Flavorful new physics models in the light of the B decay anomalies

Current experimental data on the flavor observables R_K and R_K^* shows evidence for a violation of lepton universality – an essential feature of the Standard Model of particle physics. Together with several deviations seen in other b -> sµ^+ µ^− observables as well as R_D and R_D^*, these results constitute the so-called B decay anomalies. In this thesis we investigate new physics models that provide potential solutions to these anomalies and put a special emphasis on their flavor structure. To this end, we consider an A4 x U(1)_FN based flavor symmetry, which addresses the SM flavor puzzle, and study patterns that it imposes on the couplings of leptoquark models. We find that flavorful leptoquarks provide good explanations of R_K^(*) , while constraints from rare kaon decays and charged lepton flavor violating processes are too strong to allow to accommodate the deviations in R_D^(*). As another consequence of the imposed flavor structure, flavorful leptoquarks are light enough to be produced at current and future hadron colliders. We compute estimates for the production cross sections of the S_3 , V_1 and V_3 leptoquarks in different flavor scenarios, focusing on single production, which is sensitive to the leptoquark coupling and its flavor structure. We find that future hadron colliders with higher center of mass energies are needed to cover the full parameter space and determine leptoquark mass bound for benchmark scenarios

Flavorful leptoquarks at hadron colliders

$B$-physics data and flavor symmetries suggest that leptoquarks can have masses as low as few {\cal{O}}(\mbox{TeV}), predominantly decay to third generation quarks, and highlight $pp \to b \mu \mu$ signatures from single production and $pp \to b b \mu \mu$ from pair production. Abandoning flavor symmetries could allow for inverted quark hierarchies, and cause sizable $pp \to j \mu \mu$ and $jj \mu \mu$ cross sections, induced by second generation couplings. Final states with leptons other than muons including lepton flavor violation (LFV) ones can also arise. The corresponding couplings can also be probed by precision studies of the $B \to (X_s, K^*,\phi) ee$ distribution and LFV searches in $B$-decays. We demonstrate sensitivity in single leptoquark production for the LHC and extrapolate to the high luminosity HL-LHC. Exploration of the bulk of the phase space requires a hadron collider beyond the reach of the LHC, with $b$-identification capabilities.Comment: 17 page

Flavorful leptoquarks at the LHC and beyond: Spin 1

Evidence for electron-muon universality violation that has been revealed in $b\to s \ell\ell$ transitions in the observables $R_{K,K^*}$ by the LHCb Collaboration can be explained with spin-1 leptoquarks in $SU(2)_L$ singlet $V_1$ or triplet $V_3$ representations in the ${\cal{O}}(1-10)$ TeV range. We explore the sensitivity of the high luminosity LHC (HL-LHC) and future proton-proton colliders to $V_1$ and $V_3$ in the parameter space connected to $R_{K,K^*}$-data. We consider pair production and single production in association with muons in different flavor benchmarks. Reinterpreting a recent ATLAS search for scalar leptoquarks decaying to $b \mu$ and $j \mu$, we extract improved limits for the leptoquark masses: For gauge boson-type leptoquarks ($\kappa=1$) we obtain $M_{V_1}> 1.9$ TeV, $M_{V_1}> 1.9$ TeV, and $M_{V_1}> 1.7$ TeV for leptoquarks decaying predominantly according to hierarchical, flipped and democratic quark flavor structure, respectively. Future sensitivity projections based on extrapolations of existing ATLAS and CMS searches are worked out. We find that for $\kappa=1$ the mass reach for pair (single) production of $V_1$ can be up to 3 TeV (2.1 TeV) at the HL-LHC and up to 15 TeV (19.9 TeV) at the FCC-hh with $\sqrt{s}=100$ TeV and 20 \, \mbox{ab}^{-1}. The mass limits and reach for the triplet $V_3$ are similar or higher, depending on flavor. While there is the exciting possibility that leptoquarks addressing the $R_{K,K^*}$-anomalies are observed at the LHC, to fully cover the parameter space $pp$-collisions beyond the LHC-energies are needed.Comment: 16 pages, 8 figures; v2: Clarifying comments, four plots and few references added. Few typos corrected. Conclusions unchange

Multiplex PCR method for MinION and Illumina sequencing of Zika and other virus genomes directly from clinical samples

