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Dissecting celastrol with machine learning to unveil dark pharmacology
Coallescing bespoke machine learning and bioinformatics analyses with cell-based assays we unveil pharmacology of celastrol. Celastrol is a direct modulator of the progesterone and cannabinoid receptors, and its effects correlate with the antiproliferative activity. We demonstrate how in silico methods may drive systems biology studies for natural products.We thank the Royal Society (URF\R\180019), H2020 (ERC StG, GA no. 676832, 743640 ad 807281) and FCT Portugal (IF/00624/2015 and 02/SAICT/2017, Grant 28333) for funding
Multivariate discrimination and the Higgs + W/Z search
A systematic method for optimizing multivariate discriminants is developed
and applied to the important example of a light Higgs boson search at the
Tevatron and the LHC. The Significance Improvement Characteristic (SIC),
defined as the signal efficiency of a cut or multivariate discriminant divided
by the square root of the background efficiency, is shown to be an extremely
powerful visualization tool. SIC curves demonstrate numerical instabilities in
the multivariate discriminants, show convergence as the number of variables is
increased, and display the sensitivity to the optimal cut values. For our
application, we concentrate on Higgs boson production in association with a W
or Z boson with H -> bb and compare to the irreducible standard model
background, Z/W + bb. We explore thousands of experimentally motivated,
physically motivated, and unmotivated single variable discriminants. Along with
the standard kinematic variables, a number of new ones, such as twist, are
described which should have applicability to many processes. We find that some
single variables, such as the pull angle, are weak discriminants, but when
combined with others they provide important marginal improvement. We also find
that multiple Higgs boson-candidate mass measures, such as from mild and
aggressively trimmed jets, when combined may provide additional discriminating
power. Comparing the significance improvement from our variables to those used
in recent CDF and DZero searches, we find that a 10-20% improvement in
significance against Z/W + bb is possible. Our analysis also suggests that the
H + W/Z channel with H -> bb is also viable at the LHC, without requiring a
hard cut on the W/Z transverse momentum.Comment: 41 pages, 5 tables, 29 figure
Characterization of Lifestyle in Spinocerebellar Ataxia Type 3 and Association with Disease Severity
BACKGROUND: Lifestyle could influence the course of hereditary ataxias, but representative data are missing. OBJECTIVE: The objective of this study was to characterize lifestyle in spinocerebellar ataxia type 3 (SCA3) and investigate possible associations with disease parameters. METHODS: In a prospective cohort study, data on smoking, alcohol consumption, physical activity, physiotherapy, and body mass index (BMI) were collected from 243 patients with SCA3 and 119 controls and tested for associations with age of onset, disease severity, and progression. RESULTS: Compared with controls, patients with SCA3 were less active and consumed less alcohol. Less physical activity and alcohol abstinence were associated with more severe disease, but not with progression rates or age of onset. Smoking, BMI, or physiotherapy did not correlate with disease parameters. CONCLUSION: Differences in lifestyle factors of patients with SCA3 and controls as well as associations of lifestyle factors with disease severity are likely driven by the influence of symptoms on behavior. No association between lifestyle and disease progression was detected. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
Apraxia and motor dysfunction in corticobasal syndrome
Background: Corticobasal syndrome (CBS) is characterized by multifaceted motor system dysfunction and cognitive disturbance; distinctive clinical features include limb apraxia and visuospatial dysfunction. Transcranial magnetic stimulation (TMS) has been used to study motor system dysfunction in CBS, but the relationship of TMS parameters to clinical features has not been studied. The present study explored several hypotheses; firstly, that limb apraxia may be partly due to visuospatial impairment in CBS. Secondly, that motor system dysfunction can be demonstrated in CBS, using threshold-tracking TMS, and is linked to limb apraxia. Finally, that atrophy of the primary motor cortex, studied using voxel-based morphometry analysis (VBM), is associated with motor system dysfunction and limb apraxia in CBS. Â Methods: Imitation of meaningful and meaningless hand gestures was graded to assess limb apraxia, while cognitive performance was assessed using the Addenbrooke's Cognitive Examination - Revised (ACE-R), with