We show that lateral fluidity in membranes containing quenched protein obstacles belongs to the universality class of the two-dimensional random-field Ising model. The main feature of this class is the absence of a phase transition: there is no critical point and macroscopic domain formation does not occur. Instead there is only one phase. This phase is highly heterogeneous with a structure consisting of microdomains. The presence of quenched protein obstacles thus provides a mechanism to stabilize lipid rafts in equilibrium. Crucial for two-dimensional random-field Ising universality is that the obstacles are randomly distributed and have a preferred affinity to one of the lipid species. When these conditions are not met standard Ising or diluted Ising universality applies. In these cases a critical point does exist which then marks the onset toward macroscopic demixing.

In systems belonging to the universality class of the random field Ising model, the standard hyperscaling relation between critical exponents does not hold, but is replaced with a modified hyperscaling relation. As a result, standard formulations of finite-size scaling near critical points break down. In this work, the consequences of modified hyperscaling are analyzed in detail. The most striking outcome is that the free-energy cost ΔF of interface formation at the critical point is no longer a universal constant, but instead increases as a power law with system size, ΔF∝L(θ), with θ as the violation of hyperscaling critical exponent and L as the linear extension of the system. This modified behavior facilitates a number of numerical approaches that can be used to locate critical points in random field systems from finite-size simulation data. We test and confirm the approaches on two random field systems in three dimensions, namely, the random field Ising model and the demixing transition in the Widom-Rowlinson fluid with quenched obstacles.

Vaccines based on live virus are excellent inducers of longterm immunity by eliciting protective humoral and cell-mediated immune responses against the inserted antigen. To this end, poxviruses are one of the most versatile expression systems for foreign antigens and have been considered as vectors for human and veterinary live vaccines (37, 41). Long-term immunity induced by vaccinia virus (VACV) or other poxviruses, however, might result in unsuccessful revaccination or reduced protection against VACV-encoded foreign antigens (5, 23, 48). For safety reasons, different strategies are used to develop attenuated, host-restricted, or replication-deficient poxviruses, which retain their ability to activate the host's immune response (for review, see references 38 and 39). The host range-restricted attenuated VACV strain MVA (modified VACV Ankara) was found to induce lower levels of VACVneutralizing antibodies than wild-type VACV (45) and is currently widely used as a vector vaccine. It cannot grow in human cells (8) and is propagated on primary chicken embryo fibroblasts (CEFs). Avipoxvirus vectors, which show an abortive replication in mammalian cells, are also produced in CEFs (42). However, products from CEFs do not represent optimal safety profiles due to different adventitious contaminants, in contrast to production in permanent cell lines.Recently, the genus Parapoxvirus (PPV) of the family Poxviridae, and in particular the type species Orf virus (ORFV), has been proposed as candidate for novel vector vaccines. Arguments in favor of an ORFV vector include the very restricted host range (sheep and goats), its tropism restricted to the skin, the lack of systemic infection, a short-term vectorspecific protective immunity, and the exceptionally strong stimulation of fast innate cellular immune mechanisms at the site of infection (for review, see references 4 and 47). In addition to cytokines, chemokines, and alpha/beta interferon (IFN-␣/␤) as part of the host's inflammatory response against the infection, major histocompatibility complex class II-positive dendritic cells accumulate in the infected skin, which represent professional antigen-presenting cells for the subsequent induction of a specific immune response (4, 13). CD4 ϩ T cells dominate the local accumulation of B and T cells and were found to be of importance for the development of ORFV-specific antibodies (24). It is worthwhile to stress the short-lived duration of ORFV-specific immunity, which allows frequent reinfections (14). A most important feature of ORFV in the context with its use as a vaccine is the absence of systemic virus spread, even in immunocompromised individuals or after intravenous injection of high virus doses (4,18,47,59). Occasional transmission of wild-type ORFV to humans often remains unrecognized (4,14).A prime candidate for use as a recombinant vector is the highly attenuated, cell culture-adapted ORFV strain D1701, which is almost apathogenic in sheep (31). This attenuated

Mutations in the gene encoding the microtubule-severing protein spastin (spastic paraplegia 4 [SPG4]) cause hereditary spastic paraplegia (HSP), associated with neurodegeneration, spasticity, and motor impairment. Complicated forms (complicated HSP [cHSP]) further include cognitive deficits and dementia; however, the etiology and dysfunctional mechanisms of cHSP have remained unknown. Here, we report specific working and associative memory deficits upon spastin depletion in mice. Loss of spastin-mediated severing leads to reduced synapse numbers, accompanied by lower miniature excitatory postsynaptic current (mEPSC) frequencies. At the subcellular level, mutant neurons are characterized by longer microtubules with increased tubulin polyglutamylation levels. Notably, these conditions reduce kinesin-microtubule binding, impair the processivity of kinesin family protein (KIF) 5, and reduce the delivery of presynaptic vesicles and postsynaptic α-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid (AMPA) receptors. Rescue experiments confirm the specificity of these results by showing that wild-type spastin, but not the severing-deficient and disease-associated K388R mutant, normalizes the effects at the synaptic, microtubule, and transport levels. In addition, short hairpin RNA (shRNA)-mediated reduction of tubulin polyglutamylation on spastin knockout background normalizes KIF5 transport deficits and attenuates the loss of excitatory synapses. Our data provide a mechanism that connects spastin dysfunction with the regulation of kinesin-mediated cargo transport, synapse integrity, and cognition.

We present Monte Carlo simulation results of the two-dimensional Zwanzig fluid, which consists of hard line segments which may orient either horizontally or vertically. At a certain critical fugacity, we observe a phase transition with a two-dimensional Ising critical point. Above the transition point, the system is in an ordered state, with the majority of particles being either horizontally or vertically aligned. In contrast to previous work, we identify the transition as being of the liquid-gas type, as opposed to isotropic-to-nematic one. This interpretation naturally accounts for the observed Ising critical behavior. Furthermore, when the Zwanzig fluid is extended to more allowed particle orientations, we argue that in some cases the symmetry of a q-state Potts model with q > 2 arises. This observation is used to interpret a number of previous results.