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To determine the fetal ultrasound findings associated with Sotos syndrome caused by deletions at 5q35 including the NSD1 and a point mutation in this gene.This was a retrospective study of eight pregnancies with fetal Sotos syndrome identified by chromosomal microarray (CMA)/whole exome sequencing (WES). Clinical and laboratory data were collected and reviewed for these cases.Two cases had no significant fetal abnormalities, and were only diagnosed after birth. One case presented in the first trimester with increased nuchal translucency. The remaining five fetuses were identified at late gestation. One of the five fetuses presented in the second trimester with mild ventriculomegaly, and four in the third trimester with mild ventriculomegaly, macrocephaly and polyhydramnios. CMA was done on all cases and revealed 5q35 deletions in seven cases, and WES detected a maternally inherited NSD1 variant in one case.The fetal ultrasound findings in cases with Sotos syndrome, associated with deletions at 5q35 and a point mutation in the NSD1 are not specific with the most common finding being mild ventriculomegaly.

An intramolecular selenocyclizations of olefins mediated by a commercially available hypervalent iodine(III) reagent, PhIO, was developed. This method provided access to a wide range of selenenylated heterocycles under ambient conditions. The striking advantages of this protocol over all previous methods include mild reaction conditions, easy operation, good yields, high levels of functional group compatibility, large–scale application and suitability for the late-stage functionalization of complex molecules of biological importance.

Raffinose and its precursor galactinol accumulate in plant leaves during abiotic stress. RAFFINOSE SYNTHASE (RAFS) catalyzes raffinose formation by transferring a galactosyl group of galactinol to sucrose. However, whether RAFS contributes to plant drought tolerance and, if so, by what mechanism remains unclear. In this study, we report that expression of RAFS from maize (or corn, Zea mays) (ZmRAFS) is induced by drought, heat, cold, and salinity stresses. We found that zmrafs mutant maize plants completely lack raffinose and hyper-accumulate galactinol and are more sensitive to drought stress than the corresponding null-segregant (NS) plants. This indicated that ZmRAFS and its product raffinose contribute to plant drought tolerance. ZmRAFS overexpression in Arabidopsis enhanced drought stress tolerance by increasing myo-inositol levels via ZmRAFS-mediated galactinol hydrolysis in the leaves due to sucrose insufficiency in leaf cells and also enhanced raffinose synthesis in the seeds. Supplementation of sucrose to detached leaves converted ZmRAFS from hydrolyzing galactinol to synthesizing raffinose. Taken together, we demonstrate that ZmRAFS enhances plant drought tolerance through either raffinose synthesis or galactinol hydrolysis, depending on sucrose availability in plant cells. These results provide new avenues to improve plant drought stress tolerance through manipulation of the raffinose anabolic pathway.

Extracts of Aquilaria sinensis possess pharmacological activity that has been widely used in traditional medicines since ancient times. In this study, techno-economic assessment was conducted for extraction of volatile oil from abundant biomass (lignified ring) and resin of A. sinensis to evaluate their respective economic feasibility using supercritical carbon dioxide (SC-CO2) extraction in Malaysia. The assessment revealed that for a production capacity of 5280 kg/y volatile oil, the total capital investment (TCI) was $ 7.11 million from summation of fixed capital cost and working capital. In terms of operating expenditure (OPEX), the volatile oil extracted from resin and lignified ring of A. sinensis required $ 81.96 million and $ 52.39 million, respectively. The selling price of volatile oil from resin and lignified ring were estimated to be $ 0.025 million/kg and $ 0.0125 million/kg, respectively. Both volatile oil extracted from resin and lignified ring showed a positive net profit which indicated their profitability. In addition, a cradle-to-gate analysis of life-cycle assessment (LCA) was performed, whereby the extraction process contributed the highest impact towards the environment due to its high energy consumption. Nevertheless, this study estimated that the process might reduce the environmental impacts by approximately 90% when the technology readiness levels (TRLs) reach the level of 9–10. These findings are beneficial in providing preliminary insights in terms of economic and environmental aspects for volatile oil extraction using SC-CO2 technology.