particular emphasis placed on the visuospatial subtask. Patients underwent TMS, to assess cortical function, and VBM. Â Results: In total, 17 patients with CBS (7 male, 10 female; mean age 64.4+/2 6.6 years) were studied and compared to 17 matched control subjects. Of the CBS patients, 23.5% had a relatively inexcitable motor cortex, with evidence of cortical dysfunction in the remaining 76.5% patients. Reduced resting motor threshold, and visuospatial performance, correlated with limb apraxia. Patients with a resting motor threshold <50% performed significantly worse on the visuospatial sub-task of the ACE-R than other CBS patients. Cortical function correlated with atrophy of the primary and pre-motor cortices, and the thalamus, while apraxia correlated with atrophy of the pre-motor and parietal cortices. Â Conclusions: Cortical dysfunction appears to underlie the core clinical features of CBS, and is associated with atrophy of the primary motor and pre-motor cortices, as well as the thalamus, while apraxia correlates with pre-motor and parietal atrophy
Biophysical Characterization and Membrane Interaction of the Two Fusion Loops of Glycoprotein B from Herpes Simplex Type I Virus
The molecular mechanism of entry of herpesviruses requires a multicomponent fusion system. Cell invasion by Herpes simplex virus (HSV) requires four virally encoded glycoproteins: namely gD, gB and gH/gL. The role of gB has remained elusive until recently when the crystal structure of HSV-1 gB became available and the fusion potential of gB was clearly demonstrated. Although much information on gB structure/function relationship has been gathered in recent years, the elucidation of the nature of the fine interactions between gB fusion loops and the membrane bilayer may help to understand the precise molecular mechanism behind herpesvirus-host cell membrane fusion. Here, we report the first biophysical study on the two fusion peptides of gB, with a particular focus on the effects determined by both peptides on lipid bilayers of various compositions. The two fusion loops constitute a structural subdomain wherein key hydrophobic amino acids form a ridge that is supported on both sides by charged residues. When used together the two fusion loops have the ability to significantly destabilize the target membrane bilayer, notwithstanding their low bilayer penetration when used separately. These data support the model of gB fusion loops insertion into cholesterol enriched membranes
Stochastic Gravity: Theory and Applications
Whereas semiclassical gravity is based on the semiclassical Einstein equation
with sources given by the expectation value of the stress-energy tensor of
quantum fields, stochastic semiclassical gravity is based on the
Einstein-Langevin equation, which has in addition sources due to the noise
kernel. In the first part, we describe the fundamentals of this new theory via
two approaches: the axiomatic and the functional. In the second part, we
describe three applications of stochastic gravity theory. First, we consider
metric perturbations in a Minkowski spacetime, compute the two-point
correlation functions of these perturbations and prove that Minkowski spacetime
is a stable solution of semiclassical gravity. Second, we discuss structure
formation from the stochastic gravity viewpoint. Third, we discuss the
backreaction of Hawking radiation in the gravitational background of a black
hole and describe the metric fluctuations near the event horizon of an
evaporating black holeComment: 100 pages, no figures; an update of the 2003 review in Living Reviews
in Relativity gr-qc/0307032 ; it includes new sections on the Validity of
Semiclassical Gravity, the Stability of Minkowski Spacetime, and the Metric
Fluctuations of an Evaporating Black Hol
Stochastic Gravity: Theory and Applications
Whereas semiclassical gravity is based on the semiclassical Einstein equation
with sources given by the expectation value of the stress-energy tensor of
quantum fields, stochastic semiclassical gravity is based on the
Einstein-Langevin equation, which has in addition sources due to the noise
kernel.In the first part, we describe the fundamentals of this new theory via
two approaches: the axiomatic and the functional. In the second part, we
describe three applications of stochastic gravity theory. First, we consider
metric perturbations in a Minkowski spacetime: we compute the two-point
correlation functions for the linearized Einstein tensor and for the metric
perturbations. Second, we discuss structure formation from the stochastic
gravity viewpoint. Third, we discuss the backreaction of Hawking radiation in
the gravitational background of a quasi-static black hole.Comment: 75 pages, no figures, submitted to Living Reviews in Relativit
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