Genome sequencing has become a powerful tool for studying emerging infectious diseases; however, genome sequencing directly from clinical samples (i.e., without isolation and culture) remains challenging for viruses such as Zika, for which metagenomic sequencing methods may generate insufficient numbers of viral reads. Here we present a protocol for generating coding-sequence-complete genomes, comprising an online primer design tool, a novel multiplex PCR enrichment protocol, optimized library preparation methods for the portable MinION sequencer (Oxford Nanopore Technologies) and the Illumina range of instruments, and a bioinformatics pipeline for generating consensus sequences. The MinION protocol does not require an Internet connection for analysis, making it suitable for field applications with limited connectivity. Our method relies on multiplex PCR for targeted enrichment of viral genomes from samples containing as few as 50 genome copies per reaction. Viral consensus sequences can be achieved in 1-2 d by starting with clinical samples and following a simple laboratory workflow. This method has been successfully used by several groups studying Zika virus evolution and is facilitating an understanding of the spread of the virus in the Americas. The protocol can be used to sequence other viral genomes using the online Primal Scheme primer designer software. It is suitable for sequencing either RNA or DNA viruses in the field during outbreaks or as an inexpensive, convenient method for use in the lab

Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity.

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant

Exponential growth, high prevalence of SARS-CoV-2, and vaccine effectiveness associated with the Delta variant

SARS-CoV-2 infections were rising during early summer 2021 in many countries associated with the Delta variant. We assessed RT-PCR swab-positivity in the REal-time Assessment of Community Transmission-1 (REACT-1) study in England. We observed sustained exponential growth with average doubling time (June-July 2021) of 25 days driven by complete replacement of Alpha variant by Delta, and by high prevalence at younger less-vaccinated ages. Unvaccinated people were three times more likely than double-vaccinated people to test positive. However, after adjusting for age and other variables, vaccine effectiveness for double-vaccinated people was estimated at between ~50% and ~60% during this period in England. Increased social mixing in the presence of Delta had the potential to generate sustained growth in infections, even at high levels of vaccination

Hospital admission and emergency care attendance risk for SARS-CoV-2 delta (B.1.617.2) compared with alpha (B.1.1.7) variants of concern: a cohort study

Background: The SARS-CoV-2 delta (B.1.617.2) variant was first detected in England in March, 2021. It has since rapidly become the predominant lineage, owing to high transmissibility. It is suspected that the delta variant is associated with more severe disease than the previously dominant alpha (B.1.1.7) variant. We aimed to characterise the severity of the delta variant compared with the alpha variant by determining the relative risk of hospital attendance outcomes. Methods: This cohort study was done among all patients with COVID-19 in England between March 29 and May 23, 2021, who were identified as being infected with either the alpha or delta SARS-CoV-2 variant through whole-genome sequencing. Individual-level data on these patients were linked to routine health-care datasets on vaccination, emergency care attendance, hospital admission, and mortality (data from Public Health England's Second Generation Surveillance System and COVID-19-associated deaths dataset; the National Immunisation Management System; and NHS Digital Secondary Uses Services and Emergency Care Data Set). The risk for hospital admission and emergency care attendance were compared between patients with sequencing-confirmed delta and alpha variants for the whole cohort and by vaccination status subgroups. Stratified Cox regression was used to adjust for age, sex, ethnicity, deprivation, recent international travel, area of residence, calendar week, and vaccination status. Findings: Individual-level data on 43 338 COVID-19-positive patients (8682 with the delta variant, 34 656 with the alpha variant; median age 31 years [IQR 17–43]) were included in our analysis. 196 (2·3%) patients with the delta variant versus 764 (2·2%) patients with the alpha variant were admitted to hospital within 14 days after the specimen was taken (adjusted hazard ratio [HR] 2·26 [95% CI 1·32–3·89]). 498 (5·7%) patients with the delta variant versus 1448 (4·2%) patients with the alpha variant were admitted to hospital or attended emergency care within 14 days (adjusted HR 1·45 [1·08–1·95]). Most patients were unvaccinated (32 078 [74·0%] across both groups). The HRs for vaccinated patients with the delta variant versus the alpha variant (adjusted HR for hospital admission 1·94 [95% CI 0·47–8·05] and for hospital admission or emergency care attendance 1·58 [0·69–3·61]) were similar to the HRs for unvaccinated patients (2·32 [1·29–4·16] and 1·43 [1·04–1·97]; p=0·82 for both) but the precision for the vaccinated subgroup was low. Interpretation: This large national study found a higher hospital admission or emergency care attendance risk for patients with COVID-19 infected with the delta variant compared with the alpha variant. Results suggest that outbreaks of the delta variant in unvaccinated populations might lead to a greater burden on health-care services than the alpha variant. Funding: Medical Research Council; UK Research and Innovation; Department of Health and Social Care; and National Institute for Health Research

Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant