A radio and infrared exploration of the Cygnus X-3 environments

To confirm, or rule out, the possible hot spot nature of two previously detected radio sources in the vicinity of the Cygnus X-3 microquasar. We present the results of a radio and near infrared exploration of the several arc-minute field around the well known galactic relativistic jet source Cygnus X-3 using the Very Large Array and the Calar Alto 3.5~m telescope. The data this paper is based on do not presently support the hot spot hypothesis. Instead, our new observations suggest that these sources are most likely background or foreground objects. Actually, none of them appears to be even barely extended as would be expected if they were part of a bow shock structure. Our near infrared observations also include a search for extended emission in the Bracket $\gamma$ (2.166 $\mu$m) and $H_{2}$ (2.122 $\mu$m) lines as possible tracers of shocked gas in the Cygnus X-3 surroundings. The results were similarly negative and the corresponding upper limits are reported.Comment: Accepted for publication in A&A; 5 pages, 4 figure

Soybean protein concentrate as a protein source for totoaba (Totoaba macdonaldi) juveniles: Effect on intermediary metabolism and liver histological organization

This study aimed to investigate the effects of replacing fish meal (FM) with soybean protein concentrates (SPC) on the intermediary metabolism and health of Totoaba macdonaldi juveniles. Fish (initial weight 50 ± 1 g) were fed for 60 days with eight diets: a reference diet (RD) and seven experimental diets where FM was replaced gradually with 15 to 100% SPC (SPC15, SPC30, SPC45, SPC60, SPC75, SPC90, and SPC100, respectively). Hexokinase (HK), glucokinase (GK), and alanine aminotransferase (ALT) enzyme activities showed highly significant differences (p < 0.01) between fish fed RD (0% SPC) compared to fish fed the diets with 60, 75, 90, and 100% SPC. The ALT enzyme shows a highly significant (p < 0.01) decrease in activity for fish fed 75, 90, and 100% SPC inclusions compared to fish fed the RD. The aspartate aminotransferase AST/ALT ratio showed a significant increase in activity for fish fed 100% soybean compared only with fish fed the control diet. The histological organization of the liver in totoaba juveniles fed RD, SPC15, SPC30 and SPC45 diets were similar. Totoaba fed with SPC90 and SPC100 showed histological alterations in hepatic and pancreatic parenchyma. Overall, according to the findings in this study, 45% of dietary FM could be replaced by SPC without causing adverse changes in metabolism, histological organization of liver, and health of juveniles of totoaba when cultured for 60 days. However, levels greater than 60% of SPC could compromise the health status of fish.info:eu-repo/semantics/acceptedVersio

The Advent of CAR T-Cell Therapy for Lymphoproliferative Neoplasms: Integrating Research Into Clinical Practice

Research on CAR T cells has achieved enormous progress in recent years. After the impressive results obtained in relapsed and refractory B-cell acute lymphoblastic leukemia and aggressive B-cell lymphomas, two constructs, tisagenlecleucel and axicabtagene ciloleucel, were approved by FDA. The role of CAR T cells in the treatment of B-cell disorders, however, is rapidly evolving. Ongoing clinical trials aim at comparing CAR T cells with standard treatment options and at evaluating their efficacy earlier in the disease course. The use of CAR T cells is still limited by the risk of relevant toxicities, most commonly cytokine release syndrome and neurotoxicity, whose management has nonetheless significantly improved. Some patients do not respond or relapse after treatment, either because of poor CAR T-cell expansion, lack of anti-tumor effects or after the loss of the target antigen on tumor cells. Investigators are trying to overcome these hurdles in many ways: by testing constructs which target different and/or multiple antigens or by improving CAR T-cell structure with additional functions and synergistic molecules. Alternative cell sources including allogeneic products (off-the-shelf CAR T cells), NK cells, and T cells obtained from induced pluripotent stem cells are also considered. Several trials are exploring the curative potential of CAR T cells in other malignancies, and recent data on multiple myeloma and chronic lymphocytic leukemia are encouraging. Given the likely expansion of CAR T-cell indications and their wider availability over time, more and more highly specialized clinical centers, with dedicated clinical units, will be required. Overall, the costs of these cell therapies will also play a role in the sustainability of many health care systems. This review will focus on the major clinical trials of CAR T cells in B-cell malignancies, including those leading to the first FDA approvals, and on the new settings in which these constructs are being tested. Besides, the most promising approaches to improve CAR T-cell efficacy and early data on alternative cell sources will be reviewed. Finally, we will discuss the challenges and the opportunities that are emerging with the advent of CAR T cells into clinical routine

