Bioconjugates are an important class of therapeutic molecules. To date,
O-
glycan-based metabolic glycoengineering has had limited use in this field, due to the complexities of the endogenous
O-
...glycosylation pathway and the lack of an
O-
glycosylation consensus sequence. Here, we describe the development of a versatile on-demand
O-
glycosylation system that uses a novel, widely applicable 5 amino acid
O-
glycosylation tag, and a metabolically engineered UDP-galactose-4-eperimase (GALE) knock-out cell line. Optimization of the primary sequence of the tag enables the production of Fc-based proteins with either single or multiple
O-
glycans with complexity fully controlled by media supplementation. We demonstrate how the uniformly labeled proteins containing exclusively N-azido-acetylgalactosamine are used for CLICK chemistry-based bioconjugation to generate site-specifically fluorochrome-labeled antibodies, dual-payload molecules, and bioactive Fc-peptides for applications in basic research and drug discovery. To our knowledge, this is the first description of generating a site-specific
O-
glycosylation system by combining an
O-
glycosylation tag and a metabolically engineered cell line.
Mott insulators can host a surprisingly diverse set of quantum phenomena when their frozen electrons are perturbed by various stimuli. Superconductivity, metal-insulator transition, and colossal ...magnetoresistance induced by element substitution, pressure, and magnetic field are prominent examples. Here we report strong diamagnetism in the Mott insulator calcium ruthenate (Ca₂RuO₄) induced by dc electric current. The application of a current density of merely 1 ampere per centimeter squared induces diamagnetism stronger than that in other nonsuperconducting materials. This change is coincident with changes in the transport properties as the system becomes semimetallic. These findings suggest that dc currentmay be a means to control the properties of materials in the vicinity of a Mott insulating transition.
Synthesis of FeH Pépin, C. M.; Geneste, G.; Dewaele, A. ...
Science (American Association for the Advancement of Science),
07/2017, Volume:
357, Issue:
6349
Journal Article
Peer reviewed
High pressure promotes the formation of polyhydrides with unusually high hydrogen-tometal ratios. These polyhydrides have complex hydrogenic sublattices. We synthesized iron pentahydride (FeH₅) by a ...direct reaction between iron and H₂ above 130 gigapascals in a laser-heated diamond anvil cell. FeH₅ exhibits a structure built of atomic hydrogen only. It consists of intercalated layers of quasicubic FeH₃ units and four-plane slabs of thin atomic hydrogen. The distribution of the valence electron density indicates a bonding between hydrogen and iron atoms but none between hydrogen atoms, presenting a two-dimensional metallic character. The discovery of FeH₅ suggests a low-pressure path to make materials that approach bulk dense atomic hydrogen.
Molecular piezoelectrics are highly desirable for their easy and environment-friendly processing, light weight, low processing temperature, and mechanical flexibility. However, although 136 years ...have passed since the discovery in 1880 of the piezoelectric effect, molecular piezoelectrics with a piezoelectric coefficient d
33 comparable with piezoceramics such as barium titanate (BTO; ~190 picocoulombs per newton) have not been found. We show that trimethylchloromethyl ammonium trichloromanganese(II), an organic-inorganic perovskite ferroelectric crystal processed from aqueous solution, has a large d
33 of 185 picocoulombs per newton and a high phase-transition temperature of 406 kelvin (K) (16 K above that of BTO). This makes it a competitive candidate for medical, micromechanical, and biomechanical applications.
Bidirectional replication from eukaryotic DNA replication origins requires the loading of two ring-shaped minichromosome maintenance (MCM) helicases around DNA in opposite orientations. MCM loading ...is orchestrated by binding of the origin recognition complex (ORC) to DNA, but how ORC coordinates symmetrical MCM loading is unclear. We used natural budding yeast DNA replication origins and synthetic DNA sequences to show that efficient MCM loading requires binding of two ORC molecules to two ORC binding sites. The relative orientation of these sites, but not the distance between them, was found to be critical for MCM loading in vitro and origin function in vivo. We propose that quasi-symmetrical loading of individual MCM hexamers by ORC and directed MCM translocation into double hexamers acts as a unifying mechanism for the establishment of bidirectional replication in archaea and eukaryotes.
