Retinoic acid-inducible gene-I (RIG-I) is a cytoplasmic immune receptor sensing viral RNA. It triggers the release of type I interferons (IFN) and proinflammatory cytokines inducing an adaptive ...cellular immune response. We investigated the therapeutic potential of systemic RIG-I activation by short 5'-triphosphate-modified RNA (ppp-RNA) for the treatment of acute myeloid leukemia (AML) in the syngeneic murine C1498 AML tumor model. ppp-RNA treatment significantly reduced tumor burden, delayed disease onset and led to complete remission including immunological memory formation in a substantial proportion of animals. Therapy-induced tumor rejection was dependent on CD4
and CD8
T cells, but not on NK or B cells, and relied on intact IFN and mitochondrial antiviral signaling protein (MAVS) signaling in the host. Interestingly, ppp-RNA treatment induced programmed death ligand 1 (PD-L1) expression on AML cells and established therapeutic sensitivity to anti-PD-1 checkpoint blockade in vivo. In immune-reconstituted humanized mice, ppp-RNA treatment reduced the number of patient-derived xenografted (PDX) AML cells in blood and bone marrow while concomitantly enhancing CD3
T cell counts in the respective tissues. Due to its ability to establish a state of full remission and immunological memory, our findings show that ppp-RNA treatment is a promising strategy for the immunotherapy of AML.
Central nervous system infection of neonatal and adult rats with Borna disease virus (BDV) results in neuronal destruction and behavioral abnormalities with differential immune-mediated involvement. ...Neuroactive metabolites generated from the kynurenine pathway of tryptophan degradation have been implicated in several human neurodegenerative disorders. Here, we report that brain expression of key enzymes in the kynurenine pathway are significantly, but differentially, altered in neonatal and adult rats with BDV infection. Gene expression analysis of rat brains following neonatal infection showed increased expression of kynurenine amino transferase II (KATII) and kynurenine-3-monooxygenase (KMO) enzymes. Additionally, indoleamine 2,3-dioxygenase (IDO) expression was only modestly increased in a brain region- and time-dependent manner in neonatally infected rats; however, its expression was highly increased in adult infected rats. The most dramatic impact on gene expression was seen for KMO, whose activity promotes the production of neurotoxic quinolinic acid. KMO expression was persistently elevated in brain regions of both newborn and adult BDV-infected rats, with increases reaching up to 86-fold. KMO protein levels were increased in neonatally infected rats and colocalized with neurons, the primary target cells of BDV infection. Furthermore, quinolinic acid was elevated in neonatally infected rat brains. We further demonstrate increased expression of KATII and KMO, but not IDO,
in BDV-infected C6 astroglioma cells. Our results suggest that BDV directly impacts the kynurenine pathway, an effect that may be exacerbated by inflammatory responses in immunocompetent hosts. Thus, experimental models of BDV infection may provide new tools for discriminating virus-mediated from immune-mediated impacts on the kynurenine pathway and their relative contribution to neurodegeneration.
BDV causes persistent, noncytopathic infection
yet still elicits widespread neurodegeneration of infected neurons in both immunoincompetent and immunocompetent hosts. Here, we show that BDV infection induces expression of key enzymes of the kynurenine pathway in brains of newborn and adult infected rats and cultured astroglioma cells, shunting tryptophan degradation toward the production of neurotoxic quinolinic acid. Thus, our findings newly implicate this metabolic pathway in BDV-induced neurodegeneration. Given the importance of the kynurenine pathway in a wide range of human infections and neurodegenerative and neuropsychiatric disorders, animal models of BDV infection may serve as important tools for contrasting direct viral and indirect antiviral immune-mediated impacts on kynurenine pathway dysregulation and the ensuing neurodevelopmental and neuropathological consequences.
Cytoplasmic double-stranded RNA is sensed by RIG-I-like receptors (RLRs), leading to induction of type I interferons (IFN-Is), proinflammatory cytokines, and apoptosis. Here, we elucidate signaling ...mechanisms that lead to cytokine secretion and cell death induction upon stimulation with the bona fide RIG-I ligand 5'-triphosphate RNA (3p-RNA) in tumor cells. We show that both outcomes are mediated by dsRNA-receptor families with RLR being essential for cytokine production and IFN-I-mediated priming of effector pathways but not for apoptosis. Affinity purification followed by mass spectrometry and subsequent functional analysis revealed that 3p-RNA bound and activated oligoadenylate synthetase 1 and RNase L. RNase L-deficient cells were profoundly impaired in their ability to undergo apoptosis. Mechanistically, the concerted action of translational arrest triggered by RNase L and up-regulation of NOXA was needed to deplete the antiapoptotic MCL-1 to cause intrinsic apoptosis. Thus, 3p-RNA-induced apoptosis is a two-step process consisting of RIG-I-dependent priming and an RNase L-dependent effector phase.
