Causality of genetically determined blood metabolites on irritable bowel syndrome: A Mendelian randomization study.

BACKGROUND: Irritable bowel syndrome (IBS) is one of the most common functional bowel disorders and dysmetabolism plays an important role in the pathogenesis of disease. Nevertheless, there remains a lack of information regarding the causal relationship between circulating metabolites and IBS. A two-sample Mendelian randomization (MR) analysis was conducted in order to evaluate the causal relationship between genetically proxied 486 blood metabolites and IBS. METHODS: A two-sample MR analysis was implemented to assess the causality of blood metabolites on IBS. The study utilized a genome-wide association study (GWAS) to examine 486 metabolites as the exposure variable while employing a GWAS study with 486,601 individuals of European descent as the outcome variable. The inverse-variance weighted (IVW) method was used to estimate the causal relationship of metabolites on IBS, while several methods were performed to eliminate the pleiotropy and heterogeneity. Another GWAS data was used for replication and meta-analysis. In addition, reverse MR and linkage disequilibrium score regression (LDSC) were employed for additional assessment. Multivariable MR analysis was conducted in order to evaluate the direct impact of metabolites on IBS. RESULTS: Three known and two unknown metabolites were identified as being associated with the development of IBS. Higher levels of butyryl carnitine (OR(95%CI):1.10(1.02-1.18),p = 0.009) and tetradecanedioate (OR(95%CI):1.13(1.04-1.23),p = 0.003)increased susceptibility of IBS and higher levels of stearate(18:0)(OR(95%CI):0.72(0.58-0.89),p = 0.003) decreased susceptibility of IBS. CONCLUSION: The metabolites implicated in the pathogenesis of IBS possess potential as biomarkers and hold promise for elucidating the underlying biological mechanisms of this condition.

Hybrid Mimulus flowers attract a new pollinator.

Hybridization is common in flowering plants and is believed to be an important force driving adaptation and speciation. The flowers of hybrids often exhibit new trait combinations, which, theoretically, could attract new species of pollinators. In this study, we found that the hybrids between a hummingbird-pollinated species Mimulus cardinalis and a self-pollinated species Mimulus parishii attract bumblebees (Bombus impatiens), a pollinator not attracted to either of the progenitor species. This novel attraction is explained by new combinations of floral traits in hybrids, including, most importantly, petal color, in addition to nectar concentration and corolla size. To understand how petal color variation is perceived by bumblebees, we performed reflectance spectroscopy and multispectral imaging to model the flower appearance in bee vision. This analysis showed that color variation would impact the ease of detection. We also found that YUP, the genetic locus responsible for a large portion of floral color variation and previously shown to be important in bee interactions with other Mimulus species, also played an important role in this novel attraction. These results together suggest that the attraction of new pollinators to hybrid plants could be an underexplored avenue for pollinator shift and speciation.

Causal relationship of genetically predicted gut microbiota with thyroid cancer: a bidirectional two-sample mendelian randomization study.

Background: Previous investigations have demonstrated a correlation between the composition of gut microbiota and the development of thyroid cancer (TC). Nonetheless, there was no consensus on the causal effect of gut microbiota composition on TC risk. Therefore, the present study aimed to perform a bidirectional two-sample Mendelian randomization (MR) analysis to explore potential causal associations between gut microbiota and TC risk. Methods: Utilizing data from the MiBioGen consortium's genome-wide association studies (GWAS) meta-analysis involving a sample size of 18,340, we identified instrumental variables for 211 gut microbiota taxa. The summary statistics for TC was from relevant large-scale GWAS conducted by the FinnGen consortium. In the first stage, the Inverse-variance weighted (IVW) method was used as the primary estimate method, and the stability of estimations was tested by a battery of sensitivity analyses. In the second stage, a reverse MR analysis was applied to determine whether reverse causality existed. Results: According to the IVW method, we identified 9 genetically predicted gut microbiota that were causally correlated with TC risk. Among them, we observed a positive causal effect of Family Christensenellaceae (OR = 1.664, 95% CI: 1.103-2.511, P = 0.015), Family Victivallaceae (OR = 1.268, 95% CI: 1.009-1.594, P = 0.042), Genus Methanobrevibacter (OR = 1.505, 95% CI: 1.049-2.159, P = 0.027), Genus Ruminococcus2 (OR = 1.846, 95% CI: 1.261-2.704, P = 0.002), Genus Subdoligranulum (OR = 1.907, 95% CI: 1.165-3.121, P = 0.010), Phylum Verrucomicrobia (OR = 1.309, 95% CI: 1.027-1.668, P = 0.029) on TC risk, while Class Betaproteobacteria (OR = 0.522, 95% CI: 0.310-0.879, P = 0.015), Family Family XI (OR = 0.753, 95% CI: 0.577-0.983, P = 0.037), Genus Sutterella (OR = 0.596, 95% CI: 0.381-0.933, P = 0.024) might be correlated with a decreased risk of TC. Subsequently, various sensitivity analyses indicated no heterogeneity, directional pleiotropy or outliers. In addition, reverse analysis demonstrated a negative causal effect of TC risk on the abundance of the gut microbiota (Genus Ruminococcus2, OR = 0.947, 95% CI: 0.907-0.989, P = 0.014). Conclusion: Genetic evidence suggested that bidirectional causal associations of specific bacteria taxa and the risk of TC, highlighting the association of the "gut-thyroid" axis. Further exploration of the potential microbiota-related mechanisms might have profound implications for public health in terms of the early prevention and treatment of TC.

