Minimal within-host dengue models highlight the specific roles of the immune response in primary and secondary dengue infections

In recent years, the within-host viral dynamics of dengue infections have been increasingly characterized, and the relationship between aspects of these dynamics and the manifestation of severe disease has been increasingly probed. Despite this progress, there are few mathematical models of within-host dengue dynamics, and the ones that exist focus primarily on the general role of immune cells in the clearance of infected cells, while neglecting other components of the immune response in limiting viraemia. Here, by considering a suite of mathematical within-host dengue models of increasing complexity, we aim to isolate the critical components of the innate and the adaptive immune response that suffice in the reproduction of several well-characterized features of primary and secondary dengue infections. By building up from a simple target cell limited model, we show that only the innate immune response is needed to recover the characteristic features of a primary symptomatic dengue infection, while a higher rate of viral infectivity (indicative of antibody-dependent enhancement) and infected cell clearance by T cells are further needed to recover the characteristic features of a secondary dengue infection. We show that these minimal models can reproduce the increased risk of disease associated with secondary heterologous infections that arises as a result of a cytokine storm, and, further, that they are consistent with virological indicators that predict the onset of severe disease, such as the magnitude of peak viraemia, time to peak viral load, and viral clearance rate. Finally, we show that the effectiveness of these virological indicators to predict the onset of severe disease depends on the contribution of T cells in fuelling the cytokine storm.     

Organokines,Sarcopenia, and Metabolic Repercussions: The Vicious Cycle and the Interplay with Exercise

Sarcopenia is a disease that becomes more prevalent as the population ages, since it is directly linked to the process of senility, which courses with muscle atrophy and loss of muscle strength. Over time, sarcopenia is linked to obesity, being known as sarcopenic obesity, and leads to other metabolic changes. At the molecular level, organokines act on different tissues and can improve or harm sarcopenia. It all depends on their production process, which is associated with factors such as physical exercise, the aging process, and metabolic diseases. Because of the seriousness of these repercussions, the aim of this literature review is to conduct a review on the relationship between organokines, sarcopenia, diabetes, and other metabolic repercussions, as well the role of physical exercise. To build this review, PubMed-Medline, Embase, and COCHRANE databases were searched, and only studies written in English were included. It was observed that myokines, adipokines, hepatokines, and osteokines had direct impacts on the pathophysiology of sarcopenia and its metabolic repercussions. Therefore, knowing how organokines act is very important to know their impacts on age, disease prevention, and how they can be related to the prevention of muscle loss.     

The New Microtubule-Targeting Agent SIX2G Induces Immunogenic Cell Death in Multiple Myeloma

Microtubule-targeting agents (MTAs) are effective drugs for cancer treatment. A novel diaryl [1,2]oxazole class of compounds binding the colchicine site was synthesized as cis-restricted-combretastatin-A-4-analogue and then chemically modified to have improved solubility and a wider therapeutic index as compared to vinca alkaloids and taxanes. On these bases, a new class of tricyclic compounds, containing the [1,2]oxazole ring and an isoindole moiety, has been synthetized, among which SIX2G emerged as improved MTA. Several findings highlighted the ability of some chemotherapeutics to induce immunogenic cell death (ICD), which is defined by the cell surface translocation of Calreticulin (CALR) via dissociation of the PP1/GADD34 complex. In this regard, we computationally predicted the ability of SIX2G to induce CALR exposure by interacting with the PP1 RVxF domain. We then assessed both the potential cytotoxic and immunogenic activity of SIX2G on in vitro models of multiple myeloma (MM), which is an incurable hematological malignancy characterized by an immunosuppressive milieu. We found that the treatment with SIX2G inhibited cell viability by inducing G2/M phase cell cycle arrest and apoptosis. Moreover, we observed the increase of hallmarks of ICD such as CALR exposure, ATP release and phospho-eIF2α protein level. Through co-culture experiments with immune cells, we demonstrated the increase of (i) CD86 maturation marker on dendritic cells, (ii) CD69 activation marker on cytotoxic T cells, and (iii) phagocytosis of tumor cells following treatment with SIX2G, confirming the onset of an immunogenic cascade. In conclusion, our findings provide a framework for further development of SIX2G as a new potential anti-MM agent.     

