Autonomía y emancipación: los significados de la independencia durante el proceso de surgimiento de las provincias-estado del Litoral (1811-1816)

Sostener que el 9 de julio de 1816 se declaró la independencia que terminó de configurar la Nación Argentina inconscientemente implica reproducir una operación cultural que niega los múltiples proyectos de organización que se dieron en el ámbito rioplatense en la segunda década del siglo XIX. Esta percepción excluye a las provincias del Litoral, que por entonces formaban parte de la Liga Federal, por lo que no enviaron diputados a Tucumán. En este ámbito la palabra “independencia” no remitía solamente a la emancipación respecto a España, sino también a la autonomía de las provincias y a su separación de la Intendencia de Buenos Aires, a la que estaban subordinadas hasta entonces. Muchas de estas ideas estuvieron influenciadas por la experiencia revolucionaria paraguaya, a la cual hasta ahora le dio poca importancia la historiografía argentina. Es válido, entonces, hablar de “independencias” para poner en evidencia esta multiplicidad de sentidos posibles

Comparing black-carbon- and aerosol-absorption-measuring instruments

We report on an inter-comparison of black-carbon- and aerosol-absorption-measuring instruments with laboratory-generated soot particles coated with controlled amounts of secondary organic matter (SOM). The aerosol generation setup consisted of a miniCAST 5201 Type BC burner for the generation of soot particles and a new automated oxidation flow reactor based on the micro smog chamber (MSC) for the generation of SOM from the ozonolysis of α-pinene. A series of test aerosols was generated with elemental to total carbon (EC  TC) mass fraction ranging from about 90 % down to 10 % and single-scattering albedo (SSA at 637 nm) from almost 0 to about 0.7. A dual-spot Aethalometer AE33, a photoacoustic extinctiometer (PAX, 870 nm), a multi-angle absorption photometer (MAAP), a prototype photoacoustic instrument, and two prototype photo-thermal interferometers (PTAAM-2λ and MSPTI) were exposed to the test aerosols in parallel. Significant deviations in the response of the instruments were observed depending on the amount of secondary organic coating. We believe that the setup and methodology described in this study can easily be standardised and provide a straightforward and reproducible procedure for the inter-comparison and characterisation of both filter-based and in situ black-carbon-measuring (BC-measuring) instruments based on realistic test aerosols

Development of a highly effective combination monoclonal antibody therapy against Herpes simplex virus.

BACKGROUND Infections with Herpes simplex virus (HSV)-1 or -2 usually present as mild chronic recurrent disease, however in rare cases can result in life-threatening conditions with a large spectrum of pathology. Monoclonal antibody therapy has great potential especially to treat infections with virus resistant to standard therapies. HDIT101, a humanized IgG targeting HSV-1/2 gB was previously investigated in phase 2 clinical trials. The aim of this study was to develop a next-generation therapy by combining different antiviral monoclonal antibodies. METHODS A lymph-node derived phage display library (LYNDAL) was screened against recombinant gB from Herpes simplex virus (HSV) -1 and HDIT102 scFv was selected for its binding characteristics using bio-layer interferometry. HDIT102 was further developed as fully human IgG and tested alone or in combination with HDIT101, a clinically tested humanized anti-HSV IgG, in vitro and in vivo. T-cell stimulating activities by antigen-presenting cells treated with IgG-HSV immune complexes were analyzed using primary human cells. To determine the epitopes, the cryo-EM structures of HDIT101 or HDIT102 Fab bound to HSV-1F as well as HSV-2G gB protein were solved at resolutions < 3.5 Å. RESULTS HDIT102 Fab showed strong binding to HSV-1F gB with Kd of 8.95 × 10-11 M and to HSV-2G gB with Kd of 3.29 × 10-11 M. Neutralization of cell-free virus and inhibition of cell-to-cell spread were comparable between HDIT101 and HDIT102. Both antibodies induced internalization of gB from the cell surface into acidic endosomes by binding distinct epitopes in domain I of gB and compete for binding. CryoEM analyses revealed the ability to form heterogenic immune complexes consisting of two HDIT102 and one HDIT101 Fab bound to one gB trimeric molecule. Both antibodies mediated antibody-dependent phagocytosis by antigen presenting cells which stimulated autologous T-cell activation. In vivo, the combination of HDIT101 and HDIT102 demonstrated synergistic effects on survival and clinical outcome in immunocompetent BALB/cOlaHsd mice. CONCLUSION This biochemical and immunological study showcases the potential of an effective combination therapy with two monoclonal anti-gB IgGs for the treatment of HSV-1/2 induced disease conditions

How to conceptualize and implement a PhD program in health sciences - the Basel approach

Over the past decade, several excellent guidelines have been published on how to enhance the quality of PhD education in Europe. Aimed primarily at preparing students for innovative roles in their fields, they include variously structured approaches to curricular offerings, as well as other program components applicable across specialties (eg: supervisor support, scientific conduct, transferable skills). Since 2012, the interdisciplinary PhD Program in Health Sciences (PPHS) at the Faculty of Medicine of the University of Basel in Switzerland has focused on translating these guidelines into a 21st-century health sciences PhD program.; The PPHS started in 2012 based on the European Union (EU) guidelines for PhD education. This article describes the resulting interdisciplinary PhD program's conceptual underpinnings, rationale, structures, and 10 building blocks, like student portfolios, thematic training, interdisciplinary research seminars, student-initiated interdisciplinary activities, financial support of course participation, top-up and extension stipends, PhD supervision, research integrity, alumni follow-up network, and promotional tools including a dedicated website. Students enter from Clinical Research, Medicine Development, Nursing Science, Epidemiology and Public Health including Insurance Medicine, Sport Science (all from the Faculty of Medicine), and Epidemiology (Faculty of Science).; The Basel PPHS exemplifies state-of-the-art PhD education in Health Sciences based on European guidelines and offers guidance to other groups from conceptualization to rollout of an interdisciplinary health sciences PhD program

Structures and dynamics of the novel S1/S2 protease cleavage site loop of the SARS-CoV-2 spike glycoprotein.

