Prolactin receptor potentiates chemotherapy through miRNAs-induced G6PD/TKT inhibition in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies, with a notoriously dismal prognosis. As a competitive inhibitor of DNA synthesis, gemcitabine is the cornerstone drug for treating PDAC at all stages. The therapeutic effect of gemcitabine, however, is often hindered by drug resistance, and the underlying mechanisms remain largely unknown. It is unclear whether their response to chemotherapeutics is regulated by endocrine regulators, despite the association between PDAC risk and endocrine deregulation. Here, we show that prolactin receptor (PRLR) synergizes with gemcitabine in both in vitro and in vivo treatment of PDAC. Interestingly, PRLR promotes the expression of miR-4763-3p and miR-3663-5p, two novel miRNAs whose functions are unknown. Furthermore, the analysis of transcriptome sequencing data of tumors from lactating mouse models enriches the PPP pathway, a multifunctional metabolic pathway. In addition to providing energy, the PPP pathway mainly provides a variety of raw materials for anabolism. We demonstrate that two key enzymes of the pentose phosphate pathway (PPP), G6PD and TKT, are directly targeted by miR-4763-3p and miR-3663-5p. Notably, miR-4763-3p and miR-3663-5p diminish the nucleotide synthesis of the PPP pathway, thereby increasing gemcitabine sensitivity. As a result, PRLR harnesses these two miRNAs to suppress PPP and nucleotide synthesis, subsequently elevating the gemcitabine sensitivity of PDAC cells. Also, PDAC tissues and tumors from LSL-KrasG12D/+, LSL-Trp53R172H/+, and PDX1-cre (KPC) mice exhibit downregulation of PRLR. Bisulfite sequencing of PDAC tissues revealed that PRLR downregulation is due to epigenetic methylation. In this study, we show for the first time that the endocrine receptor PRLR improves the effects of gemcitabine by boosting two new miRNAs that block the PPP pathway and nucleotide synthesis by inhibiting two essential enzymes concurrently. The PRLR-miRNAs-PPP axis may serve as a possible therapeutic target to supplement chemotherapy advantages in PDAC.

Genome-wide identification of the GRF family in sweet orange (Citrus sinensis) and functional analysis of the CsGRF04 in response to multiple abiotic stresses.

BACKGROUND: Citrus is one of the most valuable fruits worldwide and an economic pillar industry in southern China. Nevertheless, it frequently suffers from undesirable environmental stresses during the growth cycle, which severely restricts the growth, development and yield of citrus. In plants, the growth-regulating factor (GRF) family of transcription factors (TF) is extensively distributed and plays an vital part in plant growth and development, hormone response, as well as stress adaptation. However, the systematic identification and functional analysis of GRF TFs in citrus have not been reported. RESULTS: Here, a genome-wide identification of GRF TFs was performed in Citrus sinensis, 9 members of CsGRFs were systematically identified and discovered to be scattered throughout 5 chromosomes. Subsequently, physical and chemical properties, phylogenetic relationships, structural characteristics, gene duplication events, collinearity and cis-elements of promoter were elaborately analyzed. In particular, the expression patterns of the CsGRF genes in response to multiple phytohormone and abiotic stress treatments were investigated. Predicated on this result, CsGRF04, which exhibited the most differential expression pattern under multiple phytohormone and abiotic stress treatments was screened out. Virus-induced gene silencing (VIGS) technology was utilized to obtain gene silenced plants for CsGRF04 successfully. After the three stress treatments of high salinity, low temperature and drought, the CsGRF04-VIGS lines showed significantly reduced resistance to high salinity and low temperature stresses, but extremely increased resistance to drought stress. CONCLUSIONS: Taken together, our findings systematically analyzed the genomic characterization of GRF family in Citrus sinensis, and excavated a CsGRF04 with potential functions under multiple abiotic stresses. Our study lay a foundation for further study on the function of CsGRFs in abiotic stress and hormone signaling response.

Pectin demethylation-mediated cell wall Na+ retention positively regulates salt stress tolerance in oilseed rape.

