Two Antagonistic MALT1 Auto-Cleavage Mechanisms Reveal a Role for TRAF6 to Unleash MALT1 Activation.

The paracaspase MALT1 has arginine-directed proteolytic activity triggered by engagement of immune receptors. Recruitment of MALT1 into activation complexes is required for MALT1 proteolytic function. Here, co-expression of MALT1 in HEK293 cells, either with activated CARD11 and BCL10 or with TRAF6, was used to explore the mechanism of MALT1 activation at the molecular level. This work identified a prominent self-cleavage site of MALT1 isoform A (MALT1A) at R781 (R770 in MALT1B) and revealed that TRAF6 can activate MALT1 independently of the CBM. Intramolecular cleavage at R781/R770 removes a C-terminal TRAF6-binding site in both MALT1 isoforms, leaving MALT1B devoid of the two key interaction sites with TRAF6. A previously identified auto-proteolysis site of MALT1 at R149 leads to deletion of the death-domain, thereby abolishing interaction with BCL10. By using MALT1 isoforms and cleaved fragments thereof, as well as TRAF6 WT and mutant forms, this work shows that TRAF6 induces N-terminal auto-proteolytic cleavage of MALT1 at R149 and accelerates MALT1 protein turnover. The MALT1 fragment generated by N-terminal self-cleavage at R149 was labile and displayed enhanced signaling properties that required an intact K644 residue, previously shown to be a site for mono-ubiquitination of MALT1. Conversely, C-terminal self-cleavage at R781/R770 hampered the ability for self-cleavage at R149 and stabilized MALT1 by hindering interaction with TRAF6. C-terminal self-cleavage had limited impact on MALT1A but severely reduced MALT1B proteolytic and signaling functions. It also abrogated NF-κB activation by N-terminally cleaved MALT1A. Altogether, this study provides further insights into mechanisms that regulate the scaffolding and activation cycle of MALT1. It also emphasizes the reduced functional capacity of MALT1B as compared to MALT1A

Priority water research questions for South Africa developed through participatory processes

This paper describes a collaborative process of identifying and prioritising current and future water research questions from a wide range of water  specialists within South Africa. Over 1 600 questions were collected,  reduced in number and prioritised by specialists working in water research and practice. A total of 59 questions were finally proposed as an outcome of the study and are categorised under the themes of change, data, ecosystems, governance, innovation and resources. The questions range in scale, challenge and urgency, and are also aligned with prevailing  paradigms in water research. The majority of the questions dealt with relatively short- to medium-term research requirements and most focused on immediate issues such as water supply, service delivery and technical solutions. Formulations of long-term research questions were sparse,  partly because some of the principles and methods used in this study were difficult to apply in the South African context, and also because researchers are influenced by addressing what are believed to be the more immediate, short-term water-related challenges in South Africa. This is the first  initiative of its kind to produce a comprehensive and inclusive list of research priorities for water in South Africa.Keywords: research, questions, collaboration, prioritisation, South Afric

Views on unlawful water abstractions along the Liebenbergsvlei River, South Africa

As a result of the growing demand for additional water supplies, officials at the National Department of Water Affairs (DWA) continually monitor consumption patterns. The unlawful abstraction of water for irrigation purposes along the Axle and Liebenbergsvlei water transfer scheme, a South African river catchment, has been identified as a potential over-consumption hotspot. An investigation into the evolution of modern farming and irrigation developments along this important water transfer scheme found that restrictions on irrigation water abstraction have primarily focused on the water security of downstream urban and industrial users who receive water at a high assurance of supply. During periods of normal rainfall the authorities paid little attention to the existing use of water from the Liebenbergsvlei water transfer scheme. Subsequent restrictions placed on local water abstraction for irrigation has achieved mixed results. This paper focuses on the perspectives of irrigation farmers who may be unlawfully using water from the transfer scheme. Their views are compared with those expressed by the authorities on this issue, and the way in which the authorities attempt to regulate water use in the region within the confines of existing legislation. The responses from the different sectors were qualitatively analysed and suggested solutions have been formulated for further discussion. The study’s major findings reveal that the contestation around water use for agricultural purposes will continue as long as the misunderstandings surrounding legal or illegal water use persist. As demand on water is escalating, it is considered important to put in place water security measures designed to safeguard the available water in light of scarcity

An Economic Toolkit for Identifying the Cost of Emergency Medical Services (EMS) Systems: Detailed Methodology of the EMS Cost Analysis Project (EMSCAP)

