Tetraspanins, Another Piece in the HIV-1 Replication Puzzle

Despite the great research effort placed during the last decades in HIV-1 study, still some aspects of its replication cycle remain unknown. All this powerful research has succeeded in developing different drugs for AIDS treatment, but none of them can completely remove the virus from infected patients, who require life-long medication. The classical approach was focused on the study of virus particles as the main target, but increasing evidence highlights the importance of host cell proteins in HIV-1 cycle. In this context, tetraspanins have emerged as critical players in different steps of the viral infection cycle. Through their association with other molecules, including membrane receptors, cytoskeletal proteins, and signaling molecules, tetraspanins organize specialized membrane microdomains called tetraspanin-enriched microdomains (TEMs). Within these microdomains, several tetraspanins have been described to regulate HIV-1 entry, assembly, and transfer between cells. Interestingly, the importance of tetraspanins CD81 and CD63 in the early steps of viral replication has been recently pointed out. Indeed, CD81 can control the turnover of the HIV-1 restriction factor SAMHD1. This deoxynucleoside triphosphate triphosphohydrolase counteracts HIV-1 reverse transcription (RT) in resting cells via its dual function as dNTPase, catalyzing deoxynucleotide triphosphates into deoxynucleosides and inorganic triphosphate, and as exonuclease able to degrade single-stranded RNAs. SAMHD1 has also been related with the detection of viral nucleic acids, regulating the innate immune response and would promote viral latency. New evidences demonstrating the ability of CD81 to control SAMHD1 expression, and as a consequence, HIV-1 RT activity, highlight the importance of TEMs for viral replication. Here, we will briefly review how tetraspanins modulate HIV-1 infection, focusing on the latest findings that link TEMs to viral replication.This work was supported by grants BFU2014-55478-R; BIO2017-86500-R; Fundacion Ramon Areces and RYC-2012-11025 to MY-M; and was co-funded by Fondo Europeo de Desarrollo Regional (FEDER). HS was supported by a FPI-UAM Fellowship.S

Antifungal, Acute Toxicity and Mutagenicity Activity of Extracts from Datura stramonium, Jacquinia macrocarpa and Krameria erecta on Fusarium verticillioides

The effect of Baccharis glutinosa, Jacquinia macrocarpa, and Krameria erecta extracts was investigated on the growth and the spore germination of Fusarium verticillioides (ATCC 52539). Brine shrimp (Artemia salina) was used to evaluate the potential acute toxicity of the fractions obtained from plant extracts. The butanol fraction of J. macrocarpa totally inhibited the radial growth for 144 h and up to 95% after 168 h. The ethyl acetate fraction of B. glutinosa caused 100% of radial growth inhibition for 96 h. The ethyl acetate fractions of B. glutinosa and K. erecta caused the higher inhibitory effect on F. verticillioides spore germination, 100 and 95%, respectively. All plant fractions tested at a concentration of 5.0 mg mL-1 caused 100% brine shrimp lethality after 24 h. The Ames test did not reveal the presence of an evident mutagenic activity.Keywords: Antifungal Activity, Plant Extracts, Brine Shrimp Bioassay, Mutagenicity Assay, Fusarium verticillioide

ALCAM/CD166 is involved in the binding and uptake of cancer-derived extracellular vesicles

Colorectal cancer (CRC) and ovarian cancer (OvC) patients frequently develop peritoneal metastasis, a condition associated with a very poor prognosis. In these cancers, tumor-derived extracellular vesicles (EVs) cause immunosuppression, facilitate the direct attachment and invasion of cancer cells through the mesothelium, induce the conversion of peritoneal mesothelial cells (PMCs) into cancer-associated fibroblasts (CAFs) and transfer a more aggressive phenotype amongst cancer cells. Although the promoting role of EVs in CRC and OvC peritoneal metastasis is well established, the specific molecules that mediate the interactions between tumor-derived EVs and immune and non-immune target cells remain elusive. Here, we employed the SKOV-3 (ovarian adenocarcinoma) and Colo-320 (colorectal adenocarcinoma) human cell lines as model systems to study the interactions and uptake of EVs produced by ovarian carcinoma and colorectal carcinoma cells, respectively. We established that the adhesion molecule ALCAM/CD166 is involved in the interaction of cancerderived EVs with recipient cancer cells (a process termed “EV binding” or “EV docking”) and in their subsequent uptake by these cells. The identification of ALCAM/CD166 as a molecule mediating the docking and uptake of CRC and OvC-derived EVs may be potentially exploited to block the peritoneal metastasis cascade promoted by EVs in CRC and OvC patient

