Mitochondrial Dysfunction and Coenzyme Q10 Supplementation in Post-Viral Fatigue Syndrome: An Overview

Post-viral fatigue syndrome (PVFS) encompasses a wide range of complex neuroimmune disorders of unknown causes characterised by disabling post-exertional fatigue, myalgia and joint pain, cognitive impairments, unrefreshing sleep, autonomic dysfunction, and neuropsychiatric symptoms. It includes myalgic encephalomyelitis, also known as chronic fatigue syndrome (ME/CFS); fibromyalgia (FM); and more recently post-COVID-19 condition (long COVID). To date, there are no definitive clinical case criteria and no FDA-approved pharmacological therapies for PVFS. Given the current lack of effective treatments, there is a need to develop novel therapeutic strategies for these disorders. Mitochondria, the cellular organelles responsible for tissue energy production, have recently garnered attention in research into PVFS due to their crucial role in cellular bioenergetic metabolism in these conditions. The accumulating literature has identified a link between mitochondrial dysfunction and low-grade systemic inflammation in ME/CFS, FM, and long COVID. To address this issue, this article aims to critically review the evidence relating to mitochondrial dysfunction in the pathogenesis of these disorders; in particular, it aims to evaluate the effectiveness of coenzyme Q10 supplementation on chronic fatigue and pain symptoms as a novel therapeutic strategy for the treatment of PVFS

Modular classes of skew algebroid relations

Skew algebroid is a natural generalization of the concept of Lie algebroid. In this paper, for a skew algebroid E, its modular class mod(E) is defined in the classical as well as in the supergeometric formulation. It is proved that there is a homogeneous nowhere-vanishing 1-density on E* which is invariant with respect to all Hamiltonian vector fields if and only if E is modular, i.e. mod(E)=0. Further, relative modular class of a subalgebroid is introduced and studied together with its application to holonomy, as well as modular class of a skew algebroid relation. These notions provide, in particular, a unified approach to the concepts of a modular class of a Lie algebroid morphism and that of a Poisson map.Comment: 20 page

Evaluating the simulated radiative forcings, aerosol properties, and stratospheric warmings from the 1963 Mt Agung, 1982 El Chichón, and 1991 Mt Pinatubo volcanic aerosol clouds

Accurately quantifying volcanic impacts on climate is a key requirement for robust attribution of anthropogenic climate change. Here we use the Unified Model – United Kingdom Chemistry and Aerosol (UM-UKCA) composition–climate model to simulate the global dispersion of the volcanic aerosol clouds from the three largest eruptions of the 20th century: 1963 Mt Agung, 1982 El Chichón, and 1991 Mt Pinatubo. The model has interactive stratospheric chemistry and aerosol microphysics, with coupled aerosol–radiation interactions for realistic composition–dynamics feedbacks. Our simulations align with the design of the Interactive Stratospheric Aerosol Model Intercomparison (ISA-MIP) “Historical Eruption SO2 Emissions Assessment”. For each eruption, we perform three-member ensemble model experiments for upper, mid-point, and lower estimates of SO2 emission, each re-initialised from a control run to approximately match the observed transition in the phase of the quasi-biennial oscillation (QBO) in the 6 months after the eruptions. With this experimental design, we assess how each eruption's emitted SO2 translates into a tropical reservoir of volcanic aerosol and analyse the subsequent dispersion to mid-latitudes. We compare the simulations to the volcanic forcing datasets (e.g. Space-based Stratospheric Aerosol Climatology (GloSSAC); Sato et al., 1993, and Ammann et al., 2003) that are used in historical integrations for the two most recent Coupled Model Intercomparison Project (CMIP) assessments. For Pinatubo and El Chichón, we assess the vertical extent of the simulated volcanic clouds by comparing modelled extinction to the Stratospheric Aerosol and Gas Experiment (SAGE-II) v7.0 satellite measurements and to 1964–1965 Northern Hemisphere ground-based lidar measurements for Agung. As an independent test for the simulated volcanic forcing after Pinatubo, we also compare simulated shortwave (SW) and longwave (LW) top-of-the-atmosphere radiative forcings to the flux anomalies measured by the Earth Radiation Budget Experiment (ERBE) satellite instrument. For the Pinatubo simulations, an injection of 10 to 14 Tg SO2 gives the best match to the High Resolution Infrared Sounder (HIRS) satellite-derived global stratospheric sulfur burden, with good agreement also with SAGE-II mid-visible and near-infra-red extinction measurements. This 10–14 Tg range of emission also generates a heating of the tropical stratosphere that is consistent with the temperature anomaly present in the ERA-Interim reanalysis. For El Chichón, the simulations with 5 and 7 Tg SO2 emission give best agreement with the observations. However, these simulations predict a much deeper volcanic cloud than represented in the GloSSAC dataset, which is largely based on an interpolation between Stratospheric Aerosol Measurements (SAM-II) satellite and aircraft measurements. In contrast, these simulations show much better agreement during the SAGE-II period after October 1984. For 1963 Agung, the 9 Tg simulation compares best to the forcing datasets with the model capturing the lidar-observed signature of the altitude of peak extinction descending from 20 km in 1964 to 16 km in 1965. Overall, our results indicate that the downward adjustment to SO2 emission found to be required by several interactive modelling studies when simulating Pinatubo is also needed when simulating the Agung and El Chichón aerosol clouds. This strengthens the hypothesis that interactive stratospheric aerosol models may be missing an important removal or re-distribution process (e.g. effects of co-emitted ash) which changes how the tropical reservoir of volcanic aerosol evolves in the initial months after an eruption. Our model comparisons also identify potentially important inhomogeneities in the CMIP6 dataset for all three eruption periods that are hard to reconcile with variations predicted in the interactive stratospheric aerosol simulations. We also highlight large differences between the CMIP5 and CMIP6 volcanic aerosol datasets for the Agung and El Chichón periods. Future research should aim to reduce this uncertainty by reconciling the datasets with additional stratospheric aerosol observations

