The chikungunya virus (CHIKV) has become a substantial global health threat due to its massive re-emergence, the considerable disease burden and the lack of vaccines or therapeutics. We discovered a ...novel class of small molecules (1,2,3triazolo4,5-dpyrimidin-7(6H)-ones) with potent in vitro activity against CHIKV isolates from different geographical regions. Drug-resistant variants were selected and these carried a P34S substitution in non-structural protein 1 (nsP1), the main enzyme involved in alphavirus RNA capping. Biochemical assays using nsP1 of the related Venezuelan equine encephalitis virus revealed that the compounds specifically inhibit the guanylylation of nsP1. This is, to the best of our knowledge, the first report demonstrating that the alphavirus capping machinery is an excellent antiviral drug target. Considering the lack of options to treat CHIKV infections, this series of compounds with their unique (alphavirus-specific) target offers promise for the development of therapy for CHIKV infections.
Interaction between the hypothalamus and the immune system Soto‐Tinoco, Eva; Guerrero‐Vargas, Natalí N.; Buijs, Ruud M.
Experimental physiology,
1 December 2016, 2016-12-01, 2016-12-00, 20161201, Letnik:
101, Številka:
12
Journal Article
Recenzirano
Odprti dostop
New Findings
What is the topic of this review?
Both branches of the autonomic nervous system are involved in the regulation of the inflammatory response. We explore how the hypothalamus may influence ...this process.
What advances does it highlight?
We analyse how a lipopolysaccharide signal is transmitted to the brain and which areas participate in the response of the brain to lipopolysaccharide. Recent studies show that the hypothalamus can influence the inflammatory response by modifying the autonomic output. The biological clock, the suprachiasmatic nucleus, is integrated into this circuit, putting a time stamp on the intensity of the inflammatory response.
The brain is responsible for maintaining homeostasis of the organism, constantly adjusting its output via hormones and the autonomic nervous system to reach an optimal setting in every compartment of the body. Also, the immune system is under strong control of the brain. Apart from the conventional systemic responses evoked by the brain during inflammation, such as hypothalamic–pituitary–adrenal axis activation and the induction of sickness behaviour, the autonomic nervous system is now recognized to exert regulatory effects on the inflammatory response. Both branches of the autonomic nervous system are proposed to influence the inflammatory process. Here, we focus on those areas of the brain that might be involved in sensing inflammatory stimuli, followed by how that sensing could change the output of the autonomic nervous system in order to regulate the inflammatory response. Finally, we will discuss how the defenses of the body against a lipopolysaccharide challenge are organized by the hypothalamus.
Abstract
Wide-field surveys for transiting planets are well suited to searching diverse stellar populations, enabling a better understanding of the link between the properties of planets and their ...parent stars. We report the discovery of HAT-P-69 b (TOI 625.01) and HAT-P-70 b (TOI 624.01), two new hot Jupiters around A stars from the Hungarian-made Automated Telescope Network (HATNet) survey that have also been observed by the
Transiting Exoplanet Survey Satellite
. HAT-P-69 b has a mass of
M
Jup
and a radius of
R
Jup
and resides in a prograde 4.79 day orbit. HAT-P-70 b has a radius of
R
Jup
and a mass constraint of
M
Jup
and resides in a retrograde 2.74 day orbit. We use the confirmation of these planets around relatively massive stars as an opportunity to explore the occurrence rate of hot Jupiters as a function of stellar mass. We define a sample of 47,126 main-sequence stars brighter than
T
mag
= 10 that yields 31 giant planet candidates, including 18 confirmed planets, 3 candidates, and 10 false positives. We find a net hot Jupiter occurrence rate of 0.41 ± 0.10% within this sample, consistent with the rate measured by
Kepler
for FGK stars. When divided into stellar mass bins, we find the occurrence rate to be 0.71 ± 0.31% for G stars, 0.43 ± 0.15% for F stars, and 0.26 ± 0.11% for A stars. Thus, at this point, we cannot discern any statistically significant trend in the occurrence of hot Jupiters with stellar mass.
Light at night creates a conflicting signal to the biological clock and disrupts circadian physiology. In rodents, light at night increases the risk to develop mood disorders, overweight, disrupted ...energy metabolism, immune dysfunction and cancer. We hypothesized that constant light (LL) in rats may facilitate tumor growth via disrupted metabolism and increased inflammatory response in the host, inducing a propitious microenvironment for tumor cells.