A series of novel nitric oxide (NO)-releasing 5,8-quinolinedione/furoxan hybrids (8a-h and 9a-h) were designed and synthesized through coupling different alkanolamine substituted phenylsulfonyl furoxan with 5,8-quinolinedione. Most compounds displayed high cytotoxic activity against drug-sensitive/-resistant cancer cells. In particular, the ICsub50/subof 9a (0.42 µM) was about 9-fold lower than that of β-lap (3.69 µM) and 12-fold lower than that of SAHA (5.24 µM) in drug-resistant cancer cells. Also, 9a was demonstrated to selectively inhibit the growth of Bel7402/5-FU cancer cells. Mechanistic studies demonstrated that 9a could serve as an NO donor and nicotinamide quinone oxidoreductase 1 (NQO1) inhibitor (ICsub50/sub = 0.8 µM), which could induce the highest level of NO and reactive oxygen species (ROS) in Bel-7402/5-FU cancer cells. Furthermore, 9a could promote tumor cell apoptosis and autophagy via regulation of apoptosis-related protein (Bax, Bcl-2, and Caspase 3) and autophagy-associated proteins (LC3 and p62) in Bel-7402/5-FU cells. Taken together, 9a may be considered as a promising candidate for a further comprehensive study involving drug-resistant hepatocellular carcinoma.

Computer-aided drug design and structure-based drug design techniques were used to find 18 novel hydrazidoarylaminopyrimidine-based BTK/FLT3 dual inhibitors. At 1 μM and 0.05 μM, the majority of the target compounds inhibited BTK and FLT3 by more than 80%, respectively. Among these, compound RSH-7 inhibited BTK and FLT3 most effectively, with IC

Natural pyrites contain high contents of adsorbed and structurally-incorporated arsenic (As), which may in turn affect the oxidation rates of pyrite as well as the transformation and immobilization behaviors of As contaminants. However, the speciation and distribution of As on the oxidation reactivity of pyrites is still not clear yet. In this study, the oxidation reactivity of three different pyrites, namely, pure pyrite (Py-free), As(III)-adsorbed pyrite [Py*-As(III)ad] and As(III)-structurally-incorporated pyrite [Py-As(III)in, including Py-0.02 and Py-0.04] will be compared. In Py-As(III)in, As(III) replaces S(-I) and changes the relative ratio of Fe: S. The XPS results reveal that Fe(III)-S(-II) site densities on the pyrite surface increase with incorporated As, indicating that Py-As(III)in with more As carries more surface defects. The oxidation rates of pyrites are accelerated at pHs 7.0 and 9.0 by both structurally-incorporated and adsorbed As(III), which is more significant in structurally-incorporated As(III). At pH 2.5, structurally-incorporated As(III) promotes the oxidation of pyrite, whereas adsorbed As(III) inhibits its oxidation. The Tafel plots and the electrochemical impedance spectroscopy (EIS) analysis further support that As in Py-As(III)in decreases the charge transfer resistance on the pyrite surface and facilitates electron transfer between dissolved oxygen (DO) and the pyrite surface, thus enhancing the oxidation rates of pyrites. Variations of H2O2 in Py-As(III)in in the full pH range also indicate that As increases the two-electron transfer from pyrite to DO, resulting in the formation of more H2O2. At pH 2.5, the generated OH from H2O2 is the predominant species in pyrite oxidation, and at pHs 7.0 and 9.0, H2O2, Fe(IV) and OH all contribute to pyrite oxidation. Compared with Py-As(III)in, As in Py*-As(III)ad is more readily to be mobilized, with more As(V) being detected at pH 2.5. Subsequent decreases of As(III) and As(V) suggest re-immobilization of the released As via the adsorption or co-precipitation pathways. Solid characterizations further reveal that dissolved or adsorbed As(III) significantly inhibit the development of lepidocrocite, goethite and magnetite, whereas structurally-incorporated As(III) does not, triggering differences in the speciation of secondary Fe minerals. The present study reveals that the speciation and distribution of As(III) significantly affects the chemical and electronic properties of different pyrites, thus affecting the corresponding oxidation reactivity of different pyrites.

Ghrelin(1–7)-NH2 is the active N-terminal hepta-peptide of ghrelin as an agonist at the ghrelin receptor GHS-R1α. The biological functions of ghrelin(1–7)-NH2 have not been well investigated. Therefore in this study, we were interested in exploring the effects and molecular mechanisms of ghrelin(1–7)-NH2 in pain modulation at the supraspinal level using the tail withdrawal test in mice. Intracerebroventricular (i.c.v.) injection of ghrelin(1–7)-NH2 (0.002, 0.02, 0.2 and 2 nmol/kg) induced a dose- and time-related antinociceptive effect. This antinociceptive effect was fully antagonized by co-injection with the GHS-R1α antagonist [D-Lys3]-GHRP-6, indicating that this effect induced by ghrelin(1–7)-NH2 was mediated through the activation of GHS-R1α. Interestingly, naloxone, β-funaltrexamine, naloxonazine, and naltrindole, but not nor-binaltorphimine, could also antagonize the antinociceptive effect markedly, suggesting that OPRM (primary μ1 subtype) and OPRD were involved in the antinociceptive response induced by ghrelin(1–7)-NH2. Furthermore, the qRT-PCR and Western blot results indicated that both mRNA and protein levels of PENK and OPRD were up-regulated significantly. Using the fluorescence labeling method, our results showed that ghrelin(1–7)-NH2 (i.c.v.) was mainly distributed at the dorsal 3rd ventricle and hippocampus where there are regions with high expressions of ghrelin, GHS-R1α and ORs. All these results indicated that ghrelin(1–7)-NH2 initially activated the GHS-R1α, then activated the OPRM, as well as increased the release of endogenous PENK to activate of OPRD to produce antinociception. These results contributed to understanding the mechanisms of antinociception induced by ghrelin(1–7)-NH2. Furthermore, ghrelin(1–7)-NH2 as the active fragment of ghrelin may be a promising peptide for developing new analgesic drugs.