KEY MESSAGE: Integrated phenomics, ionomics, genomics, transcriptomics, and functional analyses present novel insights into the role of pectin demethylation-mediated cell wall Na+ retention in positively regulating salt tolerance in oilseed rape. Genetic variations in salt stress tolerance identified in rapeseed genotypes highlight the complicated regulatory mechanisms. Westar is ubiquitously used as a transgenic receptor cultivar, while ZS11 is widely grown as a high-production and good-quality cultivar. In this study, Westar was found to outperform ZS11 under salt stress. Through cell component isolation, non-invasive micro-test, X-ray energy spectrum analysis, and ionomic profile characterization, pectin demethylation-mediated cell wall Na+ retention was proposed to be a major regulator responsible for differential salt tolerance between Westar and ZS11. Integrated analyses of genome-wide DNA variations, differential expression profiling, and gene co-expression networks identified BnaC9.PME47, encoding a pectin methylesterase, as a positive regulator conferring salt tolerance in rapeseed. BnaC9.PME47, located in two reported QTL regions for salt tolerance, was strongly induced by salt stress and localized on the cell wall. Natural variation of the promoter regions conferred higher expression of BnaC9.PME47 in Westar than in several salt-sensitive rapeseed genotypes. Loss of function of AtPME47 resulted in the hypersensitivity of Arabidopsis plants to salt stress. The integrated multiomics analyses revealed novel insights into pectin demethylation-mediated cell wall Na+ retention in regulating differential salt tolerance in allotetraploid rapeseed genotypes. Furthermore, these analyses have provided key information regarding the rapid dissection of quantitative trait genes responsible for nutrient stress tolerance in plant species with complex genomes.

Analysis of tumor microenvironment alterations in partially responsive rectal cancer patients treated with neoadjuvant chemoradiotherapy.

PURPOSE: Achieving a pathologic complete response (pCR) after neoadjuvant chemoradiotherapy (NCRT) remains a challenge for most patients with rectal cancer. Exploring the potential of combining NCRT with immunotherapy or targeted therapy for those achieving a partial response (PR) offers a promising avenue to enhance treatment efficacy. This study investigated the impact of NCRT on the tumor microenvironment in locally advanced rectal cancer (LARC) patients who exhibited a PR. METHODS: This was a retrospective, observational study. Five patients demonstrating a PR after neoadjuvant treatment for LARC were enrolled in the study. Biopsy samples before treatment and resected specimens after treatment were stained with a panel of 26 antibodies targeting various immune and tumor-related markers, each labeled with distinct metal tags. The labeled samples were then analyzed using the Hyperion imaging system. RESULTS: Heterogeneity within the tumor microenvironment was observed both before and after NCRT. Notably, tumor-associated macrophages, CD4 + T cells, CD8 + T cells, CD56 + natural killer cells, tumor-associated neutrophils, cytokeratin, and E-cadherin exhibited slight increase in abundance within the tumor microenvironment following treatment (change ratios = 0.78, 0.2, 0.27, 0.32, 0.17, 0.46, 0.32, respectively). Conversely, the number of CD14 + monocytes, CD19 + B cells, CD45 + CD4 + T cells, collagen I, α-smooth muscle actin, vimentin, and ß-catenin proteins displayed significant decreases post-treatment (change ratios = 1.73, 1.92, 1.52, 1.25, 1.52, 1.12, 2.66, respectively). Meanwhile, Foxp3 + regulatory cells demonstrated no significant change (change ratio = 0.001). CONCLUSIONS: NCRT has diverse effects on various components of the tumor microenvironment in LARC patients who achieve a PR after treatment. Leveraging combination therapies may optimize treatment outcomes in this patient population.

A two-step electrochemical biosensor based on Tetrazyme for the detection of fibrin.

