Controlling intracellular protein delivery, tumor colonization and tissue distribution using the master regulator flhDC in a clinically relevant ΔsseJ Salmonella strain.

Effectively targeting intracellular pathways in cancers requires a system that specifically delivers to tumors and internalizes into cancer cells. To achieve this goal, we developed intracellular-delivering (ID) Salmonella with controllable expression of flhDC, to regulate flagella production and cell invasion. We hypothesized that controlling flhDC would overcome the poor colonization seen in prior clinical trials.

Intracellular delivery of oncolytic viruses with engineered Salmonella causes viral replication and cell death.

As therapies, oncolytic viruses regress tumors and have the potential to induce antitumor immune responses that clear hard-to-treat and late-stage cancers. Despite this promise, clearance from the blood prevents treatment of internal solid tumors. To address this issue, we developed virus-delivering Salmonella (VDS) to carry oncolytic viruses into cancer cells.

Intracellular delivery of an exogenous immunization antigen refocuses CD8 T cells against cancer cells, eliminates pancreatic tumors and forms antitumor immunity.

Introduction: Immunotherapies have shown great promise, but are not effective for all tumors types and are effective in less than 3% of patients with pancreatic ductal adenocarcinomas (PDAC). To make an immune treatment that is effective for more cancer patients and those with PDAC specifically, we genetically engineered Salmonella to deliver exogenous antigens directly into the cytoplasm of tumor cells. We hypothesized that intracellular delivery of an exogenous immunization antigen would activate antigen-specific CD8 T cells and reduce tumors in immunized mice.

Build-a-bug workshop: Using microbial-host interactions and synthetic biology tools to create cancer therapies.

Many systemically administered cancer therapies exhibit dose-limiting toxicities that reduce their effectiveness. To increase efficacy, bacterial delivery platforms have been developed that improve safety and prolong treatment. Bacteria are a unique class of therapy that selectively colonizes most solid tumors.

Microbial Imbalance Induces Inflammation by Promoting Penetration through the Mucosal Barrier.

The balance of microbial species in the intestine must be maintained to prevent inflammation and disease. Healthy bacteria suppress infection by pathogens and prevent disorders such as inflammatory bowel diseases (IBDs). The role of mucus in the relation between pathogens and the intestinal microbiota is poorly understood.

Intracellular delivery of protein drugs with an autonomously lysing bacterial system reduces tumor growth and metastases.

Critical cancer pathways often cannot be targeted because of limited efficiency crossing cell membranes. Here we report the development of a Salmonella-based intracellular delivery system to address this challenge. We engineer genetic circuits that (1) activate the regulator flhDC to drive invasion and (2) induce lysis to release proteins into tumor cells.

A circular economy model for waste management in India.

Management of waste is one of the major challenges faced by many developing countries. This study therefore attempts to develop a circular economy (CE) model to manage wastes and closing the loop and reducing the generation of residual wastes in Indian municipalities. Through extant literature review, the researchers found 30 success factors of CE implementation.

Swimming back Toward Stiffer Polyetheylene Glycol Coatings, Increasing Contact in Flow.

Bacterial swimming in flow near surfaces is critical to the spread of infection and device colonization. Understanding how material properties affect flagella- and motility-dependent bacteria-surface interactions is a first step in designing new medical devices that mitigate the risk of infection. We report that, on biomaterial coatings such as polyethylene glycol (PEG) hydrogels and end-tethered layers that prevent adhesive bacteria accumulation, the coating mechanics and hydration control the near-surface travel and dynamic surface contact of cells in gentle shear flow (order 10 s).

Mucus blocks probiotics but increases penetration of motile pathogens and induces TNF-α and IL-8 secretion.

The mucosal barrier in combination with innate immune system are the first line of defense against luminal bacteria at the intestinal mucosa. Dysfunction of the mucus layer and bacterial infiltration are linked to tissue inflammation and disease. To study host-bacterial interactions at the mucosal interface, we created an experimental model that contains luminal space, a mucus layer, an epithelial layer, and suspended immune cells.

The motility regulator flhDC drives intracellular accumulation and tumor colonization of Salmonella.

Background: Salmonella have potential as anticancer therapeutic because of their innate tumor specificity. In clinical studies, this specificity has been hampered by heterogeneous responses. Understanding the mechanisms that control tumor colonization would enable the design of more robust therapeutic strains.

Architecture of the Human and Yeast General Transcription and DNA Repair Factor TFIIH.

TFIIH is essential for both RNA polymerase II transcription and DNA repair, and mutations in TFIIH can result in human disease. Here, we determine the molecular architecture of human and yeast TFIIH by an integrative approach using chemical crosslinking/mass spectrometry (CXMS) data, biochemical analyses, and previously published electron microscopy maps. We identified four new conserved "topological regions" that function as hubs for TFIIH assembly and more than 35 conserved topological features within TFIIH, illuminating a network of interactions involved in TFIIH assembly and regulation of its activities.