Accumulating evidences suggest that heat shock protein 60 (HSP60) and toll-like receptor 4 (TLR4) are involved in triggering inflammatory response in microglia. Paraquat (PQ) evokes microglial inflammation by up-regulating expression of HSP60-TLR4-myeloid differentiation factor 88 (Myd88)-nuclear factor-kappa B (NF-κB) in vitro. The aim of this study is to investigate the potential modulatory roles of HSP60 and TLR4 in PQ-induced inflammation. Before treated with PQ, microglia BV2 cells were pretreated using siRNA to knockdown HSP60 or with specific inhibitor to inhibit TLR4 expression. Expression of TLR4 and MyD88, and nuclear translocation of NF-κB subunit p65 were studied with immunoblotting and immunofluorescence, respectively. Expression of pro-inflammatory factors was assessed with quantitative real-time PCR. Knockdown of HSP60 or inhibition of TLR4 significantly reduced the expression of TLR4 and MyD88 and decreased the accumulation of NF-κB p65 in the nucleus. Gene expression of tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), interleukin-6 (IL-6) and inducible nitric oxide synthase (iNOS) were also significantly decreased in response to PQ. These results suggest that HSP60 and TLR4 can modulate intracellular signaling of PQ-induced inflammation. Inhibiting HSP60 or TLR4 reduces significantly the intensity of inflammation in PQ-activated microglia.

Activated microglia play an active role in the pathogenesis of PD and paraquat (PQ) induces PD. The study was to understand the time relationship between microglial activation and dopaminergic neuron loss in the substantia nigra (SN) of PQ-induced PD mice. Male C57BL/6 mice were injected intraperitoneally with PQ, twice a week for six weeks. Some mice underwent behavioral assessments each week and were sacrificed for SN tissues, in which histopathological analysis, dopaminergic neuron loss, microglial activation and phenotypic characteristics were evaluated. The results showed that motor retardation, coordination disorders and limb stiffness occurred four weeks after PQ exposure, as well as the degeneration and loss of dopaminergic neurons in the SN. Activated microglia and increased CD68 expression appeared two weeks after PQ exposure in time-dependent manners. Increased CD86 and decreased CD206 expression were observed four weeks after PQ exposure, accompanied by increased TNF-α and IL-6 levels and decreased IL-10 and TGF-β levels. These results indicate that PQ can activate microglia in vivo, and microglial activation precedes neuronal loss in the SN. Activated microglia are characterized by mixed M1/M2 polarization in the early stage and M1 polarization in the late stage of PQ-induced PD development.

A new type of steel-UHPC composite slabs (SUCS) with PBL shear connectors are used as bridge decks in an ultra-long-span composite cable-stayed bridge under construction in China. SUCS can be prefabricated in the factory and then transported to the construction site for assembly. The steel parts of the adjacent SUCS shall be welded together and UHPC wet joints, which are the weak parts of the bridge deck, shall be cast in-situ to finish the assembly. Full-scale tests of three SUCS with dovetail-shaped wet joint or newly-proposed construction-friendly rectangular wet joint were conducted to investigate the flexural behavior under hogging moment. Flexural failure of the interface section occurred in all specimens. The ultimate capacity and crack resistance of rectangular wet joints can be close to the dovetail-shaped wet joints with the same notch length. The phenomenon that tenons were pulled out from the rectangular notch appeared in rectangular wet joints during loading, which was especially prominent when the notch length was short, and the ultimate capacity and crack resistance would be reduced. Experimental results showed significant differences between cracking behavior of the interface and the non-interface, revealing the importance influence of wet joints on durability. The ultimate capacity was analyzed theoretically, and discussions were made on the reduction of ultimate capacity caused by wet joints. In addition, a crack width prediction model was obtained by modifying the model in GB50010-2010, which was based on the comprehensive analysis method combining bond-slip method and non-slip method. The modified model can give satisfactory prediction results of crack width for both interfacial and non-interfacial cracks.