Membrane-destabilizing activity of pH-responsive cationic lysine-based surfactants: role of charge position and alkyl chain length

Many strategies for treating diseases require the delivery of drugs into the cell cytoplasm following internalization within endosomal vesicles. Thus, compounds triggered by low pH to disrupt membranes and release endosomal contents into the cytosol are of particular interest. Here, we report novel cationic lysine-based surfactants (hydrochloride salts of N¿- and N¿-acyl lysine methyl ester) that differ in the position of the positive charge and the length of the alkyl chain. Amino acid-based surfactants could be promising novel biomaterials in drug delivery systems, given their biocompatible properties and low cytotoxic potential. We examined their ability to disrupt the cell membrane in a range of pH values, concentrations and incubation times, using a standard hemolysis assay as a model of endosomal membranes. Furthermore, we addressed the mechanism of surfactant-mediated membrane destabilization, including the effects of each surfactant on erythrocyte morphology as a function of pH. We found that only surfactants with the positive charge on the ¿-amino group of lysine showed pH-sensitive hemolytic activity and improved kinetics within the endosomal pH range, indicating that the positive charge position is critical for pH-responsive behavior. Moreover, our results showed that an increase in the alkyl chain length from 14 to 16 carbon atoms was associated with a lower ability to disrupt cell membranes. Knowledge on modulating surfactant-lipid bilayer interactions may help us to develop more efficient biocompatible amino acid-based drug delivery devices.

The glucose transporter 4 FQQI motif is necessary for Akt Substrate of 160-Kilodalton-dependent plasma membrane translocation but not Golgi-localized g-ear-containing Arf-binding protein-dependent entry into the insulin-responsive storage compartment.

Newly synthesized glucose transporter 4 (GLUT4) enters into the insulin-responsive storage compartment in a process that is Golgi-localized γ-ear-containing Arf-binding protein (GGA) dependent, whereas insulin-stimulated translocation is regulated by Akt substrate of 160 kDa (AS160). In the present study, using a variety of GLUT4/GLUT1 chimeras, we have analyzed the specific motifs of GLUT4 that are important for GGA and AS160 regulation of GLUT4 trafficking. Substitution of the amino terminus and the large intracellular loop of GLUT4 into GLUT1 (chimera 1-441) fully recapitulated the basal state retention, insulin-stimulated translocation, and GGA and AS160 sensitivity of wild-type GLUT4 (GLUT4-WT). GLUT4 point mutation (GLUT4-F5A) resulted in loss of GLUT4 intracellular retention in the basal state when coexpressed with both wild-type GGA and AS160. Nevertheless, similar to GLUT4-WT, the insulin-stimulated plasma membrane localization of GLUT4-F5A was significantly inhibited by coexpression of dominant-interfering GGA. In addition, coexpression with a dominant-interfering AS160 (AS160-4P) abolished insulin-stimulated GLUT4-WT but not GLUT4-F5A translocation. GLUT4 endocytosis and intracellular sequestration also required both the amino terminus and large cytoplasmic loop of GLUT4. Furthermore, both the FQQI and the SLL motifs participate in the initial endocytosis from the plasma membrane; however, once internalized, unlike the FQQI motif, the SLL motif is not responsible for intracellular recycling of GLUT4 back to the specialized compartment. Together, we have demonstrated that the FQQI motif within the amino terminus of GLUT4 is essential for GLUT4 endocytosis and AS160-dependent intracellular retention but not for the GGA-dependent sorting of GLUT4 into the insulin-responsive storage compartment.

Controlling anomalous stresses in soft field-responsive systems

We report a phenomenon occurring in field-responsive suspensions: shear-induced anomalous stresses. Competition between a rotating field and a shear flow originates a multiplicity of anomalous stress behaviors in suspensions of bound dimers constituted by induced dipoles. The great variety of stress regimes includes nonmonotonic behaviors, multiresonances, negative viscosity effect, and blockades. The reversibility of the transitions between the different regimes and the self-similarity of the stresses make this phenomenon controllable and therefore applicable to modify macroscopic properties of soft condensed matter phases.

Corrigendum stable matchings and preferences of couples

We correct an omission in the definition of our domain of weakly responsive preferences introduced in Klaus and Klijn (2005) or KK05 for short. The proof of the existence of stable matchings (KK05, Theorem 3.3) and a maximal domain result (KK05, Theorem 3.5) are adjusted accordingly.

