HIV-1 tat addresses dendritic cells to induce a predominant th1-type adaptive immune response that appears prevalent in the asymptomatic stage of infection

Tat is an early regulatory protein that plays a major role in human HIV-1 replication and AIDS pathogenesis, and therefore, it represents a key target for the host immune response. In natural infection, however, Abs against Tat are produced only by a small fraction (∼20%) of asymptomatic individuals and are rarely seen in progressors, suggesting that Tat may possess properties diverting the adaptive immunity from generating humoral responses. Here we show that a Th1-type T cell response against Tat is predominant over a Th2-type B cell response in natural HIV-1 infection. This is likely due to the capability of Tat to selectively target and very efficiently enter CD1a-expressing monocyte-derived dendritic cells (MDDC), which represent a primary target for the recognition and response to virus Ag. Upon cellular uptake, Tat induces MDDC maturation and Th1-associated cytokines and β-chemokines production and polarizes the immune response in vitro to the Th1 pattern through the transcriptional activation of TNF-αgene expression. This requires the full conservation of Tat transactivation activity since neither MDDC maturation nor TNF-α production are found with either an oxidized Tat, which does not enter MDDC, or with a Tat protein mutated in the cysteine-rich region (cys22 Tat), which enters MDDC as the wild-type Tat but is transactivation silent. Consistently with these data, inoculation of monkeys with the native wild-type Tat induced a predominant Th1 response, whereas cys22 Tat generated mostly Th2 responses, therefore providing evidence that Tat induces a predominant Th1 polarized adaptive immune response in the host. Copyright © 2009 by The American Association of Immunologists, Inc

Leber's Hereditary Optic Neuropathy: A Report on Novel mtDNA Pathogenic Variants

Leber's hereditary optic neuropathy (LHON) is due to missense point mutations affecting mitochondrial DNA (mtDNA); 90% of cases harbor the m.3460G>A, m.11778G>A, and m.14484T>C primary mutations. Here, we report and discuss five families with patients affected by symptomatic LHON, in which we found five novel mtDNA variants. Remarkably, these mtDNA variants are located in complex I genes, though without strong deleterious effect on respiration in cellular models: this finding is likely linked to the tissue specificity of LHON. This study observes that in the case of a strong clinical suspicion of LHON, it is recommended to analyze the whole mtDNA sequence, since new rare mtDNA pathogenic variants causing LHON are increasingly identified

Continued Decay of HIV Proviral DNA Upon Vaccination With HIV-1 Tat of Subjects on Long-Term ART: An 8-Year Follow-Up Study

Introduction: Tat, a key HIV virulence protein, has been targeted for the development of a therapeutic vaccine aimed at cART intensification. Results from phase II clinical trials in Italy (ISS T-002) and South Africa (ISS T-003) indicated that Tat vaccination promotes increases of CD4+ T-cells and return to immune homeostasis while reducing the virus reservoir in chronically cART-treated patients. Here we present data of 92 vaccinees (59% of total vaccinees) enrolled in the ISS T-002 8-year extended follow-up study (ISS T-002 EF-UP, ClinicalTrials.gov NCT02118168).Results: Anti-Tat antibodies (Abs) induced upon vaccination persisted for the entire follow-up in 34/92 (37%) vaccinees, particularly when all 3 Ab classes (A/G/M) were present (66% of vaccinees), as most frequently observed with Tat 30 μg regimens. CD4+ T cells increased above study-entry levels reaching a stable plateau at year 5 post-vaccination, with the highest increase (165 cells/μL) in the Tat 30 μg, 3 × regimen. CD4+ T-cell increase occurred even in subjects with CD4+ nadir ≤ 250 cells/uL and in poor immunological responders and was associated with a concomitant increase of the CD4+/CD8+ T-cell ratio, a prognostic marker of morbidity/mortality inversely related to HIV reservoir size. Proviral DNA load decreased over time, with a half-life of 2 years and an estimated 90% reduction at year 8 in the Tat 30 μg, 3 × group. In multivariate analysis the kinetic and amplitude of both CD4+ T-cell increase and proviral DNA reduction were fastest and highest in subjects with all 3 anti-Tat Ab classes and in the 30 μg, 3 × group, irrespective of drug regimens (NNRTI/NRTI vs. PI). HIV proviral DNA changes from baseline were inversely related to CD4+/CD8+ T-cell ratio and CD4+ T-cell changes, and directly related to the changes of CD8+ T cells. Further, HIV DNA decay kinetics were inversely related to the frequency and levels of intermittent viremia. Finally, Tat vaccination was similarly effective irrespective of the individual immunological status or HIV reservoir size at study entry.Conclusions: Tat immunization induces progressive immune restoration and reduction of virus reservoirs above levels reached with long-term cART, and may represent an optimal vaccine candidate for cART intensification toward HIV reservoirs depletion, functional cure, and eradication strategies

