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Cancer stem cells (CSC) are supported by the tumor microenvironment, and non-CSCs can regain CSC phenotypes in certain niches, leading to limited clinical benefits of CSC-targeted therapy. A better understanding of the mechanisms governing the orchestration of the CSC niche could help improve the therapeutic targeting of CSCs. Here, we report that Rab13, a small GTPase, is highly expressed in breast CSCs (BCSC). Rab13 depletion suppressed breast cancer cell stemness, tumorigenesis, and chemoresistance by reducing tumor-stroma cross-talk. Accordingly, Rab13 controlled the membrane translocation of C-X-C chemokine receptor type 1/2 (CXCR1/2), allowing tumor cells to interact with tumor-associated macrophages and cancer-associated fibroblasts to establish a supportive BCSC niche. Targeting the Rab13-mediated BCSC niche with bardoxolone-methyl (C-28 methyl ester of 2-cyano-3, 12-dioxoolen-1, 9-dien-28-oic acid; CDDO-Me) prevented BCSC stemness in vitro and in vivo. These findings highlight the novel regulatory mechanism of Rab13 in BCSC, with important implications for the development of therapeutic strategies for disrupting the BCSC niche.Significance:Targeting Rab13 perturbs formation of the breast cancer stem cell niche by inhibiting cross-talk between cancer cells and the tumor microenvironment, providing a therapeutic opportunity for niche-targeted breast cancer treatment.

Supplementary Data from Rab13 Sustains Breast Cancer Stem Cells by Supporting Tumor–Stroma Cross-talk

Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is a bridging therapy for refractory cardiogenic shock, and limb ischemia is a concern with femoral cannulation. Because of the rich collateral pelvic circulatory supply, buttock ischemia is not common and is usually a complication after aneurysmal aortic repair or internal iliac artery embolization after pelvic trauma. Gluteal necrosis occurring as an extracorporeal membrane oxygenation complication has not been reported in the literature. In this case series, we report three patients with ischemic buttock after initiating VA-ECMO and discuss the risk factors and the clinical and radiological features supportive of the diagnosis. We review the gluteal and pelvic vascular anatomy, postulate how cannula size, ethnicity, catecholamines, and reversal of gluteal arterial flow contributed to this rare entity in our patients and explain how these findings have changed our institution's practice.

We report the synthesis of novel charge transfer complexes consisting of TTF or TTN, and DPNI. A spectroscopic and computational approach is taken to elucidate charge transfer in these complexes.

We present an approximate approach for the calculation of ionization potential (IP) and electron affinity (EA) by exploiting the complementary energy non-linearity errors for a species M and its one-electron-ionized counterpart (M

This paper systematically examines the performance of contemporary wavefunction and density functional theory methods to identify robust and cost-efficient methods for predicting gas-phase anion binding energies. This includes the local coupled cluster LNO-CCSD(T) and DLPNO-CCSD(T), as well as double-hybrid DSD-PBEP86-D3(BJ) and various hybrid functionals M06-2X, B3LYP-D3(BJ), ωB97M-V, and ωB97X-V. The focus is on dual-hydrogen-bonding anion receptors that are commonly found in supramolecular chemistry and organocatalysis, namely, (thio)ureas, deltamides, (thio)squaramides, and croconamides as well as the yet-to-be-explored rhodizonamides. Of the methods examined, M06-2X emerged as the overall best performing method as the other functionals including DSD-PBEP86-D3(BJ) and the local coupled cluster DLPNO-CCSD(T) method displayed systematic errors that increase with the degree of carbonylation of the receptors. Hybrid ONIOM models that employed semiempirical methods (PM7, GFN1-xTB, and GFN2-xTB) and "threefold"-corrected small-basis set potentials (HF-3c, B97-3c, and PBEh-3c) were explored, and the best models resulted in 50- to 500-fold reduction in CPU time compared to W1-local. These calculations provide important insight into the structure-binding relationships where there is a direct correlation between Brønsted acidity and anion binding affinity, though the strength of the correlation also depends on other factors such as hydrogen-bonding geometry and the geometrical distortion that the receptor needs to undergo to bind the anion.

Nanoconfinement offers opportunities to tune physical properties of molecular entities by altering their assembled structures. This also applies to acene-based molecules with potentially rich π–π interactions. Unlike most of the previous cases with acene-based guests directly incorporated into hosts, we take a further step by oligomerizing a fluorescent anthryl monomer, 9-vinylanthracene, inside nanochannels of a metal–organic framework, which is a pillared three-dimensional kagome net of [Zn2(bdc)2(dabco)] (bdc2– = 1,4-benzenedicarboxylate; dabco = 1,4-diazabicyclo[2.2.2]octane). The fluorescence emission of the guest can be significantly enhanced after oligomerization, which is likely due to the suppressed nonemissive interaction between the oligomerized molecules in the nanospace and the MOF wall. The case we have demonstrated for fluorescence enhancement via confined oligomerization provides inspiration for the design of luminescent composites and is encouraging for further exploration of molecules in a nanoconfined space.

