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Enantioselective cyclopropanation of α-carbonyl sulfoxonium ylides (SY) has so far been limited to addition/ring closure reactions on electron-poor olefins. Herein, we report the iridium-catalyzed intramolecular cyclopropanation of SY in the presence of a chiral diene in up to 96% yield and 98% enantioselectivity. Moreover, density functional theory calculations suggest that the re face of the olefin preferably attacks an iridium carbene intermediate in an asynchronous concerted step that is independent of the geometry of the olefin.

Sodium ferulate (SF) is the sodium salt of ferulic acid, which is one of the effective components of Angelica sinensis and Lignsticum chuanxiong , and plays an important role in protecting the cardiovascular system. In this study, myocardial hypertrophy was induced by angiotensin II 0.1 μmol/L in neonatal Sprague-Dawley rat ventricular myocytes. Nine groups were designed, that is, normal, normal administration, model, L-arginine (L-arg 1000 μmol/L), SF (50, 100, 200 μmol/L) group, and N G -nitro-L-arg-methyl ester 1500 μmol/L combined with SF 200 μmol/L or L-arg 1000 μmol/L group, respectively. Cardiomyocyte hypertrophy was confirmed by observing histological changes and measurements of cell diameter, protein content and atrial natriuretic factor, and β-myosin heavy chain levels of the cells. Notably, SF could inhibit significantly myocardial hypertrophy of neonatal rat cardiomyocytes in a concentration-dependent manner without producing cytotoxicity, and the levels of nitric oxide, NO synthase (NOS), endothelial NOS, and cyclic guanosine monophosphate were increased, but the level of cyclic adenosine monophosphate was decreased in cardiomyocytes. Simultaneously, levels of protein kinase C beta, Raf-1, and extracellular regulated protein kinase 1/2 (ERK1/2) were downregulated, whereas levels of mitogen-activated protein kinase phosphatase-1 were significantly upregulated. All the beneficial effects of SF were blunted by N G -nitro-L-arg-methyl ester. Overall, these findings reveal that SF can inhibit angiotensin II-induced myocardial hypertrophy of neonatal rat cardiomyocytes, which is closely related to activation of endothelial NOS/NO/cyclic guanosine monophosphate, and inhibition of protein kinase C and mitogen-activated protein kinase signaling pathways.

Understanding mechanistic details of the nickel-catalyzed coupling reactions of Csp3 alcohol derivatives is key to developing selective reactions of this widely prevalent functional group. In this manuscript, we utilize a combination of experimental data and DFT studies to define the key intermediates, stereochemical outcome, and competing pathways of a nickel-catalyzed cross-electrophile coupling reaction of 1,3-dimesylates. Stereospecific formation of a 1,3-diiodide intermediate is achieved in situ by the Grignard reagent. The overall stereoablative stereochemical outcome is due to a nickel-catalyzed halogen atom abstraction with a radical rebound that is slower than epimerization of the alkyl radical. Finally, lifetimes of this alkyl radical intermediate are compared to radical clocks to enhance the understanding of the lifetime of the secondary alkyl radical.

Although the combination antiretroviral treatment (cART) has considerably lowered the risk of HIV associated dementia (HAD), the incidence of neurocognitive impairments(NCI) have not decreased likely due to the insidious and slow progressive nature of HIV infection. Recent studies show that the rest state functional magnetic resonance imaging (rs-fMRI) is a prominent technique in helping the non-invasive analysis of neucognitive impairment. Our study is to explore the neuroimaging characteristics among people living with HIV(PLW-HIV) with or without NCI in terms of cerebral regional and neural network by rs-fMRI, based on the hypothesis that HIV patients with and without NCI have independent brain imaging characteristics. 33 HIV subjects with NCI and 33 HIV subjects without NCI, classified into HIV-NCI group and HIV-control group respectively according to Mini-Mental State Examination(MMSE) results. The fraction amplitude of low-frequency fluctuation (fALFF) and functional connectivity (FC) were calculated to characterize the cerebral regional and neural network alterations. Finally, the correlation among fALFF/FC values in certain cerebral regions and clinical characteristics were calculated. Compared to the HIV-control group, the fALFF values of bilateral calcarine gyrus, bilateral superior occipital gyrus, left middle occipital gyrus, left cuneus in the HIV-NCI group were increased. The FC values between right superior occipital gyrus and right olfactory cortex, bilateral gyrus rectus, right orbital part of middle frontal gyrus in the HIV-NCI group were increased. The FC values between left hippocampus and bilateral medial prefrontal gyrus, bilateral superior frontal gyrus were decreased. The fALFF values of left cuneus in both two groups was negatively correlated with international HIV dementia scale scores (IHDS) (R=-0.255, P=0.037) ; The fALFF values of left calcarine gyrus in both two groups was negatively correlated with MMSE scores (R=-0.316, P=0.009) ; The FC values between right superior occipital gyrus and right olfactory cortex (R=-0.396, P=0.001) in both two groups was negatively correlated with MMSE scores. Our study showed that the abnormal fMRI patterns in specific brain regions of the occipital cortex, while the defects in brain network mostly associated with prefrontal cortex, were associated with HIV-related cognitive impairment. The variation of fALFF and FC in given brain regions can be used to distinguish HIV subjects with and without cognitive impairment.