In this study, an electrochemical biosensor was constructed for the detection of fibrin, specifically by a simple two-step approach, with a novel artificial enzyme (Tetrazyme) based on the DNA tetrahedral framework as signal probe. The multichannel screen-printed electrode with the activated surface cannot only remove some biological impurities, but also serve as a carrier to immobilize a large number of antigen proteins. The DNA tetrahedral nanostructure was employed to ensure the high sensitivity of the probe for biological analysis. The hemin was chimeric into the G-quadruplex to constitute the complex with peroxidase catalytic activity (hemin/G4-DNAzyme), subsequently, Tetrazyme was formed through combining of this complex and DNA tetrahedral nucleic acid framework. The artificial enzyme signal probe formed by the covalent combination of the homing peptide (Cys-Arg-Glu-Lys-Ala, CREKA), which is the aptamer of fibrin and the new artificial enzyme is fixed on the surface of the multichannel carbon electrode by CREKA-specific recognition, so as to realize the sensitive detection of fibrin. The feasibility of sensing platform was validated by cyclic voltammetry (CV) and amperometric i-t curve (IT) methods. Effects of Tetrazyme concentration, CREKA concentrations and hybridization time on the sensor were explored. Under the best optimal conditions of 0.6 µmol/L Tetrazyme, 80 µmol/L CREKA, and 2.5 h reaction time, the immunosensor had two linear detection ranges, 10-40 nmol/L, with linear regression equation Y = 0.01487X - 0.011 (R2 = 0.992), and 50-100 nmol/L, with linear regression equation Y = 0.00137X + 0.6405 (R2 = 0.998), the detection limit was 9.4 nmol/L, S/N ≥ 3. The biosensor could provide a new method with great potential for the detection of fibrin with good selectivity, stability, and reproducibility.

Does government environmental attention drive green total factor productivity? Evidence from China.

Based on city-level panel data spanning 2008 to 2021, this study investigates the impact of government environmental attention (GEA) on green total factor productivity (GTFP). The findings suggest that increased GEA substantially enhances the growth of GTFP. After conducting robustness and endogeneity tests, the study's results consistently show reliability and robustness. Further analysis elucidates several mechanisms through which GEA influences GTFP, including fostering green technology innovation, optimizing resource allocation, and promoting upgrades in industrial structure. Heterogeneity analyses reveal that the impact of GEA on GTFP is notably pronounced in eastern cities, as well as in cities characterized by low resource dependency, mature industrial development, and high market competition. Conversely, the influence of GEA on GTFP is less discernible in cities prioritizing economic development goals, possibly due to differing policy orientations and resource allocation strategies. This study offers a novel perspective on understanding how GEA shape green development and provides empirical support for policy formulation.

Exercise Alleviates Behavioral Disorders but Shapes Brain Metabolism of APP/PS1 Mice in a Region- and Exercise-Specific Manner.

Exercise plays a beneficial role in the management of Alzheimer's disease (AD), but its effects on brain metabolism are still far from being understood. Here, we examined behavioral changes of APP/PS1 mice after high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) and analyzed metabolomics profiles in the hippocampus, cortex, and hypothalamus by using nuclear magnetic resonance spectroscopy to explore potential metabolic mechanisms. The results demonstrate that both HIIT and MICT alleviated anxiety/depressive-like behaviors as well as learning and memory impairments of AD mice. Metabolomics analysis reveals that energy metabolism, neurotransmitter metabolism, and membrane metabolism were significantly altered in all three brain regions after both types of exercises. Amino acid metabolism was detected to be affected in the cortex and hypothalamus after HIIT and in the hippocampus and hypothalamus after MICT. However, only HIIT significantly altered astrocyte-neuron metabolism in the hippocampus and hypothalamus of AD mice. Therefore, our study suggests that exercise can shape brain metabolism of AD mice in a region- and exercise-specific manner, indicating that the precise modification of brain metabolism by a specific type of exercise might be a novel perspective for the prevention and treatment of AD.

Low iron ameliorates the salinity-induced growth cessation of seminal roots in wheat seedlings.

Wheat plants are ubiquitously simultaneously exposed to salinity and limited iron availability caused by soil saline-alkalisation. Through this study, we found that both low Fe and NaCl severely inhibited the growth of seminal roots in wheat seedlings; however, sufficient Fe caused greater growth cessation of seminal roots than low Fe under salt stress. Low Fe improved the root meristematic division activity, not altering the mature cell sizes compared with sufficient Fe under salt stress. Foliar Fe spray and split-root experiments showed that low Fe-alleviating the salinity-induced growth cessation of seminal roots was dependent on local low Fe signals in the roots. Ionomics combined with TEM/X-ray few differences in the root Na+ uptake and vacuolar Na+ sequestration between two Fe levels under salt stress. Phytohormone profiling and metabolomics revealed salinity-induced overaccumulation of ACC/ethylene and tryptophan/auxin in the roots under sufficient Fe than under low Fe. Differential gene expression, pharmacological inhibitor addition and the root growth performance of transgenic wheat plants revealed that the rootward auxin efflux and was responsible for the low Fe-mediated amelioration of the salinity-induced growth cessation of seminal roots. Our findings will provide novel insights into the modulation of crop root growth under salt stress.

