progesterone concentration. Ovarian cycles were classified as: normal (18-24 days), short (<18 days) or prolonged (>24 days). For cows that became pregnant within 100 days after VWP, a VWP-200 d was related with fewer days until pregnancy after end of the VWP (19.4 d) compared with VWP-50 or VWP-125 (35.5, 37.3 d respectively). During 100 days (-50 until 50 d) around the end of VWP, cows in VWP-200 had a greater percentage of normal cycles (91.9 vs 58.0 %, P < 0.01) and a lower percentage of prolonged cycles (6.0 vs 32.7 %, P = 0.01) compared with cows in VWP-50. In the 4 weeks around the end of the VWP, cows in VWP-125 and VWP-200 had a lower milk yield compared with cows in VWP-50 (32.0, 27.5 vs 37.4 kg/d, P < 0.01). Inseminations continued until 300 days in milk, resulting in fewer pregnant cows for longer VWPs. In conclusion, extending the VWP from 50 to 125 or 200 days resulted in a greater percentage of cows with normal ovarian cycles and a lower milk yield around the end of VWP. Moreover, VWP-200 reduced days open after the end of the VWP, compared with VWP-50.

Metabolomics and Network Pharmacology-Based Investigation into the Mechanisms Underlying the Therapeutic Effect of a New Chinese Traditional Medicine (Cui Nai Ling) on Bromocriptine-Induced Hypogalactia.

As a traditional veterinary medicine to promote lactation, Cui Nai Ling (CNL) can not only increase milk supply and promote health but also improve the overall physiological function and immunity of the animals. In order to further improve CNL's effect on lactation, we have previously made a new CNL (NCNL) by adding Tetrapanacis Medulla and replacing Vaccariae Semen with fried Vaccariae Semen in CNL. We have demonstrated that the lactation-promoting effect of NCNL is better than that of CNL. However, the underlying mechanisms by which NCNL promotes lactation are unclear. In this study, we performed metabolomics, network pharmacology, and pharmacodynamic studies to explore the underlying mechanisms by which NCNL promotes lactation in rats with bromocriptine-induced hypogalactia. The results showed that NCNL significantly improved the loss of appetite in female adult rats and the weight loss of pups caused by the disorder of lactation. Biochemical analysis showed that NCNL could regulate the levels of PRL, T4, E2, Ca, UREA, GLU, ALT, AST, TCHO, and TG in serum. The pathological results showed that NCNL could promote lactation and increase the mammary gland index by improving breast acinar tissue morphology in rats with hypogalactia. Network pharmacology studies showed that NCNL promotes lactation through P13K-Akt, insulin resistance, and prolactin signaling pathways, among which the most frequently affected pathway was the P13K-Akt signaling pathway. Metabolomics studies showed that NCNL can significantly upregulate phenylalanine, tyrosine, and tryptophan biosynthesis and tyrosine metabolism pathways and downregulate cysteine and methionine metabolism pathways. NCNL can significantly increase the serum prolactin concentration, improve the glucose and lipid metabolism disorders, and regulate PI3K-Akt, insulin resistance, and prolactin pathways to affect the amino acids' metabolism in the mammary gland and ultimately exert its therapeutic effect on bromocriptine-induced postpartum hypogalactia. These findings revealed the effect and application value of NCNL on animals with postpartum hypogalactia.