Image_1_Efficiency and safety of vitrification of surplus oocytes following superovulation: a comparison of different clinical indications of oocyte cryopreservation in IVF/ICSI cycles.jpeg

ObjectiveTo evaluate the effectiveness and safety of utilizing the small number of remaining vitrified oocytes after the failure of adequate fresh sibling oocytes. The outcome of present study would provide more comprehensive information about possible benefits or disadvantage to cryopreserve supernumerary oocytes for patients who have plenty oocytes retrieved.MethodsThis retrospective cohort study included 791 IVF/ICSI cycles using 6344 oocytes that had been vitrified in the Reproductive Hospital affiliated to Shandong University between January 2013 and December 2019.They were divided into three groups: SOC group (supernumerary oocytes cryopreservation), relative-MOC group (relative male factor-oocyte cryopreservation), and absolute-MOC group (absolute male factor-oocyte cryopreservation). Laboratory and clinical outcomes were analysed, and multivariate regression analysis was used to study the effect of different indications of vitrification on CLBR.ResultsThe CLBR was highest in absolute-MOC, and lowest in SOC (39.0% vs 28.9%, P=0.006); however, after adjusting for confounding factors, the difference was not statistically significant. Multivariable regression analysis showed no impact of indications of vitrified oocytes on CLBR according to controlled age, BMI, preservation duration, use of donor sperm or not, use of PESA/TESA or not, number of oocytes retrieved, number of oocytes thawed, and oocyte survival rate. The preliminary data of safety showed no significant differences in the perinatal and neonatal outcoms after ET and FET between the SOC and MOC groups.ConclusionDifferent indications of vitrification did not affect CLBR. The CLBR of vitrified oocytes for different indications was correlated with age and number of warmed oocytes. For women who have plenty oocytes retrieved, the strategy of cryopreserving a small number of oocytes is a valuable option and might benefit them in the future. Additional data from autologous oocyte vitrification research employing a large-scale and variable-controlled methodology with extending follow-up will complement and clarify the current results.</p

Highly Stretchable, Soft, Low-Hysteresis, and Self-Healable Ionic Conductive Elastomers Enabled by Long, Functional Cross-Linkers

Herein, a novel strategy has been developed for the preparation of high-performance conductive elastomers featuring long functional polymer cross-linkers. The macromolecular cross-linkers containing multi boronic ester bonds in the backbone were designed via thiol/acrylate reactions between poly(ethylene glycol) diacrylate (PEGDA) and a dithiol-containing boronic ester (BDB). The obtained PEG–BDB was copolymerized with n-butyl acrylate (n-BA) to provide PBA/PEG–BDB elastomers. The resultant elastomers exhibit combined desirable properties of high stretchability, low Young’s modulus, low hysteresis, and self-healing performance, simultaneously. To demonstrate their practical applications, sensors based on PBA/PEG–BDB were successfully attached onto diverse joints (wrist, elbow, and finger) of the puppet for real-time motion detection. What is more, the elastomer sensors could well recognize other human activities like writing. This work offers a new design strategy for flexible sensors by optimizing the cross-linked dimension with long functional polymer chains as cross-linkers

Zhang et al. Plos One manuscript data

Cobalamin and thiol metabolite data are provided for the specified Figures

Maternal haemoglobin concentration and risk of preterm birth in a Chinese population