Original Article

The pancreas taken from the frog (Rana nigromaculata) was fixed in 1% OsO_4 and sliced into ultrathin sections for electron microscopic studies. The following observations were made: 1. A great \u27number of minute granules found in the cytoplasm of a pancreatic cell were called the microsomes, which were divided into two types, the C-microsome and S-microsome. 2. Electron microsopic studies of the ergastoplasm showed that it is composed of the microsome granules and A-substance. The microsomes were seen embedded in the A-substance which was either filamentous or membranous. The membranous structure, which was called the Am-membrane, was seen to form a sac, with a cavity of varying sizes, or to form a lamella. 3. The Am-membrane has close similarity to α-cytomembrane of Sjostrand, except that the latter is rough-surfaced. It was deduced that the Am-membrane, which is smooth-surfaced, might turn into the rough-surfaced α-cytomembrane. 4. There was the Golgi apparatus in the supranuclear region of a pancreatic cell. It consisted of the Golgi membrane, Golgi vacuole and. Golgi vesicle. 5. The mitochondria of a pancreatic cell appeared like long filaments, and some of them were seen to ramify. 6. The membrane of mitochondria, i. e. the limiting membrane, consisted of the Ammembrane. The mitochondria contained a lot of A-substances, as well as the C-microsomes and S-microsomes. When the mitochondria came into being, there appeared inside them chains of granules, which appeared like strips of beads, as the outgrowths of the A-substance and the microsome granules attached to the Am-membrane. They are the so-called cristae mitochondriales. 7. The secretory granules originate in the microsomes. They came into being when the microsomes gradually thickened and grew in size as various substances became adhered to them. Some of the secretory granules were covered with a membrane and appeared like what they have called the intracisternal granule of Palade.It seemed that this was a phenomenon attendant upon the dissolution and liqutefaction of the secretory granule. 8. Comparative studies were made of the ergastoplasm of the pancreatic cells from the frogs in hibernation, the frogs artificially hungered, the frogs which were given food after a certain period of fasting, the frogs to which pilocarpine was given subcutaneously, and the very young, immature frogs. The studies revealed that the ergastoplasm of the pancreatic cells greatly varied in form with the difference in nutritive condition and with different developmental stages of the cell. The change in form and structure occured as a result of transformation of the microsomes and A-substance. The ergastoplasm, even after it has come into being, might easily be inactivated if nutrition is defective. The ergastoplasm is concerned in the secretory mechanism, which is different from the secretory phenomenon of the secretory granules. It would seem that structurally the mitochondria have no direct relation to this mechanism

Social surplus approach and heterodox economics

Given the emphasis on social provisioning in heterodox economics, two of its central theoretical organizing principles are the concepts of the total social product and the social surplus. This appears to link heterodox economics to the social surplus approach associated with the classical economists and currently with Sraffian economists. However, heterodox economics connects agency with the social surplus and the social product, which the Sraffians reject as they take the level and composition of the social product as given. Therefore the different theoretical approach regarding the social surplus taken in heterodox economics may generate a different but similar way of theorizing about a capitalist economy. To explore this difference is the aim of the paper. Thus the paper is divided into four parts and a conclusion. In the first section social provisioning and the social surplus is introduced. In the second section, the Sraffian social surplus approach is delineated while in the third section the heterodox social surplus approach is delineated. In the fourth section of the paper, some of the implications emerging from the differences between the two approaches are discussed. The paper is concluded in the final section

The migration-trade nexus in the presence of vertical and horizontal product differentiation