Male Wistar rats were exposed to LL or a regular light-dark cycle (LD) for 5 weeks. Body weight gain, food consumption, triglycerides and glucose blood levels were evaluated; a glucose tolerance test was also performed. Inflammation and sickness behavior were evaluated after the administration of intravenous lipopolysaccharide. Tumors were induced by subcutaneous inoculation of glioma cells (C6). In tumor-bearing rats, the metabolic state and immune cells infiltration to the tumor was investigated by using immunohistochemistry and flow cytometry. The mRNA expression of genes involved metabolic, growth, angiogenes and inflammatory pathways was measured in the tumor microenvironment by qPCR. Tumor growth was also evaluated in animals fed with a high sugar diet.
We found that LL induced overweight, high plasma triglycerides and glucose levels as well as reduced glucose clearance. In response to an LPS challenge, LL rats responded with higher pro-inflammatory cytokines and exacerbated sickness behavior. Tumor cell inoculation resulted in increased tumor volume in LL as compared with LD rats, associated with high blood glucose levels and decreased triglycerides levels in the host. More macrophages were recruited in the LL tumor and the microenvironment was characterized by upregulation of genes involved in lipogenesis (Acaca, Fasn, and Pparγ), glucose uptake (Glut-1), and tumor growth (Vegfα, Myc, Ir) suggesting that LL tumors rely on these processes in order to support their enhanced growth. Genes related with the inflammatory state in the tumor microenvironment were not different between LL and LD conditions. In rats fed a high caloric diet tumor growth was similar to LL conditions.
Data indicates that circadian disruption by LL provides a favorable condition for tumor growth by promoting an anabolic metabolism in the host.
Abstract Introduction Muscle mass and function are amongst the most relevant factors that contribute to an optimal quality of life, and are strong predictors of mortality in the elderly. Loss of lean ...tissues and deterioration of muscle function have been described as one of the many complications of type 2 diabetes mellitus (DM2), but most studies do not isolate age as an intervening factor. Aim To study whether adult DM2 patients up to 60 years of age have decreased muscle mass and function compared with healthy non-diabetic (ND) subjects of similar age. Methodology Appendicular fat-free mass (ApFFM) by dual X-ray absorptiometry (DEXA), handgrip strength (HS), quadriceps strength (QS), 12 minute walking capacity (12MW) and the Timed Up and Go test (TUG) were measured in 100 DM2 patients and 39 ND controls. Muscle quality, or the ratio between lean mass and muscle strength of upper and lower limbs, and the functional limitations associated with pain and stiffness assessed according to the Western Ontario and McMaster Universities Arthrosis Index (WOMAC) were also recorded. Specific tests were performed to rule out microvascular diabetic complications (retinal and peripheral nerves), metabolic control, kidney function and Vitamin D status and examine their association with ApFFM and function. Results ApFFM was significantly higher among DM2 female patients and lower among diabetic men. However opposite results were obtained when individual values were corrected for body mass index (BMI), specifically among women, which were more likely to be obese. As for muscle strength and global functionality tests, significantly better performances in TUG, 12MW, QS and HS were observed among ND subjects of both sexes. These differences prevailed even after excluding diabetic patients with microvascular complications as well as those with more than 10 years of diabetes. Muscle quality was also significantly better among ND women. Higher scores of pain and stiffness in the WOMAC scale correlated with 12MW and TUG in both groups but did not correlate with ApFFM. Conclusions We found a clear deterioration of lean mass and muscle functions among adult DM2 patients of up to 60 years old, independent of length of disease, metabolic control, vitamin D status and presence of microvascular complications and pain.
Amyotrophic lateral sclerosis type 6 (ALS6) is a familial subtype of ALS linked to Fused in Sarcoma (FUS) gene mutation. FUS mutations lead to decreased global protein synthesis, but the mechanism ...that drives this has not been established. Here, we used ALS6 patient‐derived induced pluripotent stem cells (hIPSCs) to study the effect of the ALS6 FUSR521H mutation on the translation machinery in motor neurons (MNs). We find, in agreement with findings of others, that protein synthesis is decreased in FUSR521H MNs. Furthermore, FUSR521H MNs are more sensitive to oxidative stress and display reduced expression of TGF‐β and mTORC gene pathways when stressed. Finally, we show that IFNγ treatment reduces apoptosis of FUSR521H MNs exposed to oxidative stress and partially restores the translation rates in FUSR521H MNs. Overall, these findings suggest that a functional IFNγ response is important for FUS‐mediated protein synthesis, possibly by FUS nuclear translocation in ALS6.
FUS R521H motor neurons derived from IPSCs exhibit reduced viability, decreased protein synthesis, and diminished cytokine production when exposed to oxidative stress. Treatment with IFNy improves translation rates and mitigates apoptosis caused by oxidative injury.