<p>The aim was to examine the relationship between maternal haemoglobin (Hb) concentrations and risk of preterm birth by secondary analysis of data from a randomised controlled trial. This analysis included 10,430 women who were at least 20 years old and no more than 20 weeks of gestation. Results revealed neither first- nor second-trimester Hb concentrations were associated with the risk of preterm births. However, the risk of preterm birth increased when the Hb level was low (<130 g/L) in the first but high (≥130 g/L) in the second trimester, regardless of supplement type (iron-containing: AOR: 2.26, 95% CI: 1.37–3.73; non-iron-containing: AOR: 2.16, 95% CI: 1.11–4.21). In conclusion, maternal Hb concentrations were not associated with the risk of preterm birth. A low-Hb level in the first trimester but coupled with a high Hb level in the second was associated with an elevated risk of preterm birth.Impact statement</p><p><b>What is already known on this subject:</b> The relationship between maternal Hb concentration and preterm birth remains inconclusive. Some studies have shown an association between a low- or a high-Hb level and an increased risk of preterm birth. Others have not found such an association. Yet others have shown a U-shaped relationship.</p><p><b>What do the results of this study add:</b> Overall, maternal Hb concentrations in first or second trimester were not statistically associated with the risk of preterm birth. However, women with a low Hb concentration in the first trimester together with a high Hb concentration in the second trimester had an increased risk of preterm birth, compared to women who had a higher Hb concentration in the first trimester that remained similar during the second trimester.</p><p><b>What are the implications are of these findings for clinical practice and/or further research:</b> Our finding helps identify mothers who are at risk of having a preterm delivery. Investigating the underlying clinical causes of the unfavourable change in Hb levels and close follow-up to these women may help improve birth outcomes.</p><p></p> <p><b>What is already known on this subject:</b> The relationship between maternal Hb concentration and preterm birth remains inconclusive. Some studies have shown an association between a low- or a high-Hb level and an increased risk of preterm birth. Others have not found such an association. Yet others have shown a U-shaped relationship.</p> <p><b>What do the results of this study add:</b> Overall, maternal Hb concentrations in first or second trimester were not statistically associated with the risk of preterm birth. However, women with a low Hb concentration in the first trimester together with a high Hb concentration in the second trimester had an increased risk of preterm birth, compared to women who had a higher Hb concentration in the first trimester that remained similar during the second trimester.</p> <p><b>What are the implications are of these findings for clinical practice and/or further research:</b> Our finding helps identify mothers who are at risk of having a preterm delivery. Investigating the underlying clinical causes of the unfavourable change in Hb levels and close follow-up to these women may help improve birth outcomes.</p

Table1_Assessing NH300094, a novel dopamine and serotonin receptor modulator with cognitive enhancement property for treating schizophrenia.DOCX

Background: Schizophrenia is a serious psychiatric disorder that significantly affects the quality of life of patients. The objective of this study is to discover a novel antipsychotic candidate with highly antagonistic activity against both serotonin and dopamine receptors, demonstrating robust efficacy in animal models of positive, negative, and cognitive symptoms of schizophrenia.Methods: In the present study, we examined the activity of antipsychotic drug (NH300094) on 5-HT2A, 5-HT2C, 5-HT1A, 5-HT1B, 5-HT7, H1, M1, Alpha1A, D2L, D2S, Alpha2A, D3 receptor functional assay in vitro. In addition, multiple animal models, including dizocilpine (MK-801) induced hyper-locomotion; APO induced climbing; Conditioned Avoidance Response (CAR); DOI-Induced Head Twitch; Forced swimming test; Scopolamine induced cognitive impairment model, were used to verify the antipsychotic activity of NH300094 in preclinical.Results:In vitro functional assays have indicated that NH300094 is a potent antagonist of 5-HT receptors and dopamine receptors, with higher relative antagonistic activity against 5-HT2A receptor (5-HT2A IC50 = 0.47 nM) than dopamine receptors (D2L IC50 = 1.04 nM; D2S IC50 = 11.71 nM; D3 IC50 = 31.55 nM). Preclinical in vivo pharmacological study results showed that NH300094 was effective in multiple models, which is more extensive than the clinic drug Risperidone. Furthermore, the safety window for extrapyramidal side effects of NH300094 is significantly wider than that of Risperidone (For NH300094, mice catalepsy model ED50/ Mice MK-801 model ED50 = 104.6-fold; for Risperidone, mice catalepsy model ED50/ Mice MK-801 model ED50 = 12.9-fold), which suggests a potentially better clinical safety profile for NH300094.Conclusion: NH300094 is a novel potent serotonin and dopamine receptors modulator, which has good safety profile and therapeutic potential for the treatment of schizophrenia with cognition disorders.</p

Cobalamin-related redox metabolic pathways in neuronal cells.