Association between the dietary inflammatory index and all-cause mortality in the U.S. cancer survivors: A prospective cohort study using the National Health and Nutrition Examination Survey database.

Background: Cancer remains one of the leading causes of mortality worldwide. Diet can impact inflammation and consequently affect cancer outcomes. The Dietary Inflammatory Index (DII) can serve as a tool to assess the inflammatory potential of cancer survivors' diets and further predict their survival. Objectives: To investigate the relationship between the DII and the survival of cancer survivors in National Health and Nutrition Examination Survey (NHANES). Methods: An overall sample of 2359 U.S. cancer survivors from the 2005-2014 cohorts of the NHANES were studied. The DII scores were calculated using 28 dietary components and the mortality status was ascertained until December 31, 2015. Based on the multiple analyses, the relationship between DII and all-cause mortality was examined. Results: The weighted mean age at baseline was 65.17 ± 14.46 years, 53.16 % were female and 71.30 % were non-Hispanic white. The average DII was 1.51 ± 1.97. After accounting for multiple covariates, positive associations were observed (P < 0.01). Based on Kaplan-Meier survival curves, their significant relationship remains same and the survival probability was decreased among the groups of anti-inflammatory diets (DII < 0) versus pro-inflammatory diets (DII ≥ 0) significantly (Log rank test; P = 0.03). Further analyses were conducted on subgroups and the results are still robust. Conclusions: An elevated DII was associated with a rising mortality rate among cancer survivors. DII might serve as a potential inflammatory predictor of cancer mortality prognosis, as well as guide nutritional care and even clinical treatment of cancer survivors.

Causal effects of specific gut microbiota on musculoskeletal diseases: a bidirectional two-sample Mendelian randomization study.

Background: Recent observational studies and clinical trials demonstrated an association between gut microbiota and musculoskeletal (MSK) diseases. Nonetheless, whether the gut microbiota composition has a causal effect on the risk of MSK diseases remains unclear. Methods: Based on large-scale genome-wide association studies (GWAS), we performed a two-sample Mendelian randomization (MR) analysis to investigate the causal relationship between gut microbiota and six MSK diseases, namely osteoporosis (OP), fracture, sarcopenia, low back pain (LBP), rheumatoid arthritis (RA), and ankylosing spondylitis (AS). Instrumental variables for 211 gut microbiota taxa were obtained from the largest available GWAS meta-analysis (n = 18,340) conducted by the MiBioGen consortium. And the summary-level data for six MSK diseases were derived from published GWAS. The inverse-variance weighted (IVW) method was conducted as a primary analysis to estimate the causal effect, and the robustness of the results was tested via sensitivity analyses using multiple methods. The Bonferroni-corrected test was used to determine the strength of the causal relationship between gut microbiota and various MSK diseases. Finally, a reverse MR analysis was applied to evaluate reverse causality. Results: According to the IVW method, we found 57 suggestive causal relationships and 3 significant causal relationships between gut microbiota and MSK diseases. Among them, Genus Bifidobacterium (ß: 0.035, 95% CI: 0.013-0.058, p = 0.0002) was associated with increased left handgrip strength, Genus Oxalobacter (OR: 1.151, 95% CI: 1.065-1.245, p = 0.0003) was correlated with an increased risk of LBP, and Family Oxalobacteraceae (OR: 0.792, 95% CI: 0.698-0.899, p = 0.0003) was linked with a decreased risk of RA. Subsequently, sensitivity analyses revealed no heterogeneity, directional pleiotropy, or outliers for the causal effect of specific gut microbiota on MSK diseases (p > 0.05). Reverse MR analysis showed fracture may result in a higher abundance of Family Bacteroidales (p = 0.030) and sarcopenia may lead to a higher abundance of Genus Sellimonas (p = 0.032). Conclusion: Genetic evidence suggested a causal relationship between specific bacteria taxa and six MSK diseases, which highlights the association of the "gut-bone/muscle" axis. Further exploration of the potential microbiota-related mechanisms of bone and muscle metabolism might provide novel insights into the prevention and treatment of MSK diseases.