Paths to stability for matching markets with couples

We study two-sided matching markets with couples and show that for a natural preference domain for couples, the domain of weakly responsive preferences, stable outcomes can always be reached by means of decentralized decision making. Starting from an arbitrary matching, we construct a path of matchings obtained from `satisfying' blocking coalitions that yields a stable matching. Hence, we establish a generalization of Roth and Vande Vate's (1990) result on path convergence to stability for decentralized singles markets. Furthermore, we show that when stable matchings exist, but preferences are not weakly responsive, for some initial matchings there may not exist any path obtained from `satisfying' blocking coalitions that yields a stable matching.

Manipulation via endowments in exchange markets with indivisible goods

We consider exchange markets with heterogeneous indivisible goods. We are interested in exchange rules that are efficient and immune to manipulations via endowments (either with respect to hiding or destroying part of the endowment or transferring part of the endowment to another trader). We consider three manipulability axioms: hiding-proofness, destruction-proofness, and transfer-proofness. We prove that no rule satisfying efficiency and hiding-proofness (which implies individual rationality) exists. For two-agent exchange markets with separable and responsive preferences, we show that efficient, individually rational, and destruction-proof rules exist. However, for separable preferences, no rule satisfies efficiency, individual rationality, and destruction-proofness. In the case of transfer-proofness the compatibility with efficiency and individual rationality for the two-agent case extends to the unrestricted domain. For exchange markets with separable preferences and more than two agents no rule satisfies efficiency, individual rationality, and transfer-proofness.

On group strategy-proof mechanisms for a many-to-one matching model

For the many-to-one matching model in which firms have substitutable and quota q-separable preferences over subsets of workers we show that the workers-optimal stable mechanism is group strategy-proof for the workers. In order to prove this result, we also show that under this domain of preferences (which contains the domain of responsive preferences of the college admissions problem) the workers-optimal stable matching is weakly Pareto optimal for the workers and the Blocking Lemma holds as well. We exhibit an example showing that none of these three results remain true if the preferences of firms are substitutable but not quota q-separable.

Some things couples always wanted to know about stable matchings (but were afraid to ask)

It is well-known that couples that look jointly for jobs in the same centralized labor market may cause instabilities. We demonstrate that for a natural preference domain for couples, namely the domain of responsive preferences, the existence of stable matchings can easily be established. However, a small deviation from responsiveness in one couple's preference relation that models the wish of a couple to be closer together may already cause instability. This demonstrates that the nonexistence of stable matchings in couples markets is not a singular theoretical irregularity. Our nonexistence result persists even when a weaker stability notion is used that excludes myopic blocking. Moreover, we show that even if preferences are responsive there are problems that do not arise for singles markets. Even though for couples markets with responsive preferences the set of stable matchings is nonempty, the lattice structure that this set has for singles markets does not carry over. Furthermore we demonstrate that the new algorithm adopted by the National Resident Matching Program to fill positions for physicians in the United States may cycle, while in fact a stable matchings does exist, and be prone to strategic manipulation if the members of a couple pretend to be single.

A Model of ethnic conflict

We present a model of conflict, in which discriminatory government policy or social intolerance is responsive to various forms of ethnic activism, including violence. It is this perceived responsiveness -captured by the probability that the government gives in and accepts a proponed change in ethnic policy- that induces individuals to mobilize in support for their cause. Yet, mobilization is costly and demonstrators have to be compensated accordingly. Individuals have to weigh their ethnic radicalism with their material well-being to determine the size of their money contribution to the cause. Our main results are: (i) a one-sided increase in radicalism or in population size increases conflict; (ii) a one-sided increase in income has ambiguous effects depending on the elasticity of contributions to income; (iii) an increase in within-group inequality increases conflict; and (iv) an increase in the correlation between ethnic radicalism and inequality also increases conflict.

Corrigendum: stable matchings and preferences of couples

We correct an omission in the definition of the domain of weakly responsive preferences introduced in Klaus and Klijn (2005) or KK05 for short. The proof of the existence of stable matchings (KK05, Theorem 3.3) and a maximal domain result (KK05, Theorem 3.5) are adjusted accordingly.

