Guerrasvendsen9041

Activating mutations of the oncogenic KRAS in pancreatic ductal adenocarcinoma (PDAC) are associated with an aberrant metabolic phenotype that may be therapeutically exploited. Increased glutamine utilization via glutaminase-1 (GLS1) is one such feature of the activated KRAS signaling that is essential to cell survival and proliferation; however, metabolic plasticity of PDAC cells allow them to adapt to GLS1 inhibition via various mechanisms including activation of glycolysis, suggesting a requirement for combinatorial anti-metabolic approaches to combat PDAC. We investigated whether targeting the glycolytic regulator 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) in combination with GLS1 can selectively prevent the growth of KRAS-transformed cells. We show that KRAS-transformation of pancreatic duct cells robustly sensitizes them to the dual targeting of GLS1 and PFKFB3. We also report that this sensitivity is preserved in the PDAC cell line PANC-1 which harbors an activating KRAS mutation. We then demonstrate that GLS1 inhibition reduced fructose-2,6-bisphosphate levels, the product of PFKFB3, whereas PFKFB3 inhibition increased glutamine consumption, and these effects were augmented by the co-inhibition of GLS1 and PFKFB3, suggesting a reciprocal regulation between PFKFB3 and GLS1. In conclusion, this study identifies a novel mutant KRAS-induced metabolic vulnerability that may be targeted via combinatorial inhibition of GLS1 and PFKFB3 to suppress PDAC cell growth.Cytidine-to-uridine (C-to-U) RNA editing has been generally observed in land plants; however, reverse (U-to-C) RNA editing is a rare phenomenon. In this study, we investigated the U-to-C RNA editing-related genes in Arabidopsis tissues and the effects on mRNA stability, with a special focus on PPR proteins. A previous study showed the extensive occurrence of U-to-C RNA editing in 12-day and 20-dayold Arabidopsis seedlings. Here, we have demonstrated the effects of this "reverse" RNA editing on the mRNA stability for all seven edited genes. We also identified U-to-C RNA editing in the nuclear PPR gene (AT2G19280) in 12-day-old seedlings of Arabidopsis thaliana. read more The U-to-C RNA editing sites were found in the untranslated region (3' UTR) of the mature mRNA and may affect its secondary structure. We also examined the correlation between U-to-C RNA editing-related genes and their mRNA abundance. Furthermore, we investigated the effects of U-to-C RNA editing in Arabidopsis using the transcription inhibitor actinomycin D (Act D). The addition of Act D to the seedlings of transgenic Arabidopsis generated by Agrobacterium-mediated transformation showed that single nucleotide base conversion adversely affected the mRNA secondary structure and stability.

To assess whether regulatory guidance on the use of dexamethasone in hospitalised COVID-19 patients is applicable to the larger population of COVID-19 cases. The surge in worldwide demand for dexamethasone suggests that the guidance, although correct, has not emphasised the danger of its wider use.

Data from the Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial and the World Health Organisation (WHO) prospective meta-analysis have been deconstructed and analysed.

To provide context, relevant publications were identified in PubMed using the following keywords COVID-19, RECOVERY trial, WHO meta-analysis, variants, immunity, public health.

The WHO guidance 'Corticosteroids for COVID-19' was based on their prospective meta-analysis. This meta-analysis was weighted by data from the RECOVERY trial.

