Multiscale Computations on Neural Networks: From the Individual Neuron Interactions to the Macroscopic-Level Analysis

We show how the Equation-Free approach for multi-scale computations can be exploited to systematically study the dynamics of neural interactions on a random regular connected graph under a pairwise representation perspective. Using an individual-based microscopic simulator as a black box coarse-grained timestepper and with the aid of simulated annealing we compute the coarse-grained equilibrium bifurcation diagram and analyze the stability of the stationary states sidestepping the necessity of obtaining explicit closures at the macroscopic level. We also exploit the scheme to perform a rare-events analysis by estimating an effective Fokker-Planck describing the evolving probability density function of the corresponding coarse-grained observables

Penalty-free feasibility boundary convergent multi-objective evolutionary algorithm for the optimization of water distribution systems

This paper presents a new penalty-free multi-objective evolutionary approach (PFMOEA) for the optimization of water distribution systems (WDSs). The proposed approach utilizes pressure dependent analysis (PDA) to develop a multi-objective evolutionary search. PDA is able to simulate both normal and pressure deficient networks and provides the means to accurately and rapidly identify the feasible region of the solution space, effectively locating global or near global optimal solutions along its active constraint boundary. The significant advantage of this method over previous methods is that it eliminates the need for ad-hoc penalty functions, additional “boundary search” parameters, or special constraint handling procedures. Conceptually, the approach is downright straightforward and probably the simplest hitherto. The PFMOEA has been applied to several WDS benchmarks and its performance examined. It is demonstrated that the approach is highly robust and efficient in locating optimal solutions. Superior results in terms of the initial network construction cost and number of hydraulic simulations required were obtained. The improvements are demonstrated through comparisons with previously published solutions from the literature

Excretory/Secretory-Products of Echinococcus multilocularis Larvae Induce Apoptosis and Tolerogenic Properties in Dendritic Cells In Vitro

Parasitic helminths are inducers of chronic diseases and have evolved mechanisms to suppress the host immune response. Mostly from studies on roundworms, a picture is currently emerging that helminths secrete factors (E/S-products) that directly act on sentinels of the immune system, dendritic cells, in order to achieve an expansion of immunosuppressive, regulatory T cells (T-reg). Parasitic helminths are currently also intensely studied as therapeutic agents against autoimmune diseases and allergies, which is directly linked to their immunosuppressive activities. The immunomodulatory products of parasitic helminths are therefore of high interest for understanding immunopathology during infections and for the treatment of allergies. The present work was conducted on larvae of the tapeworm E. multilocularis, which grow like a tumor into surrounding host tissue and thus cause the lethal disease alveolar echinococcosis. The authors found that E/S-products from early infective larvae are strong inducers of tolerogenic DC in vitro and show that E/S-products of larvae of the chronic stage lead to an in vitro expansion of Foxp3+ T cells, suggesting that both the expansion of these T cells and poorly responsive DC are important for the establishment and persistence of E. multilocularis larvae within the host

Septin6 and Septin7 GTP binding proteins regulate AP-3- and ESCRT-dependent multivesicular body biogenesis

Septins (SEPTs) form a family of GTP-binding proteins implicated in cytoskeleton and membrane organization, cell division and host/pathogen interactions. The precise function of many family members remains elusive. We show that SEPT6 and SEPT7 complexes bound to F-actin regulate protein sorting during multivesicular body (MVB) biogenesis. These complexes bind AP-3, an adapter complex sorting cargos destined to remain in outer membranes of maturing endosomes, modulate AP-3 membrane interactions and the motility of AP-3-positive endosomes. These SEPT-AP interactions also influence the membrane interaction of ESCRT (endosomal-sorting complex required for transport)-I, which selects ubiquitinated cargos for degradation inside MVBs. Whereas our findings demonstrate that SEPT6 and SEPT7 function in the spatial, temporal organization of AP-3- and ESCRT-coated membrane domains, they uncover an unsuspected coordination of these sorting machineries during MVB biogenesis. This requires the E3 ubiquitin ligase LRSAM1, an AP-3 interactor regulating ESCRT-I sorting activity and whose mutations are linked with Charcot-Marie-Tooth neuropathies

Loss of ZnT8 function protects against diabetes by enhanced insulin secretion.