Association between inflammatory markers and bone mineral density: a cross-sectional study from NHANES 2007-2010.

PURPOSE: Monocyte-to-lymphocyte ratio (MLR), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) are acknowledged as novel inflammatory markers. However, studies investigating the correlation between inflammatory markers and osteoporosis (OP) remain scarce. We aimed to investigate the relationship between NLR, MLR, PLR and bone mineral density (BMD). METHODS: A total of 9054 participants from the National Health and Nutrition Examination Survey were included in the study. MLR, NLR and PLR were calculated for each patient based on routine blood tests. Given the complex study design and sample weights, the relationship between inflammatory markers and BMD was evaluated through weighted multivariable-adjusted logistic regression and smooth curve fittings. In addition, several subgroup analyses were conducted to assess the robustness of the outcomes. RESULTS: This study observed no significant relationship between MLR and lumbar spine BMD (P = 0.604). However, NLR was positively correlated with lumbar spine BMD (ß = 0.004, 95% CI: 0.001 to 0.006, P = 0.001) and PLR was negatively linked to lumbar spine BMD (ß = - 0.001, 95% CI: - 0.001 to - 0.000, P = 0.002) after accounting for covariates. When bone density measurements were changed to the total femur and femoral neck, PLR was still significantly positively correlated with total femur (ß = - 0.001, 95% CI: - 0.001, - 0.000, P = 0.001) and femoral neck BMD (ß = - 0.001, 95% CI: - 0.002, - 0.001, P < 0.001). After converting PLR to a categorical variable (quartiles), participants in the highest PLR quartile had a 0.011/cm2 lower BMD than those in the lowest PLR quartile (ß = - 0.011, 95% CI: - 0.019, - 0.004, P = 0.005). According to subgroup analyses stratified by gender and age, the negative correlation with PLR and lumbar spine BMD remained in males and age < 18 groups, but not in female and other age groups. CONCLUSIONS: NLR and PLR were positively and negatively correlated with lumbar BMD, respectively. And PLR might serve as a potential inflammatory predictor of osteoporosis outperforming MLR and NLR. The complex correlation between the inflammation markers and bone metabolism requires further evaluation in large prospective studies.

Decreased histidine-rich glycoprotein and increased complement C4-B protein levels in follicular fluid predict the IVF outcomes of recurrent spontaneous abortion.

BACKGROUND: Recurrent spontaneous abortion (RSA) is a common and complicated pregnancy-related disease that lacks a suitable biomarker to predict its recrudescence. METHODS: Tandem mass tag (TMT) analysis was conducted to obtain quantitative proteomic profiles in follicular fluid from patients with a history of RSA and from control group. ELISA validation of candidate differentially expressed proteins was conducted in a larger group of patients. RESULTS: A total of 836 proteins were identified by TMT analysis; 51 were upregulated and 47 were downregulated in follicular fluid from cases of RSA versus control group. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis revealed several important pathways were enriched, involving a dysregulated immunoglobulin Fc receptor signaling pathway and overactivated complement cascade pathways. ELISA validated the differential expression of two proteins, histidine-rich globulin (HRG) and complement C4-B (C4B), which were downregulated and upregulated, respectively, in follicular fluid of patients with RSA. We performed receiver operating characteristic curve analysis of the ELISA results with the outcomes of current IVF cycles as classification variables. The area under the curve results for HRG alone, C4B alone and HRG-C4B combined were 0.785, 0.710 and 0.895, respectively. CONCLUSIONS: TMT analysis identified 98 differentially expressed proteins in follicular fluid from patients with RSA, indicating follicle factors that act as early warning factors for the occurrence of RSA. Among them, HRG and C4B provide candidate markers to predict the clinical outcomes of IVF/ICSI cycles, and the potential for modeling an early detection system for RSA.