Extended abstract Over the last twenty years a vast literature, especially empirical, has been developed in order to analyze the impact of migration flows on international trade under the hypothesis that ethnic networks play a key role. The basic idea is that immigrants are connected to their home countries by various types of links including: knowledge of home institutions, available products, home-country markets, languages and preferences. International trade can be influenced by immigrants’ ties to their home countries, because these linkages could help to decrease trade transaction costs. (Gould, 1994; Head and Ries, 1998; Dunlevy and Hutchinson, 1999; Rauch, 1999, 2001; Girma and Yu, 2002; Wagner et al., 2002; Bruder, 2004; Mundra, 2005; Jansen and Piermartini, 2009; Murat and Pistoresi, 2009; Peri and Requena-Silvente, 2010; Aleksynska and Peri, 2011; Egger et al.,2012; Bratti et al., 2012; Parsons, 2012; Felbermayr et al., 2012, to name but a few). However the great bulk of the literature has not remarked sufficiently that, in order to deeply explore the relationship between migration and international trade, it becomes noteworthy to take into account the nature of trade flows. In other words, an accurate analysis of the migration-trade nexus requires the crucial distinction between inter industry and intra industry trade flows, and the further separation of vertical and horizontal components inside intra-industry trade (IIT, thereafter). In fact, the theoretical literature on IIT’s determinants (see Helpman and Krugman (1985), Falvey and Kierzkowsky (1985), Flam and Helpman (1987)) shows that transaction costs are a negative determinant of the share of intra-industry trade in total trade. In addition, changes in transaction costs have a stronger impact on trade in differentiated products than in homogeneous goods. Therefore, if immigration allows a decline in trading transaction costs, this reduction will have a larger positive effect on the volume of intra-industry trade than on the volume of inter industry trade. The further observation that transaction costs could affect product differentiation in different ways - depending on the type of product differentiation involved, vertical or horizontal – induces us to explore the migration-trade link by discriminating vertical and horizontal components of IIT. Actually the literature on IIT has largely demonstrated that theoretical explanations of vertical intra-industry (VIIT, thereafter) differ significantly from Krugman style models of horizontal intra industry trade (HIIT, thereafter), and consequently empirical tests on the industry specific determinants of IIT should be carried out separately for VIIT and HIIT (Greenaway, Hine and Milner, 1995). In analogy with these prescriptions of IIT literature, empirical tests on the migration trade nexus should be performed independently for VIIT and HIIT. On the one hand, the protrade role of immigration in terms of transaction costs reduction seems more appropriate when HIIT is involved, because the immigrants’ knowledge of home country markets and available products should enhance more “variety trade” than “quality trade”. On the other hand, growing income differentials between immigrants and natives should activate more VIIT. This last observation calls into question the relevance of differences in human capital endowment between trade partners and between immigration and emigration flows. Usually, in theoretical frameworks analyzing the migration-trade link no distinction is made between immigrants and emigrants with reference to their pro-trade role (Gould, 1994). In addition, in empirical contributions testing the relationship between migration and trade, the nexus is explored by considering the exclusive role of immigrants (except in some rare study in which the role of emigrants is explicitly explored; see Murat and Pistoresi (2009), Parsons (2012)). Nevertheless, in the presence of human capital differences between immigrants and emigrants, an in-depth analysis of the migration trade nexus shouldn’t overlook the distinction between emigrants and immigrants, given that their influence on trade flows - and on the nature of trade flows - is virtually different. Furthermore an investigation of the pro-trade effects of migration carried out separately for immigrants and emigrants turns to be particularly significant when also the nature of trade flows is explicitly considered (disentangling HIIT and VIIT). Hence an analysis conducted by crossing the two dimensions of migration (immigration and emigration) and the two dimensions of intra-industry trade (VIIT and HIIT) provides a richer set of information by improving the interpretation of empirical results. Following this line of argument, the present work investigates the existing link between migration and intra-industry trade. In particular, three major questions are addressed here: 1) does migration help to increase intra-industry trade? 2) Does migration have a different impact on vertical and horizontal intra-industry trade? 