Calculating the cost of an emergency medical services (EMS) system using a standardized method is important for determining the value of EMS. This article describes the development of a methodology for calculating the cost of an EMS system to its community. This includes a tool for calculating the cost of EMS (the “cost workbook”) and detailed directions for determining cost (the “cost guide”). The 12‐step process that was developed is consistent with current theories of health economics, applicable to prehospital care, flexible enough to be used in varying sizes and types of EMS systems, and comprehensive enough to provide meaningful conclusions. It was developed by an expert panel (the EMS Cost Analysis Project [EMSCAP] investigator team) in an iterative process that included pilot testing the process in three diverse communities. The iterative process allowed ongoing modification of the toolkit during the development phase, based upon direct, practical, ongoing interaction with the EMS systems that were using the toolkit. The resulting methodology estimates EMS system costs within a user‐defined community, allowing either the number of patients treated or the estimated number of lives saved by EMS to be assessed in light of the cost of those efforts. Much controversy exists about the cost of EMS and whether the resources spent for this purpose are justified. However, the existence of a validated toolkit that provides a standardized process will allow meaningful assessments and comparisons to be made and will supply objective information to inform EMS and community officials who are tasked with determining the utilization of scarce societal resources. ACADEMIC EMERGENCY MEDICINE 2012; 19:1–7 © 2012 by the Society for Academic Emergency MedicinePeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90144/1/j.1553-2712.2011.01277.x.pd

Low expression of the PPARγ-regulated gene thioredoxin-interacting protein accompanies human melanoma progression and promotes experimental lung metastases.

The thioredoxin system plays key roles in regulating cancer cell malignancy. Here we identify the Thioredoxin-interacting protein (TXNIP) as a gene, which expression is regulated by PPARγ in melanoma cells. We show that high TXNIP expression levels associate with benign melanocytic lesions, with tumor regression in patients on MAP kinase targeted therapy, with decreased proliferation in patients' melanoma biopsies, and with cell cycle arrest in human melanoma cell lines. In contrast, reduced TXNIP expression associates with advanced melanoma and with disease progression in patients. TXNIP depletion in human melanoma cells altered the expression of integrin beta-3 and the localization of the integrin alpha-v/beta-3 dimer at their surface. Moreover, TXNIP depletion affected human melanoma cell motility and improved their capacity to colonize mouse lungs in an in vivo assay. This study establishes TXNIP as a PPARγ-regulated gene in melanoma cells, thereby suggesting a link between these two proteins both involved in the regulation of cancer and of energy metabolism. It also reveals that the decrease in TXNIP expression, which is observed in advanced patient tumors, likely favors lung metastatic seeding of malignant cells

Priority water research questions for South Africa developed through participatory processes

This paper describes a collaborative process of identifying and prioritising current and future water research questions from a wide range of water specialists within South Africa. Over 1 600 questions were collected, reduced in number and prioritised by specialists working in water research and practice. A total of 59 questions were finally proposed as an outcome of the study and are categorised under the themes of change, data, ecosystems, governance, innovation and resources. The questions range in scale, challenge and urgency, and are also aligned with prevailing paradigms in water research. The majority of the questions dealt with relatively short- to medium-term research requirements and most focused on immediate issues such as water supply, service delivery and technical solutions. Formulations of long-term research questions were sparse, partly because some of the principles and methods used in this study were difficult to apply in the South African context, and also because researchers are influenced by addressing what are believed to be the more immediate, short-term water-related challenges in South Africa. This is the first initiative of its kind to produce a comprehensive and inclusive list of research priorities for water in South Africa

An Economic Toolkit for Identifying the Cost of Emergency Medical Services (EMS) Systems: Detailed Methodology of the EMS Cost Analysis Project (EMSCAP)

Calculating the cost of an emergency medical services (EMS) system using a standardized method is important for determining the value of EMS. This article describes the development of a methodology for calculating the cost of an EMS system to its community. This includes a tool for calculating the cost of EMS (the “cost workbook”) and detailed directions for determining cost (the “cost guide”). The 12‐step process that was developed is consistent with current theories of health economics, applicable to prehospital care, flexible enough to be used in varying sizes and types of EMS systems, and comprehensive enough to provide meaningful conclusions. It was developed by an expert panel (the EMS Cost Analysis Project [EMSCAP] investigator team) in an iterative process that included pilot testing the process in three diverse communities. The iterative process allowed ongoing modification of the toolkit during the development phase, based upon direct, practical, ongoing interaction with the EMS systems that were using the toolkit. The resulting methodology estimates EMS system costs within a user‐defined community, allowing either the number of patients treated or the estimated number of lives saved by EMS to be assessed in light of the cost of those efforts. Much controversy exists about the cost of EMS and whether the resources spent for this purpose are justified. However, the existence of a validated toolkit that provides a standardized process will allow meaningful assessments and comparisons to be made and will supply objective information to inform EMS and community officials who are tasked with determining the utilization of scarce societal resources. ACADEMIC EMERGENCY MEDICINE 2012; 19:1–7 © 2012 by the Society for Academic Emergency MedicinePeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90144/1/j.1553-2712.2011.01277.x.pd