The crystal chemistry of hydrotalcite-like compounds is investigated by powder diffraction methods such as Rietveld structure refinement, radial distribution function analysis, atom-specific radial distribution analysis obtained from anomalous diffraction data, and EXAFS spectroscopy. The topology of the brucite-type layer as well as the layer stacking arrangement and the intralayer bonding are determined for Mg,Al, Mg,Ga, and Ni,Al systems. The occurrence of long-range cation ordering in materials with M(II)/M(III) cation ratios close to 2.0 is observed only for systems with similar cation radii, and it is associated with a corrugation of the octahedral layer. The lack of ordering for systems with highly different cation radii is ascribed to the layer compression exhibited by these compounds, which prevents the layer distortion. The stacking arrangement is random for the solids investigated, except for the Mg,Al system which shows a preference for the rhombohedral polytype. It is proposed that this behavior is related to the extent of local directional bonds between the oppositely charged layers.

SUMMARY Several cell populations have been reported to possess intestinal stem cell (ISC) activity during homeostasis and injury-induced regeneration. Here, we explored inter-relationships between putative mouse ISC populations by comparative RNA-sequencing (RNA-seq). The transcriptomes of multiple cycling ISC populations closely resembled Lgr5+ ISCs, the most well-defined ISC pool, but Bmi1-GFP+ cells were distinct and enriched for enteroendocrine (EE) markers including Prox1. Prox1-GFP+ cells exhibited sustained clonogenic growth in vitro, and lineage-tracing of Prox1+ cells revealed long-lived clones during homeostasis and after radiation-induced injury in vivo. Single-cell mRNA-seq revealed two subsets of Prox1-GFP+ cells, one of which resembled mature EE cells while the other displayed low level EE gene expression but co-expressed tuft cell markers, Lgr5 and Ascl2, reminiscent of label-retaining secretory progenitors. Our data suggest that the EE lineage, including mature EE cells, comprise a reservoir of homeostatic and injury-inducible ISCs, extending our understanding of cellular plasticity and stemness.

Autophagy is a lysosome-dependent degradative process that protects cancer cells from multiple stresses. In preclinical models, autophagy inhibition with chloroquine (CQ) derivatives augments the efficacy of many anticancer therapies, but CQ has limited activity as a single agent. Clinical trials are underway combining anticancer agents with hydroxychloroquine (HCQ), but concentrations of HCQ required to inhibit autophagy are not consistently achievable in the clinic. We report the synthesis and characterization of bisaminoquinoline autophagy inhibitors that potently inhibit autophagy and impair tumor growth in vivo. The structural motifs that are necessary for improved autophagy inhibition compared with CQ include the presence of two aminoquinoline rings and a triamine linker and C-7 chlorine. The lead compound, Lys01, is a 10-fold more potent autophagy inhibitor than HCQ. Compared with HCQ, Lys05, a water-soluble salt of Lys01, more potently accumulates within and deacidifies the lysosome, resulting in impaired autophagy and tumor growth. At the highest dose administered, some mice develop Paneth cell dysfunction that resembles the intestinal phenotype of mice and humans with genetic defects in the autophagy gene ATG16L1, providing in vivo evidence that Lys05 targets autophagy. Unlike HCQ, significant single-agent antitumor activity is observed without toxicity in mice treated with lower doses of Lys05, establishing the therapeutic potential of this compound in cancer.cell death | stress responses | cancer cell survival | drug resistance | antimalarials A utophagy, the sequestration of organelles and proteins in autophagic vesicles (AVs) and degradation of this cargo through lysosomal fusion (1), allows tumor cells to survive metabolic and therapeutic stresses (2-5). Therapy-induced autophagy is a key resistance mechanism to many anticancer agents (6), and autophagy levels are increased in most cancers (7). Chloroquine (CQ; Fig. 1, compound 1) derivatives block autophagy by impairing lysosomal function (3,8,9). Studies in multiple mouse models of malignancy have demonstrated that autophagy inhibition with CQ derivatives augments the efficacy of a variety of anticancer agents. Clinical trials combining cancer therapies with hydroxychloroquine (HCQ; Fig. 1), have been launched, and preliminary results indicate these combinations have activity (6). However, pharmacokinetic (PK)-pharmacodynamic (PD) studies conducted in patients receiving HCQ for cancer therapy have indicated that the high micromolar concentrations of HCQ required to inhibit autophagy in vitro are inconsistently achieved in humans (10). There is an unmet need to develop more potent inhibitors of autophagy.The design and synthesis of dimeric analogs of CQ that exploit the thermodynamic advantages imparted by polyvalency (11, 12) has been previously studied in the context of malaria (13-15). The synthesis of heteroalkane-bridged bisquinolines did not produce sufficient antimalarial activity to warrant further investigation (14). Subsequently, a seri...

Since their original identification in Drosophila, the caudal related homologues (Cdx1 and Cdx2) have been known to be evolutionarily conserved both in molecular structure and function. In a great variety of organisms they are recognized to function critically during antero-posterior patterning and the development of the intestinal epithelium. The Cdx homologues, when expressed, modulate a diverse set of processes including proliferation, apoptosis, cell-adhesion, and columnar morphology. They are also necessary for the expression of an increasing number of intestine-specific genes. By targeting these processes and genes, the Cdx homologues promote the appearance of a mature intestinal cell phenotype. In addition to these critical roles during development, accumulating evidence suggests that the Cdx homologues may play significant roles in oncogenesis in the gastrointestinal tract and other tissues. In the colon, several studies suggest the Cdx homologues may act as tumor suppressors. However, ectopic Cdx1 and Cdx2 expression is involved in the development of the precancerous intestinal metaplasia in the stomach and esophagus, and may be a transforming event in one form of acute myelogenous leukemia. This review will explore our current understanding of the roles of the caudal homologues Cdx1 and Cdx2 in intestinal development and carcinogenesis.

The structure of the phases obtained upon dehydration and decomposition of hydrotalcite-like compounds is investigated by several experimental techniques. A reaction mechanism is proposed encompassing a change in coordination of the M(III) cations during the dehydration step. The formation of a 3-dimensional structure occurs upon the subsequent decomposition of the interlayer anions and dehydroxylation of the octahedral layers. In the decomposed material the cations are trapped in the interstices of a regular oxygen cubic close packed lattice and exhibit a considerable disorder. Strains develop during the decomposition, which are likely related to the observed increase of surface area. The thermal stability of the decomposed materials is connected to the reduced cation diffusivity in the oxygen lattice.