IntroductionControversies surround the issue if chronic consumption of a high-sugar diet is detrimental to health or not. This study investigates whether lifelong consumption of a higher sucrose diet will induce overeating, and obesity, and cause metabolic dysfunctions such as hyperglycemia and dyslipidaemia in C57BL/6N mice, compared to a lower sucrose diet.MethodsMale C57BL/6N mice at 3 weeks of age were randomized into consuming a diet with 25 or 10% kcal from sucrose for the rest of their lives. Body weight, food and water intake, fasting blood glucose, insulin, and lipid levels were measured at regular intervals. At the end of the study, organs and tissues were collected and gene expression was measured.ResultsThere was no discernible difference in the impact on food intake, body composition, glucose and lipid homeostasis, liver triglyceride content, life expectancy, as well as gene expression related to intermediary metabolism between mice fed a diet with 10 vs. 25% kcal as sucrose over their lifespan. We also showed that switching from a 25% kcal diet to a 10% kcal diet at different life stages, or vice versa, did not appear to affect these outcomes of interest.DiscussionThe results from our study suggest that lifelong consumption of a higher sugar diet generally did not induce overeating and obesity, disrupt carbohydrate metabolism and lipid homeostasis, and reduce life expectancy compared with a lower sugar diet. Our unorthodox findings disagreed with the popular belief that higher sugar consumption is detrimental to health, which should be confirmed in future studies.

In the present study, we introduce the accurate Wn-P34 quantum chemistry composite methods with applicability to heavy p-block elements up to xenon. For a set of thermochemical properties for prototypical third- and fourth-row species and for a diverse set of small light-main-group species, they show accuracies of ∼3 kJ mol-1 or better. Overall, the Wn-P34 methods are comparable in accuracy to Wn, with a widened applicability to heavier elements. We have used Wn-P34 to compile the P34 set of accurate thermochemical values for heavy p-block species, and we have applied this set to assess a wide range of lower-cost methods. The results of our assessment show that the G4(MP2)-XK composite method provides adequate treatments for these species, but several widely used double-hybrid density functional theory (DH-DFT) methods show uncharacteristically large deviations. In contrast, we find it presently surprising that some pure and hybrid DFT methods such as TPSS and SCANh perform quite well. We hope that our findings and new tools would facilitate the application of computational chemistry for heavy elements, of which the properties are yet to be broadly explored.

A recent study has examined the accuracy of NIST heats of formation for a set of C, H, and O-containing species with a proposed low-cost quantum chemistry approach. In the present study, we have used high-level methods such as W1X-2 to obtain these data more rigorously, which we have then used to assess the NIST and the previously computed values. We find that many of these NIST data that are as suggested to be unreliable by the previous study are indeed inconsistent with our high-level reference values. However, we also find substantial deviations for the previously computed values from our benchmark. Thus, we have assessed the performance of alternative low-cost methods. In our assessment, we have additionally examined C, H, N, and O-containing species for which heats of formation are available from the NIST database. We find the ωB97M-V/ma-def2-TZVP, DSD-PBEP86/ma-def2-TZVP, and CCSD(T)-F12b/aug'-cc-pVDZ methods to be adequate for obtaining heats of formation with the atomization approach, once their atomic energies are optimized with our benchmark. Notably, the low-cost ωB97M-V method yields values that agree to be within 10 kJ mol

Hypertension and type 2 diabetes mellitus (T2DM) are important, intertwined public health issues. People with both conditions face significantly elevated risks of cardiovascular (CV) and renal complications. To optimize patient care, a multidisciplinary expert panel met to review recent evidence on optimal blood pressure (BP) targets, implications of albuminuria, and treatment regimens for hypertensive patients with T2DM, with the aim of providing recommendations for physicians in Hong Kong. The panel reviewed the relevant literature, obtained by searching PubMed for the publication period from January 2015 to June 2021, to address five discussion areas: (i) BP targets based on CV/renal benefits; (ii) management of isolated systolic or diastolic hypertension; (iii) roles of angiotensin II receptor blockers; (iv) implications of albuminuria for CV/renal events and treatment choices; and (v) roles and tools of screening for microalbuminuria. The panel held three virtual meetings using a modified Delphi method to address the discussion areas. After each meeting, consensus statements were derived and anonymously voted on by every panelist. A total of 17 consensus statements were formulated based on recent evidence and expert insights regarding cardioprotection and renoprotection for hypertensive patients with T2DM.