At the end of 2019, a new highly virulent coronavirus known under the name SARS-CoV-2 emerged as a human pathogen. One key feature of SARS-CoV-2 is the presence of an enigmatic insertion in the spike glycoprotein gene representing a novel multibasic S1/S2 protease cleavage site. The proteolytic cleavage of the spike at this site is essential for viral entry into host cells. However, it has been systematically abrogated in structural studies in order to stabilize the spike in the prefusion state. In this study, multi-microsecond molecular dynamics simulations and ab initio modeling were leveraged to gain insights into the structures and dynamics of the loop containing the S1/S2 protease cleavage site. They unveiled distinct conformations, formations of short helices and interactions of the loop with neighboring glycans that could potentially regulate the accessibility of the cleavage site to proteases and its processing. In most conformations, this loop protrudes from the spike, thus representing an attractive SARS-CoV-2 specific therapeutic target

Structures and dynamics of the novel S1/S2 protease cleavage site loop of the SARS-CoV-2 spike glycoprotein

At the end of 2019, a new highly virulent coronavirus known under the name SARS-CoV-2 emerged as a human pathogen. One key feature of SARS-CoV-2 is the presence of an enigmatic insertion in the spike glycoprotein gene representing a novel multibasic S1/S2 protease cleavage site. The proteolytic cleavage of the spike at this site is essential for viral entry into host cells. However, it has been systematically abrogated in structural studies in order to stabilize the spike in the prefusion state. In this study, multi-microsecond molecular dynamics simulations and ab initio modeling were leveraged to gain insights into the structures and dynamics of the loop containing the S1/S2 protease cleavage site. They unveiled distinct conformations, formations of short helices and interactions of the loop with neighboring glycans that could potentially regulate the accessibility of the cleavage site to proteases and its processing. In most conformations, this loop protrudes from the spike, thus representing an attractive SARS-CoV-2 specific therapeutic target.ISSN:1095-8657ISSN:2590-152

Fusion Domains Guide the Oriented Insertion of Light-Driven Proton Pumps into Liposomes

ISSN:0006-3495ISSN:1542-008

Protein-enriched outer membrane vesicles as a native platform for outer membrane protein studies

Most studies characterizing the folding, structure, and function of membrane proteins rely on solubilized or reconstituted samples. Whereas solubilized membrane proteins lack the functionally important lipid membrane, reconstitution embeds them into artificial lipid bilayers, which lack characteristic features of cellular membranes including lipid diversity, composition and asymmetry. Here, we utilize outer membrane vesicles (OMVs) released from Escherichia coli to study outer membrane proteins (Omps) in the native membrane environment. Enriched in the native membrane of the OMV we characterize the assembly, folding, and structure of OmpG, FhuA, Tsx, and BamA. Comparing Omps in OMVs to those reconstituted into artificial lipid membranes, we observe different unfolding pathways for some Omps. This observation highlights the importance of the native membrane environment to maintain the native structure and function relationship of Omps. Our fast and easy approach paves the way for functional and structural studies of Omps in the native membrane.ISSN:2399-364

Fusion Domains Guide the Oriented Insertion of Light-Driven Proton Pumps into Liposomes.

One major objective of synthetic biology is the bottom-up assembly of minimalistic nanocells consisting of lipid or polymer vesicles as architectural scaffolds and of membrane and soluble proteins as functional elements. However, there is no reliable method to orient membrane proteins reconstituted into vesicles. Here, we introduce a simple approach to orient the insertion of the light-driven proton pump proteorhodopsin (PR) into liposomes. To this end, we engineered red or green fluorescent proteins to the N- or C-terminus of PR, respectively. The fluorescent proteins optically identified the PR constructs and guided the insertion of PR into liposomes with the unoccupied terminal end facing inward. Using the PR constructs, we generated proton gradients across the vesicle membrane along predefined directions such as are required to power (bio)chemical processes in nanocells. Our approach may be adapted to direct the insertion of other membrane proteins into vesicles

Protein-enriched outer membrane vesicles as a native platform for outer membrane protein studies.

Most studies characterizing the folding, structure, and function of membrane proteins rely on solubilized or reconstituted samples. Whereas solubilized membrane proteins lack the functionally important lipid membrane, reconstitution embeds them into artificial lipid bilayers, which lack characteristic features of cellular membranes including lipid diversity, composition and asymmetry. Here, we utilize outer membrane vesicles (OMVs) released from to study outer membrane proteins (Omps) in the native membrane environment. Enriched in the native membrane of the OMV we characterize the assembly, folding, and structure of OmpG, FhuA, Tsx, and BamA. Comparing Omps in OMVs to those reconstituted into artificial lipid membranes, we observe different unfolding pathways for some Omps. This observation highlights the importance of the native membrane environment to maintain the native structure and function relationship of Omps. Our fast and easy approach paves the way for functional and structural studies of Omps in the native membrane