International audience; We report a Rh(III)-catalyzed ortho-C-H bond functionalization of nitroarenes with 1,2-diarylalkynes and carboxylic anhydrides. The reaction unpredictably affords 3,3-disubstituted oxindoles with the formal reduction of the nitro group under redox-neutral conditions. Besides good functional group tolerance, this transformation allows the preparation of oxindoles with a quaternary carbon stereocenter using nonsymmetrical 1,2-diarylalkynes. This protocol is facilitated by the use of a functionalized cyclopentadienyl (Cp(TMP)*)Rh(III) [Cp(TMP)* = 1-(3,4,5-trimethoxyphenyl)-2,3,4,5-tetramethylcyclopentadienyl] catalyst we developed, which combines an electron-rich character with an elliptical shape. Mechanistic investigations, including the isolation of three rhodacyle intermediates and extensive density functional theory calculations, indicate that the reaction proceeds through nitrosoarene intermediates via a cascade of C-H bond activation─O-atom transfer─[1,2]-aryl shift─deoxygenation─N-acylation.

We report that structurally complex guanidinium heterocycles can be prepared in one step by regio- and stereoselective [4 + 2]-cycloadditions of N-amidinyliminium ions with indoles or benzothiophene. In contrast to reactions of these heterodienes with alkenes, density functional theory (DFT) calculations show that these cycloadditions take place in a concerted asynchronous fashion. The [4 + 2]-cycloaddition of N-amidinyliminium ions (1,3-diaza-1,3-dienes) with indoles and benzothiophene are distinctive, as related [4 + 2]-cycloadditions of N-acyliminium ions (1-oxa-3-aza-1,3-dienes) are apparently unknown.

The effects of local factors on activation of immune cells infiltrating the central nervous system (CNS) in a rat model of traumatic brain injury (TBI) remain elusive. The cytokine, interleukin (IL)-15, is crucial for development and activation of CD8 T lymphocytes, a prominent lymphocytic population present in TBI lesions. We investigated whether IL-15 originates from astrocytes and whether IL-15 can evoke the CD8 T-lymphocyte response in TBI. We observed that astrocytes were activated in a rat model of TBI and that IL-15 was overexpressed on the surface of astrocytes. Further, CD8 T lymphocytes infiltrating TBI lesions colocalized with IL-15-expressing astrocytes. Activated CD8 T lymphocytes released granzyme B (Gra-b), which, in turn, activated caspase-3-induced poly(ADP-ribose) polymerase cleavage and, ultimately, neuronal apoptosis. Conversely, inhibition of astrocyte activation by pre-treatment with the specific inhibitor, fluorocitrate (FC), that reduces carbon flux through the Krebs cycle in astrocytes resulted in improved neurological function and memory. FC pre-treatment was also associated with downregulated IL-15 expression and CD8 T-cell activation as well as decreased levels of neuronal apoptosis, suggesting that IL-15 initiated a domino effect toward apoptosis. In contrast, rats pre-treated with recombinant rat IL-15 showed upregulated CD8 T-cell numbers and Gra-b levels, in addition to induction of neuronal apoptosis. Together, our results indicated that IL-15 could induce neuronal apoptosis by enhancing CD8 T-cell function in a rat model of TBI.

Parabens, as suspected endocrine disruptors, are widely used in personal care products and pharmaceuticals. However, variability, predictors, and risk assessments of human exposure to parabens are not well characterized.To evaluate within-day variability, predictors, and risk assessments of exposure to parabens among Chinese adult men.We measured four parabens including methylparaben (MeP), ethylparaben (EtP), propylparaben (PrP), and butylparaben (BuP) in repeated urine samples from 850 Chinese adult men. We examined the variability by intraclass correlation coefficients (ICCs) and identified the predictors by multivariable linear mixed models. We assessed risks of paraben exposures based on the estimated daily intake (EDI).The four parabens were detected in76% of urinary samples. We observed fair to good to high reproducibility (ICCs: 0.71 to 0.86) for urinary paraben concentrations within one day. Use of facial cleanser was associated with higher four urinary paraben concentrations. Increasing age, taking medicine, intravenous injection, and interior decoration in the workplace were related to higher urinary concentrations of specific parabens. Smoking and drinking were associated with lower urinary concentrations of specific parabens. The maximum EDIs for the four parabens ranged from 13.76 to 848.68 μg/kg bw/day, and 0.9% of participants had the hazard quotient values 1 driven by PrP exposure.Urinary paraben concentrations were less variable within one day. Several lifestyle characteristics including use of facial cleanser and pharmaceuticals may contribute to paraben exposures.

