Two closely related ABC transporters in streptococcus mutans are involved in disaccharide and/or oligosaccharide uptake.

Streptococcus mutans has a large number of transporters apparently involved in the uptake of carbohydrates. At least two of these, the multiple sugar metabolism transporter, MsmEFGK, and the previously uncharacterized MalXFGK, are members of the ATP-binding cassette (ABC) superfamily. Mutation analysis revealed that the MsmEFGK and MalXFGK transporters are principally involved in the uptake of distinct disaccharides and/or oligosaccharides. Furthermore, the data also indicated an unusual protein interaction between the components of these two related transporters. Strains lacking msmE (which encodes a solute binding protein) can no longer utilize raffinose or stachyose but grow normally on maltodextrins in the absence of MalT, a previously characterized EII(mal) phosphotransferase system component. In contrast, a mutant of malX (which encodes a solute binding protein) cannot utilize maltodextrins but grows normally on raffinose or stachyose. Radioactive uptake assays confirmed that MalX, but not MsmE, is required for uptake of [U-14C]maltotriose and that MalXFGK is principally involved in the uptake of maltodextrins with as many as 7 glucose units. Surprisingly, inactivation of the corresponding ATPase components did not result in an equivalent abolition of growth: the malK mutant can grow on maltotetraose as a sole carbon source, and the msmK mutant can utilize raffinose. We propose that the ATPase domains of these ABC transporters can interact with either their own or the alternative transporter complex. Such unexpected interaction of ATPase subunits with distinct membrane components to form complete multiple ABC transporters may be widespread in bacteria

The Ethnic and Class Dimensions in Neighborhood: A Means for the Reorganization of Human Service Delivery Systems

Excerpt from the full-text article: Human service delivery systems get criticized by both users and providers of the services, regardless of countless reforms, evaluations, models, decentralization efforts and re-evaluations. In order to determine directions for the future, this article will discuss past policy initiatives, and review the literature which links human service needs to ethnicity and social class in a neighborhood context

Medication decision-making for patients with renal insufficiency in inpatient and outpatient care at a US Veterans Affairs Medical Centre: a qualitative, cognitive task analysis.

BackgroundMany studies identify factors that contribute to renal prescribing errors, but few examine how healthcare professionals (HCPs) detect and recover from an error or potential patient safety concern. Knowledge of this information could inform advanced error detection systems and decision support tools that help prevent prescribing errors.ObjectiveTo examine the cognitive strategies that HCPs used to recognise and manage medication-related problems for patients with renal insufficiency.DesignHCPs submitted documentation about medication-related incidents. We then conducted cognitive task analysis interviews. Qualitative data were analysed inductively.SettingInpatient and outpatient facilities at a major US Veterans Affairs Medical Centre.ParticipantsPhysicians, nurses and pharmacists who took action to prevent or resolve a renal-drug problem in patients with renal insufficiency.OutcomesEmergent themes from interviews, as related to recognition of renal-drug problems and decision-making processes.ResultsWe interviewed 20 HCPs. Results yielded a descriptive model of the decision-making process, comprised of three main stages: detect, gather information and act. These stages often followed a cyclical path due largely to the gradual decline of patients' renal function. Most HCPs relied on being vigilant to detect patients' renal-drug problems rather than relying on systems to detect unanticipated cues. At each stage, HCPs relied on different cognitive cues depending on medication type: for renally eliminated medications, HCPs focused on gathering renal dosing guidelines, while for nephrotoxic medications, HCPs investigated the need for particular medication therapy, and if warranted, safer alternatives.ConclusionsOur model is useful for trainees so they can gain familiarity with managing renal-drug problems. Based on findings, improvements are warranted for three aspects of healthcare systems: (1) supporting the cyclical nature of renal-drug problem management via longitudinal tracking mechanisms, (2) providing tools to alleviate HCPs' heavy reliance on vigilance and (3) supporting HCPs' different decision-making needs for renally eliminated versus nephrotoxic medications

The utility of whole body vibration exercise in haemodialysis patients: a pilot study

Background: Exercise improves physical capacity in patients with end-stage renal disease on haemodialysis (HD), but few patients engage in it. Whole-body vibration exercise (WBVE) is a novel protocol that has been shown to benefit frail elderly patients’ rehabilitation. We assessed the utility of WBVE before HD sessions and tested methods to inform the design of a randomized controlled trial (RCT). Methods: Physical condition and quality of life were assessed at enrolment and repeated 2 weeks later in a pilot study of 49 patients undergoing regular HD. All patients then undertook 8 weeks of WBVE, thrice weekly for 3 min, after which the assessments were repeated and results compared (paired t-tests). Further assessments were made after a 4-week layoff. Patients completed a post-study questionnaire about their experiences of using WBVE. The reproducibility of WBVE and effects on measures of functionality, muscle strength, indirect exercise capacity, nutritional status, bone health and quality of life were recorded to undertake a power calculation for an RCT. Results: Of 49 patients enrolled, 25 completed all assessments. The dropout rate was high at 49%, but overall, WBVE was an acceptable form of exercise. Functionality as assessed by the 60-s sit-to-stand test (STS-60) improved significantly by 11% (P = 0.002). Some quality of life domains also improved significantly. All improvements were maintained 4 weeks after discontinuing WBVE. Conclusions: WBVE was acceptable, safe, easily incorporated into the routine of HD and was associated with useful improvements in physical function sufficient to justify a RCT