A rare loss-of-function allele p.Arg138* in SLC30A8 encoding the zinc transporter 8 (ZnT8), which is enriched in Western Finland, protects against type 2 diabetes (T2D). We recruited relatives of the identified carriers and showed that protection was associated with better insulin secretion due to enhanced glucose responsiveness and proinsulin conversion, particularly when compared with individuals matched for the genotype of a common T2D-risk allele in SLC30A8, p.Arg325. In genome-edited human induced pluripotent stem cell (iPSC)-derived β-like cells, we establish that the p.Arg138* allele results in reduced SLC30A8 expression due to haploinsufficiency. In human β cells, loss of SLC30A8 leads to increased glucose responsiveness and reduced KATP channel function similar to isolated islets from carriers of the T2D-protective allele p.Trp325. These data position ZnT8 as an appealing target for treatment aimed at maintaining insulin secretion capacity in T2D

Single Molecule Imaging Reveals Differences in Microtubule Track Selection Between Kinesin Motors

Molecular motors differentially recognize and move cargo along discrete microtubule subpopulations in cells, resulting in preferential transport and targeting of subcellular cargoes

Both SEPT2 and MLL are down-regulated in MLL-SEPT2 therapy-related myeloid neoplasia

<p>Abstract</p> <p>Background</p> <p>A relevant role of septins in leukemogenesis has been uncovered by their involvement as fusion partners in <it>MLL</it>-related leukemia. Recently, we have established the <it>MLL-SEPT2 </it>gene fusion as the molecular abnormality subjacent to the translocation t(2;11)(q37;q23) in therapy-related acute myeloid leukemia. In this work we quantified <it>MLL </it>and <it>SEPT2 </it>gene expression in 58 acute myeloid leukemia patients selected to represent the major AML genetic subgroups, as well as in all three cases of <it>MLL-SEPT2</it>-associated myeloid neoplasms so far described in the literature.</p> <p>Methods</p> <p>Cytogenetics, fluorescence in situ hybridization (FISH) and molecular studies (RT-PCR, qRT-PCR and qMSP) were used to characterize 58 acute myeloid leukemia patients (AML) at diagnosis selected to represent the major AML genetic subgroups: <it>CBFB-MYH11 </it>(n = 13), <it>PML-RARA </it>(n = 12); <it>RUNX1-RUNX1T1 </it>(n = 12), normal karyotype (n = 11), and <it>MLL </it>gene fusions other than <it>MLL-SEPT2 </it>(n = 10). We also studied all three <it>MLL-SEPT2 </it>myeloid neoplasia cases reported in the literature, namely two AML patients and a t-MDS patient.</p> <p>Results</p> <p>When compared with normal controls, we found a 12.8-fold reduction of wild-type <it>SEPT2 </it>and <it>MLL-SEPT2 </it>combined expression in cases with the <it>MLL-SEPT2 </it>gene fusion (p = 0.007), which is accompanied by a 12.4-fold down-regulation of wild-type <it>MLL </it>and <it>MLL-SEPT2 </it>combined expression (p = 0.028). The down-regulation of <it>SEPT2 </it>in <it>MLL-SEPT2 </it>myeloid neoplasias was statistically significant when compared with all other leukemia genetic subgroups (including those with other <it>MLL </it>gene fusions). In addition, <it>MLL </it>expression was also down-regulated in the group of <it>MLL </it>fusions other than <it>MLL-SEPT2</it>, when compared with the normal control group (p = 0.023)</p> <p>Conclusion</p> <p>We found a significant down-regulation of both <it>SEPT2 </it>and <it>MLL </it>in <it>MLL-SEPT2 </it>myeloid neoplasias. In addition, we also found that <it>MLL </it>is under-expressed in AML patients with <it>MLL </it>fusions other than <it>MLL-SEPT2</it>.</p

Membrane-Associated RING-CH Proteins Associate with Bap31 and Target CD81 and CD44 to Lysosomes

Membrane-associated RING-CH (MARCH) proteins represent a family of transmembrane ubiquitin ligases modulating intracellular trafficking and turnover of transmembrane protein targets. While homologous proteins encoded by gamma-2 herpesviruses and leporipoxviruses have been studied extensively, limited information is available regarding the physiological targets of cellular MARCH proteins. To identify host cell proteins targeted by the human MARCH-VIII ubiquitin ligase we used stable isotope labeling of amino-acids in cell culture (SILAC) to monitor MARCH-dependent changes in the membrane proteomes of human fibroblasts. Unexpectedly, we observed that MARCH-VIII reduced the surface expression of Bap31, a chaperone that predominantly resides in the endoplasmic reticulum (ER). We demonstrate that Bap31 associates with the transmembrane domains of several MARCH proteins and controls intracellular transport of MARCH proteins. In addition, we observed that MARCH-VIII reduced the surface expression of the hyaluronic acid-receptor CD44 and both MARCH-VIII and MARCH-IV sequestered the tetraspanin CD81 in endo-lysosomal vesicles. Moreover, gene knockdown of MARCH-IV increased surface levels of endogenous CD81 suggesting a constitutive involvement of this family of ubiquitin ligases in the turnover of tetraspanins. Our data thus suggest a role of MARCH-VIII and MARCH-IV in the regulated turnover of CD81 and CD44, two ubiquitously expressed, multifunctional proteins