Nanopores: maltoporin channel as a sensor for maltodextrin and lambda-phage

BACKGROUND: To harvest nutrition from the outside bacteria e.g. E. coli developed in the outer cell wall a number of sophisticated channels called porins. One of them, maltoporin, is a passive specific channel for the maltodextrin uptake. This channel was also named LamB as the bacterial virus phage Lambda mis-uses this channel to recognise the bacteria. The first step is a reversible binding followed after a lag phase by DNA injection. To date little is known about the binding capacity and less on the DNA injection mechanism. To elucidate the mechanism and to show the sensitivity of our method we reconstituted maltoporin in planar lipid membranes. Application of an external transmembrane electric field causes an ion current across the channel. Maltoporin channel diameter is around a few Angstroem. At this size the ion current is extremely sensitive to any modification of the channels surface. Protein conformational changes, substrate binding etc will cause fluctuations reflecting the molecular interactions with the channel wall. The recent improvement in ion current fluctuation analysis allows now studying the interaction of solutes with the channel on a single molecular level. RESULTS: We could demonstrate the asymmetry of the bacterial phage Lambda binding to its natural receptor maltoporin. CONCLUSION: We suggest that this type of measurement can be used as a new type of biosensors

Investigating the evolution of major Northern Hemisphere ice sheets during the last glacial-interglacial cycle

A 2.5-dimensional climate model of intermediate complexity, CLIMBER-2, fully coupled with the GREMLINS 3-D thermo-mechanical ice sheet model is used to simulate the evolution of major Northern Hemisphere ice sheets during the last glacial-interglacial cycle and to investigate the ice sheets responses to both insolation and atmospheric CO<sub>2</sub> concentration. This model reproduces the main phases of advance and retreat of Northern Hemisphere ice sheets during the last glacial cycle, although the amplitude of these variations is less pronounced than those based on sea level reconstructions. At the last glacial maximum, the simulated ice volume is 52.5×10<sup>15</sup> m<sup>3</sup> and the spatial distribution of both the American and Eurasian ice complexes is in reasonable agreement with observations, with the exception of the marine parts of these former ice sheets. <br> A set of sensitivity studies has also been performed to assess the sensitivity of the Northern Hemisphere ice sheets to both insolation and atmospheric CO<sub>2</sub>. Our results suggest that the decrease of summer insolation is the main factor responsible for the early build up of the North American ice sheet around 120 kyr BP, in agreement with benthic foraminifera δ<sup>18</sup>O signals. In contrast, low insolation and low atmospheric CO<sub>2</sub> concentration are both necessary to trigger a long-lasting glaciation over Eurasia

Relative importance of the mechanisms triggering the Eurasian ice sheet deglaciation in the GRISLI2.0 ice sheet model

The last deglaciation (21 to 8 ka) of the Eurasian ice sheet (EIS) is thought to have been responsible for a sea level rise of about 20 m. While many studies have examined the timing and rate of the EIS retreat during this period, many questions remain about the key processes that triggered the EIS deglaciation 21 kyr ago. Due to its large marine-based parts in the Barents–Kara (BKIS) and British Isles sectors, the BKIS is often considered to be a potential analogue of the current West Antarctic ice sheet (WAIS). Identifying the mechanisms that drove the EIS evolution might provide a better understanding of the processes at play in the West Antarctic destabilization. To investigate the relative impact of key drivers on the EIS destabilization, we used the three-dimensional ice sheet model GRISLI (GRenoble Ice Shelf and Land Ice) (version 2.0) forced by climatic fields from five Paleoclimate Modelling Intercomparison Project phases 3 and 4 (PMIP3, PMIP4) Last Glacial Maximum (LGM) simulations. In this study, we performed sensitivity experiments to test the response of the simulated Eurasian ice sheets to surface climate, oceanic temperatures (and thus basal melting under floating ice tongues), and sea level perturbations. Our results highlight that the EIS retreat simulated with the GRISLI model is primarily triggered by atmospheric warming. Increased atmospheric temperatures further amplify the sensitivity of the ice sheets to sub-shelf melting. These results contradict those of previous modelling studies mentioning the central role of basal melting on the deglaciation of the marine-based Barents–Kara ice sheet. However, we argue that the differences with previous works are mainly related to differences in the methodology followed to generate the initial LGM ice sheet. Due to the strong sensitivity of EIS to the atmospheric forcing highlighted with the GRISLI model and the limited extent of the confined ice shelves during the LGM, we conclude by questioning the analogy between EIS and the current WAIS. However, because of the expected rise in atmospheric temperatures, the risk of hydrofracturing is increasing and could ultimately put the WAIS in a configuration similar to the past Eurasian ice sheet.</p