We examine the theoretical underpinnings of the seminal discoveries by Reiner Sustmann about the ambiphilic nature of Huisgen's phenyl azide cycloadditions. Density functional calculations with ωB97X-D and B2PLYP-D3 reproduce the experimental data and provide insights into ambiphilic control of reactivity. Distortion/interaction-activation strain and energy decomposition analyses show why Sustmann's use of dipolarophile ionization potential is such a powerful predictor of reactivity. We add to Sustmann's data set several modern distortion-accelerated dipolarophiles used in bioorthogonal chemistry to show how these fit into the orbital energy criteria that are often used to understand cycloaddition reactivity. We show why such a simple indicator of reactivity is a powerful predictor of reaction rates that are actually controlled by a combination of distortion energies, charge transfer, closed-shell repulsion, polarization, and electrostatic effects.

Background: Long-term morphine use is associated with serious side effects, such as morphine-induced hyperalgesia and analgesic tolerance. Previous investigations have documented the association between dopamine (DA) neurons in the ventral tegmental area (VTA) and pain. However, whether VTA DA neurons are implicated in morphine-induced hyperalgesia and analgesic tolerance remains elusive. Methods: Initially, we observed behavioural effects of lidocaine administration into VTA or ablation of VTA DA neurons on morphine-induced hyperalgesia and anti-nociceptive tolerance. Subsequently, c-Fos expression in nucleus accumbens (NAc) shell-projecting and medial prefrontal cortex (mPFC)-projecting VTA DA neurons after chronic morphine treatment was respectively investigated. Afterwards, the effects of chemogenetic manipulation of NAc shell-projecting or mPFC-projecting DA neurons on morphine-induced hyperalgesia and anti-nociceptive tolerance were observed. Additionally, effects of chemogenetic manipulation of VTA GABA neurons on c-Fos expression in VTA DA neurons were investigated. Results: Lidocaine injection into VTA relieved established hyperalgesia and anti-nociceptive tolerance whereas ablation of VTA DA neurons prevented the development of morphine-induced hyperalgesia and anti-nociceptive tolerance. Chronic morphine treatment increased c-Fos expression in NAc shell-projecting DA neurons, rather than in mPFC-projecting DA neurons. Chemogenetic manipulation of NAc shell-projecting DA neurons had influence on morphine-induced hyperalgesia and tolerance. However, chemogenetic manipulation of mPFC-projecting DA neurons had no significant effects on morphine-induced hyperalgesia and anti-nociceptive tolerance. Chemogenetic manipulation of VTA GABA neurons affected the c-Fos expression in VTA DA neurons. Conclusions: These findings revealed the involvement of NAc shell-projecting VTA DA neurons in morphine-induced hyperalgesia and anti-nociceptive tolerance, and may shed new light on the clinical management of morphine-induced hyperalgesia and analgesic tolerance. Perspective: This study demonstrated that NAc shell-projecting DA neurons rather than mPFC-projecting DA neurons in the VTA were implicated in morphine-induced hyperalgesia and anti-nociceptive tolerance. Our findings may pave the way for the discovery of novel therapies for morphine-induced hyperalgesia and analgesic tolerance.

Background Epidemiological and experimental studies suggest that preeclampsia has a negative impact on maternity and offspring health. Previous studies report that dysregulation in utero-environment increases risk for elderly disease such as cardiovascular disease. However, the underlying mechanisms remain elusive. Specific microRNAs (miRNAs) are packaged in exosomes may regulate microvascular dysfunction in offspring of mothers with preeclampsia. The present study aimed to identify the differential expression profiles of microRNAs in the serum exosomes between patients with preeclampsia and normal pregnancies. Methods A comprehensive miRNA sequence-based approach was performed to compare exosomes carry miRNAs (Exo-miRNAs) expression levels in umbilical serum between normal and preeclampsia patients. Exosomes were isolated using the ExoQuick precipitation kit. Serum exosomes were then viewed under electron microscopy, and their characteristics determined by western blotting and nanoparticle-tracking analysis. Illumina platform was used to perform sequencing. Bioinformatics analysis was used to explore differentially expressed Exo-miRNAs in umbilical serum. Results Based on sequence similarity, 1733 known miRNAs were retrieved. Furthermore, 157 mature miRNAs in serum exosomes were significantly differential expressed between PE and those control groups (P2|FC| > 1). Out, of the 157 miRNAs, 96 were upregulated miRNAs whereas 61 miRNAs were downregulated. The 157 differentially expressed miRNAs targeted 51,424 differentially expressed genes. Functional analysis through KEGG pathway and Gene Ontology results uncovered that target genes of miRNAs with differential expression were significantly linked to several pathways and biological processes. Conclusion The findings of this study showed differential expression of umbilical serum Exo-miRNAs in normal compared with PE patients, implying that these Exo-miRNAs may associate with microvascular dysfunction in offspring of mothers with preeclampsia.

