2,069 research outputs found
The role of SARS-CoV-2 ORF8 protein ARKS motif on novobiocin binding
The discovery of the SARS-CoV-2 virus during the COVID-19 pandemic required scientists to develop medical solutions to reduce infectivity, severity of symptoms, and death. Although vaccines and drugs provided urgent assistance, the need to continue developing better drugs is necessary long term, and understanding the structure of the virus and finding potential inhibitors would prove vital to discovering solutions to this worldwide health problem. This experimental project focuses on targeting the unique accessory protein, Open Reading Frame 8 (ORF8) in SARS-CoV-2 through studying its interactions with a repurposable drug, novobiocin. Importantly, ORF8 specializes in helping evade immune system checks by downregulating major histocompatibility complex I (MHC-I) after infection, and is also involved in inflammatory responses from the cytokine storm, the most prominent cause of fatalities from the virus. Additionally, the ORF8 protein has been proposed to act as a histone mimic at the histone-H3 ARKS motif that causes post-translational changes in chromatin, further worsening these problems through gene transcription. Previous in silico and in vitro work from our lab has shown that novobiocin [Kd = 54.5 ± 3.14 μM] and three other computationally verified ligands (iohexol [Kd = 1185 ± 193 μM], kaempferol-7-O-glucoside [Kd = 135 ± 10.9 μM] & lercanidipine hydrochloride [Kd = 52.7 ± 5.71 μM]) bind to. To probe the role of Arg in the histone-H3 ARKS motif, specific mutation was done in position 52 from Arg to Met, Glu and Leu respectively. The above results in drastic changes in intermolecular forces such as opposing charge, polarity and different sizes of these side chains that negatively affect novobiocin’s ability to bind to the ORF8 pocket , which this research aims to experimentally prove this hypothesis. In silico analyses for the mutagenic ORF8 were initially found to require more energy to bind novobiocin to the ARKS motif than wild-type, but was still possible to dock according to Swissdock. Primers for the ORF8 R52 mutants were then designed and mutagenic plasmids were constructed and sequence verified. Each of the mutant ORF8 proteins was overexpressed, purified, and Kd values for binding to novobiocin were determined via intrinsic fluorescence spectroscopy and compared with wild-type binding. This data will help further understand the role of SARS-CoV-2 ORF8 protein ARKS motif and how its interactions affected novobiocin binding, potentially benefitting future studies attempting to repurpose novobiocin and other ligands for treatment of the spreading virus
Robustness of Physics-Informed Neural Networks to Noise in Sensor Data
Physics-Informed Neural Networks (PINNs) have been shown to be an effective
way of incorporating physics-based domain knowledge into neural network models
for many important real-world systems. They have been particularly effective as
a means of inferring system information based on data, even in cases where data
is scarce. Most of the current work however assumes the availability of
high-quality data. In this work, we further conduct a preliminary investigation
of the robustness of physics-informed neural networks to the magnitude of noise
in the data. Interestingly, our experiments reveal that the inclusion of
physics in the neural network is sufficient to negate the impact of noise in
data originating from hypothetical low quality sensors with high
signal-to-noise ratios of up to 1. The resultant predictions for this test case
are seen to still match the predictive value obtained for equivalent data
obtained from high-quality sensors with potentially 10x less noise. This
further implies the utility of physics-informed neural network modeling for
making sense of data from sensor networks in the future, especially with the
advent of Industry 4.0 and the increasing trend towards ubiquitous deployment
of low-cost sensors which are typically noisier
Thermal production of axino Dark Matter
We reconsider thermal production of axinos in the early universe, adding: a)
missed terms in the axino interaction; b) production via gluon decays
kinematically allowed by thermal masses; c) a precise modeling of reheating. We
find an axino abunance a few times larger than previous computations.Comment: 6 pages, 2 figures. Final version, to appear on JHE
Association of Sodium-Glucose Cotransporter 2 Inhibitor vs Dipeptidyl Peptidase-4 Inhibitor Use With Risk of Incident Obstructive Airway Disease and Exacerbation Events Among Patients With Type 2 Diabetes in Hong Kong
Importance
Patients with diabetes are at higher risk for obstructive airway disease (OAD). In recent meta-analyses of post hoc analyses of cardiorenal trials, sodium-glucose cotransporter 2 inhibitors (SGLT2Is) were suggested to reduce the risk of OAD adverse events. However, a clinical investigation of this association is warranted.