Abstract
Monitoring of vibrational eigenmodes of an elastic body excited by gravitational waves was one of the first concepts proposed for the detection of gravitational waves. At laboratory scale, ...these experiments became known as resonant bar detectors first developed by Joseph Weber in the 1960s. Due to the dimensions of these bars, the targeted signal frequencies were in the kHz range. Weber also pointed out that monitoring of vibrations of Earth or the Moon could reveal gravitational waves in the mHz band. His Lunar Surface Gravimeter experiment deployed on the Moon by the Apollo 17 crew had a technical failure, which greatly reduced the science scope of the experiment. In this article, we revisit the idea and propose a Lunar Gravitational-Wave Antenna (LGWA). We find that LGWA could become an important partner observatory for joint observations with the space-borne, laser-interferometric detector LISA and at the same time contribute an independent science case due to LGWA’s unique features. Technical challenges need to be overcome for the deployment of the experiment, and development of inertial vibration sensor technology lays out a future path for this exciting detector concept.
Monounsaturated fatty acids (MUFA) are emerging health biomarkers, and in particular the ratio between palmitoleic acid (9cis-16:1) and palmitic acid (16:0) affords the delta-9 desaturase index that ...is increased in obesity. Recently, other positional and geometrical MUFA isomers belonging to the hexadecenoic family (C16 MUFA) were found in circulating lipids, such as sapienic acid (6cis-16:1), palmitelaidic acid (9trans-16:1) and 6trans-16:1. In this work we report: i) the identification of sapienic acid as component of human erythrocyte membrane phospholipids with significant increase in morbidly obese patients (n = 50) compared with age-matched lean controls (n = 50); and ii) the first comparison of erythrocyte membrane phospholipids (PL) and plasma cholesteryl esters (CE) in morbidly obese patients highlighting that some of their fatty acid levels have opposite trends: increases of both palmitic and sapienic acids with the decrease of linoleic acid (9cis,12cis-18:2, omega-6) in red blood cell (RBC) membrane PL were reversed in plasma CE, whereas the increase of palmitoleic acid was similar in both lipid species. Consequentially, desaturase enzymatic indexes gave different results, depending on the lipid class used for the fatty acid content. The fatty acid profile of morbidly obese subjects also showed significant increases of stearic acid (C18:0) and C20 omega-6, as well as decreases of oleic acid (9cis-18:1) and docosahexaenoic acid (C22:6 omega-3) as compared with lean healthy controls. Trans monounsaturated and polyunsaturated fatty acids were also measured and found significantly increased in both lipid classes of morbidly obese subjects. These results highlight the C16 MUFA isomers as emerging metabolic marker provided that the assignment of the double bond position and geometry is correctly performed, thus identifying the corresponding lipidomic pathway. Since RBC membrane PL and plasma CE have different fatty acid trends, caution must also be used in the choice of lipid species for the interpretation of lipidomic profiles.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The relatively simple molecular structure of hydrogen-bonded (HB) systems is often belied by their exceptionally complex thermodynamic and microscopic behaviour. For this reason, after a thorough ...experimental, computational and theoretical scrutiny, the dynamics of molecules in HB systems still eludes a comprehensive understanding. Aiming at shedding some insight into this topic, we jointly used neutron Brillouin scattering and molecular dynamics simulations to probe the dynamics of a prototypical hydrogen-bonded alcohol, liquid methanol. The comparison with the most thoroughly investigated HB system, liquid water, pinpoints common behaviours of their THz microscopic dynamics, thereby providing additional information on the role of HB dynamics in these two systems. This study demonstrates that the dynamic behaviour of methanol is much richer than what so far known, and prompts us to establish striking analogies with the features of liquid and supercooled water. In particular, based on the strong differences between the structural properties of the two systems, our results suggest that the assignment of some dynamical properties to the tetrahedral character of water structure should be questioned. We finally highlight the similarities between the characteristic decay times of the time correlation function, as obtained from our data and the mean lifetime of hydrogen bond known in literature.
To summarize the available evidence on metabolic parameters indicating metabolic adverse effects and risk of metabolic syndrome in children and adolescents treated with antipsychotics, following a ...pre-specified protocol (PROSPERO ID 252336).
We searched PubMed, Embase and PsycINFO until May 14, 2021, to identify systematic reviews (SR), meta-analyses (MA) and network meta-analyses (NMA) examining symptoms associated to metabolic syndrome in patients <18 years of age who required treatment with oral antipsychotic drugs. Evidence from quantitative analyses for all outcomes related to anthropometric, glyco-metabolic, and blood pressure parameters (measured from baseline to intervention-end and/or follow-up, in subjects exposed to antipsychotics and placebo) was reported on the basis of their metrics (median difference medianD, mean difference MD, standardized mean difference SMD, odds ratio OR, risk ratio (RR). A qualitative synthesis was also made. A formal quality assessment of the included studies was carried out by using the AMSTAR 2. We also provided a hierarchical stratification of the evidence from meta-analyses based on the class of evidence.