Mixed quantum state detection with inconclusive results

We consider the problem of designing an optimal quantum detector with a fixed rate of inconclusive results that maximizes the probability of correct detection, when distinguishing between a collection of mixed quantum states. We develop a sufficient condition for the scaled inverse measurement to maximize the probability of correct detection for the case in which the rate of inconclusive results exceeds a certain threshold. Using this condition we derive the optimal measurement for linearly independent pure-state sets, and for mixed-state sets with a broad class of symmetries. Specifically, we consider geometrically uniform (GU) state sets and compound geometrically uniform (CGU) state sets with generators that satisfy a certain constraint. We then show that the optimal measurements corresponding to GU and CGU state sets with arbitrary generators are also GU and CGU respectively, with generators that can be computed very efficiently in polynomial time within any desired accuracy by solving a semidefinite programming problem.Comment: Submitted to Phys. Rev.

Systemic immunosuppression depletes peripheral blood regulatory B cells in patients with immune thrombocytopenia

Regulatory B (Breg) cells are potentially implicated in the pathogenesis of immune thrombocytopenia (ITP). We analysed a prospective cohort of newly diagnosed steroid naïve ITP patients enrolled in the multicentre FLIGHT trial and found that the numbers of Bregs in their peripheral blood were similar to healthy controls. In contrast, Breg numbers were significantly reduced in ITP patients treated with systemic immunosuppression (glucocorticoids or mycophenolate mofetil). We also demonstrate that glucocorticoid treatment impairs Breg interleukin-10 production via an indirect T-cell-mediated mechanism

An anti-siglec-8 antibody depletes sputum eosinophils from asthmatic subjects and inhibits lung mast cells

Background Sialic acid-binding immunoglobulin-like lectin (Siglec)-8 is expressed on mast cells and eosinophils, but information about Siglec-8 expression and function in the lung is limited. A humanized antibody, AK002, targeting Siglec-8 is undergoing development for treatment of diseases associated with mast cell and eosinophil-driven inflammation. Objective To characterize Siglec-8 expression in the airway in asthma and determine whether antibodies that target Siglec-8 (S8mAbs) can decrease airway eosinophils in asthma or inhibit lung mast cell activation. Methods Gene expression profiling and flow cytometry were used to characterize Siglec-8 expression in sputum cells from stable asthma. An antibody-dependent cellular cytotoxicity (ADCC) assay was used to determine whether an S8mAb can decrease eosinophils in sputum from asthma patients ex vivo. A mast cell activation assay was used to determine whether an S8mAb can inhibit mast cell activation in human lung tissue ex vivo. Results Gene expression for Siglec-8 is increased in sputum cells in asthma and correlates with gene expression for eosinophils and mast cells. Gene expression for Siglec-8 is inversely and significantly correlated with measures of airflow obstruction in asthma patients. Siglec-8 is prominently expressed on the surface of eosinophils and mast cells in sputum. S8mAbs decrease eosinophils in sputum from patients with asthma and inhibit Fc epsilon R1-activated mast cells in lung tissues. Conclusions and Clinical Relevance Siglec-8 is highly expressed on eosinophils and mast cells in asthmatic sputum and targeting Siglec-8 with an antibody is a plausible strategy to decrease sputum eosinophils and inhibit lung mast cells in asthma

ENU Mutagenesis Reveals a Novel Phenotype of Reduced Limb Strength in Mice Lacking Fibrillin 2