The Kitaev quantum spin liquid (KQSL) is an exotic emergent state of matter exhibiting Majorana fermion and gauge flux excitations. The magnetic insulator α-RuCl3 is thought to realize a proximate ...KQSL. We used neutron scattering on single crystals of α-RuCl3 to reconstruct dynamical correlations in energy-momentum space. We discovered highly unusual signals, including a column of scattering over a large energy interval around the Brillouin zone center, which is very stable with temperature. This finding is consistent with scattering from the Majorana excitations of a KQSL. Other, more delicate experimental features can be transparently associated with perturbations to an ideal model. Our results encourage further study of this prototypical material and may open a window into investigating emergent magnetic Majorana fermions in correlated materials.
S100A4 is a Ca
2+
-binding protein that performs an important role in metastasis. It is also known for its antitumor functions. S100A4 is expressed by a specialized subset of CD
4+
CD
25+
lymphocytes ...and is present on those cell's membranes along with peptidoglycan recognition proteins (PGRPs). There, by interacting with major heat shock protein Hsp70, S100A4 plays an important cytotoxic role. The resulting stably formed complex of PGRPs, S100A4 and Hsp70 is required for the identification and binding between a lymphocyte and a target cell. Here, we investigated the S100A4 functions in CD
4+
CD
25+
PGRPs
+
S100A4
+
lymphocyte cytotoxicity against target cells. We demonstrated that those lymphocytes do not form a stable complex with the tumor target cells that themselves have S1004A on their surface. That observation can be explained by our finding that S100A4 precludes the formation of a stable complex between PGRPs, S100A4 (on the lymphocytes’ surface), and Hsp70 (on the target cells’ surface). The decrease in S100A4 level in CD
4+
CD
25+
PGRPs
+
S100A4
+
lymphocytes inhibits their cytotoxic activity, while the addition of S100A4 in the medium restores it. Thus, the resistance of target cells to CD
4+
CD
25+
PGRPs
+
S100A4
+
lymphocyte cytotoxicity depends on their S100A4 expression level and can be countered by S100A4 antibodies.
Aumolertinib (formerly almonertinib; HS-10296) is a novel third-generation epidermal growth factor receptor tyrosine kinase inhibitor approved in China. This double-blind phase III trial evaluated ...the efficacy and safety of aumolertinib compared with gefitinib as a first-line treatment for locally advanced or metastatic
-mutated non-small-cell lung cancer (NSCLC; ClinicalTrials.gov identifier: NCT03849768).
Patients at 53 sites in China were randomly assigned 1:1 to receive either aumolertinib (110 mg) or gefitinib (250 mg) once daily. The primary end point was progression-free survival (PFS) per investigator assessment.
A total of 429 patients who were naïve to treatment for locally advanced or metastatic NSCLC were enrolled. PFS was significantly longer with aumolertinib compared with gefitinib (hazard ratio, 0.46; 95% CI, 0.36 to 0.60;
< .0001). The median PFS with aumolertinib was 19.3 months (95% CI, 17.8 to 20.8) versus 9.9 months with gefitinib (95% CI, 8.3 to 12.6). Objective response rate and disease control rate were similar in the aumolertinib and gefitinib groups (objective response rate, 73.8% and 72.1%, respectively; disease control rate, 93.0% and 96.7%, respectively). The median duration of response was 18.1 months (95% CI, 15.2 to not applicable) with aumolertinib versus 8.3 months (95% CI, 6.9 to 11.1) with gefitinib. Adverse events of grade ≥ 3 severity (any cause) were observed in 36.4% and 35.8% of patients in the aumolertinib and gefitinib groups, respectively. Rash and diarrhea (any grade) were observed in 23.4% and 16.4% of patients who received aumolertinib compared with 41.4% and 35.8% of those who received gefitinib, respectively.
Aumolertinib is a well-tolerated third-generation epidermal growth factor receptor tyrosine kinase inhibitor that could serve as a treatment option for
-mutant NSCLC in the first-line setting.
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