Transient neonatal hyperglycemia induces metabolic shifts in the rat hippocampus: a 1H NMR-based metabolomics analysis.

Diabetes has been reported to induce brain metabolic disturbance, but the effect of transient neonatal hyperglycemia (TNH) on brain metabolism remains unclear. Herein the rats were treated with a single intraperitoneal injection of 100 µg/g body weight of streptozotocin within 12 h after birth and displayed a typical clinical characteristic of TNH. Then we used NMR-based metabolomics to examine the metabolic changes in the hippocampus between TNH and normal control (Ctrl) rats at postnatal 7 days (P7) and 21 days (P21). The results show that TNH rats had significantly increased levels of N-acetyl aspartate, glutamine, aspartate and choline in the hippocampus relative to Ctrl rats at P7. Moreover, we found that the levels of alanine, myo-inositol and choline were significantly lower in TNH rats, although their blood glucose levels have been recovered to the normal level at P21. Therefore, our results suggest that TNH may have a long-term effect on hippocampal metabolic changes mainly involving neurotransmitter metabolism and choline metabolism.

Analysis of the efficacy and factors influencing survival of adjuvant radiotherapy for stage II-III biliary tract carcinoma.

BACKGROUND: To determine the efficacy of adjuvant radiotherapy for stage II-III biliary tract carcinoma. METHODS: We retrospectively analyzed the data of 37 patients who underwent radical resection of biliary tract carcinomas at the Affiliated Hospital of Inner Mongolia Medical University between 2016 and 2020. We analyzed survival differences between patients who did (n = 17) and did not (n = 20) receive postoperative adjuvant radiotherapy by using Kaplan-Meier analysis. The log-rank test and Cox univariate analysis were used. The Cox proportional risk regression model was used for the multifactorial analysis of factors influencing prognosis. RESULTS: The median survival time (28.9 vs. 14.5 months) and the 1-year (82.40% vs. 55.0%) and 2-year survival rates (58.8% vs. 25.0%) were significantly higher among patients who received adjuvant radiotherapy than among those who did not (χ2 = 6.381, p = 0.012). Multifactorial analysis showed that pathological tumor type (p = 0.004), disease stage (p = 0.021), and adjuvant radiotherapy (p = 0.001) were independent prognostic factors in biliary tract carcinoma. Subgroup analyses showed that compared to no radiotherapy, adjuvant radiotherapy significantly improved median survival time in patients with stage III disease (21.6 vs. 12.7 months; p = 0.017), positive margins (28.9 vs. 10.5 months; p = 0.012), and T3 or T4 tumors (26.8 vs. 16.8 months; p = 0.037). CONCLUSION: Adjuvant radiotherapy significantly improved the survival of patients with biliary tract carcinoma, and is recommended especially for patients with stage III disease, positive surgical margins, or ≥ T3.

Amelioration of Obesity-Related Disorders in High-Fat Diet-Fed Mice following Fecal Microbiota Transplantation from Inulin-Dosed Mice.

The role of inulin in alleviating obesity-related disorders has been documented; yet, its underlying mechanisms still need to be further investigated. This study attempted to elucidate the causative link between the gut microbiota and the beneficial effect of inulin on obesity-related disorders via transferring the fecal microbiota from inulin-dosed mice to high-fat diet (HFD)-induced obese recipient mice. The results show that inulin supplementation can decrease body weight, fat accumulation, and systemic inflammation and can also enhance glucose metabolism in HFD-induced obese mice. Treatment with inulin reshaped the structure and composition of the gut microbiota in HFD-induced obese mice, as characterized by increases in the relative abundances of Bifidobacterium and Muribaculum and decreases in unidentified_Lachnospiraceae and Lachnoclostridium. In addition, we found that these favorable effects of inulin could be partially transferable by fecal microbiota transplantation, and Bifidobacterium and Muribaculum might be the key bacterial genera. Therefore, our results suggest that inulin ameliorates obesity-related disorders by targeting the gut microbiota.

OsRAM2 Function in Lipid Biosynthesis Is Required for Arbuscular Mycorrhizal Symbiosis in Rice.