In the present study, we have investigated the applicability of long-range-corrected (LC) functionals to a Kohn-Sham (KS) Koopmans'-type theorem. Specifically, we have examined the performance of optimally tuned LCgau-core functionals (in combination with BOP and PW86-PW91 exchange-correlation functionals) by calculating the ionization potential (IP) within the context of Koopmans' prediction. In the LC scheme, the electron repulsion operator, 1/

Activation of Mas-related G protein-coupled receptor X2 (MRGPRX2) is a crucial non-IgE pathway for mast cell activation associated with allergic reactions and inflammation. Only a few peptides and small compounds targeting MRGPRX2 have been reported, with limited information on their pharmacological activity.We sought to develop novel small molecule MRGPRX2 antagonists to treat MRGPRX2 mediated allergies and inflammation.A computational approach was used to design novel small molecules as MRGPRX2 antagonists. The shortlisted molecules were synthesized and characterized by LCMS and NMR. Inhibitory activity on MRGPRX2 signalling was assessed in vitro using functional bioassays (β-hexosaminidase, calcium flux, and chemokine synthesis) and receptor activation assays (β-arrestin recruitment and Western blot) in human LAD-2 mast cells and HTLA cells. In vivo effects of the novel MRGPRX2 antagonists were assessed using a mouse model of acute allergy and systemic anaphylaxis.The novel small molecules demonstrated higher binding affinity with MRGPRX2 in the docking study. The half-maximal inhibitory concentration is in the low micromolar range (5-21μM). The small molecules inhibited not only the early phase of mast cell activation but also the late phase, associated with chemokine and prostaglandin release. Further, the Western blotting analysis showed the inhibition of downstream PLC-γ, ERK1/2 and Akt signalling pathway. Moreover, in the mouse models of allergies, the small molecule administration effectively blocks acute, systemic allergic reactions and inflammation and prevents systemic anaphylaxis.The small molecules might hold a significant therapeutic promise to treat MRGPRX2 mediated allergies and inflammation.

In the present study, we have examined density functional theory methods for the calculation of the interaction energy between a small molecule and its environment. For simple systems such as a neutral solute in a neutral solvent, good accuracy can be attained using low-cost "3c" methods, in particular r

In the present study, we have examined the electronic structures related to the fluorescence properties of small Ag42+ complexes encapsulated in zeolites. We find that interaction between Ag42+ and coordinated water molecules, which was previously proposed to be the origin of fluorescence, may not be a sufficient condition by itself. Refinement of the previously used all-silicon-cage model to include framework Al atoms leads to an asymmetric environment, and this alters the electronic structure in favor of fluorescence. We have further examined the substitution of the H2O ligands by NH3, H2S, PH3, CO and CS. Among these systems, Ag42+ binds most strongly to NH3 but the energetics for the H2S and PH3 complexes is also reasonable. The energy of the fluorescent light is related to the energy of the lowest-energy triplet state, and these energies for the H2O, NH3, H2S and PH3 systems span the range of ∼2–3 eV, i.e., roughly the visible range. Thus, the use of different ligands appears to be an attractive means for tailoring the luminescence properties., Physical Chemistry Chemical Physics, 23(3), pp.1984-1993; 2021

We have examined the use of systematic bond-separation reactions and purposely constructed chemistry-preserving isodesmic reactions for the thermochemical calculation of aromatic hydrocarbon species. The bond-separation approach yields somewhat disappointing accuracy even when the reaction energies are obtained with generally robust composite and double-hybrid (DH) density functional theory (DFT) methods. In contrast, for the purposely constructed reactions, we find a dramatic improvement in the accuracy for energies calculated with all methods examined. Notably, for medium-sized aromatic hydrocarbons, we find that an effective approach for formulating a well-balanced reaction is to split the target species into two halves with an aromatic overlapping region. Overall, the G4(MP2)-XK, MPW2PLYP, MN15, PBE, and DC-DFTB3 methods are reasonable within their respective classes of methods for the calculation of bond-separation as well as chemistry-preserving isodesmic reactions. We have further computed per-carbon atomization energy (AE) for a series of D6h benzene-type molecules, and thus obtained a formula for extrapolation to the graphene limit [AEn = 711.5 × (1 − 1/n0.640) kJ mol−1, where n = number of carbons]. It suggests that nano-graphene with a length larger than 10 nm would resemble properties of bulk graphene, and conversely, downsizing a nano-graphene beyond this point may lead to considerably altered properties from the bulk.