Development of a framework for metabolic pathway analysis-driven strain optimization methods

Genome-scale metabolic models (GSMMs) have become important assets for rational design of compound overproduction using microbial cell factories. Most computational strain optimization methods (CSOM) using GSMMs, while useful in metabolic engineering, rely on the definition of questionable cell objectives, leading to some bias. Metabolic pathway analysis approaches do not require an objective function. Though their use brings immediate advantages, it has mostly been restricted to small scale models due to computational demands. Additionally, their complex parameterization and lack of intuitive tools pose an important challenge towards making these widely available to the community. Recently, MCSEnumerator has extended the scale of these methods, namely regarding enumeration of minimal cut sets, now able to handle GSMMs. This work proposes a tool implementing this method as a Java library and a plugin within the OptFlux metabolic engineering platform providing a friendly user interface. A standard enumeration problem and pipeline applicable to GSMMs is proposed, making use by the community simpler. To highlight the potential of these approaches, we devised a case study for overproduction of succinate, providing a phenotype analysis of a selected strategy and comparing robustness with a selected solution from a bi-level CSOM.The authors thank the project “DeYeastLibrary—Designer yeast strain library optimized for metabolic engineering applications”, Ref. ERA-IB-2/0003/2013, funded by national funds through “Fundação para a Ciência e Tecnologia / Ministério da Ciência, Tecnologia e Ensino Superior”.info:eu-repo/semantics/publishedVersio

A suppressed contribution of low mass galaxies to reionization due to supernova feedback

Motivated by recent observations of the star formation rate density function out to z~7, we describe a simple model for the star formation rate density function at high redshift based on the extended Press-Schechter formalism. This model postulates a starburst following each major merger, lasting for a time t_SF and converting at most f_star of galactic gas into stars. We include a simple physical prescription for supernovae feedback that suppresses star formation in low mass galaxies. Constraining t_SF and f_star to describe the observed star formation rate density at high redshifts, we find that individual starbursts were terminated after a time t_SF~10^7 years. This is comparable to the main-sequence lifetimes of supernova progenitors, indicating that high redshift starbursts are quenched once supernovae feedback had time to develop. High redshift galaxies convert ~10% of their mass into stars for galaxies with star formation rates above ~1 solar mass per year, but a smaller fraction for lower luminosity galaxies. Our best fit model successfully predicts the observed relation between star formation rate and stellar mass at z>~4, while our deduced relation between stellar mass and halo mass is also consistent with data on the dwarf satellites of the Milky Way. We find that supernovae feedback lowers the efficiency of star formation in the lowest mass galaxies and makes their contribution to reionization small. As a result, photo-ionization feedback on low mass galaxy formation does not significantly affect the reionization history. Using a semi-analytic model for the reionization history, we infer that approximately half of the ionizing photons needed to complete reionization have already been observed in star-forming galaxies.Comment: 16 pages, 10 figures. Submitted to MNRA