Abstract
In recent years, the use of steel fibers has increased in Colombia, optimizing structure designs, quality specifications and mechanical behavior. However, the concrete durability and ...resistance to aggressive environments such as sulfates and chlorides are not commonly evaluated. This paper includes results of durability analysis for 21 MPa compressive strength concretes reinforces with steel and synthetic fibers. Performance parameters measured during tests include sulfate resistance, chlorides penetration, and carbonation according to technical standards. The Variables of experimental program were fiber type and fiber dosage. Dosages for synthetic fibers were 1.5 kg/m
3
, 3.0 kg/m
3
and 5.0 kg/m
3
, and for steel fibers were 5.0 kg/m
3
, 9.0 kg/m
3
and 18 kg/m
3
. Results of the study were used to propose recommendations for reducing concrete deterioration when exposed to these aggressive environments and for extending the durability service life.
We report the detection of a transiting super-Earth-sized planet (
R
= 1.39 ± 0.09
R
⊕
) in a 1.4-day orbit around L 168-9 (TOI-134), a bright M1V dwarf (
V
= 11,
K
= 7.1) located at 25.15 ± 0.02 pc. ...The host star was observed in the first sector of the Transiting Exoplanet Survey Satellite (TESS) mission. For confirmation and planet mass measurement purposes, this was followed up with ground-based photometry, seeing-limited and high-resolution imaging, and precise radial velocity (PRV) observations using the HARPS and
Magellan
/PFS spectrographs. By combining the TESS data and PRV observations, we find the mass of L 168-9 b to be 4.60 ± 0.56
M
⊕
and thus the bulk density to be 1.74
−0.33
+0.44
times higher than that of the Earth. The orbital eccentricity is smaller than 0.21 (95% confidence). This planet is a level one candidate for the TESS mission’s scientific objective of measuring the masses of 50 small planets, and it is one of the most observationally accessible terrestrial planets for future atmospheric characterization.
Mass spectrometric analysis of peptides contained in enzymatically digested hydrolysates of proteins is increasingly being used to characterize potentially bioactive or otherwise interesting ...hydrolysates. However, when preparations containing mixtures of enzymes are used, from either biological or experimental sources, it is unclear which of these enzymes have been most important in hydrolyzing the sample. We have developed a tool to rapidly evaluate the evidence for which enzymes are most likely to have cleaved the sample. EnzymePredictor, a web-based software, has been developed to (i) identify the protein sources of fragments found in the hydrolysates and map them back on it, (ii) identify enzymes that could yield such cleavages, and (iii) generate a colored visualization of the hydrolysate, the source proteins, the fragments, and the predicted enzymes. It tabulates the enzymes ranked according to their cleavage counts. The provision of odds ratio and standard error in the table permits users to evaluate how distinctively particular enzymes may be favored over other enzymes as the most likely cleavers of the samples. Finally, the method displays the cleavage not only according to peptides, but also according to proteins, permitting evaluation of whether the cleavage pattern is general across all proteins, or specific to a subset. We illustrate the application of this method using milk hydrolysates, and show how it can rapidly identify the enzymes or enzyme combinations used in generating the peptides. The approach developed here will accelerate the identification of enzymes most likely to have been used in hydrolyzing a set of mass spectrometrically identified peptides derived from proteins. This has utility not only in understanding the results of mass spectrometry experiments, but also in choosing enzymes likely to yield similar cleavage patterns. EnzymePredictor can be found at http://bioware.ucd.ie/∼enzpred/Enzpred.php
•A MSOGI-FLL is used to detect the frequency.•A PR harmonic-compensator is used.•Grid-connected PV system insensitive to harmonic pollution.•RTDS reinforced the final validation of the control ...algorithms.•Several algorithms are combined in this paper.
The large number of Photovoltaic plants and its utilization as agents of a Distributed Generation Systems justified the increasing efforts towards the optimal design of the overall grid-connected System. In a Distributed Generation environment the low voltage 3-phase utility grid could be affected by some disturbances such as voltage unbalanced, variations of frequency and harmonics distortion and it is mandatory that the control algorithms used in the inverter can be able to maintain the power flow between the renewable agent and the low voltage 3-phase utility grid; in addition a unitary power factor must be attained.
A Proportional-Resonant regulator is used to performance a current control with the output current of the inverter and a Multiple Second Order Generalized Integrator Frequency-Locked Loop (MSOGI-FLL) is used to detect the frequency of the low voltage 3-phase utility grid. Some low order harmonics are introduced in the low voltage 3-phase utility grid in order to see the effect of the harmonic compensator.
In order to validate the model of the Photovoltaic Renewable agent, the synchronization algorithm and the inverter control algorithm, some simulations using MATLAB/SIMULINK from The MathWorks, Inc. are shown firstly, and secondly, some Real-Time Digital Simulation tests using a Real-Time Digital Simulation (RTDS) Platform are carried out.
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