Arbuscular mycorrhiza (AM) is a mutualistic symbiosis formed between most land plants and Glomeromycotina fungi. During symbiosis, plants provide organic carbon to fungi in exchange for mineral nutrients. Previous legume studies showed that the required for arbuscular mycorrhization2 (RAM2) gene is necessary for transferring lipids from plants to AM fungi (AMF) and is also likely to play a "signaling" role at the root surface. To further explore RAM2 functions in other plant lineages, in this study, two rice (Oryza sativa) genes, OsRAM2 and OsRAM2L, were identified as orthologs of legume RAM2. Examining their expression patterns during symbiosis revealed that only OsRAM2 was strongly upregulated upon AMF inoculation. CRISPR/Cas9 mutagenesis was then performed to obtain three Osram2 mutant lines (-1, -2, and -3). After inoculation by AMF Rhizophagus irregularis or Funneliformis mosseae, all of the mutant lines showed extremely low colonization rates and the rarely observed arbuscules were all defective, thus supporting a conserved "nutritional" role of RAM2 between monocot and dicot lineages. As for the signaling role, although the hyphopodia numbers formed by both AMF on Osram2 mutants were indeed reduced, their morphology showed no abnormality, with fungal hyphae invading roots successfully. Promoter activities further indicated that OsRAM2 was not expressed in epidermal cells below hyphopodia or outer cortical cells enclosing fungal hyphae but instead expressed exclusively in cortical cells containing arbuscules. Therefore, this suggested an indirect role of RAM2 rather than a direct involvement in determining the symbiosis signals at the root surface.[Formula: see text] The author(s) have dedicated the work to the public domain under the Creative Commons CC0 "No Rights Reserved" license by waiving all of his or her rights to the work worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law, 2022.

OsADK1, a novel kinase regulating arbuscular mycorrhizal symbiosis in rice.

Arbuscular mycorrhizal (AM) symbiosis relies on the formation of arbuscules for efficient nutrient exchange between plants and AM fungi. In this study, we identified a novel kinase gene in rice named OsADK1 (Arbuscule Development Kinase 1) that is required for arbuscule development. By obtaining OsADK1pro::GUS transgenic rice plants and also generating Osadk1 mutants via CRISPR/Cas9 technique, OsADK1 was revealed to be specifically induced in the arbusculated cortical cells and mutations in OsADK1 resulted in an extremely low colonisation rate (c. 3%) of rice roots by AM fungus Rhizophagus irregularis. In the mutant roots, the very few observed arbuscules nearly all arrested at an early 'trunk-forming' phase without forming any branches. Increasing the inoculum strength of AM fungus or cocultivation with a wild-type nurse plant did not result in the rescue of the arbuscule phenotype. Transcriptome sequencing of both nursed and un-nursed Osadk1 mutants then revealed that the mutation of OsADK1 could greatly affect the AM symbiotic programme, including many key transcription factors such as RAM1 and WRI5. OsADK1 therefore represents a new rice kinase that is required for arbuscule branching. Its identification opens a new window to explore the elaborate signal transduction pathway that determines arbuscule development during plant-fungus symbiosis.

Multiomics reveals an essential role of long-distance translocation in regulating plant cadmium resistance and grain accumulation in allohexaploid wheat (Triticum aestivum).

Cadmium (Cd) is a highly toxic heavy metal that readily enters cereals, such as wheat, via the roots and is translocated to the shoots and grains, thereby posing high risks to human health. However, the vast and complex genome of allohexaploid wheat makes it challenging to understand Cd resistance and accumulation. In this study, a Cd-resistant cultivar of wheat, 'ZM1860', and a Cd-sensitive cultivar, 'ZM32', selected from a panel of 442 accessions, exhibited significantly different plant resistance and grain accumulation. We performed an integrated comparative analysis of the morpho-physiological traits, ionomic and phytohormone profiles, genomic variations, transcriptomic landscapes, and gene functionality in order to identify the mechanisms underlying these differences. Under Cd toxicity, 'ZM1860' outperformed 'ZM32', which showed more severe leaf chlorosis, poorer root architecture, higher accumulation of reactive oxygen species, and disordered phytohormone homeostasis. Ionomics showed that 'ZM32' had a higher root-to-shoot translocation coefficient of Cd and accumulated more Cd in the grains than 'ZM1860'. Whole-genome re-sequencing (WGS) and transcriptome sequencing identified numerous DNA variants and differentially expressed genes involved in abiotic stress responses and ion transport between the two genotypes. Combined ionomics, transcriptomics, and functional gene analysis identified the plasma membrane-localized heavy metal ATPase TaHMA2b-7A as a crucial Cd exporter regulating long-distance Cd translocation in wheat. WGS- and PCR-based analysis of sequence polymorphisms revealed a 25-bp InDel site in the promoter region of TaHMA2b-7A, and this was probably responsible for the differential expression. Our multiomics approach thus enabled the identification of a core transporter involved in long-distance Cd translocation in wheat, and it may provide an elite genetic resource for improving plant Cd resistance and reducing grain Cd accumulation in wheat and other cereal crops.