Association between Sensitivity to Thyroid Hormone Indices and Bone Mineral Density in US Males.

Objectives: Thyroid hormone is acknowledged as a pivotal factor in skeletal development and adult bone maintenance. However, available data about the relationship between sensitivity to thyroid hormone and bone mineral density (BMD) remain limited and conflicting. The purpose of the study was to explore the complex relationship between sensitivity to thyroid hormone indices and BMD using cross-sectional analysis. Methods: An overall sample of 3,107 males from the National Health and Nutrition Examination Survey (NHANES) was studied in the study. The thyroid hormone sensitivity indices included free triiodothyronine/tree thyroxine (FT3/FT4), thyroid-stimulating hormone index (TSHI), thyrotroph thyroxine resistance index (TT4RI), and thyroid feedback quantile-based index (TFQI). Given the complex study design and sample weights, the correlation between sensitivity to thyroid hormone indices and BMD was evaluated through multivariate linear regression models, and extra subgroup analyses were performed to examine the robustness of the results. Results: Among the 3,107 participants, we demonstrated that FT3/FT4 was negatively correlated with lumbar BMD (ß = -0.0.35, 95% CI: -0.084-0.013, P < 0.05). In the terms of central sensitivity to thyroid hormone, TFQI showed a significant negative relationship with the BMD of the lumbar (ß = -0.018, 95% CI: -0.033 to -0.003, P < 0.05), total femur (ß = -0.020, 95% CI: -0.035 to -0.006, P < 0.01), and femur neck (ß = -0.018, 95% CI: -0.031 to -0.005, P < 0.01). In the subgroup analyses stratified by body mass index (BMI), the significant negative correlation between TFQI and lumbar BMD remained in the male participants with BMI between 18.5 and 24.9 kg/m2. Conclusions: Decreased indices of sensitivity to thyroid hormones are strongly associated with increased lumbar BMD, suggesting that the dysfunction of peripheral and central response to thyroid hormone might contribute to bone loss. In addition, FT3/FT4 and TFQI were considered to be the preferable indicators to guide the prevention and clinical treatment of osteoporosis.

S100P promotes trophoblast syncytialization during early placenta development by regulating YAP1.

Recurrent pregnancy loss (RPL) is a severe complication of pregnancy that is caused by genetic abnormalities, immune dysfunction, aberrant cell biology, and tissue structure destruction. Among which, placental dysfunction is crucial in the pathogenetic progression of RPL. Although some regulatory factors associated with RPL have been reported, the placental changes correlated with RPL still need to be elucidated. Here, we found that a portion of RPL patients presented with low serum and placental S100P expression. Using a human trophoblast stem cell model, we demonstrated that S100P was exclusively expressed in syncytiotrophoblast (ST)-like syncytia (ST(2D)-TSCT) and that loss of S100P expression in ST(2D)-TSCT cells impaired ß-hCG secretion, leading to syncytialization failure during early placental development. Moreover, we found that S100P is involved in regulating trophoblast syncytialization by downregulating the protein level of Yes-associated protein 1 (YAP1), which plays a pivotal role in maintaining trophoblast stemness. Together, our findings suggest that S100P plays an essential role in regulating trophoblast syncytialization during early placental development in humans via YAP1. Additionally, lower serum S100P levels may predict poor pregnancy outcomes and represent a potentially useful marker for evaluating placental biological function during early pregnancy.

Association between sensitivity to thyroid hormone indices and the risk of osteoarthritis: an NHANES study.

