A new look at blood shear-thinning

Blood viscosity decreases with shear stress, a property essential for an efficient perfusion of the vascular tree. Shear-thinning is intimately related to the dynamics and mutual interactions of red blood cells (RBCs), the major constituents of blood. Our work explores RBCs dynamics under physiologically relevant conditions of flow strength, outer fluid viscosity and volume fraction. Our results contradict the current paradigm stating that RBCs should align and elongate in the flow direction thanks to their membrane circulation around their center of mass, reducing flow-lines disturbances. On the contrary, we observe both experimentally and with simulations, rich morphological transitions that relate to global blood rheology. For increasing shear stresses, RBCs successively tumble, roll, deform into rolling stomatocytes and finally adopt highly deformed and polylobed shapes even for semi-dilute volume fractions analogous to microcirculatory values. Our study suggests that any pathological change in plasma composition, RBCs cytosol viscosity or membrane mechanical properties will impact the onset of shape transitions and should play a central role in pathological blood rheology and flow behavior

Typing Copyless Message Passing

We present a calculus that models a form of process interaction based on copyless message passing, in the style of Singularity OS. The calculus is equipped with a type system ensuring that well-typed processes are free from memory faults, memory leaks, and communication errors. The type system is essentially linear, but we show that linearity alone is inadequate, because it leaves room for scenarios where well-typed processes leak significant amounts of memory. We address these problems basing the type system upon an original variant of session types.Comment: 50 page

Vinculacion entre las instituciones de educacion superior, empresas y gobierno en la ciudad de Talca: Transferencia Tecnologica

119 p.El problema de las relaciones Universidad-Empresa-Gobierno es de gran complejidad, y a pesar de que ha sido discutido en numerosas oportunidades, todavía no existe total claridad al respecto. Las empresas, universidades y el gobierno están conscientes de que este es un tema de suma importancia para todos, y que indudablemente requiere de mejoras. El presente estudio tiene como objetivo principal determinar la vinculación existente entre las instituciones de educación superior, las empresas y el gobierno en la ciudad de Talca, identificando el tipo de relación que existe y la percepción que tienen los participantes del proceso acerca de la actual situación de la ciudad. Para lograrlo, se realizó una investigación del tipo exploratoria, la que se llevó a cabo en dos etapas. La primera, basada en una serie de entrevistas en profundidad realizada a empresarios y a los encargados de la vinculación y la transferencia tecnológica en las universidades de la ciudad de Talca. La segunda etapa consistió en la aplicación de una encuesta, la que se distribuyó en forma balanceada entre empresarios, ejecutivos de gobierno y profesores y directores de instituciones de educación superior. Posterior a esto, se realizó un análisis factorial a fin de determinar los aspectos de mayor relevancia para los involucrados en el proceso. El análisis arrojó tres factores de importancia: la disposición a trabajar en conjunto, la comunicación entre las entidades y la confianza en los actores. Finalmente se entregan las conclusiones del estudio y las limitaciones más importantes del mismo

Varieties of creditor protection: insolvency law reform and credit expansion in developed market economies

We examine the relationship between creditor protection, law reform and credit expansion using longitudinal data for four developed market economies between 1970 and 2005. By decomposing the different elements of creditor protection, we show that civil law countries (France and Germany) have developed a high level of protection for creditors in the form of controls over the management of debtor firms, while common law countries (UK and USA) have arrived at a high degree of protection in relation to secured creditors’ contractual rights over firms’ assets. Using panel causality tests and dynamic panel data modelling, we show that laws strengthening creditors’ control over debtor firms in these four countries had a long-term positive effect on credit expansion, while reforms increasing secured creditors’ rights had a negative effect. We explore the implications of our findings for legal origin theory and the varieties of capitalism approach.This is the final version of the article. It first appeared from from Oxford University Press via https://doi.org/10.1093/ser/mww005

On a Calder\'on preconditioner for the symmetric formulation of the electroencephalography forward problem without barycentric refinements

We present a Calder\'on preconditioning scheme for the symmetric formulation of the forward electroencephalographic (EEG) problem that cures both the dense discretization and the high-contrast breakdown. Unlike existing Calder\'on schemes presented for the EEG problem, it is refinement-free, that is, the electrostatic integral operators are not discretized with basis functions defined on the barycentrically-refined dual mesh. In fact, in the preconditioner, we reuse the original system matrix thus reducing computational burden. Moreover, the proposed formulation gives rise to a symmetric, positive-definite system of linear equations, which allows the application of the conjugate gradient method, an iterative method that exhibits a smaller computational cost compared to other Krylov subspace methods applicable to non-symmetric problems. Numerical results corroborate the theoretical analysis and attest of the efficacy of the proposed preconditioning technique on both canonical and realistic scenarios

APOBEC3G Polymorphism as a Selective Barrier to Cross-Species Transmission and Emergence of Pathogenic SIV and AIDS in a Primate Host

