Generalized 2HDM with wrong-sign lepton Yukawa coupling, in light of gμ−2g_{\mu}-2 and lepton flavor violation at the future LHC

To explain the observed muon anomaly and simultaneously evade bounds from lepton flavor violation in the same model parameter space is a long cherished dream. In view of a generalized Two Higgs Doublet Model, with a Yukawa structure as a perturbation of Type-X, we are able to get substantial parameter space satisfying this criteria. We are focusing on a region with "{\bf wrong-sign}" lepton-Yukawa coupling which gives rise to an interesting phenomenological consequences. We found that in the "wrong-sign" region, it is possible to probe the low-mass pseudoscalar in flavor-violating decay mode with considerably better significance compared to the "right-sign" region. Performing a simple cut-based analysis we show that at 14 TeV run of the LHC with $300 fb^{-1}$ integrated luminosity, part of the model parameter space can be probed with significance $\geq 5\sigma$ which further improves with Artificial Neural Network analysis.Comment: 26 Pages, 9 Figures, 4 Tables. Few references are added, draft is revised, version is accepted for publication in European Physical Journal C. arXiv admin note: text overlap with arXiv:2010.0359

Revisiting Generalized Two Higgs Doublet Model in the Light of Muon Anomaly and Lepton Flavor Violating Decays at HL-LHC

One of the main motivations to look beyond the SM is the discrepancy between the theoretical prediction and observation of anomalous magnetic moment of muon. Alleviating this tension between theory and experiment and satisfying the bounds from lepton flavor violation data simultaneously is a challenging task. In this paper, we consider generalised Two Higgs Doublet Model, with a Yukawa structure as a perturbation of Type X Two Higgs Doublet Model. In view of this model, we explore muon anomaly and lepton flavor violation along with constraints coming from B-physics, theoretical constraints, electroweak observables and collider data which can restrict the model parameter space significantly. We find that within the framework of this model it is possible to obtain regions allowed by all constraints, that can provide an explanation for the observed muon anomaly and at the same time predicts interesting signatures of lepton flavor violation. Furthermore, we consider the flavor violating decay of low-mass CP-odd scalar to probe the allowed parameter space at future runs of the LHC. With simple cut-based analysis we show that part of that parameter space can be probed with significance $> 5 \sigma$. We also provide Artificial Neural Network analysis which definitely improves our cut-based results significantly.Comment: Table 1 has been revised, Figure 7, 8, 9 and 10 have been modified, Few references have been added. Version accepted for publication in Physical Review D journa

Reactivation of hepatitis B after liver transplantation: Current knowledge, molecular mechanisms and implications in management

Chronic hepatitis B (CHB) is a major global health problem affecting an estimated 350 million people with more than 786000 individuals dying annually due to complications, such as cirrhosis, liver failure and hepatocellular carcinoma (HCC). Liver transplantation (LT) is considered gold standard for treatment of hepatitis B virus (HBV)-related liver failure and HCC. However, post-transplant viral reactivation can be detrimental to allograft function, leading to poor survival. Prophylaxis with high-dose hepatitis B immunoglobulin (HBIG) and anti-viral drugs have achieved remarkable progress in LT by suppressing viral replication and improving long-term survival. The combination of lamivudine (LAM) plus HBIG has been for many years the most widely used. However, life-long HBIG use is both cumbersome and costly, whereas long-term use of LAM results in resistant virus. Recently, in an effort to develop HBIG-free protocols, high potency nucleos(t)ide analogues, such as Entecavir or Tenofovir, have been tried either as monotherapy or in combination with low-dose HBIG with excellent results. Current focus is on novel antiviral targets, especially for covalently closed circular DNA (cccDNA), in an effort to eradicate HBV infection instead of viral suppression. However, there are several other molecular mechanisms through which HBV may reactivate and need equal attention. The purpose of this review is to address post-LT HBV reactivation, its risk factors, underlying molecular mechanisms, and recent advancements and future of anti-viral therapy

Inosine and its methyl derivatives:Occurrence, biogenesis, and function in RNA

Inosine is one of the most common post-transcriptional modifications. Since its discovery, it has been noted for its ability to contribute to non-Watson-Crick interactions within RNA. Rapidly accumulating evidence points to the widespread generation of inosine through hydrolytic deamination of adenosine to inosine by different classes of adenosine deaminases. Three naturally occurring methyl derivatives of inosine, i.e., 1-methylinosine, 2′-O-methylinosine and 1,2′-O-dimethylinosine are currently reported in RNA modification databases. These modifications are expected to lead to changes in the structure, folding, dynamics, stability and functions of RNA. The importance of the modifications is indicated by the strong conservation of the modifying enzymes across organisms. The structure, binding and catalytic mechanism of the adenosine deaminases have been well-studied, but the underlying mechanism of the catalytic reaction is not very clear yet. Here we extensively review the existing data on the occurrence, biogenesis and functions of inosine and its methyl derivatives in RNA. We also included the structural and thermodynamic aspects of these modifications in our review to provide a detailed and integrated discussion on the consequences of A-to-I editing in RNA and the contribution of different structural and thermodynamic studies in understanding its role in RNA. We also highlight the importance of further studies for a better understanding of the mechanisms of the different classes of deamination reactions. Further investigation of the structural and thermodynamic consequences and functions of these modifications in RNA should provide more useful information about their role in different diseases.</p