<p>Endocytosis brings TC-bound Cbl species to lysosomes where axial ligands are removed by MMACHC and MeCbl or AdoCbl are subsequently formed by SAM and ATP-dependent pathways, respectively. MeCbl is a required cofactor for methionine synthase, whose activity supports a large number of methylation reactions, including DNA methylation, as well as dopamine-stimulated phospholipid methylation, carried out by the D4 dopamine receptor (D4R). AdoCbl supports MMACoA mutase in mitochondria. Cysteine, which is rate-limiting for GSH synthesis, can be provided either by cellular uptake via the cysteine/glutamate transporter EAAT3 (excitatory amino acid transporter 3) or by transsulfuration of HCY via cystathionine. The latter pathway is restricted in human brain, increasing the importance of growth factor-dependent cysteine uptake by EAAT3.</p

No correlation between hsa-miR-148a level and CYP3A4 mRNA (A) or protein (B) levels in livers.

<p>No correlation between hsa-miR-148a level and CYP3A4 mRNA (A) or protein (B) levels in livers.</p

Image1_Assessing NH300094, a novel dopamine and serotonin receptor modulator with cognitive enhancement property for treating schizophrenia.tif

Background: Schizophrenia is a serious psychiatric disorder that significantly affects the quality of life of patients. The objective of this study is to discover a novel antipsychotic candidate with highly antagonistic activity against both serotonin and dopamine receptors, demonstrating robust efficacy in animal models of positive, negative, and cognitive symptoms of schizophrenia.Methods: In the present study, we examined the activity of antipsychotic drug (NH300094) on 5-HT2A, 5-HT2C, 5-HT1A, 5-HT1B, 5-HT7, H1, M1, Alpha1A, D2L, D2S, Alpha2A, D3 receptor functional assay in vitro. In addition, multiple animal models, including dizocilpine (MK-801) induced hyper-locomotion; APO induced climbing; Conditioned Avoidance Response (CAR); DOI-Induced Head Twitch; Forced swimming test; Scopolamine induced cognitive impairment model, were used to verify the antipsychotic activity of NH300094 in preclinical.Results:In vitro functional assays have indicated that NH300094 is a potent antagonist of 5-HT receptors and dopamine receptors, with higher relative antagonistic activity against 5-HT2A receptor (5-HT2A IC50 = 0.47 nM) than dopamine receptors (D2L IC50 = 1.04 nM; D2S IC50 = 11.71 nM; D3 IC50 = 31.55 nM). Preclinical in vivo pharmacological study results showed that NH300094 was effective in multiple models, which is more extensive than the clinic drug Risperidone. Furthermore, the safety window for extrapyramidal side effects of NH300094 is significantly wider than that of Risperidone (For NH300094, mice catalepsy model ED50/ Mice MK-801 model ED50 = 104.6-fold; for Risperidone, mice catalepsy model ED50/ Mice MK-801 model ED50 = 12.9-fold), which suggests a potentially better clinical safety profile for NH300094.Conclusion: NH300094 is a novel potent serotonin and dopamine receptors modulator, which has good safety profile and therapeutic potential for the treatment of schizophrenia with cognition disorders.</p

Linear correlation between PXR mRNA and protein levels in human liver samples.

<p>Linear correlation between PXR mRNA and protein levels in human liver samples.</p

The relative expression of <i>PXR</i>, <i>CYP3A4</i> and hsa-miR-148a in human liver samples.

<p>The relative RNA levels of mRNAs and miRNA were measured using qPCR with the normalization to the GAPDH mRNA level and the U6 snRNA level, respectively. The relative protein levels were measured using immunoblot with the normalization to the GAPDH protein level.</p