Whether intra-myocardial delivery of hydrogel can prevent post-infarct heart failure (HF) in a long follow-up period, especially after it is degraded, remains unclear. In this study, Dex-PCL-HEMA/PNIPAAm (DPHP) hydrogel was delivered into peri-infarct myocardium of rat when coronary artery was ligated, while PBS was employed as control. Twelve weeks later, compared with control, left ventricle remodeling was attenuated and cardiac function was preserved; serum brain natriuretic peptide, cardiac aldosterone, and pulmonary congestion were suppressed in hydrogel group. Pro-fibrogenic mRNA increased in infarct area while decreased in remote zone, as well as hypertrophic mRNA. These data proves DPHP hydrogel suppresses ventricular remodeling and HF by promoting fibrotic healing in infarct area and inhibiting reactive fibrosis and hypertrophy in remote zone. Timely intra-myocardial hydrogel implantation is an effective strategy to inhibit post-infarct cardiac remodeling and have a long-term beneficial effect even after it has been biodegraded.

Disinfection byproducts (DBPs) have been shown to alter ovarian steroidogenesis and cause estrous cyclicity disturbance and prolongation in experimental studies, however human studies are lacking. We aimed to evaluate the cross-sectional associations between drinking water DBPs and menstrual cycle characteristics. A total of 1078 women attending an infertility clinic in Wuhan, China were included between December 2018 and January 2020. Characteristics of menstrual cycle were collected by questionnaires. Concentrations of dichloroacetic acid (DCAA) and trichloroacetic acid (TCAA) were measured in urine as biomarkers of drinking water DBPs. Multivariate logistic and linear regression models were used to evaluate the associations between urinary DCAA and TCAA concentrations and menstrual cycle characteristics. Higher urinary DCAA concentrations were associated with increased odds ratios (ORs) of irregular menstrual cycle (OR = 1.80; 95% CI: 0.97, 3.33 for the highest vs. lowest quartile; P for trend = 0.05) and long menstrual cycle (OR = 1.62; 95% CI: 0.97, 2.70 for the highest vs. lowest quartile; P for trend = 0.06), as well as prolonged variation in cycle length (β = 1.27 days; 95% CI: -0.11, 2.66 for the highest vs. lowest quartile; P for trend = 0.04). Higher urinary TCAA concentrations were associated with prolonged bleeding duration (β = 0.23 days; 95% CI: -0.06, 0.51 for the highest vs. lowest quartile; P for trend = 0.07). These results suggest that exposure to drinking water DBPs is associated with menstrual cycle disturbances. These findings are warranted to confirm in other studies.

Posttraumatic stress disorder (PTSD) and other anxiety disorders stem from dysregulated fear memory in which the basolateral amygdala (BLA) plays an integral role. The excitability of glutamatergic neurons in the BLA correlates with fear memory, and the afterhyperpolarization current (IAHP) mediated by small-conductance calcium-activated potassium channel subtype 2 (SK2) dominates the excitability of glutamatergic neurons. However, definitive evidence for the involvement of the SK2 channel in the BLA in fear extinction is lacking. Here, we discovered that fear conditioning decreased the levers of synaptic SK2 channels in the BLA, which were restored following fear extinction. Notably, reduced expression of synaptic SK2 channels in the BLA during fear conditioning was caused by the increased activity of protein kinase A (PKA), while increased levers of synaptic SK2 channels in the BLA during fear extinction were mediated by interactions with membrane palmitoylated protein 2 (MPP2). Collectively, our results revealed that MPP2 interacts with the SK2 channels and rescues the excitability of glutamatergic neurons by increasing the expression of synaptic SK2 channels in the BLA to promote the normalization of fear memory. These findings expand our understanding of the neurobiological mechanism of PTSD and provide a new direction for PTSD treatment.

