Living bacteria therapies have been proposed as an alternative approach to treating a broad array of cancers. In this study, we developed a genetically encoded microbial encapsulation system with tunable and dynamic expression of surface capsular polysaccharides that enhances systemic delivery. Based on a small RNA screen of capsular biosynthesis pathways, we constructed inducible synthetic gene circuits that regulate bacterial encapsulation in Escherichia coli Nissle 1917. These bacteria are capable of temporarily evading immune attack, whereas subsequent loss of encapsulation results in effective clearance in vivo. This dynamic delivery strategy enabled a ten-fold increase in maximum tolerated dose of bacteria and improved anti-tumor efficacy in murine models of cancer. Furthermore, in situ encapsulation increased the fraction of microbial translocation among mouse tumors, leading to efficacy in distal tumors. The programmable encapsulation system promises to enhance the therapeutic utility of living engineered bacteria for cancer.

The dark matter enclosed in a density perturbation with a large initial amplitude (δρ/ρ 10 −3 ) collapses shortly after recombination and forms an ultracompact minihalo (UCMH). Their high central densities make UCMHs especially suitable for detection via astrometric microlensing: as the UCMH moves, it changes the apparent position of background stars. A UCMH with a mass larger than a few solar masses can produce a distinctive astrometric microlensing signal that is detectable by the space astrometry mission Gaia. If Gaia does not detect gravitational lensing by any UCMHs, then it establishes an upper limit on their abundance and constrains the amplitude of the primordial power spectrum for k ∼ 2700 Mpc −1 . These constraints complement the upper bound on the amplitude of the primordial power spectrum derived from limits on gamma-ray emission from UCMHs because the astrometric microlensing signal produced by an UCMH is maximized if the dark-matter annihilation rate is too low to affect the UCMH's density profile. If dark matter annihilation within UCMHs is not detectable, a search for UCMHs by Gaia could constrain the amplitude of the primordial power spectrum to be less than 10 −5 ; this bound is three orders of magnitude stronger than the bound derived from the absence of primordial black holes.

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Abdominal aortic aneurysm (AAA) is a life-threatening aortic disease in the elderly. Activation of Notch1 pathway plays a critical role in the development of AAA, but the underlying mechanisms remain poorly understood. In the present study, we explored the mechanisms by which Notch1 activation regulates angiotensin II (Ang II)-induced AAA formation and evaluated the therapeutic potential of a new Notch γ-secretase inhibitor, dibenzazepine (DBZ), for the treatment of AAA. Apolipoprotein E knockout (Apo E−/−) mice infused for 4 weeks with Ang II (1000 ng/kg/min, IP) using osmotic mini-pumps were received an intraperitoneal injection of either vehicle or 1 mg/kg/d DBZ. Notch1 signaling was activated in AAA tissue from both Ang II-infused Apo E−/− mice and human undergoing AAA repair in vivo, with increased expression of Notch intracellular domain (NICD) and its target gene Hes1, and this effect was effectively blocked by DBZ. Moreover, infusion of Ang II markedly increased the incidence and severity of AAA in Apo E−/− mice. In contrast, inhibition of Notch activation by DBZ prevented AAA formation in vivo. Furthermore, DBZ markedly prevented Ang II-stimulated accumulation of macrophages and CD4+ T cells, and ERK-mediated angiogenesis, simultaneously reversed Th2 response, in vivo. In conclusion, these findings provide new insight into the multiple mechanisms of Notch signaling involved in AAA formation and suggest that γ-secretase inhibitor DBZ might be a novel therapeutic drug for treating AAAS.