The regulatory subunit of PKA-I remains partially structured and undergoes β-aggregation upon thermal denaturation

Background: The regulatory subunit (R) of cAMP-dependent protein kinase (PKA) is a modular flexible protein that responds with large conformational changes to the binding of the effector cAMP. Considering its highly dynamic nature, the protein is rather stable. We studied the thermal denaturation of full-length RIα and a truncated RIα(92-381) that contains the tandem cyclic nucleotide binding (CNB) domains A and B. Methodology/Principal Findings: As revealed by circular dichroism (CD) and differential scanning calorimetry, both RIα proteins contain significant residual structure in the heat-denatured state. As evidenced by CD, the predominantly α-helical spectrum at 25°C with double negative peaks at 209 and 222 nm changes to a spectrum with a single negative peak at 212-216 nm, characteristic of β-structure. A similar α→β transition occurs at higher temperature in the presence of cAMP. Thioflavin T fluorescence and atomic force microscopy studies support the notion that the structural transition is associated with cross-β-intermolecular aggregation and formation of non-fibrillar oligomers. Conclusions/Significance: Thermal denaturation of RIα leads to partial loss of native packing with exposure of aggregation-prone motifs, such as the B' helices in the phosphate-binding cassettes of both CNB domains. The topology of the β-sandwiches in these domains favors inter-molecular β-aggregation, which is suppressed in the ligand-bound states of RIα under physiological conditions. Moreover, our results reveal that the CNB domains persist as structural cores through heat-denaturation. © 2011 Dao et al

Tension between SN and BAO: current status and future forecasts

Using real and synthetic Type Ia SNe (SNeIa) and baryon acoustic oscillations (BAO) data representing current observations forecasts, this paper investigates the tension between those probes in the dark energy equation of state (EoS) reconstruction considering the well known CPL model and Wang's low correlation reformulation. In particular, here we present simulations of BAO data from both the the radial and transverse directions. We also explore the influence of priors on Omega_m and Omega_b on the tension issue, by considering 1-sigma deviations in either one or both of them. Our results indicate that for some priors there is no tension between a single dataset (either SNeIa or BAO) and their combination (SNeIa+BAO). Our criterion to discern the existence of tension (sigma-distance) is also useful to establish which is the dataset with most constraining power; in this respect SNeIa and BAO data switch roles when current and future data are considered, as forecasts predict and spectacular quality improvement on BAO data. We also find that the results on the tension are blind to the way the CPL model is addressed: there is a perfect match between the original formulation and that by the low correlation optimized, but the errors on the parameters are much narrower in all cases of our exhaustive exploration, thus serving the purpose of stressing the convenience of this reparametrization.Comment: 21 pages, under review in JCA

Synchronous Rotation in the (136199) Eris–Dysnomia System

We combine photometry of Eris from a 6 month campaign on the Palomar 60 inch telescope in 2015, a 1 month Hubble Space Telescope WFC3 campaign in 2018, and Dark Energy Survey data spanning 2013–2018 to determine a light curve of definitive period 15.771 ± 0.008 days (1σ formal uncertainties), with nearly sinusoidal shape and peak-to-peak flux variation of 3%. This is consistent at part-per-thousand precision with the P = 15.785 90 ± 0.00005 day sidereal period of Dysnomia's orbit around Eris, strengthening the recent detection of synchronous rotation of Eris by Szakáts et al. with independent data. Photometry from Gaia are consistent with the same light curve. We detect a slope of 0.05 ± 0.01 mag per degree of Eris's brightness with respect to illumination phase averaged across g, V, and r bands, intermediate between Pluto's and Charon's values. Variations of 0.3 mag are detected in Dysnomia's brightness, plausibly consistent with a double-peaked light curve at the synchronous period. The synchronous rotation of Eris is consistent with simple tidal models initiated with a giant-impact origin of the binary, but is difficult to reconcile with gravitational capture of Dysnomia by Eris. The high albedo contrast between Eris and Dysnomia remains unexplained in the giant-impact scenario

