Dengue and Zika virus infection patterns vary among Aedes aegypti field populations from Belo Horizonte,a Brazilian endemic city

Dengue virus (DENV) and Zika virus (ZIKV) belong to the same viral family, the Flaviviridae. They cause recurring threats to the public health systems of tropical countries such as Brazil. The primary Brazilian vector of both viruses is the mosquito Aedes aegypti. After the mosquito ingests a blood meal from an infected person, the viruses infect and replicate in the midgut, disseminate to secondary tissues and reach the salivary gland (SG), where they are ready to be transmitted to a vertebrate host. It is thought that the intrinsic discrepancies among mosquitoes could affect their ability to deal with viral infections. This study confirms that the DENV and ZIKV infection patterns of nine Ae. aegypti field populations found in geographically separate health districts of an endemic Brazilian city vary. We analyzed the infection rate, disseminated infection, vector competence, and viral load through quantitative PCR. Mosquitoes were challenged using the membrane-feeding assay technique and were tested seven and fourteen days post-infection (early and late infection phases, respectively). The infection responses varied among the Ae. aegypti populations for both flaviviruses in the two infection phases. There was no similarity between DENV and ZIKV vector competencies or viral loads. According to the results of our study, the risk of viral transmission overtime after infection either increases or remains unaltered in ZIKV infected vectors. However, the risk may increase, decrease, or remain unaltered in DENV-infected vectors depending on the mosquito population. For both flaviviruses, the viral load persisted in the body even until the late infection phase. In contrast to DENV, the ZIKV accumulated in the SG over time in all the mosquito populations. These findings are novel and may help direct the development of control strategies to fight dengue and Zika outbreaks in endemic regions, and provide a warning about the importance of understanding mosquito responses to arboviral infections.     

Autophagy in Spinocerebellar ataxia type 2, a dysregulated pathway,and a target for therapy

Spinocerebellar ataxia type 2 (SCA2) is an incurable and genetic neurodegenerative disorder. The disease is characterized by progressive degeneration of several brain regions, resulting in severe motor and non-motor clinical manifestations. The mutation causing SCA2 disease is an abnormal expansion of CAG trinucleotide repeats in the ATXN2 gene, leading to a toxic expanded polyglutamine segment in the translated ataxin-2 protein. While the genetic cause is well established, the exact mechanisms behind neuronal death induced by mutant ataxin-2 are not yet completely understood. Thus, the goal of this study is to investigate the role of autophagy in SCA2 pathogenesis and investigate its suitability as a target for therapeutic intervention. For that, we developed and characterized a new striatal lentiviral mouse model that resembled several neuropathological hallmarks observed in SCA2 disease, including formation of aggregates, neuronal marker loss, cell death and neuroinflammation. In this new model, we analyzed autophagic markers, which were also analyzed in a SCA2 cellular model and in human post-mortem brain samples. Our results showed altered levels of SQSTM1 and LC3B in cells and tissues expressing mutant ataxin-2. Moreover, an abnormal accumulation of these markers was detected in SCA2 patients’ striatum and cerebellum. Importantly, the molecular activation of autophagy, using the compound cordycepin, mitigated the phenotypic alterations observed in disease models. Overall, our study suggests an important role for autophagy in the context of SCA2 pathology, proposing that targeting this pathway could be a potential target to treat SCA2 patients.Subject terms: Diseases of the nervous system, Molecular neuroscience     

The signatures of organellar calcium

Recent insights about the transport mechanisms involved in the in and out of calcium ions in plant organelles, and their role in the regulation of cytosolic calcium homeostasis in different signaling pathways.

The transport of Ca²⁺ across the membranes of subcellular compartments contributes to cytosolic Ca²⁺ homeostasis as well as environmental and developmental responses.     

The rational modulation of autophagy sensitizes colorectal cancer cells to 5-fluouracil and oxaliplatin

Colorectal cancer (CRC) is the third most common and deadliest cancer globally. Regimens using 5-fluorouracil (5FU) and Oxaliplatin (OXA) are the first-line treatment for CRC, but tumor recurrence is frequent. It is plausible to hypothesize that differential cellular responses are triggered after treatments depending on the genetic background of CRC cells and that the rational modulation of cell tolerance mechanisms like autophagy may reduce the regrowth of CRC cells. This study proposes investigating the cellular mechanisms triggered by CRC cells exposed to 5FU and OXA using a preclinical experimental design mimicking one cycle of the clinical regimen (i.e., 48 h of treatment repeated every 2 weeks). To test this, we treated CRC human cell lines HCT116 and HT29 with the 5FU and OXA, combined or not, for 48 h, followed by analysis for two additional weeks. Compared to single-drug treatments, the co-treatment reduced tumor cell regrowth, clonogenicity and stemness, phenotypes associated with tumor aggressiveness and poor prognosis in clinics. This effect was exerted by the induction of apoptosis and senescence only in the co-treatment. However, a week after treatment, cells that tolerated the treatment had high levels of autophagy features and restored the proliferative phenotype, resembling tumor recurrence. The pharmacologic suppression of early autophagy during its peak of occurrence, but not concomitant with chemotherapeutics, strongly reduced cell regrowth. Overall, our experimental model provides new insights into the cellular mechanisms that underlie the response and tolerance of CRC cells to 5FU and OXA, suggesting optimized, time-specific autophagy inhibition as a new avenue for improving the efficacy of current treatments.     