We report that structurally complex guanidinium heterocycles can be prepared in one step by regio- and stereoselective [4 + 2]-cycloadditions of

Disinfection by-products (DBPs) have been shown to impair female reproductive function. However, epidemiological evidence on reproductive hormones is scarce.To investigate the associations between DBP exposures and reproductive hormones among women undergoing assisted reproductive technology.We included 725 women from the Tongji Reproductive and Environmental (TREE) Study, an ongoing cohort conducted in Wuhan, China during December 2018 and January 2020. Urine samples collected at recruitment were quantified for dichloroacetic acid (DCAA) and trichloroacetic acid (TCAA) as biomarkers of DBP exposures. At day 2-5 of menstruation, serum reproductive hormones including luteinizing hormone (LH), estradiol (EAfter adjusting for relevant confounders, we observed that higher urinary DCAA levels were associated with increased serum PRGE (9.2%; 95% CI: -0.55%, 19.8% for the highest vs. lowest tertile; P for trend = 0.06). Based on NCS models, we observed U-shaped associations of urinary DCAA with serum PRGE and PRL; each ln-unit increment in urinary DCAA concentrations above 3.61 μg/L and 6.30 μg/L was associated with 18.9% (95% CI: 4.8%, 34.7%) and 23.3% (95% CI: -0.92%, 53.5%) increase in serum PRGE and PRL, respectively. The U-shaped associations were further confirmed in RCS models (P for overall association ≤0.01 and P for non-linear associations ≤0.04). We did not observe evidence of associations between urinary TCAA and reproductive hormones.Urinary DCAA but not TCAA was associated with altered serum PRGE and PRL levels among women undergoing assisted reproductive technology.

Background Preeclampsia and gestational hypertension can cause vascular function impairment in offspring. In our previous work, we described the protein expression profiles of umbilical artery tissues from patients with preeclampsia. Methods To gain insights into the mechanisms of vascular dysfunction in adult rats born to preeclamptic dams, we analyzed thoracic aorta tissues by using iTRAQ isobaric tags and 2D nano LC-MS/MS. Results By using the iTRAQ method, we analyzed 1825 proteins, of which 106 showed significantly different expression in the thoracic aortic. Ingenuity pathway analysis (IPA) showed that the majority of differentially expressed proteins (DEPs) were associated with cardiovascular function. Further analysis indicated that glucose-6-phosphate dehydrogenase (G6PD), which is inhibited by miR-423-5p and activated by TP53, had the strongest effect on cardiovascular function. The expression of G6PD was upregulated in thoracic aorta tissues, as confirmed by Western blotting. The expression of two other vascular function-related proteins, cysteine- and glycine-rich protein 2 (CSRP2) and tubulin alpha-4 A (TUBA4A), was upregulated, as demonstrated by mass spectrometry (MS). Conclusions Although the results require further functional validation, these data provide novel findings related to vascular function impairment in the adult offspring of preeclamptic mothers.

Background: Preeclampsia and gestational hypertension can cause impaired vascular function in offspring. In our previous work, we described the profiles of protein expression in umbilical artery tissues of patients with preeclampsia. Methods: In order to gain insights into the mechanisms of vascular dysfunction in adult rats born by preeclampsia dams, we present analysis of thoracic aortic tissues by using iTRAQ isobaric tags and 2D nano LC-MS/MS. Results: By using iTRAQ method, we analyzed 1825 proteins in which 106 proteins have shown significantly differential expression in thoracic aortic. Results from ingenuity pathway analysis (IPA) showed majority of proteins with differential expression (DEP)were associated with cardiovascular function. Further analysis indicated that glucose-6-phosphate dehydrogenase (G6PD), which is inhibited by miR-423-5p and activated by TP53, was most affect the cardiovascular function. The expression level of G6PD was up-regulated in thoracic aortic tissues as confirmed by western blot results. Two other vascular function proteins Cysteine and glycine-rich protein 2 (CSRP2) and Tubulin alpha-4A (TUBA4A) were upregulated as demonstrated by mass spectrometry (MS). Conclusions: Although the results need further functional validation, these data provide novel findings relating to impaired vascular function in adult offsprings of preeclamptic mothers.

Solvents act as a powerful control of stereospecificity in Ni-catalyzed Miyaura borylation of allylic pivalates. Low polar solvents lead to stereoretentive borylation, whereas highly polar solvents...