Mitochondria function associated genes contribute to Parkinson's Disease risk and later age at onset

Mitochondrial dysfunction has been implicated in the etiology of monogenic Parkinson’s disease (PD). Yet the role that mitochondrial processes play in the most common form of the disease; sporadic PD, is yet to be fully established. Here, we comprehensively assessed the role of mitochondrial function-associated genes in sporadic PD by leveraging improvements in the scale and analysis of PD GWAS data with recent advances in our understanding of the genetics of mitochondrial disease. We calculated a mitochondrial-specific polygenic risk score (PRS) and showed that cumulative small effect variants within both our primary and secondary gene lists are significantly associated with increased PD risk. We further reported that the PRS of the secondary mitochondrial gene list was significantly associated with later age at onset. Finally, to identify possible functional genomic associations we implemented Mendelian randomization, which showed that 14 of these mitochondrial functionassociated genes showed functional consequence associated with PD risk. Further analysis suggested that the 14 identified genes are not only involved in mitophagy, but implicate new mitochondrial processes. Our data suggests that therapeutics targeting mitochondrial bioenergetics and proteostasis pathways distinct from mitophagy could be beneficial to treating the early stage of PD

An Evolutionary Trade-Off between Protein Turnover Rate and Protein Aggregation Favors a Higher Aggregation Propensity in Fast Degrading Proteins

We previously showed the existence of selective pressure against protein aggregation by the enrichment of aggregation-opposing ‘gatekeeper’ residues at strategic places along the sequence of proteins. Here we analyzed the relationship between protein lifetime and protein aggregation by combining experimentally determined turnover rates, expression data, structural data and chaperone interaction data on a set of more than 500 proteins. We find that selective pressure on protein sequences against aggregation is not homogeneous but that short-living proteins on average have a higher aggregation propensity and fewer chaperone interactions than long-living proteins. We also find that short-living proteins are more often associated to deposition diseases. These findings suggest that the efficient degradation of high-turnover proteins is sufficient to preclude aggregation, but also that factors that inhibit proteasomal activity, such as physiological ageing, will primarily affect the aggregation of short-living proteins

The prion-like RNA-processing protein HNRPDL forms inherently toxic amyloid-like inclusion bodies in bacteria

BACKGROUND: The formation of protein inclusions is connected to the onset of many human diseases. Human RNA binding proteins containing intrinsically disordered regions with an amino acid composition resembling those of yeast prion domains, like TDP-43 or FUS, are being found to aggregate in different neurodegenerative disorders. The structure of the intracellular inclusions formed by these proteins is still unclear and whether these deposits have an amyloid nature or not is a matter of debate. Recently, the aggregation of TDP-43 has been modelled in bacteria, showing that TDP-43 inclusion bodies (IBs) are amorphous but intrinsically neurotoxic. This observation raises the question of whether it is indeed the lack of an ordered structure in these human prion-like protein aggregates the underlying cause of their toxicity in different pathological states. RESULTS: Here we characterize the IBs formed by the human prion-like RNA-processing protein HNRPDL. HNRPDL is linked to the development of limb-girdle muscular dystrophy 1G and shares domain architecture with TDP-43. We show that HNRPDL IBs display characteristic amyloid hallmarks, since these aggregates bind to amyloid dyes in vitro and inside the cell, they are enriched in intermolecular β-sheet conformation and contain inner amyloid-like fibrillar structure. In addition, despite their ordered structure, HNRPDL IBs are highly neurotoxic. CONCLUSIONS: Our results suggest that at least some of the disorders caused by the aggregation of human prion-like proteins would rely on the formation of classical amyloid assemblies rather than being caused by amorphous aggregates. They also illustrate the power of microbial cell factories to model amyloid aggregation. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12934-015-0284-7) contains supplementary material, which is available to authorized users