OBJECTIVES: Thyroid hormones play an instrumental role in chondrogenic differentiation and matrix maturation. However, studies investigating the relationship between thyroid function and the risk of osteoarthritis (OA) remain scarce. This study was designed to investigate the correlation between thyroid status and OA from a novel perspective of sensitivity to thyroid hormones. METHODS: The study included 8478 people from the National Health and Nutrition Examination Survey (NHANES) 2007-2010. The sensitivity to thyroid hormone indices included Thyrotroph Thyroxine Resistance Index (TT4RI), Thyroid-stimulating hormone (TSHI), Thyroid Feedback Quantile-based Index (TFQI), and Free Triiodothyronine /Free thyroxine (FT3/FT4), which were calculated based on serum free triiodothyronine (FT3), free thyroxine (FT4), and thyroid stimulating hormone (TSH). Considering the complex survey design and sample weights, we employed multivariate linear regression models and stratified analysis to evaluate the correlation between sensitivity to thyroid hormone indices and OA. RESULTS: Study results indicated that participants with OA had elevated TT4RI, TSHI, and TFQI levels, and lower FT3/FT4 levels compared to those with non-arthritis. After adjusting for other covariates, FT3/FT4 was negatively associated with the risk of OA (OR = 1.162, 95%CI 1.048-1.478, P = 0.021); (OR = 1.261, 95%CI 1.078-1.623, P = 0.042). In subgroup analyses stratified by gender and BMI, participants with OA had higher TFQI levels compared to those without OA in both genders. (OR = 1.491, 95%CI 1.070-2.077, P = 0.018); (OR = 2.548, 95%CI 1.929-3.365, P < 0.001). The higher TFQI levels were consistently associated with the increased prevalence of OA in the BMI (< 18.5 kg/m2) group after adjusting for different covariates, but not in other BMI groups. In, addition, TFQI performed better than FT3/FT4, TSHI, and TT4RI on ROC analyses for OA prediction. CONCLUSIONS: The levels of FT3/FT4, TSHI, TT4RI, and TFQI are strongly associated with the prevalence of OA, which illustrates the complex correlation between the thyroid system and chondrogenic differentiation. TFQI may be used as a helpful indicator to predict OA and provide novel ideas for the evaluation and treatment of OA.

Loss of Neuropilin2a/b or Sema3fa alters olfactory sensory axon dynamics and protoglomerular targeting.

BACKGROUND: Olfactory Sensory Neuron (OSN) axons project from the zebrafish olfactory epithelium to reproducible intermediate target locations in the olfactory bulb called protoglomeruli at early stages in development. Two classes of OSNs expressing either OMP or TRPC2 exclusively target distinct, complementary protoglomeruli. Using RNAseq, we identified axon guidance receptors nrp2a and nrp2b, and their ligand sema3fa, as potential guidance factors that are differentially expressed between these two classes of OSNs. METHODS: To investigate their role in OSN axon guidance, we assessed the protoglomerular targeting fidelity of OSNs labeled by OMP:RFP and TRPC2:Venus transgenes in nrp2a, nrp2b, or sema3fa mutants. We used double mutant and genetic interaction experiments to interrogate the relationship between the three genes. We used live time-lapse imaging to compare the dynamic behaviors of OSN growth cones during protoglomerular targeting in heterozygous and mutant larvae. RESULTS: The fidelity of protoglomerular targeting of TRPC2-class OSNs is degraded in nrp2a, nrp2b, or sema3fa mutants, as axons misproject into OMP-specific protoglomeruli and other ectopic locations in the bulb. These misprojections are further enhanced in nrp2a;nrp2b double mutants suggesting that nrp2s work at least partially in parallel in the same guidance process. Results from genetic interaction experiments are consistent with sema3fa acting in the same biological pathway as both nrp2a and nrp2b. Live time-lapse imaging was used to examine the dynamic behavior of TRPC2-class growth cones in nrp2a mutants compared to heterozygous siblings. Some TRPC2-class growth cones ectopically enter the dorsal-medial region of the bulb in both groups, but in fully mutant embryos, they are less likely to correct the error through retraction. The same result was observed when TRPC2-class growth cone behavior was compared between sema3fa heterozygous and sema3fa mutant larvae. CONCLUSIONS: Our results suggest that nrp2a and nrp2b expressed in TRPC2-class OSNs help prevent their mixing with axon projections in OMP-specific protoglomeruli, and further, that sema3fa helps to exclude TRPC2-class axons by repulsion from the dorsal-medial bulb.

Icariin, an Up-and-Coming Bioactive Compound Against Neurological Diseases: Network Pharmacology-Based Study and Literature Review.