Ni-catalyzed C(sp(3))-O bond activation provides a useful approach to synthesize enantioenriched products from readily available enantioenriched benzylic alcohol derivatives. The control of stereospecificity is key to the success of these transformations. To elucidate the reversed stereospecificity and chemoselectivity of Ni-catalyzed Kumada and cross-electrophile coupling reactions with benzylic ethers, a combined computational and experimental study is performed to reach a unified mechanistic understanding. Kumada coupling proceeds via a classic cross-coupling mechanism. Initial rate-determining oxidative addition occurs with stereoinversion of the benzylic stereogenic center. Subsequent transmetallation with the Grignard reagent and syn reductive elimination produces the Kumada coupling product with overall stereoinversion at the benzylic position. The cross-electrophile coupling reaction initiates with the same benzylic C-O bond cleavage and transmetallation to form a common benzylnickel intermediate. However, the presence of the tethered alkyl chloride allows a facile intramolecular S(N)2 attack by the benzylnickel moiety. This step circumvents the competing Kumada coupling, leading to the excellent chemoselectivity of cross-electrophile coupling. These mechanisms account for the observed stereospecificity of the Kumada and cross-electrophile couplings, providing a rationale for double inversion of the benzylic stereogenic center in cross-electrophile coupling. The improved mechanistic understanding will enable design of stereoselective transformations involving Ni-catalyzed C(sp(3))-O bond activation.

Protein kinase C(PKC) is a kind of kinase which is widely involved in cell proliferation and development. PKC(Wp-PKC) in Whitmania pigra body belongs to classic PKC. In order to investigate the effect of Wp-PKC on the development of Wh. pigra germ cells, 17β-estradiol(17β-E2)(100 ng·mL~(-1)) and methyltestosterone(MT)(150 μg·L~(-1)), 150 μg·L~(-1)(MT)+0.5 mg·L~(-1) PKC, 0.5 mg·L~(-1) PKC inhibitor were added to Wh. pigra culture water, and no addition group(control group) was added, and the effects on the development of Wh. pigra germ cells and the expression of Wp-PKC were observed. The results showed that: Wp-PKC in male gonads was always higher than that in female gonads; MT promoted the development of male gonads in Wh. pigra, while the expression of Wp-PKC was significantly higher than that in the control; 17β-E2 promoted the development of female gonads in Wh. pigra and Wp-PKC expression significantly lower than that of the control; while the development of the female and male gonads in the PKC inhibitor group was inhibited, the expression of Wp-PKC was significantly lower than that of the control. In summary, Wp-PKC may promote the development of Wh. pigra, especially the development of male gonads.

Protein kinase C(PKC) is a type of protein kinase widely involved in cell proliferation and development, but the developmental mechanism in the gonads of androgynous animals is still unclear. In order to explore the role of protein kinase C in the development of Whitmania pigra germ cells, the Wh. pigra PKC(Wp-PKC) gene was cloned, bioinformatics analysis was conducted, and fluorescent quantitative PCR was used to analyze the expression of female and male gonads. The results showed that:(1)The cloned Wp-PKC had a full length of 2 580 bp, a relative molecular weight of 76 555.19, and contains an open reading frame encoding 670 amino acids, Wp-PKC was closely related to Danio rerio PKC-α and rat PKC-γ. The similarity of amino acid sequence was 55% and 58%.(2)The protein encoded by Wp-PKC had no signal peptide and was a hydrophilic protein. The secondary structure is mainly composed of random coils, α-helices, extended chains, folds and folds, with the largest proportion of random coils and α-helices. Wp-PKC protein does not contain a transmembrane domain. Multiple sequence alignment and domain prediction analysis show that Wp-PKC contains 4 conserved domains of classical protein kinase C.(3)Fluorescence quantitative results showed that the expression of Wp-PKC in Wh. pigra gonads was positively correlated with the development of germ cells, and the expression in male gonads was significantly higher than that in female gonads. In summary, Wp-PKC is a classic PKC, and Wp-PKC may promote the development of Wh. pigra, especially the development of male gonads, and provide references for further research on the developmental mechanisms of Wh. pigra.

Background: Bisphenol A (BPA) can cause detrimental effects on fetal growth. However, the effects of BPA alternatives, such as bisphenol F (BPF) and bisphenol S (BPS), on fetal growth are less known. Objective: To investigate the relationships of prenatal BPA, BPF, and BPS exposures with fetal growth parameters and gestational age. Methods: Urinary BPA, BPF, and BPS were measured in 1,197 pregnant women before delivery in a Chinese cohort. The associations of prenatal exposure to BPA, BPF, and BPS with fetal growth parameters and gestational age were examined, and associations stratified by fetal sex were also conducted. We used a restricted cubic splines (RCS) model to examine the dose–response associations between exposures and outcomes. Results: Maternal urinary BPA and BPF were negatively related to birth length (-0.30 cm, 95% CI: −0.44, −0.15 and −0.21 cm, 95% CI: −0.36, −0.07 comparing the extreme exposure groups, respectively, both p for trends