A total of 23 articles (13 MA, 4 NMA and 6 SR) were included for review. As compared with placebo, an increase in triglyceride levels was associated with olanzapine (medianD 95% CI: 37 12.27, 61.74 mg/dL; MD 95% CI: 38.57 21.44, 55.77 mg/dL) and quetiapine (medianD 95% CI: 21.58 95% CI: 4.27, 38.31 mg/dL; MD 95% CI: 34.87 20.08, 49.67 mg/dL; SMD 95% CI: 0.37 0.06, 0.068), whereas decreased triglyceride levels were found for lurasidone. Increased total cholesterol level was associated with asenapine (medianD 95% CI: 9.1 1.73, 16.44 mg/dL), quetiapine (medianD 95% CI: 15.60 7.30, 24.05 mg/dL; olanzapine (MD 95% CI from 3.67 1.43, 5.92 mg/dL to 20.47 13.97, 26.94 mg/dL; and lurasidone (medianD 95% CI: 8.94 1.27, 16.90 mg/dL). Change in glucose levels did not differ among antipsychotics or placebo. Lurasidone, molindone, and ziprasidone were the best tolerated in terms of weight gain. According to the AMSTAR 2 scoring system, 13 (56.5%) reviews were rated as very low quality. According to classes of evidence, most MA were level 4, especially because of their limited total sample size.
By collating meta-analyses assessing biochemical markers of metabolic syndrome in antipsychotic-treated children, we conclude that olanzapine should not be the antipsychotic of choice in patients at risk for hypertriglyceridemia or hypercholesterolemia. Aripiprazole and lurasidone appear to be better tolerated in terms of metabolic adverse events. Insufficient meta-analytic data are available to provide a precise risk estimate of metabolic syndrome, and, overall, the quality of evidence is low.
Association between the use of antipsychotic drugs and alterations of the parameters defining the Metabolic Syndrome (MetS) in children and adolescents: an umbrella review; https://www.crd.york.ac.uk/prospero/; CRD42021252336.
Different carbonates have been detected on Ceres, and their abundance and spatial distribution have been mapped using a visible and infrared mapping spectrometer (VIR), the Dawn imaging spectrometer. ...Carbonates are abundant and ubiquitous across the surface, but variations in the strength and position of infrared spectral absorptions indicate variations in the composition and amount of these minerals. Mg-Ca carbonates are detected all over the surface, but localized areas show Na carbonates, such as natrite (Na
CO
) and hydrated Na carbonates (for example, Na
CO
·H
O). Their geological settings and accessory NH
-bearing phases suggest the upwelling, excavation, and exposure of salts formed from Na-CO
-NH
-Cl brine solutions at multiple locations across the planet. The presence of the hydrated carbonates indicates that their formation/exposure on Ceres' surface is geologically recent and dehydration to the anhydrous form (Na
CO
) is ongoing, implying a still-evolving body.
We report epidemiological investigations of transmission of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 41 classes of 36 schools in Reggio Emilia province, northern Italy, ...from their reopening on 1 September to 15 October 2020. The overall secondary case attack rate was 3.2%, reaching 6.6% in middle and high schools. More timely isolation and testing of classmates could be effective in reducing virus transmission in this setting.
Background
Since the introduction of minimally invasive surgery, new techniques like transabdominal preperitoneal (TAPP) repair have progressively gained acceptance for the treatment of groin hernia. ...Laparoscopic TAPP (LTAPP) is recommended for bilateral repairs. Likewise, the introduction of robotic platforms has promised additional surgical benefits for robotic TAPP (RTAPP), which are yet to be confirmed. This study compared multicenter data obtained from patients undergoing bilateral inguinal hernia repair with RTAPP, performed during the preliminary learning curve period, versus conventional LTAPP.
Materials and methods
All consecutive bilateral inguinal hernia patients from four Italian centers between June 2015 and July 2020 were selected. A propensity score model was used to compare patients treated with LTAPP versus RTAPP, considering sex, age, body mass index, current smoking status, overall comorbidity, hernia classification (primary or recurrent), and associated procedures as covariates. After matching, intraoperative details and postoperative outcomes were evaluated.
Results
In total, 275 LTAPP and 40 RTAPP were performed. After matching, 80 and 40 patients were allocated to the LTAPP and RTAPP cohorts, respectively. No intraoperative complications or conversion to open surgery occurred. However, a longer operative time was recorded in the RTAPP group (79 ± 21 versus 98 ± 29 min;
p
< 0.001). Postoperative visual analog scale (VAS) pain scores (
p
= 0.13) did not differ and complication rates were similar. There were no clinical recurrences in either group, with mean follow-up periods of 52 ± 14 (LTAPP) and 35 ± 8 (RTAPP) months. A statistical difference in length of hospital stay was found between the groups (1.05 ± 0.22 vs 1.50 ± 0.74 days;
p
< 0.001).
Conclusion
In this patient population, outcomes for bilateral inguinal hernia repair appear comparable for RTAPP and LTAPP, except for a shorter recovery after laparoscopic surgery. A longer operative time for robotic surgery could be attributable to the learning curve period of each center.
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