Most patients with triple negative breast cancer (TNBC) do not respond to anti-PD1/PDL1 immunotherapy, indicating the necessity to explore immune checkpoint targets. B7H3 is a highly glycosylated ...protein. However, the mechanisms of B7H3 glycosylation regulation and whether the sugar moiety contributes to immunosuppression are unclear. Here, we identify aberrant B7H3 glycosylation and show that N-glycosylation of B7H3 at NXT motif sites is responsible for its protein stability and immunosuppression in TNBC tumors. The fucosyltransferase FUT8 catalyzes B7H3 core fucosylation at N-glycans to maintain its high expression. Knockdown of FUT8 rescues glycosylated B7H3-mediated immunosuppressive function in TNBC cells. Abnormal B7H3 glycosylation mediated by FUT8 overexpression can be physiologically important and clinically relevant in patients with TNBC. Notably, the combination of core fucosylation inhibitor 2F-Fuc and anti-PDL1 results in enhanced therapeutic efficacy in B7H3-positive TNBC tumors. These findings suggest that targeting the FUT8-B7H3 axis might be a promising strategy for improving anti-tumor immune responses in patients with TNBC.
The iridium-catalyzed enantioselective coupling reaction of vinyl azides and allylic electrophiles is presented and provides access to β-chiral carbonyl derivatives. Vinyl azides are used as ...acetamide enolate or acetonitrile carbanion surrogates, leading to γ,δ-unsaturated β-substituted amides as well as nitriles with excellent enantiomeric excess. These products are readily transformed into chiral N-containing building blocks and pharmaceuticals. A mechanism is proposed to rationalize the chemoselectivity of this coupling reaction.
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IJS, KILJ, NUK, PNG, UL, UM
A relay Cu(I)/Brønsted base catalyzed one‐pot phospha‐Michael addition/5‐exo‐dig cyclization/isomerization of in situ generated aza‐alkynyl o‐quinone methides (N‐o‐AQMs) from ...1‐(o‐aminophenyl)prop‐2‐ynols with P(O)‐compounds has been established to afford C3‐phosphorylated indoles. It demonstrates that the 1,4‐conjugate addition adduct from N‐o‐AQMs could undergo further cyclization with the tethered alkyne moiety to afford N‐heterocyclic compounds.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Abstract
The widespread use of azoles has led to increasing azole resistance among Candida albicans strains. One mechanism of azole resistance involves point mutations in the ERG11 gene, which ...encodes the target enzyme (cytochrome P450 lanosterol 14α-demethylase). In the present study, we amplified and sequenced the ERG11 gene of 23 C. albicans clinical isolates. Seventeen mutations encoding distinct amino acid substitutions were found, of which seven (K143Q, Y205E, A255V, E260V, N435V, G472R, and D502E) were novel. We further verified the contribution of the amino acid substitutions to azole resistance using site-directed mutagenesis of the ERG11 gene to recreate these mutations for heterologous expression in Saccharomyces cerevisiae. We observed that substitutions A114S, Y132H, Y132F, K143R, Y257H, and a new K143Q substitution contributed to significant increases (≧ fourfold) in fluconazole and voriconazole resistance; changes in itraconazole resistance were not significant (≦ twofold).
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
A urease inhibitor with good in vivo profile is considered as an alternative agent for treating infections caused by urease-producing bacteria such as Helicobacter pylori. Here, we report a series of ...N-monosubstituted thioureas, which act as effective urease inhibitors with very low cytotoxicity. One compound (b19) was evaluated in detail and shows promising features for further development as an agent to treat H. pylori caused diseases. Excellent values for the inhibition of b19 against both extracted urease and urease in intact cell were observed, which shows IC
50
values of 0.16 ± 0.05 and 3.86 ± 0.10 µM, being 170- and 44-fold more potent than the clinically used drug AHA, respectively. Docking simulations suggested that the monosubstituted thiourea moiety penetrates urea binding site. In addition, b19 is a rapid and reversible urease inhibitor, and displays nM affinity to urease with very slow dissociation (k
off
=1.60 × 10
−3
s
−1
) from the catalytic domain.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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•s-ZVI-coupled Myriophyllum aquaticum-derived biochar favors C storage more than I.H.•Biochar nature or feedstock may control C trap and N removal gains from Fe-C coupling.•Biochars ...trigger C dynamics depending on trade-offs between priming and increased MBC.•Enhanced iron gate contributes to synergistic C sequestration and C sink augmentation.•β-glucosidase activity and Fe-OC increases jointly drive C cumulation in Fe-C ditches.
Carbon dioxide (CO2) is a more powerful greenhouse gas due to its enhanced instantaneous radiative forcing. Since agricultural ecological ditches (eco-ditches) controlling agricultural non-point source pollution are potential CO2 hotspots, carbon capture technologies must be deployed immediately to sequester carbon and combat climate change. Zero-waste biochar, a negative-carbon technology, remains contentious regarding C sequestration. Iron (Fe) enhances long-term organic carbon (OC) preservation, but the cascading effects of Fe-biochar interactions on the promotion of C accumulation are unclear in eco-ditches. In this paper, we fill these research gaps and employ sponge iron (s-ZVI) and biochar coupling (Fe-C) to enhance the iron gate C protection in eco-ditches. The results reveal that Myriophyllum aquaticum(M.A.)-derived biochar prepared by low-temperature pyrolysis (Biochar_M.A.) enjoys the highest FI, the lowest SUVA254 and SUVA280 and moderate dissolution stability. The coupling of s-ZVI and environmentally compatible Biochar_M.A. achieve a triple benefit situation of C sequestration, C sink, and pollutant removal. Overall carbon gain is jointly determined by abiotic controls and biotic controls. The carbon burial effects of biochar-amended eco-ditches are mainly controlled by the trade-offs between Fe-bound OC mineralization via the biochar-induced prime effect and preservation of OC derived from microbial biomass. The unique Fe-C boosts the rusty sink and yields a negative priming as a result of the dominance of Fe-OC. The upregulated β-glucosidase activity and new-formed Fe-OC indirectly and directly contribute to overall C gain in Fe-C-filled eco-ditches, respectively. These findings provide novel insights into the coupled biotic-abiotic contribution mechanisms underlying the iron gate and reverse enzyme latch phenomenon and advance more robust and prospective theoretical knowledge of C dynamics that are not restricted to eco-ditches, soil, constructed wetlands C storage.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
BACKGROUND AND PURPOSE—Stroke is a major public health concern worldwide. Although clinical treatments have improved in the acute period after stroke, long-term therapeutics remain limited to ...physical rehabilitation in the delayed phase. This study is aimed to determine whether nNOS (neuronal NO synthase)-CAPON (carboxy-terminal postsynaptic density-95/discs large/zona occludens-1 ligand of nNOS) interaction may serve as a new therapeutic target in the delayed phase for stroke recovery.