Supplemental material, sj-pdf-1-jop-10.1177_0269881120985183 for Projection-specific dopamine neurons in the ventral tegmental area participated in morphine-induced hyperalgesia and anti-nociceptive tolerance in male mice by Guo-Lin Sun, Zhi-Jing Song, Xiao-Han Peng, Pan-Pan Chen, Ying Song, Xia Qin, Rong Hua and Yong-Mei Zhang in Journal of Psychopharmacology

Organochlorine pesticides (OCPs) are endocrine-disrupting chemicals and may alter male reproductive hormone concentrations.To explore the associations between multiple OCP exposures and serum testosterone concentrations among Chinese men.We investigated 421 men who provided serum samples from an infertility clinic in Wuhan, China. Each man completed a questionnaire concerning demographic characteristics and lifestyle habits. Serum concentrations of 18 OCPs and total testosterone were measured. Linear regression models were used to explore whether serum OCP levels were associated with altered testosterone concentrations, and potential effect modifications by age and body mass index (BMI) were also examined.After adjusting for potential confounders, elevated dieldrin and p,p'-DDD levels had monotonically negative and positive exposure-response associations with testosterone concentrations, respectively (-30.98 ng/dL, 95% CI: -72.34, 10.37; P for trend = 0.12 and 41.31 ng/dL, 95% CI: -0.32, 82.93; P for trend = 0.06 for the highest vs. non-detectable exposure category, respectively). After stratification by age and BMI, dieldrin in relation to decreased testosterone concentrations was more pronounced among men aged30 years old, and p,p'-DDD in relation to increased testosterone concentrations was stronger among men aged ≥30 years old and among men with a BMI24 kg/mThe study found evidence that serum dieldrin and p,p'-DDD concentrations might be associated with altered serum testosterone concentrations.

Prenatal exposure to metals has been linked with adverse pregnancy outcomes. Oxidative stress and epigenetic changes are potential mechanisms of action.We aimed to examine the associations of individual and mixtures of metal exposures with oxidative stress and DNA methylation among pregnant women.We measured a panel of 16 metals and 3 oxidative stress biomarkers including 8-hydroxydeoxyguanosine (8-OHdG), 4-hydroxy-2-nonenal-mercapturic acid (HNE-MA) and 8-isoprostaglandin F2α (8-isoPGF2α) in urine from 113 pregnant women in a Chinese cohort. Biomarkers of global DNA methylation including Alu and long interspersed nucleotide element-1 (LINE-1) in cord blood were measured. Multivariable linear regression and Bayesian kernel machine regression (BKMR) models were separately applied to estimate the associations between individual and mixtures of metal exposures and biomarkers of oxidative stress and global DNA methylation.In single-metal analyses, we observed positive associations between 11 metals [arsenic (As), cadmium (Cd), thallium (Tl), barium (Ba), nickel (Ni), vanadium (V), cobalt (Co), zinc (Zn), copper (Cu), selenium (Se) and molybdenum (Mo)] and at least one of oxidative stress biomarkers (all FDR-adjusted P-values0.05). In mixture analyses, we found positive overall associations of metal mixtures with 8-OHdG and 8-isoPGF2α, and Se was the most important predictor. There was no evidence on associations of urinary metals as individual chemicals and mixtures with Alu and LINE-1 methylation.Urinary metals as individual chemicals and mixtures were associated with increased oxidative stress, especially Se.

Studies indicate that phthalates can disrupt spermatogenesis and lead to the reduction of semen quality. However, the underlying mechanisms remain unclear. This study aimed to examine the associations of phthalate exposures as individual chemicals and mixtures with spermatogenesis-related miRNA106a. We detected eight phthalate metabolites in repeated urine samples and a single seminal plasma specimen among 111 men from an infertility clinic in Wuhan, China. Spermatogenesis-related miRNA106a was measured in seminal plasma. We used multivariable linear regression and Bayesian kernel machine regression (BKMR) models to separately evaluate the associations of phthalate metabolites as individual chemicals and mixtures with spermatogenesis-related miRNA106a. Elevated tertiles of urinary mono (2-ethylhexyl) phthalate (MEHP) was associated with decreased miRNA106a (−61.71%; 95%CI: 81.92, −18.93% for the highest vs. lowest tertile; P for trend = 0.01). Similarly, an inverse exposure-response relationship between seminal plasma MEHP concentrations and miRNA106a was also observed (−59.44%; 95%CI: 79.19, −20.95% for the highest vs. lowest tertile; P for trend = 0.01). The BKMR models showed that the mixtures of seminal plasma phthalate metabolites were associated with decreased miRNA106a when the chemical mixtures were ≥35th percentile compared to their medians. Nonlinear associations with miRNA106a were estimated for urinary and seminal plasma MEHP while fixing other phthalate metabolites at their medians. Our findings suggest that mixtures of phthalate metabolites in seminal plasma were negatively associated with spermatogenesis-related miRNA106a, and individual MEHP was the major contributor to the adverse effects.