Objective
This study aimed to investigate the association of SGLT2I use vs dipeptidyl peptidase-4 inhibitor (DPP4I) use with OAD incidence and exacerbation events in patients with type 2 diabetes.
Design, Setting, and Participants
This retrospective population-based cohort study used electronic health data from a territory-wide electronic medical database in Hong Kong. Data were collected for patients with type 2 diabetes who were prescribed SGLT2Is or DPP4Is between January 1, 2015, and December 31, 2018. Patients were followed for a median of 2.2 years between January 1, 2015, and December 31, 2020. A prevalent new-user design was adopted to match patients based on previous exposure to the study drugs. Propensity score matching was used to balance baseline characteristics.
Exposures
Patients with type 2 diabetes using SGLT2Is (exposure of interest) or DPP4Is (active comparator).
Main Outcomes and Measures
The main outcomes were the first incidence of OAD and the count of OAD exacerbations. The risk of incident OAD was estimated using a Cox proportional hazards regression model. The rate of exacerbations was estimated using zero-inflated Poisson regression. Statistical analysis was performed on November 13, 2022.
Results
This study included 30 385 patients. The propensity score–matched non-OAD cohort (incidence analysis) consisted of 5696 SGLT2I users and 22 784 DPP4I users, while the matched OAD cohort (exacerbations analysis) comprised 381 SGLT2I users and 1524 DPP4I users. At baseline, 56% of patients in the non-OAD cohort were men and the mean (SD) age was 61.2 (9.9) years; 51% of patients in the OAD cohort were men and the mean age was 62.2 (10.8) years. Compared with DPP4I use, SGLT2I use was associated with a lower risk of incident OAD (hazard ratio, 0.65 [95% CI, 0.54-0.79]; P < .001) and a lower rate of exacerbations (rate ratio, 0.54 [95% CI, 0.36-0.83]; P = .01). The associations were consistent in sex subgroup analysis.
Conclusions and Relevance
The findings of this retrospective cohort study of patients with type 2 diabetes in Hong Kong suggest that SGLT2I use was associated with a reduced risk of incident OAD and a lower rate of exacerbations in a clinical setting compared with DPP4I use. These findings further suggest that SGLT2Is may provide additional protective effects against OAD for patients with type 2 diabetes and that further investigation is warranted
Bridging flavour violation and leptogenesis in SU(3) family models
We reconsider basic, in the sense of minimal field content, Pati-Salam x
SU(3) family models which make use of the Type I see-saw mechanism to reproduce
the observed mixing and mass spectrum in the neutrino sector. The goal of this
is to achieve the observed baryon asymmetry through the thermal decay of the
lightest right-handed neutrino and at the same time to be consistent with the
expected experimental lepton flavour violation sensitivity. This kind of models
have been previously considered but it was not possible to achieve a
compatibility among all of the ingredients mentioned above. We describe then
how different SU(3) messengers, the heavy fields that decouple and produce the
right form of the Yukawa couplings together with the scalars breaking the SU(3)
symmetry, can lead to different Yukawa couplings. This in turn implies
different consequences for flavour violation couplings and conditions for
realizing the right amount of baryon asymmetry through the decay of the
lightest right-handed neutrino. Also a highlight of the present work is a new
fit of the Yukawa textures traditionally embedded in SU(3) family models.Comment: 26 pages, 5 figures, Some typos correcte
The mu problem and sneutrino inflation
We consider sneutrino inflation and post-inflation cosmology in the singlet
extension of the MSSM with approximate Peccei-Quinn(PQ) symmetry, assuming that
supersymmetry breaking is mediated by gauge interaction. The PQ symmetry is
broken by the intermediate-scale VEVs of two flaton fields, which are
determined by the interplay between radiative flaton soft masses and higher
order terms. Then, from the flaton VEVs, we obtain the correct mu term and the
right-handed(RH) neutrino masses for see-saw mechanism. We show that the RH
sneutrino with non-minimal gravity coupling drives inflation, thanks to the
same flaton coupling giving rise to the RH neutrino mass. After inflation,
extra vector-like states, that are responsible for the radiative breaking of
the PQ symmetry, results in thermal inflation with the flaton field, solving
the gravitino problem caused by high reheating temperature. Our model predicts
the spectral index to be n_s\simeq 0.96 due to the additional efoldings from
thermal inflation. We show that a right dark matter abundance comes from the
gravitino of 100 keV mass and a successful baryogenesis is possible via
Affleck-Dine leptogenesis.Comment: 27 pages, no figures, To appear in JHE
Flavoured soft leptogenesis and natural values of the B term
We revisit flavour effects in soft leptogenesis relaxing the assumption of
universality for the soft supersymmetry breaking terms. We find that with
respect to the case in which the heavy sneutrinos decay with equal rates and
equal CP asymmetries for all lepton flavours, hierarchical flavour
configurations can enhance the efficiency by more than two orders of magnitude.