Mobile termination, network externalities, and consumer expectations

We re-examine the literature on mobile termination in the presence of network externalities. Externalities arise when firms discriminate between on- and off-net calls or when subscription demand is elastic. This literature predicts that profit decreases and consumer surplus increases in termination charge in a neighborhood of termination cost. This creates a puzzle since in reality we see regulators worldwide pushing termination rates down while being opposed by network operators. We show that this puzzle is resolved when consumers' expectations are assumed passive but required to be fulfilled in equilibrium (as defined by Katz and Shapiro, AER 1985), instead of being rationally responsive to non-equilibrium prices, as assumed until now.

The Impact of democratization: a preliminary investigation on social policies and political violence in Latin America

The recent strides of democracy in Latin America have been associated to conflicting outcomes. The expectation that democracy would bring about peace and prosperity have been only partly satisfied. While political violence has been by and large eradicated from the sub-continent, poverty and social injustice still prevail and hold sway. Our study argues that democracy matters for inequality through the growing strength of center left and left parties and by making political leaders in general more responsive to the underprivileged. Furthermore, although the pension reforms recently enacted in the region generated overall regressive outcomes on income distribution, democratic countries still benefit from their political past: where democratic tradition was stronger, such outcomes have been milder. Democratic tradition and the specific ideological connotations of the parties in power, on the other hand, did not play an equally crucial role in securing lower levels of political violence: during the last wave of democratizations in Latin America, domestic peace was rather an outcome of political and social concessions to those in distress. In sum, together with other factors and especially economic ones, the reason why recent democratizations have provided domestic peace in most cases, but have been unable so far to solve the problem of poverty and inequality, is that democratic traditions in the subcontinent have been relatively weak and, more specifically, that this weakness has undermined the growth of left and progressive parties, acting as an obstacle to redistribution. Such weakness, on the other hand, has not prevented the drastic reduction of domestic political violence, since what mattered in this case was a combination of symbolic or material concessions and political agreements among powerful élites and counter-élites.

A comparison of input-output models: ghosh reduces to leontief (but "closing" ghosh makes it more plausible)

Ghosh's model is discussed in this paper under two alternative scenarios. In an open version we compare it with Leontief's model and prove that they reduce to each other under some specific productive conditions. We then move onto reconsidering Ghosh's model alleged implausibility and we do so reformulating the model to incorporate a closure rule. The closure solves, to some extent, the implausibility problem very clearly put out by Oosterhaven for then value-added is correctly computed and responsive to allocation changes resulting from supply shocks.

Cirp function and characterisation in RNA and microRNAs

In order to search for novel genes involved in cell proliferation, the hypothesis was that by infecting primary cells with a cDNA library of immortal cells would render immortalizing genes. Consequently it has been discovered CIRP (Cold inducible RNA-binding protein). Mammalian cells exposed to mild hypothermia show a general inhibition of protein synthesis and a concomitant increase in the expression of a small number of cold-shock mRNAs and proteins. Rbm3, another RNA binding protein belonging to the same family, has been postulated to facilitate protein synthesis at mild cold shock. To investigate if the same occurs for CIRP, CIRP was overexpressed in primary cells and protein sintesis was measured. Interestingly, CIRP increased protein synthesis, however, such increase did not involve an increase in the polysome fraction or affected the ribosome profile. In addition, the effect caused by CIRP inhibition or knockdown was also analyzed. Different siRNAs against CIRP were tested. Once checked their efficiency by decreasing CIRP at mRNA and protein levels, proliferation was tested by BrdU, cell number (DAPI) and proliferation curves were performed. Interestingly, CIRP provoke a decreased proliferation in primary cells: MEFs, HMEC; and cancer cells: TERA2 and HeLa. In conclusion, we describe for the first time that CIRP bypasses replicative senescence when over-expressed at physiological temperature (37ºC) by increasing a general protein synthesis. This effect is achieved through ERK1/2 activation in MEFs.The decrease in growth rate found in mammalian cells treated with mild cold stress is not entirely attributable to arrested metabolism. This decrease may also involve an active process in which CIRP and other stress-responsive proteins play a fundamental role in stimulating proliferation. Although most cell proteins are down-regulated or inhibited with cold stress, CIRP is activated to maintain cells in an active proliferative status and its overexpression at 37°C might be potentially oncogenic.

Tema per Elgg

Desenvolupament d'un tema pel gestor de continguts Elgg: usabilitat, experiència d'usuari i "responsive".