Background: Fibrillins 1 (FBN1) and 2 (FBN2) are components of microfibrils, microfilaments that are present in many connective tissues, either alone or in association with elastin. Marfan's syndrome and congenital contractural arachnodactyly (CCA) result from dominant mutations in the genes FBN1 and FBN2 respectively. Patients with both conditions often present with specific muscle atrophy or weakness, yet this has not been reported in the mouse models. In the case of Fbn1, this is due to perinatal lethality of the homozygous null mice making measurements of strength difficult. In the case of Fbn2, four different mutant alleles have been described in the mouse and in all cases syndactyly was reported as the defining phenotypic feature of homozygotes.Methodology/Principal Findings: As part of a large-scale N-ethyl-N-nitrosourea (ENU) mutagenesis screen, we identified a mouse mutant, Mariusz, which exhibited muscle weakness along with hindlimb syndactyly. We identified an amber nonsense mutation in Fbn2 in this mouse mutant. Examination of a previously characterised Fbn2-null mutant, Fbn2(fp), identified a similar muscle weakness phenotype. The two Fbn2 mutant alleles complement each other confirming that the weakness is the result of a lack of Fbn2 activity. Skeletal muscle from mutants proved to be abnormal with higher than average numbers of fibres with centrally placed nuclei, an indicator that there are some regenerating muscle fibres. Physiological tests indicated that the mutant muscle produces significantly less maximal force, possibly as a result of the muscles being relatively smaller in Mariusz mice.Conclusions: These findings indicate that Fbn2 is involved in integrity of structures required for strength in limb movement. As human patients with mutations in the fibrillin genes FBN1 and FBN2 often present with muscle weakness and atrophy as a symptom, Fbn2-null mice will be a useful model for examining this aspect of the disease process further

Effects of deletion of the Streptococcus pneumoniae lipoprotein diacylglyceryl transferase gene lgt on ABC transporter function and on growth in vivo

Lipoproteins are an important class of surface associated proteins that have diverse roles and frequently are involved in the virulence of bacterial pathogens. As prolipoproteins are attached to the cell membrane by a single enzyme, prolipoprotein diacylglyceryl transferase (Lgt), deletion of the corresponding gene potentially allows the characterisation of the overall importance of lipoproteins for specific bacterial functions. We have used a Δlgt mutant strain of Streptococcus pneumoniae to investigate the effects of loss of lipoprotein attachment on cation acquisition, growth in media containing specific carbon sources, and virulence in different infection models. Immunoblots of triton X-114 extracts, flow cytometry and immuno-fluorescence microscopy confirmed the Δlgt mutant had markedly reduced lipoprotein expression on the cell surface. The Δlgt mutant had reduced growth in cation depleted medium, increased sensitivity to oxidative stress, reduced zinc uptake, and reduced intracellular levels of several cations. Doubling time of the Δlgt mutant was also increased slightly when grown in medium with glucose, raffinose and maltotriose as sole carbon sources. These multiple defects in cation and sugar ABC transporter function for the Δlgt mutant were associated with only slightly delayed growth in complete medium. However the Δlgt mutant had significantly reduced growth in blood or bronchoalveolar lavage fluid and a marked impairment in virulence in mouse models of nasopharyngeal colonisation, sepsis and pneumonia. These data suggest that for S. pneumoniae loss of surface localisation of lipoproteins has widespread effects on ABC transporter functions that collectively prevent the Δlgt mutant from establishing invasive infection

A comparative analysis of contraceptive use in Africa: evidence from DHS

The aim of this article is to show a comparative analysis of contraceptive use in areas of traditionally high fertility that have gone through profound changes. Data have been taken from the latest Demographic and Health Surveys (DHS). Logistic regression models were adopted for four selected representative countries, namely Egypt, Mali, Namibia and Niger. There were two selection criteria: data should be recent, and selected countries should have high (Egypt 57.4%; Namibia 46.4%) or low (Mali 7.5%; Niger 10.0%) contraceptive use. The probability of using contraception when a woman has had one to four children is 2.4 times higher than when they have had no children. Contraception data are always gathered at a point of time, but crosssectional data are not sufficient to understand all the mechanisms hidden behind contraceptive use. Different contraceptive behaviours need good estimation tools to develop specific family planning programmes.Web of Scienc