Cellular restriction factors, which render cells intrinsically resistant to viruses, potentially impose genetic barriers to cross-species transmission and emergence of viral pathogens in nature. One such factor is APOBEC3G. To overcome APOBEC3G-mediated restriction, many lentiviruses encode Vif, a protein that targets APOBEC3G for degradation. As with many restriction factor genes, primate APOBEC3G displays strong signatures of positive selection. This is interpreted as evidence that the primate APOBEC3G locus reflects a long-term evolutionary “arms-race” between retroviruses and their primate hosts. Here, we provide direct evidence that APOBEC3G has functioned as a barrier to cross-species transmission, selecting for viral resistance during emergence of the AIDS-causing pathogen SIVmac in captive colonies of Asian macaques in the 1970s. Specifically, we found that rhesus macaques have multiple, functionally distinct APOBEC3G alleles, and that emergence of SIVmac and simian AIDS required adaptation of the virus to evade APOBEC3G-mediated restriction. Our evidence includes the first comparative analysis of APOBEC3G polymorphism and function in both a reservoir and recipient host species (sooty mangabeys and rhesus macaques, respectively), and identification of adaptations unique to Vif proteins of the SIVmac lineage that specifically antagonize rhesus APOBEC3G alleles. By demonstrating that interspecies variation in a known restriction factor selected for viral counter-adaptations in the context of a documented case of cross-species transmission, our results lend strong support to the evolutionary “arms-race” hypothesis. Importantly, our study confirms that APOBEC3G divergence can be a critical determinant of interspecies transmission and emergence of primate lentiviruses, including viruses with the potential to infect and spread in human populations

The HIV-1 late domain-2 S40A polymorphism in antiretroviral (or ART)-exposed individuals influences protease inhibitor susceptibility.

BackgroundThe p6 region of the HIV-1 structural precursor polyprotein, Gag, contains two motifs, P7TAP11 and L35YPLXSL41, designated as late (L) domain-1 and -2, respectively. These motifs bind the ESCRT-I factor Tsg101 and the ESCRT adaptor Alix, respectively, and are critical for efficient budding of virus particles from the plasma membrane. L domain-2 is thought to be functionally redundant to PTAP. To identify possible other functions of L domain-2, we examined this motif in dominant viruses that emerged in a group of 14 women who had detectable levels of HIV-1 in both plasma and genital tract despite a history of current or previous antiretroviral therapy.ResultsRemarkably, variants possessing mutations or rare polymorphisms in the highly conserved L domain-2 were identified in seven of these women. A mutation in a conserved residue (S40A) that does not reduce Gag interaction with Alix and therefore did not reduce budding efficiency was further investigated. This mutation causes a simultaneous change in the Pol reading frame but exhibits little deficiency in Gag processing and virion maturation. Whether introduced into the HIV-1 NL4-3 strain genome or a model protease (PR) precursor, S40A reduced production of mature PR. This same mutation also led to high level detection of two extended forms of PR that were fairly stable compared to the WT in the presence of IDV at various concentrations; one of the extended forms was effective in trans processing even at micromolar IDV.ConclusionsOur results indicate that L domain-2, considered redundant in vitro, can undergo mutations in vivo that significantly alter PR function. These may contribute fitness benefits in both the absence and presence of PR inhibitor

Natural Variation in Vif: Differential Impact on APOBEC3G/3F and a Potential Role in HIV-1 Diversification

The HIV-1 Vif protein counteracts the antiviral activity exhibited by the host cytidine deaminases APOBEC3G and APOBEC3F. Here, we show that defective vif alleles can readily be found in HIV-1 isolates and infected patients. Single residue changes in the Vif protein sequence are sufficient to cause the loss of Vif-induced APOBEC3 neutralization. Interestingly, not all the detected defects lead to a complete inactivation of Vif function since some mutants retained selective neutralizing activity against APOBEC3F but not APOBEC3G or vice versa. Concordantly, independently hypermutated proviruses with distinguishable patterns of G-to-A substitution attributable to cytidine deamination induced by APOBEC3G, APOBEC3F, or both enzymes were present in individuals carrying proviruses with completely or partly defective Vif variants. Natural variation in Vif function may result in selective and partial neutralization of cytidine deaminases and thereby promote viral sequence diversification within HIV-1 infected individuals

Dengue virus co-opts UBR4 to degrade STAT2 and antagonize type I interferon signaling.

An estimated 50 million dengue virus (DENV) infections occur annually and more than forty percent of the human population is currently at risk of developing dengue fever (DF) or dengue hemorrhagic fever (DHF). Despite the prevalence and potential severity of DF and DHF, there are no approved vaccines or antiviral therapeutics available. An improved understanding of DENV immune evasion is pivotal for the rational development of anti-DENV therapeutics. Antagonism of type I interferon (IFN-I) signaling is a crucial mechanism of DENV immune evasion. DENV NS5 protein inhibits IFN-I signaling by mediating proteasome-dependent STAT2 degradation. Only proteolytically-processed NS5 can efficiently mediate STAT2 degradation, though both unprocessed and processed NS5 bind STAT2. Here we identify UBR4, a 600-kDa member of the N-recognin family, as an interacting partner of DENV NS5 that preferentially binds to processed NS5. Our results also demonstrate that DENV NS5 bridges STAT2 and UBR4. Furthermore, we show that UBR4 promotes DENV-mediated STAT2 degradation, and most importantly, that UBR4 is necessary for efficient viral replication in IFN-I competent cells. Our data underscore the importance of NS5-mediated STAT2 degradation in DENV replication and identify UBR4 as a host protein that is specifically exploited by DENV to inhibit IFN-I signaling via STAT2 degradation