Octreotide treatment of patients with hepatocellular carcinoma - a retrospective single centre controlled study

<p>Abstract</p> <p>Background</p> <p>Studies of treatment with octreotide of patients with hepatocellular carcinoma (HCC) gave conflicting results. We analyzed retrospectively the survival of our patients treated with octreotide monotherapy and compared it to stage-matched patients who received either TACE, multimodal therapy or palliative care.</p> <p>Methods</p> <p>95 patients seen at the department of Gastroenterology and Hepatology, Medical University of Vienna with HCC in BCLC stage A or B, who received either TACE, multimodal therapy, long-acting octreotide or palliative care were reviewed for this retrospective study.</p> <p>Results</p> <p>Survival rates of patients with BCLC stage B and any "active" treatment (long-acting octreotide, TACE or multimodal therapy) were significantly higher (22.4, 22.0, 35.5 months) compared to patients who received palliative care only (2.9 months). Survival rates of patients with BCLC stage A and "active" treatment (31.4, 37.3, 40.2 months) compared to patients who received only palliative care (15.1 months) did not show statistically significant differences. Octreotide monotherapy showed a similar outcome compared to patients who received TACE or multimodal therapy.</p> <p>Conclusion</p> <p>Survival under octreotide treatment was not different compared to TACE or multimodal therapy and might be a therapeutic option for patients with HCC.</p

Krüppel-Like Factor 8 Is a New Wnt/Beta-Catenin Signaling Target Gene and Regulator in Hepatocellular Carcinoma

Krüppel-like factor 8 (KLF8) plays important role in cell cycle and oncogenic transformation. Here we report the mechanisms by which KLF8 crosstalks with Wnt/β-catenin signaling pathway and regulates hepatocellular carcinoma (HCC) cells proliferation. We show that overexpression of KLF8 and nucleus accumulation of β-catenin in the human HCC samples are positively correlated. More importantly, KLF8 protein levels plus nucleus accumulation of β-catenin levels were significantly elevated in high-grade HCC compared to low-grade HCC. Using HCC HepG2 cells we find that, on the one hand both protein and mRNA of KLF8 are up-regulated under Wnt3a stimulation, on the other hand overexpression of KLF8 increases the cytoplasm and nucleus accumulation of β-catenin, recruits p300 to β-catenin/T-cell factor 4 (TCF4) transcription complex, enhances TOP flash report gene transcription, and induces Wnt/β-catenin signaling target genes c-Myc, cyclin D1 and Axin1 expression. Knockdown of KLF8 using shRNA inhibits Wnt3a induced transcription of TOP flash report gene and expression of c-Myc, cyclin D1 and Axin1. Knockdown of β-catenin by shRNA rescues the enhanced HepG2 and Hep3B cells proliferation ability induced by overexpression of KLF8