The PDZ-adaptor protein syntenin-1 regulates HIV-1 entry

Syntenin-1 is a cytosolic adaptor protein involved in several cellular processes requiring polarization. Human immunodeficiency virus type 1 (HIV-1) attachment to target CD4(+) T-cells induces polarization of the viral receptor and coreceptor, CD4/CXCR4, and cellular structures toward the virus contact area, and triggers local actin polymerization and phosphatidylinositol 4,5-bisphosphate (PIP(2)) production, which are needed for successful HIV infection. We show that syntenin-1 is recruited to the plasma membrane during HIV-1 attachment and associates with CD4, the main HIV-1 receptor. Syntenin-1 overexpression inhibits HIV-1 production and HIV-mediated cell fusion, while syntenin depletion specifically increases HIV-1 entry. Down-regulation of syntenin-1 expression reduces F-actin polymerization in response to HIV-1. Moreover, HIV-induced PIP(2) accumulation is increased in syntenin-1–depleted cells. Once the virus has entered the target cell, syntenin-1 polarization toward the viral nucleocapsid is lost, suggesting a spatiotemporal regulatory role of syntenin-1 in actin remodeling, PIP(2) production, and the dynamics of HIV-1 entry

Atypical AT Skew in Firmicute Genomes Results from Selection and Not from Mutation

The second parity rule states that, if there is no bias in mutation or selection, then within each strand of DNA complementary bases are present at approximately equal frequencies. In bacteria, however, there is commonly an excess of G (over C) and, to a lesser extent, T (over A) in the replicatory leading strand. The low G+C Firmicutes, such as Staphylococcus aureus, are unusual in displaying an excess of A over T on the leading strand. As mutation has been established as a major force in the generation of such skews across various bacterial taxa, this anomaly has been assumed to reflect unusual mutation biases in Firmicute genomes. Here we show that this is not the case and that mutation bias does not explain the atypical AT skew seen in S. aureus. First, recently arisen intergenic SNPs predict the classical replication-derived equilibrium enrichment of T relative to A, contrary to what is observed. Second, sites predicted to be under weak purifying selection display only weak AT skew. Third, AT skew is primarily associated with largely non-synonymous first and second codon sites and is seen with respect to their sense direction, not which replicating strand they lie on. The atypical AT skew we show to be a consequence of the strong bias for genes to be co-oriented with the replicating fork, coupled with the selective avoidance of both stop codons and costly amino acids, which tend to have T-rich codons. That intergenic sequence has more A than T, while at mutational equilibrium a preponderance of T is expected, points to a possible further unresolved selective source of skew

The Formation of a Disk Galaxy within a Growing Dark Halo

We present a dynamical model for the formation and evolution of a massive disk galaxy, within a growing dark halo whose mass evolves according to cosmological simulations of structure formation. The galactic evolution is simulated with a new 3D chemo-dynamical code, including dark matter, stars and a multi-phase ISM. The simulations start at redshift z=4.85 with a small dark halo in a LCDM universe and we follow the evolution until the present epoch. The energy release by massive stars and SNe prevents a rapid collapse of the baryonic matter and delays the maximum star formation until z=1. The galaxy forms radially from inside-out and vertically from halo to disk. The first galactic component that forms is the halo, followed by the bulge, the disk-halo transition region, and the disk. At z=1, a bar begins to form which later turns into a triaxial bulge. There is a pronounced deficiency of low-metallicity disk stars due to pre-enrichment of the disk ISM with metal-rich gas from the bulge and inner disk (G-dwarf problem). The mean rotation and the distribution of orbital eccentricities for all stars as a function of metallicity are not very different from those observed in the solar neighbourhood, showing that homogeneous collapse models are oversimplified. The approach presented here provides a detailed description of the formation and evolution of an isolated disk galaxy in a LCDM universe, yielding new information about the kinematical and chemical history of the stars and the ISM, but also about the evolution of the luminosity, the colours and the morphology of disk galaxies.Comment: 23 pages, LaTeX, 18 figures, A&A accepted, a high resolution version of the paper can be found at http://www.astro.unibas.ch/leute/ms.shtm

Energy Contents of Some Well-Known Solutions in Teleparallel Gravity

In the context of teleparallel equivalent to General Relativity, we study energy and its relevant quantities for some well-known black hole solutions. For this purpose, we use the Hamiltonian approach which gives reasonable and interesting results. We find that our results of energy exactly coincide with several prescriptions in General Relativity. This supports the claim that different energy-momentum prescriptions can give identical results for a given spacetime. We also evaluate energy-momentum flux of these solutions.Comment: 16 pages, accepted for publication in Astrophys. Space Sc