Background: ABCB1, EPHX1 and SCN1A gene polymorphisms have been reported play important roles in individual variability carbamazepine (CBZ) metabolism and resistance, but the result of that association still remains controversial. Objective: To clarify the associations among ABCB1, EPHX1 and SCN1A gene polymorphisms and CBZ metabolism and resistance. Methods: The PubMed, EMBASE, Cochrane library, Chinese National Knowledge Infrastructure, Chinese Science and Technique Journals Database, China Biology medicine disc and Wan Fang Database were searched for appropriate studies up to April 2020. Results: A total of 18 studies involving 3293 related epilepsy patients were included. ABCB1 c.3435C>T polymorphism was significantly associated with adjusted concentrations of CBZ (CC vs. CT, P=0.004), and EPHX c.416A>G polymorphism was significantly associated with carbamazepine-10, 11-trans dihydrodiol (CBZD) (AA vs. GG, P=0.045; AG vs. GG, P=0.010). Furthermore, ABCB1 c.3435C>T polymorphism was also observed to be significantly influenced CBZ resistance (CT vs TT, P=0.01; CC+CT vs TT, P=0.006). Conclusion: ABCB1 c.3435C>T polymorphism may affect the CBZ metabolism and resistance, EPHX1 c.416A>G polymorphism may only affect CBZ metabolism. These findings provided further evidence for individualized therapy of epilepsy patients in clinics. Nevertheless further large studies are still warranted to provide conclusive evidences.

Rolf Huisgen explored the Diels-Alder reactions of 1,3,5-cycloheptatriene (CHT) and cyclooctatetraene (COT) with the dienophiles maleic anhydride and 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD) to determine the kinetics and mechanisms of various electrocyclizations and Diels-Alder reactions. These reactions have been examined with density functional theory. Modern computational chemistry has provided information not previously available by experiment. Transition states for all the reactions have been identified, and their Gibbs energies are used to explain the experimental reactivities. Zwitterionic intermediates were not found in the [4+2] cycloadditions of both CHT or COT with PTAD and are thus not involved in these reactions. [2+2+2] cycloadditions, as an alternative path to the Diels-Alder products, are highly disfavored. Rapid double nitrogen inversion was found for the cycloaddition products with PTAD.

Cross-electrophile coupling reactions of two Csp(3)–X bonds remain challenging. Herein we report an intramolecular nickel-catalyzed cross-electrophile coupling reaction of 1,3-diol derivatives. Notably, this transformation is utilized to synthesize a range of mono- and 1,2-disubstituted alkylcyclopropanes, including those derived from terpenes, steroids, and aldol products. Additionally, enantioenriched cyclopropanes are synthesized from the products of proline-catalyzed and Evans aldol reactions. A procedure for direct transformation of 1,3-diols to cyclopropanes is also described. Calculations and experimental data are consistent with a nickel-catalyzed mechanism that begins with stereoablative oxidative addition at the secondary center.

Background Exposure to air pollution has been linked with altered immune function in adults, but little is known about its effects on early life. This study aimed to investigate the effects of exposure to air pollution during prenatal and postnatal windows on cell-mediated immune function in preschoolers. Methods Pre-school aged children (2.9 ± 0.5 y old, n = 391) were recruited from a mother-child cohort study in Wuhan, China. We used a spatial-temporal land use regression (LUR) model to estimate exposures of particulate matter with aerodynamic diameters ≤2.5 μm (PM2.5) and ≤10 μm (PM10), and nitrogen dioxide (NO2) during the specific trimesters of pregnancy and the first two postnatal years. We measured peripheral blood T lymphocyte subsets and plasma cytokines as indicators of cellular immune function. We used multiple informant models to examine the associations of prenatal and postnatal exposures to air pollution with cell-mediated immune function. Results Prenatal exposures to PM2.5, PM10, and NO2 during early pregnancy were negatively associated with %CD3+ and %CD3+CD8+ cells, and during late pregnancy were positively associated with %CD3+ cells. Postnatal exposures to these air pollutants during 1-y or 2-y childhood were positively associated with IL-4, IL-5, IL-6, and TNF-α. We also observed that the associations of prenatal or postnatal air pollution exposures with cellular immune responses varied by child's sex. Conclusions Our results suggest that exposure to air pollution during different critical windows of early life may differentially alter cellular immune responses, and these effects appear to be sex-specific.