The odd side of torsion geometry

We introduce and study a notion of `Sasaki with torsion structure' (ST) as an odd-dimensional analogue of K\"ahler with torsion geometry (KT). These are normal almost contact metric manifolds that admit a unique compatible connection with 3-form torsion. Any odd-dimensional compact Lie group is shown to admit such a structure; in this case the structure is left-invariant and has closed torsion form. We illustrate the relation between ST structures and other generalizations of Sasaki geometry, and explain how some standard constructions in Sasaki geometry can be adapted to this setting. In particular, we relate the ST structure to a KT structure on the space of leaves, and show that both the cylinder and the cone over an ST manifold are KT, although only the cylinder behaves well with respect to closedness of the torsion form. Finally, we introduce a notion of `G-moment map'. We provide criteria based on equivariant cohomology ensuring the existence of these maps, and then apply them as a tool for reducing ST structures.Comment: 34 pages; v2: added a small generalization (Proposition 3.6) of the cone construction; two references added. To appear on Ann. Mat. Pura App

High-Resolution Phenotypic Profiling Defines Genes Essential for Mycobacterial Growth and Cholesterol Catabolism

The pathways that comprise cellular metabolism are highly interconnected, and alterations in individual enzymes can have far-reaching effects. As a result, global profiling methods that measure gene expression are of limited value in predicting how the loss of an individual function will affect the cell. In this work, we employed a new method of global phenotypic profiling to directly define the genes required for the growth of Mycobacterium tuberculosis. A combination of high-density mutagenesis and deep-sequencing was used to characterize the composition of complex mutant libraries exposed to different conditions. This allowed the unambiguous identification of the genes that are essential for Mtb to grow in vitro, and proved to be a significant improvement over previous approaches. To further explore functions that are required for persistence in the host, we defined the pathways necessary for the utilization of cholesterol, a critical carbon source during infection. Few of the genes we identified had previously been implicated in this adaptation by transcriptional profiling, and only a fraction were encoded in the chromosomal region known to encode sterol catabolic functions. These genes comprise an unexpectedly large percentage of those previously shown to be required for bacterial growth in mouse tissue. Thus, this single nutritional change accounts for a significant fraction of the adaption to the host. This work provides the most comprehensive genetic characterization of a sterol catabolic pathway to date, suggests putative roles for uncharacterized virulence genes, and precisely maps genes encoding potential drug targets

Performance of CMS muon reconstruction in pp collision events at sqrt(s) = 7 TeV

The performance of muon reconstruction, identification, and triggering in CMS has been studied using 40 inverse picobarns of data collected in pp collisions at sqrt(s) = 7 TeV at the LHC in 2010. A few benchmark sets of selection criteria covering a wide range of physics analysis needs have been examined. For all considered selections, the efficiency to reconstruct and identify a muon with a transverse momentum pT larger than a few GeV is above 95% over the whole region of pseudorapidity covered by the CMS muon system, abs(eta) < 2.4, while the probability to misidentify a hadron as a muon is well below 1%. The efficiency to trigger on single muons with pT above a few GeV is higher than 90% over the full eta range, and typically substantially better. The overall momentum scale is measured to a precision of 0.2% with muons from Z decays. The transverse momentum resolution varies from 1% to 6% depending on pseudorapidity for muons with pT below 100 GeV and, using cosmic rays, it is shown to be better than 10% in the central region up to pT = 1 TeV. Observed distributions of all quantities are well reproduced by the Monte Carlo simulation.Comment: Replaced with published version. Added journal reference and DO

Performance of CMS muon reconstruction in pp collision events at sqrt(s) = 7 TeV

The performance of muon reconstruction, identification, and triggering in CMS has been studied using 40 inverse picobarns of data collected in pp collisions at sqrt(s) = 7 TeV at the LHC in 2010. A few benchmark sets of selection criteria covering a wide range of physics analysis needs have been examined. For all considered selections, the efficiency to reconstruct and identify a muon with a transverse momentum pT larger than a few GeV is above 95% over the whole region of pseudorapidity covered by the CMS muon system, abs(eta) < 2.4, while the probability to misidentify a hadron as a muon is well below 1%. The efficiency to trigger on single muons with pT above a few GeV is higher than 90% over the full eta range, and typically substantially better. The overall momentum scale is measured to a precision of 0.2% with muons from Z decays. The transverse momentum resolution varies from 1% to 6% depending on pseudorapidity for muons with pT below 100 GeV and, using cosmic rays, it is shown to be better than 10% in the central region up to pT = 1 TeV. Observed distributions of all quantities are well reproduced by the Monte Carlo simulation.Comment: Replaced with published version. Added journal reference and DO