Sub-0.6 eV Inverted Metamorphic GaInAs Cells Grown on Inp and GaAs Substrates for Thermophotovoltaics and Laser Power Conversion

Inverted metamorphic Ga_0.3In_0.7As photovoltaic converters with sub-0.60 eV bandgaps grown on InP and GaAs are presented. Threading dislocation densities are 1.3 ± 0.6 × 10⁶ and 8.9 ± 1.7 × 10⁶ cm⁻² on InP and GaAs, respectively. The devices generate open-circuit voltages of 0.386 and 0.383 V, respectively, under irradiance producing a short-circuit current density of ≈10 A cm⁻², yielding bandgap-voltage offsets of 0.20 and 0.21 V. Power and broadband reflectance measurements are used  to estimate thermophotovoltaic (TPV) efficiency. The InP-based cell is estimated to yield 1.09 W cm⁻² at 1100 °C versus 0.92 W cm⁻² for the GaAs-based cell, with efficiencies of 16.8 versus 9.2%. The efficiencies of both devices are limited by sub-bandgap absorption, with power weighted sub-bandgap reflectances of 81% and 58%, respectively, the majority of which is assumed to occur in the graded buffers. The 1100 °C TPV efficiencies are estimated to increase to 24.0% and 20.7% in structures with the graded buffer removed, if previously demonstrated reflectance is achieved. These devices also have application to laser power conversion in the 2.0–2.3 µm atmospheric window. Peak laser power converter efficiencies of 36.8% and 32.5% are estimated under 2.0 µm irradiances of 1.86 and 2.81 W cm⁻², respectively.     

Cleavage and release of a soluble form of the receptor tyrosine kinase ARK in vitro and in vivo

The receptor tyrosine kinase ARK (also called AXL or UFO) is the murine prototype of a small family of receptors with an extracellular domain resembling cell adhesion molecules and a conserved tyrosine kinase domain. ARK is capable of homophilic binding, as well as of binding to GAS6, a secreted member of the class of vitamin K dependent proteins whose expression is up-regulated in growth-arrested cells. To gain understanding of the physiological role of ARK signaling, we have investigated the ARK forms which are expressed by cells in culture as well as by mouse organs. We found that ARK is not only expressed as a transmembrane protein, but is also cleaved in the extracellular domain to generate a soluble ARK form of about 65 kDa, which is easily detected in conditioned media of ARK expressing cells, in serum and plasma and in mouse organs. Soluble ARK is also produced by tumor cells in vivo. The function of these molecules could be that of binding GAS6, thereby inhibiting the interaction of this ligand with its cell-associated receptor, or they could be involved in binding to ARK itself. © 1996 Wiley-Liss, Inc.     

The discovery of IDX21437: Design,synthesis and antiviral evaluation of 2′-α-chloro-2′-β-C-methyl branched uridine pronucleotides as potent liver-targeted HCV polymerase inhibitors

Herein we describe the discovery of IDX21437 35b, a novel R_P d-aminoacid-based phosphoramidate prodrug of 2′-α-chloro-2′-β-C-methyluridine monophosphate. Its corresponding triphosphate 6 is a potent inhibitor of the HCV NS5B RNA-dependent RNA polymerase (RdRp). Despite showing very weak activity in the in vitro Huh-7 cell based HCV replicon assay, 35b demonstrated high levels of active triphosphate 6 in mouse liver and human hepatocytes. A biochemical study revealed that the metabolism of 35b was mainly attributed to carboxyesterase 1 (CES1), an enzyme which is underexpressed in HCV Huh-7-derived replicon cells. Furthermore, due to its metabolic activation, 35b was efficiently processed in liver cells compared to other cell types, including human cardiomyocytes. The selected R_P diastereoisomeric configuration of 35b was assigned by X-ray structural determination. 35b is currently in Phase II clinical trials for the treatment of HCV infection.     

The defensive behavioral patterns of captive white-lipped and collared peccary (Mammalia,Tayassuidae): an approach for conservation of the species

Defensive behavioral patterns in response to human-induced rapid environmental change can affect animals’ fitness and may play a role in species conservation status. To test this hypothesis, we compared the risk assessment and defensive behavioral responses of captive white-lipped peccary (WLP; Tayassu pecari) and collared peccary (CP; Pecari tajacu), which retain different conservation status; WLP are considered vulnerable and CP of least concern. We used an adapted paradigm of the mouse defense test battery (MDTB) comprising four consecutive tests. Two of these tests simulated a novel environment, while the other two stimulated the expression of defensive behavioral patterns. Besides differences in risk assessment and defensive threat/attack behavioral patterns between species, we compared flight initiation distance, flight speed, and plasma glucocorticoid concentrations. When facing a novel environment and risk challenges from humans’ predator-like cues, the white-lipped peccary showed more exploratory and defensive threat/attack behavioral patterns, shorter flight initiation distances, and lower flight speeds, whereas the collared peccaries showed more cautious and retreat patterns, longer flight initiation distances, and higher flight speeds. There were also correlations between physiological and behavioral parameters. We confirmed our hypothesis that the collared peccary’s cautiousness may help to prevent a decrease in its population, while the white-lipped peccary’s exploratory and confrontational behavioral patterns in overhunted areas, together with other simultaneous factors as forest fragmentation, might contribute to placing this species in the vulnerable category.