This translates in more than three order of magnitude with respect to the
one-flavour approximation. We verify that lepton flavour equilibration effects
related to off-diagonal soft slepton masses are ineffective for damping these
large enhancements. We show that soft leptogenesis can be successful for
unusual values of the relevant parameters, allowing for and for values of the washout parameter up to .Comment: 23 pages, 5 figures postscript, Minor changes to match the published
version in JHE
Asymmetric WIMP dark matter
In existing dark matter models with global symmetries the relic abundance of
dark matter is either equal to that of anti-dark matter (thermal WIMP), or
vastly larger, with essentially no remaining anti-dark matter (asymmetric dark
matter). By exploring the consequences of a primordial asymmetry on the coupled
dark matter and anti-dark matter Boltzmann equations we find large regions of
parameter space that interpolate between these two extremes. Interestingly,
this new asymmetric WIMP framework can accommodate a wide range of dark matter
masses and annihilation cross sections. The present-day dark matter population
is typically asymmetric, but only weakly so, such that indirect signals of dark
matter annihilation are not completely suppressed. We apply our results to
existing models, noting that upcoming direct detection experiments will
constrain a large region of the relevant parameter space.Comment: 32 pages, 6 figures, updated references, updated XENON100 bounds,
typo in figure caption correcte
PCR-based detection and genetic characterization of porcine parvoviruses in South Korea in 2018
with the advantage of sequencing technology, many novel porcine parvoviruses (PPV) rather than PPV1 has been reported. This study ultilized specific PCR- based method and gene- based analysis to study the presence and genetic diversity of porcine parvoviruses in South Korea in 2018.
The present study was conducted in 2018 and found PPV1 and PPV7 in nine out of 151 field samples (organs and semen) by the PCR method. Among these, the complete genome sequences of five strains (N2, N91, N108, N133, and N141) were recovered. Phylogenic analysis revealed that the strains N2, N91, and N108 belong to the PPV1 genotype, while N133 and N141 belong to PPV7 genotype. The PPV7 strains collected in this study had deletion mutations in the VP2 gene but differed from that of PPV7 strains collected in 2017. Among the PPV1 strains, the amino acid variations in the B cell epitopes of the VP2 protein were observed between three Korean PPV1 field strains (N2, N91, and N108) and the reference PPV1 strains. Those substitutions resulted in six out of 12 predicted epitopes having significant differences in antigenic index compared to the other PPV1 strains.
This study confirmed the presence of different genotypes of porcine parvoviruses in South Korea. The PPVs circulating in South Korea were phylogenetically classified as PPV1 and PPV7 genotypes. Three Korean PPV1 strains collected in 2018 were predicted to have antigenic alteration in VP2 compared to several reference strains of PPV1.This study was supported by Boehringer Ingelheim Vetmedica Korea Ltd.
(Grant no. 20180002). The funder had no role in this study design, data
collection and analysis, decision to publish, or preparation of the manuscript
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