Relocation of active site carboxylates in major facilitator superfamily multidrug transporter LmrP reveals plasticity in proton interactions

The expression of polyspecific membrane transporters is one important mechanism by which cells can obtain resistance to structurally different antibiotics and cytotoxic agents. These transporters reduce intracellular drug concentrations to subtoxic levels by mediating drug efflux across the cell envelope. The major facilitator superfamily multidrug transporter LmrP from $\textit{Lactococcus}$ lactis catalyses drug efflux in a membrane potential and chemical proton gradient-dependent fashion. To enable the interaction with protons and cationic substrates, LmrP contains catalytic carboxyl residues on the surface of a large interior chamber that is formed by transmembrane helices. These residues co-localise together with polar and aromatic residues, and are predicted to be present in two clusters. To investigate the functional role of the catalytic carboxylates, we generated mutant proteins catalysing membrane potential-independent dye efflux by removing one of the carboxyl residues in Cluster 1. We then relocated this carboxyl residue to six positions on the surface of the interior chamber, and tested for restoration of wildtype energetics. The reinsertion at positions towards Cluster 2 reinstated the membrane potential dependence of dye efflux. Our data uncover a remarkable plasticity in proton interactions in LmrP, which is a consequence of the flexibility in the location of key residues that are responsible for proton/multidrug antiport.A.V.N. is a research associate funded by the Biotechnology and Biological Sciences Research Council (BBSRC). H.S., S.R. and Z.T. received scholarships from the Cambridge Commonwealth, European and International Trust. A.N. is the recipient of a Herchel-Smith Scholarship. K.A. is funded through a programme grant from the Human Frontier Science Program

Role of mitochondrial raft-like microdomains in the regulation of cell apoptosis

Lipid rafts are envisaged as lateral assemblies of specific lipids and proteins that dissociate and associate rapidly and form functional clusters in cell membranes. These structural platforms are not confined to the plasma membrane; indeed lipid microdomains are similarly formed at subcellular organelles, which include endoplasmic reticulum, Golgi and mitochondria, named raft-like microdomains. In addition, some components of raft-like microdomains are present within ER-mitochondria associated membranes. This review is focused on the role of mitochondrial raft-like microdomains in the regulation of cell apoptosis, since these microdomains may represent preferential sites where key reactions take place, regulating mitochondria hyperpolarization, fission-associated changes, megapore formation and release of apoptogenic factors. These structural platforms appear to modulate cytoplasmic pathways switching cell fate towards cell survival or death. Main insights on this issue derive from some pathological conditions in which alterations of microdomains structure or function can lead to severe alterations of cell activity and life span. In the light of the role played by raft-like microdomains to integrate apoptotic signals and in regulating mitochondrial dynamics, it is conceivable that these membrane structures may play a role in the mitochondrial alterations observed in some of the most common human neurodegenerative diseases, such as Amyotrophic lateral sclerosis, Huntington's chorea and prion-related diseases. These findings introduce an additional task for identifying new molecular target(s) of pharmacological agents in these pathologies

Inequalities in higher education in low‐ and middle‐income countries:A scoping review of the literature

Motivation:  Higher  education  is  regarded  as  a  key  instrument  to  enhance  socioeconomic  mobility  andreduce inequalities. Recent literature reviews have examined inequalities in the higher education systemsof  high-income  countries,  but  less  is  known  about  the  situation  in  low-  and  middle-income  countries,where higher education is expanding fast.Purpose:  The  article  reviews  the  academic  literature  on  higher  education  in  low-  and  middle-incomecountries using a research framework inspired by social justice and capability approaches. It considers the financial,  socio-cultural,  human,  and  political  resource  domains  on  which  people  draw,  and  how  they relate to access, participation, and outcomes in higher education.Methods: A literature search for studies explicitly discussing in-country  inequalities  in  higher  education revealed  22  publications. Substantial  knowledge  gaps remain,  especially  regarding  the  political  (and decision-making)  side  of  inequalities;  the  ideologies  and  philosophies  underpinning  higher  education systems; and the linkages between resource domains, both micro and macro.Findings:  The  review  highlights  key  elements  for  policy-makers  and  researchers:  (1)  the  financial  lens alone  is  insufficient  to  understand  and  tackle  inequalities,  since  these  are  also  shaped  by  human  and other non-financial factors; (2) socio-cultural constructs are central in explaining unequal outcomes; and (3) inequalities develop throughout one’s life and need to be considered during, but also before and afterhigher education.  The scope  of  inequalities  is  wide, and  the literature  offers a  few ideas  for short-term fixes such as part-time and online education.Policy implications: Inclusive policy frameworks for higher education should include explicit goals related to (in)equality,  which  are  best  measured in  terms  of  the  extent  to  which  certain  actions  or  choices are feasible for all. Policies in these frameworks, we argue, should go beyond providing financial support, and also address socio-cultural and human resource constraints and challenges in retention, performance, and labour market outcomes. Finally, they should consider relevant contextual determinants of inequalities.</p

