We report that the many Eph-related receptor tyrosine kinases, and their numerous membrane-bound ligands, can each be grouped into only two major specificity subclasses. Receptors in a given subclass bind most members of a corresponding ligand subclass. The physiological relevance of these groupings is suggested by viewing the collective distributions of all members of a subclass. These composite distributions, in contrast with less informative patterns seen with individual members of the family, reveal that the developing embryo is subdivided into domains defined by reciprocal and apparently mutually exclusive expression of a receptor subclass and its corresponding ligands. Receptors seem to encounter their ligands only at the interface between these domains. This reciprocal compartmentalization implicates the Eph family in the formation of spatial boundaries that may help to organize the developing body plan.

Dysbiosis, departure of the gut microbiome from a healthy state, has been suggested to be a powerful biomarker of disease incidence and progression. Diagnostic applications have been proposed for inflammatory bowel disease diagnosis and prognosis, colorectal cancer prescreening and therapeutic choices in melanoma. Noninvasive sampling could facilitate large-scale public health applications, including early diagnosis and risk assessment in metabolic and cardiovascular diseases. To understand the generalizability of microbiota-based diagnostic models of metabolic disease, we characterized the gut microbiota of 7,009 individuals from 14 districts within 1 province in China. Among phenotypes, host location showed the strongest associations with microbiota variations. Microbiota-based metabolic disease models developed in one location failed when used elsewhere, suggesting that such models cannot be extrapolated. Interpolated models performed much better, especially in diseases with obvious microbiota-related characteristics. Interpolation efficiency decreased as geographic scale increased, indicating a need to build localized baseline and disease models to predict metabolic risks.

Vascular development depends on the highly coordinated actions of a variety of angiogenic regulators, most of which apparently act downstream of vascular endothelial growth factor (VEGF). One potential such regulator is delta-like 4 ligand (Dll4), a recently identified partner for the Notch receptors. We generated mice in which the Dll4 gene was replaced with a reporter gene, and found that Dll4 expression is initially restricted to large arteries in the embryo, whereas in adult mice and tumor models, Dll4 is specifically expressed in smaller arteries and microvessels, with a striking break in expression just as capillaries merge into venules. Consistent with these arterial-specific expression patterns, heterozygous deletion of Dll4 resulted in prominent albeit variable defects in arterial development (reminiscent of those in Notch knockouts), including abnormal stenosis and atresia of the aorta, defective arterial branching from the aorta, and even arterial regression, with occasional extension of the defects to the venous circulation; also noted was gross enlargement of the pericardial sac and failure to remodel the yolk sac vasculature. These striking phenotypes resulting from heterozygous deletion of Dll4 indicate that vascular development may be as sensitive to subtle changes in Dll4 dosage as it is to subtle changes in VEGF dosage, because VEGF accounts for the only other example of haploid insufficiency, resulting in obvious vascular abnormalities. In summary, Dll4 appears to be a major trigger of Notch receptor activities previously implicated in arterial and vascular development, and it may represent a new opportunity for pro-and anti-angiogenic therapies.

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tRNA-derived small RNAs (tsRNAs; also called tRNA-derived fragments (tRFs)) are an abundant class of small non-coding RNAs whose biological roles are not well defined. We show that inhibition of a specific tsRNA, LeuCAG3′tsRNA, induces apoptosis in rapidly dividing cells in vitro and in a patient-derived orthotopic hepatocellular carcinoma model in mice. This tsRNA binds at least two ribosomal protein mRNAs (for RPS28 and RPS15) to enhance their translation. Reduction of RPS28 mRNA translation blocks pre-18S ribosomal RNA processing, resulting in a decrease in the number of 40S ribosomal subunits. These data establish another post-transcriptional mechanism that can fine-tune gene expression during different physiological states and provide a potential new target for treating cancer.