GLP-1 mimetics as a potential therapy for nonalcoholic steatohepatitis.

Nonalcoholic steatohepatitis (NASH), as a severe form of nonalcoholic fatty liver disease (NAFLD), is characterized by liver steatosis, inflammation, hepatocellular injury and different degrees of fibrosis. The pathogenesis of NASH is complex and multifactorial, obesity and type 2 diabetes mellitus (T2DM) have been implicated as major risk factors. Glucagon-like peptide-1 receptor (GLP-1R) is one of the most successful drug targets of T2DM and obesity, and its peptidic ligands have been proposed as potential therapeutic agents for NASH. In this article we provide an overview of the pathophysiology and management of NASH, with a special focus on the pharmacological effects and possible mechanisms of GLP-1 mimetics in treating NAFLD/NASH, including dual and triple agonists at GLP-1R, glucose-dependent insulinotropic polypeptide receptor or glucagon receptor.

Clinical Efficacy of Potato Extract for Alleviating Chemoradiotherapy-Related Leukopenia: a Randomized, Single-Blind, Placebo-Controlled Trial.

BACKGROUND: Leukopenia is the most common adverse event in chemotherapy, which natural products can prevent and treat. The aim of this study was to investigate the clinical efficacy of potato extract for alleviating chemoradiotherapy-induced leukopenia in cancer patients. METHODS: This was a single-blinded randomized placebo-controlled trial that enrolled 184 cancer patients. The participants were scheduled to undergo chemoradiotherapy in two hospitals, where they were randomized to receive potato extract or a placebo in a 1:1 ratio for a period of 49 days. Change in leukocyte value was considered the primary outcome of this clinical trial. Secondary outcomes included tumor response rate, blood test, and quality of life score. RESULTS: The leukopenia was relieved in the potato extract group compared with the placebo group. Of note, a significant difference in leukopenia between the two groups was found after 14 days (p = 0.04). In addition, there was no statistically significant difference in leucocyte levels in the potato extract group (before and after potato extract treatment; p = 0.13), but in the placebo group, the leukocyte value significantly decreased compared to before treatment (p = 0.06). CONCLUSIONS: Potato extract can alleviate chemoradiotherapy-induced leukopenia in cancer patients. These results show the potential function of potato extract as a protective agent in management of cancer chemoradiotherapy.

Association between Neutrophil Levels on Admission and All-Cause Mortality in Geriatric Patients with Hip Fractures: A Prospective Cohort Study of 2,589 Patients.

Objective: To evaluate the association between neutrophil levels and all-cause mortality in geriatric hip fractures. Methods: Elderly patients with hip fractures were screened between January 2015 and September 2019. Demographic and clinical characteristics of the patients were collected. Linear and nonlinear multivariate Cox regression models were used to identify the association between neutrophil levels and mortality. Analyses were performed using Empower Stats and R software. Results: A total of 2,589 patients were included in this study. The mean follow-up period was 38.95 months. During the study period, 875 (33.80%) patients died due to various causes. Linear multivariate Cox regression models showed that neutrophil levels were associated with mortality after adjusting for confounding factors, when neutrophil concentration increased by 1∗109/L, the mortality risk increased by 3% (HR = 1.03, 95% CI: 1.00-1.06, and P=0210). Neutrophil concentration was used as a categorical variable; we only found statistically significant differences when neutrophil levels were high (HR = 1.27, 95% CI:1.05-1.52, and P=0.0122). In addition, the results are stable in P for trend and propensity score matching sensitivity analysis. Conclusions: Neutrophil levels are associated with mortality in geriatric hip fractures and could be considered a predictor of death risk in the long-term. This study is registered with the Chinese Clinical Trial Registry (ChiCTR) as number ChiCTR2200057323.