Icariin is a biologically active substance in Epimedii herba that is used for the treatment of neurologic disorders. However, a comprehensive analysis of the molecular mechanisms of icariin is lacking. In this review, we present a brief history of the use of icariin for medicinal purposes; describe the active chemical components of Epimedii herba; and examine the evidence from experimental studies that have uncovered molecular targets of icariin in different diseases. We also constructed a protein-protein interaction network and carried out Gene Ontology and Kyoto Encyclopedia of Genes and Genomes functional enrichment analyses to predict the therapeutic actions of icariin in nervous system diseases including Alzheimer disease, Parkinson disease, ischemic stroke, depressive disorder, multiple sclerosis, glioblastoma, and hereditary spastic paraplegias. The results of our analyses can guide future studies on the application of icariin to the treatment of neurologic disorders.

Investigation of the Potential Mechanism Governing the Effect of the Shen Zhu San on COVID-19 by Network Pharmacology.

BACKGROUND: Since December 2019, coronavirus disease 2019 (COVID-19) due to SARS-CoV-2 infection has emerged in Wuhan and rapidly spread throughout China and even to other countries. Combined therapy with modern medicine and traditional Chinese medicine has been proposed, in which Shen Zhu San (SZS) was regarded as one of the basic prescriptions. METHODS: Network pharmacological approaches along with candidate compound screening, target prediction, target tissue location, protein-protein interaction network, gene ontology (GO), KEGG enrichment analyses, and gene microarray analyses were applied. RESULTS: A total of 627 targets of the 116 active ingredients of SZS were identified. Targets in immune cells and tissues were much more abundant than those in other tissues. A total of 597 targets were enriched in the GO biological cellular process, while 153 signaling pathways were enriched according to the KEGG analysis. A total of 450 SARS-related targets were integrated and intersected with the targets of SZS to identify 40 common targets that were significantly enriched in five immune function aspects of the immune system process during GO analysis. Several inflammation-related pathways were found to be significantly enriched throughout the study. CONCLUSIONS: The therapeutic mechanisms of the effects of SZS on COVID-19 potentially involve four effects: suppressing cytokine storms, protecting the pulmonary alveolar-capillary barrier, regulating the immune response, and mediating cell death and survival.

Abnormal Cullin1 neddylation-mediated p21 accumulation participates in the pathogenesis of recurrent spontaneous abortion by regulating trophoblast cell proliferation and differentiation.

The study explores the role of neddylation in early trophoblast development and its alteration during the pathogenesis of recurrent spontaneous abortion (RSA). Immunofluorescence and western blot were conducted to evaluate the expression pattern of NEDD8 protein in the first-trimester placentas of healthy control and RSA patients. Neddylated-cullins, especially neddylated-cullin1, were downregulated and their substrate, p21, was accumulated in RSA samples. NEDD8 cytoplasmic recruitment was observed in extravillous trophoblast (EVT) progenitors of RSA placentas. Consistent with the results of clinical samples, neddylation inhibition using MLN4924 in trophoblast cell lines caused obvious p21 accumulation and free NEDD8 cytoplasmic recruitment. Further in vitro study demonstrated neddylation inhibition attenuated proliferation of Jeg-3 cells via p21 accumulation. Moreover, when trophoblast stem (TS) cells derived from first-trimester placentas were cultured for differentiation analyses. MLN4924 impaired the differentiation of TS cells towards EVTs by downregulating HLA-G and GATA3. p21 knockdown could partly rescue MLN4924-suppressed HLA-G and GATA3 expression. In conclusion, cullin1 neddylation-mediated p21 degradation is required for trophoblast proliferation and can affect trophoblast plasticity by affecting HLA-G and GATA3 expression. The results provide insights into the pathological mechanism of RSA and the biological regulation of trophoblast development.

Intracellular ion and protein nanoparticle-induced osmotic pressure modify astrocyte swelling and brain edema in response to glutamate stimuli.

Intracellular tension activity plays a crucial role in cytotoxic brain edema and astrocyte swelling. Here, a few genetically encoded FRET-based tension probes were designed to detect cytoskeletal structural tension optically, including their magnitude and vectors. The astrocyte swelling resulted in GFAP tension increment, which is associated with the antagonistic effect of inward microfilaments (MFs) and microtubules (MTs) forces. In glutamate-induced astrocyte swelling, GFAP tension rise resulted from outward ion and protein nanoparticle-induced osmotic pressure (PN-OP) increases, where PN-OP could be elicited by MF and MT depolymerization, protein nanoparticle production, and activation of cofilin and stathmin-1. Attenuation of both ion osmotic pressure and PN-OP by drug combinations, together with free-radical scavenger, relieved cerebral edema in vivo. The study suggests that intracellular osmotic pressure (especially PN-OP) has a pivotal role in glutamate-induced astrocyte swelling and brain edema. Recovery of cytoplasmic potential is a promising target to develop new drugs and cure brain edema.

