Identification of Novel Biallelic TLE6 Variants in Female Infertility With Preimplantation Embryonic Lethality

Preimplantation embryonic lethality is a rare cause of primary female infertility. It has been reported that variants in the transducin-like enhancer of split 6 (TLE6) gene can lead to preimplantation embryonic lethality. However, the incidence of TLE6 variants in patients with preimplantation embryonic lethality is not fully understood. In this study, we identified four patients carrying novel biallelic TLE6 variants in a cohort of 28 patients with preimplantation embryonic lethality by whole-exome sequencing and bioinformatics analysis, accounting for 14.29% (4/28) of the cohort. Immunofluorescence showed that the TLE6 levels in oocytes from patients were much lower than in normal control oocytes, suggesting that the variants result in the lower expression of the TLE6 protein in oocytes. In addition, a retrospective analysis showed that the four patients underwent a total of nine failures of in vitro fertilization and intracytoplasmic sperm injection attempts, and one of them became pregnant on the first attempt using donated oocytes. Our study extends the genetic spectrum of female infertility caused by variants in TLE6 and further confirms previously reported findings that TLE6 plays an essential role in early embryonic development. In such case, oocyte donation may be the preferred treatment

Ligand recognition and G-protein coupling selectivity of cholecystokinin A receptor.

Cholecystokinin A receptor (CCKAR) belongs to family A G-protein-coupled receptors and regulates nutrient homeostasis upon stimulation by cholecystokinin (CCK). It is an attractive drug target for gastrointestinal and metabolic diseases. One distinguishing feature of CCKAR is its ability to interact with a sulfated ligand and to couple with divergent G-protein subtypes, including Gs, Gi and Gq. However, the basis for G-protein coupling promiscuity and ligand recognition by CCKAR remains unknown. Here, we present three cryo-electron microscopy structures of sulfated CCK-8-activated CCKAR in complex with Gs, Gi and Gq heterotrimers, respectively. CCKAR presents a similar conformation in the three structures, whereas conformational differences in the 'wavy hook' of the Gα subunits and ICL3 of the receptor serve as determinants in G-protein coupling selectivity. Our findings provide a framework for understanding G-protein coupling promiscuity by CCKAR and uncover the mechanism of receptor recognition by sulfated CCK-8

Palladium-catalyzed condensation of N-aryl imines and alkynylbenziodoxolones to form multisubstituted furans

A palladium(II) catalyst promotes condensation of an N-aryl imine and an alkynylbenziodoxolone derivative to afford a multisubstituted furan, whose substituents are derived from the alkynyl moiety (2-position), the imine (3- and 4-positions), and the 2-iodobenzoate moiety (5-position), along with an N-arylformamide under mild conditions. The 2-iodophenyl group of the furan product serves as a versatile handle for further transformations. A series of isotope-labeling experiments shed light on the bond reorganization process in this unusual condensation reaction, which includes cleavage of the C–C triple bond and fragmentation of the carboxylate moiety.NRF (Natl Research Foundation, S’pore)Accepted versio

Possible challenges faced by the knowledge manager : roles and competencies.

With the onset of the knowledge era, Knowledge management (KM) and thus knowledge manager have become very important for a company's success. In order to effectively implement KM practices, it is essential for the company to identify possible challenges of KM. As such, the purpose of this study is to discover some of these challenges so that the companies could be prepared beforehand

Controllable Construction of Temperature-Sensitive Supramolecular Hydrogel Based on Cellulose and Cyclodextrin

In temperature sensitive hydrogels, the swelling degree or light transmittance of the gel itself changes with variations in ambient temperature, prompting its wide application in controlled drug release, tissue engineering, and material separation. Considering the amphiphilic structure of β-cyclodextrin (β-CD), a cellulose-based supramolecular hydrogel with superior temperature sensitivity was synthesized based on a combination of cellulose and β-CD as well as the host–guest interaction between β-CD and polypropylene glycol (PPG). In the one-pot tandem reaction process, chemical grafting of β-CD on cellulose and the inclusion complexation of β-CD with PPG were performed simultaneously in a NaOH/urea/water system. The obtained supramolecular hydrogel had a lower critical solution temperature (LCST) of 34 °C. There existed covalent bonding between the cellulose and β-CD, host–guest complexation between the β-CD and PPG, and hydrogen bonding and hydrophobic interactions between the components in the network structure of the supramolecular hydrogel. The combination of various covalent and non-covalent bonds endowed the resulting supramolecular hydrogel with good internal network structure stability and thermal stability, as well as sensitive temperature responsiveness within a certain range—implying its potential as a smart material in the fields of medicine, biology, and textiles. This work is expected to bring new strategies for the fabrication of cellulose-based thermosensitive materials, benefitting the high-value utilization of cellulose

Mechanochemical Activation of Class-B G-Protein-Coupled Receptor upon Peptide–Ligand Binding

Glucagon binding to the class B G-protein-coupled glucagon receptor (GCGR) triggers the release of glucose from the liver during fasting. Recently, GCGR crystal structures have highlighted the conformation and molecular details of inactive and active receptor states. However, the dynamics of the conformational changes accompanying GCGR activation remains unclear. Here, we use multiplex force-distance curve-based atomic force microscopy (FD-based AFM) to probe in situ glucagon-binding to individual GCGRs and monitor dynamically the transition to the active conformer. After a “dock” step, in which glucagon is partially bound to the GCGR extracellular domain, further interactions of the N-terminus with the transmembrane domain trigger an increase in the stiffness of the complex adopting a highly stable and rigid “lock” conformer. This mechanotransduction is key for G-protein recruitment

Palladium-Catalyzed Condensation of <i>N</i>‑Aryl Imines and Alkynylbenziodoxolones To Form Multisubstituted Furans

A palladium­(II) catalyst promotes condensation of an <i>N</i>-aryl imine and an alkynylbenziodoxolone derivative to afford a multisubstituted furan, whose substituents are derived from the alkynyl moiety (2-position), the imine (3- and 4-positions), and the 2-iodobenzoate moiety (5-position), along with an <i>N</i>-arylformamide under mild conditions. The 2-iodophenyl group of the furan product serves as a versatile handle for further transformations. A series of isotope-labeling experiments shed light on the bond reorganization process in this unusual condensation reaction, which includes cleavage of the C–C triple bond and fragmentation of the carboxylate moiety