Transcriptome analysis of Macrobrachium rosenbergii: Identification of precocious puberty and slow-growing information.

Macrobrachium rosenbergii is an important economic aquatic animal and has been cultivated worldwide. However, it has suffered a disease of precocious puberty and growth retardation. This disease was also called iron prawn syndrome (IPS) in recent years. However, the cause of this disease has thus far remained a mystery . The present work utilized transcriptome sequencing technology to acquire gene expression information of gonads and to find the differentially expressed genes(DEGs) between diseased and normal male prawn. Finally, 426 significantly expressed genes were identified(p less than 0.01, |log2FC|≥1), of which 171 genes were up-regulated and 255 were down-regulated. Furthermore, DEGs were annotated to 36 GO terms and 202 KEGG pathways. Enrichment analysis of DEGs resulted in 10 significantly enriched GO terms and a total of 12 significantly enriched KEGG pathways. Analysis of the transcriptome sequences and DEGs identified several unigenes and pathways involved in precocious puberty and growth retardation. Quantitative PCR was performed to validate accuracy of the RNA-seq and the expression level of 10 genes, calculated by two analysis method, was mostly consistent. This is the first time to report precocious puberty and growth retardation male M. rosenbergii by transcriptome sequencing. The data presented here reveals key insights into the genetic markers of precocious puberty and growth retardation of male M. rosenbergii.

A validated LC-MS/MS method for the determination of hederasaponin C: Application to pharmacokinetics-pharmacodynamics studies in the therapeutic area of acetic acid-induced ulcerative colitis in rats.

Hederasaponin C (HSC), one of the main components of Pulsatilla chinensis, is considered as a potential drug for the treatment of inflammatory bowel disease. In the present research, we developed a pharmacokinetics-pharmacodynamics model to describe the concentration-effect course of drug action following the intraperitoneal injection of HSC in colitis rats. A sensitive UPLC-MS/MS method was established for the the determination of HSC in rat plasma to explore the pharmacokinetics properties. The separation was performed on an Accucore C18 column (2.1 × 100 mm, 2.6 µm) with a flow phase consisting of acetonitrile and 0.1% formic acid water. The assay method was validated and demonstrated good adaptability for application in the pharmacokinetics study. Then the levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1ß (IL-1ß) in colon tissues were measured using an ELISA assay. The levels of TNF-α, IL-1ß and IL-6 were decreased after HSC administration, suggesting that HSC can significantly improve the level of inflammatory syndrome factor. The pharmacokinetics study showed that the time to peak concentration of HSC was 1 h. The concentration-effect curves showed a hysteresis loop. There was also a hysteresis between the peaked concentration and the maximum effect of HSC. The present study established in vivo pharmacokinetics-pharmacodynamics models and the results showed a great potential of HSC for treating ulcerative colitis.

BMRMI Reduces Depressive Rumination Possibly through Improving Abnormal FC of Dorsal ACC.

Rumination is a common symptom of major depressive disorder (MDD) and has been characterized as a vulnerability factor for the onset or recurrence of MDD. However, the neurobiological mechanisms underlying rumination and appropriate treatment strategies remain unclear. In the current study, we used resting-state functional magnetic resonance imaging to investigate the effects of body-mind relaxation meditation induction (BMRMI) intervention in MDD with rumination. To this aim, we have recruited 25 MDD and 24 healthy controls (HCs). Changes in functional connectivity (FC) of the anterior cingulate cortex (ACC) subregion and the scores of clinical measurements were examined using correlation analysis. At baseline, MDD showed stronger FC between the right dorsal ACC (dACC) and right superior frontal gyrus than did the HC group. Compared to baseline, the HC group showed a significantly enhanced FC between the right dACC and right superior frontal gyrus, and the MDD group demonstrated a significantly weaker FC between the left dACC and right middle frontal gyrus (MFG) after the intervention. Furthermore, the FC between the right dACC and right superior frontal gyrus was positively associated with rumination scores across all participants at baseline. The above results indicate that BMRMI may regulate self-referential processing and cognitive function through modulating FC of the dACC in MDD with rumination.