The ciliary neurotrophic factor (CNTF) receptor complex is shown here to include the CNTF binding protein (CNTFR alpha) as well as the components of the leukemia inhibitory factor (LIF) receptor, LIFR beta (the LIF binding protein) and gp130 [the signal transducer of interleukin-6 (IL-6)]. Thus, the conversion of a bipartite LIF receptor into a tripartite CNTF receptor apparently occurs by the addition of the specificity-conferring element CNTFR alpha. Both CNTF and LIF trigger the association of initially separate receptor components, which in turn results in tyrosine phosphorylation of receptor subunits. Unlike the IL-6 receptor complex in which homodimerization of gp130 appears to be critical for signal initiation, signaling by the CNTF and LIF receptor complexes depends on the heterodimerization of gp130 with LIFR beta. Ligand-induced dimerization of signal-transducing receptor components, also seen with receptor tyrosine kinases, may provide a general mechanism for the transmission of a signal across the cell membrane.

The Eph receptor tyrosine kinases and their membrane-tethered ephrin ligands provide critical guidance cues at points of cell-to-cell contact. It has recently been reported that the ephrin-B2 ligand is a molecular marker for the arterial endothelium at the earliest stages of embryonic angiogenesis, while its receptor EphB4 reciprocally marks the venous endothelium. These findings suggested that ephrin-B2 and EphB4 are involved in establishing arterial versus venous identity and perhaps in anastamosing arterial and venous vessels at their junctions. By using a genetically engineered mouse in which the lacZ coding region substitutes and reports for the ephrin-B2 coding region, we demonstrate that ephrin-B2 expression continues to selectively mark arteries during later embryonic development as well as in the adult. However, as development proceeds, we find that ephrin-B2 expression progressively extends from the arterial endothelium to surrounding smooth muscle cells and to pericytes, suggesting that ephrin-B2 may play an important role during formation of the arterial muscle wall. Furthermore, although ephrin-B2 expression patterns vary in different vascular beds, it can extend into capillaries about midway between terminal arterioles and postcapillary venules, challenging the classical conception that capillaries have neither arterial nor venous identity. In adult settings of angiogenesis, as in tumors or in the female reproductive system, the endothelium of a subset of new vessels strongly expresses ephrin-B2, once again contrary to earlier views that such new vessels lack arterial/venous characteristics and derive from postcapillary venules. While earlier studies had focused on a role for ephrin-B2 during the earliest embryonic stages of arterial/venous determination, our current findings using ephrin-B2 as an arterial marker in the adult challenge prevailing views of the arterial/venous identity of quiescent as well as remodeling adult microvessels and also highlight a possible role for ephrin-B2 in the formation of the arterial muscle wall.

The conventional inorganic semiconductors are not suitable for in vivo therapeutic nanomedicine because of the lack of an adequate and safe irradiation source to activate them. This work reports on the rational design of titania (TiO)-based semiconductors for enhanced and synergistic sono-/photoinduced tumor eradication by creating an oxygen-deficient TiO layer onto the surface of TiO nanocrystals, which can create a crystalline-disordered core/shell structure (TiO@TiO) with black color. As found in the lessons from traditional photocatalysis, such an oxygen-deficient TiO layer with abundant oxygen defects facilitates and enhances the separation of electrons (e) and holes (h) from the energy-band structure upon external ultrasound irradiation, which can significantly improve the efficacy of sono-triggered sonocatalytic tumor therapy. Such an oxygen-deficient TiO layer can also endow black titania nanoparticles with high photothermal-conversion efficiency (39.8%) at the NIR-II biowindow (1064 nm) for enhanced photothermal hyperthermia. Both in vitro cell level and systematic in vivo tumor-bearing mice xenograft evaluations have demonstrated the high synergistic efficacy of combined and enhanced sonodynamic therapy and photothermal ablation as assisted by oxygen-deficient black titania, which has achieved complete tumor eradication with high therapeutic biosafety and without obvious reoccurrence. This work not only provides the paradigm of high therapeutic efficacy of a combined sono-/photoinduced tumor-treatment protocol but also significantly broadens the nanomedical applications of semiconductor-based nanoplatforms by rational design of their nanostructures and control of their physiochemical properties.