Dormant Mycobacterium tuberculosis fails to block phagosome maturation and shows unexpected capacity to stimulate specific human T lymphocytes

Dormancy is defined as a stable but reversible nonreplicating state of Mycobacterium tuberculosis. It is currently thought that dormant M. tuberculosis (D-Mtb) is responsible for latent tuberculosis (TB) infection. Recently, D-Mtb was also shown in sputa of patients with active TB, but the capacity of D-Mtb to stimulate specific immune responses was not investigated. We observed that purified protein derivative-specific human CD4(+) T lymphocytes recognize mycobacterial Ags more efficiently when macrophages are infected with D-Mtb instead of replicating M. tuberculosis (R-Mtb). The different Ag recognition occurs even when the two forms of mycobacteria equally infect and stimulate macrophages, which secrete the same cytokine pattern and express MHC class I and II molecules at the same levels. However, D-Mtb but not R-Mtb colocalizes with mature phagolysosome marker LAMP-1 and with vacuolar proton ATPase in macrophages. D-Mtb, unlike R-Mtb, is unable to interfere with phagosome pH and does not inhibit the proteolytic efficiency of macrophages. We show that D-Mtb downmodulates the gene Rv3875 encoding for ESAT-6, which is required by R-Mtb to block phagosome maturation together with Rv3310 gene product SapM, previously shown to be downregulated in D-Mtb. Thus, our results indicate that D-Mtb cannot escape MHC class II Ag-processing pathway because it lacks the expression of genes required to block the phagosome maturation. Data suggest that switching to dormancy not only represents a mechanism of survival in latent TB infection, but also a M. tuberculosis strategy to modulate the immune response in different stages of TB

Immunogenicity of viral vaccines in the italian military

Military personnel of all armed forces receive multiple vaccinations and have been doing so since long ago, but relatively few studies have investigated the possible negative or positive interference of simultaneous vaccinations. As a contribution to fill this gap, we analyzed the response to the live trivalent measles/mumps/rubella (MMR), the inactivated hepatitis A virus (HAV), the inactivated trivalent polio, and the trivalent subunits influenza vaccines in two cohorts of Italian military personnel. The first cohort was represented by 108 students from military schools and the second by 72 soldiers engaged in a nine-month mission abroad. MMR and HAV vaccines had never been administered before, whereas inactivated polio was administered to adults primed at infancy with a live trivalent oral polio vaccine. Accordingly, nearly all subjects had baseline antibodies to polio types 1 and 3, but unexpectedly, anti-measles/-mumps/-rubella antibodies were present in 82%, 82%, and 73.5% of subjects, respectively (43% for all of the antigens). Finally, anti-HAV antibodies were detectable in 14% and anti-influenza (H1/H3/B) in 18% of the study population. At mine months post-vaccination, 92% of subjects had protective antibody levels for all MMR antigens, 96% for HAV, 69% for the three influenza antigens, and 100% for polio types 1 and 3. An inverse relationship between baseline and post-vaccination antibody levels was noticed with all the vaccines. An excellent vaccine immunogenicity, a calculated long antibody persistence, and apparent lack of vaccine interference were observed

Identifying and Validating Tankyrase Binders and Substrates: A Candidate Approach.

The poly(ADP-ribose)polymerase (PARP) enzyme tankyrase (TNKS/ARTD5, TNKS2/ARTD6) uses its ankyrin repeat clusters (ARCs) to recognize degenerate peptide motifs in a wide range of proteins, thereby recruiting such proteins and their complexes for scaffolding and/or poly(ADP-ribosyl)ation. Here, we provide guidance for predicting putative tankyrase-binding motifs, based on the previously delineated peptide sequence rules and existing structural information. We present a general method for the expression and purification of tankyrase ARCs from Escherichia coli and outline a fluorescence polarization assay to quantitatively assess direct ARC-TBM peptide interactions. We provide a basic protocol for evaluating binding and poly(ADP-ribosyl)ation of full-length candidate interacting proteins by full-length tankyrase in mammalian cells

Le dimensioni dell’innovazione sociale per il design e l’implementazione di politiche pubbliche efficaci

Le recenti trasformazioni socio-economiche hanno fatto emergere, con forza crescente, l’importanza dell’innovazione sociale. Di pari passo, i decisori pubblici hanno implementato un numero sempre maggiore di politiche orientate a supportare lo sviluppo di iniziative di innovazione sociale. Nonostante l’attualità e la rilevanza del tema, manca tutt’oggi una delineazione univoca delle dimensioni fondanti e dei confini definitori d el concetto. La social innovation, infatti, si contraddistingue per essere un “concetto-ombrello” che include un insieme molto ampio e variegato di iniziative, attività, soggetti e contesti. Tale caratterizzazione ha favorito l’adozione di un approccio inclusivo nel tracciarne i confini enunciativi, contribuendo all’attuale varietà definitoria. Partendo da queste premesse, questo saggio propone una review dell’attuale dibattito (accademico e non) al fine di delineare un modello che permetta di sintetizzare e interpretare le differenti dimensioni definitorie del concetto di innovazione sociale. In particolare, tale modello intende offrire un framework di riferimento sia per la definizione di possibili percorsi di ricerca futuri sia per il design e l’implementazione di politiche pubbliche dall’elevato impatto sociale

Business-Bankruptcy After the BAPCPA: Evidence From the Stock Market

Little is known about how the Bankruptcy Abuse Prevention and Consumer Protection Act (BAPCPA) affects the business-bankruptcy landscape in the United States. This study addresses this gap in the literature by investigating the stock price dynamics of firms filing for Chapter 11 under both the 1978 Bankruptcy Act and the BAPCPA. Results show that, on average, shareholders of firms filing for Chapter 11 under the new Act lose significantly more both at and shortly after the event date than their 1978 counterparts do. Given the economic magnitude and robustness of these findings, this article's empirical evidence suggests the market perceives the BAPCPA to be more creditor-friendly than its predecessor is.School of Economics- University of the Algarve; FCT -Portuguese Foundation for Science and TechnologyPortuguese Foundation for Science and Technology [UID/ECO/04007/2019