Skp is a multivalent chaperone of outer membrane proteins

The trimeric chaperone Skp sequesters outer-membrane proteins (OMPs) within a hydrophobic cage, thereby preventing their aggregation during transport across the periplasm in Gram-negative bacteria. Here, we studied the interaction between Escherichia coli Skp and five OMPs of varying size. Investigations of the kinetics of OMP folding revealed that higher Skp/OMP ratios are required to prevent the folding of 16-stranded OMPs compared with their 8-stranded counterparts. Ion mobility spectrometry–mass spectrometry (IMS–MS) data, computer modeling and molecular dynamics simulations provided evidence that 10- to 16-stranded OMPs are encapsulated within an expanded Skp substrate cage. For OMPs that cannot be fully accommodated in the expanded cavity, sequestration is achieved by binding of an additional Skp trimer. The results suggest a new mechanism for Skp chaperone activity involving the coordination of multiple copies of Skp in protecting a single substrate from aggregation

Formulations of Plant Growth-Promoting Microbes for Field Applications

Development of a plant growth-promoting (PGP) microbe needs several steps starting with isolation of a pure culture, screening of its PGP or antagonistic traits by means of different efficacy bioassays performed in vitro, in vivo or in trials under greenhouse and/or field conditions. In order to maximize the potential of an efficient PGP microbe, it is essential to optimize mass multiplication protocols that promote product quality and quantity and a product formulation that enhances bioactivity, preserves shelf life and aids product delivery. Selection of formulation is very crucial as it can determine the success or failure of a PGP microbe. A good carrier material should be able to deliver the right number of viable cells in good physiological conditions, easy to use and economically affordable by the farmers. Several carrier materials have been used in formulation that include peat, talc, charcoal, cellulose powder, farm yard manure, vermicompost and compost, lignite, bagasse and press mud. Each formulation has its advantages and disadvantages but the peat based carrier material is widely used in different part of the world. This chapter gives a comprehensive analysis of different formulations and the quality of inoculants available in the market, with a case study conducted in five-states of India

Outer membrane protein folding from an energy landscape perspective

The cell envelope is essential for the survival of Gram-negative bacteria. This specialised membrane is densely packed with outer membrane proteins (OMPs), which perform a variety of functions. How OMPs fold into this crowded environment remains an open question. Here, we review current knowledge about OFMP folding mechanisms in vitro and discuss how the need to fold to a stable native state has shaped their folding energy landscapes. We also highlight the role of chaperones and the β-barrel assembly machinery (BAM) in assisting OMP folding in vivo and discuss proposed mechanisms by which this fascinating machinery may catalyse OMP folding

JAK-STAT Signaling: A Double-Edged Sword of Immune Regulation and Cancer Progression

Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling mediates almost all immune regulatory processes, including those that are involved in tumor cell recognition and tumor-driven immune escape. Antitumor immune responses are largely driven by STAT1 and STAT2 induction of type I and II interferons (IFNs) and the downstream programs IFNs potentiate. Conversely, STAT3 has been widely linked to cancer cell survival, immunosuppression, and sustained inflammation in the tumor microenvironment. The discovery of JAK-STAT cross-regulatory mechanisms, post-translational control, and non-canonical signal transduction has added a new level of complexity to JAK-STAT governance over tumor initiation and progression. Endeavors to better understand the vast effects of JAK-STAT signaling on antitumor immunity have unearthed a wide range of targets, including oncogenes, miRNAs, and other co-regulatory factors, which direct specific phenotypical outcomes subsequent to JAK-STAT stimulation. Yet, the rapidly expanding field of therapeutic developments aimed to resolve JAK-STAT aberrations commonly reported in a multitude of cancers has been marred by off-target effects. Here, we discuss JAK-STAT biology in the context of immunity and cancer, the consequences of pathway perturbations and current therapeutic interventions, to provide insight and consideration for future targeting innovations

Intratumoral administration of the Toll-like receptor 7/8 agonist 3M-052 enhances interferon-driven tumor immunogenicity and suppresses metastatic spread in preclinical triple-negative breast cancer

Objectives: Loss of tumor-inherent type I interferon (IFN) signalling has been closely linked to accelerated metastatic progression via decreased immunogenicity and antitumor immunity. Previous studies in murine models of triple-negative breast cancer (TNBC) demonstrate that systemic IFN inducers are effective antimetastatic agents, via sustained antitumor CD8+ T-cell responses. Repeated systemic dosing with recombinant IFNs or IFN inducers is associated with significant toxicities; hence, the use of alternate intratumoral agents is an active area of investigation. It is critical to investigate the impact of intratumoral agents on subsequent metastatic spread to predict clinical impact. Methods: In this study, the local and systemic impact of the intratumoral Toll-like receptor (TLR) 7/8 agonist 3M-052 alone or in combination with anti-PD1 was evaluated in metastatic TNBC models. The IFN-α receptor (IFNAR1) blocking antibody, MAR1-5A3, along with immune-deficient mice and ex vivo assays are utilised to examine the key targets of this agent that are critical for an antimetastatic response. Results: Single intratumoral administration of 3M-052 reduced mammary tumor growth, induced a T-cell-inflamed tumor microenvironment (TME) and reduced metastatic spread to lung. Metastasis suppression was reliant on IFN signalling and an antitumor immune response, in contrast to primary tumor growth inhibition, which was retained in NSG and CD8+ T-cell-depleted mice. 3M-052 action was demonstrated via dendritic cell activation and production of type I IFN and other pro-inflammatory cytokines to initiate a T-cell-inflamed TME and promote tumor cell antigen presentation. Conclusion: This work supports neoadjuvant TLR agonist-based immunotherapeutics as realistic options for immune activation in the TME and long-term metastatic protection in TNBC

Interdisciplinary approaches in career studies

This is the opening article in a Human Relations special issue on 'Interdisciplinary approaches to contemporary career studies'. After introducing a story of an 'exceptional - but real' career, we argue for an urgent shift toward greater interdisciplinary inquiry. We reflect on the story to describe differences in the way each of psychology, sociology, social psychology, and economics views the concept of career. We turn to explore what career researchers, representing each of the above social sciences, might not see on their own. In contrast, we highlight how social scientists can move toward a) appreciating the limitations of our separate approaches, b) introducing more appropriate research methods, c) maintaining a wider cross-disciplinary conversation, and d) better serving the client - the person - in our future research. We continue with a preview of the remaining five articles in this special issue, and propose that these can serve as stimuli for a wider conversation. © 2011 The Author(s)