The role of the mitochondria and the endoplasmic reticulum contact sites in the development of the immune responses

Abstract Mitochondria and endoplasmic reticulum (ER) contact sites (MERCs) are dynamic modules enriched in subset of lipids and specialized proteins that determine their structure and functions. The MERCs regulate lipid transfer, autophagosome formation, mitochondrial fission, Ca2+ homeostasis and apoptosis. Since these functions are essential for cell biology, it is therefore not surprising that MERCs also play a critical role in organ physiology among which the immune system stands by its critical host defense function. This defense system must discriminate and tolerate host cells and beneficial commensal microorganisms while eliminating pathogenic ones in order to preserve normal homeostasis. To meet this goal, the immune system has two lines of defense. First, the fast acting but unspecific innate immune system relies on anatomical physical barriers and subsets of hematopoietically derived cells expressing germline-encoded receptors called pattern recognition receptors (PRR) recognizing conserved motifs on the pathogens. Second, the slower but very specific adaptive immune response is added to complement innate immunity. Adaptive immunity relies on another set of specialized cells, the lymphocytes, harboring receptors requiring somatic recombination to be expressed. Both innate and adaptive immune cells must be activated to phagocytose and process pathogens, migrate, proliferate, release soluble factors and destroy infected cells. Some of these functions are strongly dependent on lipid transfer, autophagosome formation, mitochondrial fission, and Ca2+ flux; this indicates that MERCs could regulate immunity

Learners’ access to tools and experience with technology at the University of the South Pacific: readiness for e-learning

Technology in higher education has become exceedingly popular and useful; however, a digital divide generally applies to the use of technology in education in many developing countries. The Pacific Island countries differ in their technological capacities and infrastructure, with the Fijian capital Suva being most technologically and infrastructurally advanced compared with other towns in Fiji and in other Pacific Island countries. This led the researchers to investigate access to e-learning tools and experience with technology amongst a group of 92 students, ranging from 18 to over 55 years of age, enrolled in postgraduate courses in education at the University of the South Pacific. A survey consisting of questions on age, gender, qualification, professional experience, ethnicity and access to and experience with technology was carried out for one cohort. The findings indicate an encouraging level of readiness for e-learning

Not Available

Not AvailableEight new potato (Solanum tuberosum L.) hybrids including two checks (Kufri Giriraj and Kufri Jyoti) were evaluatedat Ranichauri, Tehri Garhwal, Uttarakhand during kharif 2008. Most of the traits differed significantly except shoot numbers hill-1, number of compound leaves plant-1, shoot weight, ‘A’ and ‘B’ grade tubers and specific gravity. Among hybrids, SM/91-1515 gave highest yield and most tolerant to late blight, even at the late stage of the crop. Thus SM/91- 1515 hybrid was found to be suitable for Garhwal Himalayas of Uttarakhand.Not Availabl

Building Blocks for Volume-Oriented Changeability in Personnel Cost Structure of Manufacturing Companies

Part 1: Knowledge-Based Performance ImprovementInternational audienceVolatilities in global markets lead to rising importance of volume-oriented changeability (VoC) in the manufacturing industry. If the production demand is fluctuating, manufacturing companies often struggle to adapt their overhead costs, which are causing high variances in unit costs. Personnel is a main cost driver in overhead cost structure, in particular in high-wage countries. Therefore, this paper conceptualizes building blocks and analyzes impact relations for configuring VoC in personnel cost structure in production plants