3) Do the trade effects of immigration and emigration have different magnitudes? We try to answer these questions focusing on the Italian and German case which, in our opinion, seem to be the right countries for this type of analysis. For instance, Italy was a land of emigration and has also become a land of immigration over time, and the share of its bilateral intra-industry trade has increased in the early twenty first century (from 44% in 2000 to 47% in 2010) together with migration flows. Moreover, Italy lends itself to the separated analysis of the two components of IIT, since, especially for Italy, the “quality” trade (VIIT) represents the predominant amount of all IIT (63% in 2010). Furthermore the Italian outward and inward flows of migrants, other than a different historical importance, are different because of countries from which they come, or to which they go; also differing in educational level. Italian emigrates mostly go to developed countries, and instead immigrants in Italy are coming from developing countries. This circumstance – supported by other sources of information (Fondazione Migrantes) - signals that Italian emigrants are mostly more skilled than immigrants arriving in Italy. Moreover, we are dealing with two European countries that have different national dynamics of the labor market. In particular, among the big European countries, Italy and Germany are those which better represent the two significantly different trends characterizing labor market. We use country-level data that combines the bilateral intra-industry trade indexes and both the stock of immigrants and emigrants by countries (data sources include: EUROSTAT, Comext database, for trade data at the 8 digit level of disaggregation; ISTAT, migration trends and foreign population, Istat annuals on line, and Federal Statistic Office, with reference to Italian and German immigration data respectively; Anagrafe Italiani Residenti all’Estero, AIRE database, for data on Italian emigration). Then, following the methodology proposed by Greenaway, Hine and Milner (1995) and based on unit values of imports and exports as proxies of quality, the intraindustry trade has been divided in its two components, horizontal and vertical, in order to check which one is more affected by migration. The empirical model, departing from Hummels and Levinshon (1995), is developed adding to the basic specification our key variables: the stock of immigrants and the stock of emigrants. Since intra-industry trade index varies between 0 and 1, the method of ordinary least squares (OLS) is not appropriate and cannot be directly used for the model’s estimate (estimated coefficients would not be efficient). On this regard, Caves (1981) noted that OLS method has the disadvantage of not ensuring that predicted values of the dependent variable will be within its feasible range from 0 to 1. As the literature suggests (Balassa, 1986), in order to overcome this problem, we apply a logistic transformation to IIT and then we use OLS to estimate the model. The estimation’s results suggest that our hypotheses are consistent with the data: for instance, in the case of Italy, both emigration and immigration exert a positive influence on the share of intra-industry trade between Italy and its partner countries, even if the coefficient of the emigration variable is not statistically significant in all regressions (it becomes statistically different from zero only with reference to HIIT, confirming in any case the relevance of disentangling VIIT and HIIT in empirical tests). This result could be related to the fact that immigrants in Italy mostly come from developing countries which represent economies dissimilar to the Italian one so that the information brought by immigrants is more valuable (in terms of trade transaction costs’ reduction) than the information carried by Italians who go to developed countries. With regard to the VIIT and the HIIT, we find that the discrimination between these two components of IIT leads to a deep investigation of the link migration-IIT and improves the interpretation of empirical results, suggesting that migration has different effects on the two types of IIT. Indeed, the estimated coefficients are very different between them and the impact on the VIIT and HIIT is quite different. In particular, always with reference to the Italian case, the effect of immigration and emigration on international trade turns to be more relevant and significant when the “variety” trade (HIIT) is explicitly considered. Therefore, not to separate IIT in its two components leads to underestimate the potential effect of migration on IIT since it rules out the notable effect on the horizontal intra-industry trade. These results seem encouraging, in particular in light of the fact we used a very highly disaggregated data and, unlike other studies, our calculations are based on a dataset where both manufacturing and non manufacturing industries are included

The role of migration in the variety and quality of trade. Evidence from Germany

We explore the migration-trade nexus in the case of Germany over the period 2000–09, disentangling the two dimensions of intra-industry trade (vertical and horizontal). We find that immigration is positively and significantly related to intra- industry trade. However, the magnitude and statistical significance of migration’s impact on trade are considerably higher for horizontal intra-industry trade and increase with the difference in the level of development between Germany and the partner coun- tries. This pattern is consistent with the view that information flows between migrant communities and their country of origin may be more important for consumer goods (where trade in varieties prevails) and that this information effect is more important if trading countries are very different