Predicting nearest neighbor free energies of modified RNA with LIE: Results for pseudouridine and N1-methylpseudouridine within RNA duplexes

Pseudouridine and N1-methylpseudouridine are the key modifications in the field of mRNA therapeutics and vaccine research. The accuracy of the design and development of therapeutic RNAs containing such modifications requires the accuracy of the secondary structure prediction, that depends on the nearest neighbor (NN) thermodynamic parameters for the standard and modified residues. The development of such NN thermodynamic parameters requires expensive and time-consuming experimental studies. There were some earlier attempts to predict the NN free energies of modified RNA using computational methods but those are either computationally expensive or not accurate enough. Here, we propose a new protocol based on MD simulations, which is able to predict the NN free energy parameters (ΔG◦37) for U-A, Ψ-A and m1Ψ-A pairs in general agreement with the recent experimental reports. We report the NN thermodynamic parameters for different U, Ψ and m1Ψ base pairs, which might be helpful for a deeper understanding of the effect of these modifications in RNA. The presence of m1Ψ resulted in more stable NN pairs compared to those containing U or Ψ. The predicted NN free energy parameters in this study are able to closely reproduce the folding free energies of duplexes containing internal Ψ for which the thermodynamic data were available. Additionally, we report the predicted folding free energies for the duplexes containing internal m1Ψ

Data-informed reparameterization of modified RNA and the effect of explicit water models:application to pseudouridine and derivatives

Pseudouridine is one of the most abundant post-transcriptional modifications in RNA. We have previously shown that the FF99-derived parameters for pseudouridine and some of its naturally occurring derivatives in the AMBER distribution either alone or in combination with the revised γ torsion parameters (parmbsc0) failed to reproduce their conformational characteristics observed experimentally (Deb et al. in J Chem Inf Model 54:1129–1142, 2014; Deb et al. in J Comput Chem 37:1576–1588, 2016; Dutta et al. in J Chem Inf Model 60:4995–5002, 2020). However, the application of the recommended bsc0 correction did lead to an improvement in the description not only of the distribution in the γ torsional space but also of the sugar pucker distributions. In an earlier study, we examined the transferability of the revised glycosidic torsion parameters (χ(IDRP)) for Ψ to its derivatives. We noticed that although these parameters in combination with the AMBER FF99-derived parameters and the revised γ torsional parameters resulted in conformational properties of these residues that were in better agreement with experimental observations, the sugar pucker distributions were still not reproduced accurately. Here we report a new set of partial atomic charges for pseudouridine, 1-methylpseudouridine, 3-methylpseudouridine and 2′-O-methylpseudouridine and a new set of glycosidic torsional parameters (χ(ND)) based on chosen glycosidic torsional profiles that most closely corresponded to the NMR data for conformational propensities and studied their effect on the conformational distributions using REMD simulations at the individual nucleoside level. We have also studied the effect of the choice of water model on the conformational characteristics of these modified nucleosides. Our observations suggest that the current revised set of parameters and partial atomic charges describe the sugar pucker distributions for these residues more accurately and that the choice of a suitable water model is important for the accurate description of their conformational properties. We have further validated the revised sets of parameters by studying the effect of substitution of uridine with pseudouridine within single stranded RNA oligonucleotides on their conformational and hydration characteristics. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10822-022-00447-4

Data-informed reparameterization of modified RNA and the effect of explicit water models: Application to pseudouridine and derivatives

Pseudouridine is the most abundant post-transcriptional modification in RNA. We have previously shown that the FF99-derived parameters for pseudouridine and some of its naturally occurring derivatives in the AMBER distribution either alone or in combination with the revised torsion parameters (parmbsc0) failed to reproduce their conformational characteristics observed experimentally (Deb I, et al. J. Chem. Inf. Model. 2014, 54 (4):1129–1142; Deb I, et al. J. Comput. Chem., 2016, 37:1576−1588; Dutta N, et al. J. Chem. Inf. Model. 2020, 60 (10):4995–5002). However, the application of the recommended bsc0 correction did lead to an improvement in the description not only of the distribution in the torsional space but also of the sugar pucker distributions. In an earlier study, we examined the transferability of the revised glycosidic torsion parameters (IDRP) for Ψ to its derivatives. We noticed that although these parameters in combination with the AMBER FF99-derived parameters and the revised torsional parameters resulted in conformational properties of these residues that were in better agreement with experimental observations, the sugar pucker distributions were still not reproduced accurately. Here we report a new set of partial atomic charges for pseudouridine, 1-methylpseudouridine, 3-methylpseudouridine and 2′-O-methylpseudouridine and a new set of glycosidic torsional parameters (ND) based on chosen glycosidic torsional profiles that most closely corresponded to the NMR data for conformational propensities and studied their effect on the conformational distributions using REMD simulations at the individual nucleoside level. We have also studied the effect of the choice of water model on the conformational characteristics of these modified nucleosides. Our observations suggest that the current revised set of parameters and partial atomic charges describe the sugar pucker distributions for these residues more accurately and that the choice of a suitable water model is important for the accurate description of their conformational properties