METHODS—Photothrombotic stroke and transient middle cerebral artery occlusion were induced in mice. Adeno-associated virus (AAV)-cytomegalovirus (CMV)-CAPON-125C-GFP (green fluorescent protein)-3Flag and the other 2 drugs (Tat-CAPON-12C and ZLc-002) were microinjected into the peri-infarct cortex immediately and 4 to 10 days after photothrombotic stroke, respectively. ZLc-002 was also systemically injected 4 to 10 days after transient middle cerebral artery occlusion. Grid-walking task and cylinder task were conducted to assess motor function. Western blotting, immunohistochemistry, Golgi staining, and electrophysiology recordings were performed to uncover the mechanisms.
RESULTS—Stroke increased nNOS-CAPON association in the peri-infarct cortex in the delayed period. Inhibiting the ischemia-induced nNOS-CAPON association substantially decreased the number of foot faults in the grid-walking task and forelimb asymmetry in the cylinder task, suggesting the promotion of functional recovery from stroke. Moreover, dissociating nNOS-CAPON significantly facilitated dendritic remodeling and synaptic transmission, indicated by increased dendritic spine density, dendritic branching, and length and miniature excitatory postsynaptic current frequency but did not affect stroke-elicited neuronal loss, infarct size, or cerebral edema, suggesting that nNOS-CAPON interaction may function via regulating structural neuroplasticity, rather than neuroprotection. Furthermore, ZLc-002 reversed the transient middle cerebral artery occlusion–induced impairment of motor function.
CONCLUSIONS—Our results reveal that nNOS-CAPON coupling can serve as a novel pharmacological target for functional restoration after stroke.
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•Irradiation stents were significantly associated with a decrease in the rate of stent restenosis.•Patients in the irradiation stent group obtained longer survival time.•Placement of ...irradiation stent did not add to the difficulty of technique.•The use of irradiation stent did not increase the incidence of treatment related complications.
Placement of an irradiation stent has been demonstrated to offer longer patency and survival than an uncovered self-expandable metallic stent (SEMS) in patients with unresectable malignant biliary obstruction (MBO). We aim to further assess the efficacy of an irradiation stent compared to an uncovered SEMS in those patients.
We performed a randomized, open-label trial of participants with unresectable MBO at 20 centers in China. A total of 328 participants were allocated in parallel to the irradiation stent group (ISG) or the uncovered SEMS group (USG). Endpoints included stent patency (primary), technical success, relief of jaundice, overall survival, and complications.
The first quartile stent patency time (when 25% of the patients experienced stent restenosis) was 212 days for the ISG and 104 days for the USG. Irradiation stents were significantly associated with a decrease in the rate of stent restenosis (9% vs. 15% at 90 days; 16% vs. 27% at 180 days; 21% vs. 33% at 360 days; p = 0.010). Patients in the ISG obtained longer survival time (median 202 days vs. 140 days; p = 0.020). No significant results were observed in technical success rate (93% vs. 95%; p = 0.499), relief of jaundice (85% vs. 80%; p = 0.308), and the incidence of grade 3 and 4 complications (8.5% vs. 7.9%; p = 0.841).
Insertion of irradiation stents instead of uncovered SEMS could improve patency and overall survival in patients with unresectable MBO.
For patients with unresectable malignant biliary obstruction (MBO), placement of a self-expandable metallic stent (SEMS) is a recommended palliative modality to relieve pruritus, cholangitis, pain, and jaundice. However, restenosis is a main pitfall after stent placement. Data from this first multicenter randomized controlled trial showed that insertion of an irradiation stent provided longer patency and better survival than a conventional metal stent.
ClinicalTrials.gov ID: NCT02001779.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Summary
In neurons, increased protein–protein interactions between neuronal nitric oxide synthase (nNOS) and its carboxy‐terminal PDZ ligand (CAPON) contribute to excitotoxicity and abnormal ...dendritic spine development, both of which are involved in the development of Alzheimer's disease. In models of Alzheimer's disease, increased nNOS–CAPON interaction was detected after treatment with amyloid‐β in vitro, and a similar change was found in the hippocampus of APP/PS1 mice (a transgenic mouse model of Alzheimer's disease), compared with age‐matched background mice in vivo. After blocking the nNOS–CAPON interaction, memory was rescued in 4‐month‐old APP/PS1 mice, and dendritic impairments were ameliorated both in vivo and in vitro. Furthermore, we demonstrated that S‐nitrosylation of Dexras1 and inhibition of the ERK–CREB–BDNF pathway might be downstream of the nNOS–CAPON interaction.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
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