Design, synthesis, and evaluation of VEGFR-targeted macromolecular MRI contrast agent based on biotin-avidin-specific binding.

Developing magnetic resonance imaging (MRI) contrast agents with high relaxivity and specificity was essential to increase MRI diagnostic sensitivity and accuracy. In this study, the MRI contrast agent, vascular endothelial growth factor receptor (VEGFR)-targeted poly (l-lysine) (PLL)-diethylene triamine pentacetate acid (DTPA)-gadolinium (Gd) (VEGFR-targeted PLL-DTPA-Gd, VPDG), was designed and prepared to enhance the MRI diagnosis capacity of tumor. Biotin-PLL-DTPA-Gd was synthesized first, then, VEGFR antibody was linked to biotin-PLL-DTPA-Gd using biotin-avidin reaction. In vitro cytotoxicity study results showed that VPDG had low toxicity to MCF-7 cells and HepG2 cells at experimental concentrations. In cell uptake experiments, VPDG could significantly increase the internalization rates (61.75%±5.22%) in VEGFR-positive HepG2 cells compared to PLL-DTPA-Gd (PDG) (25.16%±4.71%, P<0.05). In MRI studies in vitro, significantly higher T1 relaxivity (14.184 mM-1 s-1) was observed compared to Magnevist® (4.9 mM-1 s-1; P<0.01). Furthermore, in vivo MRI study results showed that VPDG could significantly enhance the tumor signal intensity and prolong the diagnostic time (from <1 h to 2.5 h). These results indicated that macromolecular VPDG was a promising MRI contrast agent and held great potential for molecular diagnosis of tumor.

Maternal common variant rs2305957 spanning PLK4 is associated with blastocyst formation and early recurrent miscarriage.

OBJECTIVE: To investigate whether the common variant rs2305957 spanning PLK4 (Polo-like kinase 4) confers risk to embryo development in Northern Chinese Han (CHN) women. DESIGN: Genetic association study. SETTING: University hospital. PATIENT(S): A total of 2,015 infertile women who underwent in vitro fertilization (IVF), 530 women with early recurrent miscarriage (ERM), and 600 fertile control women in the CHN population. INTERVENTION(S): Genotyping of rs2305957 was performed by means of high-resolution melting analysis. MAIN OUTCOME MEASURE(S): Blastocyst formation, implantation, early miscarriage, and live birth rates in infertile women; genotype distribution at rs2305957 in ERM case and control subjects. RESULT(S): In the first cohort of this study, infertile women with AA genotype had a lower blastocyst formation rate than those with AG or GG genotype. No significant differences were observed in implantation rate, early miscarriage rate, or live birth rate among AA, AG, and GG subgroups. In the second cohort, common variant rs2305957 was related to ERM. Genotype frequency differences were also significant in both additive model and dominant model. CONCLUSION(S): Common variant rs2305957 is associated with blastocyst formation and ERM in CHN women. Further investigations of PLK4 gene during embryo development could be worthwhile.

The impact of serum uric acid on the natural history of glomerular filtration rate: a retrospective study in the general population.

Serum uric acid (SUA) level has been proposed to have important connections with chronic kidney disease (CKD), while the impact of SUA level on the natural history of glomerular filtration rate (GFR) decline remains unknown. The present study aims to study the association of the SUA level with the GFR decline in a general population. Two thousand, seven hundred and eighty-nine subjects who visited the Health Checkup Clinic both at 2008 and 2013 were identified. A significant inverse correlation was observed between change in SUA from 2008-2013 (ΔSUA) and change in eGFR (ΔeGFR) during the same period. Multivariate regression analysis of ΔeGFR indicated that the increase in SUA over time were a negative predictor of the change in eGFR. Our result indicates that the decline of eGFR over years is larger in subjects with an increased SUA level, which helps to underline the importance of SUA level management in the context of kidney function preservation.