In terms of COVID-19, dexamethasone has value in a narrow indication, namely, in hospitalised patients requiring respiratory support. The media blitz likely resulted in the wider use of dexamethasone iD-19 could benefit from clarification and the addition of a cautionary note.Centre of mass (CoM) motion during human balance recovery is largely influenced by the ground reaction force (GRF) and the centre of pressure (CoP). During gait, foot placement creates a region of possible CoP locations in the following double support (DS). This study aims to increase insight into how humans modulate the CoP during DS, and which CoP modulations are theoretically possible to maintain balance in the sagittal plane. Three variables sufficient to describe the shape, length and duration of the DS CoP trajectory of the total GRF, were assessed in perturbed human walking. To counteract the forward perturbations, braking was required and all CoP variables showed modulations correlated to the observed change in CoM velocity over the DS phase. These correlations were absent after backward perturbations, when only little propulsion was needed to counteract the perturbation. Using a linearized inverted pendulum model we could explore how the observed parameter modulations are effective in controlling the CoM. The distance the CoP travels forward and the instant the leading leg was loaded largely affected the CoM velocity, while the duration mainly affected the CoM position. The simulations also showed that various combinations of CoP parameters can reach a desired CoM position and velocity at the end of DS, and that even a full recovery in the sagittal plane within DS would theoretically have been possible. However, the human subjects did not exploit the therefore required CoP modulations. Overall, modulating the CoP trajectory in DS does effectively contributes to balance recovery.Although most head impacts in soccer are headers, limited knowledge exists about how header magnitude varies by on-field scenario. This study aimed to compare head kinematics during on-field headers by play state (i.e., corner kick, goal kick, free kick, throw-in, drill, or live ball), intent (i.e., pass, shot, or clearance), and outcome (i.e., successful or unsuccessful). Fifteen female collegiate soccer players were instrumented with mouthpiece-based head impact sensors during 72 practices and 24 games. A total of 336 headers were verified and contextualized via film review. Play state was associated with peak linear acceleration, rotational acceleration, and rotational velocity (all p less then .001) while outcome was associated with peak linear acceleration (p less then .010). Header intent was not significantly associated with any kinematic metric. Headers during corner kicks (22.9 g, 2189.3 rad/s2, 9.87 rad/s), goal kicks (24.3 g, 2658.9 rad/s2, 10.1 rad/s), free kicks (18.0 g, 1843.3 rad/s2, 8.43 rad/s), and live balls (18.8 g, 1769.7 rad/s2, 8.09 rad/s) each had significantly greater mean peak linear acceleration (all p less then .050), rotational acceleration (all p less then .001), and rotational velocity (all p less then .001) than headers during drills (13.0 g, 982.4 rad/s2, 5.28 rad/s). Headers during goal kicks also had a significantly greater mean rotational acceleration compared to headers during live ball scenarios (p less then .050). Successful headers (18.3 g) had a greater mean peak linear acceleration compared to unsuccessful headers (13.8 g; p less then .010). Results may help inform efforts to reduce head impact exposure in soccer.The elastic abdominal aorta and muscular femoral artery are susceptible to aneurysm and atherosclerosis, respectively. The vessel wall mechanics should be an important element for the difference. The objective of the study is to demonstrate a comparison of vessel wall mechanics between elastic and muscular arteries of juvenile and adult rats to show the changes of mechanical properties relevant to aging. The passive and active mechanical tests, theoretical analysis, and histological evaluation were carried out to investigate mechanical properties of vessel walls in the abdominal aorta and carotid and femoral arteries of young and adult rats. There are stiffening femoral artery, unchanged carotid artery, and distensible abdominal aorta in adult rats as compared with the young. The opening angle has values of 54 ± 13°, 82 ± 13°, and 94 ± 13° in the abdominal aorta and carotid and femoral arteries of adult rats, respectively, as well as 80 ± 22°, 93 ± 19°, and 100 ± 23° in the young. The findings are explained by the significantly reduced width of collagen fibers in the abdominal aorta, relatively unchanged width in the carotid artery, and significantly increased width in the femoral artery of adult rats as compared with the young. In conjunction with available literatures, we concluded that inconsistency for nonlinear age-related changes of artery wall mechanics occurs between arteries of different types, which may be a risk factor for the occurrence of abdominal aorta aneurysm and femoral artery atherosclerosis.Both inflammatory proteins and microRNAs (miRNA) have been reported to be associated with various psychiatric disorders. However, the association between inflammatory proteins and miRNAs remains largely unknown, especially for patients with depression, anxiety, or stress- and adjustment disorders. In this study, we analyzed plasma levels of 92 inflammatory proteins from 178 patients with depression, anxiety, or stress- and adjustment disorders at baseline and after 8-week psychological treatments which resulted in a significant decrease in the Montgomery Åsberg Depression Rating Scale (MADRS-S) score. We investigated the response of the proteins after treatment and the correlation with miR-144-5p. After Benjamini-Hochberg correction for multiple testing, a total of 36 inflammatory proteins changed significantly after 8-week psychological treatments. Among the 36 significantly changed proteins, 21 proteins showed a decrease, and 17/21 proteins were inversely associated with plasma miR-144-5p levels at baseline. In addition, decreases in these proteins were associated with increases in miR-144-5p after treatment. The findings were similar after stratification by use of medications. The associations between the proteins and depression at baseline, measured by MADRS-S, as well as the change in protein levels and treatment response were, however, less clear. These findings need to be examined in future studies.Zika virus (ZIKV), alongside Dengue virus (DENV), Chikungunya virus (CHIKV), and Yellow Fever Virus (YFV) are prevalent arboviruses in the Americas. Each of these infections is associated with the development of associated disease immunopathology. Immunopathological processes are an outcome of counter-balancing impacts between effector and regulatory immune mechanisms. In this context, regulatory T cells (Tregs) are key in modulating the immune response and, therefore, in tissue damage control. However, to date, Treg phenotypes and mechanisms during acute infection of the ZIKV in humans have not been fully investigated. The main aim of this work was to characterize Tregs and their immunological profile related to cytokine production and molecules that are capable of controlling the exacerbated inflammatory profile in acute Zika infected patients. Using whole blood analyses of infected patients, an ex vivo phenotypical characterization of Tregs, circulating during acute Zika virus infection, was conducted by flow cytometry. We found that though there are no differences in absolute Treg frequency between infected and healthy control groups. However, pro-inflammatory cytokine up-regulation such as IFN-γ and LAP was observed in the acute disease. Furthermore, acute ZIKV patients expressed increased levels of CD39/CD73, perforin/granzyme B, PD-1, and CTLA-4, all markers involved in mechanisms used by Tregs to attempt to control strong inflammatory responses. Thus, the data indicates a potential contribution of Tregs during the inflammatory ZIKV infection response.