Bitopic binding mode of an M1 muscarinic acetylcholine receptor agonist associated with adverse clinical trial outcomes

The realisation of the therapeutic potential of targeting the M1 muscarinic acetylcholine receptor (M1 mAChR) for the treatment of cognitive decline in Alzheimer's disease has prompted the discovery of M1 mAChR ligands showing efficacy in alleviating cognitive dysfunction in both rodents and humans. Among these is GSK1034702, described previously as a potent M1 receptor allosteric agonist, which showed pro-cognitive effects in rodents and improved immediate memory in a clinical nicotine withdrawal test but induced significant side-effects. Here we provide evidence using ligand binding, chemical biology and functional assays to establish that rather than the allosteric mechanism claimed, GSK1034702 interacts in a bitopic manner at the M1 mAChR such that it can concomitantly span both the orthosteric and an allosteric binding site. The bitopic nature of GSK1034702 together with the intrinsic agonist activity and a lack of muscarinic receptor subtype selectivity reported here, all likely contribute to the adverse effects of this molecule in clinical trials. We conclude that these properties, whilst imparting beneficial effects on learning and memory, are undesirable in a clinical candidate due to the likelihood of adverse side effects. Rather, our data supports the notion that "pure" positive allosteric modulators showing selectivity for the M1 mAChR with low levels of intrinsic activity would be preferable to provide clinical efficacy with low adverse responses

m-Calpain is required for preimplantation embryonic development in mice

BACKGROUND: μ-calpain and m-calpain are ubiquitously expressed proteases implicated in cellular migration, cell cycle progression, degenerative processes and cell death. These heterodimeric enzymes are composed of distinct catalytic subunits, encoded by Capn1 (μ-calpain) or Capn2 (m-calpain), and a common regulatory subunit encoded by Capn4. Disruption of the mouse Capn4 gene abolished both μ-calpain and m-calpain activity, and resulted in embryonic lethality, thereby suggesting essential roles for one or both of these enzymes during mammalian embryogenesis. Disruption of the Capn1 gene produced viable, fertile mice implying that either m-calpain could compensate for the loss of μ-calpain, or that the loss of m-calpain was responsible for death of Capn4(-/- )mice. RESULTS: To distinguish between the alternatives described above, we deleted an essential coding region in the mouse Capn2 gene in embryonic stems cells and transmitted this mutant allele through the mouse germline. Breeding of heterozygous animals failed to produce homozygous mutant live offspring or implanted embryos. A nested PCR genotyping protocol was established, and homozygous preimplantation mutant embryos were detected at the morula but not at the blastocyts stage. CONCLUSION: We conclude that homozygous disruption of the Capn2 gene results in pre-implantation embryonic lethality between the morula and blastocyst stage. This establishes that μ-calpain and m-calpain have distinct functions, and that m-calpain is vital for development of the preimplantation murine embryo

Sufficient conditions for two-dimensional localization by arbitrarily weak defects in periodic potentials with band gaps

We prove, via an elementary variational method, 1d and 2d localization within the band gaps of a periodic Schrodinger operator for any mostly negative or mostly positive defect potential, V, whose depth is not too great compared to the size of the gap. In a similar way, we also prove sufficient conditions for 1d and 2d localization below the ground state of such an operator. Furthermore, we extend our results to 1d and 2d localization in d dimensions; for example, a linear or planar defect in a 3d crystal. For the case of D-fold degenerate band edges, we also give sufficient conditions for localization of up to D states.Comment: 9 pages, 3 figure

The Armadillo Repeat Protein PF16 Is Essential for Flagellar Structure and Function in Plasmodium Male Gametes

Malaria, caused by the apicomplexan parasite Plasmodium, threatens 40% of the world\u27s population. Transmission between vertebrate and insect hosts depends on the sexual stages of the life-cycle. The male gamete of Plasmodium parasite is the only developmental stage that possesses a flagellum. Very little is known about the identity or function of proteins in the parasite\u27s flagellar biology. Here, we characterise a Plasmodium PF16 homologue using reverse genetics in the mouse malaria parasite Plasmodium berghei. PF16 is a conserved Armadillo-repeat protein that regulates flagellar structure and motility in organisms as diverse as green algae and mice. We show that P. berghei PF16 is expressed in the male gamete flagellum, where it plays a crucial role maintaining the correct microtubule structure in the central apparatus of the axoneme as studied by electron microscopy. Disruption of the PF16 gene results in abnormal flagellar movement and reduced fertility, but does not lead to complete sterility, unlike pf16 mutations in other organisms. Using homology modelling, bioinformatics analysis and complementation studies in Chlamydomonas, we show that some regions of the PF16 protein are highly conserved across all eukaryotes, whereas other regions may have species-specific functions. PF16 is the first ARM-repeat protein characterised in the malaria parasite genus Plasmodium and this study opens up a novel model for analysis of Plasmodium flagellar biology that may provide unique insights into an ancient organelle and suggest novel intervention strategies to control the malaria parasite