Identification of a Maturation Plasma Cell Index through a Highly Sensitive Droplet Digital PCR Assay Gene Expression Signature Validation in Newly Diagnosed Multiple Myeloma Patients

DNA microarrays and RNA-based sequencing approaches are considered important discovery tools in clinical medicine. However, cross-platform reproducibility studies undertaken so far have highlighted that microarrays are not able to accurately measure gene expression, particularly when they are expressed at low levels. Here, we consider the employment of a digital PCR assay (ddPCR) to validate a gene signature previously identified by gene expression profile. This signature included ten Hedgehog (HH) pathways’ genes able to stratify multiple myeloma (MM) patients according to their self-renewal status. Results show that the designed assay is able to validate gene expression data, both in a retrospective as well as in a prospective cohort. In addition, the plasma cells’ differentiation status determined by ddPCR was further confirmed by other techniques, such as flow cytometry, allowing the identification of patients with immature plasma cells’ phenotype (i.e., expressing CD19+/CD81+ markers) upregulating HH genes, as compared to others, whose plasma cells lose the expression of these markers and were more differentiated. To our knowledge, this is the first technical report of gene expression data validation by ddPCR instead of classical qPCR. This approach permitted the identification of a Maturation Index through the integration of molecular and phenotypic data, able to possibly define upfront the differentiation status of MM patients that would be clinically relevant in the future.     

Incidental sadness biases social economic decisions in the Ultimatum Game.

Recent dual-process models of decision making have suggested that emotion plays an important role in decision making; however, the impact of incidental moods (i.e., emotions unrelated to the immediate situation) on decisions remains poorly explored. This question was investigated by inducing 2 basic emotional states (amusement or sadness) that were compared with a neutral-emotion control group. Decision making was assessed with a well-studied social task, the Ultimatum Game. In this task, participants had to make decisions to either accept or reject monetary offers from other players, offers that varied in their degree of unfairness. Emotion was induced with short movie clips. Induced sadness interacted with offer fairness, with higher sadness resulting in lower acceptance rates of unfair offers. Induced amusement was not associated with any significant biases in decision making. These results demonstrate that even subtle incidental moods can play an important role in biasing decision making. Implications of these results in regards to the emotion, cognitive neuroscience, and clinical literatures are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Credit risk in the pool—implications for private capital investments in Brazilian power generation

The new Brazilian Electric Sector Regulation of 2004 introduced two negotiation markets: the regulated pool and the free market. Competition in the pool is enforced via energy auctions, where the winning generator has to sign long-term power purchase agreements simultaneously with all distributors at the bidding-price.

To estimate the appropriate credit risk spread of the pool, we implement a clustering methodology to rank and rate the distributors. The results show an average spread between 5.75% and 8.5%, which corresponds to a credit rating of B− according to the spreads available in Reuters 2004. This estimation is at least 208 basis points higher than the credit rating Ba1/BB+ assigned to the distributors by the National Electric Energy Agency (ANEEL) in the periodic tariff revisions. Distributors with higher risk/spread are located in the South–Southeast, compared to the low risk/spread ones concentrated in the North–Northeast.

We estimate the opportunity cost of capital in real terms in the range of 13–16% to account for the credit risk of the pool. Essential to determine the bidding price at the auctions, this estimation is higher than the 11.26% opportunity cost estimated by ANEEL. The pool's credit risk has to be taken into consideration, especially for compensating new private capital investments in Brazilian power generation.     

Preparation,alumina-pillaring and oxidation catalytic performances of synthetic Ni-saponite

Synthetic saponite containing Ni²⁺ as octahedral cations has been prepared by a simple hydrothermal procedure, and has been intercalated with Al₁₃-polycations. The catalytic performance of the pillared solids in the epoxidation of (Z)-cyclooctene and the oxidation of cyclohexanone in the presence of benzonitrile, Baeyer–Villiger reaction, using hydrogen peroxide (70%) as a clean oxidant have been studied. For comparison, Mg-saponite was synthesized under the same conditions and tested for the same reaction.